THE CAMBRIDGE HISTORICAL DICTIONARY OF DISEASE THE CAMBRIDGE HISTORICAL DICTIONARY OF DISEASE

Edited by KENNETHKENNETHF.KIPLE F. KIPLE Bowling Green State University    Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo

Cambridge University Press The Edinburgh Building, Cambridge  , United Kingdom Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521808347

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Cambridge University Press has no responsibility for the persistence or accuracy of s for external or third-party internet websites referred to in this book, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. In memory of K. David Patterson Contents

Preface I xiii 15 Beriberi I 44 Melinda S. Meade 1 Acquired Immune Deficiency Syndrome (AIDS) I 1 16 Black Death I 49 Allan M. Brandt Katharine Park

2 African Trypanosomiasis (Sleeping 17 Black and Brown Lung Disease I 52 Sickness) I 7 Daniel M. Fox Maryinez Lyons 18 Bleeding Disorders I 54 3 Ainhum I 14 Oscar D. Ratnoff Donald B. Cooper 19 Botulism I 57 4 Alzheimer’s Disease I 14 WilliamH. Barker Joseph A. Kwentus 20 Brucellosis (Malta Fever, Undulant Fever) 5 Amebic Dysentery I 19 I 58 K. David Patterson Lise Wilkinson

6 Anemia I 21 21 Bubonic Plague I 60 Alfred Jay Bollet and Audrey K. Brown Ann G. Carmichael

7 Anorexia Nervosa I 26 22 Cancer I 63 Heather Munro Prescott Thomas G. Benedek and Kenneth F. Kiple

8 Anthrax I 29 23 Carrion’s Disease (Oroya Fever) I 67 Lise Wilkinson Oscar Urteaga-Ballon

9 Apoplexy and Stroke I 31 24 Catarrh I 69 Jacques Poirier and Christian Derouesne Roger K. French

10 Arboviruses I 34 25 Cestode Infection I 70 Wilbur G. Downs K. David Patterson

11 Arenaviruses I 38 26 Chagas’Disease I 70 Wilbur G. Downs Marvin J. Allison

12 Arthritis (Rheumatoid) I 39 27 Chlorosis I 71 Howard Duncan and James C. C. Leisen Robert P. Hudson

13 Ascariasis I 42 28 Cholera I 74 K. David Patterson Reinhard S. Speck

14 Bacillary Dysentery I 43 29 Cirrhosis I 79 K. David Patterson Thomas S. N. Chen and Peter S. Y. Chen

vii Contents

30 Clonorchiasis I 81 48 Enterobiasis I 116 K. David Patterson K. David Patterson

31 Croup I 81 49 Epilepsy I 116 James D. Cherry Jerrold E. Levy

32 Cystic Fibrosis I 83 50 Ergotism I 120 Thomas G. Benedek John S. Haller, Jr.

33 Cytomegalovirus Infection I 84 51 Erysipelas I 121 R. H. Kampmeier Ann G. Carmichael

34 Dengue I 85 52 Fascioliasis I 123 James McSherry K. David Patterson

I 35 Diabetes I 88 53 Fasciolopsiasis 123 Leslie Sue Lieberman K. David Patterson

I 36 Diarrheal Diseases (Acute) I 92 54 Favism 123 Herbert L. DuPont Peter J. Brown 55 Filariasis I 125 37 Diphtheria I 94 Todd L. Savitt Ann G. Carmichael 56 Fungus Infections (Mycoses) I 128 38 Down Syndrome I 96 Geoffrey C. Ainsworth Christine E. Cronk 57 Fungus Poisoning I 132 39 Dracunculiasis I 98 Geoffrey C. Ainsworth Donald R. Hopkins 58 Gallstones (Cholelithiasis) I 134 40 Dropsy I 100 R. Ted Steinbock J. Worth Estes 59 Gangrene I 136 I 41 Dysentery 105 Diane Quintal and Robert Jackson K. David Patterson 60 Genetic Disease I 138 I 42 Dyspepsia 105 Eric J. Devor James Whorton 61 Giardiasis I 144 I 43 Ebola Virus Disease 107 K. David Patterson Wilbur G. Downs 62 Glomerulonephritis (Bright’s Disease) I 44 Echinococcosis (Hydatidosis) I 110 144 K. David Patterson Donald M. Larson

45 Eclampsia I 110 63 Goiter I 146 Sally McMillen Clark T. Sawin

46 Emphysema I 112 64 Gonorrhea I 150 Ronald J. Knudson Richard B. Rothenberg

47 Encephalitis Lethargica I 114 65 Gout I 153 R. T. Ravenholt Thomas G. Benedek

viii Contents

66 Heart-Related Diseases I 156 83 Leprosy (Hansen’s Disease) I 192 Joel D. Howell Ann G. Carmichael

67 Herpes Simplex I 161 84 Leptospirosis I 195 R. H. Kampmeier Otto R. Gsell

68 Herpesviruses I 162 85 Leukemia I 196 R. H. Kampmeier Gordon J. Piller

I 69 Histoplasmosis I 163 86 Lupus Erythematosus 199 Scott F. Davies Thomas G. Benedek 87 Lyme Borreliosis (Lyme Disease) I 201 70 Hookworm Infection I 165 Robert D. Leff John Ettling 88 Malaria I 203 71 Huntington’s Disease (Chorea) I 168 Frederick L. Dunn Eric J. Devor 89 Marburg Virus Disease I 207 I 72 Hypertension 169 Wilbur G. Downs Thomas W. Wilson and Clarence E. Grim 90 Mastoiditis I 208 I 73 Infectious Hepatitis 171 John L. Kemink, John K. Niparko, and Steven A. Francis L. Black Telian

74 Infectious Mononucleosis I 174 91 Measles I 211 R. H. Kampmeier Robert J. Kim-Farley

75 Inflammatory Bowel Disease (Crohn’s 92 Meningitis I 214 Disease, Ulcerative Colitis) I 175 K. David Patterson Joseph B. Kirsner 93 Milk Sickness (Tremetol Poisoning) I 218 76 Influenza I 178 Thomas E. Cone, Jr. Alfred W. Crosby 94 Multiple Sclerosis I 220 77 Japanese B Encephalitis I 181 W. I. McDonald Edward H. Kass 95 Mumps I 222 78 Lactose Intolerance and Malabsorption I Robert J. Kim-Farley 182 96 Muscular Dystrophy I 224 Norman Kretchmer Thomas G. Benedek I 79 Lassa Fever 184 97 Myasthenia Gravis I 225 Wilbur G. Downs Bernard M. Patten

80 Lead Poisoning I 185 98 Nematode Infection I 227 Arthur C. Aufderheide K. David Patterson

81 Legionnaires’Disease (Legionellosis, 99 Onchocerciasis I 228 Pontiac Fever, Legionella Pneumonia) I 189 K. David Patterson David W. Fraser 100 Ophthalmia (Trachoma, Conjunctivitis) 82 Leishmaniasis I 191 I 230 Marvin J. Allison Mary C. Karasch

ix Contents

101 Osteoarthritis I 234 118 Rabies I 270 Charles W. Denko K. David Patterson

102 Osteoporosis I 236 119 Relapsing Fever I 275 R. Ted Steinbock Anne Hardy

103 Paget’s Disease of Bone I 238 120 Rheumatic Fever and Rheumatic Heart Roy D. Altman Disease I 277 Thomas G. Benedek 104 Paragonimiasis I 240 K. David Patterson 121 Rickets and Osteomalacia I 280 R. Ted Steinbock 105 Parkinson’s Disease (Parkinsonism) I 240 122 Rickettsial Diseases I 282 Bernard M. Patten Victoria A. Harden

106 Pellagra I 242 123 Rocky Mountain Spotted Fever and Elizabeth W. Etheridge Related Diseases I 283 Victoria A. Harden 107 Periodontal Disease (Pyorrhea) I 244 Jeffrey Levin 124 Rubella I 285 Robert J. Kim-Farley 108 Pica I 247 Brian T. Higgins 125 Saint Anthony’s Fire I 287 Ann G. Carmichael 109 Pinta I 250 Don R. Brothwell 126 Scarlet Fever I 288 Anne Hardy 110 Plague of Athens I 251 Ann G. Carmichael 127 Schistosomiasis I 290 John Farley 111 Pneumocystis Pneumonia (Interstitial Plasma Cell Pneumonia, Pneumocystosis) I 128 Scrofula I 292 254 Roger K. French K. David Patterson 129 Scurvy I 295 112 Pneumonia I 255 Roger K. French Jacalyn Duffin 130 Sickle-Cell Anemia I 298 113 Poliomyelitis I 258 Georges C. Benjamin H. V. Wyatt 131 Smallpox I 300 114 Protein-Energy Malnutrition I 261 Alfred W. Crosby James L. Newman 132 Streptococcal Diseases I 304 115 Protozoan Infection I 265 Peter C. English K. David Patterson 133 Strongyloidiasis I 306 116 Puerperal Fever I 265 K. David Patterson K. Codell Carter 134 Sudden Infant Death Syndrome (SIDS) 117 Q Fever I 267 I 306 S. R. Palmer Todd L. Savitt

x Contents

135 Sudden Unexplained Death Syndrome 149 Trichuriasis I 336 (Asian SUDS) I 309 K. David Patterson Neal R. Holtan 150 Tuberculosis I 336 136 Sweating Sickness I 311 WilliamD. Johnston Ann G. Carmichael 151 Tularemia I 342 137 Syphilis I 312 Patrick D. Horne Jon Arrizabalaga 152 Typhoid Fever I 345 138 Syphilis, Nonvenereal I 317 Charles W. LeBaron and David N. Taylor Kenneth F. Kiple 153 Typhomalarial Fever I 349 I 139 Tapeworm Infection 319 Dale Smith K. David Patterson 154 Typhus, Epidemic I 352 I 140 Tay-Sachs Disease 320 Victoria A. Harden Bradford Towne 155 Typhus, Murine I 355 141 Tetanus I 323 Victoria A. Harden Robert J. T. Joy 156 Typhus, Scrub (Tsutsugamushi) I 355 142 Tetanus, Neonatal I 326 Victoria A. Harden Sally McMillen 157 Urolithiasis I 357 143 Tetany I 328 R. Ted Steinbock Kenneth F. Kiple 158 144 Toxoplasmosis I 330 Varicella-Zoster Virus Disease (Chickenpox) I 359 K. David Patterson R. H. Kampmeier 145 Trematode Infection I 331 I K. David Patterson 159 Whooping Cough 360 Anne Hardy 146 Trench Fever I 331 I Victoria A. Harden 160 Yaws 362 Don R. Brothwell 147 The Treponematoses I 331 Kenneth F. Kiple 161 Yellow Fever I 365 Donald B. Cooper and Kenneth F. Kiple 148 Trichinosis I 333 Donald E. Gilbertson Index I 371

xi Preface

The Cambridge World History of Human Disease (CWHHD) was first pub- lished by Cambridge University Press in 1993 and reprinted in 2001. Part VIII, the last section of the work, comprises a history and description of the world’s major diseases of yesterday and today in chapters that are organized alphabetically from “Acquired Immune Deficiency Syndrome (AIDS)” to “Yellow Fever.” The pages that follow in this Dictionary rep- resent an effort to make these essays, along with three chapters from other parts of the CWHHD on “Heart-Related Diseases,” “Cancer,” and “Genetic Disease,” available to a wider audience in paperback form. To achieve this in one manageable volume, the chapters were condensed, and bibliographies and graphics are omitted. As a consequence, readers requiring more than a dictionary treatment of an illness will still need the CWHHD. A revised edition of that work is still a few years in the future; thus, most of the chapters in the Dictionary have not been updated. Indeed, because they are less than a decade old (admittedly still a long time in science), most would not have benefited substantially from what in effect would have been a partial revision of just one part of the larger work, and a revision that would have to be repeated for the upcoming full-scale re- vision. A few diseases, however, such as AIDS, Alzheimer’s disease, Ebola virus disease, and tuberculosis, have been subjects of intense scrutiny, generating much media coverage, even best-selling books. In these in- stances, postscripts seemed essential to sketch out recent major events in their respective histories. There were legions of authors and board members to thank whose collective effort brought forth the CWHHD. I thank themall again. Ob- viously much of that effort undergirds this volume. I also thank Steve Beck, who has worked on our various projects for many years. He did a wonderful job of paring the essays to fit this volume. In addition, I am grateful to Cambridge University Press Publishing Director Frank Smith for his support of this first paperback to emerge from the CWHHD. Finally, the late K. David Patterson was involved in that project as both enthusiastic board member and prolific author, and this book (containing many of his essays) is dedicated to him.

Kenneth F. Kiple

xiii 1. Acquired Immune Deficiency intravenous drug users were at greatest risk.Re- Syndrome (AIDS) search focused on searching for an infectious agent transmitted sexually or through blood.In Acquired immune deficiency syndrome 1983, in French and American laboratories, an (AIDS), first identified in 1981, is an infectious unknown human retrovirus was identified and disease characterized by failure of the body’s named HIV-1 for “human immunodeficiency immunologic system.Affected individuals be- virus.” Although the biological and geographic come increasingly vulnerable to many normally origins of the organism remain obscure, the harmless microorganisms, eventually leading AIDS epidemic appears to mark the first time to severe morbidity and high mortality.The in- it has spread widely in human populations.No fection, spread sexually and through blood, has evidence exists for casual transmission of HIV. a high fatality rate, approaching 100 percent. Following identification of HIV-1, tests to de- Caused by a human retrovirus known as HIV-1, tect antibodies against it were devised in 1984. AIDS can now be found throughout the world – Although these tests do not detect the virus in both industrialized countries and developing itself, they are generally effective in identify- nations.Public-health officials throughout the ing infection because high levels of antibody world have focused attention on this pandemic are produced in most infected individuals.The and its potentially catastrophic impact on enzyme-linked immunosorbent assay (ELISA), health, resources, and social structure.Treat- followed by Western blot testing, has enabled ments for the disease have been developed, but the screening of donated blood to protect the no cure or vaccine currently exists. blood supply from HIV, as well as testing for epi- demiological and diagnostic purposes. Characteristics As HIV infection precedes the development Beginning in the late 1970s, physicians in New of AIDS, often by several years, the precise pa- York and California reported increasing in- rameters of the epidemic have been difficult cidence of a rare cancer, Kaposi’s sarcoma, to define.Although “cofactors” that may deter- and a variety of infections including pneumo- mine the onset of symptoms remain unknown, cystis pneumonia among previously healthy evidence suggests that HIV-infected individuals young homosexual men.Because of the un- will eventually develop AIDS. usual character of these diseases, which are typ- Researchers have identified three epidemi- ically associated with failure of the immune ological patterns of HIV transmission, which system, epidemiologists began seeking clues roughly follow geographic boundaries.Pattern that might link these cases.A IDS was first for- I includes North America, Western Europe, mally described in 1981, although it now ap- Australia, New Zealand, and many urban cen- pears that the virus causing the disease was ters in Latin America.In these industrial, highly silently spreading in a number of populations developed areas, transmission has been pre- during the previous decade.Early epidemiolog- dominantly among homosexual and bisexual ical studies suggested that homosexual men, men.Since the introduction of widespread blood recipients (especially hemophiliacs), and blood screening, transmission via blood in

1 1. Acquired Immune Deficiency Syndrome (AIDS) these areas now occurs principally among HIV cripples the body’s immunologic sys- intravenous drug users who share injection tem, making an infected individual vulnerable equipment.Although little evidence exists of to other disease-causing agents in the environ- widespread infection among heterosexuals in ment.The most common of these opportunistic these countries, heterosexual transmission from infections in AIDS patients has been pneumo- those infected intravenously has increased, cystis pneumonia, previously seen principally leading to a rise in pediatric cases resulting from in patients receiving immunosuppressive drugs. perinatal transmission. In addition to pneumocystis, AIDS patients are Within the United States, distribution of AIDS prone to other infectious agents such as cy- has been marked by disproportionate repre- tomegalovirus, Candida albicans (a yeastlike sentation of minorities and the poor.As the fungus), and Toxoplasma gondii (a protozoan principal mode of transmission has shifted to parasite).Moreover, a resurgence of tuberculo- intravenous drug use, AIDS has increasingly be- sis has been reported in nations with high AIDS come an affliction of the urban underclass.Sur- incidence. veys reveal that 50 percent or more of intra- Immunologic damage occurs by depletion of venous drug users in New York City are infected a specific type of white blood cell called a helper with HIV.Women are typically infected by in- T4 lymphocyte.Destruction of these cells ac- travenous drug use or by sexual contact with a counts for the vulnerability to normally harm- drug user. less infectious agents.In some cases, infection of In pattern II countries, comprised of the central nervous system with HIV may cause sub-Saharan Africa and, increasingly, Latin damage to the brain and spinal column, result- America, transmission of HIV occurs predomi- ing in severe cognitive and motor dysfunction. nantly through heterosexual contact.In some In its late manifestations, AIDS causes severe urban areas in these countries, up to 25 percent wasting.Death may occur from infection, func- of all sexually active adults are reported to tional failure of the central nervous system, or be infected, and a majority of female prosti- starvation. tutes are seropositive.Transfusion remains a HIV infection has a wide spectrum of clini- mode of transmission because universal blood cal manifestations.After infection, an individ- screening is not routine.Unsterile injections ual may remain free of symptoms for years, and medical procedures may also contribute to even a decade or longer.Some individuals ex- the spread of infection.In these areas, perinatal perience fever, rash, and malaise at the time of transmission is an important aspect of the infection when antibodies are first produced. epidemic. Patients commonly present with general lym- Pattern III countries, including North Africa, phadenopathy, weight loss, diarrhea, or an op- the Middle East, Eastern Europe, Asia, and portunistic infection.Diagnosis is confirmed by the Pacific, initially experienced less morbidity finding antibodies for HIV or by a decline in T4 and mortality from the pandemic.Apparently, cells.Most experts now agree that HIV infec- HIV-1 was not present in these areas until the tion itself be considered a disease, regardless of mid-1980s.The nature of world travel, however, symptoms. has diminished the significance of geographic Because the virus becomes encoded within isolation as a means of protecting a population the genetic material of the host cell and is highly from contact with a pathogen. mutable, the problem of finding safe and ef- In 1985, a related virus, HIV-2, was discov- fective therapies has been extremely difficult. ered in West Africa.Although early reports sug- Studies have attempted to determine the anti- gested that HIV-2 is less pathogenic, the natural HIV properties of many drugs, but the ethical history of this agent remains unclear, as does its and economic obstacles to clinical trials with prevalence. experimental drugs are formidable.Given the

2 1. Acquired Immune Deficiency Syndrome (AIDS) immediacy of the epidemic, it is difficult to ease and had focused its resources and attention structure appropriate randomized clinical tri- on systemic, noninfectious ailments.Thus, AIDS als, which often take considerable time, to as- appeared at a historical moment comprising lit- sess the safety and efficacy of a drug.Since tle social or political experience in confronting the beginning of the epidemic, clinical research such a public-health crisis.The epidemic frac- has refined the treatment of opportunistic tured a widely held belief in medical security. infections. Not surprisingly, early sociopolitical re- sponses were characterized by denial.Initial History theories, when few cases had been reported, In its first decade, AIDS created considerable centered on aspects of “fast-track” gay sex- suffering and generated an ongoing worldwide ual culture that might explain the outbreak health crisis.During this brief period, the epi- of immune-compromised men.Additional cases demic was identified and characterized epi- among blood recipients, however, soon led the demiologically, basic modes of transmission U.S. Centers for Disease Control and Preven- specified, a causal organism isolated, and effec- tion to the conclusion that an infectious agent tive tests for infection developed.In spite of this was the likely link.Nevertheless, in the earli- remarkable progress, which required the appli- est years of the epidemic, few wished to con- cation of sophisticated epidemiological, clini- front openly the possibility of spread beyond cal, and scientific research, the barriers to con- the specified “high-risk” groups.During this pe- trolling AIDS are imposing and relate to the riod, when government interest and funding most complex biomedical and political ques- lagged, grassroots organizations, especially in tions.AIDS has already sorely tested the capa- the homosexual community, were created to bilities of research, clinical, and public-health meet the growing need for education, counsel- institutions throughout the world. ing, patient services, and – in some instances – Because HIV is related to other recently iso- clinical research.Such groups worked to over- lated primate retroviruses, such as simian T lym- come the denial, prejudice, and bureaucratic in- photropic virus (STLV)-III in African green mon- ertia that limited governmental response. keys, many have speculated that HIV originated As the nature and extent of the epidemic in Africa.Antibodies to HIV were discovered became clearer, however, hysteria sometimes in stored blood dating back to 1959 in Zaire. replaced denial.Because the disease was pow- According to experts, it is likely that HIV has erfully associated with behaviors identified as existed for many years in isolated groups in immoral or illegal (or both), the stigma of those central Africa.Because outside contacts were infected was heightened.Victims were often di- minimal, the virus rarely spread, and epidemics vided into categories: those who acquired their could not be sustained.Once a sizable reservoir infections through transfusions or perinatally, of infection was established, however, HIV be- the “innocent victims”; and those who engaged came pandemic.As with other sexually trans- in high-risk, morally condemnable behaviors, mitted diseases, such as syphilis, no country the “guilty perpetrators” of disease.Since the wished the stigma of association with the virus’s early recognition of behavioral risks for infec- “origin.” tion, there has been a tendency to blame those The epidemic began at a moment of rela- who became infected through drug use or ho- tive complacency, especially in the developed mosexuality, behaviors viewed as “voluntary.” world, concerning epidemic infectious disease. Some religious groups in the United States and Not since the influenza of 1918–20 had an epi- elsewhere saw the epidemic as an occasion to demic appeared with such devastating poten- reiterate particular moral views about sexual tial.The developed world had experienced a behavior, drug use, sin, and disease.AIDS was health transition from infectious to chronic dis- viewed as “proof” of a certain moral order.

3 1. Acquired Immune Deficiency Syndrome (AIDS)

AIDS victims have been subjected to a range Because biomedical technologies to prevent of discriminatory behavior, including loss of transmission appear to be some years away, employment, housing, and insurance.Since the the principal public-health approaches to con- onset of the epidemic, violence against gays trolling the pandemic rest on education and in the United States has increased. Despite behavior modification.Heightened awareness the well-documented modes of HIV transmis- of the dangers of unprotected anal intercourse sion, fears of casual transmission persist.In among gay men, for example, has led to a signif- some communities, parents protested when icant decline in new infections among this pop- HIV-infected schoolchildren were permitted to ulation.Nevertheless, as many public-health attend school.In one instance, a family with an officials have noted, encouraging the modifica- HIV-infected child was driven from a town by tion of risk behaviors, especially those relating the burning of their home. to sexuality and drug abuse, presents no simple By 1983, as potential ramifications of the task, even in the face of a dread disease. epidemic became evident, national and inter- In the developing world, AIDS threatens to national scientific and public-health institu- reverse recent advances in infant and child sur- tions began to mobilize.In the United States, vival.The epidemic is likely to have a sub- congressional appropriations for research and stantial impact on demographic patterns.Be- education began to rise significantly.The Na- cause the disease principally affects young and tional Academy of Sciences issued a con- middle-aged adults (ages 20–49), it has already sensus report on the epidemic in 1986.A had tragic social and cultural repercussions. presidential commission held public hearings Transmitted both horizontally (via sexual con- and eventually issued a report calling for tact) and vertically (from mother to infant), it protection of AIDS sufferers against discrimina- has the potential to depress the growth rate of tion and a more extensive federal commitment human populations, especially in areas of the to drug treatment.The World Health Organi- developing world.In this respect, the disease zation (WHO) established a Global Program on could destabilize the work force and depress lo- AIDS in 1986 to coordinate international efforts cal economies. in epidemiological surveillance, education, pre- AIDS has clearly demonstrated the complex vention, and research. relationship of biological and behavioral forces Despite growing recognition of the epidemic’s in determining patterns of health and disease. significance, considerable debate continued Altering the course of the epidemic by human over the most effective public-health responses. design has already proved to be no easy matter. Although some nations – such as Cuba – The lifelong infectiousness of carriers; the pri- experimented with programs mandating iso- vate, biopsychosocial nature of sexual behav- lation of HIV-infected individuals, the World ior and drug abuse; and the stigma already at- Health Organization lobbied against coercive tached to those at greatest risk – all have made measures.Given the lifelong nature of HIV in- effective public policy intervention even more fection, effective isolation would require life- difficult. Finally, the very nature of the virus time incarceration.With the available variety itself – its complex and mutagenic nature – of less restrictive measures, most nations re- makes a short-term technological breakthrough jected quarantine as both unduly coercive and unlikely. unlikely to achieve control.Traditional public- The remarkable progress in understanding health approaches to communicable disease, in- AIDS is testimony to the sophistication of con- cluding contact tracing and mandatory treat- temporary bioscience; the epidemic, however, ment, have less potential for control because is also a sobering reminder of the limits of no means exist to render an infected individual that science.Any historical assessment of the noninfectious. AIDS epidemic must be considered provisional.

4 1. Acquired Immune Deficiency Syndrome (AIDS)

Nevertheless, it is already clear that AIDS has of schoolteachers has developed because they forced us to confront a new set of biological are dying of AIDS faster than replacements can imperatives. be trained. Allan M. Brandt In the United States – although the millions of cases of HIV infection that had been gloomily predicted by some did not materialize – 774,647 cases were reported between 1981 and 2001, Postscript and there were 448,060 deaths.By age and By way of a caveat, recent estimates of the num- sex, the breakdown of those infected was ber of HIV/AIDS infections, the competing theo- 79 percent adult males, and by ethnicity 61 per- ries of origin, conflicting interpretations of new cent were black or Hispanic.The major avenues evidence, and announcements of therapeutic of transmission have been through male ho- and preventive progress are sometimes contra- mosexual contact (48 percent) and intravenous dictory and thus constitute especially treacher- drug abuse (26 percent), although HIV infec- ous terrain. tion via heterosexual contact – generally be- Beginning with the estimates, in June of tween infected males and uninfected females – 1990 the WHO estimated that there were some is on the rise.Today the fastest growing groups 8 million HIV cases worldwide; the following of newly infected individuals are reported to year that estimate was raised to between 10 be women and their children, and gay black million and 12 million.Toward the end of the males – the latter group accounting for 42 per- decade the WHO warned that the number of cent of all new infections.The U.S.casesare cases would reach between 20 million and 30 almost all HIV-1.Despite fears of HIV-2 also million cases by the year 2000.In retrospect, spreading in North America, only 64 cases have it seems that this estimate was much too con- been documented, and these were all directly servative; by 1997 the number of cases already linked with West Africa. exceeded 30 million. By 2001, HIV had in- Among HIV/AIDS researchers a consensus fected some 56 million individuals worldwide gradually emerged that simian immunode- and killed more than 20 million of them.Left ficiency virus (SIV) had somehow managed behind were an estimated 36 million living with to jump the species barrier from African pri- HIV/AIDS and millions more expected to be- mates (for whom it seems to be a relatively be- come infected in the early years of the twenty- nign infection) to first infect humans in Cen- first century. tral and West Africa and, somewhere along the Of the 30 million cases in 1997,almost 21 mil- line, became human immunodeficiency virus or lion were in sub-Saharan Africa alone (where HIV-1 and its subtypes (the most common form in some places, such as Botswana, upwards of worldwide) and HIV-2. 36 percent of the adult population has become Another question had to do with how the infected with HIV), while South and South- species barrier was hurdled.Again a consen- east Asia and the Pacific accounted for another sus took shape; SIV had entered the blood of 6 million cases.In all, the developing world con- Africans engaged in chimpanzee butchering, af- tained 95 percent of the cases, and in 1998 it ter which it became HIV-1 (although the pos- was estimated that 70 percent of all new infec- sibility of SIV evolving into HIV in the chim- tions and 80 percent of all AIDS deaths occurred panzee was not ruled out).Moreover, lineages in sub-Saharan Africa.By 2001, average life ex- of HIV transmitted by sooty mangabeys (also pectancy south of the Sahara had declined by called the green monkey) were believed to have 10 years and infant death rates had doubled. reached humans in like fashion to become HIV- Illustrative of the impact of AIDS mortality is 2.Some, however, suspected that medicine had the example of Zambia, where a dire shortage something to do with HIV becoming a human

5 1. Acquired Immune Deficiency Syndrome (AIDS) infection and, therefore, that AIDS had an iatro- the drug azidothymidine (AZT) was shown genic or medical cause. to extend the period of latency for AIDS.It is Initially, the WHO smallpox vaccination cam- one of five drugs called nucleosides licensed paign in Africa from 1967 to 1980 came un- by the U.S. Food and Drug Administration, all der scrutiny for the possibility that HIV had of which are inhibitors of the viral enzyme been propelled through countless bodies with reverse transcriptase (RT), which performs the repeated use of inadequately sterilized nee- reverse transcription – the conversion of RNA dles, or even that the vaccine had been contam- into DNA that HIV must undergo to be infec- inated.These hypotheses, of course, dealt with tive.In the second half of the 1990s, protease HIV transmission and did not really confront inhibitors (which cripple a viral enzyme vital to the question of its origin.Another hypothesis, HIV reproduction) came into use and two nu- however, did – this one focusing on the polio cleoside inhibitors and one protease inhibitor vaccination campaign conducted in Africa (and were blended together into what was called the elsewhere) during the late 1950s.In the (then “antiviral cocktail.” The results were miraculous. Belgian) Congo, chimpanzee kidneys were used Individuals on the verge of death were going to culture the poliovirus, which in turn, it was back to jobs and resuming normal lives, the argued, could have contaminated the oral polio mortality rate from AIDS in the United States vaccine used in a widespread vaccination effort fell dramatically, and it seemed that a major during 1957–58.Buttressing the case was that battle against the disease had been won. this region subsequently became the major epi- But it was an incomplete victory, because the center of the burgeoning AIDS epidemic.Also “cocktail” can produce unpleasant side effects, bolstering it was the announcement in 1999 by and just one missed dose can give the virus a group of University of Alabama researchers the opportunity to quickly mutate into a strain that they had determined that a kind of chim- that resists the drugs.In fact, drug-resistant panzee once common in West Africa was indeed strains of HIV are already complicating AIDS the source of HIV. treatment, which has led to different combina- Yet other recent evidence was not so support- tions of “cocktail” ingredients, each of which in- ive.Most recently, in 2001, it was announced terferes with certain steps in the HIV infection that a vial of the suspected polio vaccine had process.Still other drugs have been brought been found and that analysis had revealed no effectively to bear on some of the “killer” oppor- trace of HIV.Moreover, a study published in tunistic infections such as pneumocystis pneu- 2000 in Science had already cast considerable monia and tuberculosis, which are the principal doubt on the contaminated vaccine hypothe- cause of AIDS deaths worldwide.But whether sis by showing that HIV-1 may well have been the miracle will continue indefinitely remains to present in human African populations since at be seen.The therapy is new and consequently least the 1930s – almost 30 years before the the long-term success rate is unknown.More- polio vaccination campaign in the Congo.That over, a per-patient annual cost of some 10,000– date, however, is for the time that the HIV-1 12,000 U.S. dollars limits this costly drug treat- group of viruses began to diversify, and not for ment to a relatively few victims in the devel- when they were transmitted to humans.Thus, oped world.Thus far, pressure on pharmaceu- vital questions of transmission and origin re- tical manufacturers to make low- or no-cost main unresolved – that of origin because even if drugs available to the developing world’s mil- chimpanzees did pass on HIV to humans, they lions stricken with HIV/AIDS has produced little may also have been infected from yet another in the way of results. source. Work is also being done to develop a vac- Great strides have been made recently toward cine that could be both protective by preventing the goals of treatment and prevention.In 1986, infection and therapeutic for those infected,

6 2. African Trypanosomiasis (Sleeping Sickness) by prolonging survival and decreasing immune advances made and, indeed, very little research system destruction.At the turn of the twenty- done between the 1930s and the 1980s.How- first century, vaccines were being tested that ever, in the mid-1980s field trials of a promising had proven effective in protecting monkeys new drug demonstrated its efficacy in late-stage from HIV, and large-scale trials were under disease when there is central nervous system way to test them for human safety.In addi- involvement.In addition, there have been ex- tion, Merck and Company, with its enormous re- citing recent developments in the field of tsetse sources, announced in 1999 that it would begin eradication with the combined use of fly traps human trials on two vaccines.However, pro- and odor attractants. vided that a safe vaccine does become available, the problems of administering it – especially Characteristics to the millions at high risk in the developing An acute form of sleeping sickness caused by world – are daunting because it appears that one Trypanosoma brucei rhodesiense with a short primary injection will be required, followed by incubation period of 5–7 days occurs in east- three booster shots.The good news, of course, is ern and southern Africa.A chronic form ( Try- that the question seems no longer to be whether panosoma brucei gambiense) of western and there will be a vaccine, but rather when a vac- central Africa can take from several weeks to cine will be available. months or even years to manifest itself.There Moreover, gene therapy holds out promise of are many species of tsetse flies, but only six act inhibiting HIV by introducing a gene into cells as vectors for the human disease.The Glossina that interferes with the viral regulatory proteins, palpalis group, or riverine tsetse, is responsi- or even one that will protect cells from HIV in- ble for the transmission of T. b. gambiense dis- fection.But all of these measures, even when ease.The Glossina morsitans group, or savanna they do bear fruit, will probably be too late tsetse, is the vector for T. b. rhodesiense, the to stop AIDS from becoming the biggest killer- cause of the rhodesiense form of sleeping sick- disease in human history. ness.Although tsetse flies are not easily infected Kenneth F. Kiple with trypanosomes, once infected they remain vectors of the disease for life. After being bitten by an infected fly, most victims experience local inflammation, or the 2. African Trypanosomiasis trypanosomal chancre; parasites migrate from (Sleeping Sickness) this site to multiply in blood, lymph, tissue fluids, and eventually the cerebrospinal fluid. African trypanosomiasis, or “sleeping sick- The blood trypanosome count oscillates cycli- ness,” is a fatal disease caused by a protozoan cally, with each successive wave, manifesting hemoflagellate parasite, the trypanosome.It is different surface antigens.In this manner, try- transmitted through the bite of a tsetse fly, a panosomes evade the antibodies raised against member of the genus Glossina.Sleeping sick- them by the host.Eventually, all organs are ness is endemic, sometimes epidemic, across a invaded, with central nervous system involve- wide band of sub-Saharan Africa, the so-called ment, ultimately leading to death. tsetse belt that covers some 11 million square The epidemiological pattern of sleeping sick- kilometers.Although the disease was not sci- ness varies considerably from place to place, entifically understood until the first decade of but two features are well recognized.First, the twentieth century, it had been recognized in trypanosomiasis is exceptionally focal, occur- West Africa as early as the fourteenth century. ring at or around specific geographic loca- Chemotherapy to combat trypanosomiasis tions; and second, the number of tsetse flies has remained archaic, with no significant is apparently not as important for disease

7 2. African Trypanosomiasis (Sleeping Sickness) incidence as is the nature of the human-fly voirs in the eastern African savannas.In the case contact. of T. b. rhodesiense, the usual mammalian hosts The focal nature of sleeping sickness means are wild ungulates, with humans as adventitious that the ecological settings in which it occurs hosts.Transmission of rhodesiense disease is are of vital importance for understanding its more haphazard and directly relates to occupa- epidemiology. Seemingly impossible to destroy, tions such as searching for firewood, hunting, many historical foci tend to flare up in spite fishing, honey gathering, poaching, cultivation, of concentrated eradication efforts since the cattle keeping, and being a game warden or a 1930s.Very often, villages and regions that were tourist.Whereas the gambiense form of the dis- affected decades ago remain problem areas to- ease is site related, the rhodesiense form is occu- day.The disease involves humans, parasites, pation related, which helps to explain why the tsetse flies, and wild and domesticated animals, latter characteristically affects many more men and increasing population movements have and boys than women and girls.However, when complicated the epidemiology.Tsetse species a community moves near bush infested with in- have varying food preferences, ranging from the fected flies, the entire population is at risk. blood of wild and domestic animals to that of The animal reservoir of trypanosomes is an humans, but they require a daily blood meal, important factor in the epidemiology and his- thereby making a single fly potentially highly tory of sleeping sickness.It is well established infective. that the trypanosomiases are ancient in Africa. Gambiense sleeping sickness is classically Indeed, it is conjectured that the presence of a disease of the frontier of human environ- sleeping sickness may explain why the ungulate ments, where human-created habitat meets syl- herds of the African savanna have survived van biotope.Humans are the principal reservoir human predators for so long; the wild-animal of T. b. gambiense, and they maintain the typical reservoir of trypanosomes firmly restricted the endemic cycle of the disease.It is now known, boundaries of early human settlement.Al- however, that some animals, including domestic though the wild ungulate herds became trypo- pigs, cattle, sheep, and even chickens, can act as tolerant, domestic cattle still succumb to the reservoirs.The key to understanding the gam- disease, and the vast majority of research and biense form is its chronicity and the fact that funding has been aimed at solving the problem there are usually very low numbers of parasites of animal – not human – sleeping sickness. present in the lymph and other tissue fluids. In evolutionary terms, the presence of try- Gambiense disease can be maintained by a mere panosomes in Africa may have precluded the handful of peridomestic flies – that is, those that development of some ground-dwelling faunas, have invaded bush or cultivations near human thus encouraging certain resistant primates, in- settlements.This is known as close human-fly cluding the early ancestors of humankind, to contact. fill the empty ecological niches.If so, then hu- Riverine G. palpalis are most commonly mans were exposed to trypanosomal infection found near waterways and pools; during dry at the time of their very remote origin.The par- seasons, when humans and flies are brought asites are on the whole poorly adapted to hu- together through their shared need for water, mans, which accounts for the variety of clinical the flies become particularly infective.Other symptoms and ever-changing epidemiological common foci for the disease are sacred groves, patterns.A perfectly adapted parasite does not which are often small clearings in the forest kill its host – at least in the short run. where the high humidity allows the flies to ven- An estimated 50 million people in 42 coun- ture farther from water sources. tries are at risk for trypanosomal infection, while The virulent rhodesiense sleeping sickness is it is estimated that only about 5 million to 10 a true zoonosis maintained in wild animal reser- million people have access to some form of

8 2. African Trypanosomiasis (Sleeping Sickness) protection against or treatment for the disease. derives its name.Some of the initial symp- Sleeping sickness is endemic across the wide toms of sleeping sickness are also character- band of sub-Saharan Africa known as the “tsetse istic of early malaria, which can make dif- ◦ ◦ belt” lying roughly between 20 north and 20 ferentiation between the two diseases diffi- south of the equator, where it also can attain cult in the field.A common, easily recogniz- epidemic proportions. able symptom is swelling of lymph nodes. An- The actual number of cases will never be other common symptom is called “moon face,” known, as it is a disease of remote rural ar- an edema caused by leaking of small blood eas, and even today people in such places of- vessels.A most common complication dur- ten die undiagnosed and uncounted.Most na- ing trypanosomiasis is pneumonia, which is tional statistics are grossly underreported, with a frequent cause of death.The chronic gam- the World Health Organization being notified biense form can take as long as 15 years to of about only 10 percent of new cases.The cur- develop after the victim has left an endemic rent estimate of incidence is 20,000 to 25,000 area. cases annually.Most of the victims are concen- The prospect of a vaccine for human trated in Zaire, Uganda, and southern Sudan. trypanosomiasis is bleak.The phenomenon Some villages had infection rates of up to 25 of “antigenic variation” greatly reduces the percent.In the late 1970s and 1980s, severe prospect of producing an effective vaccine, and outbreaks occurred in Cameroon, Angola, the at present very little research is under way on Central African Republic, the Ivory Coast, and vaccine development. Tanzania, as well as in Sudan, Zambia, Uganda, and Zaire. History Although trypanosomiasis has been studied The history of sleeping sickness in Africa is long for more than 80 years, much is still unknown and complex, and its complicated ecology has about the pathology of the disease.Three dramatically affected demographic patterns in phases follow the bite of an infected fly: first the sub-Saharan Africa.The parameters and den- chancre itself; then the hemolymphatic or “pri- sity of human settlement have been limited mary stage”; and finally the meningocephalitic in many regions until the present time, while or “secondary stage.” On average, people in- cattle-keeping has been prevented across vast fected with T. b. gambiense live 2–3 years before regions of the continent, thereby seriously af- succumbing, although there are recorded cases fecting the nutrition of entire populations. of infection spanning as much as 2 decades.In The “African lethargy,” or “sleepy distemper,” contrast, infection with the more virulent T. b. as trypanosomiasis has been called, was well rhodesiense, if untreated, usually leads to death known to Europeans in West Africa from as early within 6–18 weeks. as the fourteenth century, through good de- The disease manifests a bewildering array of scriptions given by Portuguese and Arab writ- clinical symptoms, which can vary from place ers.For centuries slave traders rejected Africans to place.Progressing through the two stages, with the characteristic swollen cervical glands, there is increasing parasitemia with eventual in- for it was common knowledge that those with volvement of the central nervous system.Clini- this symptom sooner or later died in the New cal symptoms can include fever, headache, and World or North Africa.As European explo- psychiatric disorders such as nervousness, iras- ration and trade along the West African coast cibility, emotionalism, melancholia, and insom- increased between 1785 and 1840, the disease nia, which reflect neuronal degeneration.Other was reported in Gambia, Sierra Leone, and west- symptoms include loss of appetite, gross emaci- ern Liberia, whereas between 1820 and 1870 it ation, sleep abnormalities, stupor, and the char- was also commonly noted along the Liberian acteristic coma from which sleeping sickness coast.

9 2. African Trypanosomiasis (Sleeping Sickness)

Certainly the disease was an important factor tific research teams were dispatched to study in the history of colonial Africa.In the begin- sleeping sickness.They began with the Liver- ning, colonial administrators were concerned pool School of Tropical Medicine’s expedition to mainly with the health of Europeans and those Senegambia in 1901 and the Royal Society’s ex- few Africans in their service. But the threat of pedition to Uganda in 1902; other expeditions epidemics of sleeping sickness eventually forced followed until World War II. colonial authorities to take much more seri- Many of these were sent by new institutions ously the health of entire African populations. especially designed to investigate the exotic dis- In those colonies affected by sleeping sick- eases of warm climates.The British, for example, ness, medical services often developed in di- opened schools of tropical medicine at Liverpool rect response to this one disease, which re- and London in 1899, while other such schools sulted in the development of “vertical” health came into being in Germany, Belgium, France, service – programs aimed at controlling a Portugal, and the United States.This new field specific disease while neglecting other crucial of scientific endeavor offered the opportunity public health issues.As recently as the 1970s, for bright young men to gain international the World Health Organization urged de- acclaim and a place in the history of medicine. veloping countries to move toward “hori- It should be noted that sleeping sickness was zontal” health services that take into ac- not the only disease to receive such attention count the multifactoral nature of disease and as Europeans sought to establish themselves health. permanently in regions of the globe where Sleeping sickness, along with malaria and yel- health conditions were difficult and mortality low fever, played an important role in the de- was high.There were major discoveries by Man- velopment of the new specialties of parasitology son, who was the first to demonstrate insects and tropical medicine.In 1898, Patrick Manson, as vectors of human disease (filariasis); and by the “father of tropical medicine,” published the Ronald Ross, who found that the malaria para- first cogent discussion of the new scientific dis- site was transmitted by the Anopheles mosquito. cipline.He explained that tropical diseases were Yet, despite the fact that endemic malaria was very often insect-borne parasitical diseases, the probably the cause of far more morbidity, the chief example being trypanosomiasis. trypanosomiases attracted much attention in Trypanosomiasis at the time was very much the new field of tropical medicine for the next 2 on the minds of colonial officials.In the decade or 3 decades. between 1896 and 1906, devastating epidemics International meetings were convened to dis- killed more than 250,000 Africans in the new cuss sleeping sickness, beginning with one at British protectorate of Uganda, as well as an es- the British Foreign Office in 1907.As the num- timated 500,000 residents of the Congo basin. ber of “tryps” specialists increased, sleeping Understandably, the new colonial powers, in- sickness became a key factor in the interna- cluding Britain, France, Germany, Portugal, and tional exchange of research findings in tropi- King Leopold’s´ Congo Free State, perceived cal medicine.The Sleeping Sickness Bureau was sleeping sickness to be a grave threat to African opened in London in 1908 to facilitate commu- laborers and taxpayers, which in turn could dra- nication of research findings on all aspects of matically reduce the utility of the new territo- the disease.Its work continues to the present ries.Moreover, the fears were not limited to the time. continent of Africa; the British also speculated After World War I and the formation of that sleeping sickness might spread to India, the the League of Nations’ Health Organization “jewel” of their empire. (the antecedent of the World Health Organiza- Thus ensued one of the most dramatic cam- tion), two major conferences in 1925 and 1928 paigns in the history of medicine, as scien- were convened to focus on African sleeping

10 2. African Trypanosomiasis (Sleeping Sickness) sickness.These conferences, following the pat- not occur to the intruders that in many cases tern of the nineteenth-century sanitation and Africans were withdrawing from areas because hygiene conferences, sought international col- of the brutal nature of colonial conquest.Half a laboration and cooperation in implementing century would pass before researchers began to public-health solutions. In Africa, special re- examine the deeper socioeconomic and political search centers on tsetse flies and sleeping causes of the dramatic changes in the African sickness appeared in many colonies includ- disease environment that had resulted in the ing Uganda, Kenya, Tanganyika (now Tanzania), spread and increased incidence of sleeping Belgian Congo (Zaire), Nigeria, Ghana, and sickness. French Equatorial Africa (Chad, Central African Medical experts at the turn of the nine- Republic, Congo-Brazzaville, and Gabon).Sleep- teenth century tended to favor the theory of ing sickness thus became an important catalyst circumstantial epidemiology, which held that for cooperation among the colonial powers in diseases were spread mainly through human Africa, which in turn aided the rapid growth agency within specific sets of circumstances. of tropical medicine as a field.In fact, sleeping Because of a lack of effective treatments, the sickness early in the twentieth century attracted principal methods of control of epidemic dis- international attention to Africa with an ur- ease consisted of segregation or isolation and gency that was repeated in the early 1980s with disinfection with acrid smoke or strong fumes AIDS. such as sulfur and vinegar.Disease was per- Response to the disease occurred within the ceived as an invader to be demolished.This private sector as well.Concerned at the possible view accounts for much of the imagery and loss of increasingly important African markets, idiom of war used in early public-health cam- the European business community encouraged paigns.A major adjunct to this theory was the and sometimes initiated research into tropical belief that once the circumstances had been diseases.For example, the principal founder of identified, most diseases in Africa could and the Liverpool School of Tropical Medicine in would be controlled, even eliminated, with tech- 1899 was the influential and powerful capital- niques and technology developed in Europe. ist Alfred Lewis Jones, chairman of a Liverpool- The European colonials assumed they would based shipping line that plied a lucrative trade succeed where Africans had failed and that along the West African coast.The businessman they would transform the continent by con- shared the imperialist’s dismay at the poten- quering the problems of tsetse and the try- tial devastation that could be caused by sleep- panosome, among others.Most colonists be- ing sickness, and together they were keen to lieved that much of the backwardness they support attempts to prevent the decimation of saw in African society was attributable, at least African populations. in part, to endemic diseases such as sleeping The politics of colonialism often reflected sickness. contemporaneous perceptions of the epidemiol- Powerful notions of the potential of West- ogy of sleeping sickness.By 1900, for example, it ern technology for solving health problems in was widely accepted that the disease had been Africa, sleeping sickness among them, have endemic in West Africa for centuries but had survived until quite recently.Rarely, if ever, only recently begun spreading into the Congo did colonial authorities consider the possibil- basin and eastward. ity that Africans not only possessed some ideas From the earliest days of colonial settlement, about the ecology of sleeping sickness but had it was not uncommon to blame sleeping sick- gained fairly effective control of their environ- ness for the abandoned villages and depopu- ment.An example of one such African strat- lated regions that Europeans encountered dur- egy was the warnings to early European travel- ing their push into the interior.It usually did ers not to travel through certain regions during

11 2. African Trypanosomiasis (Sleeping Sickness) daylight hours when tsetse flies were active and mans, tsetse flies, and trypanosomes were dis- might infect their transport animals.Moreover, rupted by European activities with the result throughout the tsetse-infested regions, there that endemic sleeping sickness flared into epi- were instances of African residence patterns demic proportions.Vivid examples of the re- that allowed coexistence with the ubiquitous sults of such ecological upheaval were the tsetse flies yet avoided population concentra- sleeping sickness epidemics in Uganda and tions conducive to epidemic outbreaks.Euro- the Congo basin that had killed hundreds of pean colonizers, by contrast, often disrupted – thousands. or destroyed – indigenous practices and sur- Epidemics continued throughout much of the vival strategies with the result that endemic colonial period, especially prior to World War sleeping sickness spread and sometimes became II, when there were serious outbreaks in both epidemic with disastrous effects. West and East Africa.Public-health regulations The colonial powers, however, held their own to control the disease affected other areas of version of the history of sleeping sickness and administration.In some colonies, sleeping sick- its evolution.Prior to their arrival, ancient, in- ness programs became so extensive and bu- tractable foci of the disease had existed in West reaucratic that they came into conflict with Africa and in the Congo basin around which, other departments, exacerbating competition from time to time, the disease would flare into for scarce staffing and financial resources within epidemic proportions.Colonials believed that colonial administrations.In addition, sleeping it really began to spread only after the Euro- sickness regulations were often responsible for pean newcomers had suppressed local wars and confrontations between the private and public slave raiding among African peoples and estab- sectors as members of the former were increas- lished law and order.This in turn allowed many ingly hindered in their attempts to exploit the Africans, for the first time ever, to move freely people and resources of Africa. and safely away from their home regions.Pro- Two major patterns emerged in the colonial tected by Pax Brittannica, Pax Belgica, and the campaigns against sleeping sickness.In one, like, the increased movements of Africans car- the focus was on tsetse eradication, whereas in ried sleeping sickness from old endemic foci to the other, the focus was on the medicalization new populations.There was some basis for this of victims.Most campaigns were a combination hypothesis, especially in West Africa such as in of features from both approaches.Within this Ghana and Rukuber of Nigeria.This widely ac- framework, national variations emerged in cepted notion of the spread of sleeping sick- the colonial campaigns.The British took a ness had an important consequence in the enor- more broadly ecological approach to control mous effect expended by the Europeans in of the disease, whereas the French and the trying to regulate African life at every level, Belgians took a more “medical” approach to and especially to limit strictly any freedom of the problem of human infection.British policy movement. was to break the chain of sleeping sickness John Ford, a British entomologist who spent transmission by separating people from flies. more than 25 years researching sleeping sick- Thus, while British administrators implemented ness, was one of the first to challenge this social policies aimed at protecting people from “classical view” of the pacification of Africa disease, the scientific community, especially and the spread of the disease.He argued the new entomologists, searched for solutions that it was not the pacific character of Eu- to the “tsetse fly problem” in Africa.The com- ropean colonization but, on the contrary, pulsory mass resettlement of Ugandans, which its brutal nature, that greatly disrupted and probably helped save lives, from lakeshore stressed African populations.In particular, the communities in Buganda and Busoga in 1908, balanced ecological relationships among hu- and the huge Anchau (northern Nigeria)

12 2. African Trypanosomiasis (Sleeping Sickness) scheme begun in 1936 are good examples the effect of removing the store of antibodies of breaking transmission chains.Likewise, from humans that had been built up through in some regions where it was ecologically long contact with the parasites. feasible, Belgians resettled groups of people Sterilization of the human reservoir was made such as those along the Semliki River in eastern possible in 1905 when the first trypanocidal Congo. drug became available in the form of an ar- Unfortunately, in the context of recently con- senical compound, atoxyl.Discovered by the quered and colonized Africans, who had rural German chemist Paul Ehrlich and adapted subsistence economies and whose culture and for use with sleeping sickness by Wolferstan tradition were intricately linked to locale, com- Thomas of the Liverpool School of Tropi- pulsory relocation sometimes had calamitous cal Medicine, atoxyl, alone or in combina- effects on those it was meant to protect.In the tion with other compounds, remained the only Belgian Congo an extraordinary amount of leg- chemotherapy for 2 decades.Atoxyl was toxic islation and effort was directed at the control of for 38 percent of patients, with dreadful side ef- populations in relation to sleeping sickness.It fects suffered by those whom it did not kill out- is not surprising that many Africans regarded right, among them the blinding of 30 percent sleeping sickness as the colonial disease be- of those injected.Later, new drugs – suramin cause of the sometimes overwhelming amount (1916-20), tryparsamide (1919–25), and pen- of administrative presence it elicited. tamidine (early 1940s) – came into use for early- French and Belgian efforts were directed stage rhodesiense and gambiense disease.An- chiefly at “sterilizing the human reservoir” of other most problematic arsenical with serious trypanosomes through mass campaigns of med- side effects, including up to 5 percent mortal- icalization, or injections.To achieve this, they ity, was and is used for second-stage disease. conducted systematic surveys of entire pop- This drug, melarsoprol (along with suramin and ulations, hoping to locate, isolate, and treat pentamidine), has remained the drug of choice all victims.Eug ene` Jamot, a French parasitolo- since the 1940s. gist, developed this method in Ubangui-Chari In the early 1960s, which saw independence (French Equatorial Africa) and later introduced for many African territories, colonial rulers con- it in affected parts of Cameroon and French curred that human sleeping sickness was under West Africa.In 1916, he organized an am- control in Africa.But political upheavals, accom- bitious sleeping sickness campaign based on panied by the breakdown of medical infrastruc- mobile teams, which systematically scoured tures and large-scale population displacements, the country for victims of the disease to be once again seriously affected the epidemiology injected. of the disease.Some countries – Zaire, Uganda, A grid system was devised to ensure com- Sudan, and Ivory Coast, for instance – witnessed plete surveys, and the mobile teams worked epidemics of sleeping sickness, and it has been with true military efficiency.Between July 1917 estimated that by 1969 there were up to and August 1919, more than 90,000 individu- 1 million victims in the Congo alone. als had been examined, and 5,347 victims were Tsetse flies and the trypanosomes that cause identified and treated.Jamot’s design for a sleep- sleeping sickness will continue actively to shape ing sickness service was soon adopted by the the future of humankind in Africa.Because the Belgians in the Congo, and by 1932 there were most effective means of control is continual and five such teams operating annually in northern thorough surveillance, present-day health plan- Congo alone.Admirable as it was for its sheer ners and administrators must be aware of the scale of organization, the policy of mass medi- history of this disease and the ease with which calization did not affect the fundamental ecol- that history can repeat itself. ogy of the parasites; indeed, this approach had Maryinez Lyons

13 3. Ainhum

3. Ainhum of the Alzheimer’s type is the most com- monly acquired progressive brain syndrome. The word ainhum is derived from a term in Alzheimer’s disease begins with insidious intel- the Nagos language of East Africa meaning “to lectual and memory loss as the brain becomes saw.” It describes the development of constrict- shrunken from nerve cell loss and advances ing bands about digits, almost always the fifth, over 5–15 years to a chronic vegetative state. or smallest, toe, which ultimately undergoes Progressive cognitive, psychological, and social self-amputation.Typically the disease is bilat- dysfunction has a profound effect on family and eral (i.e., affecting both small toes). friends.Alzheimer’s disease may be the fourth Ainhum is ordinarily a disease of middle-aged leading cause of death in the United States. black Africans of both sexes accustomed to go- D.K.Kay and colleagues showed the average ing barefoot.The disease is common in Nigeria survival for demented men to be 2.6 years after and East Africa and has been reported less fre- the diagnosis of illness, whereas the survival pe- quently in other tropical areas, including India, riod for nondemented men of the same age was Burma, Panama, the Antilles, and Brazil. 8.7 years. However, there is great variability in Ainhum was noticed frequently among slaves survival statistics from different studies. in Brazil and was first described in detail in 1867 Although Alzheimer’s disease is the leading by J.da Silva Lima, who also named the disease. cause of dementia, its etiology remains un- Silva Lima’s description is outstandingly accu- known, and treatment is supportive.The illness rate and has not been bettered.In one case, is a major problem among the elderly.Approx- he wrote that the toe had taken the shape of a imately 4 percent of the population over the small oval potato; the covering skin was coarse age of 65 is affected, and, by age 80, prevalence and scabrous and tender to touch.As the dis- reaches 20 percent.As the elderly population ease progressed, a strong constriction appeared of the United States increases, the number of at the base of the toe, and, as blood flow to the persons with Alzheimer-type dementia will also toe was impeded, the bones ceased to exist.In increase.Even though pathological changes in time, spontaneous amputation occurred. presenile and senile forms of the illness are sim- The cause of ainhum is unknown.Chronic ilar, there is evidence that early- and late-onset trauma, infection, hyperkeratosis, decreased Alzheimer-type dementia differ clinically. vascular supply, and impaired sensation may alone or in combination produce excessive fi- Characteristics broplasia and lead to ainhum.It is an acquired Alzheimer-type senile dementia is associated condition, although a hereditary predisposition with behavioral signs and symptoms that divide has not been ruled out.Surgery is the mainstay into corresponding stages.In the early stage, of therapy: In most cases, prompt amputation subjective memory deficit may be difficult to may save the patient pain and infection. differentiate from benign senile forgetfulness. Donald B. Cooper However, elderly persons with benign forgetful- ness are unable to recall unimportant details, whereas patients with Alzheimer-type senile de- mentia forget important and unimportant infor- 4. Alzheimer’s Disease mation randomly. Typically, patients with Alzheimer’s disease In 1906, Alois Alzheimer first described a forget where things are placed, become lost eas- neurological disorder of the brain associated ily, and have difficulty remembering appoint- with global deterioration of cognitive func- ments.Both recent and remote memory are tioning and resulting in severe social impair- affected.When patients recognize their cogni- ment.Once thought rare, senile dementia tive and social losses, many develop feelings of

14 4. Alzheimer’s Disease hopelessness and despondency.As Alzheimer- or even to admission to the hospital for evalu- type senile dementia progresses, the patient en- ation.These acute changes probably represent ters a confusional phase with more global im- withdrawal of orienting stimuli and emotional pairment of cognitive functioning.Changes in distress rather than progression of the disease higher cortical functions, such as language, spa- process. tial relationships, and problem solving, become Psychometric tests may be useful in delineat- more apparent. ing patterns of cognitive deficit at various stages During the confusional phase, obvious de- of severity and in identifying the qualitative as- nial begins to replace anxiety, and cognitive pects of performance deficit.Although labora- deficits are noticeable to family and friends.In tory tests are sometimes used to support the di- the final phase, the patient becomes aimless and agnosis of Alzheimer’s disease, the laboratory is may hallucinate or be restless and agitated.Lan- actually more useful in excluding other causes guage disorders can occur in late stages.Abnor- of cognitive deterioration.Atrophy of the cere- mal neurological reflexes, indicative of loss of bral cortex is often seen on computed tomogra- higher neural inhibition, are common.Not all phy, but it is frequently overinterpreted. patients with Alzheimer-type senile dementia Alzheimer’s disease may be difficult to distin- demonstrate the classic evolution of symptoms. guish from the progressive dementias that are Although almost all patients have some mem- caused by many other disease conditions.For ory impairment, other focal cortical deficits may example, dementia is common in patients with predominate initially.Spatial relationship im- terminal cancer and may result from a variety pairment is common early.The patient may also of causes. complain of word-finding difficulty or demon- The evaluation of a patient presenting with strate mild problems in speaking and under- dementia often reveals untreatable causes, but standing.In cases where damage to the frontal treatable dementia is discovered in 20–25 lobes of the brain predominates, the patient percent of such patients.Of the many treat- presents with judgment problems. able causes of dementia, multi-infarct demen- In the absence of biological markers for the tia may be the most difficult to differentiate illness, it is not surprising that clinical diagnosis from Alzheimer’s disease.Risk factors for stroke may be less than accurate and, in fact, may be should be evaluated and controlled when pos- correct in as few as one-half of Alzheimer-type sible in every patient with early dementia. senile dementia cases.Not only do cognitive Depression is the most common treatable ill- changes associated with normal aging overlap ness that may masquerade as Alzheimer-type those found in the early stages of dementia, but senile dementia.Cognitive abilities return to also a wide spectrum of conditions may produce baseline levels when depression is treated.Be- dementia.In any given patient, several condi- cause some patients with early dementia have tions leading to progressive cognitive decline secondary depression, dementia and pseudo- may occur simultaneously.The clinical diagno- dementia may be difficult to differentiate.The sis of Alzheimer-type senile dementia always re- depression that occurs in the early stages of quires documentation of progression.Reports Alzheimer-type senile dementia tends to resolve from family and friends provide the most valid as the disease progresses.Pseudodemented, de- measures of cognitive decline in elderly persons pressed patients are apt to have poor attention, and support the clinician’s judgment that global inconsistent cognitive changes, absence of cor- intellectual deterioration has occurred. tical signs, weight loss, sleep disturbance, guilt, Progression is usually gradual but with fluc- poor self-esteem, a past personal family psychi- tuation of symptom severity.The patient may atric history, and a more rapid onset. react very dramatically to changes in the liv- In contrast, patients with cortical dementia of ing situation, to losses of friends or relatives, the Alzheimer type often show insidious onset,

15 4. Alzheimer’s Disease slow progression, early loss of insight, amnesia consistent with Alzheimer-type senile demen- for remote and recent events, spatial disorienta- tia if they live to adult life.Because Down syn- tion, reduction in spontaneous speech, and oc- drome represents a disorder of chromosome 21, casionally aphasia.Agnosia, apraxia, increased a point of origin for the search for the genetic de- muscular tension, and abnormal neurological terminants of Alzheimer’s disease is suggested. reflexes may also be present. Recent data favor the hypothesis of a genetically A wide variety of gross morphological and induced overproduction of amyloid protein as a microscopic changes occur in the brains of pa- factor in the cause of Alzheimer’s disease. tients with Alzheimer’s disease.Unfortunately, When families request genetic counseling, many of these changes are difficult to distin- one can explain only what is known about guish from alterations that occur in the brains the genetic factors.In a family with a single of normal elderly persons, who also show some Alzheimer victim, the lifetime risk for a close atrophy of white matter and, to a lesser extent, relative also to develop dementia is approxi- gray matter. mately 10 percent.Because most dementia de- Although it is generally recognized that ge- velops after the age of 70, this is a relatively netic influences are important in Alzheimer’s small probability.In families with dementia oc- disease, the exact nature of these genetic influ- curring over several generations, an autoso- ences also remains unclear.Some families have mal dominant inheritance is probable, and the a large number of members with the clinical or risk for children of an affected parent may ap- pathological diagnosis of Alzheimer’s disease. proach 50 percent.In these families, optimum The most important practical point regarding health management indicates the suspicion of these kindreds is that most of them meet cri- dementia in every elderly person with altered teria for autosomal dominant inheritance.Pen- environmental-social interactional skills, multi- etrance of the gene exceeds 90 percent in most ple physical complaints in the absence of objec- of these families.As a result, the children of an tive disease, or vague and unclear history.Au- affected person have a 50 percent risk of de- topsy can be suggested to confirm diagnosis to veloping dementia if they survive to the age at trace the pedigree more accurately. which dementia begins in that family.The ex- Environmental causes for Alzheimer’s disease act proportion of familial cases is unknown, but have also been suggested.Some investigators they may account for as many as 10 percent have linked focal intranuclear accumulation of of all cases of Alzheimer-type dementia.There aluminum to the presence of neurofibrillary is some familial clustering in families with- degeneration in hippocampal neurons.The rela- out dominant inheritance.It appears that con- tionship of aluminum to Alzheimer-type senile cordance for dementia is somewhat higher in dementia, however, is not well accepted.Gen- monozygotic versus dizygotic twins, suggesting eral decline of immunologic competence with genetic factors.On the other hand, concordance aging suggests an autoimmune mechanism.Al- is not 100 percent, so environmental factors though elevated levels of brain antibody have must have a role.Because age of onset varies been demonstrated in Alzheimer’s disease, an- within a twin pair, it may be difficult to be cer- tineuronal antibodies have not been demon- tain whether a given pair is truly discordant. strated in the central nervous system.Serum An association has been shown also be- protein abnormalities have been demonstrated, tween Alzheimer’s disease and families that notably changes in haptoglobin functions.Fi- produce children with Down syndrome.Fur- nally, a viral cause has been proposed but not ther support for a link between Down syn- substantiated. drome and Alzheimer’s disease is provided by Alzheimer’s disease remains a major chal- the fact that patients with Down syndrome lenge not only to modern medicine but also to tend to demonstrate neuropathological findings the health care delivery system and to society at

16 4. Alzheimer’s Disease large.Not only is further research necessary in illness “Alzheimer’s disease” in honor of his for- the diagnosis and management of the disease mer pupil. itself, but also major changes are necessary in The question then became one of determin- the health care delivery system if patients af- ing if this disease was the same as senile de- flicted with this illness are to get the care that mentia.It revolved around the ancient prob- they need. lem of what pathological changes can be at- tributed to aging as opposed to other causes. History Kraepelin had emphasized the presenile nature Although Alzheimer’s disease has only recently of Alzheimer’s disease, yet because of its simi- become widely known, it doubtless has a long larity to senile dementia some investigators sug- history under such rubrics as “senility,” “hard- gested that Alzheimer’s disease might be caused ening of the arteries,” and “dementia,” to name by “a premature onset of the aging process.” Also but a few.Certainly senility and dementia are confusing the picture was the nineteenth cen- conditions that have been recognized for mil- tury notion that extended also into the twenti- lennia.The Assyrians, Greeks, and Romans all eth century: that cerebral arteriosclerosis might knew and described them.J.Esquirol, how- be the cause of senile dementia.By the late ever, has been credited for the first modern de- 1920s, there had been a sufficient accumulation scription, in 1838, of what seems to have been of case descriptions of dementia among the el- Alzheimer’s disease.Esquirol wrote of a “se- derly that statistical analysis could be brought nile dementia” that increases with age.Seven to bear on the problem.It was found that most years later, Wilhelm Griesinger published a text- of the cases did in fact occur between the ages of book on mental disease that clearly recognized 50 and 60, sustaining the notion of its presenile the condition of “presenile dementia” caused by nature.In 1955 Martin Roth showed that mental brain atrophy found at autopsy.Neither of these changes could be triggered by a variety of both reports, however, seems to have had much in- “functional” and “organic” diseases, and by the fluence on investigators at the time. 1960s two major groups of researchers were at It was during the latter half of the nineteenth work on Alzheimer’s disease.One, headed by century that public as well as scientific con- Robert Terry, was based at Albert Einstein Uni- cern for problems of the elderly increased con- versity, and the other, headed by Bernard Tom- siderably.With that concern came the birth of linson, Gary Blessed, and Roth, was located at the field of geriatrics and increasing attention Newcastle upon Tyne.From their work and from paid to dementia in the elderly.Much of the ef- other studies, it became apparent, among other fort during these decades focused on whether things, that the changes in the brain found in it was an inevitable product of aging or an ac- cases of presenile dementia were the same as tual disease.Emil Kraepelin, one of the founders those in senile dementia. of modern psychiatry, pointed out the difficulty The discovery broadened the definition of in separating normal senility from senile de- Alzheimer’s disease and thereby increased enor- mentia.In applying the new technique of sil- mously the number of individuals viewed as ver staining, Alzheimer, his student, identified victims of it.It also created major semantic a new neuropathological marker of dementia problems.Previously, the presenile nature of in the brain of a patient who had died at age Alzheimer’s disease was a defining factor.Now 55 after a 4-year illness.This marker was the the illness, shown to be a major affliction of the neurofibrillary tangle, which he speculated was elderly population, was called senile dementia the marker of a dead cell.Alzheimer thus made of the Alzheimer type (SDAT), which psychia- the first correlation between clinical character- trists call “primary degenerative dementia.” Se- istics of dementia in a patient and pathological nile dementia has been used to mean either lesions in the brain.Kraepelin later named the SDAT or Alzheimer’s disease, but it may also

17 4. Alzheimer’s Disease refer to other forms of dementia in the elderly.In 50 million.Given the fact that an individual addition, Alzheimer’s disease and senile demen- who lives to be 80 has an almost 1:4 chance tia were often lumped together as senility or of developing Alzheimer’s disease or a related as cerebral arteriosclerosis.This latter concept disorder, estimates suggest that the number of proved to be so tenacious that even as late as the these victims will increase to about 4 million middle 1970s it was called “probably the most by the turn of the century.As the 1990s began, common medical misdiagnosis” of the cause of it was further estimated that fully half of all mental deterioration in the elderly. nursing home patients in the United States In the early 1980s, Alzheimer’s disease was were Alzheimer victims. defined as an “age-associated cognitive de- The implications of the growing number of cline of gradual onset and course, accompa- these victims for health care delivery systems nied by Alzheimer-type neuropathologic brain are staggering.In 1967 a White House con- changes” with “no distinction with respect to ference on aging resulted in the creation of age of onset,” and was thought to be responsible the National Institute on Aging, which greatly for 50 percent or more of all dementias.Experts facilitated research on Alzheimer’s disease.In at a 1990 conference on the illness believed that 1983, a Task Force on Alzheimer’s Disease Alzheimer’s disease is being diagnosed correctly was created by the Department of Health and in about 80 percent of cases, even though such Human Services, which has emphasized the diagnoses can be confirmed only after death, need for increased research and increased re- and even though the etiology and epidemiol- search funding, and in 1987 the international ogy of the disease remain obscure. journal Alzheimer’s Disease and Associated Dis- It may well be determined that Alzheimer’s orders was founded to report such research.As disease is not a single disease but, rather, many more and more resources are brought to bear, different diseases with multiple causes ranging the outlook for breakthroughs in understand- from genetics to exogenous toxins.The extent ing the causes of Alzheimer’s disease and treat- to which age and aging will rank among those ing it are more optimistic than in former times. causes remains a subject of debate.Reports of But it remains a devastating disease whose eti- the condition among individuals in their 30s ology is unknown. have been used to support the contention that Joseph A. Kwentus the disease is unrelated to aging.On the other hand, there is a rising prevalence with age, such that by age 85 and over, some 20 percent or Postscript more are demented.If, of course, Alzheimer’s disease is a specific disease or diseases (as op- There are now some 4 million Alzheimer’s pa- posed to an inevitable product of the aging pro- tients in the United States.Around 10 percent cess for some 5–7 percent of the population over of those over age 65 are affected; in the over- age 65), then, of course, there is hope for a cure. 85 category, upward of 45 percent have the The question, however, of why Alzheimer’s disease.Typically, death follows diagnosis by disease has been called the disease of this cen- 7–10 years, although the range can vary from tury – one that has only recently burst upon 3–20 years. the developed world in epidemic proportions – To the discovery in the 1980s of a type of pro- is certainly bound up with advancing age for tein in plaques (called amyloid protein) that ap- many and with the demographic changes that peared to be toxic to neurons, scientists have this has wrought.In 1900, there were only subsequently added another – a protein called 3 million Americans aged 65 or older.Today “tau” that may be associated with Alzheimer’s there are more than 27 million, and it has been characteristic tangles.In healthy brains, the estimated that in the year 2030 there will be tau protein provides neurons with structural

18 5. Amebic Dysentery support, but in Alzheimer’s disease the struc- supportive.There are, however, a number of tural support becomes twisted and tangled. pharmacologic interventions mostly aimed at The cause of the disease remains a mystery, mild-to-moderate Alzheimer’s patients to slow although much promising research has been the course of the disease.Inflammation of the conducted – especially in the field of genet- brain ( perhaps associated with amyloid), has ics, where, it is increasingly believed, lie most been implicated in the etiology of the dis- of the important solutions to the Alzheimer’s ease and is now treated with anti-inflammatory mystery.One recent and important finding is drugs.Other drugs (including ginkgo biloba) that carriers of a fairly uncommon apolipopro- are administered to help with memory and tein E gene (APOE4) are far more likely to slow down its loss.Estrogen therapy has proven develop Alzheimer’s disease than those who beneficial for women with Alzheimer’s, and carry the common (APOE3) version.Almost vitamin A is frequently administered.However, half of late-onset Alzheimer’s patients have there is difficulty in determining which medica- APOE4.Another discovery, especially in the tions work best in various patients, and in the case of early-onset Alzheimer’s, has linked a absence of a “miracle” drug, at this point pre- genetic mutation with the production of the vention in the form of the Alzheimer’s vaccine protein amyloid–the protein in plaques that is seems far more promising than treatment. suspected of neuron destruction.Interestingly, Kenneth F. Kiple the mutation occurs in genetic territory where Down syndrome is also found, and those af- flicted with this genetic disorder also develop plaques and tangles in the brain as they grow 5. Amebic Dysentery older. Because thus far the only positive diagnosis Amebiasis is an infection of the colon caused of Alzheimer’s is at autopsy, diagnosis in living by a parasitic protozoan, the ameba Entamoeba patients is a matter of ruling out the possibil- histolytica.Several species of ameba inhabit the ity of other problems (such as stroke or alco- large intestine.Most are harmless commen- holism), a physical examination, mental tests, sals or minor parasites, usually causing little or brain scans, and a scrutiny of family medical his- no clinical damage.The closely related species tory.Thus, Alzheimer’s disease is (probably in- Entamoeba coli and Entamoeba hartmanni are evitably) at times confused with other forms of commensals, and infection with E. histolytica dementia and misdiagnosed in 10–20 percent of is also often asymptomatic.Pathogenic amebas cases or not diagnosed at all in its early stages.In cause light to severe intestinal damage (amebic 2000, however, it was announced at the World dysentery) and sometimes spread to the liver, Congress on Alzheimer’s in Washington, D.C., lungs, brain, and other organs. that scientists had located an enzyme that can determine with 95 percent accuracy whether a Characteristics person has Alzheimer’s in its early stages. The parasite exists in two forms during its In terms of prevention, there is a vaccine that life cycle.Active adults, trophozoites, multiply has proven effective with mice, which was re- in the lumen of the colon.They frequently cently (in 2000) pronounced safe for humans. live there harmlessly, feeding on the contents Vaccine trials in humans now under way ap- of the intestine.Some strains are generally pear promising and have prompted some to op- commensal; others are highly pathogenic.Un- timistically predict the end of “the disease of der conditions of stress, lowered host resistance, the [twentieth] century” early in the twenty- or when a particularly pathogenic strain is in- first.But there is still no cure for Alzheimer’s volved, amebas invade the intestinal wall and disease, and much of the treatment remains cause abscesses.As they pass lower into the

19 5. Amebic Dysentery large intestine, the drier environment stimu- 1979–84.The disease was concentrated in Texas lates them to form a cyst wall.The original cell and California and probably resulted from in- nucleus divides twice, producing four daughter creased immigration from Mexico and South- nuclei.Cysts are passed with the feces and east Asia.But annual case rates may be signifi- are infective when swallowed.Excystation takes cantly underreported. place in the small intestine, and the young Asymptomatic and clinical amebiasis is much trophozoites, four from each cyst, are carried more common in Third World countries.Sur- in the fecal stream to the large intestine.When veys have shown prevalence rates of up to dysentery occurs, trophozoites are swept out 60 percent, reflecting real differences as well too rapidly to encyst.Even though huge num- as technical difficulties.It is clearly a major bers of amebas may be passed, they die quickly public-health problem in much of South and and are not infective.Persons with mild or no Southeast Asia, China, Africa, and parts of Latin symptoms produce infective cysts, and it is they, America.Mexico appears to have an unusually not the patients with dysentery, who spread the high prevalence.Estimates in the latter part of disease. the twentieth century indicated that about 480 Infection is by the fecal-oral route.Direct in- million people were infected throughout the fection can take place in circumstances of ex- world: 290 million in Asia, 80 million in Africa, treme crowding, among inmates of institutions, 90 million in the Americas, and – remarkably – and among male homosexuals. Indirect spread, 20 million in Europe.Serious disease, however, however, by fecal contamination of food and wa- strikes only a small percentage of those infected, ter, is more common.Waterborne epidemics of and those who die of it constitute a very tiny amebic dysentery are not so frequent as those fraction indeed. of bacillary dysentery, but the former do oc- Amebas cause disease when they invade the cur when sewage contaminates wells or water mucosal and submucosal layers of the large pipes.Fruits and vegetables can become cov- intestine, producing characteristic flask-shaped ered with cysts when human feces are used as lesions.In severe cases, the lesions become large fertilizer, or when fruits are washed in contam- and confluent, resulting in substantial tissue de- inated water or are handled by a carrier.Flies struction, bleeding, loss of fluids, and sloughing and cockroaches can transmit cysts from feces of patches of mucosa.Damage to the intestinal to food.The disease thus flourishes in poor san- wall reduces water absorption, and loose stools itary conditions but is rare where good personal with blood and mucous are passed.In addition hygiene is practiced and where water and sewer to severe and perhaps fatal damage to the gut, systems function properly.Dogs, cats, and mon- amebas sometimes penetrate through the mus- keys can be infected in the laboratory, but there cular coat of the bowel, where they enter the is no evidence that animal reservoirs have an bloodstream and are carried to other organs, epidemiological significance. especially the liver.Intestinal perforation may Infection with E. histolytica occurs around the result in fatal peritonitis.Large abscesses may world, although both commensal and patholog- form in the liver, with grave and sometimes fatal ical amebiasis is more common in poor, tropical consequences.Amebas may also migrate from countries.Prevalence rates vary greatly, as does the liver through the diaphragm to the lungs the proportion of infections that result in clini- and cause new abscesses there.Brain abscesses cal disease. are rare, but lethal.Very destructive skin ulcera- Amebiasis, especially clinical disease, is rare tions can also occur, especially around the anus. today in developed countries.In the United Clinical symptoms of intestinal amebiasis States, 3,000–4,000 cases were reported an- range from mild diarrhea and abdominal dis- nually through the late 1970s.However, a comfort to frequent loose stools with blood mu- spurt to roughly twice that level occurred in cus, severe pain, emaciation, and prostration.

20 6. Anemia

Onset is generally insidious.Liver involvement Then in 1890, Canadian Henri Lafleur and may develop without evidence of intestinal American William Councilman published a disease.Symptoms include severe, continuous definitive study of the pathology of the disease. pain, enlarged and tender liver, fever, and weak- German researchers H.Quincke and E.Roos dis- ness.Chronic amebiasis, both intestinal and tinguished between pathogenic and commensal hepatic, is sometimes very difficult to identify. human amebas. Differential diagnosis must rule out bacil- Still, the situation remained confused, as lary dysentery.Amebic dysentery tends to be a ameba identification and taxonomy was con- chronic disease with a gradual onset and little troversial, and many research results could not or no fever.The stools tend to be more abun- be replicated.Doubts about the significance dant but less frequent and not to be bright red of pathogenic amebas were widespread in the with blood, as is common in bacillary dysentery. early 1900s.Even Patrick Manson, perhaps the Amebic dysentery has a longer incubation pe- most important figure in tropical medicine, riod, 20–90 days or more, compared to 7 days expressed skepticism about the role of amebas or less for the bacillary form.Finally, with its in dysentery as late as 1909.In 1913, American shorter incubation period and greater probabil- scientist Ernest Walker established the basic ity of water transmission, bacillary dysentery is outline of the life cycle of E. histolytica and more likely to occur in dramatic epidemics. cleared some of the confusion about non- pathogenic forms.The discovery in 1925 of History methods to raise amebas in culture has con- Amebiasis probably did not become a serious tributed to further clarification.Many mysteries problem until people began to adopt a seden- remain, however, as to distinctions between tary, agricultural way of life.Dysentery has been pathogenic and nonpathogenic strains, and described in early medical writings of Europe factors such as diet, stress, and concomi- and Asia, and outbreaks were frequent in mil- tant infections that trigger invasiveness in itary units, on slave ships, and in prisons.It longstanding, asymptomatic infections. is generally impossible, however, to determine K. David Patterson whether amebic or bacillary dysentery was in- volved in any particular outbreak of the “flux.” British doctors in India provided good clinical accounts of amebiasis in the early nineteenth 6. Anemia century.In 1828, James Annesley clearly linked the intestinal and hepatic aspects of the disease. Anemia, an insufficiency of red blood cells The pathogen was described in 1875 by Russian (RBC) and hemoglobin for oxygen-carrying physician Fedor Losch,¨ who noted the clini- needs, results from a variety of disease pro- cal course of the disease, identified the ameba, cesses, some of which have existed since ancient and induced similar lesions in dogs by feed- times.It was defined in quantitative terms in the ing them ameba-rich stools from his patient. mid-nineteenth century, but before that the ev- Losch,¨ however, believed that something else idence of anemia is found in the descriptions initially caused the disease and that the ameba of pallor or in the occurrence of diseases that merely “sustained” it.Technical problems, es- we now know cause anemia.For example, lead pecially in identifying amebas and determining poisoning decreases RBC production and was which were pathogenic and which were harm- apparently widespread in Rome.Intestinal par- less, greatly impeded further research. asites cause iron deficiency anemia and were Stephanos Kartulis kept interest in the subject known to exist in ancient times.Parasites found alive in the 1880s, establishing that an ameba in paleopathological specimens include many was the probable cause of “tropical” dysentery. that can cause intestinal blood loss and anemia.

21 6. Anemia

Congenital abnormalities in RBC metabolism George Richards Minot of Harvard Univer- (including glucose 6-phosphate dehydroge- sity became interested in the dietary history nase [G6PD] deficiency and various forms of his patients following the first reported syn- of thalassemia and sickle-cell anemia) were dromes due to deficiency of micronutrients. He probably also present in ancient times.All of focused attention on liver after Whipple’s ob- these, including thalassemia, protect against servations in dogs; in trying to increase the iron malaria, and the incidence of the relatively and purines in the diet of patients with PA, he mild, heterozygotic thalassemia minor proba- fed them 100–240 grams of liver a day.He ob- bly increased in the Mediterranean region after served that the reticulocytes (an index of bone the appearance of falciparum malaria, the most marrow activity) started to rise 4–5 days after fatal type of the disease. the liver diet was begun.In fact, patients showed Iatrogenic anemia was also common a consistent rise in RBC count and hemoglobin throughout most of recorded history, be- levels whenever they consumed liver in ade- cause bleeding was considered therapeutic quate amounts.In an attempt to purify the pro- from Greek and Roman times until the mid- tein in liver, it was found that extracts were nineteenth century. effective, and subsequently, cyanocobalamin –

vitamin B12 – was identified.It was purified in Pernicious Anemia 1948 and synthesized in 1973. Awareness of this type of anemia appears The possible role of the stomach in PA was in the second half of the nineteenth cen- pointed out by Austin Flint in 1860, only 5 years tury.Thomas Addison of Guy’s Hospital de- after Addison’s description of the ailment ap- scribed a severe, usually fatal form of anemia in peared.In 1921, P.Levine and W.S.Ladd estab- 1855.Macrocytes were recognized by George lished that there was a lack of gastric acid in pa- Hayem in 1877; he also noted a greater re- tients with PA even after stimulation.William B. duction of hemoglobin than of RBCs in per- Castle established that gastric juice plus beef nicious anemia (PA).In 1880, Paul Ehrlich muscle were effective in treating PA, although found large nucleated RBCs in the peripheral either alone was not.An autoimmune basis for blood containing dispersed nuclear chromatin; development of PA has been established in re- he called them megaloblasts, correctly con- cent years. cluding that they were precursors of Hayem’s giant red cells that had escaped from the Iron Deficiency Anemia marrow. Iron deficiency anemia is by far the most com- In 1894, T.R.Fraser of Edinburgh became mon cause of anemia in every part of the world the first physician reported to have fed liver to today.It undoubtedl y existed in ancient times patients with PA.Although he achieved a remis- as well.In this condition, fingernails develop sion in one patient, others could not immedi- double concave curvature, giving them a spoon ately repeat his success.But in 1918, George H. shape (koilonychia).A Celtic temple at Nodens, Whipple bled dogs and then fed them canned in Gloucestershire, England, built in Ascelpian salmon and bread.After the dogs became ane- style after the Romans had left Britain in the mic, he needed to remove very little blood to fourth century A.D., contains a votive offering of keep the hemoglobin low, although when the an arm fashioned crudely proximally but with basal diet was supplemented, he found that he increasing detail distally; it shows characteristic needed to bleed them more often.It turned out koilonychia. that liver was the most potent supplement, but Pallor, the hallmark or cardinal sign of ane- it was not until 1936 that hematologists real- mia, is seen especially in the face, lips, and nails, ized that the potency of liver was due to its iron often imparting a greenish tint to Caucasians, content. a presenting sign that led to the diagnosis of

22 6. Anemia chlorosis or the “green sickness” in the six- gestion of beans was probably recognized in an- teenth century.In the seventeenth century, pal- cient Greece, forming the basis for the myth lor became associated in the popular mind with that Demeter, Greek goddess of harvest, forbade purity and femininity, and chlorosis became members of her cult to eat beans.Pythagoras, known as the “virgin’s disease.” Constantius I, physician and mathematician of the fifth cen- father of Constantine the Great, was called Con- tury B.C. who had a great following among the stantius Chlorus, because of his pale complex- Greek colonists in southern Italy, also seems to ion, and it seems most likely that he had a con- have recognized the disorder, since he, too, for- genital form of chronic anemia.(He came from bade his followers to eat beans.It is in that area an area known today to have a relatively high of southern Italy that the incidence of G6PD de- frequency of thalassemia.) ficiency is highest. Preparations containing iron were used ther- In 1956, the basis for many instances of this apeutically in Egypt around 1500 B.C. and later type of anemia was recognized as a hereditary in Rome, suggesting the existence of iron defi- deficiency of the enzyme G6PD within the red ciency.In 1681, Thomas Sydenham mentioned cell.Inheritance of G6PD is now recognized to “the effect of steel upon chlorosis.The pulse be a sex-linked characteristic with the gene lo- gains in strength and frequency, the surface cus residing on the X chromosome. warmth, the face (no longer pale and death like) It is estimated that currently over 100 mil- a fresh ruddy coulour ...Next to steel in sub- lion people in the world are affected by stance I prefer a syrup ...made by steeping iron this deficiency.Nearly 3 million Americans or steel filings in cold Rhenish wine.” In 1832 carry the trait for G6PD deficiency, which P.Blaud described treatment of chlorosis by use is also found among Sephardic and Kurdish of pills of ferrous sulfate and potassium carbon- Jews, Sardinians, Italians, Greeks, Arabs, and ate that “returns to the blood the exciting prin- in the Orient among Filipinos, Chinese, Thais, ciple which it has lost, that is to say the coloring Asiatic Indians, and Punjabis.It has not substance.” been found among North American Indians, Children have increased needs for iron dur- Peruvians, Japanese, or Alaskan Eskimos. ing growth, as do females during menstruation, The first documented report of drug-induced pregnancy, and lactation.Chronic diarrhea, (as opposed to fava-bean-induced) hemolytic common in the tropics where it is often associ- anemia appeared in 1926 following the admin- ated with parasitism, decreases iron absorption istration of the antimalarial drug pamaquine whereas parasitism increases iron losses.Esti- (Plasmoquine).During World War II, after the mates indicate that the needs of pregnant and world’s primary sources of quinine were cap- lactating women in tropical climates are about tured by the Japanese, about 16,000 drugs were twice those of women in temperate zones.In the tested for antimalarial effectiveness.In 1944, an tropics, high-maize/low-iron diets are common, Army Medical Research Unit at the University and soils are iron deficient in many areas. of Chicago studying these potential antimalar- ial drugs encountered the problem of drug- Glucose-6-Phosphate Dehydrogenase induced anemia.Research by this group over (G6PD) Deficiency the next decade elucidated the basic informa- Favism,orhemolytic anemia due to inges- tion on G6PD deficiency. tion of fava beans, is now known to occur Pamaquine was found to cause hemolysis in individuals deficient in G6PD.The Mediter- in 5–10 percent of American blacks (about ranean type of G6PD deficiency is found in an 10–14 percent of black American males are area extending from the Mediterranean basin G6PD-deficient) but only rarely in Caucasians, to northern India, an area corresponding to and the severity of the hemolysis was observed Alexander’s empire.Sickness resulting from in- to be dependent on the dose of the drug.Similar

23 6. Anemia sensitivity to the related drug primaquine and “crisis,” was the first to suggest that the ane- many other related drugs was demonstrated, mia was hemolytic, and reported the first au- and the term “primaquine sensitivity” came to topsy describing the typical lesions of the ill- be used to designate this form of hemolytic ane- ness including a scarred, atrophic spleen.He mia.It was subsequentl y demonstrated that the was also the first to describe sickle-cell anemia hemolysis was due to an abnormality in the ery- in childhood, noting the peculiar susceptibility throcytes of susceptible individuals and that it of victims to infection, with a high mortality was self-limited even if administration of pri- rate. maquine was continued.Several biochemical The first case of sickle-cell anemia to be re- abnormalities of the sensitive red cells, includ- ported from Africa was described in 1925 in a ing glutathione instability, were described.In 10-year-old Arab boy in Omdurman, and the 1956, Paul E.Carson and colleagues reported first survey of the frequency of sickle-cell trait that G6PD deficiency of red cells was the com- in the African population was reported in 1944 mon denominator in individuals who devel- by R.Winston Evans, a pathologist in the West oped hemolysis after one of these drugs was African Military Hospital.In a study of almost administered, and the term G6PD deficiency be- 600 men of Gambia, the Gold Coast, Nigeria, came synonymous with primaquine sensitivity. and the Cameroons, he found approximately 20 It was soon found that this deficiency was ge- percent to have the trait, a sickling rate about netically transmitted. three times that in the United States. In East Africa, E.A.Beet found a positive test Sickle-Cell Disorders for sickling in 12.9 percent of patients in the Sickle-cell disorders have existed in human pop- Balovale district of northern Rhodesia.He also ulations for thousands of years.However, the reported striking tribal differences in the preva- discovery of human sickle cells and of sickle- lence of sickle-cell trait.By 1945, H.C.Trowell cell anemia was first announced in the form of had concluded that sickle-cell anemia was prob- a case report by James Herrick at the Association ably the most common and yet the least fre- of American Physicians in 1910.In 19 04, Her- quently diagnosed disease in Africa.He noted rick had examined a young black student from that in his own clinic in Uganda no cases had Grenada who was anemic; in the blood film been recognized before 1940, but 21 cases were he observed elongated and sickle-cell-shaped seen within the first 6 months of 1944 when he RBCs. began routine testing for sickling. By 1922, there had only been three cases of For many years, it was thought that sickle- this type of anemia reported.But in that year cell anemia was rare in Africa in contrast to Verne R.Mason, a resident physician at Johns the greater prevalence observed in the Americas Hopkins Hospital, described the first patient rec- (Especially North America), and some thought ognized to have that disease at that institution. that interbreeding with white persons brought Mason introduced the term “sickle cell anemia,” out the hemolytic aspect of the disease.It was which became the standard designation. not until the mid-1950s that it was under- In 1923, C.G.Guthrie and John Huck per- stood that few homozygous sickle-cell cases formed the first genetic investigation of this dis- came to medical attention because of a high in- ease and developed a technique that became an fant mortality rate from that disease.This was indispensable tool for the identification of sickle demonstrated in Leopoldville´ when J.and C. trait in later investigations, population surveys, Lambotte-Legrand found that only two cases and genetic studies. of sickle-cell anemia had been reported among Virgil P.Sidenstricker, of Georgia, recorded adults in the Belgian Congo, although sickling many of the clinical and hematologic features occurred in about 25 percent of the black popu- of sickle-cell disease.He introduced the term lation.They subsequently followed 300 infants

24 6. Anemia with sickle-cell anemia.They found that 72 died quency of the gene increased significantly in before the end of the first year of life, and 144 the hyperendemic malarial areas of Africa and had perished by the age of 5. spread northward across the Sahara along an- Subsequent research by others, however, es- cient trade routes.Because the eastern and tablished the fact that sickle-cell anemia pa- western Arabian types of sickle-cell disease tients who did survive to adolescence came are different, spread must have occurred along from the higher social groups, and that the sea trade routes, accounting for similarities in standard of living, the prevalence of infection sickle-cell anemia in eastern Africa, eastern and nutritional deficiency, and the level of gen- Arabia, and southern India. eral health care were the principal factors af- Obviously then, there was much interest gen- fecting the mortality rate from sickle-cell ane- erated in the cause of the very high frequency mia in young children.By 1971, as improved of the sickle-cell gene in Africa.In 1946, Beet health care became available, the course of in Rhodesia noted that only 9.8 percent of the disease was altered; at the Sickle Cell- sicklers had malaria, whereas 15.3 percent of Hemoglobinopathy Clinic of the University of nonsicklers were affected.P.Brain, of Southern Ghana, it was reported that 50 percent of the Rhodesia, suggested that RBCs of sicklers might patients with sickle-cell anemia survived past offer a less favorable environment for survival age 10. of malarial parasites.In 1954, J.P.Mackey and Geographic distribution of sickle-cell gene F.Vivarelli suggested that “the survival value frequency was mainly charted by the mid- [of the trait] may lie in there being some ad- twentieth century.The prevalence of sickling vantage to the heterozygous sickle cell indi- in black populations of the United States was vidual in respect of decreased susceptibility of well established by 1950.Numerous studies a proportion of his RBC to parasitization by performed in Central Africa and South Africa P. falciparum.” also revealed that, although the frequency of A relationship between sickle-cell trait and sickling varied, the occurrence of the gene falciparum malaria was reported by A.C.Alli- that caused it was confined mostly to black son in 1954.He noted that the frequency of populations. heterozygous sickle-cell trait was as high as In Africa, after World War II, surveys estab- 40 percent in some African tribes, suggesting lished that across a broad belt of tropical Africa, some selective advantage or else the gene would more than 20 percent of some populations were be rapidly eliminated because most homozy- carriers of the sickle-cell trait.Significantly, a gotes die without reproducing.He decided that high frequency of sickle trait was also found a high spontaneous mutation rate could not ac- among whites in some areas of Sicily, south- count for the high but varying frequencies of ern Italy, Greece, Turkey, Arabia, and southern the gene and postulated that sickle-cell trait oc- India.Yet, by contrast, sickling was virtually ab- curs as a true polymorphism and that the gene sent in a large segment of the world extending is maintained by selective advantage to the het- from northern Europe to Australia.These obser- erozygous. Comparing the distribution of falci- vations led to several hypotheses about where parum malaria and sickling, Allison found that the mutant gene had had its origin and how high frequencies of the trait were invariably such high frequencies of a deleterious gene are found in hyperendemic malarial areas.He also maintained. found that people with sickle-cell trait suffer Hermann Lehmann presented evidence that from malaria not only less frequently but also sickling arose in Neolithic times in Arabia, and less severely than other persons, and he con- that the gene was then distributed by migra- cluded that, where malaria is hyperendemic, tions eastward to India and westward to Africa. children with the sickle-cell trait have a survival He and others have speculated that the fre- advantage.

25 7. Anorexia Nervosa

Thalassemia Many New World natives whose diet con- Thalassemia, an inherited form of anemia, re- sisted primarily of corn (maize) and beans had sults from the deficient synthesis of a portion a diet deficient in iron and protein.Moreover, of the globin molecule and is also thought by when cooked in water for long periods of time, some to have stabilized in the face of malaria.A the food in the diet was also low in ascorbate variety of forms exist, based on the chain and and folate.Ascorbate helps convert dietary site within a specific chain at which the ge- ferric to ferrous iron, which is more easily netically determined defect exists.It has been absorbed; therefore, deficiency of this vitamin suggested that thalassemia originated in Greece increased the problem of deficient dietary iron. and spread to Italy when it was colonized by A high incidence of iron deficiency has been Greeks between the eighth and sixth century demonstrated by modern studies of infants B.C. At present, it is most frequent in areas and children in populations living on a diet where ancient Greek immigration was most in- consisting mostly of maize and beans. It is tense: Sicily, Sardinia, Calabria, Lucania, Apulia, not surprising then, in North America, that and the mouth of the Po. porotic hyperostosis was found in 54 percent of skeletons in the canyons of northern Arizona Porotic Hyperostosis and northern New Mexico, among a population Chronic anemia from any cause produces bone that ate little meat and subsisted mainly on changes, which can be recognized in archaeo- maize.By contrast, plains dwellers in southern logical specimens.These changes, called porotic Arizona and southern New Mexico, who used hyperostosis (or symmetrical hyperostosis) re- more animal foods, had an incidence of only sult from an overgrowth of bone marrow tissue, 14.5 percent. Absence of evidence for malaria or which is apparently a compensatory process.To- hemoglobinopathies in the New World before day, porotic hyperostosis is seen classically in the arrival of the Europeans argues against X-rays of patients with congenital hemolytic these possible causes of porotic hyperostosis. anemias, as well as in children with chronic iron Alfred Jay Bollet and Audrey K. Brown deficiency anemia.This is especiall y the case when the iron deficiency occurs in premature infants or is associated with protein malnutri- tion or rickets. 7. Anorexia Nervosa Porotic hyperostosis has been observed in ar- chaeological specimens from a variety of sites, Anorexia nervosa is a psychophysiological dis- including areas of Greece, Turkey, Peru, Mexico, order especially prevalent among young women the United States, and Canada.In most areas, and characterized by refusal to eat or maintain the findings are considered evidence of iron- normal body weight, intense fear of becoming deficiency anemia, although thalassemia was obese, a disturbed body image in which the apparently responsible in some areas.Around emaciated patient feels overweight, and absence the shores of the Mediterranean, malaria was of any physical illness accounting for extreme probably the most frequent cause of chronic weight loss.The term anorexia is actually a mis- anemia at certain times. nomer, because genuine loss of appetite is rare Archaeological specimens from the Near East and usually occurs only late in the illness.Most show an incidence of anemia of only 2 percent anorectics are actually obsessed with food and in early hunters (15,000–8000 B.C.), who in- constantly deny natural hunger. gested a lot of animal protein and thus took in reasonable amounts of dietary iron.By contrast, Characteristics farming populations of 6500–2000 B.C. showed In anorexia nervosa, normal dieting escalates an anemia incidence of 50 percent. into a preoccupation with being thin, profound

26 7. Anorexia Nervosa changes in eating patterns, and weight loss of even more resistant to therapy than their female at least 25 percent, usually accomplished by se- counterparts. vere restriction of caloric intake.Anorectics may Among North American minorities, there are couple fasting with emetics, laxatives, diuretics, few reported cases.However, this reflects so- and exercise. cioeconomic status rather than ethnic charac- The most consistent medical consequences teristics.Similarly, anorexia nervosa is confined of anorexia nervosa are amenorrhea (ceasing to highly industrialized areas.The absence of or irregularity of menstruation) and estrogen the disorder in developing nations and its high deficiency.The decrease in estrogens causes incidence among affluent social groups in West- many anorectics to develop osteoporosis.Fur- ernized countries have led many clinicians to ther complications arising from severe mal- classify anorexia nervosa as a “culture-bound” nutrition include bradycardia, hypotension, syndrome. lethargy, hypothermia, constipation, and vari- Although the etiology of anorexia nervosa ous other metabolic and systemic changes. is an area of intense investigation, researchers Anorectics also display a relatively consistent have yet to reach a consensus about its origin. cluster of emotional and behavioral character- The most sophisticated thinking on the subject istics and unusual eating habits that include regards anorexia nervosa as a disorder that in- monotonous or eccentric diets, hoarding or hid- volves the interplay of biological, psychological, ing food, and obsessive preoccupation with food and cultural factors. and cooking for others. Emotionally, anorexic patients are often described as perfectionis- History tic, dependent, introverted, and overly compli- Anorexia nervosa’s past prevalence has been a ant.Frequently reported neurotic traits include subject of much historical debate.Some clin- obsessive-compulsive, hysterical, hypochondri- icians and medical historians have postulated acal, and depressive symptoms.A distorted that it was first identified in 1689 by Richard body image is an almost universal characteristic Morton, physician to James II.Others have of anorectics, with many patients insisting that dated the origins of anorexia nervosa even they are overweight even when their bodies are earlier, claiming that certain medieval female extremely emaciated.As a result, most individu- saints, who were reputed to live without eating als with anorexia nervosa deny or minimize the anything except the eucharist, actually suffered severity of their illness and are thus resistant to from anorexia nervosa.Some historians, how- therapy. ever, have argued that attempts to label all his- Once considered extremely rare, the inci- torical instances of food refusal and appetite loss dence of anorexia nervosa more than doubled as anorexia nervosa are simplistic and maintain in the late twentieth century.As many as 1 in that the historical record is insufficient to make 250 females 12–18 years old may develop the conclusive diagnoses of individual cases. disorder.Onset occurs almost exclusively dur- The modern disease classification of anorexia ing the teens, although some patients have be- nervosa emerged in the second half of the nine- come anorectic as early as age 11 and others teenth century.In 1859, William Stout Chipley as late as the sixth decade of life.Patients are published the first North American description typically from middle- or upper-class families. of sitomania, a type of insanity characterized by Approximately 5–10 percent of anorectics are an intense dread or loathing of food.Although male, whose clinical picture is much different Chipley found sitomania in a broad range of so- from that of women.In general, male anorec- cial and age groups, he identified a special form tics tend toward greater psychopathology, are of the disease that afflicted adolescent girls. often massively obese before acquiring the dis- Chipley’s work was ignored, however, and not order, are less likely to be affluent, and are until British physician William Withey Gull and

27 7. Anorexia Nervosa

French alienist Charles Lasegue` published two trogen, and a host of other hormones were influential studies in the 1870s did physicians also employed in the treatment of anorexia begin to pay significant attention to anorexia in nervosa. girlhood. The second major approach grew out of the Gull’s primary accomplishment was to name field of dynamic psychiatry, which emerged dur- and establish anorexia nervosa as a coherent ing the 1890s and early 1900s.Practitioners in disease entity.Despite widespread acclaim for dynamic psychiatry increasingly focused on the his work with anorectic patients, however, clin- life history of individual patients and the emo- icians during the late nineteenth century gen- tional sources of nervous disease.Two of the erally rejected the conception of anorexia ner- leading pioneers in this new field – Sigmund vosa as an independent disease.Instead, they Freud and Pierre Janet – were the first to suggest conceptualized it either as a variant of hysteria a link between the etiology of anorexia nervosa that affected the gastrointestinal system, or as a and the issue of psychosexual development.Ac- juvenile form of neurasthenia. cording to Freud, all appetites were expressions Nineteenth century physicians also tended of libido or sexual drive.Thus, not eating rep- to focus on the physical symptom of not eat- resented a repression of normal sexual appetite. ing and ignored the anorectic patient’s psy- Similarly, Janet asserted that anorectic girls re- chological reasons for refusing food.An impor- fused food in order to retard normal sexual de- tant exception was Lasegue,` who was the first velopment and forestall adult sexuality. to suggest the significance of family dynam- Because of the enormous popularity of en- ics in the genesis and perpetuation of anorexia docrinologic explanations of disease, the idea nervosa.Because of the somatic emphasis of of anorexia nervosa as a psychosexual distur- nineteenth century medicine, however, most bance was generally overlooked for more than nineteenth century medical practitioners dis- 30 years.By the 1930s, however, the failure of regarded Lasegue’s` therapeutic perspective.In- endocrinologic models to establish either a pre- stead, they directed medical intervention to- dictable cure or a definitive cause of anorexia ward restoring the anorectic to a reasonable nervosa, the growing reputation of the Freudian weight and pattern of eating rather than explor- psychoanalytic movement, and increased atten- ing the underlying emotional causes of the pa- tion to the role of emotions in disease led a tient’s alleged lack of appetite. number of practitioners to assert the value and In the twentieth century, the treatment of importance of psychotherapy in the treatment anorexia nervosa changed to incorporate new of anorexia nervosa.Although biomedical treat- developments within medical and psychiatric ment of the disorder continued, most clinicians practice.Before World War II, two distinct and realized that successful, permanent recovery isolated models dominated medical thinking on depended on uncovering the psychological ba- anorexia nervosa.The first approach was rooted sis for the anorectic’s behavior. in late nineteenth century research in organoth- After World War II, a new psychiatric view of erapy, a form of treatment based on the prin- eating disorders, shaped largely by the work of ciple that disease resulted from the removal Hilde Bruch, encouraged a more complex inter- or dysfunction of secreting organs and glands. pretation of the psychological underpinnings of Between 1900 and 1940, a variety of different anorexia nervosa.Although Bruch agreed that endocrinologic deficiencies were proposed as the anorectic was unprepared to cope with the the cause of anorexia nervosa.Many clinicians psychological and social consequences of adult- assumed that a pituitary hormone deficiency hood and sexuality, she also stressed the impor- underlay the conditions; others implicated thy- tance of individual personality formation and roid insufficiency as the cause.Throughout factors within the family to the psychogenesis of the 1920s and 1930s, insulin, antuitrin, es- anorexia nervosa.Here, Bruch revived Las egue’s`

28 8. Anthrax work on the role of family dynamics in anorexia The species of domestic animals most com- nervosa.According to Bruch, the families of monly affected are cattle, sheep, and goats; most anorectic patients were engaged in a dys- pigs, dogs, and cats are less susceptible.An en- functional style of familial interaction known as larged spleen is a classic observation in animals “enmeshment”: Such families are characterized with anthrax, thus the disease has also been by extreme parental overprotectiveness, lack of known as “splenic fever” or “splenic apoplexy.” privacy of individual members, and reluctance In humans, the cutaneous form is known as or inability to confront intrafamilial conflicts. “malignant pustule,” and the pulmonary or in- Although superficially these families appeared testinal (industrial) type as “woolsorters’ dis- to be congenial, said Bruch, this harmony was ease” or “industrial anthrax.” In French, the achieved through excessive conformity on the equivalent of splenic fever is sang de rate,in part of the child, which undermined the child’s German Milzbrand; other French synonyms in- development of an autonomous self.Anorexia clude charbon and pustule maligne. nervosa, according to Bruch, was therefore a young woman’s attempt to exert control and Characteristics self-direction in a family environment in which Because B. anthracis produces resistant spores she otherwise felt powerless. in suitable soils, the disease has long been en- Bruch was also primarily responsible for the demic in many areas throughout the world, with tremendous growth in the popular awareness most outbreaks occurring in Europe and Asia. of anorexia nervosa and other eating disor- Once contaminated with anthrax spores, an area ders in the 1970s and 1980s.Through both can be extremely difficult to clear, as has been scholarly and popular writings, Bruch brought demonstrated on the island of Gruinard off the anorexia nervosa into common North American west coast of Scotland, which was experimen- parlance.At the same time that the North Amer- tally contaminated during World War II.This is ican public was becoming increasingly aware of prime importance for the epidemiology of the of anorexia nervosa, the number of reported disease because it is rarely spread directly from cases of the disorder grew tremendously.This animal to animal, but almost always through in- phenomenon has led some clinicians and social gestion of contaminated food, either by grazing commentators to suggest that the populariza- or, in cooler climates, through imported winter tion process itself may promote a “sympathetic foodstuffs.The infectivity of the anthrax bacil- host environment” for the disorder. lus for people is low, and therefore, even where Heather Munro Prescott large numbers of spores and bacilli are found in an industrial environment, only relatively few cases occur. Cutaneous anthrax, the nonindustrial type 8. Anthrax in humans, affects those in professions such as veterinary surgery, pathology, farming, butch- Anthrax is an acute zoonotic disease, primarily ery, and the like and takes the form of malig- of herbivorous animals, which is transmissible nant pustule – a lesion caused by contamina- to humans.The causative organism is Bacillus tion of skin with material from infected ani- anthracis, often referred to in earlier, and espe- mals. Pulmonary anthrax, the industrial type, cially in French, texts as bact´eridie, the name may present as either malignant pustule or first bestowed on it by Casimir Davaine in 1863. pulmonary disease and is acquired in the Humans are infected only secondarily through woolen industries, especially through contam- contact with animals or animal products, and inated air.The disease approached an epi- thus the disease must be considered in relation demic situation during the late-eighteenth and to anthrax in animals. nineteenth centuries in France and England

29 8. Anthrax in factories processing imported horsehair and intestinal disturbances, and respiratory or car- sheep’s wool. diac distress.Death follows septicemia and ac- Outbreaks in animals in Europe (mainly cat- companying severe toxic manifestations. tle) and in Asia (sheep and goats) heavily out- Anthrax in people may take the form of a ma- weigh those in the United States and Africa, lignant pustule (cutaneous anthrax) where the whereas Australia and Canada are rarely af- bacilli enter through the skin, producing a pri- fected.Extensive enzootic areas with a constant mary lesion developing into a characteristic area presence of infection include China, Ethiopia, of inflammation surrounding a dark necrotic and Iran, and, in the Americas, Mexico and some center; or it may take the form of the pulmonary South American countries.Available data sug- or – less commonly – the intestinal type, which gest an annual average total of some 10,000 out- follows inhalation of dust containing anthrax breaks throughout the world.Since World War spores, as has occurred in the woolen indus- II, fatal cases in humans have been substantially tries.Monkeys exposed to artificially generated reduced by antibiotic therapy. aerosols of anthrax spores develop symptoms The immunogenic behavior of the anthrax mimicking woolsorters’ disease.Postmodern bacillus is complex, and it is not certain whether findings include hemorrhages in the lung, hem- or to what extent immunity develops in cases orrhagic mediastinitis and lymphadenitis, and of recovery from infection.The existence of sometimes hemorrhagic meningitis. an extracellular toxin produced by B. anthracis (which in part determines its virulence) was History demonstrated only during the 1980s.Certain In the past, outbreaks of anthrax (along with strains of certain animal species possess high other epizootic diseases) among animals have natural resistance, which introduced confusion undoubtedly helped to prepare the way for ma- and fed much of the controversy surrounding jor outbreaks of epidemic disease in humans. early work on anthrax.The live attenuated vac- When anthrax has decimated herds of cattle or cines used by Louis Pasteur have undergone sheep, for example, human populations have continued development and improvement over faced starvation, which in turn has lowered the years, but early claims of reductions in in- their ability to resist those epidemics.Anthrax cidence and fatality rates following their use has been known from antiquity, although until were not readily sustained.Thus, the early vac- relatively recently it was not clearly separated cines have gradually been replaced by spore- from other diseases with similar manifestations. based vaccines and prepared antiserum.Un- Possibly, sudden death of animals at pasture, til recently, vaccines have not been considered blamed by Aristotle (and subsequently by his safe for use in humans, but serum treatment followers over the centuries) on the shrew- has been used extensively for prophylactic and mouse and its “poisonous bite,” may in many therapeutic purposes.For occupational reasons, cases have resulted from the peracute form of women are less liable to exposure than men, anthrax commonly known as splenic apoplexy. but the disease, when established, is more com- Nineteenth century authors speculated that monly fatal in females. the fifth and sixth plagues of the Egyptians (as In its principal animal hosts, anthrax may described in Exodus), which struck their herds take one of three forms: a peracute type (splenic and the Egyptians themselves, might have been apoplexy), where sudden death occurs almost anthrax.Evidence centers on the Israelites, who simultaneously with the first symptoms; an were installed on sandy ground above the level acute type characterized by acute fever, usually of the Nile.They escaped the plagues, whereas followed by death after 2–12 days; and a sub- those who did not lived in areas subject to flood- acute type often followed by recovery.Classical ing, which could have provided perfect condi- signs include fever, stupor, spasms, convulsions, tions for growth of the bacillus.Three decades

30 9. Apoplexy and Stroke before the birth of Christ, Virgil vividly de- the results obtained by Aloys Pollender, then scribed an animal plague that had much in com- by Pierre Rayer, and finally by Davaine who, mon with anthrax and warned against its trans- during extensive work with guinea pigs in the mission to people through contact with infected 1860s, bestowed on it the name of bact´eridie, hides. which survived in the literature for a long time. Through the centuries, there are many From 1876 onward, the anthrax bacillus be- records of animal plagues that almost certainly came a cornerstone of both Koch’s theories were anthrax but were often confused with and his development of pure culture methods; other complaints.By 1769, when identification in the late 1870s, W.Greenfield and H.Tou- of epidemic diseases of animals and humans ssaint reported studies of acquired immunity had become more precise, Jean Fournier in Di- against anthrax in animals.Pasteur took over jon, France, classified a number of different le- the field and in 1881 demonstrated that immu- sions as a single disease entity (anthrax), which nity could be produced through vaccination of he called charbon malin.More importantly, he sheep. recognized the transmission of the disease to Lise Wilkinson people and drew attention to cases occurring in workers who handled raw hair and wool, a theme developed in several French accounts during the following decade.From the mid- 9. Apoplexy and Stroke nineteenth century, the disease became a prob- lem in English factories as well, and subse- The old, very popular, and quite international quently in Scotland.About the same time, the term apoplexy (or its equivalents “apoplectic woolen industries began experiencing the prob- attack,” “apoplectic ictus,” and “ictus”) today lem as wool and hair from the East were intro- generally means stroke.The word “apoplexy” duced into British trade.Woolsorting, until then comes from the Greek meaning “stroke” and “to considered a particularly healthful occupation, strike.” To define apoplexy is therefore to relate suddenly produced an alarming increase in the the history of the word and its different succes- number of deaths and extent of disease among sive significations.This is followed by the med- workers.The workers themselves suspected an ical details of stroke. association between the disease and the grow- ing proportion of wool and hair imported from History the East.By the late 1870s, concern in Yorkshire In the Hippocratic corpus, “apoplexy” appears factories was acute, but by then the new bac- as an obviously clinical term.For many cen- teriology had identified the cause of anthrax: turies after Galen’s writings of the second cen- J.Bell demonstrated that both woolsorters’ dis- tury A.D., it was thought that apoplexy involved ease and malignant pustule in humans derived brain matter, whereas epilepsy represented a from anthrax in animals. disturbance of brain function.From the inven- Bell’s work was made possible by the work tion of the printing press to the late nineteenth of Davaine and that of Robert Koch in the century, several hundred monographs were de- 1860s and 1870s.During the nineteenth cen- voted to apoplexy. tury, the study of anthrax and its use of ani- The first autopsies involving examination of mal models had become an important part of the brain were performed in the seventeenth the framework for the emergence of bacteriol- century.In 1761, Giovanni Battista Morgagni ogy as an academic discipline.In France, Eloy reported numerous cases of postmortem exam- Barthelemy´ established the transmissibility of inations of apoplexy, which he separated into anthrax in 1823.From 1850 onward, study of “serous apoplexy” (apoplexia serosa) and “san- the putative agent was pursued, beginning with guineous apoplexy” (apoplexia sanguinea).

31 9. Apoplexy and Stroke

In 1820, John Cooke wrote that he considered was often used synonymously with cerebral hemorrhagic lesions the commonest and that hemorrhage. other types of lesions (e.g., tumors, suppura- Thus, Trousseau and Charcot, along with tion, cysts) were questionable cases of apoplexy. others, concluded that apoplexy could arise In a book published in 1812, John Cheyne from conditions other than intracerebral hem- thought that apoplexy might be “serous” or orrhage, and that the use of the term should be “sanguineous,” but he was skeptical of the restricted to the clinical syndrome that involved former entity.Periodic apnea, now known as a sudden loss of brain functions.Surprisingly, in Cheyne-Stokes respiration, was first described 1921 J.Lhermitte nonetheless persisted in the by Cheyne in 1818.For John Abercrombie, writ- use of apoplexy as a synonym for hemorrhage ing in 1828, the cerebral lesion of apoplexy and opposed “hemiplegy of the apoplexy” and might be either a hemorrhage or a serous ef- “hemiplegy of the infarctus.” fusion, but sometimes there seemed to be no The term “apoplexy” has since become ob- apparent anatomic lesions. solete and disappeared from most contempo- Jean Cruveilhier, professor of morbid ana- rary textbooks and from the usual vocabulary of tomy in Paris, used the word “apoplexy” as a syn- the modern physician.Nevertheless, it remains onym for “hemorrhage” (in its anatomic, patho- widely used in popular language and literature. logical meaning).He distinguished “apoplexy Its proper use, however, should be restricted to without loss of consciousness” from “apo- the history of medicine, from Hippocrates to the plexy with loss of consciousness” and wrote of beginning of the twentieth century.In present pontine or spinal apoplexies as well as cerebral medical vocabulary, the term “apoplexy” must ones.This pathological point of view was be replaced by either “stroke” or “hemorrhage,” strengthened by Richard Bright, who described according to the context. and illustrated under the term “apoplexy” several cases of cerebral hemorrhage.This association of apoplexy with hemorrhage in Characteristics of Stroke the central nervous system led gradually to According to the World Health Organization, a the use of apoplexy as a synonym for hemor- stroke consists of “rapidly developing clinical rhage and to the creation of expressions such signs of focal (at times global) disturbance of as “spinal apoplexy” (in place of “spinal hem- cerebral function, lasting more than 24 hours or orrhage”), “pulmonary apoplexy” (in place of leading to death with no apparent causes other “hemorrhagic pulmonary infarct”), “abdominal than that of vascular origin.” “Global” refers to apoplexy” (in place of “massive abdominal patients in deep coma and those with subarach- hemorrhage”), “renal apoplexy” (in place of “re- noid hemorrhage.This definition excludes tran- nal hemorrhage”), “splenic apoplexy” (in place sient ischemic attacks (TIAs), a condition in of “hemorrhage of the spleen”), and so forth. which signs last less than 24 hours. From the second half of the nineteenth cen- Strokes are the most common life-threatening tury to the early twentieth century, the semantic neurological disease and the third leading cause confusion between apoplexy and hemorrhage of death, after heart disease and cancer, in continued.Russell Reynolds, for example, in Europe and the United States.Death rates from 1866 stated that an apoplectic attack could re- strokes vary with age and sex; for example, in sult from congestion, hemorrhage, tumor, ure- the United States, the rates for males are 11.9 mia, or vascular obstruction.But A.Trousseau, per 100,000 for those aged 40–44 and 1,217 a professor in Paris, had attacked this prob- per 100,000 for those aged 80–84.F or females, lem of confusion in 1865, and French neurolo- the respective rates are 10.9 and 1,067. Large gist J.Charcot later emphasized that apoplexy differences in cerebrovascular disease (CVD) was a clinical syndrome that unfortunately mortality have been noted among races.For

32 9. Apoplexy and Stroke example, in the United States, mortality is 344 (15–30 percent of ischemic strokes) is mainly per 100,000 for nonwhites but 124 per 100,000 caused by atrial fibrillation related to valvular for whites.Among countries, differences in mor- disease or ischemic heart disease.Other causes tality from stroke ranged from 70 per 100,000 in of cerebral infarction are multiple, resulting Switzerland to 519 per 100,000 in Japan. from various diseases, hemopathies, or coagu- Decline in CVD deaths has occurred in all de- lation abnormalities.However, in 20 percent of veloped countries since 1915, and the decline cases, the cause of cerebral infarction remains accelerated in recent decades.The acceleration undetermined. seems related to a decline in incidence.Strokes, Intracranial hemorrhage (ICH) accounts for however, are more disabling than lethal: 20– 37 percent of strokes.The main cause of ICH 30 percent of survivors become permanently is the rupture of miliary aneurysms that have and severely handicapped.Moreover, recurrent developed in the walls of interior arteries be- strokes are observed in 15–40 percent of stroke cause of hypertensive disease.Nonhypertensive survivors. causes of ICH are numerous. Apart from age, the most important risk fac- Clinical manifestations of strokes depend on tor for CVD is arterial hypertension.Control of both the nature of the lesion (ischemic or hem- severe and moderate, and even mild, hyperten- orrhagic) and the part of the brain involved.In sion has been shown to reduce stroke occur- the 1960s, a classification of strokes according rence and stroke fatality.Cardiac impairment to temporal profile was proposed to promote ranks third, following age and hypertensive dis- common terminology in discussion of history ease.At any level of blood pressure, people with and treatment. cardiac disease, occult or overt, have more than The term “incipient stroke” (also TIA) was de- twice the risk of stroke.Other risk factors are fined as brief (less than 24 hours), intermittent, cigarette smoking, increased total serum choles- and focal neurological deficits from cerebral is- terol, blood hemoglobin concentration, obesity, chemia, with the patient normal between at- and use of oral contraceptives. tacks.The term “reversible ischemic neurolog- Strokes are a heterogeneous entity caused by ical deficit” was coined for entirely reversible cerebral infarction or, less commonly, cerebral deficits occurring over more than 24 hours.The hemorrhage.Cerebral infarction accounts for term “progressing stroke” (stroke-in-evolution) the majority of strokes.When perfusion pres- is applied to focal cerebral deficits observed by sure falls in a cerebral artery below critical lev- the physician to progress in severity of neuro- els, brain ischemia (deficiency of blood) devel- logical deficit over a period of hours or, occa- ops, progressing to infarction if the effect per- sionally, a few days. sists long enough.In most cases, ischemia is The term “completed stroke” is used when caused by occlusion of an intracerebral artery neurological signs are stable and no progres- by a thrombus or an embolus arising from ex- sion has been noted over 18–72 hours.“Ma- tracranial artery disease or a cardiac source.The jor stroke” is applied when immediate coma main cause of ischemic strokes is atheroscle- or massive neurological deficit occurs.In these rotic brain infarction, the result of either intra- cases, chances of recovery and effective treat- cerebral artery thrombosis or embolism arising ment are minimal.“Minor stroke,” by contrast, is from stenosed (narrowed or restricted) or oc- applied to cases where deficits relate to only a re- cluded extracranial arteries. stricted area of a cerebral hemisphere, or where Lacunar infarction (14 percent of ischemic the symptoms experienced are of only moder- strokes) is a small, deep infarct in the territory ate intensity.With minor strokes, diagnosis and of a single penetrating artery, occluded by the institution of treatment should be rapidly com- parietal changes caused by hypertensive dis- bined to avoid further deterioration and, if pos- ease.Cerebral embolism from a cardiac source sible, facilitate the regression of deficit.

33 10. Arboviruses

These definitions contain some obvious un- virus from an infected host.The arthropods certainties, particularly in categorizing a stroke serve as vectors of the virus, from an infected during the early hours.However, they under- vertebrate host to an uninfected one.The virus score the fact that the management of a stroke must multiply in the arthropod, a process re- often depends more on its temporal profile and quiring several days, and reach a concentration on the severity of neurological deficit than on sufficient to be passed, in a later feeding, to the the nature of the lesion. host, and to induce an infection in that host.The Jacques Poirier and Christian Derouesne host, in turn, must have a viremic phase in or- der to pass the virus back to a biting or sucking arthropod. This rigid definition can give rise to confu- 10. Arboviruses sion but is uncompromising.The confusion is compounded when it is realized that although Arbovirus is a truncated term for arthropod- an arthropod, with mouth parts freshly contam- borne viruses, all of which require multiplica- inated by feeding on an infected host, may pos- tion in their vectors for transmission. Arboviral sibly transmit virus mechanically, a defined vec- diseases may be simpler to understand when tor must be capable of multiplying the virus viewed solely from the position of the end internally over a period of several days and of product, which is disease in humans or other transmitting it by then biting a susceptible host vertebrates.The diseases fall into a few rec- in later feedings.This is referred to as the bio- ognizable sets: (1) encephalitides; (2) diseases logical transmission cycle.Mechanical transmis- with fever and rash, often fairly benign; (3) dis- sion must be quite unusual and with respect to eases with hemorrhagic manifestations, often arboviruses has never been observed in nature, fatal; and (4) mild fevers, quite undiagnosable but has been achieved in the laboratory under except through laboratory study.A common controlled conditions.Again, from the point of feature of all of these is periodic outbreaks, view of the virus, it must be capable of multi- with dozens, hundreds, or thousands of cases. plying in one or more vertebrate hosts, usually A second common feature is lack of specific over a period of several days, reaching a level in treatment.In addition, vaccines exist for only the bloodstream adequate to infect a foraging a very few of the diseases.Possibility of disease vector. control is real, however, and is based on a The above considerations define (1) the in- knowledge of the epidemiology of arbovirus terval between the arthropod’s ingestion of in- infections in general, the role that vectors play, fected blood and the ability to transmit virus bi- and the particular features in regard to the ologically, again by biting, to a susceptible host transmission of the specific disease in question. (the extrinsic incubation period); and (2) the pe- riod, in the host, before the viremia level rises General Characteristics to a height necessary to infect the biting arthro- Arboviruses, numbering at latest count 512 sep- pod (the intrinsic incubation period).The min- arate and identifiable agents, are placed in 11 imum interval between infection in one verte- families, with a few unclassified agents.There is brate host and acquisition of infection by the no simple delimiting definition of an arbovirus next vertebrate host is the sum of the extrinsic on a taxonomic basis, or even on a biochemical and intrinsic incubation periods.It is frequently basis.Viruses must qualify in several important a week or more, and the maximum interval points to be considered arboviruses.The life from one infection to the next may be weeks cycle of an arbovirus involves an arthropod or months. (usually insect, tick, or mite) that is capable of Arboviruses that are of importance to hu- becoming infected itself when it imbibes the mans or other vertebrates are not all alike.Size

34 10. Arboviruses varies considerably – as does shape – and there The resistance of various vertebrates to vari- are other differential characteristics.Again, the ous arboviruses can be of use to the investiga- common bond is biological transmission by tor because it permits the production of large arthropod to vertebrate.How, in the evolution quantities of immune sera in such vertebrates. of viruses, this ability to exploit two phyla of Such immune sera are of minimal importance living creatures arose again and again in such in treating disease in humans, but are of car- widely different taxa, is not known. dinal importance in the design of specific sero- When the science of epidemiology of the logic tests for virus identification.Modern tech- nineteenth century was applied to the study of niques, founded on studies carried out over a yellow fever, epidemiologists were hampered period of half a century, involving basic labora- by a lack of knowledge of infectious agents tory techniques of complement fixation, precip- and of vector arthropods in the transmission itation, electrophoresis, centrifugation, hemag- cycle.Consequently, there was great confu- glutination inhibition, and virus neutralization, sion and an endless diatribe surrounding vari- have been extended by later advances such as ous hypotheses on how infection could travel “tagged” antibodies – that is, the use of mono- so mysteriously from place to place, with in- clonal antibodies in combination with “tagged fections occurring in people who apparently probes” in electron microscopy.Such new tech- never had contact with a case.With Theobald niques, involving the use of specific “probes,” Smith’s demonstration in cattle of transmission are currently a fertile area of research, from of the Texas redwater fever organism by ticks, which is emerging a more rational and com- Ronald Ross’s demonstration of transmission plete knowledge of the virus particle itself and of the parasite of malaria by mosquitoes, and its interactions with vertebrate and invertebrate Walter Reed’s demonstration of transmission of hosts. the virus of yellow fever by mosquitoes, came the dawn of modern epidemiological studies on Dengue arthropod-transmitted diseases. Geographic distribution of viruses and disease is A mysterious specificity exists between cer- determined by the characteristics of the vectors tain feeding arthropods and certain viruses; rather than by the characteristics of the viruses. furthermore, a preferential feeding of certain Taking dengue viruses (genus Flavivirus)asan arthropods (mosquitoes, for example) on certain example, the limits of their distribution are food sources is shown.Some vertebrates react defined by the limits of the distribution of the to a specific virus with severe disease.Yellow principal vector, Aedes aegypti.This mosquito, fever, for example, produces severe illness in hu- originally found in Southeast Asia, spread mans, laboratory white mice, rhesus monkeys, worldwide, traveling wherever humans traveled and Alouatta monkeys.On the other hand, yel- and established itself in tropical and subtropi- low fever may infect dogs, cats, Cebus monkeys, cal and often temperate regions, but not in Arc- cows, and horses without producing overt dis- tic and Antarctic polar extremes.The dengue ease.Among the encephalitides, eastern equine viruses moved with the vectors and became es- encephalitis (EEE) virus (endemic strains) can tablished worldwide, particularly in tropical and produce severe disease and death in humans, subtropical regions.The viruses may have had, laboratory mice, certain other vertebrates, and in their original territories of Southeast Asia, cy- very specifically equines.But cattle do not de- cles involving A. aegypti and/or Aedes albopic- velop illness with this agent, nor do sheep, goats, tus and subhuman forest primates, but as the dogs, or cats.By contrast, the South Ameri- viruses left their original home, they adapted to can EEE strain that kills horses produces no ill- a vector-human-vector cycle, allowing them to ness in humans but does produce detectable exist in endemic form wherever humans exist antibodies. and to appear in epidemic form at intervals.

35 10. Arboviruses

The other Southeast Asian vector, A. albopic- cycle into a mosquito-human-mosquito cycle. tus, has of recent years established itself in other An infected forest worker in the early stage countries such as the United States, with un- of illness can migrate to an urban setting in- known potential for involvement in the life cy- fested with A. aegypti and establish the dreaded cles of still other viruses such as yellow fever. urban mosquito-human-mosquito cycle. Re- There are also other aedine vectors of dengue cently, several large outbreaks of this type in Polynesia.The dengues are placed in four have occurred in Africa and in South Amer- serotypes, one or more of which are associ- ica, some of them involving the deaths of thou- ated with often-fatal manifestations of dengue sands of people such as in the Nigeria epidemic hemorrhagic fever and dengue shock syn- in 1986. drome.These are important causes of mortal- A completely effective attenuated yellow ity in small children in countries of Southeast fever vaccine (17D) has been available since Asia, with scattered cases being seen elsewhere. 1935, but governments in regions where yel- It is hypothesized that sequential infections in low fever is endemic have failed to react ade- the same individual by different serotypes of quately in getting the population at risk immu- dengue may lead to these serious complications. nized.Mosquito-control programs often suffer from a similar bureaucratic inefficiency. Yellow Fever Yellow fever, a Flavivirus serologically related to Encephalitides the dengues, is also capable of being transmit- Another group of arboviruses, the encepha- ted from human to human by A. aegypti and can litides, present mechanisms quite different from maintain itself endemically in a human popula- the dengue or yellow fever models.The vec- tion by such means.The virus is found in Africa tors in question – mosquitoes and ticks – are south of the Sahara and in the equatorial South themselves geographically delimited, and there- American jungle regions.In both Africa and fore the specific viruses associated with spe- South America (here including Central America, cific vectors have little chance of spread beyond and the West Indies), and in the United States, natural ecological barriers.The viruses them- Spain, France, Gibraltar, and England, periodic selves have a basic vertebrate cycle in birds outbreaks of the disease have been observed, and small mammals.Certain of the viruses, as A. aegypti may establish itself in subtropical such as Venezuelan equine encephalitis, EEE, and even temperate locales.Although A. aegypti and western equine encephalitis, can escape (and A. albopictus) is prevalent in Asia and Aus- from their natural cycle between mosquitoes tralia, yellow fever has never established itself and small vertebrates and spread like wildfire in in these regions.With vectors present, as well one or another of the larger vertebrates, caus- as millions of nonimmune humans, there is a ing widespread mortality, and humans may be continuing threat of its introduction. thus involved.These epidemics are sporadic and A reason yellow fever has been able to main- unpredictable. tain itself in tropical South America and Africa Other viruses are associated particularly with is that the virus can utilize a different set of birds and mosquitoes.These viruses include vectors.Using various endemic Haemagogus or St. Louis encephalitis virus of the Ameri- Aedes species, the virus remains established as cas, Japanese encephalitis virus of the Orient, an endemic virosis in various subhuman pri- Murray Valley encephalitis of Australia and mates of these regions.This maintenance cycle New Guinea, Ilheus virus of South America is referred to as “sylvan” or “jungle” yellow fever. and Trinidad, Rocio virus of southeast Brazil, The sylvan Haemagogus or Aedes can and of- and West Nile virus of Africa, the Middle ten does bite humans, and thus can transfer the East, and India (now a threat in the United virus out of the mosquito-monkey-mosquito States).The viruses are often very prevalent in a

36 10. Arboviruses region, in birds, with the disease usually being in differential diagnosis.Such specific manifes- uncommon in humans, but sometimes occur- tations include rashes, eruptions, nausea and ring in large epidemics.Heron rookeries and vomiting, diarrhea, cough, and encephalitis. pig farms in the Orient have been shown to Definitive diagnosis demands the assistance be Japanese encephalitis virus-amplifying local- of experienced virologists working in ade- ities, providing opportunities for infection of quate laboratory diagnostic facilities.Only a large numbers of mosquito vectors and thus fa- few dozen such facilities exist in the world, cilitating large-scale transmission of virus to hu- supported by the World Health Organization, mans.Immunity rates in populations are often governments, military establishments, and, in a high (bespeaking inapparent infections), and few instances, private philanthropy.Such labo- encephalitis rates low. ratories usually combine laboratory diagnostic In the central United States, a recent arrival methodology and facilities for carrying out field on the virus scene, La Crosse virus, a member epidemiological studies. of the California virus group, has established Specific diagnosis rarely benefits the patient its position as the commonest arboviral cause but is of vital importance in alerting health of encephalitis.This endemic disease has some departments of the presence of a potentially unusual features.It is transmitted by woodland threatening epidemic.Appropriate control pro- aedine mosquitoes and has as vertebrate hosts cedures directed at the vectors can then be ap- certain small mammals of the region.It has been plied on an emergency basis.In the special case further established that the virus can be trans- of yellow fever, mass immunization of exposed mitted transovarially (TOT) from mosquito to populations can successfully halt an epidemic mosquito, vertically through the egg, and lat- in its tracks.Such an immunization campaign erally from female to male or from male to fe- is usually combined with emergency mosquito male during copulation.This mechanism has control. been hypothesized to explain the long persis- Aside from provision of nursing care, and tence of virus in a vector, serving to carry it over maintaining nutrition and fluid balance, there periods of inclement weather or drought.Sim- are no specific remedies for infections.Nonspe- ilar TOT has been shown for dengue, Japanese cific measures, particularly treatment of shock encephalitis, and yellow fever. (maintaining fluid and electrolyte balance), may Tick-borne encephalitis (Russian spring- be lifesaving in dengue shock syndrome cases. summer encephalitis [RSSE] in the Eurasian Vector control is applicable in certain situa- continent and Powassan virus encephalitis in tions.Fred Soper and co-workers in the 1930s North America) are delimited by the range of eradicated A. aegypti from all of Brazil, thus specific tick vectors; these viruses are endemic eliminating the risk of urban yellow fever.The in small mammals and present themselves in mosquito, however, has reinvaded much of humans as sporadic cases. its former territory, and the threat of yellow fever has returned.Short-term vector control is Treatment and Control widely practiced, particularly when epidemics The early days of onset of most arboviral in- threaten.This may include airplane spraying fections are usually accompanied by fevers, of insecticides, treatment of interior walls of aching, and general malaise and cannot be buildings with residual insecticides, insecti- distinguished from early stages of other very cide treatment of mosquito breeding places, common diseases such as influenza, malaria, destruction or drainage of mosquito breed- measles, pneumonias, meningitis, other res- ing places, screening of dwellings, use of in- piratory afflictions, and even Lassa fever and secticidal fogs in and around dwellings, use smallpox.As diseases progress in their course, of insect repellents, and wearing of protective specific later manifestations may provide aid clothing.

37 11. Arenaviruses

The attenuated live yellow fever virus vaccine In 1957,a virus named Tacaribe was recovered (17D) has been used for over 50 years in the from a fruit-eating bat in Trinidad.This agent successful immunization of millions of people. remained unclassified.Meanwhile, fieldworkers A live attenuated dengue virus vaccine is being in Argentina suffered a disease that occurred tried.A killed Japanese encephalitis virus vac- at harvest and caused considerable mortality. cine is given to millions of people in the Ori- A virus named Junin was recovered from these ent.A killed RSSE virus vaccine is used exten- patients, and the disease was named Argentine sively in parts of the former Soviet Union.Killed hemorrhagic fever.Cases occur annually, and virus vaccines against EEE, western equine en- epidemics occasionally. cephalitis, Venezuelan equine encephalitis, and A particularly virulent infection – later named Rift Valley fever virus are used primarily to Bolivian hemorrhagic fever – attacked the small protect livestock.Laboratory workers studying town of San Joaquin, Bolivia.The outbreak was these viruses are routinely immunized. checked after the rodent host of the Machupo Wilbur G. Downs virus was implicated and rodent-control mech- anisms were instituted.Since then Machupo virus has “gone underground,” with no further outbreaks and little research in progress. 11. Arenaviruses In January 1969, another arenavirus attracted attention with an outbreak among medical per- Several of the Arenaviridae are important hu- sonnel in Lassa, Nigeria.At least seven more man disease viruses.They are not arboviruses outbreaks of Lassa fever have occurred since but have been discovered largely by arbovirol- then.The virus appears to have a natural cy- ogists.Most of the 14 arenaviruses have ro- cle of transmission in rodents but, as previously dents as reservoir hosts but occasionally infect mentioned, can spread from human to human. humans in contact with rodent-contaminated The other Arenaviridae are apparently non- environments. Lassa virus, however, is known pathogenic for humans.Epidemiological infor- to pass directly from person to person, par- mation about them is scanty, although several – ticularly in hospital settings.Others are Junin particularly Tacaribe and Pichinde – have been virus (Argentine hemorrhagic fever), Machupo studied intensively in the laboratory. virus (Bolivian hemorrhagic fever), and the virus that causes lymphocytic choriomeningi- General Characteristics tis (LCM).Six arenaviruses – Junin, Machupo, A rodent association is usually found.Excep- Pichinde, Tacaribe, Lassa, and LCM – have in- tions are Tacaribe, isolated several times from fected laboratory workers. bats in Trinidad, and two recently associated agents, Quaranfil and Johnston Atoll, found in History birds and tick ectoparasites of birds. The first arenavirus discovered was that caus- A fascinating feature is the geographic host ing LCM in mice and monkeys.It was reported range of the Arenaviridae.Each rodent species in 1934 by C.Armstrong and R.D.Lillie.Stud- involved has its ecologically determined range, ies showed that it was present in feral Mus mus- thus delimiting the distribution of its virus.The culus (the common house mouse) and afflicted exception is the house mouse. M. musculus is a few humans annually in Europe and North well adapted to human environments and has America.Usually, such cases involved personnel worldwide distribution, particularly in temper- handling laboratory animals, particularly mice ate regions of North America, Europe, and Asia. and hamsters.No serologic relatives of the virus It moves where humans move, although in the were found, and only scattered cases and out- tropics it remains more restricted to coastal and breaks have ever been reported. riverine settlements.

38 12. Arthritis (Rheumatoid)

Praomys natalensis, the multimammate Convalescence lasts several weeks after se- mouse, is also common and commensal with vere illness, and recovery is usually complete. humans.Widely distributed in Africa, it is No specific antiviral agents are known but re- associated with Lassa virus and Mopeia virus. cent reports describe successful treatment with Praomys jacksoni is associated with Mobala immune plasma.When given before the eighth virus in central Africa. (Currently, Mastomys, day of illness, it markedly reduces mortality. Myomys, and Myomyscus are all considered Rodent control appears an obvious prevention synonymous with Praomys.) measure but is impractical given the vast areas New World rodents hosting arenaviruses are of endemicity.A live attenuated vaccine shows all in the family Cricetidae.It is likely that there promise for preventing the disease in humans. have been many opportunities for virus disper- Another possibility being explored utilizes the sal as well as adaptation of viruses to new rodent avirulent Tacaribe virus to induce immunity hosts, and it seems evident that the whole world against Junin. is at risk for species radiation of Arenaviridae. Bolivian Hemorrhagic Fever (Machupo) Lymphocytic Choriomeningitis (LCM) This disease is localized in several provinces LCM has been found in the Americas, Europe, of Bolivia in the Amazonian lowlands and is and Asia, but not in Africa and Australia.The endemic in local rodent (Calomys) populations. disease in humans is usually benign, with symp- Exposed humans have an incubation period of toms resembling influenza.Inapparent cases about 2 weeks.Patients manif est high fever for are frequent during outbreaks. Meningitis may at least 5 days, along with myalgia, headache, occur as a primary symptom or more usually conjunctivitis, cutaneous hyperesthesia, nau- as a relapse several days after apparent recov- sea, and vomiting.Hemorrhagic manifestations ery.In some cases, meningoencephalitic symp- occur in some 30 percent of patients; serious toms occur, with reflex changes, paralyses, cu- bleeding is possible. Hypotension in the second taneous anesthesias, and somnolence.Fatal week of illness is seen in about 50 percent of cases are rare.When infections occur in preg- patients – in many proceeding to hypovolemic nancy, complications in the fetus and newborn shock and death.Symptoms of central nervous may be seen.Treatment is limited to supportive system involvement appear in almost half of care.Control is limited to control of residential the cases.The death rate in several epidemics mouse populations and to vigilant supervision has been about 25 percent.Convalescence of laboratory colonies of mice and hamsters. is protracted.Pathological findings include generalized adenopathy and focal hemorrhages Argentine Hemorrhagic Fever (Junin) in various organs.No specific therapy is known. This disease occurs in the heavily agricultural Treatment is limited to supportive measures. pampas west of Buenos Aires.It is seen in rural Rodent control in homes and villages has regions, mostly in farm workers.Several hun- proven effective in controlling epidemics as dred cases occur annually, mainly in the har- well as sporadic cases. vest season between April and July.Infection in Wilbur G. Downs humans results from contact with field rodents. The incubation period is 10–14 days, and an insidious onset begins with malaise, fever, chills, head and back pains, nausea, vomiting, and di- 12. Arthritis (Rheumatoid) arrhea or constipation.Hemorrhagic manifesta- tions may proceed to death (in about 10 percent Rheumatoid arthritis, the major crippling ill- of cases).In some cases, neurological symptoms ness among chronic rheumatic disorders, is predominate. a systemic disease affecting joints with an

39 12. Arthritis (Rheumatoid) inflammatory reaction lasting months or years. or more joints, but more often there is progres- Frequently, the small joints of hands and feet are sion to multiple joint involvement.The disease affected first, although often the larger periph- may remit spontaneously in the first year or di- eral joints of the wrists, hips, knees, elbows, and minish in intensity, only to recur in the same or shoulders are involved as well. Some remissions additional joints at intervals. occur, but the illness progresses to damage and The more troublesome cases affect many deformity.Its etiology is unknown. joints with sustained inflammatory reactions for months or years, with marked bone and joint Characteristics damage, ulna drift, and consequent deviation of The prevalence of rheumatoid arthritis is con- fingers, leading to limited function and instabil- sistently between 1 and 2 percent of the adult ity.Signs of systemic involvement may also be population in all parts of the globe.Females suf- seen: nodules at the elbows, cutaneous degen- fer the illness about two and a half times more eration at the fingertips or elbow, pulmonary frequently than males, although prevalence in- fibrosis, inflammation of the sac enclosing the creases for both sexes over age 35, making it heart, anemia, fever, rash and peripheral ulcers normally a disease of the middle years.The in the lower limbs, disease of the nervous sys- number of new cases per year ranges from 0.68 tem, and wrist weakness occasioned by carpal- to 2.9 per 1,000 population. tunnel syndrome.In addition, there is usually Despite years of intensive study of endocrine, gradual weight loss as well as loss of muscle vol- metabolic, and nutritional factors as well as ge- ume and power. ographic, occupational, and psychological vari- Although there is no cure, a number of medi- ables, the etiology of rheumatoid arthritis has cal and surgical modalities are available to man- not been elucidated.A genetic predisposition age patients over the course of the disease.Drug is suspected; however, bacterial and viral in- therapy is an important part of this management fections are often associated with acute pol- as it is directed toward controlling the destruc- yarthritis in humans, and thus an infection fol- tive inflammatory processes within the joint. lowed by an altered or sustained immunologic response could be instrumental. History Certainly, immunologic abnormalities appear The clinical term “rheumatoid arthritis” was to play a role in both aggravation and perpetua- first introduced in medical literature by A.B. tion of the inflammatory process.Immunologic Garrod in 1859.It was not in common us- reactions occur at the local site (joints) and often age, however, until “officially recognized” in systemically.Production of antiimmunoglobu- Britain by the Department of Health in 1922 and lins or rheumatoid factors occurs initially in by the American Rheumatism Association in the inflammatory tissue of joints and can sub- 1941.Until recent times, many names were used sequently be detected in the serum of 80 per- to describe the condition: “rheumatic gout,” cent of patients; those who are seropositive for “chronic rheumatic arthritis,” goutte asthenique rheumatoid factor show a more marked pro- primative, rheumatismus nodosus, and “rheuma- gression of the disease than do those who are toid osteoarthritis.” Broader terms such as gout, seronegative. arthritis, and rheumatism also encompassed The onset and course of rheumatoid arthritis rheumatoid arthritis as well as numerous other are particularly variable.Usually, fatigue, weight conditions. loss, and generalized aching and stiffness, espe- Evidence for the existence of rheumatoid cially on awakening in the morning, precede lo- arthritis in earlier times, however, must be calization of symptoms and joint swelling.These gleaned from literature, from art, and from pale- symptoms at times develop explosively in one opathological studies of ancient bones; to date

40 12. Arthritis (Rheumatoid) that evidence has been far from overwhelming. disease in question manifested itself as swollen, Indeed, the lack of early descriptions of this dis- painful joints – initially in hands and feet and ease has led some authors to suggest that it is then the whole body.The ailment was reported recent in origin (i.e., since the seventeenth cen- to be protracted, difficult to cure, and associated tury) and is evolving to develop a peak inci- with anorexia. dence before ultimately disappearing. In art, attention is drawn to representations of By contrast, other arthritic disorders such hand deformities in works of Flemish painters as ankylosing spondylitis, osteoarthritis, and (1400–1700), who otherwise painted the ideal spinal hyperostosis have been recognized in unaffected limb with considerable accuracy. skeletons thousands of years old and appear no Some works of Peter Paul Rubens show changes different from present illnesses.In fact, given typical of rheumatoid arthritis, suggesting that the lack of evidence of rheumatoid arthritis Rubens, who himself suffered from rheumatoid until relatively recent times, it has also been arthritis, painted the progressive phases of his suggested that rheumatoid arthritis evolved own disease in the hands of his subjects during from ankylosing spondylitis.Uncertainty about the years 1609–38. the antiquity of rheumatoid arthritis results at As for paleopathology, thousands of ancient least partly from our methods of examining the mummies and skeletons have been examined, evidence of a disease whose current definition but surprisingly few show features compatible includes clinical, radiological, and serologic with rheumatoid arthritis.Of course, determi- criteria. nation of the required symmetrical pattern of European accounts of a disease that was prob- joint disease is not possible when one or more ably rheumatoid arthritis appeared in 1676, long bones are missing, and the small bones of 1770, 1800, and 1818.Each described a long- hands and feet are frequently lost. term, chronic, debilitating disease affecting Although rheumatoid arthritis is at present multiple joints, including typical hyperexten- a major cause of symmetrical erosive pol- sion deformity of the interphalangeal joints of yarthritis, other causes do exist, and thus it the fingers. seems appropriate to employ the term erosive Before these dates, there are several descrip- joint disease (which may or may not have tions of disease that could represent phases of been rheumatoid arthritis) when describing the rheumatoid arthritis, ranging from acute ex- arthritis seen in ancient bones.Some possible plosive attack to chronic sustained disability. ancient cases of rheumatoid arthritis include re- This is particularly so in the case of Emperor ports of an Egyptian mummy 5,500 years old, Constantine IX (c.980–1055), who at age 63 two or three skeletons in Britain dating from suffered from polyarthritis in the feet and sub- Saxon to Roman and British medieval times, and sequently hands, shoulders, and knees, lead- a well-preserved Eskimo mummy. ing to nodularity and residual deformity in More recently, reports of erosive polyarthri- the fingers, and flexion and swelling of the tis occurring in ancient bones ranging from knees.This description does not absolutely ex- 5,000 to 1,000 years old in North America have clude polyarticular gout or some other ero- been identified.In fact, the researchers inves- sive joint disease, but it is very suggestive. tigating these remains have speculated that In the thirteenth century, Bartolemeus Angli- rheumatoid arthritis could have had a viral ori- cus penned a less complete but also suggestive gin in North America and then migrated to Eu- description. rope in the post-Columbian period, where it Perhaps the earliest known description sug- manifested itself as a more severe disease in gestive of rheumatoid arthritis is in the Caraka subsequent centuries.This, they argue, might Samhita of India, written about 123 A.D. The account for the apparent relative infrequency of

41 13. Ascariasis the disease in Europe prior to the seventeenth to establish themselves as adults in the small century. intestine. Today, the disease afflicts most ethnic groups This nematode was known to ancient writ- in all parts of the world.Thus, only detailed ers in China, India, Mesopotamia, and Europe studies and precise reports on skeletal remains and was present in pre-Columbian America. can establish whether erosive arthritis, which The World Health Organization has estimated may have been rheumatoid arthritis, was more that between 800 and 1,300 million people or less prevalent in the past than it is currently. harbor an average of six worms each.The These findings could impact considerably upon true figure may be even higher.Surveys have our understanding of the disease and perhaps demonstrated infection in more than 50 percent also suggest whether it is likely to disappear, as of sampled populations in countries such as some have argued. Bangladesh, Brazil, China, Colombia, India, Iran, Howard Duncan and James C. C. Leisen Kenya, Mexico, Tanzania, and Vietnam, and the rate approaches 100 percent in many rural ar- eas.In China, it was estimated that the 1947 As- caris population produced 18,000 tons of eggs a 13. Ascariasis year; they may be even more productive today. The worm is also common in developed coun- The giant intestinal roundworm, Ascaris lum- tries, although improved sanitation has greatly bricoides, is a common parasite with worldwide reduced prevalence in recent decades. distribution.Adult worms are 15–35 cm (6–14 Symptoms of ascariasis vary widely.As is of- inches) long and reside in the lumen of the small ten true of helminthic infections, low worm- intestine.Sometimes, however, they are passed loads may cause few or no symptoms.Large in the feces and, if vomited into the oral cavity, numbers of larvae in the lungs may produce may exit from the host’s mouth or nostrils; thus ascaris pneumonitis, with symptoms resem- they have been known to medical observers for bling pneumonia.Allergic reactions can cause millennia.Female worms produce up to 200,000 asthma attacks.Larvae can reach atypical (ec- fertilized eggs daily, which are passed in the fe- topic) sites such as the brain, eye, or kidney, ces.Eggs incubate in soil for at least 2–3 weeks where they may produce grave, life-threatening to produce an infective larval stage within them. conditions, but such events are fortunately rare. The eggs are resistant to chemicals, desiccation, Adult worms in the intestine can cause fever, ab- and extreme temperatures but mature or “em- dominal discomfort, diarrhea, and allergic reac- bryonate” most rapidly in warm, moist, shady tions to their proteins.Fever may induce worms conditions in clay soils.People become infected to wander to the larynx, where they can cause by eating embryonated eggs in contaminated suffocation, or to exit the mouth or nostrils. food or water; or, in the case of toddlers, infec- Heavy infection robs the host of nutrients, and tion occurs by direct ingestion of eggs with dirt. tangled masses of worms can result in fatal in- Poor rural sanitation and the use of human feces testinal obstruction if not treated promptly. In- for fertilizer obviously favor transmission.Ma- testinal ascariasis is especially serious in young ture eggs hatch in the small intestine, and the children.In the Third World, ascariasis may pro- larvae then undergo a remarkable migration in duce signs of protein-energy malnutrition in the host.They penetrate the intestinal wall and many children and often retard their growth. are carried in blood or lymph vessels to the liver Even if severe effects occur in only a small and heart, and then the lungs.Here they break percentage of cases, the ubiquity of the worm out into the air sacs, develop, and molt for about makes it an important cause of morbidity in 3 weeks, and then climb up the trachea to the many countries. throat, where they are subsequently swallowed K. David Patterson

42 14. Bacillary Dysentery

14. Bacillary Dysentery mostly confined to the tropics and East Asia; a much less pathogenic form, S. sonnei,isthe Bacteria from several genera, including Campy- most abundant species in the United States.All lobacter, Salmonella, and Yersinia, as well as age groups are vulnerable, but severe disease some strains of the common intestinal bacil- is most common in children and among the el- lus Escherichia coli, can invade mucosa of the derly.No racial or ethnic immunity is apparent, large intestine and cause dysentery, but mem- although populations can acquire considerable bers of the genus Shigella are by far the most resistance to locally prevalent strains.Travel- important agents. Shigellosis is a common dis- ers may become ill when they encounter unfa- ease that afflicts persons of all races and age miliar strains.Accurate incidence rates are im- groups.In addition, Campylobacter appears to possible to obtain, but shigellosis is a serious be an emerging pathogen, at least in the United health problem in most underdeveloped coun- States.It lives in the small intestine and pro- tries and a major cause of infant and child mor- duces a dysentery-like condition that is usually tality.The disease is commonl y endemic, but self-limiting. great epidemics also take place.During World War II, acute dysentery, apparently introduced Characteristics by Japanese and/or Allied troops, attacked in- Four species or subgroups of Shigella cause hu- digenous groups in western New Guinea, caus- man disease. Shigella dysenteriae, the first to ing thousands of deaths despite the efforts of be discovered, is the most virulent. Shigella Australian authorities.In 1969, an epidemic of flexneri, Shigella boydii, and Shigella sonnei are S. dysenteriae caused 110,000 cases and 8,000 less dangerous.More than 40 serotypes are rec- deaths in Guatemala. ognized and are useful in tracing the spread of Shigellosis is also a constant threat in devel- outbreaks. oped countries, especially when sanitary stan- Shigella organisms are passed in the feces and dards are weakened.For example, two impor- spread from person to person by the fecal-oral tant S. sonnei outbreaks occurred in the United route.Bacteria are excreted during the illness States in 1987.One took place among Ortho- and for about 4 weeks after recovery, but some dox Jews in New York, New Jersey, Ohio, and asymptomatic individuals act as carriers for a Maryland, with the majority of cases occurring year or more.Contaminated food and water are among small children in religious schools.Pat- the most common modes of transmission.Di- terns of spread were consistent with person-to- rect fecal contamination or mechanical carriage person transmission among religious communi- by flies can introduce bacteria into food, milk, ties in the four states.The first outbreak was in or water.Sick, convalescent, or even healthy New York City, where 132 cases were reported food handlers with poor hygienic practices are and at least 13,000 were suspected.Smaller epi- especially dangerous; proper handwashing af- demics in upstate New York and other states ter defecation is a simple but effective pre- appeared to be linked with Passover visits to rel- ventive measure.Crowding and poor sanita- atives in the city.The second epidemic began tion favor transmission, and outbreaks are com- with the annual meeting of a counter-culture mon in jails and institutions.Epizootics have group, the Rainbow Family, in a national forest been reported in colonies of primates, and two in North Carolina in early July.Poor hygiene and species have been isolated from dogs, but ani- inadequate latrines allowed infection to spread mal reservoirs have no known epidemiological among the campers, who caused at least four significance. clusters of cases in Missouri and Pennsylvania Shigellosis occurs worldwide but is especially when they dispersed. common in countries with poor water and The disease begins when bacteria invade sewage systems.The virulent S. dysenteriae is mucosa of the large intestine, where they

43 15. Beriberi cause mucus secretion, edema, and, usually, su- tality rates of 10 per 1,000.Dysentery outbreaks perficial ulceration and bleeding.The watery were problems for all belligerents in World War diarrhea is probably caused by a toxin that in- I, especially in the Gallipoli and Mesopotamian creases the secretions of cells of the intestinal campaigns. wall. Bacterial dysenteries took a heavy toll among Incubation is from 1 to 4 days. Onset is infants and young children in Western coun- sudden in children, with fever, drowsiness or tries until recent times.During the late nine- irritability, anorexia, nausea, abdominal pain, teenth and early twentieth centuries, the de- tenesmus, and diarrhea.Blood, pus, and mu- cline in breast-feeding and the growing use of cus appear in diarrheal stools within 3 days.In- cows’ milk in European and American cities creasingly frequent watery stools cause dehy- exposed infants and toddlers to a variety of dration, and death occurs as early as 12 days. bacterial and other agents of dysentery and di- If the patient survives, recovery usually begins arrhea.As milk is an excellent growth medium after about 2 weeks.In adults, there is usu- for Shigella and many other pathogens, con- ally no fever, and the disease resolves itself in taminated milk and lack of refrigeration led 1– 6 weeks.Symptoms in both children and to especially high death rates in hot weather. adults may vary from simple, transient diarrhea Milk-borne shigellosis was a significant contrib- to acute dysentery and death. utor to the “summer complaint,” which took A variety of antibiotics can be effective thousands of young lives annually in cities like against various Shigella species, but drug resis- Paris and New York.Infant health movements, tance is a growing problem.Many strains of S. public-health education, and pasteurization of sonnei in the United States have developed such milk largely eliminated the problem in West- resistance; thus, in cases in which drug therapy ern Europe and North America by about is essential, new agents must frequently be em- 1920.Shigellosis, however, still contributes to ployed. the “weanling diarrhea,” which afflicts tens of millions of Third World children every History year. Medical writers have described dysentery or Japanese bacteriologist Kiyoshi Shiga isolated “the flux” since ancient times, but the bacterial S. dysenteriae in 1898 and confirmed its role as form of the disease was not clearly distinguished a pathogen.The other species were discovered until late in the nineteenth century.Dysentery early in the twentieth century, and much re- ravaged Persian armies invading Greece in 480 search has been directed to immunologic stud- B.C., and the disease has always been a com- ies of various strains.The role of Campylobacter panion of armies, often proving more destruc- species as common human pathogens has been tive than enemy action.This disease was, and recognized only since the 1970s. remains, common among both rural and urban K. David Patterson poor people around the world.An epidemic of what must have been shigellosis swept France in 1779, causing especially severe damage in some rural areas of the western part of the coun- 15. Beriberi try.Troop movements for a planned invasion of England helped spread the disease.At least Beriberi is a disease caused by a deficiency of 175,000 people died, with some 45,000 deaths thiamine that is expressed in three major clus- in Brittany alone.Children constituted the ma- ters of symptoms, which vary from person to jority of the fatalities.During the U.S.CivilWar, person.It may involve edema, or swelling, of Union soldiers had annual morbidity rates of the legs, arms, and face.The nerves may be af- 876 per 1,000 from dysentery, and annual mor- fected, causing, first, a loss of sensation in the

44 15. Beriberi peripheral nerves and, later, paralysis.The car- from glucose, the preferred food of nerve cells, diovascular system may be involved, evidenced and from other carbohydrates.It is more indi- by enlargement of the heart and extremely low rectly involved in the metabolism of the amino diastolic blood pressure.In its chronic form, acids isoleucine, leucine, and valine. beriberi may result in disability for months or Thiamine is a water-soluble vitamin that is years; or it may be acute and produce death in found widely in foods.It is most concentrated in a few weeks.Until major tissue damage occurs, whole grains, yeast, and legumes; in liver, heart, it is curable and reversible by consumption of and kidneys of most mammals; and in oysters. thiamine. It is available also in most green vegetables and The name “beriberi” derives from a Sinhalese pork.An antagonistic enzyme produced by bac- word, meaning weakness.It has been known in teria – thiaminase – is found in a few diverse Japan since antiquity and is described in the foods such as raw fish and tea.Thiamine de- earliest Chinese medical treatises.The several ficiency usually results from a shortage of thi- forms of beriberi have often been considered as amine in the diet, but it can sometimes be exac- separate diseases.In wet beriberi, swelling and erbated by the consumption of large amounts heart complications occurred, although often of foods high in thiaminase. with loss of the sense of touch, pain, or temper- The epidemiology of beriberi follows from the ature.In dry beriberi, there was little swelling, role of thiamine in energy metabolism and its but instead a progressive loss of those senses deficiency in restricted diets.The populations and then of motor control followed by atrophy in which beriberi has been most prevalent have of the muscles of the paralyzed limbs and a gen- been of two kinds: people confined to institu- eral wasting syndrome.Today it is thought that tions, such as prisons, asylums, and naval ships, dry beriberi was partly due to a deficiency of who are limited to monotonous and restricted riboflavin. Shoshin beriberi was a term used diets such as bread and water or fish and rice; to denote a fulminating, or acute, form with and people who derive a large portion of their severe heart complications. Infantile beriberi calories from rice from which milling has re- was the last form to be recognized; in addition moved most of the bran in which thiamine is to swelling, heart enlargement, and other car- found. diovascular complications, suckling infants also Beriberi is in large part a disease of rice cul- had symptoms such as loss of voice and gas- ture.When rice is the staple food, it is eaten in trointestinal disturbances, neither of which oc- large quantities and commonly provides 80 per- curred in adults. cent or more of caloric energy.When the hulls The discovery that beriberi was caused by a are removed manually, enough bran remains nutritional deficiency led to the identification on the rice to provide the necessary thiamine. and study of vitamins.The isolation and later When the rice is milled in modern plants, how- synthesis of thiamine resulted in the enrich- ever, it is polished into white rice and thiamine ment of key foods as a public-health interven- is almost entirely eliminated. tion.Beriberi was not only a cause of much Cooking methods are also important in the suffering and death, but also one of the most etiology of the disease.In northern China, important diseases in the development of med- Korea, and Japan, the rice hulls were tradition- ical science. ally removed before shipment in order to reduce bulk, and cooking procedures called for the rice Characteristics to be thoroughly washed several times, remov- Thiamine is vital to every living thing, both ing the thiamine.In Burma and other parts of plant and animal.It is an essential component of Southeast Asia, the custom has been to cook rice dozens of enzymes that metabolize food.In par- with excess water that is then discarded with the ticular, thiamine is necessary to derive energy thiamine it assimilated.By contrast, in the lower

45 15. Beriberi

Ganges Valley of India, the custom has been to Beriberi has afflicted poor Americans subsist- parboil rice.Steaming the rice before drying and ing mainly on white bread and poor Europeans milling it for distribution preserves most of the consuming a monotonous diet of potatoes with- thiamine in white rice and is protective against out meat or vegetables, but the disease is and beriberi.However , the different taste and tex- has been most prevalent among the large Asian ture produced have not been widely acceptable populations that consume white rice.In the first among other peoples in Asia. decade of the twentieth century, mortality from Numerous variations in practice are involved beriberi was significant in Japan, Malaya, and in the regional etiology of beriberi.In north- the Philippines, and even in recent years the eastern Thailand and Laos, for example, people disease still occurred throughout Southeast and usually steam their glutinous variety of rice – a South Asia as well as in parts of Africa and South protective behavior.But, unlike other Thailand America. natives, they have very limited supplies of fresh The true contemporary incidence of beriberi fruit or vegetables or meat.They eat fish, most cannot be determined.As it is so easily treated of which is in the form of a fermented raw paste upon detection by the administration of thi- and is high in thiaminase, the destroyer of thi- amine, it has almost ceased to be fatal.As a nu- amine. tritional deficiency, it is rarely reportable at any In eighteenth and nineteenth century Brazil, governmental statistical level.At the subclinical beriberi was likely endemic among slaves and level, however, it probably still occurs widely.In other workers.The deficiency resulted from a a study in Australia, one in five healthy blood diet of manioc flour and a little dried meat.Man- donors and one in three alcoholics were found ioc flour actually contains less thiamine than to be deficient in thiamine. does milled rice, and the lean dried meat not There was an epidemic of beriberi in the only was low in thiamine but also increased the decades following World War II.Before the war, body’s need for the vitamin. hand-milling of rice was common except in Another population at risk has recently been the largest cities.With political and economic recognized.In urbanized and industrial coun- development, power-milling spread to the rural tries, beriberi occurs most frequently among hinterland and eventually even to the remote alcoholics.Chronic alcohol consumption im- hill country.In the late 1950s, beriberi was pairs both the absorption of thiamine by the thought to be responsible for a quarter or more intestine and its storage and utilization in the of the infant mortality in parts of Burma and the liver; moreover, relatively enormous amounts Philippines and to be the tenth greatest cause of thiamine are required to metabolize the alco- of overall mortality in Thailand.Enrichment of hol.When the alcoholic substitutes alcohol for rice has greatly reduced clinical beriberi, but it other foods in his diet and curtails consump- still occurs. tion of thiamine, Wernicke’s encephalopathy The complex of symptoms resulting from and other neuropsychiatric disorders associated thiamine deficiency has often been confused with beriberi may occur.Other groups at risk by the simultaneous occurrence of other vi- of beriberi include individuals undergoing long- tamin deficiencies.Thus, some of the symp- term dialysis for renal failure and long-term in- toms that distinguished dry beriberi were in- travenous feeding. dicative of riboflavin deficiency.A diet defi- Beriberi is entirely preventable by the con- cient in thiamine would usually be deficient sumption of adequate amounts of thiamine.In in other B vitamins as well.Some of the dif- the United States, enrichment of white bread ferences in the manifestation of thiamine de- with the vitamin virtually eliminated the dis- ficiency disease among laboring adults, suck- ease except among alcoholics.More recently, ling infants, and alcoholics result from such rice enrichment has also proved beneficial. complications.

46 15. Beriberi

A person with beriberi classically entered paralysis of the respiratory muscles, ending in the medical system when he or she developed heart failure. symptoms of the weakness that gave the disease its name: malaise, heaviness in the lower limbs, History loss of strength in the knees and wrists, some In the nineteenth century, beriberi was com- loss of sensation, tightness in the chest, palpita- mon among troops and institutionalized people tions, restlessness, and loss of appetite.Infants around the globe.Apparent epidemics occurred also vomited, had diarrhea, and had difficulty on British ships in the Bay of Bengal, Dutch ships breathing. in the East Indies, Norwegian whalers, ships ply- Edema is one of the important signs and is ing the China trade in the Sea of Japan, and ships always present in the early stages.Edema, or bringing workers home to India from labor in dropsy, commonly progresses until the lower the French Antilles. extremities and the face are swollen.Pain and Medical historian August Hirsch noted many sensitivity in the calf muscles is an early sign, as contradictions as he described the changing muscles begin to swell, degenerate, and atrophy. pattern of beriberi in the latter half of the Swelling of the lining of the intestines can also nineteenth century.In a few places, notably congest them.Edema of the lungs often causes Japan, the Malay archipelago, and the state of sudden respiratory distress and, with heart fail- Minas Gerais in Brazil, the disease was endemic. ure, death. Beriberi first appeared in Bahia in Brazil in 1866 Heart palpitations, even at rest, and a diastolic and then spread – to Sao Paulo and Rio Grande blood pressure below 60 millimeters of mercury do Sul by 1874, along the Brazilian seacoast, are usually diagnostic.There is an enlarged and on into the interior provinces and Paraguay. heart, particularly the right ventricle.A heart Similarly, the disease had been known on the murmur may be heard.An EKG may be nor- coast of Japan but had now spread into interior mal in a mild case but shows abnormal waves towns.Earlier opinion had held that a distance of sinus origin in advanced ones. of 40–60 miles from a seacoast or great river was First the autonomic, then the sensory, and enough to give immunity, but the disease now finally the motor nerves are affected.Chronic occurred hundreds of miles into the interior of cases exhibit progressive degeneration of nerve Burma and India as well as Brazil.Its appearance fibers and loss of coordination, sometimes even in new places showed that it was not caused by of the eyes.Sensibility to tactile stimulation, climate, and yet it was associated with the rainy then to pain, and finally to temperature is lost. season and hot, humid weather.It also seemed When the motor nerves are affected, paralysis associated with a period of “acclimatization” to begins in the lower extremities.Then the fin- an affected area.Beriberi afflicted people of dif- gers weaken, and the hand drops limp at the ferent modes of life, and no particular societal wrist and contracts into a claw.Eventually, even group was spared.Tainted water, however, was the intercostal muscles, diaphragm, and speech contraindicated. control muscles are affected. Evidence for a dietary cause was confusing. Other symptoms that commonly occur in- There seemed to be an association with insuf- clude a full sensation or cramping of the ficient diet, especially lack of fat and albumin, epigastrium, heartburn, constipation, and men- and with preponderance of rice and dried fish tal confusion.Thiamine reverses most of the in the diet.Rice, however, was eaten widely in mental symptoms, but some patients are left places where beriberi did not occur, and cases permanently with an inability to form new had been observed in Borneo where troops memories (Korsakoff’s psychosis).In classic eating beef and eggs contracted the disease beriberi, death results eventually from severe whereas laborers on a diet of rice and fish did disturbances of the circulatory system and not.

47 15. Beriberi

Hirsch concluded from the global evidence entist at the Bureau of Science in Manila, to that the cause of beriberi was a peculiar, spe- isolate the active factor.Soon a Filipino doc- cific poison and not the climate, weather, soil, tor, Jose Albert, identified infantile beriberi and manner of living, or diet.The complexity of the suggested its connection with the poor diets of disease was not clarified until the twentieth cen- breast-feeding Filipino mothers. tury, when the concept of a nutritional defi- In 1911, Casimir Funk at the Lister Institute in ciency was developed and replaced the idea of a London isolated a crystalline substance, which positive poison.But there were early suspicions he erroneously thought was the antiberiberi that diet was responsible.K.Takaki observed as factor, and called it a “vitamine.” In 1926, two a student in Europe the low incidence of beriberi Dutch chemists in Java, B.C.P.Jansen and W.F. among European navies.In 1885, as surgeon Donath, succeeded in isolating and crystallizing general of the Japanese navy, he altered the diet the active substance from rice bran.They mis- of sailors who had previously been much af- characterized it, however, by missing its sulfur flicted with beriberi.The results provided con- atom, and other scientists were unable to repeat vincing evidence of beriberi’s nutritional etiol- the isolation. ogy.He subsequently ordered the protein ration Williams, then a chemist at Bell Laboratories, increased for all naval personnel, and barley was continued on his own time and money to try added to their diet. to isolate the antiberiberi factor and succeeded By the late nineteenth century, the Dutch in in 1933.He and those working with him char- Indonesia had also become convinced that diet acterized it chemically and, finally in 1936, syn- was somehow involved.Experiments were car- thesized it.Williams named it “thiamin,” later al- ried out at the penitentiaries of Java in which tered to “thiamine.” Taking out a patent whose hand-milled rice was substituted for white rice, royalties funded the Williams-Waterman Fund and beriberi almost disappeared among the pris- for the Combat of Dietary Disease, Williams oners.In 1890, Christian Eijkman, a Dutch offi- interested Merck & Company in developing a cer in Java, discovered that a paralytic disease commercial process.Production of thiamine in- with nerve damage characteristic of beriberi creased from 100 kilograms in 1937 to 200,000 could be induced in chickens fed polished rice. kilograms in 1967, and synthetic thiamine be- He and his successor, Gerrit Grijns, demon- came cheaper than any that could be extracted strated in 1900 that this condition could be from natural sources. prevented or cured by feeding rice bran.Later From his position on the Food and Nutri- Grijns extracted the water-soluble factor from tion Board of the National Research Council, the bran and used it to treat people. Williams pioneered and supported the enrich- These Dutch efforts were the first experi- ment of food with synthetic thiamine.Russell mental characterization of nutritional deficien- M.Wilder led the effort to enrich flour, which cies, and a model essential for later nutritional General Mills supported, and in 1941 the first work had been developed.Its immediate im- definitions and standards for enrichment were pact was limited, however, because American established. The principle espoused was to raise and Japanese physicians did not read Dutch.In thiamine to “high natural levels” in the milled much of the world, the belief continued that flour.However, enrichment of bread in the beriberi must arise from some toxin or microbe, United States was not fully accomplished un- although none could be found, or from food til a popular movement was organized during spoilage. World War II. In 1910 in the Philippines, U.S. Army physi- Other methods of preventing beriberi had cian Edward B.Vedder began treating beriberi been practiced for decades in Asia.There was cases with an extract from rice bran and en- considerable success in both Japan and Indone- rolled the efforts of Robert R.Williams, a sci- sia in limiting the extent of milling so that bran

48 16. Black Death remained on the rice.Public-health profession- northwest of the Caspian Sea.Until recently, als stressed the importance of educating the most historians claimed that the epidemic orig- public and improving diets.In some nations, inated somewhere east of the Caspian, in Mon- however, enrichment was viewed with suspi- golia, Yunnan, or Tibet, where plague is en- cion as a commercial practice not tending to zootic in rodents.From there, it supposedly advance the public good.The result was that spread along trade routes, east to China, south even as a beriberi epidemic followed the spread to India, and west to the Kipchak Khanate, of power rice-milling and development through Crimea, and Mediterranean.This account has Southeast Asia, the United Nations Food and been contested, however, on the grounds that Agriculture Organization continued to resist early sources are too vague to identify the dis- rice enrichment.Finally, in the 1970s the gov- ease(s) in question as plague.Alternative theo- ernment of Thailand began the process, and ries notwithstanding, much more work on Chi- others followed this example.The success of nese and Mongol sources is required before we these efforts portends that, although marginal can say anything definite about the course of and subclinical beriberi may persist forever, the Black Death before 1346 and its eastern ge- the scourge of beriberi as a significant killer is ography and chronology after that date. ended. The epidemic’s westward trajectory, however, Melinda S. Meade is well established.It reached Crimea in the win- ter of 1346–47 and Constantinople shortly after- ward.From there it followed two great, roughly circular paths.The first swirled counterclock- 16. Black Death wise through the eastern Mediterranean and the Middle East.The Black Death reached lower The “Black Death” is the name given to the Egypt in the autumn of 1347 and moved slowly great pandemic of plague that ravaged parts of up the Nile over the next 2 years.By early 1348, Asia, the Middle East, North Africa, and Europe it had also hit Cyprus and Rhodes, and during in the mid-fourteenth century.Contemporaries the late spring and summer it moved through knew it by many names, including the “Great the cities of the Mediterranean littoral – Gaza, Pestilence,” the “Great Mortality,” and the “Uni- Jerusalem, Damascus, Aleppo – and then east versal Plague.” This epidemic was the first and to Mecca, Armenia, and Baghdad, where it ap- most devastating of the second known cycle peared in 1349. of widespread plague, which recurred in waves The second circle described by the plague through the eighteenth century.Some later and was greater in length and duration and moved milder “plagues” seem to have also involved clockwise, west and north and finally east again, other diseases, including influenza, smallpox, through the western Mediterranean and Eu- and dysentery.Nonetheless, most historians rope.According to Italian chroniclers, Genoese agree that the Black Death was a massive epi- ships brought the disease to Sicily from the demic of plague (a disease of rodents – caused Black Sea in the autumn of 1347, at about the by the bacillus Yersinia pestis – that is transmit- same time it appeared in Alexandria.From there ted to humans by fleas).The Black Death mani- it spread to Tunisia, the Italian mainland, and fested itself most commonly as bubonic plague Provence.By the summer of 1348 it had moved but also appeared in the forms of pneumonic westward into the Iberian Peninsula and as far plague and septicemic plague. north as Paris and the ports of southern Eng- The geographic origins and full extent of the land.During 1349 it ravaged the rest of the Black Death are still unclear.The earliest in- British Isles and northern France, parts of the disputable evidence locates it in 1346 in cities Low Countries and Norway, and southern and of the Kipchak Khanate of the Golden Horde, western Germany.In 1350 it was in northern

49 16. Black Death and eastern Germany, Sweden, and the Baltics, that range.Some areas are known to have suf- and in 1351, in the eastern Baltics and northern fered more than others.It is frequently claimed Poland.During the following 2 years, it attacked that central Italy, southern France, East Anglia, Russia, reaching as far eastward as Moscow in and Scandinavia were most severely affected, al- the summer of 1353. though the evidence for this claim is uneven. Although the Black Death lasted in all at least Clearly, however, certain regions were relatively 7 years, no single city or region suffered for fortunate; Milan, for example, Bohemia, and more than a small fraction of that period.The parts of the Low Countries seem to have expe- plague moved like a wave through the Mid- rienced losses of less than 20 percent, whereas dle East and Europe, and the average dura- Nuremberg, for some reason, escaped entirely. tion of the epidemic in any given place seems In general, however, the trend in recent re- to have been about 5 to 6 months.The Black search is to move the estimated mortality rates Death was above all a disease of spring, sum- upward. mer, and early autumn, typically receding in Some groups also suffered more than others, the last months of the year.For this reason, ar- even within a single city or region.A number eas first affected in early spring, like Tunis or of contemporary observers in various parts of the cities of central Italy, in general suffered Europe commented on the relatively high death longer and more severely than those, like north- rates among the poor.These assertions are plau- ern France and Flanders, affected in August or sible; the poor lived in crowded and flimsy September. houses, which would have allowed the easy The disease was clearly propagated by hu- transmission of plague from rats to humans and mans; rather than moving slowly across fields from person to person, and they did not have and forests from one group of rodents to an- the luxury of fleeing, like the rich, to plague-free other, it progressed quickly along major routes areas or to their country estates.Conversely, of trade and communication, traveling faster by death rates seem to have been somewhat lower sea than by land.Thus in virtually every area than average among the high European aristoc- in which its trajectory is known (the Black Sea, racy and royalty, who lived in stone buildings the Mediterranean, the North Sea, the Baltic), and were relatively mobile.People whose occu- it appeared first in ports and then spread more pations brought them into contact with the sick, slowly along roads and rivers to inland cities and such as doctors, notaries, and hospital nurses, from there into the surrounding countryside. appear to have suffered disproportionately, at A number of extremely remote areas, includ- least in some areas, as did people who lived in ing parts of the Pyrenees, the central Balkans, large communal institutions, such as the Mam- and the sub-Atlas region, seem to have escaped luks of Egypt and Syria or members of Christian largely or entirely. religious orders.For all these groups, the main It is difficult to judge mortality rates during factor seems to have been increased exposure the Black Death with any precision, except in a rather than susceptibility. few areas.Contemporary chroniclers tended to For those who could afford it, the most com- give impossibly high estimates, whereas other mon reaction sanctioned by established medical records – necrologies, testaments, hearth taxes, authorities was flight; even in the Islamic world, and so forth – are incomplete or reflect only the where religious authorities inveighed against experience of particular groups or require ex- the practice and exhorted believers to accept tensive interpretation.Nonetheless, historians the mortality as a martyrdom and a mark of di- generally agree that death rates most commonly vine mercy, people abandoned infected cities in ranged between about 30 and 50 percent in search of more healthful territory.Those who both Europe and the Middle East, with the best remained sought spiritual remedies.In both Is- records indicating mortality in the upper end of lamic and Christian countries, religious leaders

50 16. Black Death organized prayers, processions, and special reli- epidemics as the result of air corrupted by hu- gious services, supplicating God to lift the epi- mid weather, decaying corpses, fumes gener- demic.The European reaction, however, had ated by poor sanitation, and particular astro- a unique perspective, which was lacking for logical events.Thus both Muslim and Christian the most part among Muslims, for whom the doctors recommended (with some differences in epidemic was a morally neutral event: Draw- emphasis) a similar set of preventive and cu- ing on traditional teachings concerning sin and rative practices that included a fortifying diet, penance, Christians on every level of society in- rest, clean air, and moderate bloodletting for the terpreted the plague as a mark of divine wrath healthy, together with salves, internal medica- and punishment for sin and, in some cases, even tion, and minor surgery for the sick. as a sign of the approaching apocalypse. Where Europe and the Islamic world clearly The most extreme and shocking example diverged was in their attitudes toward pub- of Christian religious reaction to the Black lic health.There is little evidence that Islamic Death was directed against Jewish communi- communities (where theological teachings com- ties in Provence, Catalonia, Aragon, Switzer- bined with the classical medical tradition to land, southern Germany, and the Rhineland. deemphasize contagion as a cause of infec- Jews in these areas were accused of spreading tion) engaged in large-scale social measures to the plague by poisoning Christian springs and prevent plague, beyond religious ceremonies wells.This kind of scapegoating was not un- and occasional public bonfires to purify the precedented, but the violence of the popular air.From the very beginning of the epidemic, reaction was extraordinary, in some places re- however, the populations of a number of Euro- sisted and in some places abetted by rulers and pean cities – above all, in central and northern municipal governments.Despite the protests of Italy, which boasted a highly developed order of the pope, hundreds of Jewish communities were municipal and medical institutions – reacted ag- completely destroyed in 1348 and 1349, their gressively in a largely futile attempt to protect members exiled or burned en masse, while the themselves from the disease.Initially they fell residents of many others were imprisoned and back on existing sanitary legislation, most of it tortured and their property confiscated.The de- dating from the thirteenth and early fourteenth struction was great enough to shift the center centuries; this emphasized street cleaning and of gravity of the entire European Jewish pop- the control of particularly odoriferous practices ulation significantly eastward.There is no evi- like butchery, tannery, dyeing, and the empty- dence for practices of this sort in Islamic com- ing of privies. munities, which could boast both a long tradi- As the plague moved closer, however, a num- tion of religious pluralism and tolerance and a ber of Italian governments instituted novel mea- less morally loaded theological interpretation of sures to fight contagion as well as corrupt and the epidemic. fetid air.They imposed restrictions on travel A second set of defensive reactions belonged to and from plague-stricken cities and on the to the realm of medicine and public health.Al- import and sale of cloth from infected regions though both Muslims and Christians identified and individuals.They passed laws against pub- Divine Will as the ultimate cause of plague, lic assemblies and regulated the burial of the most accepted that God worked through sec- dead.They hired doctors to study the disease ondary causes belonging to the natural world, and treat its victims (many physicians had fled and this allowed them to interpret the epidemic the cities along with others of their class), and within the framework of contemporary medical they appointed temporary boards of officials to learning.Both societies shared a common medi- administer these measures.In Milan the ducal cal tradition based on the works of Greek writers government boarded up the houses of plague such as Hippocrates and Galen, which explained victims, and in Avignon, the pope created a

51 17. Black and Brown Lung Disease settlement of wooden huts outside the city walls History to receive the sick and isolate them from the rest For many centuries, medical observers, work- of the community. ers, and employers have recognized respira- These measures against contagion were un- tory distress and its consequences as an oc- precedented in the context of both contem- cupational hazard among underground min- porary medical theory and municipal practice; ers and employees of industries that generate they seem initially to have been a response to considerable dust (notably, refineries, foundries, the experience of pneumonic plague, which rav- and the manufacturing of cotton, flax, and aged the cities of Italy and southern France in hemp).Pliny described the inhalation of “fa- the winter and spring of 1347–8.The ecology tal dust” in the first century.In the sixteenth of plague and problems of enforcement made century, Agricola indicated that miners, physi- such measures largely ineffective, although it cians, and engineers were aware of shortness is striking that Milan, which applied anticon- of breath and suffered premature death.In the tagion practices most drastically, was the least early nineteenth century, pathologists observed affected of all major Italian cities.Nonethe- that some miners in Scotland had black le- less, such measures represent the beginnings sions on the lung at autopsy.The term pneu- of large-scale public health organizations in moconiosis appears to have been invented in Europe; succeeding epidemics saw their elab- 1867.Brown lung seems to have been named oration and spread to other parts of the conti- by analogy with black lung, apparently in the nent, where they eventually became the basis 1960s. for widespread practices such as quarantines The contemporary, imprecise medical syn- and cordons sanitaires. onym for black lung is coal workers’ pneu- Katharine Park moconiosis (CWP).CWP occurs in two forms: simple CWP and progressive massive fibrosis. Both forms have characteristic lesions.Agen- cies awarding compensation for disability usu- ally use the designation “black lung” as a rough 17. Black and Brown Lung Disease synonym for pathologicallydefined CWP and for obstructive airways disease among coal Black lung and brown lung are the names miners. given by workers in the coal and textile in- Most medical authors, epidemiologists, and dustries, respectively, and by some physicians compensation agencies usually use “brown and public officials, to symptoms of respira- lung” as a popular synonym for byssinosis or tory distress associated with dusty work.Most chronic dust-induced respiratory disease.The physicians and epidemiologists have, however, pathology in these descriptions resembles that preferred to categorize these symptoms as they of chronic bronchitis. relate to findings at autopsy and studies of pul- The rich literature on the history of black monary function and to name their appear- and brown lung cannot be summarized in con- ance in particular patients as, respectively, coal ventional terms.Many authors have attempted workers’ pneumoconiosis and byssinosis.The to describe the history of these conditions, but terms “black lung” and “brown lung” are his- they have almost invariably done so on the basis torical legacies of intense negotiations about of the precise definition of symptomatology ac- the causes of respiratory distress and mortality cepted at the time they were writing.The re- among workers in the coal and textile industries ported geography of the conditions is consistent of Europe and North America, especially since with the distribution of industries in which dust the nineteenth century. is a by-product.

52 17. Black and Brown Lung Disease

Characteristics clude the political roles of manufacturers and Each condition has been described among unions and the structure of public regulation workers exposed to coal dust (CWP) and cot- as well as different perceptions of the rela- ton dust (byssinosis).Perhaps 1 million workers tive importance of silica and coal dust and worldwide are currently exposed to both coal the amount of dust that constituted a danger- and cotton dust.The incidence of each condi- ous exposure in textile manufacturing.More- tion (and of particular diseases defined in dif- over, many epidemiological, clinical, and patho- ferent eras) has been influenced by public pol- logical investigations have yielded uncertain icy and regulations for dust suppression, by the results. characteristics of mining and manufacturing Aspects of coal miners’ lung distress that re- processes (and, for black lung, by the type of main controversial include the mechanisms by coal itself), by workers’ general state of health, which coal dust acts on the lungs; the signifi- by their exposure to other causes of respi- cance of the correlation, or lack of it, between ratory disease (notably cigarette smoke), and clinical evidence of respiratory impairment and by the availability of publicly supported pro- X-ray findings; and the absence, in some stud- grams of disability compensation and medical ies, of strong, independent correlations between care. respiratory disorders in mining communities Opinions about the distribution and inci- and work in the mines. Caplan’s syndrome is an dence of the conditions have been linked to example of the complexity and controversy sur- competing views about their clinical manifes- rounding coal miners’ lung conditions.This syn- tations and pathology.For many years and in drome, first described among Welsh coal min- many communities, physicians did not differ- ers in 1953, appears to be a consequence of entiate the symptoms of black and brown lung the interaction of characteristics of rheuma- from those of other common respiratory disor- toid arthritis with a residue of silica in the ders.In the early stages of both diseases, work- lungs; yet the syndrome seems extremely rare ers are frequently asymptomatic and without in the United States, despite the high incidence functional impairment.For black lung defined of both dust exposure and arthritis among medically as CWP, the progression of symp- miners. toms often includes chronic cough and phlegm, For byssinosis, areas of uncertainty include shortness of breath, and then functional impair- the substance in cotton dust that causes respira- ment; but some workers with lesions of CWP tory distress, lack of clear evidence linking levels at autopsy remained free of symptoms.The ini- of dust exposure to findings indicative of clini- tial symptoms of byssinosis are tightness in the cally defined disease, and the absence of widely chest, dyspnea, and a cough following a return accepted findings sufficiently specific to permit to work after a weekend or holiday.Later symp- a diagnosis of disease. toms extend to other workdays and include a Nevertheless, the literature on both condi- chronic stage, with severe continuous dyspnea, tions is widely regarded as offering considerable chronic cough, and permanent ventilatory in- guidance for public action.Most investigators sufficiency. agree that the relatively high incidence of res- Both black and brown lung have been the piratory distress in mining and textile work- focus of many studies – and are highly con- ers is evidence of exposure to toxic agents troversial.Early epidemiological studies estab- in industrial dust.Many authors have hy- lished an association between occupation and pothesized mechanisms by which these agents respiratory disease.Studies of both conditions could operate in the lung.There is consider- in the United States were, in general, initiated able agreement about clinical manifestations later than those in Britain for reasons that in- and pathology.And there is overwhelming

53 18. Bleeding Disorders consensus that reducing dust levels in the work- carriers.Necessarily, all daughters of those with place contributes to reducing the incidence of the disease are carriers, as are half the daugh- both black and brown lung and the findings de- ters of carriers.In turn, half the sons of carriers fined by medical scientists as diseases among inherit the disease.A typical family history of workers in dusty industries. bleeding inherited in the manner described is Daniel M. Fox found in about two-thirds of cases; in the rest, the disorder appears to arise de novo, either be- cause a fresh mutation has occurred or because cases were unrecognized in earlier generations. 18. Bleeding Disorders Classic hemophilia varies in severity from family to family.In the most severe cases, in The existence of a hereditary tendency to exces- which plasma is essentially devoid of factor sive bleeding was recognized in the second cen- VIII, the patients may bruise readily and bleed tury A.D. by Rabbi Judah, who exempted from apparently spontaneously into soft tissues and circumcision the son of a woman whose earlier joints, with the latter resulting in crippling joint sons had bled to death after this rite.But only disease.Trauma, surgical procedures, and den- in the twentieth century did expanding knowl- tal extractions may lead to lethal bleeding. edge of the physiology of hemostasis – the ar- The life expectancy of those with severe clas- rest of bleeding – make evident the diverse na- sic hemophilia is foreshortened, death coming ture of inherited bleeding disorders.In addition, from exsanguination, bleeding into a vital area, only recently has it been recognized that a ten- or infection.The prognosis of classic hemophilia dency to thrombosis might likewise be due to has been greatly improved by modern therapy an inherited hemostatic defect. in which episodes of bleeding are controlled by The mechanisms in mammals that stop blood transfusion of fractions of normal plasma con- loss after vascular disruption are complex.Small taining the functionally missing proteins.This vascular injuries are sealed by platelets that ad- therapy is not without hazard, for transfusion here to the site of damage, where they attract of concentrates of factor VIII derived from nor- other circulating platelets, so as to form an oc- mal plasma has been complicated by transmis- clusive aggregate or plug that can close small sion of the viruses of hepatitis and the acquired gaps.Larger defects in vessel walls are occluded immune deficiency syndrome (AIDS). by coagulation of blood, that is, by its transfor- In those families in which classic hemophilia mation from a fluid to a gel-like state.Uncon- is milder, bleeding occurs only after injury, trolled bleeding and its antithesis, thrombosis surgery, or dental extraction.The severity of (the formation of a clot within a blood vessel), clinical symptoms is paralleled by the degree of are important pathogenetic factors for human the deficiency of antihemophilic factor (factor disease, including a large variety of hereditary VIII), as measured in tests of its coagulant func- disorders.Human disorders arising from func- tion. tional deficiency of each of the factors needed Classic hemophilia appears to be distributed for the formation of a clot have been recognized worldwide, but geographic differences in in- and extensively studied. cidence have been described.Whether classic hemophilia is less prevalent in blacks than Classic Hemophilia in other groups, as has been suggested, is The best known of all the bleeding disorders is uncertain. classic hemophilia (hemophilia A, the heredi- tary functional deficiency of factor VIII), which Christmas Disease is the prototype of an X chromosome-linked dis- Christmas disease (hemophilia B), the hered- ease, limited to males but transmitted by female itary functional deficiency of Christmas factor

54 18. Bleeding Disorders

(factor IX), is clinically indistinguishable from The prevalence of von Willebrand’s disease classic hemophilia and can be differentiated is uncertain because mild cases are easily over- only by laboratory tests.It is inherited in the looked.In the United States, it is perhaps about same way as an X chromosome-linked disor- one-fourth as prevalent as classic hemophilia, der and is therefore virtually limited to males. meaning 2 or 3 cases per 100,000 individuals. As is true of classic hemophilia, the disor- Prevalence is somewhat higher in certain Eu- der varies in severity from family to family ropean countries.The disorder is relatively un- in proportion to the degree of the clotting common in blacks.The severe, autosomal reces- factor deficiency.Christmas disease is hetero- sive form of von Willebrand’s disease is unusual geneous in nature, for in some families the in most individuals of European extraction (per- plasma is deficient in Christmas factor, whereas haps 1 per 1 million) but is particularly preva- in others the plasma contains one or another lent among Israeli Arabs (about 5 per 100,000) of several nonfunctional variants of this clot- and in Scandinavia. ting factor.Therapy for hemorrhagic episodes in Christmas disease is currently best carried Unusual Disorders of Hemostasis out by transfusion of normal plasma, which Functional deficiencies of Hageman factor contains the factor deficient in the patient’s (Hageman trait), plasma prekallikrein (Fletcher plasma.An alternative therapy, infusion of con- trait), and high molecular weight kininogen centrates of Christmas factor separated from (Fitzgerald trait, Flaujeac trait,orWillimas normal plasma, may be needed in some situ- trait) are all asymptomatic, although in each ations, but its use may be complicated by the case a major defect in clotting is found in the transmission of viral diseases as well as by other laboratory.These disorders occur with equal fre- problems. quency in both sexes and are recessive traits, Worldwide, Christmas disease is perhaps one- meaning that they must be inherited from both eighth to one-fifth as prevalent as classic parents.All are quite rare, although a dispro- hemophilia.Most reported cases have been in portionately high number of cases of Hageman individuals of European origin, but, in South trait have been reported from the Netherlands. Africa and possibly in the United States, Christ- No racial predilection for Hageman trait or de- mas disease is relatively as common in blacks ficiency of high molecular weight kininogen as in whites.The disorder is said to be rare in has been described, but deficiency of plasma Japan. prekallikrein appears to be more frequent in blacks and in individuals of Mediterranean Von Willebrand’s Disease extraction. Classic hemophilia is not the only hereditary Hageman trait is a heterogeneous disorder; in deficiency of antihemophilic factor.Indeed, most families, the plasma appears to be deficient von Willebrand’s disease is a bleeding disorder in Hageman factor, but plasma in a few contains of both sexes, which in its usual form is present a nonfunctional variant of this clotting factor. in successive generations; thus, it is inherited A similar heterogeneity has been observed in as an autosomal dominant trait.The plasma plasma prekallikrein deficiency, with the plasma of affected individuals is deficient in both of Mediterranean-origin patients containing a parts of the antihemophilic factor complex, nonfunctional variant. that is, the coagulant portion (factor VIII) and The hereditary deficiency of plasma thrombo- von Willebrand factor.The disorder is usually plastin antecedent (PTA or factor XI deficiency) mild, although variants have been observed in is also inherited in an autosomal recessive man- which severe bleeding episodes are frequent. ner.The hemorrhagic symptoms are usually Inheritance in these cases is probably recessive mild; in women, excessive menstrual bleed- in nature. ing may be troublesome.Nearly all reported

55 18. Bleeding Disorders cases have been Ashkenazi Jews or Japanese, al- described in about 30 families, and some in- though cases in individuals of other heritages vestigators believe that this is the heterozygous have been recognized. state for congenital afibrinogenemia, meaning Hereditary deficiencies of factor VII, Stuart that these individuals have inherited the abnor- factor (factor X), proaccelerin (factor V), and pro- mality from but one parent.In still other fam- thrombin are rare, and no racial or geographic ilies, the concentration of fibrinogen in plasma distribution is yet apparent.In factor VII defi- is normal or only moderately decreased, but the ciency, estimates indicate 1 case per 100,000.A fibrinogen is qualitatively abnormal.This disor- still rarer syndrome, the combination of factor der, congenital dysfibrinogenemia, occurs in VII deficiency and Dubin–Johnson syndrome both sexes and in successive generations; that (the latter a disorder of bilirubin metabolism) is, it is inherited as a dominant trait.The af- has been described in Israeli Jews of Sephardic fected individuals may be asymptomatic, de- origin. tected only by chance, or they may suffer mild In each of these disorders, the deficiency ap- bleeding problems.Paradoxically, they may also pears in both sexes and is inherited as a reces- sustain thrombosis.More than 100 families with sive trait, and in a number of instances the par- dysfibrinogenemia have been described, and ents have been consanguineous.In general, the the molecular defect in each family is almost basic nature of these functional deficiencies is always unique. variable.In some instances, the plasma of the Fibrin-stabilizing factor deficiency is sim- affected individuals appears to be deficient in ilarly rare; perhaps 100 cases have been de- the factors.In others, the plasma contains an scribed thus far.In some, plasma appears to incompetent variant of the supposedly missing be deficient in fibrin-stabilizing factor; in oth- factor. ers, plasma contains a nonfunctional variant of The symptoms of deficiencies of factor VII, this agent.Patients with fibrin-stabilizing fac- Stuart factor, and proaccelerin (the last called tor deficiency have severe bleeding problems parahemophilia) are variable; some individu- beginning with the umbilicus at birth.The pa- als have hemorrhagic episodes comparable to tients may die of central nervous system hem- those of severe hemophilia, whereas others are orrhage, and in women spontaneous abortion is spared except in the event of severe trauma.In frequent.Some evidence suggests that affected women, excessive menstrual bleeding may be a males are sterile. serious problem. Another disorder of great interest is the Disorders of fibrin formation are of peculiar hereditary alpha-2-antiplasmin deficiency.In interest.Patients with congenital afibrinogen- this disease, which is inherited as a reces- emia (who have no detectable fibrinogen in sive trait, patients may have symptoms sugges- plasma) may bleed excessively from the umbili- tive of severe classic hemophilia.Bleeding ap- cus at birth and thereafter from injuries or sur- parently results from the rapid dissolution of gical procedures.In addition, they may exsan- clots by plasmin, whose proteolytic activity is guinate from relatively minor vascular injuries, unchecked because of the deficiency of alpha- and menorrhagia may be disastrous; yet they 2-plasma inhibitor.Too few cases have been rec- may have little in the way of spontaneous bleed- ognized to determine any geographic predilec- ing.Fortunately, cogenital afibrinogenemia is a tion for this disorder, but it has been reported rare recessive disorder, detected in both sexes, in Japan, the Netherlands, Norway, the United and only about 150 cases have been recorded States, and Argentina. to date.Often the parents are consanguineous. A milder form, congenital hypofibrinogenemia Hereditary Thrombotic Disorders (in which the plasma contains small but mea- In contrast to the deficiency states described surable amounts of fibrinogen), has also been to this point, a hereditary deficiency of certain

56 19. Botulism of the inhibitors of clotting results in an in- ficiency in the concentration of von Willebrand creased tendency to thrombosis.Thus, familial factor was also reported. recurrent thrombosis has been observed in indi- With few exceptions, the existence of the var- viduals of both sexes, with inherited partial de- ious clotting factors required for normal coagu- ficiencies of antithrombin III, protein C, protein lation of blood was detected by the study of pa- S, or heparin cofactor II.Aff ected individuals, tients with unusual hemorrhagic disorders.In most of whom are heterozygotes, have about each instance, a protein extracted from normal half the concentration of the inhibitory proteins plasma corrected the specific defect in the pa- of normal individuals.Only a handful of cases of tient’s plasma.Thus, current knowledge about deficiencies of heparin cofactor II, protein C, or the physiology of blood clotting has been de- protein S have been recorded, but antithrom- rived from the interplay between the clinic and bin III deficiency is relatively common. the laboratory. Most reported cases of deficiencies of these Oscar D. Ratnoff several inhibitors have been in individuals of European origin.Additional instances of an- tithrombin III deficiency have been recognized in Japanese, Algerians, and American blacks; 19. Botulism protein C deficiency has been seen in Jordanian and Israeli Arabs, and in Japanese; and protein Botulism is a potentially fatal disease caused S deficiency has been reported in Japan. by neurotoxins produced by the bacterium Clostridium botulinum.The disease usuall y oc- History curs as a food-borne intoxication; however, two The earliest record of the existence of hereditary other forms have been identified: wound bo- hemorrhagic disease is in the Babylonian Tal- tulism and infant botulism. mud.Recurrent descriptions of what was prob- ably hemophilia were recorded thereafter, but Characteristics it was only in 1803 that John Otto recognized C. botulinum, which exists naturally as a spore, that this disorder was limited to males and multiplies (and produces its powerful neurotox- transmitted by certain of their asymptomatic ins) in anaerobic conditions, such as in canned female relatives.During the nineteenth cen- foods and unclean wounds.The spores occur tury, the mode of inheritance of hemophilia naturally in soil and marine sediments and are a was delineated, and in a 1911 review of all normal contaminant of many foods.The spores published cases, investigators were unable to and toxins are inactivated by boiling canned find a single authentic case of hemophilia in a foods according to food-industry specifications. female. To date, seven distinct botulinum toxins, labeled The mechanism underlying the defect in clas- A through G, have been identified.Botulism in sic hemophilia was elucidated in 1936: It was humans is generally associated with toxins A, B, determined that patients were functionally de- E, or F, whereas the C and D toxins have been ficient in what is now called antihemophilic fac- identified in outbreaks among animals. tor.Only later was it realized that an essentially Onset usually occurs 12–36 hours after in- identical disorder, inherited in the same way, re- gestion of toxin-contaminated food.Botulism sulted from a deficiency of Christmas factor.In typically presents distressing signs of motor- 1926, E.A.von Willebrand recognized the dis- nerve dysfunction, including vision problems ease that bears his name.In 1953, several inves- and difficulty with speech and swallowing. tigators found that the titer of antihemophilic The unabated disease progresses to generalized factor was abnormally low in patients with von paralysis and death from respiratory muscle in- Willebrand’s disease, and some years later, a de- volvement.

57 20. Brucellosis (Malta Fever, Undulant Fever)

Diagnosis is confirmed by detecting bo- preserved and pickled fish are usually incrim- tulinum toxin in the blood, feces, or wound site inated.In the United States, low-acid canned of the patient.Depending on the toxic dose, vegetables, particularly beans, peppers, and untreated botulism carries a high fatality rate. mushrooms, have been the most common Early treatment with antitoxin, respiratory sup- sources, with relatively few outbreaks traced to port, and other intensive care may be lifesaving. meat or fish.Most instances everywhere are as- Infant botulism, confined to babies 2 weeks sociated with improper home canning or pick- to 9 months old, typically presents with ling, though the more serious public-health generalized weakness (“floppy baby”) and has problem of outbreaks associated with faulty been implicated as a cause of sudden infant commercial canning still occasionally occur. death syndrome.It is associated with ingestion William H. Barker of processed infant foods – honey in particular – containing botulinum spores.First described in 1976 in the United States, where most cases are reported, infant botulism has also occurred in 20. Brucellosis (Malta Fever, Europe, Australia, Asia, and South America. Undulant Fever)

History Brucellosis or undulant fever is a zoonotic Botulism derives its name from the Latin word infection caused in humans by organisms of botulus (“sausage”).In the late 1700s and early the genus Brucella: Brucella melitensis, Brucella 1800s, German physicians noted an unusual abortus, and Brucella suis, transmitted, respec- but frequently fatal disease following ingestion tively, from goats, cattle, and pigs.Human infec- of spoiled sausage.Justinius Kerner, a district tions are characterized by intermittent fevers, health officer in Wurttemberg,¨ compiled such possibly persisting for weeks, with subsequent reports, with the result that botulism is some- relapses and prolonged ill health.The causal re- times called Kerner’s disease.A similar illness lationship between organism and disease was in nineteenth-century Russia was associated first recorded by David Bruce in Malta in 1887; with eating smoked or pickled fish and labeled the name “Malta fever” reflects its prevalence on ichthiosismus. that island in the nineteenth century. In 1896, bacteriologist Emile von Ermengem, investigating a dramatic outbreak at a gather- Characteristics ing in a Belgian village, established botulism’s The type of brucellosis described by Bruce in cause as a neurotoxin produced by an anaer- 1887 is caused by B. melitensis, usually transmit- obic bacterium.In the United States, repeated ted to humans via milk from infected goats.Oc- outbreaks associated with commercially canned casional contamination by touch has also been foods led to extensive research in the 1920s. observed.The mode of transmission was not es- Sponsored by the National Canners Association, tablished until the twentieth century.In Malta these studies established safe food-processing and elsewhere in the Mediterranean, the disease practices now widespread in industry. was endemic rather than epidemic, its highest Although of low incidence and sporadic oc- incidence occurring during summer months. currence, botulism clearly exhibits significant Military officers and their families appeared case-fatality rates wherever reported.The foods more susceptible than the lower ranks; likewise, responsible vary considerably, reflecting re- among civilians the professional classes suf- gionally different dietary and food-preservation fered more than laborers. practices.In Poland, Germany, and France, Other areas show variations in epidemiolog- canned meats have accounted for most out- ical patterns.For example, in southeast France, breaks, whereas in Japan and Russia, home- where sheep and goats vastly outnumber cattle,

58 20. Brucellosis (Malta Fever,Undulant Fever) brucellosis was still widespread in the 1930s but Neither animal nor human immune systems more an occupational than a consumers’ dis- deal quickly and decisively with B. melitensis ease.Most cases occurred in farming communi- and B. abortus, which accounts for persistent in- ties, resulting from direct contact with infected fections and cases of long duration.Evans her- animals and manure, although consumption of self contracted a laboratory infection in 1922 infected milk and cheese also played some part. and suffered recurring episodes of debilitating In 1918, Alice Evans suggested that the agent fever for more than 20 years.(Despite this, she of contagious abortion (a disease of cattle) was finally recovered and lived until the age of 94.) similar to B. melitensis and might cause dis- B. abortus, in particular, can foster latent in- ease in humans.This was confirmed: brucel- fection leading to latent immunity, which oc- losis cases caused by B. abortus transmitted via curs more frequently with exposure over a pe- consumption of raw cows’ milk have occurred riod of time than with sudden heavy doses of worldwide. infective material.This may explain the low rate The third major undulant fever is caused by of disease in veterinarians, who as a group evi- B. suis, naturally hosted by pigs.The disease at- dence exceptionally high levels of immunologic tacks mainly slaughterers and packers infected response. by contaminated carcasses.Usually, B. suis in- Vaccination is possible against B. abortus in vades humans through skin lesions, although cattle and against B. melitensis in sheep and airborne infection may also be possible.The dis- goats, but a human vaccine is still experimen- ease is far less common than its counterparts in tal.The animal vaccines are too toxic for use goats and cattle.Sporadic cases among Alaskan in humans.In 1962, the British Ministry of Eskimos have resulted from infected reindeer. Agriculture introduced a free calf-vaccination Brucella melitensis follows the distribution of service. goats about the Mediterranean area (thus an- Undulant fever is essentially a septicemia other nickname is “Mediterranean fever”) as (blood poisoning) characterized by irregular well as in China, India, South Africa, and South temperatures with intermittent waves of fever, America.Pasteurization of milk has substan- usually lasting 10–30 days.Although case- tially reduced its incidence.The same applies to fatality rates are low, it is a protracted and de- B. abortus infections, which have been almost bilitating illness.Its duration varies from only completely eradicated from northern Europe, a few days to as long as a year.Subsequent re- where incidence is now quite low.In the United lapses may occur over several years, alternat- States, brucellosis is still extant, caused by, in or- ing with periods of apparent recovery.Symp- der of importance, B. abortus, B. suis, and lastly toms include weakness, muscular pain, noctur- B. melitensis.Most cases occur sporadically, al- nal sweats, anorexia, chills, and nervous irri- though occasional minor outbreaks have been tability.Recorded postmortem appearances in- reported.The situation constantly changes be- clude congestion and enlargement of the liver cause of various eradication programs. and hypertrophy of the spleen; cultures from Bruce’s discovery of the causal agent had these organs are positive for B. melitensis in all no immediate impact on incidence; only after cases. identification of the mode of transmission was Once established, B. abortus – despite its ten- there a dramatic fall in number of cases, first dency to produce latent infection – seems to among British troops, whose consumption of develop in similar fashion, lasting an average goats’ milk was curtailed by 1906.But control of 13 weeks and possibly becoming chronic. B. brucellosis among civilians was more difficult.It abortus also causes a short influenza-like ill- was achieved, in Malta and elsewhere, only af- ness and a persistent low fever.Undulant fever ter World War II, when pasteurization became caused by B. suis is clinically similar to the generally accepted. others.

59 21. Bubonic Plague

History demonstrated in 1878, and just before the turn In the Mediterranean region, a low fever with of the century Bernhard Bang in Copenhagen regular remissions has been recorded since the isolated and identified the causal agent.Only in time of Hippocrates.Its geographic origins are 1918, however, did Evans note the similarity be- indicated by many synonyms, of which the best tween B. melitensis and B. abortus; within a few known are “Malta fever” and “Mediterranean years, B. abortus was shown to be pathogenic fever,” although other variants involve Naples, for humans, causing brucellosis in many areas Constantinople, Crete, and Gibraltar. around the world. In 1863, J.A.Marston provided the first differ- Last of the undulant fevers to attract attention ential description of Malta fever; describing sev- was that caused by B. suis.The first known case eral cases, he called it “gastric remittent fever.” was apparently diagnosed in the United States In 1887, Bruce – surgeon to the Malta garrison in 1922, although the agent’s identity was not like Marston before him – recorded his discov- immediately recognized.Clinically and bacteri- ery of a microorganism in the spleens of fa- ologically, the disease is similar to the other bru- tal cases.He established its causal role, call- celloses although less extensively distributed in ing it Micrococcus melitensis, although in the either pigs or humans. B. suis infection of swine 1920s it was renamed Brucella melitensis in his began to cause concern in hog-raising areas of honor. the American Midwest during the 1930s.It has Returning from Malta, Bruce taught at the since been reported in several other countries, Army Medical College at Netley in England; but cases are mostly sporadic, with only a few among his students was Matthew Louis Hughes recognized outbreaks. who, posted to Malta in 1890, enthusiastically Lise Wilkinson embraced Bruce’s interest in the fever.Hughes wrote several papers on the disease during the next decade, until he died under enemy fire while tending casualties in South Africa in 1899. In 1897, he published a clinical description of 21. Bubonic Plague Malta fever still quoted today as a model of its kind. Plague is often a synonym for pestilence, which After Bruce’s time, brucellosis received par- refers nonspecifically to any acute epidemic ac- ticular attention in Malta.The British Mediter- companied by high mortality.But the term also ranean Fever Commission began work in 1905, refers to the recurrent waves of bubonic plague during which time Themistocles Zammit es- punctuating European history from 1348 to tablished the presence of the disease in goats 1720.Bubonic plague epidemics occurred as and the role of goats’ milk in transmitting it to Yersinia pestis, a rodent disease, was commu- humans.His research caused British troops to nicated to humans through the bite of in- cease drinking goats’ milk; within a year, the dis- fected fleas.Humans have exceedingly poor im- ease had all but disappeared from British forces mune defenses to this organism, and within in Malta.As already mentioned, control of the 6 days of infection most victims develop a disease among civilians proved far more diffi- grossly swollen lymph node, a bubo, signifying cult.Although pasteurization eventuall y solved the body’s attempt to contain and arrest mul- this problem, the disease in goats still resists tiplication of Y. pestis.On the average, around control. 60 percent of those infected died within a With B. abortus infections, the sequence of week after the appearance of the bubo.Thus, events was rather different.During the nine- bubonic plague brought high and dramatic teenth century, several authors had described mortality rates when it extended into human the disease in cattle.Its transmissibility was communities.

60 21. Bubonic Plague

Characteristics Today, in regions where plague routinely in- With the historically ironic exception of West- fects resistant rodents, ecologists and public- ern Europe, Y. pestis occurs naturally through- health officials try to monitor passage of the dis- out the world among a wide variety of rodents ease to susceptible species.In such regions – the and lagomorphs (rabbits and related species). American Southwest, south-central Eurasia, and Some of the more than 300 rodent species af- Southeast Asia – humans likely to encounter in- fected are relatively resistant to the disease fection must be revaccinated often, for human and can survive and reproduce while techni- immunity to Y. pestis is short-lived. cally infected by the organism. Y. pestis infects Yersinia pestis was once called Pasteurella new animals either because fleas transmit it or pestis, a name that has persisted from much because the microbe is shed and survives in historical literature about European plagues. warm rodent burrows.This part of the plague In 1971, the name was changed to honor cycle may be termed “sylvatic” or “enzootic” Alexandre Yersin, a French microbiologist and plague. student of Louis Pasteur.Working in Southeast The “disease,” then, is not always a disease, Asia during the late nineteenth century out- and it is ecologically complex.Indeed, ecolog- break of plague, Yersin successfully cultured the ical change or disturbance is what brings sus- microorganism. ceptible rodents into contact with Y. pestis.His- The antigens (components of the organism torically, the most important of these rodents is that stimulate an immune response) vary in Rattus rattus, the common black or brown house virulence, such that vaccines can be created rat that literally “shares man’s table.” When in- from mild plague strains. Y. pestis causes se- fected by Y. pestis, these susceptible animals die vere human disease when it contains antigens quickly of overwhelming infection, with blood that facilitate its entry into cells and impede levels of the microbe so high that rat fleas im- the body’s white blood cells’ attempts to kill bibe large numbers of organisms. infected cells. Y. pestis can liberate both endo- The oriental rat flea (Xenopsylla cheopis) and toxins and exotoxins, leading to circulatory col- the human flea (Pulex irritans) are considered lapse.These activities stimulate – and can de- historically important arthropod vectors trans- feat – immune mechanisms, explaining why the mitting “epizootic” plague to humans. X. cheopis disease produces extremely high case-fatality is an efficient vector because a bend in its feed- rates.With a typical virulent strain of the bac- ing tube creates a location for growth of Y. terium, more than 60 percent of untreated vic- pestis, such that the flea becomes “blocked,” un- tims die within 10 days of infection.If the organ- able to swallow a full blood meal.Attempting ism reaches the lungs, there is even less chance to dislodge this bolus or wad, the flea infects of survival.A victim with infected lungs can new mammalian hosts. P. irritans has an impor- cough out highly virulent, encapsulated organ- tant historical role because it feeds indifferently isms that are rapidly absorbed by the mucous upon both humans and the common house membranes of any nearby susceptible person. rat. This can lead to “primary” pneumonic plague, Human plague usually arises after an epi- in which the ordinary mode of transmission by zootic plague has produced high mortality fleas is bypassed, and the disease spreads di- among susceptible rodents, when infected fleas, rectly from human to human.When this has deprived of rodent hosts, begin to feed on hu- occurred, case-fatality rates have been close to mans.Humans do not normally carry Y. pestis 100 percent. and thus cannot infect fleas or otherwise pass Once a human is infected with Y. pestis, the disease to new hosts.For human communi- the organism rapidly replicates at the site of ties, plague is an acute infection ultimately de- the fleabite.This area can subsequently become rived from infected rodents. necrotic, and dead tissue blackens to produce

61 21. Bubonic Plague a carbuncle or pustule.But in many cases the History progress of infection is too rapid for this to Most of the historical literature of plague iden- happen.The lymphatic system attempts to drain tifies three lengthy time periods when bubonic the infection to the regional lymph node, where plague repeatedly assaulted human communi- organisms and infected cells can be ingested by ties.The first known cycle of widespread human macrophages and white blood cells. That node plague occurred during late Greco-Roman an- becomes engorged with blood and cellular de- tiquity.Byzantine historian Procopius described bris, creating the grossly swollen “bubo.” Be- the devastating epidemic of 542 A.D. in Con- cause infected fleas usually bite an exposed area stantinople, dubbed the “Plague of Justinian” of the body, the location of the subsequent bubo because of his dramatic account.The wave is often visible.Frequent sites are the groin, the of epidemic reached western Europe by 547, axilla, and the cervical lymph nodes. which was also powerfully described by Gregory But drainage can occur to an internal lymph of Tours.Virulent, epidemic plague recurred node, or the infection can proceed too rapidly throughout the Mediterranean for the next 200 for the lymphatic system to effect a defense.In years. the latter case, blood-borne septicemic plague The second cycle, at least in its early stages, has occurred, seeding the organism quickly is often called the Black Death and is treated in many organs.Victims of septicemic plague in this work as a separate entry, for certainly it become rapidly moribund and often develop is the most heavily studied of the plague cy- neither eschar nor bubos, although the more cles.Beginning about 1300, the cycle is gener- usual clinical course is the formation of a bubo, ally considered to have ended at about 1800, described in historical accounts as reaching although the ending date is disputed.This man- the size of an egg, orange, or even grapefruit. ifestation of the disease took a heavy toll in the The area is inflamed, boggy or doughy to the Middle East as well as Europe and appears to touch, and exquisitely painful.Patients often de- have also invaded Asia. manded that a physician or surgeon incise and The plague has been viewed as pivotal in drain the bubo, a process that could have liber- many areas of historical inquiry.Surely it was to ated infective organisms. some significant extent responsible for stagnant The bubo often appears 4–6 days after in- demographic performance in Europe prior to fection, and because of the multiple ways in the mid-eighteenth century, and surely, too, the which Y. pestis is virulent to humans, disease plague stimulated new and important public- progresses quickly after this point.In 5–15 per- health efforts in European urban centers.The cent of cases the lungs are infected, but more of- continued presence of the disease in Europe ten a high fever with headache and mental dis- presents a mystery, because at no other time was orientation are characteristic symptoms.Occa- it able to survive in northern Europe without sionally, circulatory collapse and hemorrhagic constant reintroduction from the Middle East. sepsis occurs, blackening the body’s surface. Historians frequently credit fifteenth through Death typically occurs within another 4–6 days. seventeenth century public-health measures In the past, a diagnosis of plague might have devised to combat the plague with some miti- been made on the basis of this rapid clinical pro- gation of the disease and its ultimate disappear- gression from health to death alone, although ance.However, in the light of modern medical clearly this could have been caused by count- knowledge, it is clear that such measures – quar- less other conditions.But the acute formation of antine of healthy individuals, isolation of the bubos, visible in 60 percent of bubonic plague sick and their households, large pesthouses or victims, is pathognomonic of plague, meaning lazarettoes, and even the elaboration of a the- that no other disease commonly causes this re- ory of contagion – would have had little effect action. on its course.

62 22. Cancer

Certainly the most important questions about otic therapy.In the Americas, as elsewhere, these 500 years of plague in Europe have to do smoldering enzootic foci of plague demand a with its disappearance and demographic conse- constant global effort in surveillance and con- quences.In the latter case, much of the mor- trol. tality credited to the plague resulted from its Ann G. Carmichael indirect impact rather than infection.When an epidemic struck, panic ensued, and this alone, by halting normal sanitary and social services while precipitating headlong flight, would have 22. Cancer taken a significant number of lives, as would isolating both ill and well in hospitals and pest- In past centuries, people feared epidemic dis- houses.Chief among these victims would have eases, with ghastly symptoms, agonizing death, been the very young, the very old, and the eco- and sometimes disfigurement for survivors.To- nomically disadvantaged. day, especially in the developed world, the dread Beginning in the early eighteenth century, Eu- of epidemic contagion has been replaced by the rope was increasingly protected against plague dread of cancer.The basic causes of cancer re- invasions from Ottoman lands by a staunch main shrouded in mystery. Austrian barrier.Manned by more than 100,000 Cancer is a process whereby uncontrolled cell men and featuring numerous quarantine and multiplication produces a tumor that can in- checkpoint stations, this famous sanitary cor- vade adjacent tissues and metastasize – that don limited both trade and human traffic, which is, implant cancerous cells at a noncontiguous may have helped to spare Europe from the third site, where abnormal multiplication continues. or most recent cycle of the plague that seems to Cancer in connective tissues (mainly bone or have had its beginning in central Asia about the muscle) is called sarcoma; cancer in epithelial middle of the eighteenth century.From there, tissues (lining tissues and organs) is called car- the plague spread to China and India and then, cinoma.Carcinoma is by far more common. aided by rapid sea transportation, radiated glob- In Egypt, tumors have been found in third- ally from Hong Kong, Bombay, and Calcutta. millennium B.C. mummies, and ancient physi- But if Europe was bypassed, the Americas cians there knew and treated different cancers. were not.Rather, along with Australia and east- The ancient Greeks, too, were familiar with ern Africa, North and South America were in- cancers.Hippocrates is credited with naming fected for the first time, and by the early years the disease “cancer” from karcinos (Greek for of the nineteenth century some regions of the “crab”), perhaps because some breast cancers Western Hemisphere were experiencing rela- appear crablike or perhaps because the pain tively minor but nonetheless panic-inspiring of cancer resembles the pinching of a crab. epidemics.Those that struck San Francisco are The terms neoplasm (“new formation”) and on- among the best documented in this pandemic cology (“study of masses”) are also derived cycle, although the disease killed millions in In- from Greek, as is the word tumor.Hippocratic dia and Africa. medicine attributed tumors – including all sorts If the Americas and Australia did not suffer of swellings – to abnormal accretion of humors. greatly from this third cycle of plague, one con- Galen sought to differentiate cancers from in- sequence was that the disease established itself flammatory lesions and gangrene.Cancer was among the rodents and lagomorphs of the New held to be caused by black bile. Worlds.In North America, the geographic ex- Breast cancer was probably the first to tent of plague has subsequently widened each be treated by attempting surgical eradication. year, and sporadic cases of human plague claim Some ancient surgeons performed total mas- 8–15 victims annually despite effective antibi- tectomies, and although the healing of these

63 22. Cancer terrible procedures was little reported, Rhazes Rudolph Virchow postulated that neoplasms de- warned in the ninth century that operating on veloped from immature cells.In 1867, Edwin a cancer generally only caused it to worsen un- Klebs suggested that most cancers originated in less it was completely removed.It seems likely, epithelial tissues. however, that few cancers were treated surgi- Despite its antiquity, cancer is viewed as cally until relatively modern times.Ambroise largely a modern phenomenon.Along with Pare´ wrote toward the end of the sixteenth cardiovascular disease, it is perceived as the century that those who pretended to cure can- greatest health problem facing the developed cer surgically only transformed a nonulcer- world.Thus far, the World Health Organiza- ous cancer into an ulcerated one.Nevertheless, tion has classified some 100 kinds of cancer in the seventeenth century, Wilhelm Fabricius according to sites of origin.Estimates indicate provided adequate descriptions of operations that one-third of the inhabitants of the indus- for breast and other cancers. trialized world will develop some form of can- The discovery of the lymphatic system by cer.Cancer cures have largely eluded scientific Gasparro Aselli in 1622 directed attention to- medicine.Nor has Virchow’s observation that ward lymphatic abnormalities in the causation irritants could summon forth cancerous cells of cancer.Basically, the idea was that cancer proved very helpful in cancer prevention – al- was an inflammatory reaction to extravasated though irritants are among the foci of cancer lymph.About 15 0 years later, John Hunter mod- research today. ified the lymph theory by defining “coagulat- The concept of autonomy suggests that once ing lymph” (i.e., blood serum). Hunter viewed a cell has become truly cancerous it is beyond this substance (when contaminated by “can- bodily control.This idea was established around cerous poison”) as the cause of cancer.Quite the turn of the twentieth century by Arthur presciently, he described metastases as “con- Hanau, Leo Loeb, and Carl Jensen, who trans- sequent cancers” that traveled via lymphatic planted cancer cells into healthy animals and channels. plants, subsequently observing the growth of Another hypothesis (advocated particularly new cancers in the previously healthy hosts. by the German Daniel Sennert and the Por- Yet the fact that established cancers can enter a tuguese Zacutus Lusitanus) early in the seven- stage of remission – sometimes permanently – teenth century was that cancers, at least when argues that the body can retard or even reverse ulcerated, were contagious – a popular fear that previously uncontrolled cell proliferation. persisted well into the twentieth century.The The next advances were made when cancer first accurate etiologic observation about can- was induced experimentally in plants and an- cer is attributed to London surgeon Percival imals by various chemical, physical, and bio- Pott, who reported in 1775 that many long- logical agents.For example, some 150 different time chimney sweeps suffered scrotal cancer. viruses caused tumors, and ultraviolet light, X- He linked this observation to the men’s chronic rays, radium, uranium, coal tars, certain dyes, contact with soot and thereby identified the first and other substances also induced cancer.Even occupational cancer. natural bodily compounds such as estrogen The impact of microscopy on cancer research have caused cancer in experimental animals. came slowly.Robert Hooke, the pioneering sev- Cancer is predominantly an illness of mid- enteenth century microscopist who coined the dle age and, with a few exceptions, is relatively term “cell,” thought that tissues were composed rare in children.Thus, people in the developed of fibers – a hypothesis that persisted into the world, having escaped famine and epidemic dis- nineteenth century.Not until after 1830, when ease, have extended their life expectancy into Joseph J.Lister designed the first achromatic mi- the ages in which cancer frequency is increas- croscope lenses, did progress begin.In 1855, ingly high.

64 22. Cancer

The three most common cancers of men – Cigarette smoking is also associated with prostate cancer, lung cancer, and colon can- neoplasms of other organs (such as bladder cer – comprise about 50 percent of new cases cancer), but this does not obscure the clearly and 55 percent of cancer deaths.The three most quantitative relationship between smoking and common cancers of women – breast cancer, increased probability of lung cancer.Neverthe- colon cancer, and lung cancer – also comprise less, lung cancer occurs in only a small minor- about 50 percent of new cases and account for ity of even heavy smokers.This may indicate a 50 percent of deaths.Cancer deaths in women predisposition that could warn persons at risk, peak at 41.0 percent in the 35–54 age group. but investigations have thus far failed to yield In contrast, men’s average age of cancer death useful results.Finally, there have been no repro- peaks at 30.2 percent in the 55–74 age group. ducible experiments showing tobacco smoke to This difference is mostly attributable to the dif- cause lung cancer in experimental animals. ference in age distribution of women with breast No potent pulmonary carcinogens have as yet cancer and men with prostate cancer. been identified in tobacco smoke, but a 1970s Survival has improved variably since the finding appears to clinch the causal relationship 1960s.The greatest improvements have oc- between smoking and lung cancer: A 20-year curred in stomach cancer (both sexes) and fe- investigation showed that the risk diminishes male uterine cancer.Lung cancer has increased increasingly after smoking has been discontin- in incidence in both sexes, as has male prostate ued for several years, which cannot be ascribed cancer.The decrease in stomach-cancer deaths to genetic or psychological factors.However, has resulted from a decline in incidence rather even 15 years after cessation, the risk among than any significant improvement in treatment. former smokers remained twice that of similar- Survival generally has been and remains poorer aged men who had never smoked. for black than for white patients, a difference of- Smoking has now been common among ten attributed to the black population’s poorer women long enough to be reflected in an alarm- access to medical care.However, there are no ing increase in lung-cancer incidence, begin- apparent race-related differences in survival of ning in the mid-1960s and now half that of men certain common carcinomas (lung cancer, kid- in the United States.By 1986, the lung-cancer ney cancer, and stomach cancer). death rate of U.S. women equaled that for breast The greatest problem of exogenous carcino- cancer. genesis today is not exposure to industrial pol- Of the half-million women worldwide who lutants, as many believe, but rather the use of develop breast cancer annually, half reside in tobacco products.Cigarette smoke appears to North America and Europe, which contain less exert the most potent carcinogenic effect, al- than 20 percent of the world’s population.But though cigar smoke and chewing tobacco are more localized questions arise as well.For ex- also implicated.Historically, the possibility that ample, why is the breast-cancer death rate in an increase in lung cancer was related to an in- Finland and Denmark more than triple the rate crease in cigarette smoking was first raised in in Sweden, and why is the rate in Scotland quin- Germany in the 1920s.In the United States, in- tuple that of England? terest was stimulated by the 1950 publication of A daughter or sister of a woman with breast three studies showing that lung-cancer patients cancer has a nearly three times greater risk of were likely to be heavy smokers.Resistance to a developing it than a woman without such as- causal relationship between smoking and lung sociations.The risk is greater if the relative’s cancer was based initially on doubt that lung cancer appears at an early age, and greater still cancer incidence was actually increasing, and if both mother and sister have been affected. then on a failure to appreciate the long preclin- This suggests a genetic predisposition, as does ical phase of the disease. the increased risk of a second breast cancer.

65 22. Cancer

However, evidence indicates that environmen- In the United States, colorectal cancer has re- tal factors must also be involved.For example, mained stable in white men and decreased mod- breast-cancer prevalence in Japan is about one- erately in white women but increased in the fourth that in Europe or North America.Nev- black population. ertheless, among Japanese-descended women The ultraviolet component of sunlight is a in North America, the incidence of breast can- major cause of skin cancer.Susceptibility is cer by the second generation matches that of related to paleness, poor tanning ability, and indigenous whites.But what factors are impli- chronic exposure.Overall incidence of non- cated remains unresolved. melanoma skin cancers in the white U.S. pop- Prostate cancer is the second most frequent ulation is about 165 per 100,000.However, the cancer among U.S. men and the fifth worldwide. prevalence in Texas is three times that in Iowa. It is more prevalent among U.S. blacks than any The incidence of melanoma is only about 4 per other population – about 80 percent more com- 100,000, but 65 percent of skin-cancer deaths mon in black than white men in the United are caused by this disease.The lesion occurs States.It is also common in black Caribbean twice as often on the legs of white women as on populations, whereas information from Africa those of white men.It occurs nearly twice as indicates much lower prevalence.The incidence frequently on the male trunk than the female of prostate cancer is more highly correlated with trunk.Melanoma is uncommon in blacks, and increasing age above 50 than any other neo- its location tends to be on palms or soles and plasm.It is six to seven times more prevalent in within the mouth – less heavily pigmented ar- the 75–84 than in the 55–64 age group, and the eas.Melanoma incidence has been increasing black/white difference diminishes with age.In- everywhere, and mortality has nearly doubled. creased risk is associated with chronic cigarette Whether the increase is attributable to changes smoking, and there is an apparent correlation in ultraviolet intensity is unknown. between above-average sexual drive and sus- X-rays and related radiation are estimated to ceptibility to prostatic carcinoma.This could cause no more than 3 percent of cancers.Radon mean that an alteration in sexual hormones has gas exposure is clearly a cause of lung can- a predisposing role.Alternatively, a correlation cer in uranium miners.If the concentration of between promiscuity and (male) prostate can- radon in some homes were found to be suf- cer would suggest an analogy to the better- ficiently carcinogenic, presumably the propor- documented correlation between promiscuity tion of known cases of radiation-caused cancer and (female) cer vixcancer , and the possibility would increase substantially. Thyroid cancer that a sexually transmitted virus is the patho- results from small-to-moderate radiation expo- genetic agent.None of these hypotheses, how- sure to the neck, with a latency period of about ever, explains the increased incidence of this a decade.Bone marrow is another radiosensi- disease in the late 1900s. tive organ.Increased risk of leukemia begins as With regard to possible roles of diet in car- early as 2 years after radiation exposure, reaches cinogenesis, both low-fiber and high-fat diets peak probability after 6–8 years, and then di- have been proposed to be pathogenetic for col- minishes. orectal cancer.The best evidence now indicates Suspicion of potential carcinogens in con- a carcinogenic effect of increased fat consump- sumer goods led to the 1958 passage of the De- tion, particularly in women.The predominant laney amendment to the U.S. Food, Drug, and hypothesis for this association is: Higher fat Cosmetic Act, which bans any food additives consumption increases excretion of bile acids that cause cancer in any experimental animals and growth of colonic bacteria; therefore, the in any dosage.One result has been the forced conversion of bile acids into carcinogenic sub- withdrawal of some products based on dubious stances by bacterial metabolism is facilitated. and unrealistic experiments.

66 23. Carrion’s´ Disease (Oroya Fever)

Worldwide, stomach cancer, now relatively In summary, the concept of cancer has uncommon in the United States, is the most evolved from the idea of a single illness prevalent visceral cancer (second for men, to one of many diseases with many causes. fourth for women).Nevertheless, death rates Most prevalent are carcinomas of the stom- have declined to about 35 percent of 1930s ach, lungs, breast, cervix, colon and rectum, figures.The decrease has been worldwide and prostate, and liver.Chief among carcinogens is unexplained.It remains the most prevalent are tobacco, certain metals, radiation, specific carcinoma in East Asia – the rate in Japan is chemical compounds, helminthic parasites, and more than seven times that in the United States, possibly viruses.Various carcinogens constantly accounting for one-third of all Japanese can- bombard everyone, but cancer develops in a mi- cer deaths.Repetitive ingestion of high concen- nority of people.A few uncommon neoplasms trations of salt has been proposed as a cause clearly are genetically determined.Resistance of gastric cancer; indeed, the decline in inci- to carcinogens also appears to have a genetic dence has correlated with the decline in salt basis. preservation of foods.In regions where stom- Available treatments are generally drastic, ach cancer remains common, salted seafood re- poorly selective, and in many circumstances mains a staple.The incidence of gastric cancer not curative.Earlier diagnosis improves the among first-generation Japanese immigrants to cure rate of many but not all cancers.There- the West is similar to that in their homeland, but fore, public education about cancer and fur- it declines to the incidence of the Western com- ther improvements in diagnostic methods are munity where the next generation resides.Be- important.Until our understanding of the fun- cause this is not a genetic disease, a generation damental biology of cancer improves, preven- that is not exposed to salt at a critical age pre- tive measures, such as minimizing exposure to sumably will not suffer inordinately from this carcinogens, will constitute the greatest benefit neoplasm. to public health. Cervix cancer is apparently related not to ge- Thomas G. Benedek and Kenneth F. Kiple ography but to cultural sexual practice.Sexual intercourse during adolescence, multiple part- ners, or partners who have had numerous part- ners are all risk factors, as is frequent pregnancy. 23. Carrion’s´ Disease (Oroya Fever) Thus the disease is rare among nuns and com- mon among prostitutes.A sexually transmitted Carrion’s ´ disease is an infectious disease virus is suspected to be a causative factor.In the caused by microorganisms of the genus Bar- United States, cervix cancer occurs twice as fre- tonella.Two species have been described, the quently among black as white women, whereas bacilliformis and verrugiformis types.These bac- uterine cancer occurs two to four times as often teria are parasites of human erythrocytes and in white women. histiocytic cells.The bacilliformis produces two Liver cancer is much more prevalent in devel- stages of disease, a febrile acute hemolytic ane- oping countries than in the industrialized world. mia known as “Oroya fever,” followed by a gran- China alone accounts for 45 percent of cases. ulomatous mucocutaneous eruption known as The liver is subject to two principal types of can- verruga peruana.The verrugiformis produces cer: one in liver cells, predisposed by a history only the second (verrucose) stage. of hepatitis B infection; another in bile-duct cells, predisposed by liver flukes and similar in- Characteristics festations.The geographic distribution of such Bartonella bacilliformis are pleomorphic bacte- parasites is reflected in the prevalence of this ria.In red blood cells and histiocytic cells, the disease. bartonella assumes a rodlike or coccoid shape.

67 23. Carrion’s´ Disease (Oroya Fever)

It grows well in liquid and semisolid blood At the end of the anemia stage, immunore- media.In 1913, Charles Townsend identified sponse occurs against active bartonellas, which the female sandfly Phlebotomus verrucarum as are converted into resistant coccoids.This is the insect vector of the disease.Transmission the most dangerous period of the disease.At occurs at night. Carrion’s´ disease is a rural least 30 percent of untreated patients die af- disease.Like yellow fever, it requires no hu- ter physical collapse.Another 40 percent die man reservoir because the bartonella lives in from secondary complications: Most frequent small animals as well.However, inoculation of are salmonellosis, tuberculosis, malaria, and humans with a live germ appears to produce amebiasis. immunity. From the clinical viewpoint, the patient has The “anemic stage” of Carrion’s´ disease is recovered, but the bartonellas still live in ad- characterized by acute febrile anemia with bar- ventitial cells surrounding subcutaneous capil- tonellas in the red blood cells, and the “verru- laries.Blood and bone marrow cultures are still cose stage” is characterized by a disseminated positive.In time, the bartonellas start a new cy- verrucous eruption in skin and mucous mem- cle of reproduction in the histiocytes, beginning branes.In severe infection, erythrocyte levels the second stage of the disease.The histopathol- plummet to less than a million in a few days. ogy of the granulomatous phase shows a prolif- The parasitic index in these cells reaches 80– eration with large, pale histiocytes and endothe- 100 percent. lial cells, some filled with coccobacillus bar- Onset is abrupt, with fever, chills, and osteal tonellas.The rupture of these cells results in dis- pain.Bone-marrow hyperplasia, reticulocyto- semination of the bartonellas through the skin, sis, and jaundice present, with increased biliru- and new verrucose eruptions appear.The erup- bin in blood and urine.The blood culture is tive phase tends to heal spontaneously without positive, even in the earliest days of the ane- scars. mia.The verrucose stage is usually separated Before antibiotics, mortality from Carrion’s´ from the anemic stage by an asymptomatic in- disease was high.Antibiotics have a p ower- terval of several months to over a year.Several ful bactericidal effect; the anemia is arrested, types of eruption may occur: “miliary,” “nodu- and blood regeneration starts immediately. lar,” and “mular.” The eruption becomes painful Chloromycetin has been the most effective an- only with a secondary infection or increased tibiotic in the anemic stage, and streptomycin is bleeding. ideal during the eruptive phase. In the verrugiformis type, the clinical picture is that of a diffuse granulomatous eruption sim- History ilar to the bacilliformis type, but less intense. Carrion’s´ disease was probably depicted thou- The verrugiformis-type eruption can recur two sands of years ago in pottery of the ancient or more times during a lifetime. Peruvian civilization.The disease flourished in The main pathogenic feature is the reproduc- inter-Andean valleys of western South America. tion of the bartonella inside endothelial cells, The focus of endemic transmission is in Peru, which swell with tremendous numbers of bac- although some cases exist in Colombia and teria.The resulting pressure ruptures the cell Ecuador.Endemic areas are confined to narrow membrane, releasing millions of bacteria, which valleys at elevations of 2,100–7,500 feet. then colonize other endothelial cells.The bar- The disease was probably described during tonellas also parasitize peripheral erythrocytes, the Spanish conquest but attracted attention inducing the anemia.Severe cases show throm- only in 1870, when an epidemic of the acute bosis and infarction in the spleen, necrosis of febrile form killed thousands of workers during the liver, and lung congestion. construction of a railroad from Lima to Oroya.In

68 24. Catarrh

1885, Peruvian medical student Daniel Carrion´ quantity that passed down through the pores contracted the disease by self-inoculation with in the palate and by way of the trachea to the verruga and died of Oroya fever, thus establish- lungs.This unspoken assumption behind the ing the connection between the two conditions. name is paralleled by that behind the modern In 1909, Peruvian physician Alberto Barton de- definition: We make the assumption that the scribed organisms in the red blood corpuscles “inflammation” of the definition results from in- of Oroya-fever victims, and later these findings fection by an organism.The identity of the or- were confirmed.However, some still felt that ganism gives us the ontology of the disease.A Oroya fever and verruga peruana were caused similar situation existed in all historical periods; by two distinct agents.H.Noguchi and T.Bat- that is to say, definitions of disease have al- tistine resolved the controversy, reporting in ways carried with them some part of a the- 1926 that the illnesses were different manifes- ory of causation.(Purely empirical accounts of tations of the same disease.In 1942, M.Hertig disease are descriptions of symptoms.) To put definitively described both the disease and its it another way, disease in Western medicine vector. has traditionally been seen as disordered func- Oscar Urteaga-Ballon tion.But function is a process, and knowledge of it depends on knowledge of how the body works. In the eighteenth and nineteenth centuries, 24. Catarrh there were a number of different so-called sys- tems of physiological knowledge, in each of Catarrh is now regarded as inflammation of the which what was indicated by a single disease mucous membranes, especially of the air pas- name was seen differently.For example Francis- sages, together with the production of a mu- cus de Le Boe¨ (F.Sylvius), as an iatrochemist, coid exudate.Simple though this definition is, divided catarrhs into groups distinguished by it bears evident traces of the history of the the chemical qualities of the humor produced. disease. As a hydraulically inclined mechanist, Hermann The name derives from Hippocrates’ use of Boerhaave thought of catarrh in terms of ob- katarrhoos, a “flowing down” of humors from struction of the small vessels, which caused the head.In that use, the term was probably not swelling.Indeed, his most frequent use of the yet technical, and so akin to a Latin word such as term was as an adjective to describe angina. defluxio.In commenting on Hippocrates, how- “Angina” was any difficulty in breathing, and ever, Galen distinguishes general “downflow- catarrhous angina was the result of swollen ing” from a more precise meaning of “catarrh” – membranes.Although membranes also played that is, defluxion from head to lungs, producing an important part in the new tissue pathology of hoarseness and coughing. early nineteenth century Paris, the Parisian view The Greek word became catarrhus in Latin of the body, and therefore disease, was again dif- and a technical term with, increasingly, Galen’s ferent.Marie Franc¸ois Bichat stressed the sym- meaning attached to it.Although it is tempt- pathies between membranes and their ability ing to identify catarrhus with catarrh, we have to secrete and imbibe the fluids of the cavity to remember that for Galen and doctors down they lined.To this were added the new tech- to the seventeenth century, catarrhus could not niques of physical diagnosis by percussion and be defined without reference to Galenic pathol- stethoscope. ogy. Catarrhus was a process in which the brain, Catarrh again became a disease of mem- preternaturally affected by cold, produced a branes, of excessive secretion, and of fluids qualitatively unbalanced humor in excessive moving audibly in their cavities.Some Bichatian

69 25. Cestode Infection sympathy of membranes seems to lie behind the cluding the Caribbean islands and the United early nineteenth century notion of a catarrh of States. T. cruzi has over 100 vertebrate hosts, in- the urinary bladder.This opinion was recorded cluding dogs, cats, armadillos, opossums, mon- by R.Hooper, who also sharply distinguished keys, and humans.Unlike other trypanosomes, common catarrh – a cold, and particularly a cold which multiply in the bloodstream, it lives in the head – from epidemic catarrh, which is within various tissues of the host and repro- identified with influenza.The modern meaning duces by binary fission.It is transmitted by re- is derived from the former. duvid bugs that ingest it from a host during a Roger K. French blood meal. The trypanosomes develop in the intestines of the bug.They neither enter its saliva nor are injected when it bites but do pass out in 25. Cestode Infection its feces.Thus the infection is transmitted when the infected insect defecates following its blood Cestodes are a class of flatworms in the phy- meal, thereby contaminating the site of the bite. lum Platyhelminthes.The adult stages of four Infection can also occur when feces are rubbed species and the larval stages of two are im- into the eyes or reach oral mucosa, and possibly portant parasites of humankind.Several other via contaminated foods as well.The insect vec- species, most of which normally parasitize other tor flourishes in huts in poor rural areas, where vertebrates, can also cause human disease.See: it lives in cracks in the walls and in thatching Tapeworm Infection. and mats used as roofing.Cases may be few de- K. David Patterson spite large numbers of infected bugs, if the bugs are not adapted to living in houses. The disease takes several different forms, but, in all cases, no effective treatment exists.The 26. Chagas’ Disease acute form ends in death in 10 percent of cases, and, although the chronic form may last as Chagas’ disease (also American trypanosomi- long as 40 years, few individuals remain asymp- asis or trypanosomiasis cruzi) can be either tomatic for life.Chronic cardiac disease, mega- an acute febrile infection or a chronic process. colon, and megaesophagus all can shorten life. The cause is a protozoan, Trypanosoma cruzi, The acute form of the disease, occurring pri- harbored by domestic and wild animals.When marily in young children, is usually a febrile ill- transmitted to humans by insects, this essen- ness.When death occurs, it is generally caused tially untreatable disease presents with fever, by myocarditis or a complicating broncho- edemas, and lymph node enlargement and can pneumonia.The latent form is seen in patients cause dilation in the digestive tract, leading who have recovered from the acute form, as to megacolon and megaesophagus as well as well as others who have harbored the parasite cardiac enlargement and failure.In parts of without displaying symptoms.Examinations of- South America, Chagas’ disease is the leading ten reveal changes in esophageal and peri- cause of cardiac death in young adults. staltic motility as well as electrocardiographic changes.The subacute form is normally seen in Characteristics young adults, who suffer a rapidly progressive Probably originating in Brazil, the disease is lim- cardiac failure. ited to the Western Hemisphere, with heavy The chronic form of the illness is the lead- concentrations in Brazil, Argentina, Chile, and ing cause of death in endemic areas.The heart Venezuela.Cases are also reported in Peru, becomes tremendously enlarged, and in about Mexico, and most other American countries, in- 30 percent of cases, parasites are found within

70 27. Chlorosis pseudocysts in muscle fibers.Although survival throughout the Americas and has a notable may be as long as 5 years, death usually inter- presence in Argentina.In fact, a mid-twentieth venes within 6–12 months. century Argentine study established that the The digestive form of Chagas’ disease disease was much more widespread than pre- presents as megacolon or megaesophagus. Vic- viously believed and stimulated other studies, tims suffer degeneration and diminution of leading to recognition that Chagas’ disease was nerve cells in the muscular layers of these or- a serious health threat in South America.In- gans, leading to their enlargement.The con- deed, since the 1950s, it has become increas- dition by itself is normally not fatal, but ingly common in southern Peru, although the patients often experience difficulty swallowing vector (called chirimacha) is known throughout because of the enlarged esophagus, and consti- all of Peru. pation normally accompanies megacolon.These Marvin J. Allison difficulties in turn can promote other illnesses that are life-threatening.The congenital form of the disease has long been known.The fetus is infected transplacentally, resulting in premature 27. Chlorosis fetal death or a newborn with Chagas’ disease in its acute stage. Diseases are categorized as degenerative, ma- lignant, genetic, endocrine, and so on in cur- History rent nosology.For the history of disease, we Chagas’ disease is unusual in that its etiolog- must add a category that we might term ical agent, its vector, and major features of its “ephemeral.” This requires some license, be- epidemiology were described before the first cause many “ephemeral diseases” lasted longer human case was ever reported. Brazilian physi- than that term usually implies.Ephemeral dis- cian Carlos Chagas accomplished this in a se- eases comprise a large number of entities that ries of publications beginning in 1909, and the bore working diagnostic names (e.g., typhoma- disease appropriately bears his name.The ill- larial fever) for earlier physicians but that are ness, however, is not new.Studies of mummies no longer recognized, at least by their previous from northern Chile have revealed megacardia, names. megacolon, and megaesophagus in several in- A historical example of such a disease is dividuals who lived more than 2,000 years ago. the “green sickness,” chlorosis.Although noted The same area today is endemic for Chagas’ in two Hippocratic treatises, the condition re- disease. ceived its classic description from Johann Lange Nineteenth-century visitors to Brazil reported in 1554; he called it morbus virgineus.His de- instances of megaesophagus and the presence scription contains many elements from the Hip- of the cone-nosed bug vectors of Chagas’ dis- pocratic texts, as do accounts by Ambroise Pare´ ease.Most interesting is the case of Charles Dar- in 1561 and by Jean Varandal (credited with win, who wrote that he was bitten by a huge Tri- first using the word “chlorosis”) in 1615.For atoma bug while in South America.It has been Varandal, chlorosis was a class of syndromes. suggested that Darwin’s mysterious chronic ill- Reflecting a different approach, Thomas Syden- ness dated from this time, and some believe that ham in 1683 described many clinical features Darwin was afflicted with Chagas’ disease. relied upon two centuries later.Friedrich Hoff- Although similar to African trypanosomia- mann defined the actual clinical entity in 1731. sis (“sleeping sickness”), Chagas’ disease most likely evolved independently.Its cradle is be- Characteristics lieved to be the Bahia-Minas-Gerais area of Chlorosis was associated almost entirely with Brazil, although it has subsequently spread Caucasian girls encountering puberty.Still,

71 27. Chlorosis from clinical observations alone, the etiology of right-thing/wrong-reason in medicine’s past, remained obscure.Inconsistencies abounded. iron for chlorosis probably is not one of them. Not all young women developed the disease at When physicians employed proper iron com- the age of menarche.It struck rich as well as pounds in correct doses, the clinical results were poor.Some, but not all, suffered a morbid ap- dramatic and altogether convincing. petite termed pica (consumption of stones, clay, Even if it was correct that the central fea- chalk, and other substances of no nutritional ture of chlorosis was iron deficiency anemia, value).Even into the nineteenth century, confu- a good deal of confusion remained.Still to be sion permeated medical thinking about chloro- elucidated were a host of diseases marked by sis.But by the time of William Osler toward the pallor, wasting, and lassitude, some of which end of that century, medical opinion had be- had anemia as a secondary manifestation.These come far more confident.The clinical features included nephritis, hypothyroidism, subacute of chlorosis had been distilled to the point that bacterial endocarditis, mitral stenosis, and tu- in many instances the condition could be “rec- berculosis.What did subside was the focus on ognized at a glance.” many factors once considered central but now Developments in laboratory medicine relegated to a contributory role at most, in- brought physicians to something approaching cluding lack of fresh air and exercise, corsets, consensus regarding the pathophysiology lovesickness with its related sexual frustration, of chlorosis.By the mid-nineteenth century, and a variety of uterine disorders. reasonably accurate methods were avail- Chlorosis reminds us of the complex inter- able to determine red-blood-cell counts and action between physiology and social elements hemoglobin content.With this, it became ap- in the genesis of human disease.This interplay parent that the essential condition of chlorosis is better understood in light of current notions was iron deficiency anemia.In the minds of of iron metabolism.To protect the body against many physicians, chlorosis could now be sepa- the destructive effects of excessive iron, intesti- rated from earlier mimics such as lovesickness, nal absorption is fixed at a rate that barely re- hypochondriasis, and neurasthenia. places the small amount lost normally.This bal- The natural history of chlorosis, whether ance is so exquisite that the prolonged loss of treated with iron or not, remained a matter of 2 teaspoons of blood daily exceeds the body’s dispute.In part, this undoubtedly related to fre- ability to absorb iron from a normal diet, and quent misdiagnoses.Using iron, some physi- anemia follows.Iron deficiency anemia can re- cians reported that a single cure was lasting. sult from decreased dietary iron, increased bod- For others, the disease progressed to phthisis, ily demand for iron, or loss of blood. many cases of which probably were tubercu- In chlorosis, decreased iron intake came losis rather than chlorosis.After iron became about either from poverty that precluded the a standard treatment, there was general agree- intake of iron-rich foods or from cultural in- ment that the disease recurred when treatment fluences encouraging young women to avoid was stopped, but responded when iron was rein- meat, eggs, and even milk because of a belief stituted and continued.If patients remained on that animal foods increased sexual drive, an un- the prescribed iron long enough, chronic cases desirable result in Victorian times.The increase responded as well as those newly diagnosed. in bodily demands for iron resulted simply from Some observers might look on the use of iron the rapid growth associated with adolescence. in treating chlorosis before an iron deficiency The green skin-color of chlorosis, from which had been demonstrated as sheer luck, and one it may have derived its name, remains, like more example in the history of medicine where the origin of syphilis, one of the fascinating physicians did the right thing for the wrong problems in the history of disease.The conun- reason.Yet, although there are many examples drum appeared when chlorosis was equated

72 27. Chlorosis with iron deficiency; yet greenish skin in is surprisingly little about chlorosis as such Caucasians was rarely observed in the many in this literature.Marxist and social historians cases of hypochromic anemia then being di- have become interested in chlorosis.These re- agnosed.Another possibility is that chlorosis visionist approaches, to varying degrees, tend was a misnomer, that the word “green” was generally to diminish the importance of patho- used metaphorically to mean immature, raw, or logical physiology in explaining the rise and inexperienced. decline of chlorosis.The more committed the Significantly, green skin was included only revisionists are to their historical biases, the sporadically in clinical descriptions of chloro- more difficulty they have squaring their inter- sis over the years.Lange made no mention of pretations with those of others as well as with it in his original description.In one study of 27 more purely medical explanations.The Marxist, authors who listed signs of chlorosis, only 16 for example, must construct social and politi- mentioned greenish skin as characteristic.In an- cal conditions that produced chlorosis in young other analysis of 19 descriptions, only 3 seemed women of the capitalist class as well as the op- definitely green, 3 possibly so, and 2 yellowish- pressed poor, because the evidence is incontro- green.At least it is now reasonable to remove vertible that the condition affected both. green skin as the outstanding characteristic im- The feminists who would argue that plied by the designation chlorosis. nineteenth century physicians mistreated women consciously on the basis of gender History must account for the fact that many of the The incidence of chlorosis in earlier times is treatments accorded women by male physi- impossible to determine.From the attention it cians at the time derived from an inadequate received in literature as well as art, one may understanding of reproductive physiology and infer that the condition was not rare.By the that masculine sexual conditions were also end of the nineteenth century, it was viewed mistreated.The historian who argues that as extremely common.This conclusion is all chlorosis was nothing more than a cultural the more striking in light of the rapid exit of construction of Victorian family life, that chlorosis from center stage.By 1915, medical physicians diagnosed the condition simply observers were commenting on the disappear- because they expected to encounter it, and that ance of the green disease.Some concluded that young women simply learned to manifest the chlorosis had never been anything but a sim- clinical picture of chlorosis must explain the ple iron deficiency anemia brought on by inad- well-documented existence of the disease in equate diet and loss of menstrual blood. young men as well. But the condition was not that easily dis- Enthusiasm for new historical approaches to missed, as physicians continued to find chloro- disease should not obscure the importance of sis very much alive.In 1969, it was listed as one the final common pathway of social, politi- of five major categories of hypochromic ane- cal, and cultural forces.And that common de- mia considered diseases sui generis.In 1980, one nominator for chlorosis in the nineteenth and student of the illness concluded that chlorosis early twentieth centuries was an iron deficiency was a functional disease intimately related to anemia.Social and cultural factors certainly anorexia nervosa.Current medical dictionar- predisposed individuals to chlorosis, but per- ies still carry the term and define it as an iron sons became patients ultimately because they deficiency anemia of young women. had red blood cells that were too small and Recent revisionist historical work has em- lacked the normal amount of hemoglobin.Poor phasized the importance of general perceptions nutrition – whether from poverty or cultural of women and their role in what physicians preferences – certainly contributed.Physicians, thought and did about disease, although there with their heavy reliance on bloodletting, even

73 28. Cholera prophylactically in pregnant women, undoubt- including Celsus, Aretaeus, and Caelius Aure- edly played a part as well.Chlorotic women lianus used the term as well. By 1669, Thomas gave birth to iron-deficient children – “larval Sydenham employed it in describing an epi- chlorotics” they were called.Chlorosis, at bot- demic in London.“Cholera” was also widely tom, was a deficiency disease. Explaining it his- used to describe endemic or sporadic diarrhea torically demands an eclectic historiography. throughout the nineteenth century and ear- The biopsychosocial model emerging as the lier in Western Europe and the Americas.This proper paradigm for health professionals deal- is sometimes specifically designated as cholera ing with disease in our time has always oper- nostras. ated historically.Ockham’s razor may be useful The term cholera morbus, today limited to in logic, but it may slice too narrowly in history. the disease caused by V. cholerae, can cause Plethora rather than parsimony more often il- confusion because in the past it meant either luminates the complexities of humanity’s inter- epidemic or endemic forms of such illness. action with society at any given time and place. Synonyms include cholera asiatica, cholera epi- Chlorosis is a case in point. demica, malignant cholera, cholera asphyxia, Robert P. Hudson and cholera spasmodica.It is now generally ac- cepted that all cholera in the West prior to the nineteenth century epidemics was endemic or sporadic and not caused by V. cholerae. 28. Cholera Characteristics Cholera is an acute diarrheal disease usually The cholera bacterium, V. cholerae, was seen in accompanied by vomiting and resulting in se- the excreta and intestinal contents of cholera vere dehydration or water loss and its conse- victims by Filippo Pacini and described and quences.The disease is caused by a comma- named by him in a report published in Florence shaped bacterium, Vibrio cholerae, first isolated in 1854.The bacterium can be grown in the lab- in Egypt and Calcutta in 1883.Mortality rates oratory in an alkalinity greater than that toler- have reached up to 70 percent of infected in- ated by most other bacteria.T his characteristic dividuals during epidemics.Cholera has long is of significance for its growth in the human been endemic in India and Bangladesh, from small intestine. V. cholerae survives and multi- where it has spread in periodic epidemics to plies outside the human body in any relatively other parts of Asia and eventually to much of uncontaminated alkaline environment.It does the rest of the world.Most of this spread has not regularly infect animals; its host range is occurred since 1817, when the modern history limited to humans, who can also act as asymp- of the disease outside India begins; it is now gen- tomatic carriers.The bacteria produce a toxin, erally agreed that some seven pandemics have which causes the symptoms of the disease. occurred since its initial spread.The most re- Cholera is spread solely by infected humans, cent began in 1961 and is only now receding. whose excreta may contaminate drinking water The bacterium is disseminated by the so-called and food.This is not a direct-contact infection fecal-oral route as a consequence of sewage and as expected from such diseases as smallpox, and fecal contamination of water supplies and food- communicability was initially a highly contro- stuffs.This indirect transmission long made its versial matter. spread difficult to understand. The spread of cholera in a community de- In the course of history, the term “cholera” has pends first on the appearance of a person, either been variously applied.The word first appears in ill or well, who is discharging the cholera vibrio the Hippocratic corpus and there refers to spo- from his or her intestinal tract, and second on radic diarrheal disease.Later classical writers the state of hygiene, water supply, and sewage

74 28. Cholera disposal in promoting or impeding the transmis- History sion of the bacteria to potential victims.Unsatis- In India, a relatively sparse literature on the dis- factory sanitary facilities were a necessary con- ease serves as a prelude to the modern history dition for cholera outbreaks in Europe and the of true cholera.Modern literature on cholera Americas.Indeed, the history of the control of starts slowly in 1817 and accelerates with its ap- cholera is the history of improved sanitation. pearance in Russia in 1829, Eastern Europe in Current distribution of epidemic cholera is 1831, and Western Europe and North America largely limited to areas in India and the tropi- in 1832. cal Far East, where it persists and occasionally Portuguese explorer Gaspar Correia stated breaks out in areas with contaminated water that in the spring of 1503, many soldiers of Cali- and sewage.Since World War II, it has made spo- cut died of a “disease, sudden-like, which struck radic forays into the Middle East and other Asian with pain in the belly, so that a man did not last regions.In the 1970s, cholera appeared briefly in out eight hours time.” Correia also met cholera Europe, with outbreaks in Naples (more than 30 in an epidemic form in the spring of 1543 in deaths), Barcelona, and Lisbon (more than 2,000 Goa, where the mortality was so great that it cases).One small area of persistent infection ap- was difficult to bury all of the dead.The dis- pears to be the lower bayou country outside of ease was marked “by vomiting, with drought of New Orleans. water accompanying it, as if the stomach were The bacterial infection is limited to the intesti- parched up, and cramps that fixed the sinews of nal tract; no microbes are found to invade the the joints.” body tissues.The low bacterial population nor- The disease was repeatedly described by Eu- mally in the small intestine as well as its high ropeans in Goa in 1563, 1584, and 1585.Re- alkalinity contribute to the cholera vibrio’s abil- ports followed through the rest of the 1500s and ity to survive and grow there, usually in mas- 1600s, including that of the well-known physi- sive numbers.The bacteria adhere to the in- cian Jacobus Bontius in the earlier 1600s, who testinal wall and secrete a toxin that inhibits extended his observations to Indonesia.Notices the absorption of water and electrolytes (salts) of the disease continued to appear into the eigh- from the intestine into the circulation.Failure teenth century, when they were supplemented of this absorption results in the loss and excre- by reports by English medical men (including tion of many liters of fluid in the course of a famed naval doctor James Lind), who provided single day.This loss presents as a massive, de- good descriptions of cholera cases and symp- bilitating diarrhea, which is the major clinical toms in the 1750s and 1760s. feature of cholera.All other symptoms of the In 1781, cholera ravaged British troops in the disease are attributable to water and salt de- Ganjam district of India, requiring the hospi- pletion.These include weakening and finally talization on March 22 alone of no less than loss of pulse, thickening of the blood, suppres- 500 men of a division of 5,000.A report of the sion of urination, loss of tissue fluids giving the incident calls the disease a “pestilential disor- face a sunken appearance, cyanosis, muscular der” and does not name it cholera, although spasms, and a disastrous fall in blood pressure later writers assumed that it was.This outbreak leading to profound shock, which represents the is reported to have reached Calcutta.In April fatal conclusion of the disease. of 1783, “cholera burst out at Hurdwar, and in Modern therapy consists simply of replacing less than eight days is supposed to have cut the lost water and salts.Thus cholera is essen- off 20,000 pilgrims.” Fragmentary observations tially curable.Antibiotics play only a minor role, continued to appear, depicting the “terrible fe- in that they may shorten the duration of disease rocity” of the disease, which “destroyed an enor- and reduce the massive amounts of necessary mous number of people,” and further ravages fluid replacement. occurred at Arcot and Vellore in October 1787.

75 28. Cholera

Cholera, or cholera-like disease, continued to to Aleppo.By 1823, it was in Egypt, Astrakhan, be observed during the rest of the eighteenth and the Caspian shores and throughout Syria and into the nineteenth century.Then, in the along the shores of the Mediterranean.But it year 1814, outbreaks of cholera occurred in receded for a number of years, thereby termi- a number of Indian provinces, including the nating the First Pandemic. crowded barracks of Fort William at Calcutta By 1824, cholera had retreated to its endemic among recruits just arrived from England. area in Bengal, where it remained active in the It may well be that “it was nothing new for Ganges Delta through 1826.But in 1827, it cholera to spread over India in an epidemic form spread out again in the so-called Second Pan- prior to 1817 and 1819.” But at this point, some- demic into the Punjab, and by 1829 extended thing drastically “new” did occur, as cholera es- through Persia to the shores of the Caspian caped the bounds of India and initiated the Sea.Reaching Orenburg in August 1829, it waves of pandemics that were to engulf the soon expanded north and west into Russia.By world.This change in cholera’s pattern of activ- September of 1830, cholera was in Kharkov ity has led a few to conclude that a new disease and Moscow, and began spreading west into arose in Bengal in 1817, a contention that was Bulgaria.During the winter of 1830–31, it per- much debated.More recently, it has also been sisted in the Russian army in Poland, and then suggested that a genetic modification in the mi- in the spring invaded Warsaw and, soon af- crobe was responsible for this supposed change ter, Riga.Meanwhile, cholera was also rag- in cholera’s nature. ing through Mecca and Turkey, reaching Con- In any event, in March 1817, a death from stantinople and Alexandria by July and August. cholera took place in Fort William, but because On August 3, it entered Berlin and Vienna, and it was a solitary case no notice was taken of it.By reached Hamburg by the beginning of October. July, however, outbreaks occurred in several dis- Around the end of October, if not before, it ap- tricts in the Province of Bengal.In July and the peared in England at Sunderland, supposedly following months, Calcutta was affected; 25,000 imported from Hamburg or Riga.Late fall and of its inhabitants were under medical treatment early winter brought a brief respite; observers for the disease, of whom 4,000 died.Thus be- were sent to infected areas, and efforts were gins the modern history of Asiatic or epidemic made to prepare for the coming onslaught amid cholera, although none of the documents im- much argument about such matters as quaran- mediately surrounding the event makes ref- tine, sanitation, contagiousness, and treatment. erence to the name “cholera,” until a letter The opening of the year 1832 was soon fol- dated September 16 specifically refers to cholera lowed by a reawakening of cholera.In Febru- morbus. ary, it appeared in Newcastle, Edinburgh, and Within 3 months the disease had spread London, as well as places in between.Next it throughout the Province of Bengal, and in reached France, bursting on Paris on March November it reached the camp of the Marquis of 24, and soon engulfing all districts of the city. Hastings in Bundelcund.During 1818, it moved Within 18 days no fewer than 7,000 persons over the greater part of India including Delhi were dead.Next, cholera hurdled the Atlantic and Bombay, with estimated attack rates of up Ocean to appear on June 8 in Quebec and on to 7.5 percent of the exposed population. It con- June 19 in Montreal.Presumably, it arrived with tinued to rage through 1819 and 1820, extend- emigrants on the brig Carricks, which left in- ing into Ceylon and Burma, Siam, Malacca and fected Dublin in April and lost 42 of its 173 Singapore, and the Philippines.By 1821, it had passengers before reaching Quebec on June 3. invaded Java, Batavia, and China to the east and On June 23, cholera invaded the United States, Persia to the west, reaching Baghdad with a be- appearing in New York on that date and in sieging Persian army, and extending from there Philadelphia on July 5.From these ports of

76 28. Cholera entry, it marched westward across both North duce one of the worst cholera years on record.It American countries. was during this pandemic that John Snow made Entry into Spain, Portugal, the Caribbean, and his observations in London that in 1855 led to Latin America was delayed until 1833, and into the publication of his critical, if not immediately Italy until 1835. Havana lost 8,253 persons in appreciated, study on cholera transmission by a population of 65,000 between February 26 contaminated water.In 1855 and after, the dis- and April 20, 1833, and by August no less than ease died down in much of the West, but it con- 15,000 had perished in Mexico. tinued in a few spots there as well as in much Yet by 1834, the disease was beginning to of the East. recede, and while it persisted in a number of The Fourth Pandemic is generally dated from Mediterranean and Central American areas for 1863 and lasted 10–12 years.In 1865, an es- a few more years, it retreated once again in 1837 timated one-third of 90,000 pilgrims at Mecca to its Indian homeland.For much of the world, succumbed.As before, cholera reached Con- this pandemic was the first modern experience stantinople and spread around the Mediter- with the disease, and subsequent epidemics or ranean, reaching northern Europe in 1866 and pandemics were to follow much the same route. 1867, and the United States and Latin America Popular and governmental response to subse- in 1866.It raged over its old grounds until 1874. quent appearances was largely based on experi- The Fifth Pandemic is said by many to have ence gained during this pandemic. begun in 1881 and lasted until 1896.It was During the following decade, cholera contin- during this epidemic that the studies of Robert ued to plague India, and it entered with British Koch in Alexandria and Calcutta in 1883-84 troops into Afghanistan in 1839 and China in led to the isolation and identification of the 1840, where it remained into 1841 and 1842. causative microbe. The epidemic was at first In 1844–45, it extended into Persia and Cen- largely limited to the Mediterranean shores of tral Asia, reaching the Arabian coast as well as Africa and Europe, although it later became the Caspian and Black seas in 1846–47.Con- widespread in Russia and in Germany, where stantinople was attacked on October 24, 1847. it was marked by the explosive outbreak in In the spring of 1848, it broke out with re- Hamburg in 1892.Importation into New York newed vigor, advancing as far as a line drawn in 1887 was arrested, but outbreaks did occur through Arabia, Poland, and Sweden, reaching in Latin America.The disease was also widely Berlin in July and Hamburg and Holland by prevalent in the Far East – in China and Japan. September, and then London and Edinburgh in The Sixth Pandemic ran from 1899 through short order.After a short period of comparative 1923.It followed much the pattern of the fifth – rest, it renewed its activity in the spring, reach- largely affecting India, the Near and Far East, ing Paris in March and by now covering much Egypt, western Russia, and the Balkan Penin- the same ground as the earlier epidemic.Mean- sula.Sporadic outbreaks occurred in southern while, in December 1848 cholera had crossed Europe and Hungary in the West and China, the Atlantic to invade New York and New Or- Japan, Korea, and the Philippines in the East. leans, and spread rapidly across the continent But this time cholera did not reach the Western from these centers.In 1850, it reached Cal- Hemisphere. ifornia with wagon trains as well as by ship The Seventh Pandemic dates from about 1961 from Panama.In that year it was reported in and followed much the pattern of the previous North Africa, Europe, and both North and South epidemic.It was particularly important in pro- America.In many of these regions, it continued viding an opportunity for significant advances through 1851 and 1852. in cholera pathogenicity and therapy in studies The year 1854 found cholera widely spread in carried out in Egypt, India, Bangladesh, and the Europe, the Near East, and the Americas to pro- Philippines by several U.S. teams.

77 28. Cholera

This brief sketch provides only the barest out- by Snow of the waterborne nature of cholera line of the history of cholera.Historians do not was slow to gain acceptance, but this devel- always agree on the chronology of the pan- opment, coupled with Koch’s discoveries, fi- demics.In fact, it is sometimes not entirely clear nally proved the “contagion” of the disease, al- why or when one pandemic is said to have ter- beit allowing for the intermediary roles of in- minated and another to have begun. fected excreta, water or food, and of individuals Earlier, thoughts on the causes of cholera who can act as carriers but do not develop the were embedded in notions of disease causation disease. going back to Hippocrates, such as weather, sea- Sanitation has always played a major role in sons, geographic environment, bad air and mi- efforts to understand and control the propaga- asmas, and dietary indiscretions.If an infecting tion of cholera.As a consequence, a large body agent was even envisioned, it was as a vague of literature has been generated on the role and poison or miasma. influences of cholera epidemics on the devel- By the middle of the nineteenth century, how- opment of public-health policies, public-health ever, ideas of a microbial etiology were gaining organizations, and sanitation procedures and ground.In 1849, William Budd and two asso- techniques. ciates described microscopic bodies in cholera The definitive treatment – intravenous fluid excreta and published their findings with illus- and salt replacement – was a long time in de- trations.Frenc h botanist Charles Robin repro- veloping.As early as 1830, German chemist duced the illustrations in 1853.These were seen R.Hermann demonstrated that the change in by the German botanist Ernst Hallier, who at- the blood’s fluid balance was reflected in the tempted to grow microbes from cholera excreta. contents of the cholera excreta.A colleague He published his findings in 1867. injected 6 ounces of water into his termi- T.R.Lewis tried to confirm Hallier’s work in nally ill patients, a treatment that produced Calcutta in 1870, but failed.In the meantime, as a quick, temporary return of the pulse, al- already described, Pacini made his correct but though death nonetheless occurred 2 hours at the time largely ignored observations of the later.In October 1831, Berlin surgeon J.F.Di- actual V. cholerae in 1854.Thus it was left to effenback took the premature step of injecting the genius, persistence, and technical elegance several ounces of whole blood into three pa- of Koch in 1883 to isolate and identify the mi- tients.They died 6 minutes, 2 hours, and 6 crobe and to introduce the modern phase of un- hours later, respectively, the first during vio- derstanding of the disease.It was not, however, lent convulsions.In Britain in late 1831 and until 1959 that the toxin produced by the mi- early 1832, W.B.O’Shaughnessy published pa- crobe was discovered, along with its role in dis- pers suggesting the intravenous replacement of ease causation. salt and water.This led Thomas Latta to try The question of the “contagiousness” of the treatment on patients; he subsequently re- cholera was a matter of heated debate through- ported that 5 of 15 survived.Other attempts out most of the nineteenth century.The followed, with some success, during the 1830s. contagionists were viewed by contemporaries Sporadic trials continued through the century, as archaic, conservative, and even antisocial, but the treatment was not successful until whereas the anticontagionists were seen as Leonard Rogers perfected it in Calcutta in the modern, bourgeois, mercantile, and socially early 1900s.There were a number of techni- responsible.Most of the debate focused on cal problems to be solved first, such as effec- the question of quarantine which, of course, tive sterilization.But with these difficulties re- was anathema to mercantile interests, and the solved, the definitive treatment of cholera was anticontagionists gained ground as the nine- established. teenth century progressed.The demonstration Reinhard S. Speck

78 29. Cirrhosis

29. Cirrhosis 24 per 100,000) in Italy, France, and Germany. Statistics on cirrhosis suffer from uncertain di- Cirrhosis is a chronic disorder characterized agnoses, which are confirmed only by autopsy by liver fibrosis and nodule formation, which or liver biopsy. The prevalence rate of cirrho- produce portal hypertension and hepatocellular sis in autopsies averages 3–4 percent in Europe, failure. Cirrhosis is the end product of progres- 5–8 percent in the Americas, and 1–2 percent in sive liver injury resulting from diverse causes Japan. including toxins, drugs, viruses, and parasites. In the United States, deaths from cirrho- Clinical manifestations of cirrhosis vary with sis rose 71.7 percent from 1950 to 1974. This the underlying disease. In the West, cirrhosis is increase was marked for nonwhite males, mod- a cause of disability and death among middle- erate for nonwhite females, and only slight for aged alcoholic males. Elsewhere, cirrhosis is pre- white males and females. Among U.S. blacks, cir- dominantly an intermediate lesion in the evo- rhosis mortality was similar to or slightly lower lution from chronic hepatitis B infection to pri- than that of the white population before 1955. mary hepatocellular carcinoma. Then the pattern changed rapidly, with blacks experiencing an epidemic of cirrhosis compared Characteristics to the increase in whites. In urban America, cir- Cirrhosis is classified depending on morphology rhosis mortality in the nonwhite population is and etiology. Morphologically, there are three at least double that of the white population. types based on the size of nodules on the liver: Steadily increasing cirrhosis mortality in in- macronodular (greater than 3 millimeters in di- dustrialized nations is linked to increased per ameter), micronodular (less than 3 millimeters), capita consumption of alcohol. During the and mixed micro/macronodular (a mixture of twentieth century, mortality in the United small and large nodules). The appearance of the States, England, and France dropped whenever liver cannot alone differentiate among the many alcohol was prohibited or restricted. A national causes of cirrhosis. Indeed, the etiology is of- doubling of alcohol intake produces a fourfold ten unknown. Alcohol injury is most frequently increase in alcohol-induced disease. Risk of cir- associated with micronodular cirrhosis; other rhosis increases with daily alcohol intake much causes in this category include primary bil- faster in females than in males, and progression iary cirrhosis, primary hemochromatosis, and to severe liver injury is accelerated in women. chronic right heart failure. Macronodular cir- However, the male/female ratio remains at rhosis arises from viral, drug, and cryptogenic least 2:1 for most groups, with some notable origins and appears in any end-stage cirrhosis. exceptions. Cirrhosis is distributed worldwide, affecting In the West, alcoholic damage comprises the all races, nationalities, ages, and both sexes. majority of all cirrhosis. An estimated 75 per- Well over 300,000 persons (probably underes- cent of cirrhosis in the United States is alcoholic timated) die of it annually. The incidence of in origin; 15 percent is viral, and 10 percent cirrhosis chiefly depends on per capita con- is cryptogenic. In Britain, 50 percent is alco- sumption of alcohol and prevalence of hep- holic, 25 percent cryptogenic, and 25 percent atitis viruses. The increase in cirrhosis cases viral. In Asia and Africa, where the prevalence is attributable to an increase in one or both of hepatitis B virus is high and per capita con- of these factors. Based on mortality statistics, sumption of alcohol is low, the proportion of the incidence of cirrhosis is low (less than 10 virus-related cirrhosis to alcoholic cirrhosis is deaths per 100,000 population) in countries reversed from that of the West. However, the such as Canada, England, and Australia; inter- incidence of hepatitis B viral cirrhosis is uncer- mediate (11–23 per 100,000) in Mexico, the tain. Studies strongly support an association be- United States, and Japan; and high (more than tween chronic hepatitis B infection and primary

79 29. Cirrhosis hepatocellular carcinoma. Infection at birth re- est illustrations of cirrhosis was that by Fred- sults in chronic hepatitis, cirrhosis, and carci- erik Ruysch in the early eighteenth century. In noma 20–30 years later. How the virus causes 1716, Giovanni Morgagni introduced the term the carcinoma is unknown, but cirrhosis is in- “tubercle” for any hepatic nodule, which sowed volved, especially among males. Like hepato- confusion between carcinoma and cirrhosis for cellular carcinoma, cirrhosis is common where decades. Matthew Baillie’s accurate description hepatitis B virus is endemic. in 1793 established cirrhosis as a nosological en- Diagnosis of cirrhosis depends primarily on tity; he also strongly associated it with alcohol the two cardinal manifestations; portal hyper- intake. tension and hepatocellular failure. As cirrho- During the eighteenth century, corn sur- sis usually evolves over years, the course may pluses led England’s Parliament to promote spir- be intermittent with therapeutic intervention its in an effort to stabilize grain prices. Exces- or temporary cessation of injury. During the sive consumption of cheap spirits produced an early phase, patients often present with nonspe- epidemic of cirrhosis, popularly known as “gin cific signs including malaise, anorexia, or weight liver” in England and “brandy liver” elsewhere. gain. As the disease progresses, portal hyper- Twenty-five years after Baillie, Rene´ Laen- tension and hepatocellular failure invariably su- nec introduced the name “cirrhosis.” In 1829, pervene. These complications are interrelated Gabriel Andral suggested that hypertrophy of and often represent the initial presentation of the liver’s yellow substance accounted for the many cirrhotics. Cirrhosis can be checked –for nodules, whereas atrophy of the red substance example, in the alcoholic who abstains. Treat- represented the depressed areas of cirrhosis. ment can reverse hepatic fibrosis and improve This concept, relating cirrhogenesis to the dual the outlook for patients with chronic active substance of the liver, influenced thinking on hepatitis, primary hemochromatosis, or Wil- the subject for two decades. In 1838, Robert son’s disease. After ascites develops, however, Carswell conjectured that cirrhosis depended the 5-year survival rate falls below 50 percent. on the growth of interlobular connective tissue. Gottlieb Gluge and Dominique Lereboullet ar- History gued that hepatic fat was the basic lesion of cir- The ancient Greeks recognized clinical features rhosis. Karl von Rokitansky attributed cirrhotic of cirrhosis. About 300 B.C., Erasistratus as- “granulations” to chronic inflammation. sociated ascites with liver disease. Centuries During the mid-nineteenth century, interest later, Galen discussed the physical diagnosis in vascular studies gathered momentum, and and noted the danger of heavy wine consump- the vascular alterations in cirrhosis came un- tion for those already afflicted. His contempo- der scrutiny. Some researchers, such as Karl von rary Aretaeus suggested that cirrhosis evolved Liebermeister in 1864 and J. M. Legg in 1872, from hepatitis, and carcinoma from cirrhosis. continued to focus on interlobular connective The Greeks’ clinical descriptions remained un- tissue. Others emphasized the regenerative as- excelled until recent times. pects of cirrhosis, which represented the end In the sixteenth century, Vesalius described product of many injurious episodes. In 1911, rupture of the portal vein in a patient with Frank B. Mallory introduced the entity of “alco- an indurated nodular liver. When pathologi- holic hepatitis,” identifying it as a precursor le- cal anatomy became a discipline in the sev- sion of cirrhosis. Mallory’s concept was recently enteenth century, sporadic reports of cirrhotic revived after decades of dormancy. livers appeared. In 1616, William Harvey dis- Earlier it had been suggested that alcoholic cussed two cases of cirrhosis, antedating John fatty liver was the precursor of cirrhosis. By Browne, whose 1685 description was long con- the second half of the nineteenth century, most sidered the first in English. Among the earli- physicians accepted this thesis, believing that

80 31. Croup alcohol intake increased hepatic fat, which in penetrate and encyst the skin or muscles of fish, turn was converted into cirrhosis. However, ex- expecially those of the carp family. Humans and periments failed to demonstrate the cirrhogenic other definitive hosts become infected by eat- effect of alcohol in animals. This led to the no- ing the cysts (metacercariae) in raw or poorly tion that not alcohol but some contaminant in cooked fish. Raw fish are a delicacy in many it, such as copper, damaged the liver. Other the- Asian countries, and fish are sometimes raised ories stressed that gastric malfunction was the in ponds fertilized with human feces. Encysted underlying cause in that it produced – or al- metacercaria larvae are resistant to smoking, lowed absorption of – hepatotoxins. Hypotheses pickling, salting, and drying. Imported fish have of nutritional deficiency were bruited when caused human cases in Hawaii, and the popu- 1930s experiments showed that the fatty liver larity of Asian cuisine poses a potential danger condition caused by insulin deficiency was pre- to gourmets far beyond Asia. ventable with choline and other agents. Other Light infections are often asymptomatic. dietary models of cirrhosis soon followed, in- Heavy infections may produce diarrhea, fever, cluding lipotroph deficiency, low-fat diet, and jaundice, and abdominal pain. Bile duct block- vitamin-Edeficiency. However, nutritional the- age and liver abscesses occur in chronic cases, ories declined in popularity when Charles S. and Clonorchis sinensis has been tentatively Lieber (and others) showed in 1968 that alco- linked to liver cancer. hol was directly hepatotoxic in humans and cir- K. David Patterson rhogenic in baboons. Another technical innovation has advanced understanding of cirrhosis. Introduced by Paul Ehrlich in 1884, the liver biopsy later achieved 31. Croup wide use as a diagnostic method. Studies clari- fied the relationships among hepatitis, cirrhosis, The term croup identifies several respiratory ill- and hepatocellular carcinoma. They also helped nesses of children manifested by inspiratory stri- consolidate the various cirrhosis classifications dor, cough, and hoarseness from upper-airway proposed in the past. The recent standardiza- obstruction. Classically, croup was a manifes- tion of nomenclature was proposed by the Fog- tation of diphtheria, but nowadays, many in- arty International Center in 1976 and the World fectious and noninfectious causes of croup Health Organization in 1977. syndromes are recognized. Although long-term Thomas S. N. Chen and Peter S. Y. Chen obstruction in the glottic and subglottic regions can lead to chronic illness, croup syndromes are described here as acute diseases. Most cases of croup today are either laryngotracheitis or 30. Clonorchiasis spasmodic croup.

The Chinese liver fluke, discovered in 1875, General Characteristics is a small worm that parasitizes the bile ducts Acute epiglottitis (inflammation of the epiglot- and livers of humans, dogs, cats, pigs, and sev- tis) is virtually always caused by Haemophilus eral wild animals in China, Japan, Korea, and influenzae type B; rare cases are caused by Strep- Indochina. Estimates indicate that 20 million in- tococcus pneumoniae and Staphylococcus au- dividuals in China alone are infected. Eggs are reus. Laryngitis usually arises from viral agents, laid in the bile ducts, pass in the feces, and, if most importantly adenoviruses and influenza they reach the proper freshwater snail, undergo viruses. Laryngotracheitis and spasmodic croup a series of stages in this intermediate host. Even- are common childhood illnesses caused by tually, free-swimming larvae are formed, which viruses or Mycoplasma pneumoniae. The most

81 31. Croup important agent is parainfluenza virus type 1, tory distress. Hypoxia can occur, and, with no which, along with parainfluenza type 2 and in- intervention, asphyxial death will occur in some fluenzas A and B, causes outbreaks of disease. In children. areas without diphtheria immunization, laryn- gotracheitis is also caused by Corynebacterium Spasmodic Croup diphtheria. Unlike laryngotracheitis, in which obstruction The same viruses that cause laryngotracheitis results from inflammatory exudate and cellu- also frequently cause laryngotracheobronchi- lar damage, obstruction in spasmodic croup is tis and laryngotracheobronchiopneumonitis. caused by noninflammatory edema. Onset is al- Other causes of the latter two include S. au- ways at night and occurs in children thought to reus, Streptococcus pyogenes, S. pneumoniae, and be well or to have a mild cold. The child awak- H. influenzae. ens with sudden dyspnea, croupy cough, and Croup syndromes occur worldwide, most inspiratory stridor. There is no fever. Spasmodic caused by common “croup viruses”: parain- croup tends to run in families; affected children fluenzas 1 and 2 and influenza viruses. Out- often have repeated attacks. breaks occur during cold-weather months, and in the tropics during rainy seasons. The highest Acute Laryngotracheobronchitis and attack rate occurs in children 7–36 months old; Laryngotracheobronchiopneumonitis few cases occur after the sixth birthday. Dur- These illnesses are less common than those dis- ing their second year, about 5 percent of chil- cussed previously but are more serious. Ini- dren experience an episode of croup. Croup is tial symptoms are similar to laryngotracheitis. more common in boys than in girls and also Signs of lower respiratory involvement develop tends to be more severe in boys. A parain- 2–7 days into the illness; occasionally, upper- fluenza infection in an adult is manifested by and lower-airway obstructions occur simulta- a cold; older persons suffering trivial illnesses neously. Along with the usual croup symp- may be the source of severe croup in young toms, laryngotracheobronchiopneumonitis pa- children. tients have rales, air trapping, wheezing, and increased respiratory rate. Acute Epiglottitis This is a disease of abrupt onset, which if un- History treated causes death from airway obstruction. The word “croup” is derived from the Anglo- Illness is characterized by fever, severe sore Saxon kropan (“cry aloud”) and was first used throat, dysphasia, and drooling. Airway obstruc- in medical writing in 1765 by Scottish physi- tion is rapidly progressive and associated with cian Francis Home. Until the twentieth century, inspiratory distress, a choking sensation, irri- virtually all croup-like illnesses were confused tability, restlessness, and anxiety. The child with with diphtheria. epiglottitis insists on sitting up and exhibits The clinical history of diphtheria has been great anxiety if forced to lie down. traced to the time of Homer, and some experts believe that the Hippocratic texts demonstrate Acute Laryngotracheitis knowledge of it. In the second century A.D., Initial symptoms usually include nasal dryness, Aretaeus noted extension of the disease to the irritation, and coryza (profuse nasal discharge). lower respiratory tract, resulting in death by suf- Cough, sore throat, and fever occur. After 12– focation. Galen noted expectoration of the pseu- 48 hours, signs of upper-airway obstruction de- domembrane. In the fifth century, Aetius added velop. The cough becomes “croupy” (sounding his experience. Although both Aretaeus and like a sea lion), and respiratory stridor increases. Aetius were describing diphtheritic croup, con- Severe disease is manifested by marked respira- fusion with other illnesses – such as Ludwig’s

82 32. Cystic Fibrosis angina and streptococcal tonsillitis – clearly 32. Cystic Fibrosis existed. The historical trail of diphtheria disappeared Cystic fibrosis, also called “fibrocystic disease of in the fifth century and failed to reappear un- the pancreas” and mucoviscidosis, is a genet- til the sixteenth. In 1557, Peter Forest described ically determined disease of infants, children, an epidemic in Holland. In 1576, Guillaume and young adults. Most of its many manifes- de Baillou reported an epidemic in Paris and tations result from abnormally viscous mucus, specifically mentioned false membrane. In 1771, which interferes with pulmonary function, and Samuel Bard published the first U.S. report on insufficient production of pancreatic digestive suffocative angina. In 1826, Pierre Bretonneau enzymes, which causes nutritional deficiencies named diphtheria and recognized its infectious and developmental retardation. nature. In 1883, Edwin Klebs observed the diph- theria bacillus, and a year later Friedrich Loffler¨ Characteristics established it as the etiologic agent. Among Caucasians, cystic fibrosis (CF) is the From 1920 to 1940, the incidence of diph- most common fatal disease having an autoso- theria in the United States fell steeply because mal recessive inheritance. Despite the primary of the use of first toxin-antitoxin and then tox- involvement of several organs, the disease is oid. In association with and also predating this caused by a single defective gene that is located decline, a general realization of other cases of on chromosome 7 and is carried by about 4 per- croup occurred. Prior to 1900, only occasionally cent of the Caucasian population. Its expression were illnesses suggesting nondiphtheritic croup is similar in both sexes. specified. For example, in 1852 E. Bouchut de- CF manifests itself at birth in about 8 percent scribed false croup (possibly spasmodic croup). of cases through mechanical obstruction of the In 1887, A. Sanne´ mentioned an epidemic of small intestine by the secretion of abnormally simple croup in Germany, and in 1765 Home viscous mucus (meconium ileus). Symptoms of noted two forms of croup. Bretonneau dif- insufficient secretion of exocrine (noninsulin) ferentiated diphtheria from spasmodic croup digestive enzymes by the pancreas appear dur- in 1826. ing the first year of life in 90 percent of cases. During the first half of the twentieth century The development of such symptoms indicates in the United States, severe croup was called that pancreatic function is less than 10 percent laryngotracheal-bronchitis and understood to of normal; and the more severe the deficiency be caused by C. diphtheria – and by other bac- of pancreatic enzymes, the more severe the fecal teria as well. In 1948, Edward Rabe described excretion of undigested fat, usually as diarrhea. three forms: diphtheritic croup, H. influenzae As much as 80 percent of dietary fat may be lost. type B croup (epiglottitis), and virus croup. Loss of undigested nutrients can be corrected Soon, the viral etiology of croup was confirmed. only partially by treatment with pancreatic en- But croup resulting from bacteria other than zyme tablets. C. diphtheria was overlooked. In 1976, nondiph- Pulmonary disease is responsible for most theria/bacterial croup was rediscovered and has debility and mortality. Onset occurs during the since received considerable attention. first 2 years of life in at least 75 percent of cases, The history of spasmodic croup is unclear and by age 6 in most others. The initial pul- because its clinical and pathological aspects monary abnormality is obstruction of the small are poorly defined. In the 1940s, Francis Davi- bronchi by abnormally thick mucus. Structural son distinguished it from other forms; since deterioration of the lungs results and is exac- then, however, this entity has received little erbated by an increased susceptibility to infec- attention. tions. A few patients retain sufficient pancreatic James D. Cherry function to maintain nearly normal digestion;

83 33. Cytomegalovirus Infection such patients also tend to have fewer respiratory The CF gene was identified in 1989. With difficulties. The variability in severity results the rapid advances in gene-transfer therapy, it from different mutations on the pathogenetic may soon become possible to correct the de- gene. fect. Then, instead of merely prolonging life by The sweat of a child with CF contains a con- treating the symptoms, physicians may give CF centration of sodium chloride about five times infants a normal future. greater than normal, although salt is not lost ex- Thomas G. Benedek cessively by other routes. Determining the salt content of perspiration has become a basic di- agnostic test. The propensity to become salt- depleted makes persons with CF particularly in- 33. Cytomegalovirus Infection tolerant to heat. As a result of pulmonary and metabolic therapy, many CF patients are now Cytomegalic inclusion disease (CID) usually living into reproductive age, and thus it has occurs as a subclinical infection with periodic been found that CF men, but not CF women, are reactivation revealed by shedding of the virus. sterile. In spite of all efforts, few patients survive It may be serious in the neonate when infec- to age 40. tion is transmitted to the fetus in utero. Cytome- galic infection is characterized histologically by History the presence of large cells containing inclusion According to a medieval German saying, “The bodies in the midst of an infiltration of mononu- infant who when kissed leaves a taste of salt clear cells in any of the body organs. will not reach the first year of life.” Hence, CF was probably recognized many centuries ago. Characteristics However, it was first identified in 1936 by Swiss In prenatal infections, most infants are born pediatrician Guido Fanconi and associates and without clinical evidence of disease, although further delineated in 1938 by Dorothy Ander- some 10–15 percent may show micro- sen. The diagnostic perspirational salt loss was cephaly, mental/physical retardation, hep- quantified by Paul di Sant’Agnese and associates atosplenomegaly, jaundice, and calcifications in 1953. in the brain. There may be abnormalities in liver CF is most prevalent among people of central function tests and hematopoiesis. Some 10–30 European ancestry (1 in 2,000 to 3,000 births) percent of infants with symptomatic disease die and is somewhat less common in Scandinavia. in early life. Central nervous system involve- Inbreeding explains incidences of greater than ment can develop early – even though the 1 per 1,000 in small areas. For example, the child appears normal – and is manifested as im- prevalence of CF among nearly 11,000 Amish paired intellect, neuromuscular abnormalities, in one Ohio county was more than 1 per 600 chorioretinitis, optic atrophy, or hearing loss. (all cases within six families), whereas there Neonatal infection acquired at birth from were no cases in another Amish community an infected cervix or later from mother’s milk in a nearby county. Similar results of inbreed- usually goes unnoticed but can be identified ing have been reported from Brittany and from by the development of antibodies. Respiratory Afrikaners in Namibia. CF has been reported in symptoms including pneumonia, as well as pe- about 1 in 17,000 black Americans, and in 1 in techial rash and enlargement of the liver and 90,000 Orientals (mainly Japanese) in Hawaii. the spleen, may occur. In these cases, however, The prevalence of CF has not been investigated acute involvement of the central nervous sys- adequately in Asia and Africa. It is possible that tem is rare. its true prevalence is masked by high infant Infection in children is generally asymp- mortality in large portions of these continents. tomatic and evidenced only by development of

84 34. Dengue antibodies and shedding of virus. Occasionally, by childbearing age. In England, studies show hepatosplenomegaly and abnormal liver func- seropositivity in 50–80 percent of children in tion are found. There is no proof that pharyn- boarding schools and orphanages compared gitis occurs at the presumed portal of entry. to 10–20 percent of children attending day When infection occurs in adults, the clini- schools. In Puerto Rico, 70–80 percent of adults cal picture is similar to infectious mononucle- have antibodies, whereas in London the figure is osis: pharyngitis; lymphadenopathy; systemic only 50–60 percent. Studies in the United States symptoms of fever, chills, and headaches; and and Britain show that from 0.2 to 7.5 percent of occasionally a maculopapular rash are primary newborns are virus positive, making this disease symptoms. Atypical lymphocytosis is usual, the most common fetal infection. and there may be abnormal liver function. Antibodies develop upon infection to last for In instances where the disease is transmit- life. Nevertheless, as in other diseases caused by ted by transfusion of blood or its products, the herpesviruses, the presence of circulating the infectious mononucleosis syndrome usu- antibodies – even in large amounts – does not ally appears as a posttransfusion episode in 2– forestall recrudescences of infection. 4 weeks. Immunocompromised patients are at special risk of exogenous infection by trans- History planted organs or transfusions, or of activation Early in the twentieth century, pathologists of the latent state. Death may occur from inter- noted enlarged cells with inclusion bodies in stitial pneumonia, often complicated by super- organs of children dying of presumed con- infection with gram-negative organisms, fungi, genital syphilis. The inclusions were thought or other unusual invaders. to be amebas. In 1921, noting a similarity Studies show that CID has worldwide distri- to changes found in varicella, researchers bution. It remains asymptomatic despite pro- guessed the inclusions represented viral infec- longed shedding at periodic reactivation and tion and described the cellular enlargement as is not highly communicable. Presumably, the “cytomegaly.” The virus was isolated in 1956 virus is spread mainly by oral secretions, be- by investigators working independently in St. cause it is shed from the salivary glands. The Louis, Boston, and Bethesda. Epidemiological virus has been isolated from urine, breast milk, studies became feasible with the recognition of semen, and cervix uteri: It may therefore be sex- antibodies in 1968. Rapid expansion of knowl- ually transmitted. edge of its epidemiology, incidence, and clinical The most serious aspect of CID is as a manifestations continues. prenatal disease. Even though the mother is R. H. Kampmeier asymptomatic and immune, transmission of virus to the fetus occurs. Recurrence in the mother is the most probable explanation for pre- natal infection, although, of course, primary in- 34. Dengue fection may occur during pregnancy. Evidence suggests that infection in the offspring is more Dengue is an acute disease caused by infection serious in the latter case than the former. One with an arbovirus of four serotypes, transmit- study has shown that children infected in day- ted by infected Aedes aegypti and Aedes albopic- care centers may be the source of infection for tus mosquitoes. Endemic throughout the tropics pregnant mothers. and subtropics, uncomplicated dengue is rarely With a disease spread mainly by oral secre- fatal, although convalescence may take several tions, higher incidence is anticipated in crowded weeks. Sometimes, however, it is complicated and unhygienic surroundings. For example, 100 by hemorrhagic manifestations (hemorrhagic percent of Tanzanian women have antibodies dengue) and circulatory collapse (dengue shock

85 34. Dengue syndrome) with a potentially fatal outcome un- and two possible members. Most flaviviruses less medical facilities are available. are arboviruses, and all are serologically inter- related. They infect a wide range of vertebrate Characteristics hosts, causing asymptomatic infections and dis- Typical uncomplicated dengue incubates for 3– eases such as yellow fever, dengue, and numer- 15 days and is characterized by abrupt onset ous encephalitides. of chills, headache, lumbar backache, and se- A. aegypti and A. albopictus are responsible for vere prostration. Body temperature rises rapidly, dengue transmission in Asia. A. albopictus has ◦ as high as 40 C; bradycardia and hypotension recently been discovered in the United States accompany the fever. Conjunctival infection, and Brazil, but it has not yet been implicated lymph-node enlargement, and a pale rash, espe- in the transmission of disease. It is an aggres- cially on the face, are usually present during this sive, human-biting mosquito with both urban phase. In classical dengue, the fever lasts 48–96 and rural habitats and transmits dengue viruses hours initially, subsides for 24 hours or so, and transovarially (from female mosquitoes to their then returns (“saddle-back” fever), although the offspring through infection of the eggs) and peak temperature is usually lower in the second from person to person. Populations of A. al- phase. A characteristic red rash appears, usually bopictus found in the United States are capa- covering trunk and extremities but sparing the ble of overwinter survival in northern latitudes. face. The fever, rash, and headache are known Although recent outbreaks of dengue in Brazil as the dengue triad. have been atrributed to A. aegypti, the presence Hemorrhagic dengue usually strikes children of A. albopictus gives rise to serious concern that under 10 and has its highest mortality in infants it may become an important vector for the in- under 1. It is more likely to occur when type 2 troduction of flaviviruses into areas previously dengue virus infection follows an earlier type 1 free of them. infection or when subgroup-specific antibod- Infection with one dengue serotype confers ies have been acquired transplacentally from an long-lasting type-specific protection, a benefit immune mother. Signs of this complication in- that may be more apparent than real because clude sudden collapse with a rapid pulse of low the type-specific protection also brings a greatly volume; cyanosis of lips, ears, and nail beds; increased susceptibility to severe dengue dis- and cold, clammy extremities while the trunk ease in the event of infection with dengue virus remains warm. Nosebleeds, spontaneous bruis- of another serotype. Epidemiological studies ing, prolonged bleeding from injection sites, and clearly link the severe forms of dengue disease bleeding from both upper and lower gastroin- to previous dengue infection and to transpla- testinal tract signals gross disturbance of blood- cental acquisition of maternal dengue antibody. coagulation mechanisms. This phenomenon has important implications The word dengue comes from the Spanish, a for the development of dengue vaccine, which homonym for the Swahili Ki denga pepo (a sud- carries a serious risk of predisposing partially den cramplike seizure caused by an evil spirit); it immune populations to further and more seri- was introduced into English medical usage dur- ous disease. ing the Spanish West Indies epidemic of 1827– Dengue literally girdles the globe, with a dis- 28. The synonym “breakbone fever” dates from tribution approximately equal to that of A. ae- Philadelphia in 1780, and the term knokkel- gypti. Areas of dengue endemicity include trop- koorts comes from Batavia about the same year. ical and subtropical regions of the Americas, Dengue viruses belong to the family of fla- Africa, Asia, and Australia. There are areas of viviridae (from Latin flavus or “yellow,” refer- A. aegypti infestation in Europe and the south- ring to yellow fever). The family consists of the ern United States, where dengue has caused epi- genus Flavivirus, which has 65 related species demics in the fairly distant past, but which have

86 34. Dengue no current dengue activity although they re- caught it himself. His illness began with pain in main susceptible to its reintroduction. the joints of his right hand and arm and rapidly Dengue fever epidemics typically involve progressed to include high fever within a few large numbers of people and have high attack hours. He concluded his account by remarking rates. Up to 75 percent of susceptible persons that the disease was well known in Batavia but exposed will acquire the disease. Mosquitoes had never before reached epidemic proportions. remain infectious for life; therefore, a sin- That alone would serve to distinguish knokkel- gle mosquito can infect a number of people. koorts from dengue, given what we know of the Recurrent outbreaks of dengue in the same epidemiology of the latter. geographic region indicate either that new Patrick Macdowall participated in the Darien dengue virus types have been introduced or Scheme, an attempt to found a Scottish colony that endemic types are now affecting groups in 1699 on the Isthmus of Panama, then known of the population lacking immunity – generally as Darien. The colonists were ravaged by dis- those born since the last epidemic. ease, and Macdowall, who kept a journal that is Dengue hemorrhagic fever is especially fre- still preserved in the National Library of Scot- quent in Southeast Asia, where it is among land, gave an excellent description of his own the leading causes of hospital admissions in illness, which could well have been dengue. children and the commonest cause of death Macdowall survived an acute febrile illness last- from communicable disease at any age. Its first ing 4–5 days that was characterized by nau- reported appearance in epidemic form in the sea, vomiting, prostration, headache, disordered Western Hemisphere came in 1981. sensation of taste, bone and joint pain, general- Worldwide increase in dengue activity ap- ized rash, and faintness. His convalescence was pears to be directly related to a failure to con- prolonged and marked by general weakness and trol mosquito populations effectively, to over- a continual tendency to faintness. population, to progressive urbanization, and to Was Macdowall’s illness dengue? Classical the social and political disruptions caused by saddleback fever occurs in only 50 percent of wars. Although a jungle cycle (involving forest cases, and even lymphadenopathy is not an in- mosquitoes and wild monkeys) similar to that of variable finding. Macdowall’s personal case his- yellow fever has been demonstrated, zoonotic tory may well be the earliest recorded descrip- acquisition of dengue does not appear to be tion of dengue. a factor in the general pattern of increasing The importance of mosquitoes in the trans- prevalence. mission of dengue was recognized early in the twentieth century when T. Bancroft, using hu- History man volunteers, proved that dengue could be Dengue has been known as a distinct disease transmitted via the bite of infected mosquitoes entity for several centuries. Benjamin Rush is and that the infecting agent was neither an traditionally given credit for historical priority intracorpuscular parasite nor a bacterium, but with his account of “breakbone fever,” the epi- an ultramicroscopic organism. His observations demic that afflicted Philadelphia in 1780. Al- also incriminated A. aegypti as the likely vector, though his work is generally accepted as the but he erroneously concluded that the dengue first modern medical account of dengue, claims organism lives only for a few days in infected have also been made on behalf of David Bylon, mosquitoes. This, however, should not detract a Dutch physician who described an epidemic from the credit due him for recognizing the viral of knokkel-koorts (“knuckle-fever”) in the Dutch etiology and mosquito transmission of dengue East Indies in 1779. long before Albert Sabin cultivated the virus in Bylon, state surgeon to the city of Batavia, his late-1940s laboratory. Proof that A. albopic- treated 89 patients for knokkel-koorts and then tus is a vector of dengue came in 1931 when

87 35. Diabetes

James S. Simmons published experimental stud- History ies on dengue in the Philippines. As early as the sixth century, Hindu physi- The general pattern of dengue since World cians recognized diabetes and attributed it to War II has been of increasing prevalence and dietary indiscretion. Early descriptions of the severity within the context of unrestrained pro- classic symptoms of diabetes included the most liferation of its vectors. Today those vectors that salient – excessive urination. The term diabetes, spread yellow fever as well as dengue pose a real meaning “to run through,” was first used by Are- threat to humanity. taeus. James McSherry In 1679 Thomas Willis noted the sweet taste of urine from diabetics, and in 1776 Matthew Dobson measured the amount of sugar in the urine by evaporating it and weighing the dried residue. Dobson stated that this residue looked 35. Diabetes and tasted like “ground sugar.” Subsequently, glycosuria (sugar in the urine) became diagnos- Diabetes mellitus (DM) is an endocrine disorder tically important and was used to measure the characterized by the lack or insufficient produc- effectiveness of treatment of DM. In 1815, M. D. tion of insulin by the pancreas. DM has been Eugene` Chevreul published his discovery that recognized as a disease for at least two millen- glucose is present also in the blood of diabetics. nia, but only since the mid-1970s has there been From the mid-1700s until the 1970s, many a consensus on its classification and diagnosis. types of diabetes were described. Observations The primary diagnostic criterion for DM is el- by Apollinaire Bouchardat, culminating in his evation of blood glucose levels during fasting 1875 book on glycosuria, clearly distinguished or at 2 hours following a meal. Normal plasma two types of diabetes: In type I, the patients were glucose values for adults in the fasting state are relatively young; the onset was acute, weight 80–120 milligrams per deciliter (mg/dL). Def- loss was striking, and death ensued rapidly. In inition of unequivocal DM requires a 2-hour type II, the patients were older and tended to be postingestion plasma glucose level equal to or overweight, and the onset was slower. Some of greater than 200 mg/dL for the appearance of these individuals could control their glycosuria classical symptoms of diabetes. These symp- with a low-carbohydrate diet. toms, which include excessive urination, urine Much of the early work focused on eluci- containing sugar, hunger, thirst, fatigue, and dating the causes of polyuria. John Rollo, in weight loss, are common to all types of DM. the late 1790s, studied an obese diabetic pa- Despite the use of a plethora of different terms tient at the Greenwich Naval Hospital. He noted in the past, diabetes is now generally classified that the amount of urine excreted depended as type I DM (insulin-dependent diabetes) and upon the food consumed. Urinary production type II DM (non-insulin-dependent diabetes). increased after ingestion of vegetables and de- Other variants of DM include maturity-onset creased when the diet was high in animal fat diabetes of youth, tropical diabetes, which and protein. These findings shifted the focus shows characteristics of both insulin depen- from the kidneys to the gastrointestinal tract dence and nondependence, and gestational di- and provided a scientific basis for therapeutic abetes, which occurs during the latter part of diets high in fat and protein and low in carbo- pregnancy. hydrates. Approximately 90–95 percent of all diabetics Mid-nineteenth century autopsies revealed may be classified as type II, and about 5 percent no abnormalities in the pancreata of diabetics. as type I. Some 2 percent of diabetics have DM In 1855 French physiologist Claude Bernard dis- as a secondary result of other disease or injury. covered that the liver secretes glucose. Such

88 35. Diabetes

findings led some to believe that a liver dis- ulations that previously showed low rates. ease caused diabetes. Attention was redirected Increases are particularly marked among to the pancreas in 1889 when it was demon- Japanese, black Africans, and black Americans. strated that complete removal of the pancreas In general, these increases are associated with a did cause diabetes in dogs. “Westernization” of lifestyle since World War II. Specialized “heaps of cells” had been identi- Some nutritional factors have been suspected fied in the pancreas by Paul Langerhans in 1869. of being involved in the etiology of type I di- Continued research in the 1890s demonstrated abetes, although there is no consistent picture. that these “islets of Langerhans” were the source Excess caloric intake does not seem to be the im- of an “internal secretion” that regulated glyco- portant factor it is in type II diabetes. The range suria. This work suggested convincingly that of nutritional factors implicated in type II dia- DM is caused by a disorder of the endocrine betes is much greater and is discussed below. portion of the pancreas. In 1921, the internal se- Non-Insulin-Dependent Diabetes (Type II) cretion was isolated and named insulin. Insulin Between 90 and 95 percent of all diabetics have is largely responsible for the control of blood type II diabetes and are over the age of 35 glucose levels. years. In contrast to type I, many cases (up to Although insulin was first used in 1922, it was 50 percent) remain undiagnosed. Type II diabet- not until the 1950s that appropriate bioassays of ics produce insulin but may require more than human insulin were developed. These measure- they produce themselves. The majority of pa- ments clearly showed that type I diabetics pro- tients are treated with dietary modifications, of- duced no insulin at all, whereas type II diabetics ten with caloric reductions for weight loss, and produced varying amounts of insulin. Thus in- with oral hypoglycemic tablets. Many causative sulin therapy against type I DM was vindicated. factors have been implicated in type II diabetes. Diet, exercise, and – after 1955 – oral hypo- Genetic mechanisms interacting in complex glycemic agents were prescribed against type II ways with environmental factors are involved diabetes. in the risk for type II diabetes. Type II DM oc- Insulin-Dependent Diabetes Mellitus (Type curs more frequently in families in which one I) Insulin-dependent DM is characterized by or more members have DM than in the gen- clinically acute onset, usually at an early age, eral population. Yet family studies have not sup- reduction in the production and excretion of ported a simple mode of inheritance. insulin, weight loss, thirst, frequent urination, Both age and sex are risk factors for type and high levels of blood sugar. After the on- II diabetes. In most affluent societies, the rate set, remission may occur in some cases for up of diagnosed type II diabetes increases steadily to 15 months. After this period, all patients re- from 30 to 60 years of age. The extent to which quire insulin therapy to prevent the profound physiological aging is a risk factor is unknown. biochemical aberrations that can lead to death. Many observations have been made on sex dif- Typical type I diabetes is uncommon, affect- ferences in the frequency of type II diabetes. ing less than 0.5 percent of the world’s popula- Before 1900, diabetes was observed to be more tion. There is strong evidence for a genetic sus- frequent in men in both Europe and the United ceptibility, but of those individuals who carry States. Since 1930, however, clinicians in both the suspected antigens, only 30–50 percent de- America and Europe have repeatedly observed a velop DM; thus, environmental factors also ap- greater frequency in female diabetics. Nonethe- pear to have a role. Other possible causative fac- less, many developing nations show a male tors include infectious viruses such as mumps, predominance. Groups with a high male/female rubella, and meningitis. ratio include rural Africans, Hong Kong Chi- A number of studies indicate an increased nese, and populations in Iraq, Jordan, Japan, prevalence of type I diabetes among pop- Korea, India, and Pakistan. Populations with

89 35. Diabetes predominance of females include the United Researchers focusing on complex carbohy- States, the Caribbean countries, Sweden, Bel- drates (such as potato and wheat bread) have gium, the former Soviet Union, Thailand, and shown that these starches engender production South Pacific countries. of high levels of insulin and glucose. In fact, the Exercise seems to be a potent protective fac- glucose response to white potatoes and dextrose tor in diabetes. It enhances both carbohydrate sugar was approximately the same. metabolism and the efficient use of insulin. As It has been suggested that dietary fiber de- early as 1893, it was noted that active men creases the risk for diabetes, and different forms in India had a lower rate of diabetes than of fiber are being investigated in this connec- their more sedentary counterparts. Overall, a tion. However, it is difficult to disentangle the decrease in energy expenditure has been related effects of decreased fiber consumption from to changes in lifestyle, a relationship that has increased sugar and carbohydrate intake, in- been particularly well documented in the South creased total calories, total fat, decreased caloric Pacific. Unfortunately, quantitative data on ex- expenditure, and stresses associated with rapid ercise are limited, and the short- and long-term dietary change and modernization. Thus, there effects of exercise on carbohydrate metabolism remain many unanswered questions. are incompletely understood. Dietary fats have also been viewed as risk fac- Abundant worldwide evidence associates tors, although studies investigating fat intake obesity with type II diabetes, and experts have are often inconclusive. Fats are denser in calo- concluded that it is the most powerful risk factor ries than other nutrients, and high fat intake is for non-insulin-dependent DM. Between two- generally associated with low fiber intake. An thirds and nine-tenths of individuals may be important 1930s study presented evidence pos- classified as obese at the time of diagnosis of itively linking fat consumption to diabetes. Yet DM. The association between obesity and di- other observations have not supported this re- abetes was noted long ago, but modern con- lationship. Furthermore, evidence challenging cern with obesity began in 1921. Overwhelm- any such relationship is found among Eskimos ing data showed diabetes rates to be 6–12 times living a traditional lifestyle with diets high in greater in obese than in lean individuals. More fat and protein yet suffering little from DM. recent studies documented high frequencies of Alternatively, protein deficiency in the trop- both obesity and diabetes among a number of ics has been implicated in certain types of Amerindian tribes in Oklahoma and in Latin diabetes. American populations. Yet it does not hold true for all peoples. Tropical Diabetes High caloric intake and low caloric expendi- A type of diabetes found primarily in many trop- ture are both related to obesity. Diabetes rates ical areas of the world has characteristics of both have increased in a number of countries, such type I and type II. The clinical profile involves as Japan, Taiwan, Haiti, New Guinea, and parts the following: (1) a different genetic pattern of of Africa, where caloric consumption per capita diabetes than in temperate regions; (2) a low has also increased. Conversely, during World prevalence rate of type I DM; (3) a younger age War I and II in Europe and during World War II of onset of type II; (4) a sex ratio with male in Japan, when caloric intake was markedly de- predominance in India and Africa, but female creased, obesity and diabetes both declined. predominance in the West Indies; (5) an asso- Most researchers agree that there is no con- ciation of low calorie and protein intake with vincing evidence that a single dietary compo- underweight diabetic individuals in Old World nent increases the risk of diabetes. Furthermore, areas but overweight individuals in the West- the distinction between simple and complex ern Hemisphere; (6) the predominance of dia- carbohydrates has been questioned recently. betes in urban areas, with the exception of rural

90 35. Diabetes populations in the West Indies; and (7) intermit- therefore, permits a more accurate picture of tent need for insulin therapy. worldwide prevalence. Type II DM is a chronic Information is relatively sparse on the ge- disease with generalized symptoms; therefore, netics of diabetes in tropical countries. Recent many cases are not diagnosed. However, rates studies have shown great population variability of type II do appear to be increasing in develop- in increased susceptibility to diabetes. Genetic ing nations. Generally, investigators have been studies of Indian populations suggest a stronger cautious in interpreting an actual increase in familial factor among them compared to diabet- the incidence of insulin-dependent DM. Preva- ics in other populations. lence rates continue to rise because of increased Risk factors for tropical diabetes involve longevity of individuals with type I diabetes. In- unique dietary items. For example, some types cidence rates for type II diabetes vary exten- of cassava (manioc) may be toxic and produce sively by age and sex for different populations. pancreatic damage. However, many areas show In general, the incidence increases with age for high rates of diabetes in populations that do not both males and females until the sixth or sev- consume cassava, and some populations have enth decade of life. high cassava consumption and low rates of di- Diabetes is among the top 10 causes of death abetes. In Kenya, a local alcohol called changaa in developed countries. In Western countries, is implicated in causing the disease. Finally, DM ranks seventh as a cause of death. Data in most tropical areas carbohydrates constitute since the early twentieth century document a 70–80 percent of total calories, and such a diet decrease in early diabetes mortality because is implicated in classic malnutrition diabetes of increasing sophistication in therapeutic ap- because of low nutrient density and high fiber proaches, particularly the wide-scale use of content. insulin. Migrant populations have been prone to high Gestational Diabetes rates of diabetes. For example, Jews have shown A type of diabetes present only during preg- increased susceptibility to diabetes in European nancy was noted in 1882. However, it was not enclaves as well as in migrant groups. Jews in until the 1940s that the term “gestational dia- New York City had rates 10 times higher than betes” appeared in medical literature. This form other U.S. ethnic groups. Studies from the early of the disease is difficult to distinguish from 1900s show high rates of diabetes among Jews type II diabetes because a woman could have in Budapest, Bengal, Boston, and Cairo. Others diabetes before pregnancy but not have it diag- have shown that Sephardic Jews in Zimbabwe nosed until pregnancy. Babies born to diabetic and Turkey have high rates of diabetes. mothers usually are large but may have imma- Early reports for Chinese populations indicate ture organ systems, in which case they may not a very low prevalence of diabetes, and one re- survive. searcher in 1908 observed that none of his col- In general, cities in the United States report a leagues had ever seen a case of diabetes in a higher prevalence of gestational diabetes than Chinese patient. In modern China, rates remain do European cities. The highest reported rate very low. Most authors conclude that the Chi- of gestational diabetes occurs among the Pima nese have a reduced susceptibility to diabetes, Indians of Arizona, who also have the highest although rates are somewhat higher in immi- prevalence of type II diabetes of any known grant Chinese populations outside China. The population. Japanese also show a very low prevalence of di- abetes in their native country, but their rates of General Characteristics DM increase with migration. Because of its acute onset and obvious symp- Amerindians, in particular, have very high toms, type I diabetes is readily identified and, rates of diabetes. The highest rates occur among

91 36. Diarrheal Diseases (Acute) the southwestern Indian groups. Yet high rates associated with rural-to-urban migration result among Amerindians appear to be recent. Early in higher relative risks for type II diabetes. reports indicated very low prevalence of dia- The foregoing data indicate that we may an- betes among North American Indian groups at ticipate an increase in the worldwide prevalence the turn of this century. Moreover, rates among of DM. The focus has been and remains on treat- South American Indian groups still tend to be ment of hyperglycemia and the vascular com- low. plications of long-term diabetes. Using epidemi- Other aboriginal groups also seem to be par- ological data and historical perspectives, we are ticularly prone to diabetes, among them Poly- beginning to develop better programs aimed at nesians and Micronesians. Rates are somewhat early intervention and prevention. lower among Melanesians. Hawaiians have a di- Leslie Sue Lieberman abetes rate seven times higher than Caucasians in Hawaii. Among New World black populations in the West Indies and in the United States, there is a high prevalence of type II diabetes, 36. Diarrheal Diseases (Acute) particularly among women. Studies have also found high rates of diabetes among Mexican Acute diarrhea is the sudden onset of pas- Americans. sage of a greater than usual number of stools One explanation of the high frequency of with decreased form. It is generally accompa- type II DM among these populations is that nied by other symptoms such as fecal urgency, they developed a highly efficient carbohydrate tenesmus, abdominal cramps, pain, nausea, and metabolism under traditional lifestyles of a vomiting. In most cases, the symptom complex feast and famine cycle. The thrifty mechanisms results from intestinal infection by a viral, bac- of carbohydrate metabolism, however, became terial, or parasitic enteropathogen; occasion- detrimental with rapidly changing lifestyles as- ally it is secondary to ingestion of a microbial sociated with a decrease in physical activity, an exotoxin. increase in energy in the diet, a reduction of di- etary fiber, an increase of refined carbohydrates, Characteristics and an increase in psychosocial stress. Acute diarrhea is hyperendemic in certain pop- Among Asian Indians, diabetes rates are low. ulations: youngsters in developing countries; Diabetes is more prevalent among urban pop- visitors to developing regions; military popu- ulations, the rich, and the professional classes. lations in tropical areas; and toddlers who are In Indian men there also is a north-to-south not toilet trained and are attending day-care gradient of diabetes prevalence, with thrice the centers. Diarrhea rates in children less than 5 prevalence in the south. Yet like other migrants, years of age in developing countries range be- Asian Indians migrating to other countries show tween three and seven episodes per child each high prevalence rates compared to indigenous year. The rate for non-toilet-trained infants in populations. Indians in South Africa, in particu- day-care centers in urban areas of the United lar, were brought over as indentured servants States is comparable to rates seen in develop- and had a lifestyle not dissimilar to that of ing countries. “Travelers’ diarrhea” occurs in New World black populations. A diabetes-thrifty 20–40 percent of persons visiting high-risk ar- genotype may have developed in these popula- eas. In all populations, acute diarrhea occurs tions as well. less commonly in older children and adults than Among black Africans, DM is still compara- in infants. tively rare. Nevertheless, increased prevalence The ultimate source of most enteric has been noted for urban Africans. Apparently, pathogens is infected humans, yet for selected for susceptible genotypes, the lifestyle changes organisms, animals may serve as a reservoir.

92 36. Diarrheal Diseases (Acute)

Environmental factors play an important role The synergy between malnutrition and diar- in disease endemicity. Although microbial rhea is an important reason why death from di- contamination of water may be responsible for arrhea is so common in developing countries. exposure to diarrhea-producing organisms, the Diarrheal illnesses contribute to malnutrition: A availability of adequate water for personal and 20–60 percent decrease in caloric intake occurs environmental cleansing, even if it is contam- during a bout of diarrhea. Malnutrition con- inated, may be beneficial. Sewage removal is tributes to more severe or prolonged diarrhea a prerequisite for clean water and a healthful in several ways. The agents producing the great- environment. est frequency of dehydration are V. cholerae, en- Personal and food hygiene standards are im- terotoxigenic E. coli, and rotavirus. Rotavirus portant, too. Effective handwashing is not rou- is the major cause of death in infants with tinely practiced in many developing areas. Food diarrhea. is often improperly handled. Vegetables and fruits rarely are washed properly prior to prepa- History ration. Foods may be contaminated by unclean Diarrheal diseases have been important in all kitchen surfaces or hands. Among the most societies since the beginning of recorded his- important errors is storage of foods contain- tory. Hippocrates used the term “dysentery” to ing moisture at ambient temperatures between denote a condition wherein the affected person meals, which encourages microbial replication. passed many stools containing blood and mu- Medical care is often inadequate. Finally, med- cus. Through World War I, outbreaks of diarrhea ical conditions contribute to both diarrhea and dysentery were as important in deciding incidence and its severity. Measles and malnu- the outcome of many military campaigns as trition are two important examples. Flies also were war-related injuries. can play a role in transmitting enteric infections. The modern era of diarrheal diseases, as A basic prerequisite for infection by enteric with other infectious disorders, began with pathogens is attachment to the intestinal lin- identification of the agents involved. During ing by the microorganism. The mechanism of the mid-1800s, Giardia lamblia and Entamoeba the attachment varies from a highly specific histolytica were identified. Then during the later receptor-ligand interaction, as with enterotoxi- nineteenth century, Shigella and Salmonella or- genic Escherichia coli, to a nonspecific type of at- ganisms were characterized, and the two forms tachment, as with the protozoan Giardia, which of dysentery (bacillary dysentery and amebic possesses sucking disks. Variable degrees of in- dysentery) were distinguished. testinal damage can be seen in enteric infec- During the 1960s, studies elucidated the tion. No anatomic or structural alterations are mechanisms of disease production when found in infection by enterotoxigenic E. coli or cholera toxin was purified. As an extension Vibrio cholerae; intestinal secretion and watery of research with V. cholerae during the 1970s, diarrhea occur secondary to cyclic nucleotide enterotoxigenic E. coli were identified as stimulation. important causes of diarrhea. Soon, other In shigellosis and campylobacteriosis, ex- enterotoxin- or cytotoxin-producing bacte- tensive inflammation with microabscess forma- ria were discovered: Salmonella, Aeromonas, tion is seen. Small-bowel pathogens (rotavirus, Yersinia, Clostridium perfrigens, Clostridium Norwalk viruses, and Giardia) may deplete in- difficile, enterohemorrhagic E. coli, noncholera testinal disaccharidases and cause lactose in- vibrios, and Staphylococcus aureus. tolerance. Malnutrition, common in areas of di- Also during the 1970s, viruses were clearly arrhea endemicity, prolongs and worsens the implicated as causes of human diarrhea. Nor- disease, although malnutrition does not predis- walk virus was shown to produce gastroen- pose to its occurrence. teritis in volunteers, and the viral particle was

93 37. Diphtheria visualized by electron microscopy. Soon, larger Characteristics particles were observed in the duodenal mucosa Corynebacteria are distributed throughout the of diarrhea patients, and within a few years ro- world. C. diphtheriae occurs naturally only in taviruses were established as a cause of infan- humans, although many animals can be in- tile gastroenteritis. Additional pathogens are fected with it. Indeed, diphtheria’s wide host identified as the research laboratory discovers range helped in studying the organism during novel mechanisms of pathogenesis or as new the early bacteriologic revolution. microbiological techniques are developed. The In historical accounts, it is often described as future will bring studies of organism-specific a malignant sore throat, and among its puzzling epidemiology, therapy, and disease prevention. features was the sudden appearance of epi- Herbert L. DuPont demics. In the “throat distemper” epidemic of colonial New England, Boston avoided the high mortality experienced elsewhere, illustrating the patchy distribution of severe cases that 37. Diphtheria could be observed even during epidemics. A phage virus is associated with the virulence Diphtheria is caused by Corynebacterium diph- of the diphtheria bacilli in that the tox gene + − theriae, named from the Greek: koryne (“club”) either elaborates toxin (tox ) or not (tox ). In for its clubbed shape, and diphtheria (“shield” both cases, the presence of this gene stimulates or “membrane”) for the hide-like pseudomem- immunity. A mixture of organisms during epi- brane that forms on tonsils, palate, or phar- demics may have influenced diphtheritic viru- ynx in severe infections. Although this bacil- lence. In the 1735 Boston epidemic, for example, lus may cause only subclinical infections, its a rash accompanied “sore throats,” suggesting more virulent strains cause epidemics with coinfection with streptococcus, which is com- case-fatality rates ranging up to 50 percent mon enough. It is unknown, however, what in- of affected children. In such circumstances, fluence – if any – a copathogen has in the elab- the bacterium is itself infected by a phage oration of toxin. virus that inspires elaboration of a potent exo- In addition to respiratory transmission, the toxin, which can cause rapid fatty degeneration disease can be spread by touch and by fomites, of the heart muscle and peripheral nervous- such as schoolchildren’s pencils. Thus, an in- system damage resulting in paralysis. Chil- fection can be transmitted to a cow’s udders dren, however, often die because the airway is from an infected milker’s fingers. Unpasteurized occluded. milk can also transmit the infection. Even dust Also called the Klebs-Loffler¨ bacillus, the or- around the bed of a diphtheria patient can re- ganism usually spreads by respiratory secre- main infective for weeks. tions and droplet infection. After an incubation Early in the twentieth century, diphtheria was period of 2–4 days, it multiplies in the upper still a leading cause of death for young chil- respiratory tract, creating a membranous ex- dren, but case-fatality rates declined dramati- udate on pharyngeal tissues. The bacillus in- cally with speedier diagnosis and therapeutic in- vades local tissues and kills cells, causing necro- terventions such as antitoxin and tracheostomy. sis and, often, discoloration of the membrane. After World War II, mass immunization effected The greenish or blackened membrane is a hall- a rapid decline in overall incidence, and age mark of the disease. The organism rarely causes of incidence rose. In virulent cases, mortality a systemic infection, although skin infections remains today around 5 percent, which may are common in tropical regions. Most damage mean that antitoxin alone is not always suffi- is produced by the powerful toxin disseminated cient treatment. The organism itself is sensitive through the bloodstream. to penicillin.

94 37. Diphtheria

In temperate climates, diphtheria usually through eighteenth centuries. Historical inter- peaks in autumn and early winter. Most cases est, however, has been confined largely to the during the last 200 years were individuals under major role diphtheria played in the emergence 15 years old. Crowded conditions facilitate pas- and confirmation of the germ theory of disease. sage of the organism, and so accounts prior to French clinician Pierre Bretonneau first de- the acceptance of germ theory often described scribed and named the disease. Witnessing epi- diphtheria as a filth disease naturally favoring demics in the mid-1820s, he noted the pseu- the poor. In tropical regions, cutaneous diph- domembrane and used diphtheria in particular theria is more common, causing ulcers some- to elaborate his concept of disease specificity. times called “desert sores.” Contact with these Diphtheria was usually viewed as a disease of lesions is probably important in spreading the poverty but not an exceptional threat to hu- disease. man survival, as were cholera and yellow fever. Even virulent diphtheria begins quietly. Vic- Periodic peaks in diphtheria mortality received tims rarely suffer the fever, vomiting, or myal- no attention among clinicians. gias common in acute viral illnesses, and the Immediately after Robert Koch articulated sore throat is less pronounced than in strep- a germ theory based on his 1882 work with tococcal pharyngitis. As the organism multi- tuberculosis, Klebs and Loffler¨ demonstrated plies, however, the neck can swell dramatically, the connection between diphtheritic organisms and respiration becomes difficult. If the vic- and membranous sore throat. Loffler’s¨ 1884 pa- tim’s mouth can open, observers usually see a per also introduced some basic research prob- membrane 1–3 millimeters thick, its rough edge lems for germ theorists. He speculated that an curling away from tonsils, palate, uvula, or phar- “extraordinarily deleterious” poison was dissem- ynx. Depending upon the amount of destruc- inated through the bloodstream. Moreover, his tion of local blood vessels, this “shield” ranges work illustrated that the organism could not al- from yellowish-white to green or even black. ways be cultured from typical cases and that German pathologist Edwin Klebs first iden- healthy individuals could carry it. The latter tified C. diphtheriae in 1883 by peeling off phenomenon led Loffler¨ to an 1887 description the membrane and culturing the bleeding sur- of nonvirulent diphtheria strains. face underneath. The following year, Friedrich Emile Roux and Alexandre Yersin demon- Loffler¨ developed a medium on which to strated the probability that a toxin was in- grow the bacillus. Both noted the absence of volved in lethal cases of diphtheria. In 1888, other affected organs: The bacillus is not dis- they showed that bacteria-free filtrates repro- tributed through the body. The toxin alone duced all features of the disease in experi- seems to produce the lethal effect. Most per- mental animals except the membrane. In 1890, plexing is the characteristic progressive paral- Emil Behring and Shibasaburo Kitasato used ysis: first the palate, then eyes, heart, phar- serum from convalescing individuals to treat ynx and larynx (respiratory muscles), and finally diphtheria patients (and experimental animals). the limbs. Penicillin, antitoxin, and maintenance Thus, before the twentieth century, diphthe- of the airway are the usual means of clinical ria had provided the best model for proving intervention. the germ theory of disease and suggested the concept of the healthy carrier, the possibility History of nonbacterial disease agents, and the gen- It is unknown whether diphtheria was at any eral usefulness of serology in diagnosis and historical point a “new” disease, though it was so treatment. described during the early modern period. Dis- After a dramatic cure of a diphtheritic child eases resembling diphtheria were discussed in with the Kitasato-Behring serum, Behring esca- ancient Greek literature, and from the sixteenth lated his study of “antitoxin,” standardizing and

95 38. Down Syndrome popularizing procedures for harvesting immune than 90 percent of cells (mosaic Down syn- serum from toxin-inoculated horses. Diphthe- drome – 2–4 percent of cases). Down syndrome ria rapidly became largely curable. Behring was is the most frequent chromosome abnormal- acclaimed and elevated to the hereditary nobil- ity in live-born humans and is also among ity of Germany. Simultaneously, however, diph- the most frequently identified chromosomal ab- theria became known as a classic contagious normalities, representing about 4 percent of disease and (unlike many such diseases) as a all aborted fetuses. Down syndrome is usu- widespread, merciless killer of children. ally recognizable at birth as a cluster of phys- Diphtheria was involved in two further stages ical and neurological abnormalities that de- of research on germ theory and its appli- velop in a characteristic fashion during the life cations. First, the Schick test helped iden- cycle. tify individuals lacking immune response to small doses of toxin. In testing immunity and Characteristics anaphylactic reaction to foreign sera of people Recent estimates of overall worldwide incidence with “serum sickness” (a considerable problem of Down syndrome are around 0.8 per 1,000 live with Behring’s method), clinicians used diph- births. Figures evidence a decline from previ- theria throughout the early twentieth century ous decades in Western countries, where inci- to delineate research problems in human immu- dence was about 1.7 per 1,000. This change has nity. Second, in the 1950s, isolation of the phage probably resulted from more frequent prenatal virus infecting diphtheria bacilli greatly aided diagnosis. research into phage-bacterial relationships and, Down syndrome occurs in all races and eth- in the process, the fields of bacterial genetics nic groups, though good documentation of spe- and molecular biology. cific incidence in many groups and geographic Ann G. Carmichael areas is lacking. There is some evidence for spa- tial aggregation, such as in northern Finland and British Columbia, but these instances appear to be sporadic and are probably related to environ- 38. Down Syndrome mental sources. The presence of the additional number 21 Down syndrome, previously called “mon- chromosome in all cells of the individual with golism,” is a relatively common condition re- Down syndrome is usually the result of an error sulting from the presence of an extra chromo- in cell division called nondisjunction. In nor- some, number 21, in the cells of the body. In mal cell division, the two members of each of each human cell, 23 chromosome pairs con- the 23 chromosome pairs separate and move tain basic genetic material that organizes the into one of the two resulting cells, whereas in body’s development and physiological function- nondisjunction, both members of the chromo- ing. Each pair has a distinctive size and confor- some pair end up in a single cell. In Down syn- mation and can be readily identified on exami- drome, the nondisjunction has usually occurred nation. Chromosome pair number 21 is one of during meiosis (sex cell division) usually of the the smaller chromosomes. In Down syndrome female sex cell (the ovum). Thus, when an ovum there are usually three (trisomy) rather than with two number 21 chromosomes is fertilized, two number 21 chromosomes (trisomy 21 – three number 21 chromosomes (two from the 95–98 percent of cases). In some cases, the ex- mother and one from the father) will be passed tra number 21 chromosome is attached to chro- on to all the cells in the developing fetus. mosome 13, 14, or 15 (translocation Down The occurrence of Down syndrome is most syndrome – about 2 percent of cases). In oth- consistently associated with advanced maternal ers, the extra chromosome is present in less age: Incidence increases from 0.45 per 1,000

96 38. Down Syndrome live births for women ages 20–24 years to postcranial anomalies include wide spacing be- 9.4 per 1,000 for women ages 40–44 years. tween first and second toes, abnormal finger The largest risk increase occurs between the and palm dermatoglyphs, and shortened dis- 30–34 and 34–39 age groups. Possible causes tal long bones. About 80 percent of Down syn- of the maternal-age association include: (1) The drome patients are hypotonic and 90 percent older uterus is less selective in rejecting the are hyperflexible. There are also various major Down syndrome conceptus; (2) longer delays organ anomalies, most importantly congenital between intercourse result in a relatively “aged heart disease, which occurs in 30–50 percent ovum,” more likely to experience nondisjunc- of patients. Metabolic and hormonal systems are tion; (3) in older women, the ova themselves variably affected, including deficient vitamin A have aged longer and have an increased rate absorption, elevated serum uric acid, and abnor- of nondisjunction; (4) long-term exposure to mal serotonin metabolism. environmental agents has resulted in damage Down syndrome patients experience abnor- to the spindle mechanism that in turn produces mal physical and cognitive development. Birth meiotic nondisjunction. weight and length are near normal, but growth About 30–60 percent of Down syndrome in the first 3 years of life is significantly slower births, however, are not age dependent, occur- than normal, and most children are less than ring in mothers under 30 years old. Indeed, a the fifth percentile in height by the time they high incidence of Down syndrome births has reach age 3. Growth rate during childhood is been reported in women under 15. Younger near normal, but the adolescent growth spurt mothers are more likely to have a second Down is often absent. Some early developmental mile- syndrome birth than are older mothers. The stones are normal, but marked delays in walk- recurrence risk is 1 in 3 for mothers who are ing, talking, and other motor and cognitive skills translocation carriers. usually become apparent by the end of the first Possible environmental and metabolic mech- year of life. Mild to moderate mental retarda- anisms for Down syndrome have been evalu- tion (I.Q. 30–67) is commonly present by child- ated, among them maternal drug, tobacco, al- hood. Early intervention and special-education cohol, and caffeine use; use of hormonal and programs allow adults with Down syndrome to nonhormonal contraceptives; fluoridated wa- hold jobs in sheltered work situations. ter; and radiation exposure. However, findings from such studies have been inconsistent. Some History investigators have suggested that a recessive Probably the earliest record of Down syndrome gene producing nondisjunction might explain is a seventh century Saxon skull showing os- up to 10 percent of cases. However, studies of teological changes consistent with the condi- consanguineous marriages fail to support this tion. Sixteenth century paintings depict chil- suggestion. The association with elevated ma- dren with features of the syndrome. Not until ternal age is undoubtedly a surrogate variable the nineteenth century, however, did the first for other underlying factors, the most important accounts of Down syndrome appear. In 1846, of which are probably endocrine changes asso- E. Sequin noted a specific type of mental re- ciated with aging. tardation case with associated physical features. The most easily recognizable features of In 1866, J. Langdon Down described a congen- Down syndrome derive from abnormalities in ital defect resembling the Tartar race, which he growth of the cranium and face. These include called Kalmuc or Mongolian. Down, influenced a short, relatively broad head (brachycephaly), by racial theory and the writings of Charles hypoplastic maxilla, upslanting palpebral fis- Darwin, suggested that the entity represented sures, epicanthal folds, increased neck skin, a reversion to an earlier phylogenetic type. small ears, and flattened nasal bridge. Common This hypothesis never gained wide acceptance,

97 39. Dracunculiasis however; in fact, Down’s son (also a doctor) dis- Initially, Down syndrome was thought to oc- agreed, suggesting that the features of the syn- cur only in the Caucasian race. Subsequent drome were accidental and superficial. reports have shown that it occurs in every The next important reports, in the 1870s racial group and country, although studies have and 1880s, noted similarities between the syn- not yet provided an accurate picture of its drome and “cretinism” (congenital hypothy- distribution across racial and ethnic groups. roidism), and suggested that children with Early reports indicated low incidence in Africans the condition were actually “unfinished,” rep- and black Americans. However, investigations resenting a persistence of anatomical char- in Ibadan, Nigeria, and Memphis, Tennessee, acteristics from a particular phase of fetal found black incidence much the same as that of development. The association between the syn- whites. Similarly, although detection in Oriental drome and advanced maternal age was already populations is thought to be inhibited by same- recognized, and many Down syndrome chil- ness of features, studies in Japan reveal rates dren were the lastborn of large families. Dur- much like those in the United States. ing the end of the nineteenth and beginning A number of studies have attempted to indi- of the twentieth centuries, many reports ap- cate spatial and temporal clustering of the syn- peared, expanding the description of the syn- drome, but all have failed to give satisfactory drome’s phenotypic manifestations. Important statistical proof for clustering. A 1983 report de- among these were extensive neuropathological scribes a cluster of Down syndrome children descriptions. born to women who attended the same board- From the mid-nineteenth century to 1959, ing school in their youth. This suggests that, in many etiologic hypotheses were advanced, in- some instances, an environmental agent may in- cluding maternal syphilis, familial tuberculosis, fluence the incidence of Down syndrome. familial incidence of epilepsy, insanity, instabil- Christine E. Cronk ity, and mental retardation. Once the increased incidence of congenital heart disease in the syn- drome was recognized (in 1898), a cause in early fetal existence was sought. Among theories ad- 39. Dracunculiasis vanced were maternal alcoholism, fetal hyper- thyroidism, maternal dysthyroidism, adrenal Dracunculiasis results from infection with the hypoplasia, pituitary dysfunction, abnormality parasite Dracunculus medinensis. The adult of the thymus, chemical contraceptives, curet- worms – about 1 meter long – are usually quite tage, faulty implantation, degeneration of the evident as they slowly emerge through the skin ovum, and emotional shock in early pregnancy. of their victims. As early as 1932, a chromosomal anomaly was suggested as a possible cause of the disorder. Characteristics In 1959, shortly after the number of chromo- Dracunculiasis is found mainly in India, somes in the human cell was established, a sam- Pakistan, and several African countries, from ple of Down syndrome children were demon- Senegal in the west to Ethiopia in the east. For- strated to have an extra chromosome and a total merly, this disease was much more widespread chromosome number of 47.Later the same year, in the Middle East and Africa, and it occurred researchers concluded that the extra chromo- for some years in the Americas after introduc- some was most similar to number 21. In 1960, tion by infected Africans during the slave trade. other investigators reported a case of Down syn- Incidence of dracunculiasis is significantly drome with only 46 chromosomes, and pos- higher in endemic African communities than tulated reciprocal translocation occurring be- in endemic Asian villages. In West Africa es- tween two chromosome groups. pecially, rates of infection in affected areas

98 39. Dracunculiasis sometimes exceed 50 percent, whereas in Asia, worm is about to emerge. The blister ruptures rates usually are below 20 percent. In rural ar- when the affected part of the body is immersed eas, the disease occurs sporadically, with inci- in water, leaving a small ulcer with the worm at dence rates sometimes differing greatly in ad- the center. Most worms emerge on the foot or jacent villages. Persons at risk of this infection lower leg, but they can emerge through the skin number an estimated 120 million in Africa, with at any point. Sometimes the worm first appears another 20 million at risk in India and Pakistan. as a line beneath the skin, or at the center of a The number of persons affected annually is un- painful abscess or nodule. known. Diseases are often underreported in the Worms failing to emerge from the body die countries affected, and reporting of dracuncu- and are absorbed or calcified, in which case they liasis is especially poor. Generally, it is found appear as characteristic curled lines in X-rays. only in impoverished rural communities where Worms may invade a major joint, the central medical facilities are rare. Many victims cannot nervous system, or another vital area, produc- walk and have little incentive to seek treatment, ing more serious manifestations, but this rarely because no curative drug exists. happens. More common complications are sec- Dracunculiasis is seasonal, usually occurring ondary infections of the wound, leading to just when rural villagers plant or harvest their abscesses, local arthritis,ortetanus. In most crops. People are infected by water contain- patients, only one worm emerges at a time, al- ing copepods – tiny crustaceans of the genus though two dozen or more may present them- Cyclops that harbor the infective larvae of the selves simultaneously in one person. parasite. A year later, adult worms emerge Affected persons may be crippled for several through the skin to discharge larvae into weeks or months by the pain of the worm’s slow freshwater to be ingested by copepods, thus emergence and secondary infections. Because completing the cycle. In drier areas, the infec- the infection appears at a critical time for food tion appears during rainy seasons (summer). In production and cripples many people simulta- areas with more rainfall, the infection is trans- neously, it has an enormous economic impact. mitted during dry seasons (winter). Moreover, people who are infected develop no Most commonly affected are people 15–45 immunity, so they may be and often are infected years of age – that is, working adults. Younger year after year. children are affected, but not infants under 1 year, and not many under 5 years. Farmers are History particularly liable to infection, apparently be- Dracunculiasis is an old infection, which many cause they drink large volumes of contaminated believe was the “fiery serpent” said to have water while laboring on their farms. In some attacked the Israelites on the shores of the areas, schoolchildren also suffer high rates of Red Sea. A calcified Dracunculus worm was dis- infection. covered in an Egyptian mummy from around No drug is suitable for effective mass treat- 1000 B.C., and a treatment for the condition ment of dracunculiasis, and from time immemo- may be contained in the Ebers Papyrus. rial the disease has been treated by slowly wind- Greek and Roman writers described the in- ing the emerging worm around a stick. The dis- fection, and Galen named it “dracontiasis.” The ease can, however, be prevented by boiling or ancient treatment of winding the worm slowly filtering drinking water, by chemical treatment around a stick is thought by some to be the of contaminated water sources, and by protect- origin of the Staff of Aesculapius. Several me- ing water sources from contamination in the dieval Arabian physicians described dracuncu- first place. liasis, and one of them, Avicenna, gave the first Usually the first clinical sign of infection is a detailed description of what he called “Medina blister and severe burning sensation where the sickness” (because it was common in Medina).

99 40. Dropsy

Shortly before, Rhazes showed that the associ- but now has additional connotations, and pul- ated swelling was caused by a parasite. monary edema has been differentiated from Sixteenth century Europeans mentioned hydrothorax. Since the mid-nineteenth century, cases of dracunculiasis in Persia and Congo. It dropsy has been recognized as a sign of under- may first have been called “Guinea worm” by lying disease of the heart, liver, or kidneys, or of a European who saw it on the Guinea Coast malnutrition. Untreated dropsy was, eventually, (west Africa) early in the seventeenth century. always fatal. The disease is mentioned in the traditional leg- end of the founding of the Dahomeyans’ ances- Characteristics tral cult. Although G. H. Velschius described the The major causes of dropsy are congestive parasite clearly in 1674, it was left to Linnaeus heart failure, liver failure, kidney failure, and to provide its scientific name in 1758. malnutrition. Because these were not clearly During the nineteenth century, medical of- differentiated before the nineteenth century, a ficers reported dracunculiasis among British historical diagnosis of dropsy cannot be taken to troops in India, and an English expedition that indicate any one of these alone in the absence invaded Ethiopia in 1868 suffered greatly from of unequivocal supporting evidence, as from an the disease. The role of the copepod as interme- autopsy; however, heart failure was probably diate host in the parasite’s life cycle was discov- the most frequent of the four. ered in the 1870s by Aleksei Fedchenko. Dropsy can be explained most conveniently The distribution of dracunculiasis shrank in terms of fluid balance. One principal force considerably during the early twentieth in the maintenance of normal fluid balance century – largely because of improving stan- is the hydrostatic pressure within capillaries. dards of living, especially improved water The other major force is oncotic pressure, the supplies. The disease was eliminated from the normal tendency for sodium or large particles southern Soviet Union in the 1930s by a delib- in capillary blood to draw water out of tis- erate campaign, and from Iran in the 1970s. In sues. Thus, fluid accumulates in tissues when the 1980s, India and other endemic countries either intracapillary pressure increases or the began campaigns to eradicate dracunculiasis. blood’s ability to remove water from tissues de- It appears likely that this ancient disease will creases. In both cases, fluid that has moved soon cease to exist. out of the capillaries is poorly reabsorbed. Most Donald R. Hopkins hydrostatic defects are primary heart diseases, whereas most oncotic defects result from renal and hepatic disease. Congestive heart failure produces dropsy, or 40. Dropsy edema, when the heart becomes too weak to maintain the normal pressure of blood flow The historical diagnosis of dropsy – now ob- in the capillaries, facilitating the leakage of solete – indicated an abnormal accumulation water from capillary blood into surrounding tis- of fluid; the word derives from the Greek hy- sues. “Congestive” refers to the accumulation drops (“water”). Alternative terms included hy- and stagnation of blood in organs, especially the drothorax (fluid in the chest cavity), ascites (ex- lungs, when they are not adequately emptied. cess fluid in the abdominal cavity), anasarca The other major causes of dropsy, which fol- (generalized edema throughout the body), hy- low, are discussed here only in relation to heart drocephalus (used until the nineteenth century failure. Liver failure, producing ascites, most of- to indicate excess fluid within the skull), and ten occurs in advanced cirrhosis because the ovarian dropsy (large ovarian cysts filled with diseased liver cannot manufacture sufficient al- fluid). Edema was often a synonym for dropsy bumin to maintain the oncotic pressure of the

100 40. Dropsy blood. Right ventricular failure can also pro- of contraction, for increased resistance to arte- duce hepatic congestion and failure. Renal fail- rial outflow, and for accumulations of blood that ure causes dropsy when the filtering units be- cannot be completely removed from the ven- come so diseased that large molecules are lost tricles at each contraction. Symptoms of heart from the blood into the urine, resulting in de- failure begin to occur when no further compen- creased oncotic pressure. Malnutrition results sations can be made. “Forward failure” symp- in ascites when protein intake is so low that toms occur when the heart can no longer empty the liver is unable to manufacture its own. the left ventricle completely because of rea- Beriberi, caused by a B-vitamin deficiency, can sons such as myocardial weakness or obstruc- also weaken the heart. tion to aortic outflow. Symptoms of “backward Heart failure occurs more often in men than failure” occur when the heart chambers become in women, inasmuch as men are at greater risk incapable of complete filling, due to incom- for most forms of cardiovascular disease. The plete relaxation of the heart between beats, or risk is greater for older than younger patients: to obstructions to venous inflow into the right three-quarters of heart failure patients are over atrium. 50 years of age. Risk factors for hepatic cirrhosis Heart failure can be produced by several un- include chronic alcoholism and hepatitis, just derlying pathological causes, such as myocar- as renal causes of dropsy may be associated dial insufficiency, failure of the left or right with rheumatic fever or the nephrotic (or both) ventricles, chronic or acute cor pul- syndrome. monale (pulmonary heart disease), and dimin- The distribution of dropsy within or among ished arterial blood flow to the kidneys, al- populations parallels the distributions of its un- though seldom does any one of them occur derlying causes, such as hypertension, myocar- alone. Whatever the underlying cause, the ma- dial insufficiency, coronary artery disease, jor manifestation of heart failure is reduced car- hypercholesterolemia, valvular disease, strep- diac output in terms of the amount of blood tococcal diseases, cirrhosis, and renal glomeru- ejected from the left ventricle. The associated lar disease. Risk factors for these conditions are symptoms are usually clearly recognizable. still being identified and their clinical implica- For instance, important symptoms of heart tions evaluated. Only for malnutrition are geo- failure include shortness of breath (dyspnea), graphic distinctions clear-cut. due to insufficient delivery of oxygen to the Historically, the diagnosis of dropsy was so body’s tissues, and rapid breathing (tachyp- familiar that artists could portray it in popu- nea) as the respiratory system attempts to com- lar prints with the expectation that it would pensate for the lack of oxygen. Both dyspnea be recognized immediately. Consequently, it is and tachypnea increase as fluid from the pul- not surprising that the reported incidence of monary capillaries begins to flood the lungs. dropsy has not changed substantially over the When the lungs become sufficiently congested 400 years for which records are available. That (pulmonary edema), the patient coughs up co- is, dropsy was diagnosed in about 3–5 percent of pious sputum. A more serious form of dyspnea deaths, hospital admissions, or adult patients in is orthopnea. This term is applied to shortness London in 1583–1849, and in American villages of breath that prevents the patient from sleep- and cities in 1735–1839. Typical modern inci- ing horizontally because venous blood further dences of congestive heart failure exhibit simi- congests the lungs, causing dyspnea. An exag- lar percentages. gerated form of orthopnea called paroxysmal This discussion focuses on congestive heart nocturnal dyspnea may waken the patient sud- failure because it was probably the major under- denly at night; it is sometimes called “cardiac lying cause of dropsy. The heart is able to com- asthma” because it produces wheezing and la- pensate, up to a point, for diminished strength bored breathing.

101 40. Dropsy

Other distinctive symptoms may occur in tachycardia, palpitations, pulmonary edema, addition to the usual dyspnea and tachyp- dyspnea, and syncope (fainting or shock, which nea. Pedal edema occurs, accompanied by hy- he postulated was a sign of a weak heart) that ac- drothorax. Ascites is a late sign and may be companied dropsy were related to one another. followed by anasarca and oliguria. The skin Five centuries later, the French surgeon Am- becomes bluish, because the sluggishlymov- broise Pare´ described dropsy identically. His ing red cells are not adequately oxygenated in countryman Jean Fernel relied on similar the- the lungs. The jugular veins distend because ories in associating heart disease with palpi- increased pressure in the right heart prevents tations, syncope, and the pallor, cold sweat, them from emptying completely into the supe- and weak pulse observed in cardiogenic shock. rior vena cava. Other evidence of increased ve- Also in the sixteenth century, Paracelsus theo- nous pressure includes congestive enlargement rized that dropsy occurred when the body’s tis- of the liver and sometimes the spleen. sues dissolved. He recommended that dropsy be treated with mercuric oxide to remove superflu- History ous water, with other metallic oxides to dry the The symptoms of dropsy have not changed over patient’s body, and with sulfur, because its dry- the centuries. Its history is the story of evolv- ing action was analogous to that of the sun in ing interpretations of its clinical features over dispelling rain. 2,000 years as the relationships of dyspnea, “suf- Girolamo Capivaccio of Italy agreed with focative catarrh,” pulmonary edema, hydrotho- Galen that dropsy was due to liver disease and rax, ascites, syncope, and “fever” to heart failure impaired blood formation, so that fluid was re- were elucidated. leased into the abdominal cavity to form ascites, The first known mention of dropsy is in the which he detected by percussion, as Celsus had. Ebers Papyrus, an Egyptian medical text of about Capivaccio also attributed dropsy to disease in 1550 B.C. It associates dropsy with increased ab- other organs, such as obstruction of the path- dominal girth and possibly with a weak pulse. ways to the kidneys. He surmised that dyspnea A Hippocratic text correctly prognosticates that was caused by pressure from a pathologically there “is no hope when a patient suffering from enlarged liver on the diaphragm. dropsy develops a cough.” And Jesus defied the The sixteenth-century physician Ludovicus Pharisees by healing a man with dropsy on the Mercatus of Valladolid defined dyspnea as rapid, Sabbath. difficult breathing caused by constricted air- Soon after, Aulus Cornelius Celsus described ways or excess heat in the heart and lungs; two forms of dropsy: (1) generalized edema, he thought that respiration was for cooling which could be drained through small skin inci- the heart. Mercatus believed that hydrotho- sions above the ankle; and (2) ascites, in which rax fluid descended from the brain to produce the excess fluid could be removed by paracen- the “suffocative catarrh” described by Galen, tesis, or “tapping” (drainage via a tube inserted and that its associated dyspnea was caused by through an incision in the abdominal wall). fluid in the lungs, or even by heart disease. Galen listed several causes of dropsy in the He theorized that hydrothorax fluid was over- first century A.D., including a hardened liver, flow from ascites or from obstructed urinary as well as inadequate blood formation (which passages. he thought occurred in the liver), hemorrhoids, Throughout the seventeenth century, it be- and both amenorrhea and uterine hemor- came increasingly clear that dropsy was as- rhage. Virtually all writers on dropsy until the sociated with altered fluid dynamics. Carolus mid-seventeenth century cited the teachings of Piso of Lorraine detected hydrothorax as “bub- Hippocrates, Celsus, and Galen. In the eleventh bling” when he applied his ear to the chest. century, Avicenna of Baghdad thought that the Coupling clinical observations with autopsy

102 40. Dropsy

findings, he attributed paroxysmal nocturnal finally made it clear that suffocative catarrh and dyspnea to fluid in the chest cavity. Fabrizio Bar- acute pulmonary edema (not the result of fluid toletti of Italy used observations like Piso’s to falling from the head) were the same. hypothesize that hydrothorax fluid came from Physicians were slow to understand that the the lungs. He noted that the first clue to its pres- heart could be diseased, probably because it was ence was dyspnea, followed by “fever,” tachyp- essential to life. Raymond Vieussens of Montpel- nea, orthopnea, dry cough, thirst, syncope, leg lier, however, had concluded by 1705 that struc- and scrotal edema, and finally ascites. Bartoletti tural disease of the heart could result in dropsy. thought that hydrothorax was always fatal be- At almost the same time, Giovanni Maria Lan- cause it suffocated its victims. cisi in Rome recognized that edema, hydrotho- William Harvey postulated that if the venous rax, and ascites could be related to failure of system were maximally distended, the heart the heart’s propulsive force. Explicitly recogniz- would stop and suffocation would follow. In ing the importance of hydrostatic principles in 1628, he described the heart and lungs as “store- cardiovascular physiology, Lancisi went on to houses” for the blood, a metaphor that may explain how stagnation of blood within the pul- have led to the concepts of pulmonary engorge- monary vasculature could result in dyspnea. He ment and passive congestion, which would be concluded that right heart failure could pro- critical to further understanding of dropsy in duce engorgement and pulsation of the jugu- the chest. lar vein. Thus Lancisi and Vieussens uncovered In 1669, Richard Lower of Oxford produced the cardiac basis of dropsies of the lungs and edema and ascites in dogs by ligating the jugu- thorax. lar veins and the superior vena cava. He also Another interpretation of dropsy arose from found that excess fluid in the pericardial sac Harvey’s demonstration that the blood circu- restricted cardiac expansion. Lower postulated lates within a closed system. Dropsy could be that the two sides of the heart should be of seen as a febrile disease, because it was usu- equal strength, while noting that the left side ally accompanied by a fast pulse, which for cen- alone may be weakened. He also perceived that turies was regarded as a cardinal sign of fever. excessive pressure or flow rate of blood ad- Thus Thomas Willis defined fever as an “intes- versely affected health. He recognized Galen’s tine motion or commotion of the blood” arising “suffocative catarrh” as pulmonary edema, al- in chemical disturbances like those described though they were considered separate clinical over a century earlier by Paracelsus. entities for many years afterward. Hermann Boerhaave of Leyden believed that In 1681, Marcello Malpighi of Bologna noted dropsy was a fever and should be treated ac- the increased weight (from the stagnant blood cordingly. He argued that in dropsy, fever is within them) of dyspneic lungs. He had discov- the result of increased cardiac work and in- ered capillaries 20 years earlier and hypothe- creased vascular resistance to blood flow. There- sized that blood escaped from them into the fore dropsy was a fever because it was associ- lungs. Malpighi thought that stagnant blood ated with a fast pulse. Boerhaave postulated that in the pulmonary vessels produced palpitations dropsical fluid accumulated because defective because it precluded an orderly blood supply to veins released more fluid into body tissues than the heart. He reasoned that an imbalance be- the vessels could reabsorb. In Italy, Luca Tozzi tween arterial outflow and venous resorption of differentiated hydrothorax, pulmonary edema, water from the blood caused dropsy, but he at- and pneumonia at autopsy, which permitted tributed the imbalance to chemicals that con- him to differentiate pulmonary and thoracic stricted blood vessels or irritated the nerves that dropsies ante mortem. controlled the heart and the respiratory mus- In 1761, Leopold Auenbrugger of Vienna de- cles. One of Malpighi’s students, Giorgio Baglivi, scribed how to strike the chest with the fingers

103 40. Dropsy to estimate, by the resonance produced, the to fade, and the role of the diseased heart came amount and nature of fluid in the pleural cav- into sharper focus. ity and lungs. However, his discovery of percus- In 1806, Jean-Nicholas Corvisart of France sion was neglected until it was reintroduced in showed how heart disease could produce France in 1808. dropsy, dyspnea, and orthopnea when venous The first book devoted to dropsy alone was return was slowed. Three years later Allan Burns published in 1706 by the Leopoldine Academy of Glasgow demonstrated that ossification of the of Sciences in Breslau; its principal author was mitral and pulmonary valves leads to right heart probably Christianus Helwich. The Academi- dilation and dropsy. And in 1835, James Hope cians described the features of dropsy much as of Cheshire showed how myocardial failure re- previous works had done but attributed the es- sults in dyspnea. cape of fluid to diminished blood viscosity and In 1813, John Blackall of London suggested to defective vessel walls. that dropsy can result from noncardiac con- In 1733, Stephen Hales, a rural English cler- ditions such as liver and kidney disease. He gyman, concluded that dropsy could result demonstrated that the albumin content of urine from decreased numbers of red blood cells. He can help differentiate among the underlying thought that the body would compensate for causes of dropsy. Renal causes of dropsy were the lack of “red Globules” by heating the blood confirmed by Richard Bright, whose careful au- into a feverish state that caused dropsy. He rec- topsies at Guy’s Hospital in London led him to ognized that inadequate venous return to the report, in 1827, that albumin could be found in heart in dropsy could lead to compensatory the urine of glomerulonephritis patients who tachycardia. died of dropsy. Later, Bright showed that re- Donald Monro of Edinburgh published the nal disease could be associated with left ven- second book devoted to dropsy in 1755, as- tricular hypertrophy. In 1909, C. J. Rothberger cribing it to “a weakness and laxity of the and H. Winterberg in Austria, and Thomas fibers . . . when the vessels do not act with Lewis in London, independently showed that sufficient force,” and listed causes of weakened atrial fibrillation could produce heart fail- blood vessels: a watery diet, “any great evacu- ure, and in 1935 Paul Dudley White and ation,” kidney disease, obstruction of small or Sylvester McGinn of Boston described acute cor large vessels, or any debilitating disease. pulmonale. In 1763, Samuel Clossey of Dublin realized All investigators continue to exploit the re- that the development of hydrothorax is a long lationships discovered around the turn of the process. He computed that it would take about twentieth century by Ernest Henry Starling and 2 years to accumulate 3 pints of hydrothorax incorporated into his “Law of the Heart.” In fluid. He associated dropsy with weakness of 1936, Tinsley R. Harrison of Vanderbilt Univer- the heart but postulated that cardiac strength sity consolidated Starling’s and other concepts derived from the blood vessels. of heart failure to explain the phenomenon Thus, regardless of how they were in- more or less as we understand it today, although terpreted, the major clinical manifestations heart failure remains the subject of increasingly of dropsy had been identified by the mid- detailed investigations. eighteenth century. Some physicians thought Until the late eighteenth century, dropsy was that dropsy was caused by weak blood vessels, treated primarily with a selection of mostly inef- whereas others attributed the dyspnea to weak- fective drugs. In 1785, the most influential – and ened cardiac contraction, as did Robert James perhaps most immediately accepted – book in of London in 1745. By the end of the century, the history of dropsy appeared. An Account of the theories of dropsy based on fever, chemical dis- Foxglove, by William Withering of Birmingham, turbances, blood viscosity, and fiber tone began England, was the first prospective study of the

10 4 42. Dyspepsia efficacy and safety of any drug in the treatment Diarrhea, marked by frequent production of of disease. Withering demonstrated the thera- watery stools, may be confused with dysentery peutic benefit of digitalis (extracted from the in historical accounts, but references to “bloody purple foxglove, Digitalis purpurea, or the white flux” refer to true dysentery. The condition may species, Digitalis lanata) in patients with drop- be caused by an ameba, Entamoeba histolyt- sies unrelated to primary disease of other or- ica, or by several species of bacteria, especially gans. Although he noted that the pulse rate fell in the genus Shigella. See: Amebic Dysentery, in patients treated with the new drug, he did not Bacillary Dysentery, and Diarrheal Diseases recognize its tonic effect on the heart. (Acute). Some physicians who followed Withering K. David Patterson concluded that digitalis stimulated the “sys- tem,” whereas others concluded that it was a depressant because it reduced fast heart rates. In 1813, Blackall first suggested that digitalis ac- 42. Dyspepsia tually strengthens the heart. This concept resur- faced in the early twentieth century and was Derived from Greek roots meaning “difficult verified in 1938–44, by H. J. Stewart and John digestion,” dyspepsia has long served as a McMichael. synonym for indigestion, one of the most com- The two major goals of treatment in con- mon – and etiologically varied – of human gestive heart failure today are improved oxy- miseries. It has also been regularly employed genation of the tissues and reduction of to label symptoms of diverse organic disorders, hydrostatic pressures in the veins. Digitalis gly- with the result that some gastroenterologists cosides (chiefly digoxin and digitoxin) increase find the word uselessly elastic. Most practition- cardiac output by strengthening the force with ers, however, have reached a consensus to use which the heart contracts; diuresis occurs sec- dyspepsia to denote either the ailment of func- ondarily, because the increase in the amount tional indigestion or the symptoms of peptic of blood that is circulated to the kidneys per- ulcer. mits increased removal of water. True diuretics, which act on the kidneys alone, relieve pressure Characteristics in the venous system by removing excess fluid Peptic ulcer dyspepsia is rare in people under from the body via the urine. age 20, but by age 30, 2 percent of males and Oxygen and rest are important adjuncts to 0.5 percent of females in a population have de- drug therapy. Paracentesis and thoracentesis veloped the condition. For men, incidence in- may occasionally still be required, but the sub- creases steadily with age, reaching a peak of cutaneous leg drainage tubes described by R. around 20 percent in the sixth decade of life. Southey of France in 1871 were abandoned with Incidence for women remains low, about 1 per- the advent of true diuretic drugs. cent, until menopause, after which it climbs as J. Worth Estes rapidly as in men. Death from peptic ulcer oc- curs three times as often in men as in women. The prevalence of functional dyspepsia, by contrast, is uncertain. Having no distinct 41. Dysentery pathology, being neither communicable nor re- portable, and only occasionally motivating its Dysentery is inflammation of the large in- victims to seek medical help, it generates no testine characterized by loose stools contain- statistics. The widely shared clinical impression ing blood and mucus, and by tenesmus – is that women are affected more than men, and painful and unproductive attempts to defecate. people under age 40 more than their elders.

105 42. Dysentery

Functional dyspepsia is also believed to be more predictable and temporary discomfort brought prevalent in developed countries. on by immoderacy in diet. Although the most common, peptic ulcer The sources of intestinal turbulence came to is hardly the only organic source of dyspep- appear more numerous during the nineteenth sia. Esophagitis; hiatus hernia; gastritis; car- century. The distrust of sensuality that marked cinoma of the stomach, colon, or pancreas; the Victorian ethos more than once expressed Crohn’s disease; biliary tract disease; chronic itself in blaming physical decline on moral per- nephritis; or any of several other conditions, version. Because dyspepsia was often found in including pregnancy, can produce indigestion. patients guilty of some excess and just as of- In approximately half of dyspepsia cases, how- ten lacked any apparent organic basis, physi- ever, no lesion can be found, and symptoms cians found it easy to explain the condition arise from derangements of motor, secretory, with reference to any aberrant behavior that or absorptive functions, especially delayed gas- might plausibly have upset the patient’s system. tric motility, esophageal reflux, and hyperacid- Gluttony, of course, was still a sin, and doctors ity. This functional indigestion has been re- generally added to gluttony the bolting of in- lated to physical stress (aerophagia, fatigue, adequately chewed food, a practice that many dietary indiscretion) and, more commonly, to charged was epidemic in the dining rooms of nervous stress. Anxiety, anger, frustration, and ever-in-a-hurry America. Nevertheless, a nine- other indications of emotional turmoil can sig- teenth century attack of dyspepsia was just as nificantly impair digestive function in sensi- likely to be blamed on abuse of spirits or to- tive or tense individuals (a similar psychic bacco, reading French novels, or masturbation component – chronic tension and repression or “excessive venery.” of emotion – has been implicated in peptic ul- The nineteenth century’s list of dyspepsia’s cer). Because the symptoms of functional dys- causes was also lengthened by examples of pepsia are virtually identical to those of peptic fast living of a second type, that of the men- ulceration, the condition has also been termed tal and emotional excitation accompanying the “X-ray-negative” dyspepsia and “nonulcerative” bustling anxiety-filled life of the industrial city. dyspepsia; the term “endoscopy-negative” dys- An 1825 treatise on indigestion, which recom- pepsia has been proposed as well in recent mended against excessive venery, also warned years. in the same breath of the dangers of exces- Dyspepsia’s victims complain of gastric pain, sive work and attention to “business.” Such along with fullness or heaviness in the stom- caveats appeared with increasing regularity in ach, nausea and vomiting, belching, flatulence, medical texts and health guides alike until fi- and/or acid eructations. Finally, dyspeptics may nally becoming mandatory with the ascension suffer heartburn, a caustic pain behind the ster- of neurasthenia (nervous exhaustion) to the num that sometimes climbs into the throat, re- position of the disease of modern society dur- sulting from esophageal reflux. Heartburn is the ing the last quarter of the century. Neurasthenia special affliction of those with sliding hiatus prophet George Beard’s message that dyspepsia hernia when they bend or recline. was on the rise as the special complaint of the modern brainworker and risk-taker met with History universal acceptance. The neurasthenia era, fur- If indigestion has plagued the human race for thermore, defined “modern dyspepsia” as a ner- as long as it has eaten – and no less hoary an vous complaint that gave as good as it got, one expert than Hippocrates described its tortures – that having originated in anxiety then gener- not until the nineteenth century did dyspepsia ated more anxiety as well as irritability, depres- attain a prominent standing in pathology. Pre- sion, and other neurotic suffering in addition viously, it was regarded as a too common but to mundane heartburn. This virtual equation of

10 6 43. Ebola Virus Disease dyspepsia with nervousness led to its almost ex- be thoroughly revised. To the roster of lesser clusive definition as a functional condition pro- ailments can be added dengue, Chikungunya, duced by stress. O’Nyong Nyong, West Nile fever, and others. During the first half of the twentieth cen- The new knowledge challenges earlier descrip- tury, that same stress of coping with civilization tions of African fevers in general. seems to have engendered an abrupt increase After the discoveries of Marburg virus in in dyspepsia of organic origin as well. Between 1967 and Lassa virus in 1969 had jolted med- the two world wars, peptic ulcer (particularly ical complacency, the Ebola virus in 1976 pro- duodenal ulcer) grew from a rarely encoun- voked convulsive shudders. Almost simultane- tered condition to a significant cause of disabil- ous outbreaks of a deadly infection occurred ity, reaching a high point in the 1950s, then in neighboring regions of southern Sudan and declining sharply to the present. This pattern northern Zaire, and along the Ebola River. The suggests that ulcer dyspepsia is less a disease Sudan and Zaire foci are about 150 kilome- of civilization than a condition of adjustment ters apart, and continual traffic passes between to civilization; the first generations to confront them. the pressures of urban-industrial life are buf- feted more heavily than those born after the History turbulent transition period. Functional dyspep- The Sudan epidemic of Ebola virus disease be- sia, of course, might be expected to decrease gan in June 1976. An infected patient went to for the same reason, yet its domain has been a hospital in Maridi, where the disease spread diminished still more rapidly by the X-ray and rapidly among patients and staff. The epidemic the endoscope, improved diagnostic techniques terminated by November, with 148 deaths in having transferred many cases of “nervous 284 cases (52 percent mortality). In 1979, an- indigestion” to peptic ulcer’s column. Advances other outbreak occurred with fewer cases and a in understanding the neurohumoral mecha- small number of deaths. nisms that regulate the digestive tract and The epidemic in Zaire was traced to an in- the biochemical basis of emotion, furthermore, dex case seen in September 1976. This in- promise to provide organic interpretations for dividual received an injection of chloroquine dyspepsias now identified as functional. As a for presumptive malaria at the Yambuku Mis- consequence, the very term “dyspepsia,” histor- sion Hospital, Bumba District. He recovered, ically associated with nervous, nonorganic ill- but within a week an epidemic of fever be- ness, is becoming antiquated. In recent decades, gan in hospital patients and staff. There were medical writers have begun encapsulating the 318 cases with 288 deaths (90.5 percent mortal- word in quotation marks to call attention to its ity). As in Sudan, the epidemic ended by early quaintness, and inserting it into the index only November. The first epidemiological team sent to be followed with “see indigestion.” to the area diagnosed a “fulminating” epidemic James Whorton of typhoid fever in a vulnerable population. Fatalities, however, occurred in a hospital in Kinshasa among three nurses who had been transferred from the infected area, and as in- 43. Ebola Virus Disease vestigations continued, it became clear that the virus had passed from human to human via With recognition of new, deadly viral infec- contaminated syringes. Strict needle discipline tions – such as Lassa fever, Marburg, Ebola, and isolation of patients were reestablished and Congo-Crimean hemorrhagic fever, Rift Val- maintained. ley fever, and AIDS – the classic descriptions of In 1979, another hospital-centered outbreak diseases such as malaria and yellow fever must occurred in Zaire, 300 kilometers from the

107 43. Ebola Virus Disease original epidemic. Twenty-two of 33 patients viruses. A distinguishing characteristic between died (66 percent mortality). Ebola-Sudan and Ebola-Zaire is pathogenicity. In 1989, an epidemic – confirmed as Both cause excessive mortality, but less so for Ebola virus disease – erupted among Macaca the Sudan strain than for the Zaire strain. A new cynomolgus monkeys shipped from the Philip- family, Filoviridae, has been created for Marburg pines to a laboratory in Reston, Virginia, via and Ebola. Amsterdam and Kennedy airports. Sixty of 100 Onset was usually sudden, with progressively monkeys died. Soon, a second shipment arrived severe frontal headache as seen with Plasmod- including two infected monkeys. Extensive ium falciparum malaria, spreading occipitally. international epidemiological investigation Fever and weakness were always present. Myal- focused on this frightening episode. No human gia appeared early. Arthralgia of the large joints cases were reported and no satisfactory expla- was common. Severe generalized disease fol- nations advanced. All exposed individuals were lowed in days. Patients were lethargic, their monitored. faces expressionless with deep-set eyes. Loss Epidemiologists have attempted to trace the of appetite, sometimes accompanied by vomit- origins of the Ebola virus and its distribution, ing and weight loss, was nearly constant. Gas- locate host vertebrates, and learn its patterns trointestinal symptoms developed, frequently of maintenance, propagation, and transmission. accompanied by cramping. But efforts have been limited to a handful of In later stages, particularly in patients with dedicated investigators and a spotty sampling hemorrhagic manifestations, red blood ap- of the vast expanse of sub-Saharan Africa. Pri- peared in the stools. Vomiting continued in mate sampling has revealed at best minimal nearly half of patients with hemorrhagic signs; involvement. Associated with the 1979 Zaire vomitus was often of red or changed blood. outbreak is the unexpected finding of guinea Other common manifestations included sore pig immunes. Guinea pigs are South American throat and dysphagia, fissures and sores on the rodents, raised there as pets and for food. They lips, conjunctivitis and subconjunctival bleed- were introduced into Africa decades ago and in ing, and coughing. Jaundice occurred in some. some regions are established as inquilines in Pancreatitis was also frequent, and abortion oc- houses. In this respect, their behavior resem- curred in 23 percent of pregnant women. Hem- bles that of the multimammate rat (Mastomys orrhagic manifestations, seen in many patients natalensis), already known to be involved in the (including more than half of fatal cases), prob- maintenance and transmission of Lassa virus. ably resulted from disseminated intravascular Guinea pig immune rates up to 26.1 percent coagulation. Death occurred as early as the were found in some locations, but studies failed fourth day, more usually on the fifth or sixth to indicate transmission among guinea pigs or day, and occasionally as late as the twentieth between guinea pigs and humans. day. Several pathologists deemed differential diag- Characteristics nosis of Ebola infection to be extremely difficult The Ebola agent consists of long filamentous in settings where there might be malaria, Lassa rods, sometimes branched, often intertwined. fever, Marburg disease, yellow fever, Congo- The virion contains one molecule of single- Crimean hemorrhagic fever, typhoid, infectious stranded RNA. The particles resemble those of hepatitis, leptospirosis, brucellosis, and other the Marburg agent but with differences: For ex- fevers. Others felt the lesions observed were ad- ample, Ebola has more branching than Marburg. equately specific to permit an Ebola diagnosis. Serologically, no relationship has been demon- Plasmapheresis with plasma from recovered strated, either to Marburg or Lassa or any other patients was tried as treatment, but indications

10 8 43. Ebola Virus Disease offered little hope of effective therapy. No drugs Because the Reston monkeys (and those at have been effective. A possible vaccine remains Siena) came from the Philippines (indicating a dream. that the Filoviridae are not exclusive to Africa), Wilbur G. Downs attempts have been made to find the virus there, although so far without success. As with the other Ebola strains, researchers have no idea where it lives in nature. Postscript The other form of the virus, Ebola-Tai For- Thanks to best-selling books, a motion pic- est (or Ivory Coast) derived its name from a ture, and newspaper and magazine articles, dur- single nonfatal case in the Tai forest of the ing the 1990s Ebola virus scared the wits out Coteˆ d’Ivoire developed in 1994 by a Swiss of a public unlikely ever to be called upon researcher after performing an autopsy on an to face the explosive disease it generates. The infected chimpanzee. The case was important same, however, cannot be said for many trop- because it was the first evidence that Ebola ex- ical African populations who live in peril of isted in West Africa; since then, however, West what have become the Ebola viruses. This is African cases and fatalities have been reported because the family Filoviridae, created for the in the Coteˆ d’Ivoire, Liberia, and Gabon. The lat- Marburg and Ebola viruses, now breaks down ter experienced three outbreaks in remote areas Ebola into Ebola-Zaire, Ebola-Sudan, Ebola-Tai during a 20-month period spanning the years Forest (or Ivory Coast), and Ebola-Reston – all 1994–97, involving the deaths of nonhuman as of which reveal slight serological differences. well as human primates. Ebola-Zaire and Ebola-Sudan were the first to In the laboratory, a major difficulty with appear, whereas Ebola-Reston is named for the studying Ebola viruses is their high pathogenic- Virginia town where a form of Ebola broke out ity (classified by the CDC as Biosafety Level 4). in a laboratory among experimental monkeys In the field, the major difficulty in tracking what in 1989. But although the virus spread from is now called Ebola hemorrhagic fever (EHF) is monkey to monkey and proved deadly for many that, as in Gabon, it often strikes humans in re- of them, no human cases developed. Indeed, it mote areas. But not always: In the summer of has been suggested that, unlike the other Ebola 1995, Ebola-Zaire made a third large-scale ap- strains, Ebola-Reston may not be capable of pro- pearance when it struck the town of Kikwit, in ducing serious disease in humans, as four labo- western Zaire (now the Democratic Republic of ratory technicians were infected with the virus, the Congo). It infected 315 persons and killed but none became ill. 242 of them (77 percent). Interestingly, the virus In 1992, there was a repeat of the Reston proved to be virtually identical to that of 1976 episode in Siena, Italy, showing the wisdom of in northern Zaire. the U.S. Centers for Disease Control and Pre- Similarly, Ebola-Sudan recently (between Oc- vention (CDC) policy – developed in response tober 2000 and January 2001) resurfaced in to Reston – that embargoed importation of ex- three widely separated areas of Uganda, where perimental monkeys into the United States. This it triggered 425 presumptive cases and caused lasted about a year, after which the CDC be- 224 deaths (53 percent). One is immediately gan to re-license importers, but only those with struck by the consistently lower case-fatality approved facilities and properly trained staffs. rates generated by Ebola-Sudan (50–60 percent) However, safety concerns have created a trend than by Ebola-Zaire (77–88 percent) throughout away from wild monkeys toward the use of each of their appearances. captive-bred monkeys raised especially for the No hosts for the Ebola viruses have been medical experimentation market. discovered, although mammals (including

10 9 44. Echinococcosis (Hydatidosis) nonhuman primates), birds, reptiles, and in- Hydatid cysts in humans and animals have sects all remain suspects. Nor has new light been known since the ancient Romans, but as been shed on EHF transmission; as in the 1970s, with other tapeworms, the relationship between the blame still rests on dirty needles and close the larval cyst and the adult worm was not sus- contact with victims or objects they touched. pected until modern times. E. granulosus was de- Moreover, there has been no breakthrough scribed as a species in 1850, and its life cycle was in drug therapy and, for the moment at least, understood by 1863. there is little hope of a vaccine. Treatment The parasite first became a serious danger to of victims consists of shock prevention and humans when animals were domesticated. The supportive care, both complicated by the need expansion of European settlement spread infec- to protect medical personnel. However, studies tion to the Americas and Australasia. Echinococ- comparing the RNA sequences of the different cosis is also found in North Africa, the Middle viral strains are under way, which ultimately East, northern and central Asia, and most of sub- may help to unravel the etiology and epidemi- Saharan Africa. Iceland was a major focus in ology of EHF – a disease as mysterious as it is the mid-nineteenth century, but education, dog deadly. control, and sanitary slaughtering have elimi- Kenneth F. Kiple nated the disease. Similar methods, including mass treatment of dogs, have greatly reduced its incidence in Australia and New Zealand. The highest known prevalence of echinococ- 44. Echinococcosis (Hydatidosis) cosis is among the stock-raising Turkana of Kenya. Colonial medical authorities failed to The larval stages of three tapeworms of the recognize the disease until the 1950s, and an genus Echinococcus cause severe disease in hu- incidence of 96 per 100,000 has been esti- mans. All three normally become adults in the mated – over seven times the previous record intestines of dogs or other canids. Eggs are rate in Cyprus. The Turkana problem is linked passed in the feces and, if ingested by a her- to a close association between children and bivore, develop in the liver or other organs into dogs. a sac-like container of larvae, the hydatid cyst. Echinococcosis is often difficult to diagnose. Carnivores become infected by eating cysts with Cysts can be detected by X-rays or surgery; sev- the flesh of the herbivore. eral serologic tests are also used. Surgery was Echinococcus granulosus commonly has a the only effective therapy until the 1980s, when dog/sheep cycle but may also infect goats, cat- the drug mebendazole was employed with some tle, swine, and camels and is the most likely to success. infect humans. Human echinococcosis occurs K. David Patterson primarily in sheep-rearing areas. Dogs ingest cysts in the offal of dead sheep and pass eggs in their feces. Humans acquire the eggs from a dog’s fur or from contaminated food or water. 45. Eclampsia Cysts holding 2 or more liters of fluid and lar- vae can grow for years in the liver, lungs, brain, Eclampsia is a puzzling hypertensive disorder or other organs and exert enough mechanical affecting only women. Associated with preg- pressure to cause grave or fatal consequences. nancy and childbirth, it is an epileptic form Rupture of a cyst by trauma or surgery releases of convulsions that develops during the sec- daughter cysts, which may grow elsewhere in ond half of pregnancy. Eclampsia is associated the victim; the hydatid fluid can cause fatal with hypertension, edema, and toxemia, and anaphylactic shock. all three can cause the symptoms of the disease

110 45. Eclampsia to vary widely. Preeclampsia refers to hyperten- tics show it to be more common in urban ar- sion, abnormal edema, or proteinuria during eas, though this association may reflect only the pregnancy, whereas eclampsia is the disease’s fact that urban women who experience eclamp- most extreme form, manifested by severe con- sia or preeclampsia receive more medical assis- vulsions, coma, and even death. Eclampsia is tance in giving birth than rural women, and a leading cause of maternal and fetal mortal- thus the condition is more frequently noted ity and can cause stillbirths and premature la- and reported. Indeed, it is difficult to determine bor. Medical experts remain confused about the the frequency of eclampsia in rural areas and cause of this disorder and have no effective way Third World nations because women there sel- to cure the disease other than to terminate preg- dom seek, have access to, or can afford regular nancy by delivering the baby. Through careful prenatal care and a hospital delivery. prenatal care, however, physicians can usually Symptoms of eclampsia and preeclampsia in- control the problem, and it is now relatively rare clude excessive and sudden weight gain, edema, in the United States and Europe. hypertension, and proteinuria. Patients may Not only is the disease difficult to define, but also suffer from headache, dizziness, visual also accurate records of its existence are rare, disturbances, anorexia, nausea, vomiting, up- especially in Third World countries where pre- per abdominal pain, and swelling of face and natal care by medical attendants is uncommon. extremities. In severe cases, women experi- Although eclampsia is among the diseases most ence visual and neurological disturbances, olig- troubling to obstetricians, research is difficult uria (a deficiency of urine excretion), and, of because it is found only in humans. Its etiology course, convulsions. In addition, cardiac out- remains unknown but may be multifactorial. put increases and the kidneys (which seem to be the target organ for the disease) are af- Characteristics fected. Eclampsia can lead to lethal complica- For reasons not understood, eclampsia seems tions affecting the liver, kidney, uterus, and more common among the economically under- brain, such as abruptio placentae, acute re- privileged. The typical patient is a young woman nal failure, cerebral hemorrhage, disseminated in her first pregnancy, of low socioeconomic intravascular coagulation, and circulatory col- status, and with little or no prenatal care. It is lapse. Preeclampsia does not occur before the more common among women with diabetes, twentieth week of pregnancy, and eclampsia high blood pressure, or renal or vascular dis- rarely before the thirty-second week. ease; who suffer from poor nutrition or hydat- iform moles; who are at the age extremes of History childbearing years; and who bear twins. It oc- The writings of Egyptian, Chinese, Indian, and curs more frequently in spring and summer and Greek scholars note no convincing cases of in certain locations. It also evinces a familial ten- eclampsia other than occasional remarks de- dency, suggesting a genetic disorder. scribing a pregnant woman’s convulsion, fit, or Eclampsia is less likely to occur in women headache. For centuries, eclampsia was com- who have experienced a previous case. Few con- monly mistaken for epilepsy. If discussed at all, clusive studies indicate that race is a factor, it was attributed to uterine suffocation. Ther- though it has been suggested that black women apy focused on encouraging a retrograde mo- in the United States are more likely than their tion of the uterus to relieve pressure on the up- white counterparts to suffer eclampsia because per body and brain. Medieval writings only hint of a greater tendency to develop chronic hyper- at the disease, but perhaps this paucity of in- tension on the one hand, and less opportunity formation was because midwives monopolized for maternal care on the other. The disorder birth assistance and failed to record problems occurs in 6–8 percent of pregnancies. Statis- they encountered.

111 46. Emphysema

In the second century, Galen noted that proteinuria in preeclamptic patients. This major epilepsy could be fatal to pregnant women, breakthrough meant the disease could be con- and Eucharius Rosslin¨ in the sixteenth cen- sidered a toxemia rather than one caused by me- tury stated that convulsions and unconscious- chanical pressure. Until the twentieth century, ness were ominous signs in pregnant women. eclampsia was associated with wealthy women, Jacques Guillimeau in 1612 concluded that con- probably because they used male doctors who vulsions occurred because the fetus was striving wrote about the disorder. Not until the 1930s to come forth or improper positioning extended were poor women viewed as susceptible. Un- the womb. Franc¸ois Mauriceau in 1688 was the wed mothers were also seen as vulnerable, per- first systematically to describe eclampsia, indi- haps because their infants were more likely to cating a new concern with the disorder as men be primogravids. Early in the twentieth century, entered the field of obstetrics. He also was the eclampsia was usually associated with hyper- first to note that primogravids were at greater tension, though speculation as to its origin was risk than multigravids. Mauriceau suggested still common. several causes, including excessive hot blood Today, physicians depend on careful monitor- flowing from the uterus and malignant vapors ing of blood pressure and proteinuria during from a dead fetus. In 1694, he recommended pregnancy, while watching for edema and ex- that two or three phlebotomies be performed cessive weight gain. Early detection is essential. routinely during pregnancy should a woman ex- If a woman should suffer preeclampsia, physi- hibit eclamptic tendencies. All early medical ex- cians recommend rest and constant monitoring. perts agreed that it was a dangerous disease. If a patient suffers convulsions, attendants take During the nineteenth century, medical spec- immediate measures to prevent physical injury ulation about the causes of eclampsia was by suctioning her air passage, providing oxy- widespread. These included a woman’s rapidly gen, and employing magnesium sulfate to con- changing emotions, a sanguine or plethoric trol the seizures. Seizures can cause fetal death state, excessive hemorrhaging, blood to the because the convulsive woman is not breathing brain, nutritional deficiency, excessive protein and thus the baby is cut off from its oxygen sup- in the system, albuminuria, renal deficiency, re- ply. If the baby is near term, doctors make every tention of urinary constituents, nerve irritation, effort to deliver it once convulsions have sub- high blood pressure, seasonal changes, lethargy, sided and the patient is conscious. melancholia, wealth, improper positioning of Sally McMillen the womb, corrupt menstrual flow, a bad seed, an unstable personality, passions of the mind, and interrupted circulation. Therapy was generally “heroic.” Solutions in- 46. Emphysema cluded warm baths, doses of opium, extensive bleeding from the jugular vein or a temporal Pulmonary emphysema is defined in morpho- artery, depletion to rid the body of toxins, re- logical rather than clinical terms. In 1958, em- moval of meat or milk from the diet, mustard physema was defined as an “increase beyond poultices, ice or cold water on the head, snuff, the normal of air spaces, distal to the termi- clysters, emollients to dilate the cervix, and nal bronchiole, either from dilation or from de- plasters to the lower body to draw the uterus struction of their walls.” A 1962 statement made downward. anatomic destruction a part of the definition: In 1768, Thomas Denman wrote one of the “Emphysema is an anatomic alteration of the earliest English monographs on the disease. lung characterized by an abnormal enlargement John Lever and James Simpson in 1843 simulta- of the air spaces distal to the terminal, nonrespi- neously discovered the consistent occurrence of ratory bronchiole, accompanied by destructive

112 46. Emphysema changes of the alveolar walls. The definition ease, especially of moderate to severe forms, was further refined in 1985: “Emphysema is de- although some forms of mild emphysema are fined as a condition of the lung characterized by quite common and can occur in nonsmokers. abnormal, permanent enlargement of airspaces Greater incidence in males may reflect their distal to the terminal bronchiole, accompanied greater prevalence of smoking; if that is the case, by the destruction of their walls, and without then as more women take up cigarette smoking, obvious fibrosis.” this sex preference may change. Although em- Emphysema can also be subclassified in physema is remarkably common, it causes – or anatomic terms. If emphysematous changes contributes to – death in only a small percent- predominate in the region of respiratory bron- age of cases. chioles, the condition is termed centriacinar The patient with clinically significant emphy- or centrilobular emphysema. More uniform in- sema is typically an older male smoker with a volvement constitutes panacinar or panlobular history of breathing difficulties that increase in emphysema. Occasionally, emphysema may oc- severity over time. He is usually thin, with a tho- cur adjacent to a scar or fibrotic process and is racic configuration (barrel-chested) suggesting called paracicatricial emphysema. hyperinflation, and has markedly diminished breath sounds on auscultation. Airflow obstruc- Characteristics tion can be demonstrated. However, this “typi- Because emphysema is, by definition, a morpho- cal” clinical picture is more often the exception logical diagnosis, its presence and prevalence than the rule. In several autopsy series, moder- depend on examination and interpretation of ate to severe emphysema was found in a signifi- the lungs during autopsy. Obvious emphysema cant proportion of individuals who exhibited no is likely to be found in at least 50 percent of an clinical evidence of disease. Most often, emphy- average autopsy population, with a frequency sema occurs in conjunction with chronic bron- of about 65 percent in men and 15 percent in chitis and is accompanied by a chronic produc- women. Incidence increases with age, reaching tive cough. 30 percent by the fourth decade and 60 percent The presumptive diagnosis of emphysema by the seventh decade of life. It has been sug- cannot be made without pulmonary function gested that at least some emphysema may be a tests. Chronic airflow obstruction manifested by universal finding in elderly adults. slowing of forced expiration is characteristic of Perhaps because of a younger average age moderate to severe emphysema, although even of the population examined and a lower preva- this finding may not be universal. When em- lence of cigarette smoking, studies from Africa physema increases in severity, hyperinflation is reveal a lower frequency of emphysema than reflected by an increase in total lung capac- elsewhere. Yet even when populations are the ity and residual volume, and carbon monox- same age, and lungs examined by the same ide diffusing capacity is reduced. Loss of lung investigators, national and even regional dif- elastic recoil is commonly associated with em- ferences seem prevalent. For example, the fre- physema. Such physiological data provide more quency of emphysema is greater in parts of sensitive indicators of the presence of emphy- Britain than in Sweden or some parts of North sema than do clinical symptoms or radiological America, and lower in some North American findings. cities than in others. These differences may re- flect different levels of cigarette smoking or air History pollution, or the selection of people autopsied. In 1698, John Floyer described bullous em- Various studies agree that the severity of physema, together with hyperinflation and loss emphysema increases with advancing age. of lung elastic recoil, in a horse he dissected. Cigarette smoking is a primary cause of the dis- In 1793, Matthew Baillie described human

113 47. Encephalitis Lethargica emphysema with tissue destruction leading to of localized damage to the nervous system – airspace enlargement. Good evidence indicates occurred in three-fourths of cases. Lethargy that the lung illustrated in Baillie’s book was lasted a few days in some patients, but in oth- that of Samuel Johnson, whose lungs, at au- ers it persisted much longer, sometimes until topsy, were permanently distended and failed death from comatose respiratory failure. Spas- to collapse on opening the chest. In his clas- modic twitching and severe psychic and behav- sic Treatise on the Diseases of the Chest that ior changes often persisted long after the ill- appeared in 1819, Rene´ Laennec provided the ness. Approximately one-third of patients died first description of pulmonary emphysema, its of acute disease, and 80 percent of survivors destructive nature, and its association with later developed parkinsonism. chronic bronchitis. James Jackson accumulated The main findings were a diffuse inflamma- a series of emphysema cases and noted that tory reaction in the meninges and blood vessels the disease exhibited a familial predisposi- of the brain and spinal cord, and degenerative tion. (Though he died in 1834, his work was changes in the neurons, especially in the brain- published in 1837.) But not until 1963 was stem, basal ganglia, and cerebellum, but also in- emphysema’s genetic alpha-1-antitrypsin defi- cluding the cortex and subcortical white matter. ciency described. Physiological changes asso- In the spinal cord, both white and gray matter ciated with emphysema have attracted the at- were involved in the disease process. tention of many investigators over the years. Although epidemics of encephalitic dis- The precise mechanisms causing emphysema’s ease had occurred in conjunction with many characteristic lung destruction are under cur- influenza epidemics (1580, 1658, 1673–75, rent investigation. 1711–12, 1729, 1767, 1780–82, 1830-33, 1847– Ronald J. Knudson 78, and especially 1889–92), the pandemic as- sociated with the 1918 influenza pandemic was unparalleled in virulence and seque- lae. Along with its unique time distribution 47. Encephalitis Lethargica (1917–26), the encephalitis lethargica epidemic had a pronounced seasonal predilection for win- Foremost among recorded encephalitis epi- ter months. demics was the global pandemic of encephali- Encephalitis cases were so closely associated tis lethargica that spread from Europe during with influenza attacks that many initially be- World War I and repeatedly struck throughout lieved the disease was caused by influenza. the world during the 1920s. This pandemic both Subsequently, however, many epidemics of en- accompanied and followed the 1918 influenza cephalitis occurred when no influenza activ- pandemic. ity existed, which generated skepticism that in- fluenza could be the cause. Long latent intervals Characteristics and slow viruses were not well recognized in Encephalitis lethargica was often a sequel to in- 1918; moreover, influenza was contagious and fluenza. Patients developed the triad signs of encephalitis was not. All this was misinterpreted fever, lethargy, and disturbances of eye move- as indicating that these were unrelated diseases ment, along with other symptoms including rather than different manifestations of the same headache, tremor, weakness, depression, delir- viral agent. Even the name “encephalitis lethar- ium, convulsions, and inability to articulate gica” generated ongoing diagnostic confusion. ideas, coordinate movements, or recognize sen- Although early reports of encephalitis pre- sory stimuli, as well as psychosis and stupor. ceded the explosive dissemination of influenza Oculogyric crisis (fixed eyeballs) and other eye- in 1918, influenza was active during the winter movement disorders – the most frequent sign of 1916–17.Encephalitis was reported in Britain,

114 47. Encephalitis Lethargica

Scandinavia, Germany, the United States, and distributed and closely related in time, and other countries in 1918, but its epidemic only one agent (influenza virus) has been re- peaks occurred in 1919–20 and subsequent liably identified. Local, regional, and national winters. influenza/pneumonia epidemics preceded local, Attack rates for encephalitis lethargica during regional, and national epidemics of encephali- the pandemic years 1918–26 approached 1 case tis lethargica. A large proportion of encephalitis per 1,000 population in the United States and cases had had influenza. Later, when patterns Europe. Reports indicate that rates may have shifted from massive epidemic to sporadic en- been similar worldwide, except in some areas, demic, the relationship between the two dis- most notably American Samoa, where neither eases became progressively obscured. influenza nor encephalitis occurred during the pandemic years. The world total of encephali- History tis lethargica cases was probably more than 1.5 From among all causes of encephalitis – million, of whom about 500,000 died of acute structural, chemical, and microbiological – it illness. More died from parkinsonism and other was difficult to identify specific infectious or- complications in later stages. ganisms and routes of transmission. But in Leading researchers of the 1920s judged the the late nineteenth and twentieth centuries, relationship between influenza and encephalitis many agents and vectors of encephalitis be- to be inconsistent, and stated the etiology of en- came known, among them the syphilis spiro- cephalitis lethargica to be “unknown.” But in re- chete, the trypanosome of African sleeping cent decades, from research undertaken in Seat- sickness, the bacterial toxin of botulism, yel- tle and Samoa, the disease’s etiology seems clear. low fever, Japanese B encephalitis, equine en- Seattle records show a characteristic lag of ap- cephalitis, rabies, influenza, mumps, measles, proximately a year from influenza/pneumonia the enteroviruses, and most recently the human death peaks to onset of encephalitis lethar- immunodeficiency virus. Adding to diagnostic gica clusters, providing strong evidence that confusion were many cases of stuporous en- encephalitis cases were actually late sequelae of cephalitic reactions to various toxins and drugs, influenza. especially Reye’s syndrome, caused by aspirin, In the Samoan Islands, the sharply contrasting the etiology of which became known only in the experiences of Western and American Samoa 1980s. provided a unique basis for studying the pan- But the main causative agent of epidemic en- demic. In Western Samoa, nearly 20 percent of cephalitis during the pandemic years was the the population died of influenza during two influenza virus. Successive peaks of encephalitis months in 1918 alone. Meanwhile, American occurred in European, Asian, African, and Amer- Samoa, just 70 kilometers away and inhabited ican countries. In the United States, encephalitis by the same racial stock, avoided the infec- lethargica progressed across the country from tion. Despite the rudimentary nature of Western east to west in 1919, just as influenza had the Samoan records, it is clear that that territory suf- previous year, reaching peak occurrence in New fered heavily from both influenza/pneumonia York during January 1919; in Virginia during and encephalitis lethargica during the years February; and in Illinois, Louisiana, and Texas 1918–22. American Samoa was remarkably free during March. In California it peaked in April, of both diseases during those years. and in Seattle the first cases were reported in The evidence, then, is compelling that the October. pandemic of influenza beginning in 1918 and Research has tended to disregard the in- the pandemic of encephalitis lethargica gener- fluenza/encephalitis/parkinsonism puzzle, ap- ally beginning the following year had a com- parently on the assumption that these epi- mon etiology. Both pandemics were globally demics are of little importance to current and

115 48. Enterobiasis future health. But failure to identify influenza or appendix, but rarely cause serious harm. virus as the cause of encephalitis lethargica Rectal itching and consequent insomnia, espe- and parkinsonism has crippled progress toward cially in children, are suggestive of pinworm the understanding needed to prevent these elu- infection. sive but exceedingly important diseases. Almost The condition normally is self-limiting in the every disease of the central nervous system absence of continuing reinfection. Drug treat- (CNS) may follow influenza. Thus we should ment is safe and effective, but often an entire examine CNS damage caused by influenza at- family or living group must be treated simul- tacks during earlier life when seeking the keys taneously, and bedding and clothing must be to serious CNS disease, especially Alzheimer’s thoroughly cleaned. Even the most fastidious disease. housekeepers may find it difficult to rid a home R. T. Ravenholt of airborne eggs. Personal hygiene is the best preventive measure. K. David Patterson

48. Enterobiasis

The pinworm Enterobius vermicularis is a com- 49. Epilepsy mon parasite around the world and is the most prevalent parasitic helminth in developed coun- Epilepsy is characterized by repeated seizures tries today. Enterobiasis has afflicted humans resulting from recurrent, abnormal, excessive, from ancient times; it was known to ancient synchronous discharges of cerebral neurons. Chinese, classical, and Islamic writers and was It has probably been in existence since the present in pre-Columbian America. Humans are dawn of humanity. The condition is chronic the only hosts. Mature worms of 2–13 millime- but rarely fatal. Modern medications can con- ters inhabit the cecum and adjacent regions of trol seizures, and the limitations imposed by the intestines. Gravid females migrate out the the disorder may be negligible. Unfortunately, host’s anus and deposit thousands of eggs on epileptics are all too frequently stigmatized and the skin of the perianal region. The eggs ma- excluded from many activities. Outdated be- ture quickly and are infectious within hours. liefs and misconceptions about epilepsy have Infection by ingestion of eggs from the hands only recently shown signs of lessening in is common, as the worms induce itching and the United States and other industrialized scratching. Eggs are frequently eaten with con- societies. taminated food, and, because they are light, they are easily inhaled in household dust. Eggs Characteristics hatch in the small intestine and develop into Although epilepsy can begin at any age, most mature adults in as little as 4 weeks. Retroinfec- patients have their first seizure before 20. In tion, when eggs hatch on the perianal skin and fact, age of onset is often related to etiology. the larvae crawl back into the rectum, is possi- Perinatal injuries, severe hypoxia, developmen- ble but rare. Pinworms are especially prevalent tal brain defects, and genetic metabolic de- among small children and often become a fam- fects are common causes of epilepsy among in- ily affair. fants and the newborn. Brain infections such Enterobiasis is rarely a serious disease. In- as meningitis and encephalitis often damage testinal disturbances, if any, are minor, but brain cells, with subsequent development of pinworms can cause great discomfort, and epilepsy. Many children experience seizures scratching can lead to secondary infections. Mi- during high fever caused by infection elsewhere grating worms occasionally reach the vagina than the brain; however, only a tiny percentage

116 49. Epilepsy of such febrile seizures persist after the age and loss of consciousness, which may or may of 4. In urban ghettoes, lead poisoning and not occur in partial seizures depending upon drug addiction are among the leading causes the part of the brain initially affected and subse- of epilepsy. Head trauma is a common cause of quent involvement of other structures. The clin- seizures among adults, although brain tumor ical manifestation of the seizure approximately must also be suspected, as about 40 percent of corresponds with the brain site where electrical patients with brain tumors have seizures. Later abnormality occurs. in life, seizure may result from cerebrovascular “Epilepsy” was first used to denote the symp- attack. toms of major ( grand mal ) seizure, currently Despite medicine’s increased ability to deter- termed “tonic-clonic” seizure. Over 60 percent mine various causes of epilepsy, many seizures of all epileptics have tonic-clonic seizures. A proceed from no definitively known or reason- sudden burst of discharges involving the whole ably presumed cause. That genetic factors are brain occurs without warning. The patient falls involved, however, is indicated by the fact that to the ground unconscious. Then, in the tonic people with family histories of epilepsy have a phase, the patient goes rigid and often gives higher incidence of seizures than the general a short cry because of diaphragm and chest- population. Moreover, according to electroen- muscle contraction. The eyes may roll upward cephalograms (EEGs), asymptomatic relatives of or sidewise, and the tongue may be bitten. Af- epileptic patients exhibit greater abnormal dis- ter this, jerky clonic spasms alternately flex and charge than among the general population. extend muscles of the head, face, and extrem- Epilepsy is characterized by recurrent ities. During this phase, the patient may be- seizures; thus, a single seizure does not of come injured as well as incontinent. Cyanosis is itself indicate an epileptic condition. Nervous usually marked. Breathing is deep, with sweat- system infection, metabolic imbalance, and ing and salivation. Subsequent to the seizure, head injury may all result in a seizure episode the patient may awaken in a confused state without further risk. Among epileptics, how- (the “postictal twilight state”) and even display ever, any number of stimuli may trigger seizure some bizarre behavior. Sometimes patients are activity. Fatigue, alcohol abuse, and infection, difficult to rouse, sleep for hours, and awaken for example, commonly precipitate attacks with headache or sore muscles. Although most in people whose epilepsy is otherwise well tonic-clonic seizures last for only a few min- controlled. utes, some develop into a series of seizures Since the 1960s, epidemiological surveys of with no letup, or a continuous prolonged epilepsy have reported crude prevalence rates seizure. This serious condition (status epilep- between 3.6 and 5.5 per 1,000 population. Such ticus) may lead to death without immediate studies, however, are plagued with problems, care. most importantly a lack of agreement on the A variety of generalized seizures have been definition of epilepsy itself as well as what con- recognized. Sometimes patients exhibit only the stitutes an active or an inactive case. Moreover, tonic or clonic aspects of the seizure. Between some cases are simply not identified by survey ages 4 and 12, “absence” seizures often occur. procedures. These have been called petit mal because their Epilepsies are classified by localization of the brief duration – only a few seconds – often ren- electrical abnormality in the brain. The major di- ders them unrecognized and untreated. During vision is between generalized (centrencephalic) the brief lapse of consciousness, the child stares seizures – with brain activity throughout the vacantly, neither speaking nor hearing. Subse- cerebral cortex – and partial (focal) seizures oc- quent activity is resumed with no period of curring in only one part of the brain. Gener- stupor. Equally brief are “atonic” seizures, dur- alized seizures exhibit bilateral motor activity ing which the child simply falls to the ground;

117 49. Epilepsy

“myoclonic” seizures, which are sudden, brief, robe. Patients often stagger about uttering gut- and massive, involving the entire body or con- tural sounds. Such behavior is alarming to on- fined to extremities, face, or trunk; and “infantile lookers and often confused with psychiatric spasms,” during which the child is jerked into a disorder. fetal position with the knees drawn up. Many Secondarily generalized partial seizures be- children with infantile spasms are also mentally gin with a focal onset, then spread throughout retarded. the brain and produce generalized tonic-clonic All partial seizures begin in one part of the seizures. Because the generalized phase is so brain, and because different parts of the brain dramatic, people often overlook the focal onset. control different parts of the body (as well as The presence of an aura indicates a probable mental and sensory functions), their signs are focal onset and the need to observe the initial varied and often complex. Many patients ex- phase more closely. hibit behaviors easily mistaken for psychiatric Eliciting the type of epileptic seizure is im- problems, hindering accurate diagnosis. Victims portant in confirming diagnosis and choosing of partial seizures may display bizarre, learned, antiepileptic medication. An accurate medical culturally conditioned behavior. history is crucially important. EEGs adminis- Simple partial seizures have been variously tered between seizures may or may not re- called “focal,” “focal motor,” or “focal sensory” veal patterns suggestive of epilepsy. Neverthe- seizures. Although symptoms may be motor, less, because they often do reveal abnormal dis- autonomic, psychic, sensory, or a combination, charges, routine administration of EEGs is of sig- they are all linked to the affected area of the nificant value in evaluating any possibly epilep- brain. The patient remains conscious as a gen- tic patient. eral rule, and the attacks last no more than 30 By conservative estimates, some 50 percent seconds. One type of simple partial seizure has of patients can control recurrent seizures with- been called the “Jacksonian” – it characteristi- out side effects with optimal medical treatment. cally begins with the twitching of one foot or Another 30 percent can achieve seizure control hand. but experience some side effects of the medica- Complex partial seizures are characterized tion. For some patients whose seizures cannot by complex symptoms and impairment of con- be controlled by medication, surgery may suc- sciousness. Often the patient appears conscious ceed if a distinct piece of brain tissue causing the but later has no recollection of the episode. seizures can be identified, and if its removal will These seizures are usually associated with not cause unacceptable neurological deficits. the temporal or frontal lobe and often begin with an “aura” warning of the impending at- History tack. Auras include any number of sensations. The antiquity of epilepsy is attested to by an Some of those most commonly reported are ancient Akkadian text. The Greeks called it the nausea; faintness; dizziness; numbness of the “sacred disease” as well as epilepsy (“seizure”), hands, lips, and tongue; choking sensations; which may derive from the idea that diseases and chest pain. Less often, patients report vi- represented attacks by supernatural beings. The sions, palpitation, or disturbances of smell or term “sacred disease” is found first in the writ- hearing. Some patients’ sensations may begin ings of Heraclitus and Herodotus and is ex- hours or even days before the seizure. These plicitly identified with epilepsy in the Hippo- symptoms are called the “prodrome” and most cratic collection of medical writings (c. 400 often involve irritability or uneasiness. Psy- B.C.), which includes the earliest monograph on chomotor symptoms appearing during a seizure epilepsy we possess. are generally semipurposeful and inappropri- Underlying various explanations offered by ate actions such as clumsy attempts to dis- the ancients was the basic belief that epilepsy

118 49. Epilepsy is an affliction or possession by a higher power witchcraft, and various magical treatments. De- and that its cure must be supernatural. The spite many efforts to define epilepsy and clas- disease was also believed contagious: Epilep- sify seizures, little medical progress was made, tics were unclean, and anyone touching them although gradually the idea of epilepsy as a nat- might become prey to the demon. This sup- ural disease gained more credence, especially af- posed contagion was one of the factors that ter the Enlightenment. stigmatized epileptics and made their lives a By the beginning of the nineteenth century, misery. To the ancients, the epileptic was an epileptics were hospitalized, although unlike object of horror and disgust – not a saint the insane, they were allowed to go to church or prophet as has sometimes been contended. on Sundays. Moreover, confined epileptics be- Physicians of antiquity differentiated the sa- came subjects of systematic medical attention. cred disease from hysterical attacks as well as It was slow going at first, and only in 1838 madness. were epileptic children in Paris removed from In the struggle between supernatural and sci- the Hospital of the Incurably Ill and provided entific explanations of disease, science has grad- some kind of education. In addition, the sepa- ually emerged victorious in the Western world. ration of hospitalized epileptics from the insane The fight, however, has been long and event- was motivated less by solicitude for the epilep- ful, and in it epilepsy held one of the key posi- tics than by a belief that epilepsy was infectious tions. Showing both physical and psychic symp- and would affect the insane even more than it toms, epilepsy more than any other disease was did the healthy. The confinement of epileptics open to interpretation both as a physiological in separate wards of lunatic asylums became es- process and as the effect of supernatural influ- tablished procedure in Europe around 1850 and ences. The Hippocratic texts provide the first was soon followed by requests for special insti- record we have of the battle in an attack on tutions for epileptics. popular superstition about the “sacred disease.” Nonetheless, during the early nineteenth cen- The text maintained that epilepsy was heredi- tury, valuable contributions were made by tary, that its cause lay in the brain, and that it physicians in hospitals and asylums, and new be treated by diet and drugs as long as it was terminology, increased use of statistics, and in- not yet chronic. It is here we first find the fun- terest in the psychiatric side of epilepsy devel- damental statement that the seat of the disease oped. The terms grand mal, petit mal, “absence,” is in the brain and that the brain is the organ of status epilepticus, and “aura,” for example, came all psychic processes both normal and patholog- into common usage and survive to this day. ical. Moreover, not only epilepsy but all mental The use of statistics fostered investigation into diseases were to be explained by disturbances the heritability of epilepsy and its causes. De- in the brain. spite the increased attention, however, mod- During the Middle Ages, literature on epilepsy ern medicine’s understanding of the disease be- propounded two contrasting views. On one gan around 1880 with the work of John Jack- hand, the “falling evil” was bound to demo- son in England and Jean Charcot in France. niac beliefs and theological speculations; on the Jackson outlined a neurological theory of other, physicians clung to the idea of a definite epilepsy, while Charcot separated epilepsy from natural disease. Little effort was made to force hysteria more emphatically than any of his pre- the issue; physicians rarely discussed the the- decessors. In 1888, Jackson’s principles were ological aspects and anyway were apparently vindicated by William Macewen, who demon- unable to rid themselves of traditional defini- strated the connection between physical seizure tions and explanations. By the end of the six- symptoms and specific brain sites of abnormal teenth century, however, this changed: Debate discharge. became open, involving the role of the devil, Jerrold E. Levy

119 50. Ergotism

50. Ergotism long periods, resulting in permanent stiffness of joints, muscular weakness, optic disorders, and Ergotism is a disease condition acquired by eat- occasional imbecility. ing cereal grains infected with ergot fungus. Midwives and empirics discovered that spas- Known since the time of Galen, it was preva- modic ergotism caused abortion or miscarriage lent in medieval Europe, particularly among in pregnant women, the drying up of milk in the poor who, during famine, consumed bread lactating mothers, and amenhorrea in young made from spoiled rye. Ergot (secale cornutum, girls. This abortifacient or oxytocic effect was “spur of the corn,” “horned rye,” “womb grain”), later noted by orthodox medicine and led to the dried sclerotium of Claviceps purpurea, de- the widespread use of ergot to accelerate uterine velops on the ovary of common rye, or on corn, action. Before long, doctors began distinguish- where it was previously known as “corn smut.” ing ergot with sobriquets such as poudre ob- The actual cause of ergot in grasses was hotly stetrical, “forcing powders,” or more commonly, debated by early naturalists, some of whom “forcing drops.” Not surprisingly, it also played a thought it occurred in rainy weather and was at- major role among quacks, charlatans, and “pri- tributable to fog or impure atmosphere. Others vate specialists” who promised a quick and pain- believed it was the work of worms or butterflies, less cure for women desiring to “regulate” their whereas still others regarded it as the product menstrual cycles, a euphemism for terminating of improper fecundation or perhaps the cooking a pregnancy. For some, ergot substituted for the of the sexual parts of the plants. more common borax, cinnamon, and turpentine as an abortifacient. Characteristics Gangrenous ergotism often began with itch- Ergotism has two forms: “convulsive” or “spas- ing and formications in the feet, or sensations modic” (also known as “creeping”), which af- of extreme cold, followed by burning pain, or a fects the central nervous system; and “gan- crop of blisters. A dark spot usually appeared grenous,” which affects blood vessels and blood on the nose or affected extremity, leading to supply to the extremities. Common names for loss of sensibility in the part. Early nineteenth gangrenous ergotism are “Saint Anthony’s fire” century accounts mentioned headache, dizzi- (after the patron saint of the disease), “hid- ness, nausea, vomiting, diarrhea, and spreading den fire,” “saint’s fire,” “evil fire,” “devil’s fire,” erysipelatous redness. The epidermis was raised and “holy fire.” Early imprecision in disease by serous exudation, and the surface assumed specificity led physicians to confuse ergotism the appearance of gangrene with the extrem- with plague and various other diseases includ- ities becoming withered and blackened. Usu- ing leprosy, anthrax, typhus, smallpox, and ally the gangrene was dry, but the moist vari- scurvy. ety was not unknown. The patient suffered from Convulsive ergotism causes areas of degen- continual low fever and phthisical symptoms eration in the spinal cord. Early German ac- and faced eventual death from exhaustion or counts mentioned tingling and mortification septicemia, but recovery often followed loss of in fingers and toes – occasionally extending the affected limb. When gangrene attacked the to the rest of the body – and vomiting, diar- viscera, however, death occurred quickly. rhea, intense hunger, anxiety, unrest, headache, vertigo, noises in the ear, stupor, and insom- History nia. Often the limbs became stiff, accompa- First allusions to ergotism are concurrent with nied by convulsive muscle contractions leading French monastic hospices, which cared for the to staggering and awkward movements, often common people and took special note of the aggravated by touch. Although many victims disease. Along with these observations came recovered, symptoms sometimes remained for the designation of patron saints for ergotism,

120 51. Erysipelas including Saints Benedict of Umbria, Martial of difference in the effects of ergot on the two com- Limoges, Genevieve` of Paris, Martin of Tours, munities in close proximity caused researchers and Anthony of Egypt, whose remains were car- to undertake feeding experiments, which con- ried to France in the eleventh century. From this firmed the efficacy of vitamin A in mitigating last saint, the name “Saint Anthony’s fire” was the effects of ergotism. derived. Similarly, although some researchers believed One authority has recorded 132 epidemics of that England’s relative freedom from ergotism ergotism between 591 and 1789. The Annals resulted from abundant ingestion of meat and of the Convent at Xanten, near the Rhine, also potatoes, others demonstrated that the En- describe outbreaks, as did Franc¸ois Eudes de glish diet’s richness in milk and butter prod- Mezeray´ in the seventeenth century. French epi- ucts was actually responsible. In areas rich demics of the gangrenous type reportedly killed in dairy products, phytase and bowel bacteria 40,000 in 922 and 14,000 in Paris alone during broke down the poisonous phytates of the grain 1128–29. The spasmodic form occurred in Spain into comparatively innocuous inorganic phos- in 1581 and 1590 and in Germany in 1595; phates. Thus, the convulsive ergotism common epidemics in France, Germany, and Switzerland to nondairy areas was virtually absent in Eng- recurred throughout the seventeenth century. land and certain sections of France. The French districts of Sologne and Dauphine,´ John S. Haller, Jr. frequently subject to flooding, suffered contin- uously from outbreaks of ergotism, as did Ar- tois, Lorraine, and Limousin. The disease also af- fected the Netherlands, Sweden, Majorca, Italy, 51. Erysipelas Poland, and central Russia, where outbreaks were reported as late as 1926. Three epidemics The term erysipelas (from Greek meaning “red” were recorded in Britain. During the American and “skin”)was often used in Hippocratic times Revolutionary War, soldiers in upper New York to describe classic cellulitis. Since the late nine- reportedly sickened on ergotted flour shipped teenth century, however, erysipelas has com- from Ohio. A later American outbreak report- monly referred to infection of the derma with edly occurred at a New York prison in 1825. a streptococcal organism, usually Streptococcus Recent research has raised the possibility that pyogenes. ergotism can explain the convulsions and hal- lucinations that attended religious revivals, in- Characteristics cluding the Salem witchcraft affair, as well as Infection with a group A beta-hemolytic strep- the “Great Fear” (July 20–August 6, 1789)that tococcus can produce a painful, red, edema- swept the countryside prior to the French Rev- tous indurated skin lesion called peau d’orange olution, and even the seasonability of mortality for its resemblance to the texture of an or- and conception patterns in Europe. ange skin. Sharp borders of the infection ex- Research in the 1930s suggested that the dis- tend rapidly, dissecting the underlying dermis tribution of convulsive and gangrenous ergo- from the epidermis. Erysipelas usually appears tism was a function of the presence or absence on the face, producing a butterfly rash over of vitamin A in the diet. Analysis of the 1770 epi- cheeks and nose. The same streptococci that demic of gangrenous ergotism in Sologne and cause erysipelas also cause scarlet fever, giv- convulsive ergotism in Hanover indicated that ing both diseases a fairly distinctive age pattern: Sologne, on the left bank of the Rhine, was a Erysipelas is more common among adults, who dairy district that provided a diet rich in vita- generally escape scarlet fever, whereas the latter min A, whereas Hanover, on the right bank, was normally attacks the young. The prognosis for unable to sustain a dairy economy. The striking untreated erysipelas is especially serious when

121 51. Erysipelas this infection is secondary to some other insult two seminal studies appeared: In 1842, Oliver such as laryngeal infection, or puerperal sep- Wendell Holmes published an essay on the con- sis. Indeed distinctions are still made among tagiousness of puerperal fever, and in 1861, gangrenous erysipelas, erysipelas grave in- Philip Ignaz Semmelweis published his clas- ternum (a form of puerperal fever), surgical sic study of “childbed fever.” Both men blamed erysipelas (which occurs after a surgical proce- physicians for carrying infective particles to the dure), and traumatic erysipelas (which begins bedsides of parturient women. French clinician in a wound). Armand Trousseau, writing during the same pe- riod, regarded even trivial skin injuries as pre- History cursors to erysipelas. Early accounts of erysipelas are often confus- In 1882, following the discovery of strep- ing because they lumped purulent and gan- tococci, Friedrich Fehleisen published a study grenous afflictions under this rubric. Thus, of the etiology of erysipelas, which he as- Hippocrates distinguished between “traumatic” sociated with S. pyogenes. In follow-up stud- erysipelas, which accompanied wounds, and a ies, another German surgeon, Friedrich Rosen- myriad of other skin lesions that had no known bach, described how the erysipelas-causing external cause. Galen in turn distinguished be- streptococci spread through host tissues with- tween phlegmon (including suppurative ulcers out causing suppuration. This research was of and gangrene)and nonnecrotic celluliti – but paramount interest to surgeons trying to con- viewed both as forms of erysipelas. Celsus, in trol the omnipresent infections – occasionally the first century A.D., considered septic ulcers, called “hospitalism” – that killed survivors of “canker,” erythematous wound infections, and otherwise “successful” operations. ignes sacer (“sacred fire”)all to be types of Although the use of aseptic and antisep- erysipelas. tic techniques led to dramatic reductions in Such confusion has continued into modern postsurgical mortality rates, maternal mortal- times, with some historians interpreting epi- ity still remained high. During the 1920s and demics of ignes sacer or “Saint Anthony’s fire” 1930s, research permitted identification and as ergotism, whereas others have viewed these typing of streptococci strains. This, in turn, scourges as recurrent erysipelas. Before the led to irrefutable evidence that puerperal fever modern period, however, physicians tended to was an exogenous infection, usually transmit- embrace the distinctions made by Galen and ted from a physician, midwife, or nurse at- consequently included a wide variety of ail- tending a parturient woman. Yet even family ments among the varieties of erysipelas. and friends could communicate the strepto- During the nineteenth century, physicians be- cocci that caused puerperal sepsis in women in gan giving greater attention to the causes and labor, for these were the same streptococci that prevalence of erysipelas because, on the one caused erysipelas. Consequently, maternal mor- hand, the disease seemed connected to wound tality from puerperal fever declined only after infection, and, on the other hand, epidemics of effective antibiotics became available. Despite erysipelas were occurring simultaneously with well-known changes in the virulence of strepto- peak years of puerperal sepsis, or “childbed coccal organisms historically, no sudden, spon- fever.” Their investigations eventually led to the taneous decline in virulence can account for the discovery of streptococci and the distinctions abrupt decline in mortality from erysipelas, scar- that have provided us with our current defini- let fever, and puerperal fever. Instead, credit for tions of erysipelas. moderating these ancient scourges belongs to In 1795, Alexander Gordon first formally as- the beginning of the antibiotic era and, in par- sociated erysipelas with puerperal fever. Then, ticular, to the use of sulfonamides. around the middle of the nineteenth century, Ann G. Carmichael

122 54. Favism

52. Fascioliasis cooked. The disease can become quite prevalent in areas where such plants are cultivated with The liver fluke Fasciola hepatica is usually a par- human feces as fertilizer. asite of sheep and cattle. “Liver rot” in sheep was Mild infections are often asymptomatic, but described in a French work in 1379, and the first flukes can irritate and even ulcerate the intesti- human case was described in 1760. The fluke’s nal mucosa. Abdominal pain, diarrhea, ane- life cycle was discovered in 1881. Fascioliasis mia, and fluid accumulation in the abdomen is a significant veterinary problem, but human are common symptoms. Extreme cases can be infection is also fairly common. The fluke’s life fatal. Drug therapy is usually effective. cycle is much like that of Fasciolopsis buski (see K. David Patterson Fasciolopsiasis)with people or herbivores in- fected by eating raw watercress or other plants contaminated by the cysts of the fluke. Adult worms settle in the bile ducts after a period of 54. Favism wandering in the liver. Mild infestations may cause little damage, but fever, jaundice, and Favism is an acute hemolytic reaction triggered right upper quadrant abdominal pain radiating by exposure either to fava beans (Vicia faba)or to the shoulder blade are common symptoms. to certain drugs (e.g., sulfa-based antibiotics or Bile ducts may become partially or totally ob- primaquine)in people with an inherited defi- structed, and liver destruction can be severe. ciency of the enzyme glucose-6-phosphate de- F. hepatica is cosmopolitan in distribution, hydrogenase (G6PD). In favism, the patient can with important foci of human infection in suffer destruction of red blood cells, severe ane- southern France, Algeria, and South America. mia, and possibly death. The bean is a dietary Treatment is generally effective. staple in areas where favism is reported. Only K. David Patterson about 20 percent of those who are G6PD defi- cient are likely to experience episodes of favism. With modern medical conditions, the hemolytic anemia caused by favism is only rarely fatal 53. Fasciolopsiasis (about 1–4 percent of reported cases). Strong evidence suggests that both the gene for G6PD Fasciolopsiasis is caused by the giant intesti- deficiency and the cultural practice of fava bean nal fluke, Fasciolopsis buski. Discovered in 1843, consumption are evolutionarily adaptive traits the organism occurs in China, Korea, Southeast that protect against death from malaria. Fav- Asia, and parts of India and Indonesia. The adult ism, then, could be described as a negative out- worm, with a lifespan of only 6 months, attaches come of the interaction of the positive adaptive itself to the wall of the human small intestine. qualities of both the gene and the bean. Pigs and dogs can also be infected and some- times are important reservoir hosts. Eggs pro- Characteristics duced by the hermaphroditic adults pass out in Favism is found primarily in the Mediterranean the feces and, if they reach fresh water, produce and Middle East regions, where fava beans are motile larvae that penetrate into the tissues of a staple food and the Mediterranean variant of certain planorbid snails. After two generations G6PD-deficiency gene is relatively common. It of reproduction, another motile form leaves the is frequently encountered in Greece, Sardinia, snail, finds a plant like the water chestnut, wa- Italy, Cyprus, Egypt, Lebanon, Israel, Iran, Iraq, ter caltrop, or water bamboo, and encysts on it. Algeria, and Bulgaria and is particularly com- Humans become infected with cysts by peeling mon among Sephardic Jews. Favism has also raw fruits with their teeth or eating them un- been sporadically reported in China, Germany,

123 54. Favism

France, Poland, Romania, Yugoslavia, Britain, populations at risk, this set of symptoms is rec- and the United States. The disease is considered ognized as a distinct illness, often referred to as a serious public-health problem in Greece. “fava-bean poisoning.” Favism is generally a pediatric illness. Most victims are between 2 and 5 years old, although History cases as young as 6 months and as old as The historical puzzle of favism is that peoples 65 years have been reported. The disease has of Mediterranean and Middle Eastern societies a marked seasonal cycle corresponding to the would continue to eat a food that regularly fava bean harvest between April and July, al- causes illness and even death. From an evolu- though where beans are dried for later con- tionary perspective, both fava bean consump- sumption, cases can occur all year. tion and G6PD deficiency appear to be retained Evidence suggests that the toxic factor induc- in populations because they provide some pro- ing the favism crisis has four characteristics: It tection from malaria. The correlation between is in the skin of the bean; it is heat stable; it the geographic distribution of these traits and can enter the breast milk of lactating women; malaria is one line of evidence for this relation- and its toxicity decreases when the beans are ship. Fava bean cultivation dates back to the dried and their skin changes color. Active bio- Neolithic period in areas that have favism. An- chemical agents in the skin – vicine, isouramil, cient Indo-European culture, and particularly divicine, and L–dopa – are probably responsible. Greek culture, placed remarkable emphasis on These same agents are believed to provide some the symbolic rather than nutritional qualities of protection against malaria for people of normal the fava bean. genotype when they eat fresh fava beans. Fava beans have had three primary symbolic Boys are much more likely to suffer favism associations: the life principle, the souls of the than girls, because G6PD deficiency is a sex- dead, and the generative powers of male sex- linked trait. Only carrier males (hemizygotes) uality. They are ritualistically eaten at certain and homozygous females can suffer from fav- times of the year, a practice that continues in ism. Heterozygous females appear to have an European folk cultures. However, taboos against evolutionary advantage because they have no consumption of fava beans for certain groups, risk of favism and also enjoy some protec- particularly priests, have been reported in an- tion against malaria. Over 200 varieties of the cient Greece, Egypt, India, and Africa. The most G6PD-deficiency gene have been identified, and famous case of such a taboo was among the their distribution correlates with the historical Pythagoreans, who had the maxim, “It is an distribution of malaria. equal crime to eat beans and the heads of one’s The G6PD enzyme, found in all tissues, parents.” Although many historical analyses of has important housekeeping functions in red- this taboo have been suggested, a medically in- blood-cell metabolism. The cells of enzyme- formed hypothesis based on the risk of favism deficient individuals tend to become oxidant- appears most reasonable. sensitive, and any exogenous sources of In the history of medicine, early clinical de- increased oxidants (malaria parasites, antimalar- scriptions by Italian physician Antonio Gasbar- ial drugs, or fava beans)can result in the lysis rini were a landmark for diagnosis and treat- (explosion)of the cell, resulting in either favism ment of favism attacks. Within the tradition or protection from severe malaria infection, de- of Galenic medicine, treatment, although not pending on the context. always for favism attacks, emphasized rein- Favism is characterized by five general symp- forcement of the blood with red wine among toms: weakness, fatigue, pallor, jaundice, and other things. Understanding the evolutionary hemoglobinuria (blood in the urine). The history of favism has been a recent develop- anemia caused by hemolysis is severe. In ment paralleling the discovery of the malaria

124 55. Filariasis connection with other genetic polymorphisms Europe, Australia, and some Caribbean islands, like thalassemia and sickle-cell anemia.The and is decreasing in prevalence in the Western analytical connection with G6PD deficiency was Hemisphere generally, W. bancrofti is becoming first suggested in 1956, and development of a more prevalent in parts of Asia. At some time genetic screening technique for the trait created most regions of the tropics or subtropics as well a wealth of population genetic data during the as temperate parts of China and Japan have ex- 1960s. Such data on genetic markers in popu- perienced this infection. lations – for example, the variants of G6PD de- In 1984, the World Health Organization esti- ficiency – have a potential for historical recon- mated the number of people infected with W. struction of population movements and culture bancrofti at more than 81 million. Prevalence contact. is highest in Asia (especially China, India, and Peter J. Brown Indonesia)and Africa. The disease affects pri- marily working-age poor people in areas where mosquitoes abound. Adult W. bancrofti lie coiled in human lym- 55. Filariasis phatic vessels and lymph glands and can live up to 18 years. Within 6 months to 1 year of in- The term filariasis refers to several diseases fection, the microfilariae leave the adult female of both humans and animals caused by infec- and enter the host’s blood and lymph channels. tion with a specific group of parasitic nema- Microfilariae move freely through the lymph or todes called filarial worms. Those that affect blood. Nocturnal microfilariae (the most com- humans include Wuchereria bancrofti and Bru- mon form)reside in the arterioles of the lungs gia malayi, common causes of elephantiasis during the day, whereas the diurnal strain ap- (extreme swelling and thickening of legs, scro- pears in the peripheral blood continuously, al- tum, labia, or arms)and chyluria (lymph and though periodically in reduced numbers. Noc- emulsified fat globules in the urine); Loa loa, turnal microfilariae are generally found west ◦ the “eye worm”; and Onchocerca volvulus, the of 140 east longitude, and diurnal microfi- ◦ cause of onchocerciasis. Adult filarial worms lariae are present east of 180 east longitude. reside in the lymphatic system, subcutaneous Both types may be found between these two tissues, or peritoneal and pleural cavities. Their meridians. The largest concentrations of diurnal embryos (microfilariae)are ingested from blood microfilariae exist in the Polynesian and New or skin by an intermediate host (a mosquito, fly, Caledonian regions of the Pacific. or other arthropod). The microfilariae become Bancroftian filariasis is transmitted only by larvae in the intermediate host and then reen- mosquito. There is no known animal reservoir ter a human or animal host through skin bites of W. bancrofti. Microfilariae may be transmitted by the intermediate host. L. loa is endemic in between humans through blood sharing (as in West and central Africa, whereas onchocerciasis pregnancy)or transfusion, but such microfilar- is found in Mexico, Central America, and West iae never develop into adults. Africa. Discussion of human lymphatic filaria- Microfilariae have adapted their daily cycles sis in this chapter is, however, limited to its most to either day- or night-feeding mosquitoes, de- prevalent (90 percent of infections)form – that pending on the species present in a particu- caused by W. bancrofti. lar geographic area. Once inside a mosquito, microfilariae become infective larvae within Characteristics 2 weeks, then escape onto the skin of the next Bancroftian filariasis is widely distributed human host when the mosquito feeds. The lar- throughout the tropics. Though it no longer ex- vae burrow into the skin through the tiny punc- ists in areas such as North America, southern ture wound and find their way to lymph vessels

125 55. Filariasis where they mature and mate, producing more Uninfected adults newly arrived in an en- microfilariae. demic region generally show an inflammatory Filarial disease may not manifest itself for response to filarial infection. Their immune sys- many years despite the presence of micro- tems react strongly, sending a variety of cellu- filaremia. If reexposure to larvae does not lar defenders to the affected areas. The worms occur, infection usually disappears within 8 are surrounded, ultimately causing stenosis of years. Repeated exposure over many years the lymphatics as well as painful swellings and generally results in clinical disease during fever. Such a powerful response generally kills adulthood. Symptoms occur throughout the the worm, preventing the development of mi- body because of widespread disruption of the crofilariae but also causing disruption of the lymphatics. lymphatic system and the early development of Once the filarial larva settles in a human elephantiasis. Chronic obstructive filariasis can lymph channel and begins to mature, it pro- result in lymph gland enlargement, chyluria, vokes a localized response involving lymph- lymph scrotum, hydrocele, and elephantiasis of vessel dilation and slowing of lymph flow. the legs, scrotum, labia, arms, or (rarely)breasts. The body responds immunologically, sending Several microfilaricidal drugs exist; the most eosinophils, plasma cells, and macrophages to effective is diethylcarbamazine citrate (DEC), the site of infection. Lymphangitis (inflam- first used in 1947. This drug also kills adult mation of lymph channels)usually results in worms. When DEC is used in conjunction with a swelling and pain, and varices form when the comprehensive mosquito control plan, the rate lymph vessels become hypertrophied. Fibrosis of W. bancrofti infection in an area declines dra- of the vessel occurs, killing the adult worm, matically. Other measures of prevention and which is absorbed or calcified. Obliteration of treatment, such as mosquito control or avoid- the vessel forces extravasation of lymph into the ance by itself, or surgical treatment of the ele- tissue, where it accumulates, causing the typ- phantiasis, are usually not highly effective. ical lymphedema of filarial elephantiasis. The swelling, consisting of lymph, fat, and fibrotic History tissue under stretched and thickened skin, can Evidence indicates that bancroftian filariasis ex- become quite large. isted in the ancient tropical world. Discussions In highly endemic areas, people are exposed of something called elephantiasis appear in the to repeated infections from a young age, and the works of ancient Greek and Roman authors, but children show little effect of infection. When the many of them were probably describing lep- larvae move into lymph vessels, they fail to pro- rosy, which was called elephantiasis graecorum voke a strong immunologic response, thus al- to distinguish it from another disease, elephan- lowing new microfilariae to travel through the tiasis arabum (probably bancroftian filariasis). now-dilated lymph channels. The worms sur- Bancroftian filariasis was probably not en- vive for years, and their offspring are passed demic in the ancient Mediterranean except for on in their larval stage by mosquitoes to other certain parts of the Nile Delta. Travelers brought human hosts. As the adult worms eventually knowledge of the condition to residents of the die in their tolerant human hosts’ lymphat- region, and an occasional newcomer undoubt- ics, fibrosis and calcification occur. As lymph edly carried the disease there from his or her channels become obstructed, elephantoid man- home country. Ancient descriptions of a condi- ifestations develop, especially in the groin and tion resembling bancroftian filariasis also exist lower extremities. People in highly endemic in records from the Nile Delta, Polynesian is- areas are infected repeatedly over the years lands, and India. Moreover, medieval Arab writ- and so will manifest various stages of filariasis ers discussed an elephantiasis that was probably simultaneously. filariasis and not leprosy.

126 55. Filariasis

It has been argued that bancroftian filariasis condition further, but a second patient entered originated in Southeast Asia and spread with the hospital a few days later. Lewis now went the migration of peoples to Polynesia and Africa. beyond Demarquay and Wucherer, removing The filarial worm adapted to the mosquito vec- blood from the new patient’s finger and study- tors available in these new areas, thus explain- ing it microscopically. He found what he called ing the existence of both diurnal and nocturnal filariae in this blood and also in the patient’s strains. The continued migration of peoples and urine. Lewis’s report of these and other patients, the opening of the tropical world to trade over published in 1872, documented for the first time the past few centuries, plus the adaptability of both the presence of microfilariae and the pres- W. bancrofti, resulted in the spread of the par- ence of any microorganism in human periph- asite throughout the tropics, including China eral blood. He also described, but could not ex- and India. Filariasis came to the New World, plain, the disappearance of microfilariae from most likely via the slave trade. A legacy of the the blood. slave trade in the United States was the estab- All three of these researchers knew they had lishment of a focus of bancroftian filariasis in identified an immature form of the filarial worm. Charleston, South Carolina and its surrounding Nor were they the only ones; both T. Spencer “Low Country,” which survived until the early Cobbold of London and M. Robin of Reunion twentieth century. Island reported similar findings in the early European observers described numerous 1870s. cases of elephantiasis, endemic hydrocele, It remained for Patrick Manson to synthesize and lymph scrotum. A few even recog- the various bits of knowledge about human nized the development of elephantiasis from filarial infection and produce a useful theory. fever through lymphangitis, lymphadenitis, and Manson spent his early career, beginning in swelling. Though these writers located the dis- 1866, as a medical officer in the Chinese Cus- ease in the lymphatics, none could identify the toms Service. He treated many elephantiasis cause. That discovery awaited widespread med- patients, recognized and named the condition ical application of the microscope in the latter called “lymph scrotum,” and devised an oper- half of the nineteenth century. ation to remove scrotal tumors. On leave in The first breakthrough in understanding ele- England in 1875, he read the literature on the phantiasis occurred in 1863 when a French conditions he had been treating, including de- physician, Jean-Nicolas Demarquay, described scriptions of lymph scrotum in India, the re- microfilariae he observed in fluid drawn from lation of lymph scrotum to elephantiasis, and a Cuban patient. Demarquay could not explain Lewis’s papers on filarial worms in the blood the worms’ presence but hoped that there and lymph of tropical chyluria patients. In ar- would be some scientific value for others in ticles published in 1876–77, Manson presented publishing the case. studies to show that the three diseases were all Four years later in Brazil, Otto Wucherer caused by the filarial worm described by Lewis, found “some threadlike worms” in a patient’s seated in lymphatics. But Manson apparently blood clot. Wucherer could not identify the knew nothing of Demarquay’s and Wucherer’s species from books on human parasites, so he earlier findings. published his story “as an incentive for some of Manson tried to obtain adult filarial worms my colleagues...to attempt to shed light on a from newly deceased patients, but Chinese disease, the etiology of which is still enigmatic traditions discouraged human autopsies. He today.” suggested that physicians in India, less ham- In 1870 in India, Timothy Lewis found worms pered by such prejudice, seek out adult worms like those Wucherer had described. The patient in patients who had died with similar symp- left the hospital before Lewis could study the toms. However, the first demonstration of adult

127 56. Fungus Infections (Mycoses)

filariae in humans occurred not in India but in In 1897 in London, he studied the organs of Australia. Joseph Bancroft in Queensland stud- a patient with filariasis who had opportunely ied a number of patients with lymphatic condi- committed suicide at 8:30 in the morning, pre- tions, though not elephantiasis. His first adult sumably just after the worms left the periph- worm came from a lymphatic abscess of the eral blood for the day. Postmortem examination arm. He obtained another four from a hydro- revealed huge numbers of the parasites in the cele of the spermatic cord. small blood vessels of the lungs and others in In 1877, he forwarded these specimens to the large vessels. Cobbold, the leading British helminthologist. The next few years produced the answer to a Cobbold had previously encouraged Bancroft to question Manson had asked in 1877: How did look for the adults after Bancroft sent him im- the filariae pass from mosquitoes to humans? In mature filariae obtained from these patients. It 1900, the work of Thomas Bancroft, Joseph Ban- was Cobbold who suggested naming the filarial croft’s son, and of Manson’s proteg´ e,´ George C. worm for Bancroft, and a colleague of Wucherer Low, who studied mosquito specimens Bancroft suggested that Wucherer deserved credit for sent to Manson, suggested that filarial embryos discovering it. As a result, the filaria is known exited from the mosquito’s proboscis and en- as Wuchereria bancrofti. tered human skin while the insect was biting – How did the worm find its way into humans? a hypothesis confirmed by B. Grassi and G. Noe Manson, continuing his work in China, pub- later the same year. lished a key suggestion in 1878. The worms’ Nineteenth century physicians working in embryos, he argued, could not mature and various tropical areas had made almost every enter the bloodstream without overwhelming breakthrough in uncovering the mystery of fi- their human host by sheer numbers. Man- larial infection. By 1900, the medical world pos- son suggested and then demonstrated that the sessed an understanding of a disease that had mosquito was the “nurse” of the filarial embryo. puzzled people since ancient times. The insect ingested filariae in its blood meal, Todd L. Savitt and the young worms developed in the body of this intermediate host. The need for a spe- cific mosquito in addition to the human host, Manson concluded, explained “the limitation of 56. Fungus Infections (Mycoses) the distribution of elephantoid diseases to cer- tain districts and zones . . . where the mosquito Although some 200 fungi are established as flourishes.” pathogenic for humans, through the mid- Another filarial mystery remained: the disap- nineteenth century only two human diseases pearance and reappearance of worm embryos in caused by fungi were generally recognized. the blood of infected patients. Manson discov- These were ringworm and thrush, known since ered that the number of microfilariae increased Roman times. Two important additions came at and decreased in a regular diurnal pattern, the the end of the century: mycetoma of the foot embryos reaching their peak presence in the and aspergillosis. hours just before and after midnight. He con- Fungi were the first pathogenic microorgan- cluded that the microfilariae were “adapted to isms to be recognized. By the early nineteenth the nocturnal habits of the mosquito...another century, they had been shown to cause disease of the many wonderful instances of adaptation in plants and insects, and during the 1840s both so constantly met with in nature.” ringworm and thrush were shown to be mycotic What happened to the filariae during the rest in origin. For a short period, fungi were blamed of the day? Manson asked that question in 1879 for many diseases (for example, cholera). But but could not answer it for nearly 20 years. with recognition of the role played by bacteria

128 56. Fungus Infections (Mycoses)

(and later, viruses)in the etiology of human dis- dermatologist Raymond Sabouraud, who pub- ease, fungi were neglected. Only since the 1930s lished his research in 1910. Many ringworm has the character and ecology of pathogenic fungi were classified variously according to fungi been clarified. In general, the geographic mycologic and clinical features. Some thou- distribution of mycoses has been established, sand different names had been proposed up and the relation of mycoses to other human dis- to 1934 when C. W. Emmons in the United eases has been determined. States showed that the many species could be Some fungi causing human disease show accommodated in three genera: Microsporum, clear adaptations for the pathogenic state, Trichophyton, and Epidermophyton. Today the whereas others do not. Probably none are accepted number of ringworm fungi is around dependent on a human or animal host for 30. Evidence indicates that dermatophytes are survival. Most are also pathogenic for ani- closely related to a group of predominantly soil mals, both domesticated and wild. Many fungi fungi. Two historical landmarks in the treat- pathogenic for humans apparently belong to the ment of ringworm were the introduction of normal environmental flora. Mycoses have of- X-ray epilation for head ringworm in the open- ten been termed according to the part of the ing years of the twentieth century and the body affected (e.g., “ringworm of the scalp,” development of the antibiotic griseofulvin in “athlete’s foot”)or the name of the pathogen 1958. (e.g., aspergillosis, dermatophytosis), and they The geographic distribution of ringworm have been categorized as cutaneous, subcuta- fungi varies. Some, such as Trichophyton menta- neous, systemic, opportunistic, and iatrogenic, grophytes (causing tinea pedis, etc.)and Epider- although these divisions are not mutually mophyton floccosum (tinea cruris), occur world- exclusive. wide. Microsporum audouinii (tinea capitis; the classical ringworm of children), which appears Ringworm (Tinea, Dermatophytosis) to have originated in Europe, is now endemic Favus (Latin for “honeycomb”), a distinctive type in North America. Although frequently intro- of ringworm, was described by Celsus in the first duced into the tropics, it has never established century. He called it porrigo, a term also used by itself there. Likewise Trichophyton concentricum Pliny in the same century and by dermatologists (tinea imbricata)is endemic in Southwest Asia up to the nineteenth century. It is now, however, and the South Sea islands, where it was re- obsolete, having been replaced by tinea. Celsus ported by William Dampier in 1686. It has also described the inflammatory lesion of some other minor endemic centers in South Amer- forms of ringworm, which is termed the “kerion ica and, although frequently seen in Europe, of Celsus.” has never become endemic there. By contrast, Not until the mid-1840s was the mycotic na- Trichophyton rubrum, probably introduced into ture of favus recognized by three independent Britain by soldiers returning from the Boer workers: J. L. Schoenlein and Robert Remak in War, is now widespread in north temperate Berlin, and David Gruby in Paris. The latter regions. also differentiated microsporosis and the ec- In similar fashion, Trichophyton ferrugineum tothrix and endothrix trichophytosis, which he established itself in western parts of Russia af- showed to be caused by distinct fungi. ter introduction by troops from the Far East. A period of mycologic confusion followed, Classical favus in Western Europe is caused by complicated by the difficulty of determining Trichophyton schoenleinii, but in North Africa the life histories of the pathogens and whether and the Mediterranean by Trichophyton vio- there was one ringworm fungus or many. laceum. Microsporum canis (tinea canis [cat and Gruby’s findings were forgotten and had to dog ringworm], tinea capitis, and tinea cor- be rediscovered during the 1890s by Parisian poris), coextensive with dogs and cats as pets,

129 56. Fungus Infections (Mycoses) has become endemic in New Zealand in feral Systemic Mycoses cats. Human infections are also contracted from The first case of coccidioidomycosis was de- cattle (Trichophyton verrucosum), horses, and scribed from Argentina by Alejandro Posadas other farm animals. Microsporum gypseum has in 1892. A case was also studied in Califor- a worldwide distribution, but outbreaks in hu- nia by E. Rixford and T. C. Gilchrist, who at- mans are usually short-lived. tributed the cause to a protozoan, which in 1896 they named Coccidioides immitis.In1905, Candidiasis (Including Thrush) however, W. Opuls established its mycotic na- Reports of the diverse manifestations of can- ture. It was known only as a rare and often didiasis caused by Candida albicans and other fatal disease. In 1938, Myrnie A. Grifford and Candida species have made a major contribu- E. Dickson established that “valley fever,” preva- tion to the literature of medical mycology. As lent in the San Joaquin Valley of California, was a with ringworm, a stable taxonomic base was mild form of coccidioidomycosis. Further inves- necessary to underpin research on this mycotic tigations showed subclinical Coccidioides infec- complex. It was mainly a group of yeast special- tion to be widespread in parts of California and ists working in the Netherlands who clarified neighboring states and to induce lifelong im- the taxonomy; the genus Candida was proposed munity to subsequent attack. Emmons showed in 1923. rodents to be infected, and they were thought to Thrush (oral candidiasis), an infection of mu- constitute an animal reservoir of infection. But cous membranes (especially of the mouth)in it became clear that rodents, like humans, were infants, was mentioned in the Hippocratic cor- subject to infection by this soil-inhabiting fun- pus (400 B.C.)and later by Galen and others un- gus. The dry, airborne spores of the pathogen der the heading aphthae. Over the centuries, ref- are extremely infectious (many laboratory infec- erences to thrush in the young, as a feature of tions have occurred); coccidioidomycosis can terminal illness, and as a vaginal infection con- be contracted, for example, by servicing au- tinued. Candidiasis, like ringworm, was proved tomobiles that have been driven through en- mycotic by three independent workers in the demic areas. Although light- and dark-skinned 1840s: B. Langenbeck in Berlin, F. T. Berg in peoples appear to be equally susceptible, the Stockholm, and Gruby in Paris. In 1844, J. H. disease is more likely to be systemic in Bennett in Edinburgh described what was prob- those with pigmented skin. Coccidioidomyco- ably C. albicans from the human lung. sis is endemic in warm, dry regions of the A wide range of pathological conditions United States, Mexico, and parts of Central and attributed to Candida were subsequently South America. recorded. Numerous surveys have shown that Histoplasmosis (Histoplasma capsulatum) many apparently normal individuals carry C. shows many parallels with coccidioidomycosis albicans in the mouth, in the vagina, and in and may be a humid-region equivalent. At the feces and gut. Although C. albicans has oc- first considered a protozoan disease, it has casionally been isolated from soil, from hos- been shown to be mycotic. A mild form affects pital bedding, and from animals, it is clear millions of people in the midwestern United that most human infections have an endoge- States. nous origin. Infection seems always to be de- Blastomycosis (North American blastomyco- termined by predisposing factors that may sis, caused by B. dermatitidis)and paracoc- be environmental. Age, debility, dentures, and cidioidomycosis (South American blastomyco- drugs also can predispose one to infection. The sis, caused by Paracoccidioides brasiliensis)are patenting of the antibiotic nystatin in 1956 both diseases of the skin and internal organs, was a notable contribution to the therapy of characterized by budding cells of the pathogen candidiasis. in the infected tissues. Blastomycosis was first

130 56. Fungus Infections (Mycoses) described by Gilchrist in 1894, and paracoccid- tion “mycetoma,” wrote about it in 1874. Carter ioidomycosis by Adolfo Lutz in Brazil during suspected the disease to be mycotic and sub- 1908. Neither has a mild form, and the natu- mitted material to M. J. Berkeley, the leading ral habitats of these fungi have not been estab- British mycologist, who described a fungus he lished with certainty. Paracoccidioidomycosis is obtained from it. From the turn of the century confined to Central and South America. Blasto- onward, more than 25 diverse fungi and acti- mycosis is endemic to the western and south- nomycetes responsible for the condition were eastern United States, where epidemics occur; identified by workers in North Africa and else- there are also records of the disease from tropi- where. The color of the grains often indicates cal African countries. the pathogen’s identity. Sporotrichosis is a cutaneous and subcuta- Carter distinguished “melanoid” and neous infection characterized by nodular le- “ochroid” mycetoma. His black-grained form sions, often affecting lymph nodes. Infection is was caused by Madurella mycetomatis, the most frequently initiated by a lesion of the hand. It is important cause of mycetoma, taxonomized by caused by Sporothrix schenckii and was first de- E. Brumpt in 1905. In 1894, H. Vincent described scribed in the United States by B. R. Schenck in the actinomycete that caused yellow-grained 1898. Subsequently, many cases were reported mycetoma as Streptothrix madurae (now Acti- from Europe, especially France, where the nomadura madurae). Later, A. J. Chalmers and disease was discussed by C. L. de Beurmann R. G. Archibald in Sudan introduced the term and H. Gougerot in 1912. Sporotrichosis is “madura mycosis” for mycetoma caused by sporadic in north temperate regions and has actinomycetes. Today the terms eumycetoma been recorded in Central and South America. and actinomycetoma are preferred. In Uruguay, J. E. Mackinnon attempted to cor- Mycetoma occurs most frequently in a band relate the disease with the weather and de- of the tropics extending from India across Africa termined that infection occurred during moist to Central and South America. Incidence is par- warm weather. S. schenckii is one of the rare fun- ticularly high in India, Sudan, Senegal, and Mex- gus pathogens of humans that has been shown ico. Pseudallescheria boydii seems to favor more to cause disease in plants. The largest outbreak humid conditions, with species of Nocardia re- ever recorded occurred in gold mines in South sponsible for mycetoma in temperate Europe Africa during the 1940s. Approximately 3,000 and North America. Madurella grisea is limited miners were infected, but the epidemic was to South America, whereas cephalosporium in- brought under control. fections are cosmopolitan. Early thought held that infection was initiated by injury, particu- Opportunistic and Iatrogenic Infections larly injury from plant thorns. Sometimes the Mycetoma is a disease characterized by swelling pathogen grows as a saprobe on thorns, or the that affects subcutaneous tissues, with sinuses thorn may provide the point of entry for an or- discharging granules of the pathogen that vary ganism present in the environment. in color. The foot is most frequently involved Cryptococcosis is a chronic infection of the (“Madura foot”), but other parts may be in- lungs, skin, or other parts, caused by the yeast fected. Its geographic distribution is mainly Cryptococcus neoformans, which is widely dis- tropical. tributed in nature. Human cases have fre- The condition was first recorded in Indian quently been associated with inhalation of the vedic medical treatises (c. 2000–1000 B.C.)as pathogen when clearing pigeon roosts. The padaavalmika (“foot ant-hill”)and later de- most frequent infections are self-limiting. Fatal scribed by members of the Indian Medical and more generalized infection occurs mostly Service during the mid-nineteenth century. in debilitated patients or those “compromised” H. Vandyke Carter, who coined the designa- by drugs.

131 57. Fungus Poisoning

Identified in Europe in 1894, cryptococcosis coses.” During World War II, for example, ring- has a worldwide distribution. In 1946, L. B. Cox worm symptoms disappeared in prisoners held and Jean C. Tolhurst published 13 Australian under starvation conditions only to reappear cases termed “torulosis” caused by Torula his- on the restoration of a full diet. Tinea capitis tolytica. In 1956, a comprehensive study of the (M. audouinii )in children, although persistent, disease was published by M. L. Littman and L. E. resolves spontaneously at puberty for reasons Zimmerman. not fully understood. Tinea pedis has been Rhinosporidiosis, an infection of mucous tis- claimed as an occupational disease of work- sue (especially of the nose), forms large polyps. ers who wear heavy boots. Candida infection The causal agent, Rhinosporidium seeberi, has is affected by pregnancy, and metabolic disor- not been cultured, and its taxonomic position is ders such as diabetes are frequently associated uncertain. Outbreaks of the disease have been with it. Iatrogenic mycoses have resulted from associated with water and soil. Rhinosporidio- the use of antibacterials. Moreover, immuno- sis was first reported from Argentina in 1900. It suppressive drugs used in organ transplantation occurs sporadically throughout the tropics, es- have resulted in Candida endocarditis and my- pecially in India and Sri Lanka. cotic septicemia. Antimycotic therapy is now a Species of Aspergillus and mucoraceous fungi routine supplementary practice. are a ubiquitous component of “common mold.” Geoffrey C. Ainsworth They are frequently found as contaminants of cultures. Human infections (aspergillosis and mucormycosis)by these and similar molds occur sporadically and have been reported 57. Fungus Poisoning worldwide. Aspergillus fumigatus, widespread in the en- Two categories of fungus poisoning may be vironment on decaying vegetation, has spores distinguished: (1) mycetism, caused by eating that are readily airborne. It is favored by high poisonous fungi mistaken for an edible variety temperature. A. fumigatus is able to cause (which has a long history and worldwide inci- fatal infections, particularly in birds. It was dence); and (2) mycotoxicosis, from inadvertent first recorded early in the nineteenth cen- ingestion of food containing fungi-produced tury. J. Fresenius in 1850 proposed the name toxins. The latter, also of worldwide incidence, Aspergillus fumigatus, and Rudolf Virchow in was (with the exception of ergotism)generally Germany in 1856 described human pulmonary recognized only during the twentieth century. aspergillosis. The classical cases of this disease occurred in French squab-feeders in the late Mycetism 1890s, who chewed the same grain used for fat- Calamities tend to impress, and the first refer- tening the birds. ence to fungi in the Greek classics is an epigram Other species of Aspergillus are also patho- by Euripides (c. 450 B.C.)commemorating the genic. Aspergillus niger is associated with in- deaths of a woman and her two children after fection of the ear, whereas aspergillomas or eating poisonous fungi. During Roman times, “fungus balls” are associated with pulmonary edible fungi were a delicacy, and diverse ad- disease. Diverse mucoraceous fungi are sporadi- vice was offered by authors such as Horace, Cel- cally recorded in north temperate countries. Hu- sus, Dioscorides, Galen, and Pliny about how man infections of the rhino-facial-cerebral re- to avoid poisonous species, how to render poi- gion are often fatal. Debility is a predisposing sonous forms harmless, and how to treat fungus factor. poisoning. Several of the diseases addressed in this Much of the ancient folklore on precautions chapter might also be termed “dependent my- to ensure edibility was compiled by the authors

132 57. Fungus Poisoning of the first printed herbals in the fourteenth resulted in misidentifications or overdoses and and fifteenth centuries, and some has even sur- the need for medical attention. vived to this day. It is, however, invariably un- reliable because the distribution of poisonous Mycotoxicosis and edible species seems to be random. For Until the 1900s, the only mycotoxicosis of hu- example, the esteemed esculents Amanita cae- mans generally recognized in the West was sarea (“Caesar’s mushroom,” a Roman favorite) ergotism, although serious outbreaks of hu- and Amanita rubescens (“the blusher”)are con- man mycotoxicoses had occurred in Russia and generic with Amanita phalloides (“death cap”) Japan. Kaschin-Beck disease of children is char- and several related species (Amanita panthe- acterized by generalized osteoarthritis caused rina, Amanita verna, Amanita virosa)that have by eating moldy grain. It was prevalent among caused – and still do – most fungus-poisoning the Cossacks and endemic in both Asiatic and fatalities in north temperate regions. The only European Russia and in northern Korea and reliable guide is correct identification. China in the 1860s. A similar mycotoxicosis – The most frequent effect of fungus poison- “drunken (or intoxicating)bread syndrome” – ing is gastroenteric disturbance of greater or was also prevalent in Russia. But the most ex- lesser severity. A. phalloides toxins, symptoms tensively documented of such ills in Russia is of which occur 4 or more hours after ingestion, alimentary toxic aleukia (or septic angina);it also cause severe damage to the liver and kid- was known before World War I and became epi- neys. Other Amanita toxins have a hemolytic demic in the Russian grain belt during World effect, and hallucinogenic species cause psycho- War II, when some 10 percent of the population somatic symptoms. Fever is unusual. was affected and suffered high mortality. In af- The chemistry of toxic fungi has been un- fected districts, it was the practice to allow the der investigation since muscarine was isolated ripe cereal crop to winter under the snow. When in 1869. That name came from the “fly agaric” the snow cover was so heavy that the underly- (Amanita muscaria), which has been equated ing soil did not freeze deeply, and the spring with the Indian soma. Amanita toxins include was mild with frequent thawing and freez- amatoxins, phallotoxins, and virotoxins. ing, the grain was molded by Fusarium species The species of fungi implicated in mycetism and other fungi that produced toxins (mostly depend on the locality, and local variations trichothecines). occur in reported incidence. For example, Known in Japan from the seventeenth cen- more reports of mycetism are published in tury, a form of cardiac beriberi was shown in France, where edible fungi are widely collected 1891 to be caused by eating moldy rice. In from the wild for sale, than in Britain, where 1940, the toxin involved was identified as cit- wild forms are regarded with suspicion. Most reoviridin, produced by Penicillium citreoviride. poisonous fungi are larger basidiomycetes, but After World War II, a severe outbreak was a few ascomycetes with large fruit bodies are recorded in Japan of a similar but different my- poisonous. cotoxicosis from eating rice that had deterio- In the later twentieth century, increased in- rated in storage (“yellowed rice”). cidence of fungus poisoning originated from Several major mycotoxicoses of farm animals ethnomycological studies drawing attention to have been documented in Russia, and a few the hallucinogenic properties of some larger more have been reported elsewhere. Significant fungi, particularly species of Psilocybe contain- attention was focused on mycotoxicoses after ing psilocin, a compound that induces psy- the summer of 1960, when more than 100,000 chotropic effects similar to lysergic acid and turkeys and other poultry died in Britain af- mescalin. Collection of such forms in the ter eating a ration containing ground peanut wild for self-administration or illegal sale has (Arachis hypogea)meal imported from Brazil.

133 58. Gallstones (Cholelithiasis)

Cattle and pigs were also affected, and feeding gallbladder infection. These factors are inter- experiments induced liver cancer in rats. The related, but current thinking ascribes the pri- toxin, produced by strains of Aspergillus flavus, mary role to abnormal bile composition, related was designated aflatoxin. At first, testing for afla- to cholesterol and bile acid metabolism. This toxin was limited to using 1-day-old ducklings, in turn is affected by dietary, genetic, and hor- which are particularly sensitive to it, but a reli- monal factors. able chemical test was soon developed. A common medical maxim describes a typical Aflatoxin was shown to be widespread in gallstone patient as “fat, fair, female, and forty.” foods containing peanuts, and in parts of Africa Obesity is associated with increased choles- and Asia the incidence of human liver can- terol secretion, producing supersaturated or cer has been correlated with aflatoxin intake. lithogenic bile. Overconsumption of calories, The U.S. Food and Drug Administration has particularly through refined sugar and flour, ap- set an aflatoxin tolerance of 20 parts per bil- pears to be the major factor causing high inci- lion for peanut products. Interest in aflatoxico- dence in Western countries. It also explains the sis, because of its carcinogenic potential, is still increasing prevalence of cholesterol and mixed intense. gallstones among Japanese, Eskimo, and African Geoffrey C. Ainsworth populations adopting a more Western diet. A diet high in cholesterol-rich foods may have a secondary role. Gallstones are two to four times more com- 58. Gallstones (Cholelithiasis) mon in females than in males. Estrogen in- creases secretion of cholesterol and decreases Gallstones are common in modern populations, production of bile salts that form soluble mi- occurring in nearly 20 percent of autopsies. celles with cholesterol. Moreover, childbearing Though often asymptomatic, they can produce elevates estrogen in the third trimester and also significant morbidity, leading to cholecystitis, promotes biliary stasis; thus multiparity is a risk cholangitis, biliary cirrhosis, and pancreatitis. factor. Gallstone prevalence increases steadily with Characteristics advancing age. Clinically, symptoms of gall- Descriptively, there are four major types of gall- bladder disease related to gallstones most com- stones: pure cholesterol stones, mixed stones monly present between ages 40 and 60. (cholesterol, bilirubin, and calcium), combined Conclusions regarding geographic distribu- stones (with a cholesterol center and laminated tion of gallstones are based on autopsy, hospital- exterior of cholesterol, bilirubin, and calcium), admission, and population-survey data. The and pigmented stones (calcium bilirubinate). large Framingham, Massachusetts, study The first three types comprise the vast ma- showed prevalence of gallbladder disease jority of gallstones and are grouped together among adult (ages 30–62)males as 1.3 percent as cholesterol-based stones, related to ab- and among adult females as 5.9 percent. Many normal cholesterol and bile salt metabolism. studies have shown a higher prevalence among Black pigmented stones are associated with American Indians, particularly in the South- chronic hemolysis, particularly sickle-cell dis- west. For example, a study of the Pima Indians ease. Brown pigmented stones are associated using identical criteria and age groups as the with infection and were historically more com- Framingham study showed a prevalence of mon in China and Japan. 5.9 percent among adult males and 36 percent Though incompletely understood, the three among females. major factors in gallstone formation are ab- Gallstones are usually asymptomatic, which normal bile composition, biliary stasis, and along with increased prevalence with age

134 58. Gallstones (Cholelithiasis) explains the much higher incidence of gall- distribution of other populations with high gall- stones at autopsy. A large autopsy series span- stone risk corresponds closely to the area cov- ning the years 1920–49 demonstrated gall- ered by the last glacial epoch. stones in 7.8 percent of males and 16.8 percent of females. The incidence among blacks was less History than half that among whites. Another series of Hippocrates and Aristotle were familiar with the adult whites found gallstones in 16.0 percent of clinical findings of jaundice and biliary dis- males and 32.5 percent of females. ease, but their writings do not specifically men- Gallstones are relatively uncommon in ori- tion gallstones. Hippocrates differentiated four ental countries; prevalence rates as low as types of jaundice but did not describe any cause 1.8 percent among adult men and 3.9 per- related to obstruction. Diocles of Carystus re- cent of adult women are found. Prevalence re- ferred to possible mechanical obstruction of the mains low in Japan; however, there has been flow of bile. Accounts of Alexander the Great’s a shift from the infection-related pigmented illness prior to his death in 323 B.C. are sugges- stones to the Western diet-related cholesterol tive of gallstones and cholecystitis. stones. Most African populations demonstrate Galen described various types of jaundice, an extremely low prevalence of gallstones. A re- including obstructive jaundice. He stated that view of records shows an increasing prevalence small foreign bodies such as grain or fig and in Europe, North America, Japan, Chile, and pomegranate seeds could obstruct the common Australia. bile duct. Given the close similarity of small gall- A genetic tendency to develop gallstones stones to certain seeds, Galen may in fact be under certain dietary conditions may account referring to gallstones. Gallstones in lower an- for the high rates of gallstones noted in var- imals had been recognized for centuries, and ious American Indian groups, including Pima, crushed gallstones constituted an important in- Navajo, and Chippewa, as well as in groups with gredient in yellow pigment. The codified Tal- significant Indian admixture from Mexico, Bo- mudic law of the fourth century A.D. consid- livia, Chile, and Peru. It has been postulated that ered animals with sharp-edged gallstones unfit a genetic defect in conversion of cholesterol to to eat (terefah), but kosher if the gallstones were bile acid results in lithogenic bile. smooth. The geographic epidemiology of gallstones Sixth century Byzantine physician Alexan- indicates a susceptibility in New World popu- der of Tralles described both gallstones and lations that is not shared by their Asian an- renal calculi. Tenth century Persian physician cestral relatives. The Americas were settled by Haly Abbas (often quoted in early Renaissance crossing the Bering land bridge formed during medicine)recorded the presence of calculi in glacial epochs. Survival under the harsh climatic the gallbladder and liver. conditions depended on hunting and gather- Mundinus was professor of anatomy and ing strategies with unpredictable periods of near surgery at the University of Bologna from 1295 starvation. Individuals who could rapidly store to 1326. His manuscript on anatomy was based excess calories as fat would have had a pro- on Hippocrates, Galen, and Arabic authors and nounced survival advantage over individuals was widely used for nearly 250 years. He also lacking this trait. This is the “thrifty gene” theory mentions stones formed within the gallblad- postulated to explain the prevalence of diabetes der and kidneys. Gentile da Foligno was a among American Indians and possibly account- graduate of Bologna and professor at Padua, ing for the association of obesity, parity, and who died of plague in 1348. In 1341, he per- puberty with the formation of gallstones in In- formed one of the earliest autopsies on record, dians now exposed to a perpetual “feast” of calo- an account of which mentions a gallstone found ries and sedentary living. Indeed, the worldwide embedded in the cystic duct of the gallbladder.

135 59. Gangrene

Antonio Benivieni wrote the first book sues to repair or replace the gangrenous part. Al- devoted to pathological anatomy, published though gangrene can occur in internal organs, it posthumously in 1507. It contains 111 obser- generally means a process on the body’s surface, vations based on 20 autopsies, including two involving only skin or possibly deeper tissues as descriptions of gallstones found within the gall- well. bladder and liver. Numerous other Renaissance Gangrene is either dry or moist. Dry gangrene physicians were familiar with gallstones en- is necrosis of tissues resulting from vascular oc- countered in clinical practice or more often at clusion, as in severe arteriosclerosis of the legs. autopsy. Moist gangrene occurs when bacteria invade In 1761, Giovanni Battista Morgagni provided dead tissue, producing putrefaction. When gas- a vast array of pathological findings related forming bacteria are involved, gas gangrene oc- to the clinical picture for a large number of curs. An originally dry gangrene may be con- diseases, including gallstones. Morgagni noted verted to moist by invading bacteria. their increased frequency with age, the greater preponderance of women sufferers, variation by General Characteristics locale, and association with a sedentary life. Bile In dry gangrene, arterial supply is gradually cut stasis again figured as a prominent factor in gall- off, and drying of the tissues results. Inflam- stone formation. He also considered irritation or mation is frequently absent, but pain may pre- inflammation of the glands within the gallblad- cede the color changes. Soft tissues progres- der wall as a cause of stones. sively shrink, and the color deepens until the Gallstones have been recovered in excava- area is coal black. Constitutional symptoms may tions, which greatly extends the known antiq- occur but are less severe than in moist gan- uity of the disease. Given their frequency, more grene. such examples should be expected. The earliest Moist gangrene may be preceded by inflam- case comes from Mycenae, Greece, dating from mation or trauma. The part is initially swollen 1600–1500 B.C. Other early Old World exam- and painful. The color is red, then blue, and ples are associated with tenth century B.C. (and finally green black. There is boggy swelling later)Egypt, China in the Han Dynasty (206 B.C. and putrid odor. If the gangrene is extensive, to 220 A.D.), and early medieval Europe. constitutional symptoms such as fever may In the New World, gallstones were found at occur. the Libben site in Ohio, a Late Woodland site Gangrene has many causes. Some are now dating from 1000 to 1200 A.D., and in north- quite rare but once were common. Some have ern Chile at a site dating from 100 to 300 A.D. been of major consequence throughout history. A variable frequency in ancient human popula- tions is to be expected, and because of dietary Vascular Causes factors, gallstones may have been quite rare in Historically, ergotism resulted from ingesting many instances. rye bread contaminated by the fungus Clavi- R. Ted Steinbock ceps purpurea. It caused a permanent decrease in the caliber of arterioles, eventually leading to dry gangrene of fingers and toes and, less com- monly, of the ears and nose. Ergotism caused 59. Gangrene many gangrene epidemics in medieval Europe. Along with erysipelas, it was called “Saint An- The term gangrene describes local death of tis- thony’s fire.” Although rare, ergotism still occurs sue (necrosis)in the living body. Gangrene im- today. plies a fairly rapid process extending over a Raynaud’s syndrome is characterized by vas- visible area, with an obvious inability of the tis- cular spasms of the extremities. During an

136 59. Gangrene attack (often triggered by cold or stress), one systemically administered drugs may cause or more digits turn white. Some minutes later, gangrene. the color changes to bluish red. Normal color returns slowly. In severe cases, gangrene may Microbiological Causes ensue in fingers or toes. Once known as “relaps- Many organisms produce toxins that directly ing gangrene,” Raynaud’s syndrome may occur cause cell death. Other toxins cause vascular alone (Raynaud’s disease)or with another con- spasm or vasculitis. Some organisms produce dition such as scleroderma, lupus,orrheuma- enzymes that destroy tissue locally. Other or- toid arthritis. It may be an occupational haz- ganisms – in particular, viruses – destroy cells ard for people who operate vibratory machinery by invasion. such as jackhammers. Streptococci (including Streptococcus pyo- Embolism is the sudden occlusion of an genes)have caused certain varieties of gangrene. artery by blood-borne particles. These may be Of historical importance is hospital gangrene, dislodged atheromatous material, vegetations also known as necrotizing fasciitis and pourrit- from infected heart valves, fat particles, gas, ab- ure des hopitauxˆ . This gangrene was the scourge normal proteins, or blood clots. Acute vascular of hospitals in the preantiseptic era but today is compromise can lead to gangrene, usually dry. almost never seen. Trauma is usually the initi- Arteriosclerosis may cause embolisms and ating factor. Within days, gangrene rapidly set can also induce local vascular occlusion into a wound and characteristically was deeply (thrombosis)of large and medium- sized arter- destructive. Patients became febrile and even- ies. It is common in the elderly and therefore tually succumbed. called senile gangrene. It occurs mainly in the Organisms other than S. pyogenes (alone or foot and was previously called “Pott’s disease in combination)may give a similar clinical pic- of the toe.” A special form of arteriosclerosis is ture. Another acute streptococcal disease is thromboangiitis obliterans or Buerger’s dis- Fournier’s gangrene, localized to the scrotum. ease, occurring in men who smoke heavily. Di- Finally, anaerobic streptococci in combination abetes can predispose to arteriosclerosis with with other bacteria such as Staphylococcus au- eventual gangrene of the feet. Other factors reus are the cause of postoperative synergistic that may predispose to arteriosclerosis include gangrene. heredity, fat consumption, lack of exercise, and smoking. History Ergotism has long been a major cause of gan- Physical Causes grene epidemics. Gangrene of the limbs has Various injuries – such as frostbite, compound been recognized since ancient times, and a de- fractures, contusions, gunshot wounds, and scription of gangrene following trauma appears burns – may trigger gangrene. However, this in Hippocrates. Probably gangrene in ancient complication was more prevalent before effec- Greece and Rome resulted mainly from trauma tive medical care became widely available. infections. In temperate and arctic zones, cold injuries Chemical Causes causing frostbite and gangrene have always oc- Tissue can also be destroyed by chemicals of curred. Explorers of cold regions were often either exogenous or endogenous origin. Caus- affected, and gangrene produced by cold in- tics such as carbolic acid can cause gangrene. jury has also been a problem in military activ- Venoms of certain snakes, spiders, and jelly- ities. For example, gangrene was quite preva- fish can cause local necrosis at the site of lent during Napoleon Bonaparte’s invasion of attack. Chemotherapeutic agents may inadver- Russia. Yet frostbite was only one of the mil- tently lead to local tissue destruction. Some itary causes of gangrene. Penetrating wounds,

137 60. Genetic Disease contusions, and compound fractures were often In such a state, these patients are at increased the initial insult. In the sixteenth century, the risk of developing infectious gangrenes whose introduction of gunpowder in Europe produced agents may not be easily recognized or readily tremendous loss of life and limbs from gan- treatable. grene. Poor hygiene and overcrowding in hospi- Diane Quintal and Robert Jackson tals led to epidemic wound infections. Because hospital gangrene was rapidly progressive and lethal, many lives were lost, particularly during the Napoleonic Wars, the Crimean War, and the 60. Genetic Disease American Civil War. In many cases, gangrenous wounds killed almost as many soldiers as were The idea of physical heredity is probably as killed in action. old as our species. Clearly, the concept of “like By World War I, hospital gangrene was much begets like” found expression in the domestica- less prevalent. The art of amputation and set- tion of animals; breeding stock was chosen for ting of fractures was advanced by surgeons favorable traits. The first tangible evidence of such as Ambroise Pare´ in the sixteenth century, the notion of heredity lies in the domestication Pierre-Joseph Desault in the eighteenth, and of dogs some 10,000 years ago. Yet only in re- John Bell at the turn of the nineteenth, among cent times have we begun to understand the others. Their work significantly contributed to workings of heredity. decreased gangrene mortality. In the late nine- The term “hereditary” refers only to passage teenth century, Louis Pasteur introduced the from generation to generation. We may regard concept of antisepsis and asepsis. This concept, a hereditary trait as “genetic” only when its pas- applied to management of wounds, is known as sage from generation to generation is deter- “Listerism” in honor of Joseph Lister, who first mined at least partly by genes. In much the same recognized the clinical value of Pasteur’s dis- way, the term “congenital” signifies only that covery. Finally, the introduction of penicillin in a trait is present at birth. A congenital trait is the early 1940s totally eradicated hospital gan- not necessarily genetic or even hereditary. Thus, grene. the purview of medical genetics includes those Arteriosclerosis is probably as old as hu- traits, both congenital and otherwise, whose ori- mankind. In the fifteenth century, Leonardo da gins lie in single genes, in groups of genes, or in Vinci illustrated senile arteriosclerosis in one of the size or number of the chromosomes. his anatomic sketches. In the early nineteenth In recent years, medical geneticists have uti- century, it gradually became clear that arterial lized a battery of advanced analytic tools and occlusion could cause dry gangrene. In 1862, laboratory techniques to determine the trans- Maurice Raynaud suggested that an arterial dis- mission of various traits. These methods are ease might produce gangrene without arterial derived from what is called the multifactorial obliteration being present. Only recently were model, according to which the observed varia- diabetes, hypertension, and lifestyle recognized tion in a trait (such as clinical presentation of a as contributing factors in arteriosclerosis. Fortu- genetic disease, or liability to a complex disor- nately, widespread education is contributing to der like heart disease)is determined by the joint the decline of vascular disease and associated effects of major gene loci plus multiple minor gangrene. loci (a polygenic effect)and a nongenetic com- In advanced countries, gangrene is much ponent (an environmental effect). This model less common. Infectious gangrenes are eas- has provided a theoretical underpinning for the ily treated or avoided. But a growing num- field of genetic epidemiology and has become a ber of individuals are immunosuppressed from heuristic device through which clinical presen- chemotherapeutic agents and corticosteroids. tation of a disease can be assessed.

138 60. Genetic Disease

It is suggested that a network of effects leads the Hippocratic heredity theory. Abnormal in- from the gene to the final outward manifesta- fants received roughly the same treatment ev- tion, the phenotype. From this perspective, no erywhere in the ancient world: abandonment or gene underlying a human disease exists in a outright slaughter. Often, mothers suffered the vacuum. It exists in a milieu of its own locus, same fate as offspring. The destruction of ab- its chromosomal position and close neighbors, normal infants was advocated by Hippocrates, the various effects of other genes elsewhere in Plato, Aristotle, and virtually all others. Yet the the genome, the intercellular and intracellular practice was not universal, as evidenced by the environment, and the external environment in mummy of an anencephalic infant at Hermopo- which it ultimately finds expression. However, lis. It seems that this baby, who was stillborn or the mechanisms governing this multitude of ef- nearly so, was an object of worship. fects are only just being discovered. The mechanistic interpretation of birth de- fects was modified by the somewhat mystical History Roman attitude. In the first century A.D., Pliny As already stated, the idea that parents’ features wrote that mental impressions formed during were transmitted to offspring was applied early pregnancy were sufficient to produce monsters: in history to animal domestication. Some knowl- Such children were warnings from the gods edge of “good inheritance” (transmission of fa- transmitted to pregnant women. Thus, a black vorable features)undoubtedly came from ob- queen of ancient Ethiopia presented her hus- servations of “bad inheritance.” Thus, for some band, the black king, with a white child. It was 10,000 years we have known, in some de- concluded that the queen had gazed on a statue gree, that certain diseases are hereditary, if not of the goddess Andromeda during her preg- genetic. nancy. The description of the infant, however, By the time of the ancient Greeks, people were is reminiscent of an albino, particularly given clearly cognizant of heredity. Vertical transmis- that royalty often married close relatives. sion was widely accepted, although its workings The decline of reason that marked the Mid- were unknown. Amid scholarly speculation, the dle Ages was reflected in interpretations of Hippocratic theory of its mechanism emerged malformed infants. Such children were called to survive until the Renaissance. In the fourth “devil’s brats,” conceived in a union with Satan. century B.C., Hippocrates postulated that each As with any perceived deviation from piety, the organ and tissue produced its own specific com- fate of both infant and mother was ruthlessly ponent of semen. The composite semen, trans- determined. Later, however, astrological beliefs mitted to a woman through coitus, then incu- sometimes produced surprising outcomes. For bated to become a human baby. Hippocrates’s example, in the thirteenth century, a deformed theory accounted for inheritance of both desir- calf said to appear half human was born. The able traits and abnormal or undesirable ones, cowherd was immediately accused of an unnat- and by the same mechanism. ural act and was in danger of burning at the In discussing hereditary traits, the Greeks stake. Fortunately for him, it was noted that a usually mentioned abstract qualities such as particular conjunction of the planets – often the good and evil, or characteristics such as eye cause of oddities of nature – had recently oc- color, strength, speed, and beauty. They also curred. The cowherd’s life was spared. noted the shocking and fantastic, gross mal- As the Renaissance dawned, reason returned formations, and severe illness. Empedocles sug- to discourses on heredity. Classical works were gested in the fifth century B.C. that “monsters” rediscovered, and development of a science of (grossly malformed infants)resulted from an ex- heredity was once again under way. The writ- cess or deficit of semen. Other writers held sim- ings of Hippocrates and Aristotle were trans- ilar views, which presumably became part of lated and amplified by medical scholars such as

139 60. Genetic Disease

Fabricius and his pupil William Harvey. In ad- noted that although “bleeders” were always dition, there was a growing interest in rare and male, the trait was transmitted by females. unusual medical cases. For Harvey and many Perhaps the most remarkable instance before others, rare pathology was not a source of revul- the work of Gregor Mendel was an 1814 pub- sion or the workings of Satan but, rather, a sub- lication by British physician Joseph Adams. In ject demanding study and understanding. The this study, he distinguished between “familial” debt owed to scholars such as Harvey would be diseases (confined to a single generation)and acknowledged in the twentieth century, when “hereditary” diseases (passed from generation to medical genetics came into full bloom. generation). Moreover, Adams defined congeni- With the Enlightenment, the floodgates were tal disorders as appearing at birth and regarded opened, and medical science progressed on them as more likely familial than hereditary. He many fronts. However, despite eloquent writ- observed that familial diseases were often so se- ings on heredity in general and on rare cases vere that subsequent transmission from the af- in particular, few references to specific genetic fected individual was ruled out by early death. diseases were made before the twentieth cen- Such conditions increased among offspring and tury. Yet among those few instances were some were often found in isolated districts where brilliant insights. inbreeding was common. Clearly, Adams’s fa- Between 1745 and 1757, French natural milial diseases were what we term recessive philosopher Pierre Louis Moreau de Mau- and his hereditary diseases were what we term pertuis conducted studies on the heredity of dominant. polydactyly (an abnormal number of fingers Adams concluded that hereditary diseases (in and/or toes)and published the pedigree of the modern sense)were not always apparent at a family with polydactyly in four successive birth but might have later ages of onset, that generations. He formulated a theory of hered- correlations existed among family members ity, suggesting that particles of inheritance with regard to clinical features, and that hered- were paired in the “semens” of the father and itary diseases might be treatable. Adams hinted the mother and that hereditary pathologies at mutation in remarking that a severe disease were accidental products of the semen. He would last only a single generation except that correctly predicted genes, dominance, and normal parents occasionally produced offspring mutation. Moreover, estimating the probability in whom the disease originated. Finally, he of polydactyly at 1 per 20,000 by his own called for establishment of hereditary-disease survey, he noted that if the disorder was not registers to assist the study of these diseases. hereditary, the chance of a joint occurrence The basic hereditary laws of segregation of an affected parent and an affected offspring and independent assortment were discovered was 1 per 400,000,000 and that of an affected by Austrian monk Gregor Mendel and subse- grandparent, parent, and offspring in sequence quently rediscovered by Carl Correns, Hugo de was 1 per 8,000,000,000,000. Obviously, the Vries, and Erich von Tschermak some decades probability of his four-generation family being later. Mendel, conducting hybridization exper- the product of chance was so small as to be iments with pea plants in his monastery gar- immediately dismissed. Here, then, was also den at Brno, Czechoslovakia, demonstrated that the first use of statistics in a study of heredity. alternative hereditary “characters” for a single Various sex-linked (or X-linked)disorders trait segregated from one another each gen- such as color blindness and hemophilia were eration, and that the characters for multiple accurately described in the late eighteenth and traits assorted independently in each gener- early nineteenth centuries. In 1820, German ation. Moreover, the observed distribution of physician Christian Nasse presented a detailed characters for multiple traits followed a precise pedigree of X-linked recessive hemophilia and mathematical formulation – a binomial series.

14 0 60. Genetic Disease

Mendel reported his results to the Natural spring was precisely what would be expected Science Association of Brno in 1865 and pub- were the abnormality determined by a rare, re- lished them the following year, but his work cessive Mendelian character. was virtually ignored until 1899. By then, nu- In Bateson’s interpretation of the situation, merous researchers were investigating hered- Garrod saw the solution. In 1902, Garrod pub- ity. Dutch botanist Hugo de Vries discovered lished a landmark paper on nine families of alka- Mendel’s report, which contained the solution ptonurics, adding further clinical data, incorpo- to the problems he was studying. De Vries had rating the hereditary mechanism proposed by already formulated his own law of segregation Bateson, and suggesting that the laws of hered- but in 1900 published Mendel’s results as well, ity discovered by Mendel and relayed by Bate- stressing their importance. At the same time, son offered an explanation of the disorder as both German botanist Correns and Austrian an example of a Mendelian recessive character. botanist von Tschermak independently discov- Indeed, Garrod went beyond alkaptonuria to in- ered the Mendelian laws and recognized their clude the possibility of other disorders sharing significance. All three published translations of the same hereditary mechanism. Later, he stud- Mendel’s paper. English biologist and evolution- ied cystinuria, albinism, and pentosuria and ist William Bateson was also interested in plant classed them all with alkaptonuria. hybridization. In 1900, he read de Vries’s ac- By 1908, the impact of Mendelism was fully count of Mendel’s experiments, and soon there- felt. Few doubted that these and other dis- after, as we shall see, made an almost offhand eases were caused by Mendelian characters, and comment that became a fundamental contribu- that the study of families – particularly inbred tion to the study of human genetic diseases. ones – was crucial to obtaining new insights In 1897, London physician Sir Archibald Gar- into old disease entities. Garrod suggested that rod began studying alkaptonuria, a nonfatal the pathology of inborn errors of metabolism congenital disorder characterized by excretion consisted of a blockade in the normal pathway of homogentisic acid in the urine – turning the and that this blockade was caused by congeni- urine dark – and often accompanied in later tal deficiency of a specific enzyme. By the mid- years by arthritis and black pigmentation of twentieth century, the truth of his insight – that cartilage and collagenous tissues. At the time, transmitted enzymic defects cause disease – led the disease was considered infectious, and the to the “one gene, one enzyme” hypothesis and excretion of homogentisic acid was thought to to the theory of gene action. Garrod has since result from bacterial action in the intestine. Gar- been called the “father of chemical genetics.” rod believed instead that the condition was a From our contemporary perspective, the work congenital error of abnormal metabolism.He and insights of Garrod are landmarks. The incor- published this theory in 1899. poration of Mendelian laws of heredity into the Soon, however, Garrod made a crucial ob- study of human diseases was the turning point servation. He noted that among four families for medical genetics. Surprisingly, however, with alkaptonuric offspring and two unaffected Garrod’s theories went largely unnoticed for parents, three of the parental pairs were first several decades. One reason for this slow recog- cousins. (This circumstance would hardly have nition was that it was impossible in Garrod’s surprised Joseph Adams, who had commented time for most geneticists to reduce Mendel’s on inbreeding nearly 90 years earlier.)Garrod laws to purely chemical phenomena. Indeed, in discussed his findings with Bateson, who rec- the earliest days of the rediscovery of Mendel, ognized that the pathology was “all or none,” much effort was devoted to dealing with a grow- affected or normal. Moreover, the high inci- ing list of exceptions to those laws. dence of consanguinity and the characteristic Nevertheless, progress in understanding the pattern of normal parents having affected off- hereditary nature of numerous human diseases

141 60. Genetic Disease was made, although it failed fully to coa- sickle-cell trait, believing that the latter was lesce until the middle of the twentieth century. merely the dormant stage of the former. In 1933, Two disorders that contributed greatly to this L. W. Diggs and colleagues suggested this to be progress were sickle-cell anemia and Down incorrect, showing that hemoglobin determina- syndrome. tions among black schoolchildren with sickle- cell trait were similar to those of controls. More- Molecular Medicine over, no pathology was significantly associated The first case of sickle-cell anemia was reported with the sickle-cell trait. in 1910 by Chicago physician J. B. Herrick. On As the distinction between the trait and the examining a young black man from Grenada, anemia became accepted, the pace of research he found, among other features, an anemia in on sickle-cell anemia quickened, and in 1949 which many red blood cells had a “sickle-like two milestones were reached. First, two investi- shape.” Soon after, a similar case was reported, gators independently discovered that the sickle- and in 1917 the phenomenon was described cell trait appears as a heterozygote with the by V. E. Emmel. Emmel showed that the sick- normal allele, whereas sickle-cell anemia is the ling was developmental, with seemingly normal homozygous state of the gene, meaning that red cells undergoing the change as they ma- it must be inherited from both parents. These tured. He further showed that no red cells from findings led to recognition that most dominant controls or from any other type of anemia or genetic diseases are heterozygous. leukemia could be induced to sickle. However, Then, L. Pauling and colleagues showed that Emmel noted that a small proportion of red cells the hemoglobin molecules in individuals with from the patient’s father, who was not anemic, sickle-cell anemia and those in normal controls did undergo sickling. were fundamentally different. They predicted Even though the father showed traces of the that the abnormality would be found in the sickling trait and three of the patient’s siblings globin part of the molecule and not in the had died early of severe anemia, Emmel failed to heme groups, that the sickling process involved infer a possible hereditary factor. The first such abnormal interactions of altered molecules, suggestion was offered six years later by J. G. and that the alteration resulted in two to four Huck, who – in addition to reporting the first more net positive charges per molecule. Their large clinical sample (17 patients)– displayed predictions were all correct, as was shown by the pedigrees of two sickle-cell families. In one, V. M. Ingram in 1956. Abnormal (sickle-cell) both parents were affected but had produced hemoglobin differed in only one “spot,” which one normal offspring along with two affected had a net positive charge. Within three years it children. The significance of these families was was demonstrated that the charge was caused noted: “Apparently the ‘sickle cell’ condition in by alteration of a single amino acid through man is inherited according to the Mendelian mutation. law for the inheritance of a single factor.” More- Since the moment the puzzle of sickle-cell over, “one interesting feature of this inheritance anemia was solved, the study of mutant globins is the fact that the sickle cell condition is dom- and associated disorders has signaled nearly ev- inant over the normal condition.” In 13 years, ery major advance in molecular biology. In 1978, reports of a unique pathological finding had led R. M. Lawn and colleagues and Y. W. Kan and to recognition of a hereditary disease — sickle- A.M.Dozy independently demonstrated the first cell anemia. human restriction fragment length polymor- After this good start, study of the dis- phisms (RFLPs)in the hemoglobin molecule. ease slowed dramatically – partly because This led to recombinant-DNA-based studies on most investigators failed to differentiate be- genetic diseases as well as human gene map- tween sickle-cell anemia and the nonanemic ping. The discovery of repetitive DNA sequences

142 60. Genetic Disease in globin genes resulted in the development of Mendelian expectations – though some favored DNA probes. Moreover, other recombinant DNA “irregular dominance” as an explanation – and techniques for molecular diagnosis of genetic that the only clear correlate was late maternal diseases were pioneered by Kan and Dozy and age. Two decades later, the improvements in cy- are now applied to a wide range of disorders, tological techniques that allowed determination including cancer and infectious diseases. of the correct number of human chromosomes also provided the solution to Down syndrome. Cytogenetics In 1959, three French cytologists announced The chromosome theory of heredity, that the that patients with Down syndrome had an extra Mendelian characters were contained in the chromosome. chromosomes, developed soon after the redis- This first example of a disorder caused by at covery of Mendel’s laws and was largely a re- least one triploid chromosome in an otherwise sult of Mendel’s own observations. W. S. Sut- diploid set (now called trisomy)led to a spate of ton concluded that parallels between the or- similar findings, including Turner’s syndrome ganization and behavior of chromosomes and (lack of one X-chromosome – XO), Kleinfelter’s the laws of segregation and independent assort- syndrome (XXY), trisomy 13, and trisomy 18. ment could not be mere chance. He proposed The discovery of chromosome banding tech- that multiple characters would be found on a niques enabled chromosomes to be identified single chromosome. individually, and these techniques have been re- Spurred by the work of Sutton and others, fined to the point that regions within them can T. H. Morgan began studying inheritance of unit be identified. characters, the individual factors of Mendelian Finally, the advent of recombinant DNA tech- transmission. Using the fruit fly Drosophila,by niques and analytic tools for estimating genetic 1914 Morgan concluded that the Mendelian fac- linkage enabled one group to focus on the cause tors, or genes, were physical entities present in of the trisomy. A. C. Warren and colleagues the chromosomes in a linear manner. In 1923, demonstrated that recombination among DNA T. S. Painter suggested that the number of hu- markers that have undergone nondisjunction man chromosomes was 48, and this was ac- (the event leading to a trisomy)occurs to a sig- cepted for 23 years. Improved cytological tech- nificantly lesser extent in Down-syndrome pa- niques eventually led to establishment of the tients than it does in controls. Reduced recom- correct number as 46. So strong was the belief bination is indicative of asynapsis, or a failure in Painter’s estimate of 48 that a previous study of normal chromosome pairing. This result will had been abandoned because researchers could likely lead to the discovery of the molecular count only 46. mechanism of chromosome pairing. Not long afterward, the solution to an old In sum, the history of the study of human medical puzzle became apparent. A syndrome genetic diseases has been marked by periods called furfuraceous idiocy, described in 1846 of superstition and pseudoscience as well as by by French physician E. Seguin,´ included charac- flashes of brilliant insight such as those of Mau- teristic facial features, incomplete growth, and pertuis, Adams, and Garrod. It has also been mental retardation. In 1867,J. Langdon Down as- characterized by an exponential increase in fun- cribed these traits to the Mongol type. From his damental understanding coupled with techno- publication the term “Mongolian idiot” replaced logical and methodological breakthroughs, as the previous name, and later “Down syndrome” clearly exemplified by sickle-cell anemia and became an interchangeable term. But repeated Down syndrome. The development of recombi- studies of Down syndrome failed to produce a nant DNA technology has inaugurated a revo- viable etiologic hypothesis. In 1939, L. S. Pen- lution in the study of genetic disease matched rose noted that the disorder had failed to meet only by the revelation of Mendel’s laws in 1900.

143 61. Giardiasis

The future of medical genetics is bright of New York City’s 55 police and fire depart- indeed. Systematic screening of the human ment scuba divers had Giardia, presumably genome has revealed hundreds of DNA se- from the harbor’s heavily polluted water. Preva- quence variants, exploitation of which has made lence rates in developing countries are 8–20 it possible to establish genetic linkage and chro- percent and higher. In poor countries such as mosome map locations for a large number of Bangladesh, most children and many adults re- hereditary human illnesses. Moreover, the dis- peatedly acquire infection. ease genes themselves have been cloned. These There has been considerable dispute about successes have made a genetic map of the entire the clinical importance of Giardia infection. Al- human genome a feasible imperative. Clearly, though many cases are asymptomatic, it is now the day of an exact science of molecular medi- clear that the flagellates damage the intestinal cal genetics has dawned, and with it has come wall and heavy infestations can cause nutrition- the potential for treating and even curing ge- ally significant malabsorption of food. Symp- netic diseases. toms include diarrhea, flatulence, abdominal Eric J. Devor discomfort, and light-colored, fatty stools. Re- peated examinations and use of serologic tech- niques developed in the 1980s yield more reli- able diagnoses for either individual patients or 61. Giardiasis an entire population. Most infections are self- limiting, and treatment is effective, but reinfes- Infection with the small flagellate Giardia lam- tation must be avoided. Some evidence indi- blia is found around the world. This protozoan cates that mothers’ milk helps protect infants inhabits the small intestine of humans and is es- against infection. pecially common in children. Other mammals, K. David Patterson including beavers and muskrats, also harbor Giardia and are important reservoir hosts. The parasite was first seen by Anton van Leeuwen- hoek in 1681 and described scientifically in 62. Glomerulonephritis (Bright’s Disease) 1859. Adult parasites (trophozoites)attach to the in- Glomerulonephritis, an immunologic disease testinal wall with sucking disks. As trophozoites of the kidneys, affects the glomerulus, a clus- detach and pass down the intestinal tract, they ter of capillaries that is the filter in the func- transform themselves into cysts that are able to tioning unit of the kidney, the nephron. Inflam- resist many environmental pressures, including mation, initiated by immune complexes, injures water filtration and chlorination. Humans al- the glomerulus. Often the disease is acute, but most always acquire infection by swallowing fe- it may be completely undetected until signs of cally contaminated food or water. In developed kidney failure appear. This silent disease may countries, many cases of giardiasis have been prove fatal. traced to campers who drank from streams that The urine-secreting structure (nephron)con- appeared to be pure but had been contaminated sists of the glomerulus and its tubular sys- by animals. Because of the cysts’ resistance to tem. Each glomerulus consists of a tangle of normal water-purification methods, public wa- capillaries branching between two tiny arter- ter supplies can become infected, as happened ies (arterioles). The glomerulus is a blood fil- in two Colorado ski resorts in 1964 and 1978. ter that controls passage of molecules through Giardiasis is a frequent cause of “traveler’s di- the basement membrane. Normally red blood arrhea,” and tourist groups in Leningrad have cells and albumin are not permitted to pass. suffered well-publicized outbreaks. In 1983, 22 The tubules reabsorb, secrete, synthesize, and

14 4 62. Glomerulonephritis (Bright’s Disease) excrete solutes and metabolites, thereby main- lows streptococcal infections, as scarlet fever is taining physiological equilibrium. uncommon. Poststreptococcal glomerulonephritis, stud- ied by Richard Bright during the nineteenth History century, still bears his name (Bright’s disease). About 100 A.D., Rufus of Ephesus noted hard- Related diseases include the glomerulopathies, ened kidneys in patients who produced little seen in diabetes and amyloidosis. urine, suffered no pain, and sometimes devel- oped dropsy. This description could certainly be Characteristics chronic glomerulonephritis. Around 1000 A.D., Glomerulonephritis occurs worldwide and was Avicenna, an Arab who authored perhaps the seen frequently in Europe during the eigh- most famous medical text ever, mentioned pa- teenth and nineteenth centuries as a complica- tients with “chronic nephritis.”Gulielmus de Sal- tion of scarlet fever. Today glomerulonephritis iceto’s treatise, written in the mid-thirteenth occurs sporadically. Since the 1950s, epidemics century but not published until 1476, discusses have struck Trinidad, the United States, and dropsy, scanty urine, and hardened kidneys. Venezuela. The disease appears more prevalent This is chronic kidney disease – very likely in the Western world, probably because modern glomerulonephritis. diagnostic aids are available. Children contract Scientific urinalysis, representing a major step it more commonly than adults. Because it is of- forward from the “looking and tasting” of the ten silent, the incidence of glomerulonephritis “Pisse Prophets,” commenced with Frederick remains unknown. Dekkers, who discovered in 1695 that some Physicians have long known that swelling urine samples, like serum, coagulated when (dropsy)occurred in some individuals 10–14 heated or combined with acetic acid. In the days after bouts of scarlet fever (scarlatina). next century, Neapolitan anatomist Domenico Early physicians believed that toxins released Cotugno attended a soldier with a febrile ill- during fever caused the dropsy, and long af- ness, who “had a wonderful eruption of inter- ter Bright associated post-scarlatina dropsy with cutaneous water.” This fluid and the urine “con- kidney changes, the role of scarlet fever re- tained a coagulable matter.” Whether Cotugno mained unknown. In the latter nineteenth cen- knew of Dekkers’ observation is unknown, but tury, physicians learned that the scarlatina rash Cotugno may have been first to note albu- resulted from streptococcal toxins. min in the urine associated with dropsy. About Only in the mid-twentieth century did re- the same time, Swedish physician Nils Rosen´ searchers find that rabbits developed glomeru- von Rosenstein wrote an early, accurate account lonephritis when injected with foreign proteins. of poststreptococcal glomerulonephritis he ob- Following injections, the glomerulus sustained served during the scarlatina epidemic in Upsala injury from immune complexes. An immune in 1741. complex consists of an antigen (the protein), The relationship between scarlet fever and an antibody (produced by the rabbit), and a dropsy was well recognized over the next complement. Immune complexes localize in the 50 years. Thomas Bateman described post- glomerulus and damage the basement mem- scarlatina dropsy patients seen between 1804 brane, which leaks protein and red blood cells and 1816 in London. In 1811, William Wells ob- into the urine. Swollen cells block the glomeru- served that the urine of such patients frequently lar capillaries. contained blood constituents. Unaware of Co- In humans, events mimicking this model fol- tugno’s writings, he credited another with first low certain streptococcal infections. Before an- noting “serum” in the urine of dropsy patients. tibiotics, glomerulonephritis usually followed Wells found serum in the urine of 78 of 130 attacks of scarlet fever. Today, it often fol- such patients and also noted increased urine

145 63. Goiter volumes. He observed altered kidneys in one vessels. In later writings, he referred to glomeru- dropsical patient at autopsy but thought this lar changes, but he believed the main changes limited observation did not justify associ- were in the tubules. The first pathologist to use ating the urine anomalies with the kidney the word “glomerulonephritis” was Edwin Klebs abnormalities. in 1879. The term became synonymous with In 1818, John Blackall also observed dropsy, Bright’s disease after its incorporation in a 1914 albuminuria, and bloody urine after scarlatina. classification, which remained in use with little He also noted hardened kidneys. Soon after- modification for nearly a half century. ward, Bright, a giant of medicine, was study- The use of biopsy to evaluate kidney dis- ing patients with post-scarlatina dropsy and orders was also an important contribution. albuminuria. In 1827, he first reported his find- As biopsy experience accumulated in the ings. Bright’s meticulous account of the disease 1950s, 1960s, and 1970s, many classifications of and illustrations of the renal changes remain a Bright’s disease appeared. Understanding of the model report today, but he did not explain how role of the immune system in glomerulonephri- albumin enters the urine. This question could tis was achieved, and the glomerular basement not be answered until nephron structure was membrane was established as the site of albu- further defined. minuric leakage. The tubule is not the source Marcello Malpighi had tried to answer the of the urine protein, but altered tubular reab- question in 1666 at Bologna. He knew of the sorption possibly plays a role in albuminuria. glomeruli but was frustrated in attempting to The major contributions of the twentieth cen- establish their function. In the nineteenth cen- tury were the use of thin sections, immunoflu- tury, Johannes Peter Mueller knew of Malpighi’s orescent techniques, and electron microscopy study of the glomeruli, but he considered them in biopsy interpretation. as simply receptacles of blood. He believed that Today, Bright’s disease consists of many dis- urine was secreted by the epithelium of the orders, all of which can be considered glomeru- proximal tubules. In 1842, however, William lonephritis. Their diagnosis and management Bowman wondered, as Malpighi had, why the will continue to challenge medical science as glomerulus ended blindly in a space open- the twenty-first century progresses. ing into the tubules. Bowman suggested that Donald M. Larson protein and red cells might pass through the glomerulus under abnormal circumstances! A few years later, German physiologist Carl Ludwig supplemented Bowman’s observations 63. Goiter with the view that the glomerulus was a semipermeable filter. In 1861, Thomas Graham Goiter is an ancient disease that has always showed that membranes could block colloids been more common in some places than in oth- but permit passage of crystalloids. The glomeru- ers. It was known in China at least by the third lus was established as the source of urine, but century B.C. and possibly earlier. The Romans albuminuria was still attributed to tubular ep- knew the disease well by the second century ithelium. Even as microscopic studies advanced, A.D.; indeed, a major focus of endemic goiter pathologists adhered to this view. The source of was in the European Alps. The word “goiter” dropsical urinary albumin was not determined (goitre in Europe)derives from the Latin gut- for another century. ter, but the meaning has shifted from “throat” Rudolph Virchow established the cellular ba- to mean specifically an enlarged thyroid.An sis for pathology in 1858, and classified Bright’s ancient Greek synonym was bronchocele. Mod- disease into three categories – involving the ern synonyms are the Spanish bocio, the Ital- tubules, the connective tissue, and the blood ian gozzo, and the German Kropf. The ancient

14 6 63. Goiter

Latin word struma, probably used originally to called “cretins,” and their disease endemic cre- describe inflamed lymph nodes in the neck, was tinism. The word “cretin” probably derives from later used to indicate goiter. the French cretien, and thence from the Latin This semantical confusion is understandable christianus (“christian”)and was likely used to because the thyroid gland was unknown until make clear that these persons were truly hu- the sixteenth century. Leonardo da Vinci may man. Travelers’ observations of cretinism in the have drawn it about the year 1500, but the Alps date from the thirteenth century, but clini- drawing was not published until much later. An- cal allusions begin with Paracelsus, who around dreas Vesalius noted “laryngeal glands” in 1543, 1527 connected cretinism with goiter. Good de- but not in humans. By the end of the century, scriptions begin with Felix Platter, who probably however, anatomists had identified the human observed it in 1562 and who also associated the thyroid as a discrete structure: Bartolomeo Eu- two maladies. stachi in 1552, Realdo Colombo in 1558, and By the seventeenth century, the concept of Giulio Casserio in 1600. In 1619, Hieronymus goiter as an abnormally enlarged thyroid gland Fabricius realized that goiter arises from an en- was reasonably well established, as was its asso- largement of this gland, and in 1656 Thomas ciation with cretinism and with the alpine areas Wharfton named the gland by virtue of its prox- of Europe. Yet, cretinism in particular was rare, imity to the thyroid cartilage. and most physicians never saw it. Just as goiter could be confounded with other neck diseases, Characteristics so could cretinism with any sort of mental re- Other diseases of the neck confounded the con- tardation. Thus a certain amount of diagnostic nection between goiter and the thyroid gland. “fuzziness” persisted. The main confounder was scrofula, which in Today goiter means only an enlarged thyroid. medieval Latin meant “swelling of the glands” The thyroid may be uniformly enlarged (sim- and is still used to connote tuberculous lymph ple goiter)or have several lumps ( multinodular glands in the neck. In regions where goiter was goiter). The World Health Organization assigns endemic, affecting large portions of the popula- gradations to the disorder: tion, its connection with the thyroid was fairly Grade 0 = no goiter clear. But where only a few individuals exhib- Grade 1 = palpable but invisible goiter ited the disease, it was called sporadic goiter. Grade 2 = easily visible goiter If the swelling was small and moved with swal- Grade 3 = goiter visible at 30 meters. lowing, it was called an enlarged thyroid. But if the mass was immovable, then it was considered Some goiters are malignant (e.g., thyroid cancer to arise from tuberculous nodes. This confusion or lymphoma), but most are benign. Some are persisted until the mid-nineteenth century. Jean associated with specific thyroid diseases such Louis Alibert, for example, in 1835 classified en- as hyperthyroidism, hypothyroidism, and thy- demic goiter as a type of scrofula found in rural roiditis. These and other conditions overlap areas. Today goiter is (arbitrarily)defined as en- considerably and continue to cause confusion demic if more than 10 percent of a population in diagnosis and treatment. is goitrous. Goiter is not particularly harmful unless it Large and disfiguring goiters were cosmeti- compresses the trachea or causes emotional cally distressing and sometimes blocked breath- upset. For a large goiter requiring treatment, ing. Moreover, endemic goiter areas produced however, the only solution until the twentieth a number of people who were retarded from century was surgery. But the operation com- birth, with disfigured faces, and sometimes deaf monly killed the patient, and some surgeons and mute. Most but not all had goiter, which objected to it in principle. Others, such as was also common in their mothers. They were E. Theodor Kocher in Berne and the cousins

147 63. Goiter

Jacques-Louis and Auguste Reverdin in Geneva ciple in treating goiter. Chemist Jean-Baptiste persisted, and by the 1880s were able to remove Dumas looked for iodine in marine sponge and all or most of a goitrous thyroid with death found it. Coindet then gave iodine to goitrous rates under 1 percent. patients, with good results that were soon con- It became clear, however, that removing the firmed by other physicians. As early as 1825, an- entire thyroid caused symptoms resembling other chemist, Jean Baptiste Boussingault, sug- cretinism. In 1883, Felix Semon in London gested that iodine deficiency might be the cause suggested that cretins, thyroidectomy patients, of goiter and recommended the addition of io- and adults with a mysterious disorder called dine to table salt to prevent it, but little came of myxedema all suffered because they lacked this suggestion. thyroid glands; in 1888, he was found to be cor- A generation later, Jean-Louis Prevost,´ an- rect. Thyroid deficiency, myxedema, and hy- other Geneva physician, made the same sugges- pothyroidism are now synonyms for decreased tion as Boussingault. But iodine had fallen into or lacking thyroid function. disfavor as therapy for goiter because of toxic side effects, including hyperthyroidism. Coindet History himself had seen this and had cautioned against Many theories have attempted to explain goi- too high a dose, but to no avail. ter. One ancient idea was that goiter comes from In the 1850s, Adolphe Chatin, a French phar- an excess of phlegm descending from the head macist and botanist, found iodine in freshwater into the throat. Many saw excessive flexing of plants and suggested that these be used to pre- the head as the cause – including Michelangelo, vent goiter. He measured iodine in water sam- who suggested it in 1509. Geographic peculiari- ples from all over France, and in some foods ties and climatic factors were frequently blamed as well, and concluded that in certain areas a as well. Finally, some thought hereditary or con- lack of iodine in drinking water appeared to stitutional factors important. be the principal cause of goiter. But in 1852, During the nineteenth century, major theo- a French Academy of Sciences committee – ries of goiter focused at least in part on some although congratulating Chatin on his work – peculiarity of drinking water, lack of iodine, an viewed his association between lack of iodine infection of some sort, or some combination of and goiter as unproven. these. Climatic factors had been dismissed. High Meanwhile, in South America in 1835 and in altitude had been rejected as well, for the dis- Savoy in the 1840s there had been successful ease was not limited to mountainous regions. trials of iodine against endemic goiter. Yet the The long process of linking goiter and cre- success of iodine as a goiter preventive was not tinism to iodine deficiency began in 1811, pursued. The reluctance to accept iodine defi- when Bernard Courtois discovered iodine while ciency as a cause of goiter is understandable: making saltpeter for gunpowder during the There was then no good example of a disease Napoleonic Wars. He noticed it as a violet vapor caused by a deficiency. Further, the theory did released from the residue of burnt seaweed. It not explain why only some people in low-iodine was subsequently named iodine from the Greek areas got goiter while others did not. This prob- word for “violet.” The key was the seaweed. lem remains unresolved today. For centuries, dating from the 1100s in Europe After the discovery of the bacterial cause of and from considerably earlier in China, seaweed many diseases, it was postulated that goiter had been among the many remedies for goiter. was caused by either a bacterium or a bacterial Within a few years, iodine was detected in vari- toxin, perhaps in water. Edwin Klebs believed he ous seaweeds. had found such an agent in 1877, and August In 1818, J.-F. Coindet, a Geneva physician, Hirsch around 1885 stated flatly that “endemic suggested that iodine might be the active prin- goitre and cretinism have to be reckoned among

14 8 63. Goiter the infective diseases.” Indeed, the notion that trition officer during World War I, to measure goiter has an infectious cause persisted into the iodine in water and food. He showed that there early twentieth century despite unconvincing was a correlation between lower iodine and the evidence. But the parallel notion of a toxin in the presence of human goiter and also that rats on water, possibly of bacterial origin, is still alive a low-iodine diet got goiter. He later gathered and warrants serious consideration, particularly worldwide data to support his thesis that low where there is much goiter despite adequate io- iodine in drinking water causes goiter. dine intake. By 1924, Michigan offered iodized salt to the Until the 1890s, there was no resolution of the public after an education campaign; within 12 cause of endemic goiter or cretinism. No clear years, goiter prevalence fell from 37 percent to choice was possible among the drinking-water, 8 percent – and by 1951 to 2 percent. Since Ma- iodine-deficiency, or toxic-infective hypotheses. rine’s study, iodine intake in the United States Fear of serious side effects if everyone took io- has increased several times, not only because dine in salt or food was widespread: After all, of iodized salt but because of widespread use iodine was a known poison. Nonetheless, sub- of foods that contain iodine, such as bread and stantial advances began to be made in goiter milk. Thus, in the United States, few can develop research. George R. Murray discovered in 1891 iodine deficiency, and goiter is mostly sporadic, that a glycerin extract of sheep thyroid cured occurring either spontaneously or as a result of myxedema, and investigators began to look for factors other than iodine deficiency. Yet, some iodine in the thyroid itself. For example, while areas of endemic goiter persist in the United looking for the active compound in the thyroid, States, especially in parts of Appalachia, and may Eugen Baumann produced an extract. When an- be caused by a “goitrogen” (a substance that alyzing it, he routinely looked for iodine, not causes goiter). Goitrogens certainly exist, but expecting to find it; to his surprise it was there. how much they contribute to human goiter is From this point research diverged. One path unclear. led to the 1914 isolation of a specific thyroid In many other parts of the world, goiter hormone, thyroxine, by Edward C. Kendall. Re- remains endemic. Persons in an endemic area searchers also began to study goiter in rela- could have any of the diseases that cause tion to the iodine content of the thyroid rather sporadic goiter, which is one reason why goiter than that of the environment. By 1910, David prevalence never falls to zero even with iodine Marine in Cleveland, Ohio, had demonstrated repletion. For some areas, goiter is a major that iodine prevented goiter in brook trout. He public-health problem, and millions of people gave iodine to hospital patients and to children remain at risk. The disease is almost always of friends to prevent goiter. In fact, he tried associated with low iodine intake and iodine to give it to all schoolchildren in Cleveland, deficiency, and while there remains no good but the school board, led by a goiter surgeon, explanation of why some do not develop goiter said it would poison the children. Several years in areas of low dietary iodine, iodine does later, Marine conducted a large-scale study of prevent the disease. The issue then becomes iodine prophylaxis for goiter. The results were a social and political one of providing iodine clear-cut: Sixty-five percent of goiters became to those in deficient areas and then getting smaller, and new goiter was largely prevented. them to take it. Iodine is not, however, the This study provided the impetus for the use of answer to all endemic goiter, and we now face iodized salt in the United States. the challenge of teasing out several probable Marine had shown iodine to be both treat- factors in addition to iodine deficiency, as well ment and preventive for goiter but had not as the political challenge involved in iodine proven that his patients were iodine deficient. prophylaxis on a worldwide basis. It remained for J. F. McClendon, an army nu- Clark T. Sawin

14 9 64. Gonorrhea

64. Gonorrhea tinct syndromes been identified. This is be- cause asymptomatic infection probably occurs The name gonorrhea (“flow of seed”) and its more frequently in women. Infection of the ure- vernacular counterparts (“clap,” “dose,” “strain”) thra occurs in 70–90 percent of women with reflect a hazy comprehension of the dis- gonorrhea, but the more important manifesta- ease. The only accurate term in common use tion of the disease is infection of the uterine is “drip,” which acknowledges the white-to- cervix. yellowish milky discharge from the male penis. The major concern about gonorrhea is its But even this more realistic designation indi- potential for destruction of female reproduc- cates only the male urethral aspect of a broader tive organs. The gonococcus may spread from syndrome. the cervix to inflame the uterine lining and Gonorrhea is an infection of mucosal surfaces ultimately cause peritonitis. Once established, caused by a bacterium, the gonococcus Neisse- pelvic inflammatory disease (PID) becomes ria gonorrhoeae, whose only natural reservoir chronic, with serious consequences. About 20 is humans. Its presence in the genital tract de- percent of women will have a recurrence af- fines the condition gonorrhea; otherwise, the ter treatment. Studies in Sweden indicate that adjective “gonococcal” is used (as in gonococ- the risk of sterility is 12–16 percent after a sin- cal endocarditis). Though gonorrhea is trans- gle episode and rises to 60 percent after three mitted primarily (through sexual contact) to episodes. genital mucosa, it may disseminate elsewhere, A distinctive picture appears when the gono- with infection of the skin, heart valves, joints, coccus is spread via the bloodstream, including and central nervous system. It is rarely the infection of various sites along with character- cause of death but can produce serious se- istic skin lesions and arthritis. This is dissem- quelae. The gonococcus occupies an ecological inated gonococcal infection (DGI). The lesions niche requiring a surprisingly complex assort- are small and generally number fewer than 20. ment of attributes necessary for survival, not Infected joints usually exhibit the classic fea- least among which is a propitious set of so- tures of arthritis. Patients with DGI usually re- cial and sexual mores among its hosts. As his- spond well to routine treatment. tory demonstrates, the seemingly delicate bal- Another major mode of transmission of the ance among such factors has been universally gonococcus is from mother to child. The available. most common manifestation is gonococcal ophthalmia. The typical syndrome includes Characteristics relatively rapid progression to generalized in- In male genital infections, pus issuing from the volvement, scarring, and blindness. Children penile opening, accompanied by discomfort on may develop gonorrhea in sexual sites as well. urination, is the most frequent symptom of gon- It is apparent that the majority of infected chil- orrhea. The gonococcus adheres to cells lining dren have suffered sexual abuse. the urethra, establishing an inflammatory reac- The importance of gonorrhea is measured tion. This primary pathological process is basi- not only by its considerable burden of acute cally the same at all mucosal sites of infection. disease and long-term consequences, but The majority of men will become symptomatic also by some of its extraordinary biological in 3–5 days. In perhaps one-quarter of cases, characteristics. The virulence of the gonococ- symptoms are insufficient to cause the patient cus rests in its ability to adhere to muscosal to seek medical care. A substantial proportion surfaces, to resist immunological defenses, of men with gonorrhea will be asymptomatic. to cause asymptomatic infection, and to re- Though women have long been known to sist antibiotic killing. These qualities have harbor the organism, only recently have dis- been important in the development of four

150 64. Gonorrhea major classification schemes based upon the on developing nations is likely greater. Inci- following: dence in some African cities may be as high as 10,000 per 100,000 population. Surveys of 1. The presence or absence of pili (long, fil- women attending clinics in Africa disclose amentous projections on the surface of prevalence as high as 17 percent. Among pros- the gonococcus), which determine adher- titutes in Latin America, Asia, and Africa, the ence to mucosal cells. Their presence is, in prevalence of gonorrhea may be 30–50 percent. turn, reflected in the size, shape, and opac- These data provide some sense of the potential ity of gonococcal bacterial colonies and magnitude of the problem. formed the basis of the earliest classifica- Some industrialized nations practice system- tion scheme used. atic reporting of gonorrhea. Statistics have doc- 2. The nutritional requirements of the gono- umented the major event in the history of gon- cocci. Typing of organisms based on their orrhea: a worldwide pandemic that began in need for certain amino acids (auxotyping) the late 1950s and peaked in the mid-1970s. A has identified special strains that are more comparison of disease rates in the United States, or less sensitive to antibiotics and have a Britain, Sweden, and Canada indicates a rise in greater propensity to cause disseminated gonorrhea after World War II, with a subsequent infection. fall to a nadir in the mid-1950s. Then each na- 3. The antigenic structure of the gonococcal tion experienced an increase throughout the cell envelope, which provides a mechanism 1960s, peaking by the mid-1970s. At the peak, for classification (serovars). Serovars have rates among industrialized nations differed as been used in conjunction with auxotyping much as tenfold. Rates among developing na- to indicate distribution patterns and link tions differed even more wildly, but inconsistent cases epidemiologically. reporting clearly plays an important role. 4. Susceptibility to antibiotics. Four transfer- The impact of the pandemic is demonstrated able pieces of genetic material (plasmids) by the history of the disease in the United States help in geographic localization of cases. during this period. Between 1956 and 1985, rates of gonorrhea increased in all age groups These systems for classification reflect the of both sexes. Rates for females were higher at considerable pathogenetic repertoire available younger ages and peaked at ages 15–19. Rates to the gonococcus. In contrast, the immuno- for males peaked at ages 20–24. The origin of logic armamentarium of the host seems in- this increase, and of the pandemic in general, is adequate. Genital secretions may have some often attributed to changes in sexual mores dur- inhibitory effect but are not protective. Local ing the 1960s and 1970s. Major increases were immunoglobulin production may be counter- reported in the frequency of premarital sexual acted by the gonococcus. Serum antibody is experiences; availability of contraceptive tech- usually demonstrable, but resistance to serum nology was considerably greater; and there was killing is a typical feature of gonococci. Stud- an unusual increase (the “baby-boom” genera- ies to date simply reflect the time-honored ob- tion) in the number of people reaching the age servation that people may contract gonorrhea of sexual activity. It is likely that the pandemic again and again. There is no apparent protective has not yet had its full impact on the developing immunity. world, though the peak in industrialized nations Gonorrhea is found worldwide, but its true seems to have passed. extent is unknown. Direct comparisons of in- cidence among nations are difficult to make. History The disease is widespread in both industrial- Gonorrhea is the oldest as well as the most ized and developing countries, but the burden common of the venereal diseases. An Egyptian

151 64. Gonorrhea papyrus from approximately 3500 B.C. pre- two diseases? Why have their manifestations scribes plant extracts to soothe painful urina- appeared in the same populations at different tion. The Hebrew Bible mentions treatment of points in time? genital exudates. In the fourth century B.C., It remained, however, for Philippe Ricord, in a Hippocrates recognized the venereal nature of series of experiments in the mid-1800s, to pro- transmission, and Galen, in the second cen- vide a definitive distinction between the dis- tury A.D., is believed to have coined the name. eases. He inoculated 17 prisoners with gon- In the fourteenth century, a description of orrheal pus, producing occasional ulcers with the ailment stressed a major symptom, chaude prompt healing but no evidence of syphilis. pisse (“hot piss”), the disease’s appellation in In 1879, Albert Neisser in Breslau, Germany, French. published findings that confirmed Ricord’s con- By 1500 or so, interest centered on the clusions. Neisser described the organism that distinction between syphilis and gonorrhea. now bears his name. In 1882, the organism was Majority opinion held that they were different grown in vitro by Ernst von Bumm, and the manifestations of the same disease. But in the first major preventive action was taken in 1883, middle of the sixteenth century, French physi- when Karl Siegmund Crede´ in Leipsig instilled a cian Jean Fernel described gonorrhea as a dis- silver nitrate solution in the eyes of newborns. ease separate from syphilis, and British physi- The occurrence of gonococcal ophthalmia di- cian Francis Balfour (some two centuries later) minished rapidly with the widespread adoption also receives credit for distinguishing between of this procedure. the two. After this, however, there were no major im- In the late eighteenth century, however, John provements in the understanding of gonorrhea Hunter argued that the cause of both diseases until sulfonamides were introduced in 1937. was the same. He infected himself with dis- This success was short-lived, and true antibiosis charge from a patient he thought had gonor- for gonorrhea appeared only in the 1950s with rhea, but he developed syphilis instead. This the general availability of penicillin. It is only in was an unfortunate instance of a brilliant and recent times that gonorrhea’s effect on us and heroic use of scientific method gone wrong, and our ability to alter its course have dramatically it postponed understanding of the two diseases changed. for decades. In the late 1970s, analysis of thousands of During the same period, the most lucid lit- geocoded cases – based on the routine report- erary account of gonorrhea appeared. James ing of gonorrhea morbidity data – revealed a Boswell, the biographer of Samuel Johnson, kept general geographic pattern. Intense concentra- a diary of his own encounters with gonorrhea. tions of gonorrhea exist in a small number of The diary details 19 episodes. There is little core areas in inner cities. In a concentric circle question of the impact of gonorrhea on his surrounding the core are a group of adjacent life and on the lives of countless others in the areas with somewhat lessened gonorrhea rates. era. He is believed to have died of gonorrheal The rest of the city constitutes a peripheral area complications. with a markedly diminished gonorrhea burden. In the 1790s, Benjamin Bell of Edinburgh, who This pattern was repeated in all cities studied, disagreed with Hunter, published several tracts and all the core areas are similarly character- exploring evidence that gonorrhea and syphilis ized by high population density and low socioe- were separate entities. He posed several sim- conomic status. Such a pattern has been docu- ple questions: Why is gonorrhea more common mented in Buffalo, New York; Colorado Springs when the skin of the penis is at greater risk of and Denver, Colorado; Liverpool, England; Mi- exposure than the urethra? Why are there ge- ami, Florida; and Seville, Spain; among other ographic differences in the distribution of the localities.

152 65. Gout

It cannot be assumed that these geographic attack, and the microscopic identification of the characteristics are universal. Differences in hu- crystals in synovial fluid confirms the diagnosis. man ecology and sexuality in developing coun- Why this inflammation occurs predominantly in tries may dictate a different pattern, and data joints, and why much more commonly in some are not yet available. It might be concluded, joints (such as those of the feet or in the knee) however, that a concentric pattern of gonorrhea than in others (such as the hip or those of the risk, which diminishes outward from the cen- vertebral column) are unexplained characteris- tral inner city, exists in many major urban ar- tics. Unexplained as well is the question why eas. The potential for use of geographic patterns “tophi,” which are urate deposits that form be- in the development of disease control strate- neath the skin, are usually painless and the an- gies, and in the understanding of other sexually tiuricemic effect of estrogens. transmitted syndromes, is an area for further Ninety to 95 percent of gout patients are development. male. Gout rarely develops in women before Richard B. Rothenberg menopause. The first attack usually occurs in the fifth decade in men and the sixth decade in women. The rate of production of uric acid thereafter diminishes. The normal uric acid con- 65. Gout tent in men is about 1.2 grams, and in women 0.6 gram. Gout is a chronic, intermittently symptomatic Uric acid accumulates in part as the subcuta- disease. It is manifested primarily by small num- neous deposits called tophi. About 50 percent bers of acutely painful, swollen joints that result of untreated patients have tophi 10 years after from an inflammatory reaction to the precipita- their first attack of gout. After tophi, the most tion of crystals of monosodium urate. common uratic manifestation of gout is kidney stones (nephrolithiasis). This association has Characteristics been noted since at least the sixteenth century. The predisposing metabolic factor for primary Uric acid stones constitute no more than 5 per- gout is an abnormally high or rapidly changing cent of all kidney stones, but about 80 percent concentration of uric acid in the blood. Hyper- in cases of gout. How close the relationship be- uricemia may result from an accelerated syn- tween gout and urate nephrolithiasis may be is thesis of uric acid, or decreased excretory ca- uncertain. Allopurinol therapy, which reduces pacity for uric acid in otherwise normal kidneys the uric acid pool, decreases the incidence of as a result of unidentified but probably herita- uratic kidney stones and has the same effect in ble causes. Hyperuricemia leading to secondary nongouty urate hyperexcretors who have a his- gout occurs particularly (1) in diseases of the tory of calcium stone formation. blood-forming tissues that increase the avail- ability of precursors of uric acid; (2) in kidney History failure, which limits the excretion of uric acid; For many centuries, “gout” was a nonspecific or (3) as a result of medications that either ac- term. The differentiation of the disease was celerate the breakdown of purine-rich cells (e.g., begun in the late seventeenth century by antineoplastic drugs) or interfere with the re- Thomas Sydenham; his contemporary, Anton nal excretory mechanism (e.g., some diuretics). van Leeuwenhoek, described crystals from a Dissolved in the serum, uric acid is harmless. tophus. In 1776, Swedish pharmacist Karl W. However, because of unidentified local circum- Scheele discovered an organic acid in urinary stances it may leak from capillaries and crys- concretions – he called it “lithic acid.” In 1797 tallize. The crystals of monosodium urate elicit at Cambridge, William H. Wollaston found that the inflammatory reaction, which is the gouty tophi contained lithic acid. In 1798, lithic acid

153 65. Gout was renamed acide ourique (“uric acid”) by vere diarrhea, which was believed to consti- French chemist Antoine F. de Fourcroy because tute its therapeutic effect. Its active component, he found it was present in urine. colchicine, was isolated in 1820 and available in A half century passed. In 1847 and in 1854, pill form by 1900, but crude tinctures were still London physician Alfred B. Garrod devised two in use in the 1950s. tests whereby uric acid could be detected in Until about 1910, when cinchophen was in- hyperuricemic states such as gout. He demon- troduced, colchicine was the only remedy for strated urate in subcutaneous tissue and carti- gout. Cinchophen not only was effective against lage in cases of gout. Garrod hypothesized that gouty attacks but also was an analgesic. How- gout resulted from either loss of excretory ca- ever, by the 1930s it became evident that cin- pacity or increased formation of uric acid. A cen- chophen may cause severe, even fatal, liver tury after his 1859 monograph on gout, both damage. Its use faded, and colchicine again be- concepts were proved correct. In 1876 Garrod came the standard treatment. postulated that gout results from precipitation Two pharmaceutical breakthroughs occurred of sodium urate in or near a joint, and this was in 1951. Probenecid, a drug developed to retard proven in 1962. excretion of penicillin, was found to accelerate Beginning in 1871 numerous assays of uric the excretion of uric acid and was well toler- acid were devised, but none was sensitive ated and convenient to take. The other discov- enough. Lack of understanding of uric acid ery was phenylbutazone, which proved to have metabolism cast doubt on the relationship of effects similar to cinchophen. Like probenecid, uric acid to gout, and two effects resulted. One it increased excretion of uric acid, and like was that the old belief in a “gouty poison” – that colchicine, it counteracted attacks. However, it caused a wide variety of symptoms or diseases – proved to be toxic and has fallen into disfavor. gained new adherents. The other was that clin- Another pair of pharmaceutical products was icians virtually ceased diagnosing gout. introduced in 1963. Indomethacin counter- The first practical technique sensitive enough acts gouty attacks, and it gradually superseded to detect normal concentrations of uric acid was phenylbutazone. Allopurinol lowers uric acid devised by Otto Folin at Harvard in 1912. Its like probenecid but by a different mechanism. sensitivity was improved so that in 1938, uric Like probenecid, allopurinol lacks value against acid content was shown to be greater in men gouty attack, but it is effective during renal fail- than in women, thereby correlating with the rar- ure and is convenient. ity of gout in women. However, physicians con- Dietetic attempts to treat gout are ancient tinued to be poorly aware of true gout. Speci- and based on belief in the virtue of modera- ficity in uric acid determination was achieved tion. Gout was thought to be caused largely in 1953 with a technique employing the en- by excessive consumption of food and alcohol, zyme uricase. Nevertheless, most laboratories but in 1924 it was shown that starvation re- use less specific methods that give somewhat sults in increased uric acid concentration. Since higher than “true” values. the 1960s, it has been found that certain cir- Therapy of gout has two components: treat- cumstances may operate to block excretion of ment of the acute attack and prophylaxis to uric acid and thereby increase the possibility of decrease uric acid content. Colchicum in var- gouty attack. Starvation, alcohol ingestion (es- ious alcoholic or aqueous extracts from the pecially without eating), and uncontrolled dia- meadow saffron came into use in the nine- betes mellitus are among such conditions. teenth century in France and England. It was in- Uric acid is synthesized from foodstuffs, par- cluded in an American “Dispensatory” in 1836, ticularly those rich in nucleoproteins. A low-fat, although its use was advocated somewhat ear- largely vegetarian diet reduces uric acid con- lier. Colchicum was toxic, however, causing se- centration, but the effect such diets have on

154 65. Gout reducing gouty attacks is equivocal. Since the Edinburgh, where he had often suffered severe advent of urate-depleting drugs, dietetic ther- pains that occurred in his great toes. A medical apy has become irrelevant except for the advan- missionary in Hawaii in the early 1830s reported tages of weight reduction for obese patients. that rheumatism frequently occurred there, Gout is rarely a direct cause of death, al- and although gout might also be expected to though it is commonly associated with hyper- be common, the mild quality of the food sug- tension or arteriosclerosis, and untreated hy- gested otherwise. Similarly, a military surgeon pertension with normal renal function is fre- in New Zealand in the 1850s found that al- quently associated with hyperuricemia. Hyper- though “rheumatic affections” were much more lipidemia appears not to correlate with hy- frequent among New Zealanders than among peruricemia; rather, both are associated with the English, gout was unknown. A leading ex- hypertension and obesity. Angina pectoris is pert wrote in 1948 that gout “is common in Eng- twice as frequent among gouty men, and one land and France, less common but increasing in study found that causes of death among 427 North America. Hebrews are affected, prosper- gout patients were cardiovascular in 66 percent ous American Negroes occasionally.” Another of cases. specialist stated in 1952 that gout “is unknown Although a rough correlation does exist be- in China, Japan, and the tropics [and] is rare in tween hyperuricemia and the likelihood of a Negroes.” gouty attack, its predictive value is poor. The Such statements may have reflected either ig- most important measurable factors affecting norance or changing circumstances but clearly uric acid concentration are the protein con- are incorrect now. Probably the most ubiq- tent of the diet and overweight. Weight and uitous factor underlying an increased preva- rate of uric acid metabolism are to some ex- lence of gout is the increased proportion of tent genetically predetermined. However, the proteins in many diets, which increases the immediate cause of a gouty attack remains amount of uric acid. Comparisons of uric acid unknown. values of most adequately nourished popula- Worldwide, the prevalence of gout has tions give similar values. The exceptions remind changed since the 1940s. In developed coun- us that there are unidentified (presumably ge- tries, the disease is now rarely disabling. Else- netic) factors that result in differences among where, however, it has become more prevalent, groups that would be assumed not to differ predominantly because of “improved” diets. Hy- empirically. potheses about whether ethnic differences are Generally, the ability of gouty individuals to genetic or the result of environmental changes excrete uric acid is normal, but differences in are weakened by a lack of data. excretory capacity can be identified. One hy- Several American surveys have compared the pothesis suggests that some ethnic groups may uric acid levels of executives and either lower- include a large proportion of persons who have level employees or age-matched population a (genetically determined) relatively low limit to samples. The executives have consistently been their renal excretory capacity. As long as such found to have higher urate concentrations and individuals consume a low-protein diet, such a larger proportion of cases of hyperuricemia. as the Asian rice-based diets, or diets based on This finding, which has been inconsistently con- yams, their excretory mechanism is not satu- firmed in Europe, has not been explained by rated, urate remains in the normal range, and differences in physiognomy, blood pressure, or gout rarely occurs. When the protein consump- medications. tion of such persons increases – as their diet Most reports of gout in non-Caucasian popu- becomes “Westernized” – the excretory capacity lations are relatively recent. The first case was a is overwhelmed, urate accumulates, and gout 31-year-old African servant who died in 1807 in becomes more frequent.

155 66. Heart-Related Diseases

There is a marked difference in the preva- in South Africa that showed the lowest values lence of hyperuricemia between Caucasian and in a tribal population, higher values in a vil- various Pacific island populations. Less than 10 lage, and the highest levels, equal to those of percent of most unselected Caucasian popula- urban whites, in urban blacks. The combined tions, but more than 40 percent of many Pa- three black populations contained no cases of cific populations, exceed “normal upper lim- gout. A survey in Ethiopia similarly showed the its.” Many surveys have been conducted since lowest values among rural Ethiopians, interme- the 1960s. The hyperuricemia cannot be at- diate values among urban Ethiopians, and the tributed entirely to dietary changes, nor is al- normal, highest value among Caucasian and In- cohol consumption necessarily a factor. The dian urban professionals. highest prevalence of hyperuricemia has been Data from Israel are analogous. Desert found on the Micronesian island of Nauru. Bedouins were found to have lower uric acid The diet there had largely become Western- values than villagers of the same Arabic stock, ized by the time these surveys were conducted. and the latter results were the same as those However, some groups were hyperuricemic on that were obtained from a nearby Jewish popu- their traditional diets. The complexity of the lation in Haifa. These variations are presumed uricemia – gout relationship is illustrated by to be related to changes in nutrition associated the unexplained observation that although the with changes in life style. New Zealand Maoris, Tokelauans, and Raroton- Thomas G. Benedek gans have the same high prevalence of hype- ruricemia, a fourfold difference exists in the prevalence of gout. Surveys in the early 1960s in the Osaka dis- 66. Heart-Related Diseases trict of Japan showed an extremely low preva- lence of hyperuricemia. With continued West- In many ways, the year 1628 marks the begin- ernization of the diet, however, an anticipated ning of modern Western conceptions of heart increase in the prevalence of gout is occurring. disease. In that year, London physician William The clinical characteristics of gout are the same Harvey showed that the blood must circulate, and occur in similar frequencies as in Caucasian rather than being continuously regenerated as populations. earlier theories suggested. He also showed that A Chinese author claimed that the first case the heart drives the blood on its circuit around of gout to be described in China occurred in the body. Harvey’s revolutionary achievement 1948, and that by 1959 he could collect only failed to bring about any immediate changes in 12 cases, 10 with tophi. This almost certainly re- medicine’s approach to heart disease, but over flects socioeconomic rather than biological cir- the next few centuries many people tried to dis- cumstances. The prevalence of gout may indeed cover what was going on within the chests of have been low because of the widespread, inad- patients who showed the debilitating signs of equately low protein diet, but this would have cardiac disease. pertained particularly to the large segment of During the mid-eighteenth century, Leopold the population that lacked medical care. In re- Auenbrugger, working in Vienna, described a gard to the well-nourished upper classes, a lack new diagnostic technique. By percussing the of diagnostic acumen may have been at least chest – that is, by striking the chest and both partially responsible. listening to and feeling the reverberation – he Aside from South Africa, there is little relevant could tell, to some extent, what lay within. His information from the African continent. The ef- method enabled him to ascertain the size of the fect on uricemia of the urbanization of primi- heart and to determine the presence of fluid tive people has been well illustrated by studies in the chest, a common manifestation of heart

156 66. Heart-Related Diseases failure. However, Auenbrugger’s technique at- of diagnosis became common in the twentieth tracted little attention until after the French century. The new technology owed something Revolution. to an ancient diagnostic technique – feeling the That revolution radically changed French pulse, practiced at least since antiquity. The rate hospitals and medical schools, and physicians and pattern of the pulse were analyzed, with working in these institutions changed their per- rhythmic abnormalities of particular concern. ception of disease, emphasizing the location and John Floyer, who in 1709 constructed a portable nature of specific lesions in the body. In the early clock to time patients’ pulses, noted that rates nineteenth century, Parisian physicians daily varied according to geographic location, age, went from bedside to bedside, examining pa- and sex. tients with all manner of diseases. All too often An extremely slow pulse – among the most they had the opportunity to correlate their find- striking abnormalities – was often associated ings with autopsy results. In this milieu, Rene´ with syncope. This condition has come to be Laennec invented the stethoscope for listening known as Stokes–Adams disease after Dublin to chest sounds, and Auenbrugger’s percussion physicians Robert Adams and William Stokes, technique became widely used. Although both who described it in the first half of the nine- were used primarily to diagnose lung disease, teenth century. Today the condition is treated they also helped investigate heart problems. with pacemakers. In 1859, French physiolo- Auscultation with the stethoscope was a skill gist Etienne-Jules Marey devised an instrument requiring experience and could yield mislead- that produced a record of cardiac pulsations ing results. Moreover, it was useless in discov- on a drum of paper. With this device, Marey ering cardiac diseases, such as coronary heart recorded the pressure within a horse’s heart, disease, that produced no outward signs. (Coro- and also made pressure tracings from human nary heart disease, encompassing angina pec- surface arteries. In the 1890s, English physi- toris and myocardial infarction or “heart at- cian James Mackenzie developed the polygraph, tack,” was manifested by chest pain and is now which recorded blood-vessel pulsations onto understood to be caused by occlusion of coro- a continuous strip of paper, and he subse- nary arteries.) So, in addition to anatomic stud- quently described many pulse abnormalities, ies, practitioners published descriptions of pa- identifying the cardiac causes of several. Lon- tients’ reported symptoms. In 1768, William don physician Thomas Lewis analyzed cardiac Heberden of London coined the term “angina rhythms with the electrocardiogram (EKG), a pectoris” and differentiated it from other chest new instrument that recorded electrical signals pains. generated by the heart. Invented in 1902 by Heberden focused on the symptoms of the Willem Einthoven, the EKG earned its inventor a disease, not its cause. However, others had de- 1924 Nobel Prize. scribed disease of the coronary arteries. English James Herrick of Chicago saw that the EKG surgeon John Hunter, after performing an au- could help diagnose diseases undetectable by topsy on a person who had died in a fit of anger, the unaided senses – such as coronary artery declared: “My life is in the hands of any ras- disease. Herrick’s 1912 description of this con- cal who chooses to annoy me.” Hunter’s words dition received little attention; however, after proved true. In 1793, he collapsed and died soon collaborating in 1918–19 with Fred Smith to after leaving an acrimonious meeting. describe the characteristic EKG changes, Her- Different manifestations of coronary heart rick’s definition of coronary artery disease be- disease were noted over the next century. Al- came widely recognized. This was an early ex- though the first diagnosis before death proba- ample of a pattern repeated throughout the bly occurred in 1878, recognition of the condi- twentieth century: A disease first described clin- tion remained limited until technological means ically would become more widely accepted as a

157 66. Heart-Related Diseases disease once it was defined in terms of a labora- hemodynamic pressure and the oxygen content tory technique. of the blood at each stage of passage through In 1628, Harvey was unable to measure the the right side of the heart. They outlined the pressures and volumes in human hearts. Physi- profound effects of reduced blood volume on cians’ regular use of such measurements today cardiac output and described how to reverse largely results from a self-experiment. In 1929, the condition by blood replacement. Later, they Werner Forssmann, working in a small German used the same technique to diagnose congenital hospital, became fascinated by a nineteenth and acquired cardiac defects, particularly dis- century diagram showing Marey’s recorded eases of the heart valves. Richards and Cour- pressures from a horse’s heart. Forssmann de- nand shared a 1956 Nobel Prize with Forss- cided to perform a similar procedure on him- mann. self, passing a catheter from the main vein in Soon, the technique was extended to mea- his arm up into his heart. However, he needed sure pressures on the left side of the heart, cooperation from the surgical nurse, who con- which greatly aided understanding of various trolled access to the instruments. Forssmann forms of congestive heart failure. Other inves- was so successful in convincing the nurse that tigators have shown how injecting dye into the she insisted he perform the experiment on her. heart can aid diagnosis. Today, passing diagnos- He persuaded her to lie on a cart, where he tic catheters into the heart is so routine that strapped her down. With the nurse immobi- patients may not even spend a night in the lized, Forssmann inserted the catheter into his hospital. own arm, pushed it through the veins into his Western ideas about heart disease are based heart, and then released the nurse. She helped increasingly on technological diagnosis and the him walk downstairs, and X-rays confirmed the ability to invade the thorax for purposes of di- catheter’s placement within his heart. The ex- agnosis and intervention. Along with increased periment earned Forssmann some praise but use of technology has come the pervasive as- more hostility, and he abandoned working on sumption that diagnosis has finally become ob- cardiac catheterization. jective, transcultural, and reflective of some Others, however, went forward with Forss- inevitable underlying system. The validity of mann’s method. In 1932, Dickinson Richards this assumption is doubtful. Historical analysis and Andre´ Cournand at New York Hospital shows that definitions of heart disease are prod- needed blood samples from the right atrium, ucts of both biology and culture. the cardiac chamber that collects blood from Anatomic linkage of the heart and vessels as a the body before pumping it to the lungs to re- single unit was common in the nineteenth cen- ceive oxygen. They practiced Forssmann’s tech- tury. Around the end of that century, however, nique on animals and determined that it did not the conceptualization of heart disease changed significantly interfere with cardiac functioning. fundamentally. British physicians started to con- Although their first attempt on a patient was un- sider the heart in terms of functional capacity successful, Cournand eventually showed that it rather than anatomy. This led them to regard was safe to insert a catheter routinely into the cardiac murmurs, such as are detected by a right side of the heart. stethoscope, as less important than physiolog- During the next few years, Richards, Cour- ical measurements of function. nand, and colleagues designed a new catheter This conceptual change was particularly ap- and constructed a device that recorded four dif- parent regarding a military ailment once called ferent pressure tracings along with the EKG. DaCosta’s syndrome and later – at the start In 1942, they advanced the catheter into the of World War I – “soldier’s heart.” Afflicted right ventricle, and in 1944 into the pul- by breathlessness and a feeling of impending monary artery, making it possible to measure doom, soldiers with this syndrome were initially

158 66. Heart-Related Diseases treated with extended bedrest. The presence of ness and death were once infectious diseases. a cardiac murmur was taken as ipso facto ev- In the mid-nineteenth century, for example, tu- idence of heart disease. However, as the war berculosis caused possibly one-seventh of all continued, heart disease became a serious mil- deaths in Western Europe. Yet infectious dis- itary, economic, and political problem. It was eases have subsequently decreased in many the third most common reason for military dis- parts of the world. charge. Yet heart disease offered far more hope Two major forms of heart disease related of return to service than did the most com- to infection have undergone a dramatic shift. mon cause of discharge, “wounds and injuries.” Rheumatic fever, caused by a streptococcal in- Nonetheless, the long convalescence strained fection, was once a major agent of heart disease both military hospitals and the political fortunes in the West. In industrialized countries, it has of England’s leaders, who instituted a military now become relatively minor, but in other parts draft in 1916. Given the political exigencies, of the world, rheumatic heart disease remains physicians reconceptualized the disease as ef- a serious problem. fort syndrome. They decided that heart mur- Endocarditis, an infection of the heart valves, murs were important only insofar as they im- carried an almost certain death sentence before paired working ability and prescribed regulated the advent of antibiotics. At one time, it pri- exercise rather than hospitalization. Thus, many marily afflicted people with valvular damage soldiers previously declared unfit for service caused by rheumatic heart disease. Now endo- were reclassified as “fit.” All of this demonstrates carditis is most often a disease of intravenous that some notions about what constitutes heart drug abusers. disease are informed by social needs. There has also been an increase in average Physicians’ ideas continue to be shaped by so- life expectancy. People now live long enough cial context. For example, studies of incidence to succumb to diseases that develop slowly, of heart disease in black Americans in the early such as many cardiac diseases, particularly coro- twentieth century led many to conclude that nary heart disease. Lifestyles, too, have changed. coronary disease was rare in blacks, largely be- Lack of physical activity and changes in diet cause they were considered less likely to expe- may contribute to increased coronary heart rience stress and less intellectually alert. disease. In another example from the late twentieth Coronary disease has become the major form century, it was suggested that failure to ap- of heart disease in industrialized countries and preciate differences between the German and is a major object of attention, much of which is American concepts of heart disease could lead focused on explaining geographic and histori- to the erroneous conclusion that death rates cal changes in the pattern of disease. Account- from ischemic heart disease are lower in Ger- ing for 47 percent of all deaths in the United many than in the United States. In fact, the States in 1986, heart disease is by far the lead- rates are similar, but that condition is more ing cause of death, with myocardial infarction likely to be called “ischemic heart disease” in the most common diagnosis. Many more peo- the United States and cardiac insufficiency in ple suffer from heart disease than die from it. Germany. The physical activity of one-quarter of heart- Changes in disease classification reflect both disease patients is limited, making the condi- social and biological events. There has been a tion an important cause of disability as well as significant change in the types of disease from death. which people die. During the twentieth century, As a cause of death in the United States, classification methods helped make heart dis- heart disease was once behind pneumonia, in- ease an increasingly important cause of death fluenza, tuberculosis, diarrhea, enteritis, and and disability. The predominant causes of sick- intestinal ulceration. A sharp upward trend

159 66. Heart-Related Diseases in coronary disease became apparent around risk rapidly declines to approximately the same 1920, and it was recognized with increasing level as if the person had never smoked. High frequency throughout the first half of the blood pressure and diabetes are also important twentieth century. By 1940, only two disease risk factors. categories with death rates of more than 100 Studies have clearly demonstrated a consis- per 100,000 remained: cancer and diseases of tently positive relationship between increased the heart. serum cholesterol level in the form of low den- The death rate from heart diseases then be- sity lipoprotein and the rate of heart disease. At gan a dramatic series of changes, peaking in high levels the association is particularly strong. 1963 and declining continuously since then. Good evidence exists that lowering cholesterol However, that decline has been unevenly dis- levels with drug therapy will lower death rates tributed. Heart-disease mortality in California, from coronary disease. Exercise, too, has a ben- for example, peaked relatively early, around eficial effect on the types of lipids circulating in 1955, and the subsequent decline there was the bloodstream. repeated in other parts of the United States Alcohol intake in small quantities – two or throughout the 1960s and 1970s. By 1986, the fewer drinks per day – may diminish the risk of death rate for coronary heart disease was 55 per- coronary disease. However, alcohol in greater cent of the 1966 rate. amounts is clearly associated with greater mor- Countries such as Australia, New Zealand, bidity and mortality from both cardiac and non- and Canada have experienced similar declines cardiac disease. in coronary-disease mortality among men. In many parts of the world, other types of Other countries, however, have seen significant heart disease are more common than coro- increases, from Scotland and Northern Ireland nary disease. Endomyocardial fibrosis, for ex- (initially comparable to the United States) to ample, is common in the tropical belts of Africa Poland and Switzerland (initially having death and South America. The disease characteristi- rates much lower than the United States). cally leads to heart failure, accounting for up to Studies of changing patterns of cardiac dis- 20 percent of such patients in Uganda, Sudan, ease have contributed to the invention of “risk and Nigeria. It affects indigenous people as well factor,” a notion receiving widespread atten- as foreign visitors. Its precise cause is yet un- tion as a way of conceptualizing the causes known. of many diseases. Current explanations for his- In much of South America, the parasite Schis- torical and geographic differences in coronary- tosoma mansoni is a common cause of heart disease mortality derive much from the concept disease. Also common in South America is of risk factor. Studies have identified several fac- Chagas’ disease. Other heart diseases hav- tors contributing to the likelihood of coronary ing characteristic geographic patterns include heart disease. Some of these cannot be modi- forms of congenital heart disease that are fied. For example, men are more likely to suf- significant for people living at high altitudes, fer heart disease than women; older people are where the concentration of oxygen is reduced. more likely to develop it than younger ones; and Peripartum cardiac failure develops in up to those having a family history of early cardiac 1 percent of women in Nigeria and appears to disease are at greater risk than those without result largely from cultural patterns. In this re- such history. spect it resembles coronary heart disease, which However, other factors can be modified. is linked to Western culture in ways that we Cigarette smoking dramatically increases the identify as risk factors and in ways that we do likelihood of a coronary event and constitutes not fully understand. the greatest and most preventable cause of The heart continues to have a central place heart disease. Once a person stops smoking, the in Western medicine. In the past few decades,

16 0 67. Herpes Simplex many new approaches have been directed at than other women. Neonatal infection is usu- heart disease. Concepts of heart disease are ally HSV-2 from an infected birth canal. In drawn from general cultural concepts of what addition, some evidence links HSV-2 to cervical it means to be human, and studies of how and cancer. when they change will increase our understand- Unknown factors cause reactivation of the ing not only of the history of medicine but of virus (recurrent herpes). Studies of reccurent history in general. herpes show inexplicable differences in recur- Joel D. Howell rence: 45 percent in Britain, 40 percent in North America, 30 percent in Europe and Africa, 17 percent in Asia, and 16 percent in South America. 67. Herpes Simplex HSV-2 has been studied more intensively in recent years than HSV-1. Most observers agree Herpes simplex is caused by the herpes virus that herpes genitalis has been on the increase. hominis, of which there are two types, HSV-1 In 1983 there were an estimated 20 million and HSV-2. In general, the first causes disease cases in the United States, with 300,000– above the waist, such as cold sores; the second 500,000 new cases developing annually. causes disease below the waist, especially geni- Publicity and wider use of diagnostic tests may tal herpes. The active phase is followed by pro- account for some of the apparent increase. longed latency, but the virus can be reactivated Certainly, publicity has alerted the public and by infection, stress, exposure, or any number of the medical profession to the disease. other circumstances. The initial lesion is a small, reddened area that develops into a small, thin-walled, blister- Characteristics like vesicle filled with clear fluid. Labial herpes Herpes viruses are visible by electron mi- only occasionally represents the initial HSV-1 croscopy and may be grown in the laboratory. lesion, but the “cold sore” or “fever blister” of Some animals react differently to HSV-1 and the lip is the most common lesion of recurrent HSV-2. Infection with herpes simplex results disease. Here a cluster of vesicles appears, to from person-to-person contact. last up to 10 days. These usually appear at the HSV-1 is commonly transmitted through kiss- line of the skin of the lower lip or on the skin ing or sharing eating utensils, and thus infec- of the upper lip, at times extending to or into tion can easily spread within a family. Normally, the nostril. Conjunctivitis may also be the pri- HSV-1 infection is bothersome but has no se- mary lesion of the infection. Cutaneous herpes rious consequences, except when the virus in- (HSV-1) may involve the skin of the body, vades the cornea. Corneal herpes may produce anywhere above the waist and including the scars that impair vision. feet. HSV-2 infection is generally the result of sex- Herpes genitalis has an incubation period of ual transmission. Lesions appear on the penis, several days. It may be subclinical, especially vulva, buttocks, and adjacent areas. The preva- in women. Infection is more obvious in men lence of HSV-2 infection during pregnancy and with localized pain and development of vesi- its incidence in neonates are related to the so- cles on the penis. Urethral involvement in both cioeconomic level, age, and sexual activity of sexes is manifested by dysuria (painful urina- a population. Infants are safe from infection if tion), and a discharge may be noted in male the mother’s condition clears 3–4 weeks before patients. Pelvic pain accompanying dysuria is delivery. But women who suffer from genital common in women. Infection with HSV-2 often herpes during pregnancy may be three times is accompanied by systemic symptoms during more likely to abort during the first 20 weeks the first several days.

161 68. Herpesviruses

Some studies show recurrences within the Herpes progenitalis was discussed in 1881 by first year in 80 percent of HSV-2 infections. Boston physician F. B. Greenough. He made the Recurrent cases commonly show milder symp- important observation that one of the “three” toms, are of shorter duration, and rarely exhibit venereal diseases had existed before the ap- overt systemic symptoms. The lesions appear on pearance of herpes genitalis. In addition, Gree- the genitalia and adjacent areas. In some pa- nough made the surprising observation that tients, recurrences cease some years following he had never seen an instance of genital her- the onset of disease. In others, however, recur- pes in a woman. This prompted an investiga- rences last many years. Febrile illness may be tion into the incidence of the disease among a provoking factor in HSV-1 recurrences, but women, and in 1883 Paul Unna of Hamburg what triggers recurrent genital herpes is un- not only concluded that women did contract clear. Stress, fever, heat, trauma, and coitus have herpes, but suggested that women who were all been suggested. prostitutes contracted it at a greater rate than men. History In 1890, R. Bergh of Copenhagen confirmed a “Herpes” derives from the Greek “to creep.” The high incidence of herpes genitalis among prosti- oldest record of disease of the genitalia appears tutes, but he rejected any relationship between in the Ebers Papyrus (c. 1550 B.C.), with non- herpes genitalis and venereal disease and con- specific commentary on a patient’s inflamed cluded the lesions were of a nervous origin, re- vulva and thighs. The same papyrus, how- sulting from congestion of the parts. ever, describes “herpes of the face.” Hippocrates In 1921, B. Lipschutz¨ successfully inoculated mentioned “herpetic sores,” “ulcerations of the material from genital vesicles into the skin of mouth, [and] frequent fluxations of the genital human subjects. Four years later, S. Flexner and organs.” Herodotus described eruptions “which H. L. Amos demonstrated the herpes virus, and appear about the mouth at the crisis of simple in 1934 Albert Sabin isolated it. In 1962, K. E. fevers,” and both Hebrew and Byzantine texts Schneweiss identified two strains of herpes, a contain references to what was probably herpes. finding confirmed by W. R. Dowdle and A. I. The first definitive description of herpes was Nahmias in 1967. Research in subsequent years published by Jean Astruc in 1736. His descrip- has contributed to knowledge concerning epi- tion of vesicles strongly suggests those of her- demiology and immunology. pes genitalis. Toward the end of the eighteenth R. H. Kampmeier century, English physician Robert Willan devel- oped a classification of the many skin diseases, including a category of vesiculae. In 1818, Thomas Bateman described herpes 68. Herpesviruses labialis. He emphasized the hazard of interpret- ing a cluster of vesicles as a syphilitic chan- The family of herpesviruses (Herpetoviridae) cre. He discussed the development of the vesi- includes herpes simplex 1 and 2, vari- cles and their course to healing and noted that cella zoster, Epstein–Barr virus, and cy- the disease was “liable to recur in the same tomegalovirus. All are double-stranded DNA individual.” viruses of icosahedral form, enclosed in a Later, in 1832, Jean Louis Alibert not only de- lipid-containing envelope, and ranging in scribed herpes praeputialis but stated that the size from 120 to 180 nanometers. See: Cy- lesion may occur at the introitus of the vagina. tomegalovirus Infection, Herpes Simplex, In 1853, F. L. Legendre described herpes of the Infectious Mononucleosis, Varicella-Zoster vulva, with the observation that it may recur Virus Disease (Chickenpox). some days before menstruation. R. H. Kampmeier

162 69. Histoplasmosis

69. Histoplasmosis resulting from casual exposure to environmen- tal spores. Patients with sporadic illness proba- Histoplasmosis is an infection caused by inhal- bly inhale fewer spores and are more likely to be ing Histoplasma capsulatum, a soil fungus; the asymptomatic or minimally symptomatic. Most primary infection is in the lung. The disease is infections are never recognized and are known usually benign and self-limited, despite a strong to exist only as a result of skin-test surveys. tendency to invade the bloodstream during pri- Primary pulmonary histoplasmosis is mary infection. This fungemia seeds reticuloen- asymptomatic at least half the time. Symp- dothelial organs throughout the body. Under tomatic patients become ill about 2 weeks favorable conditions, the organism can cause after exposure, with influenza-like fever, chills, progressive disease at multiple sites, resulting myalgias, headache, and a nonproductive in a wide variety of clinical manifestations. cough. Rare manifestations include arthral- gias, arthritis, and erythema nodosum. With Characteristics or without symptoms, the chest roentgenogram H. capsulatum is most common in temperate cli- may show patchy areas of pneumonitis and mates along river valleys and has been found prominent hilar adenopathy. Following expo- in North, Central, and South America; India; sure to an unusually heavy inoculum, more Southeast Asia; and Europe. By far the most diffuse pulmonary involvement may occur, heavily endemic region in the world is the east with extensive nodular infiltrate on the chest central United States, particularly the Missis- roentgenogram. Dyspnea may appear along- sippi and Ohio river valleys. It is most prevalent side other symptoms, and symptoms are more in the states of Ohio, Kentucky, Indiana, Illinois, severe and last longer. Most patients recover Kentucky, Tennessee, and Arkansas. Surround- without treatment, but extreme cases may ing states also have many infections. progress to respiratory failure. Infection is almost universal in heavily en- Chronic cavitary histoplasmosis may occur demic areas. Skin-test surveys reveal that over anywhere in the lung but usually involves both 90 percent of persons in some central U.S. coun- upper lobes and closely resembles reinfection ties have had histoplasmosis before age 20. tuberculosis. The mechanism of infection, how- Probably 40–50 million people in the central ever, is not endogenous reactivation. Rather, United States have had histoplasmosis, and sev- the infection is the result of a primary infec- eral hundred thousand new cases occur each tion in abnormal lungs, typically the lungs of year. However, the number of serious infections middle-aged or older male smokers who have requiring diagnosis and treatment is negligible, centrilobular emphysema. Acute pulmonary perhaps 1 or 2 percent of the total. histoplasmosis in this setting usually resolves H. capsulatum grows as a fluffy white uneventfully although very slowly. In about a mycelium, which bears microconidia; the or- third of cases, infected air spaces persist. A pro- ganism is free-living in nature in this form. In gressive fibrosing and cavitary process gradu- warmer temperatures, it grows as a yeast – and ally destroys adjacent areas of the lung. Chronic takes this form in infected tissue. cough is the most common symptom. Consti- A minor disturbance of fungus-laden soil may tutional symptoms, including low-grade fever, scatter spores into the air. The microconidia are night sweats, and weight loss, increase as the inhaled, causing infection. Within the lung, the illness progresses. organism converts to the yeast phase, which Disseminated histoplasmosis is any progres- is not infectious. Person-to-person transmission sive extrapulmonary infection. There is a range does not occur. So-called epidemics of histo- of infection with different tissue responses. At plasmosis are more accurately point-source one extreme there are massive numbers of or- outbreaks. Most cases, however, are sporadic, ganisms in all reticuloendothelial organs with

163 69. Histoplasmosis little tendency to granuloma formation. This important clue. Histopathological examination type of disseminated histoplasmosis has been of tissue biopsies is the method of diagnosis in called the “infantile” form and may lead to most cases. Bone marrow biopsy is particularly death within days or weeks. Other patients, of- valuable in febrile illnesses without localizing ten older adults, have a more indolent illness, features. Cultures of blood, bone marrow, and many months in duration, characterized by low other tissues and of body fluids may also give or moderate fever, weight loss, and skin and mu- the diagnosis. cous membrane lesions. The condition can also occur as an opportunistic infection. History Disseminated histoplasmosis often presents In 1906, Samuel Darling described an infec- as a nonspecific systemic febrile illness rather tion of the reticuloendothelial system caused than as a pulmonary infection. There is usu- by an organism that he believed was protozoan. ally no cough. The chest roentgenogram may be Macrophages were filled with small organisms. normal. The disease may also present as a more Within a few years, he reported two other cases. localized infection, such as histoplasmosis of the In 1913, H. da Rocha-Lima speculated that the central nervous system; meningeal histoplas- organism might be a fungus rather than a mosis; and isolated gastrointestinal histoplas- protozoan. mosis, which often involves the terminal ileum. In 1926, W. Riley and C. Watson credited Dar- All are extremely rare. ling with being first to describe the infection in The histoplasmin skin test is a valuable epi- 1906. Later, however, some confusion arose as demiological tool that has permitted mapping to whether a 1906 report by R. Strong had de- of the endemic area. However, it is worthless scribed histoplasmosis first. But in a personal in individual case diagnosis. A positive skin test letter many years later, Strong stated that the means only that the person is one of many mil- case he had described was not histoplasmosis lions who have had histoplasmosis, probably re- but rather a rare human infection with Crypto- motely and without sequelae. It does not mean coccus farciminosus, the cause of farcy in horses. that a current illness under investigation is be- Thus credit for the first case description remains ing caused by the fungus. with Darling, who recognized the disease as pre- Primary histoplasmosis is usually not diag- viously undescribed and named the organism nosed at all. Serologic tests are most useful for and the illness. diagnosing patients who have already recov- Scattered reports of similar cases followed, ered. Patients with rapidly progressive pneu- mostly from the central United States. Then in monia not responding to antibacterial antibi- 1934, the first premortem diagnosis of such a otics need urgent diagnosis, especially if respi- patient was made. The infectious agent was iso- ratory failure is impending or actually devel- lated and proved to be a fungus, and its thermal ops. Some patients are diagnosed by serology. dimorphism was demonstrated. Others require lung biopsy for histopathologi- In 1945, a review of 78 cases concluded cal diagnosis. that histoplasmosis was a rare systemic infec- Chronic cavitary histoplasmosis is easier to tion that was nearly always fatal. However, in diagnose. The pace is slower. Tuberculosis is the same year, A. Christie and J. Peterson and suspected first, but the tuberculin skin test is also C. Palmer demonstrated that great num- negative and the sputum is negative for tuber- bers of asymptomatic persons in the central culosis. Sputum cultures for H. capsulatum are United States had been infected with the fun- usually positive, as are serologic tests. Dissem- gus. Furthermore, they showed that almost all inated histoplasmosis is difficult to diagnose tuberculin-negative persons with chest calci- because it is so nonspecific. Serologic tests are fications had positive histoplasmin skin tests. positive in over half of cases and may provide an The endemic area was mapped, and fungus was

16 4 70. Hookworm Infection isolated from the soil. The new conclusion was received further support: Unlike other immuno- that histoplasmosis is very common and almost suppressed patients, even those AIDS patients invariably benign and self-limited. Fatal cases who respond to treatment are not cured but re- were rare and exceptional. quire long-term suppressive therapy to prevent Most skin-test reactors in early surveys had relapse of infection. had asymptomatic or minimally symptomatic Scott F. Davies nonspecific infections. The retrospective discov- ery of a highly symptomatic but also self-limited form of primary histoplasmosis soon followed. Small groups of patients exposed to high con- 70. Hookworm Infection centrations of organisms, often in closed spaces, had been verified as victims of epidemics of an Ancylostomiasis,orhookworm disease,is unknown but relatively severe pulmonary ill- caused by hookworm infection and is charac- ness. An epidemiological investigation of one terized by progressive anemia. Perhaps one bil- such outbreak, which occurred in 1944 and was lion people, mostly in tropical and subtropical reported 3 years later, demonstrated convinc- regions, are afflicted to some extent with hook- ingly that H. capsulatum had been the offend- worm infection, although it is not known how ing agent. Upper-lobe cavitary histoplasmosis many thus infected can be said to be victims of resembling tuberculosis was first described in hookworm disease. A host whose diet contains 1956 among sanitorium patients being treated adequate amounts of iron may sustain a worm for tuberculosis. burden without debilitating consequences that In 1955 came the isolation of amphotericin B, would render a malnourished person anemic. and within a few years the drug was available A person exhibiting signs of the anemia, there- for treatment of a wide variety of fungal infec- fore, may be said to have hookworm disease tions. This drug, despite some toxicity, proved regardless of the number of parasites present. highly effective for histoplasmosis and remains Hookworm disease is an important contribut- the agent to which newer alternatives must be ing factor in millions of deaths annually and a compared. Ketoconazole, a nontoxic oral imida- source in its own right of widespread human zole, arrived in the 1980s. It is not as effective suffering. as amphotericin Bbut is reasonable therapy for mild to moderately ill patients with chronic cav- Characteristics itary disease and indolent forms of disseminated Two species of intestinal nematode, Ancy- disease. lostoma duodenale and Necator americanus, With the increase in the use of gluco- are the parasites that cause ancylostomiasis. corticoids and cytotoxic drugs for malignant A. duodenale can be ingested in contaminated and nonmalignant diseases, disseminated histo- food, water, or possibly breast milk, but the plasmosis assumed increasing importance. En- more common route of infection, and the only dogenous reactivation was suspected as a one for N. americanus, is through penetration mechanism in some cases because the illness of the skin. Larvae in the soil typically enter presented as a nonspecific febrile illness. Treat- through the skin of the feet, frequently causing ment with amphotericin Bwas very effective if dermatitis, once called “ground itch” or “dew the diagnosis was made quickly and if the pa- poison” in the southern United States, and “wa- tient had some degree of cell-mediated immune ter itch” or “coolie itch” in India. The parasites response. travel through the bloodstream to the alveoli Finally, AIDS brought a new level of sup- of the lungs, climb the respiratory tree, and pression of the cell-mediated immune sys- make their way into the esophagus. During tem. The concept of endogenous reactivation their migration through the airways, the host

165 70. Hookworm Infection sometimes develops a cough, wheeziness, or It is still, however, a chronic fact of life in temporary hoarseness. most of the rest of the regions within the old The hookworms are swallowed and pass into “hookworm belt.” In the Caribbean, Central and the gut, where some successfully attach them- South America, Africa, China, India, Southeast selves to the small intestinal mucosa and begin Asia, and Oceania, endemic hookworm infec- nourishing themselves on their host’s blood. In tion remains widespread and largely untreated. the small intestine, hookworms grow to about After a flurry of activity in the first three decades 1 centimeter, maturing in 6–8 weeks. Depend- of the twentieth century, hookworm preven- ing on the species, hookworms generally live tion and treatment programs have been spo- from 1–5 years, although a few apparently live radic and uncoordinated. This recent history of longer. The adult female may produce thou- neglect has made it difficult even to estimate sands of ova per day, which pass out of the the incidence of hookworm disease in areas of body with the host’s feces. If deposited on warm, the world where hookworm infection is known moist soil, the eggs produce larvae that can sur- to be prevalent. vive in a free-living state for over a month before Hookworm disease shares many of the clini- finding a host. cal symptoms accompanying other kinds of ane- Hookworms thrive on human ignorance and mia. Severely infected persons have a pale and poverty. If the billions of people living in ar- wan appearance, a telltale yellow-green pallor eas of hookworm infestation were able to eat that explains why the disease was sometimes moderately well, wear good shoes, and defecate called “Egyptian chlorosis” or “tropical chloro- in latrines, hookworm disease would soon no sis.” In children, growth may be significantly re- longer pose a serious threat to human health. tarded. A distended abdomen and pronounced, Understood as an index of socioeconomic sta- sharply pointed shoulder blades (“pot belly” and tus, hookworm infection will likely remain a “angel wings” in the American South) were once daunting public-health problem as long as there thought to identify children with hookworm are poor people, inadequately educated, living disease, although the same features often ac- in warm climates. company malnutrition as well. The earliest global survey of hookworm dis- In pregnant women, hookworm infection in- tribution, in 1910, led to a preliminary descrip- creases the likelihood of fetal morbidity. Victims tion of a “hookworm belt” girdling the Earth be- of hookworm anemia may be chronically slug- ◦ ◦ tween 30 south latitude and 36 north. Another gish, listless, and easily tired, symptoms that survey conducted at the same time estimated prompted a facetious journalist early in the that 40 percent of the inhabitants of the south- twentieth century to dub hookworm the “germ ern United States suffered in varying degrees of laziness.” Dropsy, dizziness or giddiness, in- from hookworm infection. Although infection digestion, shortness of breath, tachycardia, and has not been eliminated in the United States, in extreme cases congestive heart failure have the public-health menace of hookworm disease also all been associated with advanced hook- has disappeared, largely as an incidental conse- worm disease. Hookworm sufferers sometimes quence of the concentration of the population eat dirt, chalk, or clay as well. in cities and towns with sewer systems, and the Since the nineteenth century, dozens of general improvement in sanitary conditions and anthelmintic drugs have been tried, including the standard of living for those remaining on thymol, oil of chenopodium, carbon tetrachlo- the farms. Likewise in Europe, where the disease ride, and tetrachloroethylene. More recently was sometimes found in mines, hookworm in- developed hookworm vermifuges include fection is no longer a problem. In Japan as well, bephenium, mebendazole, pyrantel, and thi- rising living standards and antihookworm cam- abendazole. A regimen combining chemother- paigns have eradicated the disease. apy with simultaneous administration of iron

16 6 70. Hookworm Infection tablets now seems to be the most effective way remained the most widely used drug in the to eliminate the parasites and at the same time treatment of hookworm disease. to restore the hemoglobin to a normal level In 1898, Arthur Looss first suggested that quickly. The probability of reinfection is high, hookworm larvae could penetrate the skin. He however, if a person thus treated continues to had accidentally infected himself by spilling walk barefooted on ground contaminated with water contaminated with hookworm larvae on hookworm larvae. This discouraging realization his hand. Shortly afterward, the spot on his hand has bedeviled public-health workers since the where the water had spilled began to burn and days of the massive control programs. turned red. Although Looss’s announcement was initially greeted with considerable skepti- History cism, further experimentation had by 1901 con- The Ebers Papyrus (c. 1550 B.C.) describes a firmed beyond doubt the percutaneous route of mysterious affliction, “a-a-a disease,” thought by infection. Looss would later describe the migra- some to be hookworm anemia, but by oth- tory path of the hookworm within the host. ers, schistosomiasis. In the fifth century B.C., While Looss was developing his theory of skin Hippocrates described a pathological condition penetration in Egypt, a U.S. Army physician sta- marked by dirt eating, intestinal distress, and tioned in Puerto Rico, Bailey K. Ashford, dis- a yellowish complexion. A handful of other covered in 1899 that hookworm infection was sketchy descriptions from the Mediterranean rampant among agricultural workers in the cane basin in the ancient and early medieval periods fields. In 1903, Ashford persuaded the governor appear to be reports of hookworm disease. From to budget funds for the creation of the Anemia the Western Hemisphere in the centuries after Commission of Puerto Rico, the first large anti- European colonization came scattered accounts hookworm program of its kind. from English, French, Spanish, and Portuguese Ashford believed that the hookworms he settlers of epidemics among their slaves, called found in Puerto Rico were A. duodenale.At by a rich variety of colloquial names and the time of his discovery, no other species was now thought to be widespread hookworm known to infect humans. Charles Stiles exam- infestation. ined Ashford’s hookworms and others from dif- Italian physician Angelo Dubini was first ferent parts of the United States. He compared to report hookworms in a human, detecting them with samples of A. duodenale and con- them during autopsy in 1838. Dubini examined cluded in 1902 that the former were a different 100 cadavers for hookworms and found them in species indigenous to the Western Hemisphere, more than 20. He provided a detailed descrip- which he named Necator americanus.In1905, tion of the parasite, which he named “Agchy- Looss found N. americanus in Central African lostoma” (a faulty transliteration of the Greek pygmies and speculated that it originated in words for “hook” and “mouth”) duodenale.By the Eastern Hemisphere and was brought to 1846, Dubini’s parasites had been found in the Americas by African slaves. Within 2 years, Egypt and, by 1865, in Brazil. In 1878, Italian sci- N. americanus had been found extensively not entists announced their detection of hookworm only in Africa but also in India and Australia. ova in feces of anemic patients, making it pos- Whether A. duodenale might also have been in- sible for anyone with a microscope to diagnose troduced into the Americas at about the same hookworm infection. In the 1880s, Edoardo Per- time via early European contact has been dis- roncito argued that the presence of hookworms puted. The theory that A. duodenale existed in in large numbers was causally related to a ma- pre-Columbian America was bolstered by the jor epidemic of anemia. In 1881, Camillo Boz- 1974 discovery of what appears to be A. duo- zolo reported his success using thymol to treat denale in the intestine of a Peruvian mummy the infection. For the next 35 years, thymol dating from about 900 A.D. Both species are

167 71. Huntington’s Disease (Chorea) widespread in both hemispheres, although their treatment campaigns and redirected its efforts origins remain murky. toward laboratory research, with fieldwork re- In 1909, John D. Rockefeller created an or- stricted to data gathering and testing hypothe- ganization to eradicate hookworm disease in ses and drugs. the southern United States, although Stiles By the mid-1920s, disillusionment had set in maintained that eradication was an unrealis- and the days of the antihookworm crusades tic goal. With $1 million, the Rockefeller San- were over. Since then, although laboratory work itary Commission established operations in has revealed much more about the relation- 11 American states. Over its 5-year existence, ship between humans and hookworms, little it awakened the public to the nature and ex- has been done in a practical way to rid the for- tent of the threat, stimulated widespread con- mer of the latter, except where living conditions cern for improved sanitation, treated almost have improved. 700,000 people, and invigorated long-moribund John Ettling state boards of health. It failed, however, to erad- icate hookworm infection anywhere. In 1914, the Rockefeller Foundation under- took a worldwide campaign modeled on the ex- 71. Huntington’s Disease (Chorea) perience of the Rockefeller Sanitary Commis- sion, opening operations in the British West Huntington’s disease (HD) is a rare progres- Indies before extending into British Guiana, sive neurological disorder, in which normal cen- Egypt, Ceylon, and Malaya. By the end of tral nervous system development is succeeded World War I, Rockefeller programs were un- in early adulthood by premature and selec- der way or planned in Central America, Brazil, tive neuronal death. First-rank symptoms con- and China, and soon thereafter were in place in sist of rapid, involuntary jerking movements, or most tropical countries. The earlier experience chorea, caused by lesions in the putamen and in the southern United States led administra- the caudate nucleus, and a progressive demen- tors to employ a dual approach. The dispensary tia from loss of cells in the cerebral cortex. Onset method attracted people from the surrounding of symptoms is typically in the third or fourth area to a day-long demonstration conducted decade, and the clinical course is progressive by a Rockefeller physician assisted by micro- and relentless over a period of 10–30 years. At scopists, during which examinations were car- autopsy, gross examination of HD brains reveals ried out and treatments dispensed, while the severe, symmetrical atrophy of frontal and tem- crowd heard lectures on prevention and im- poral lobes as well as, to a lesser degree, the pari- proved sanitation. The intensive method in- etal and occipital lobes. The caudate nucleus is volved selection of a clearly delimited area for profoundly involved, and diffuse neuronal loss a saturation campaign of aggressive hookworm extends into the cerebral cortex, basal ganglia, treatment and latrine construction. thalamus, and spinal motor neurons. Various Beginning in the early 1920s, the Rocke- neurotransmitter systems are also progressively feller Foundation began to rethink its basic ap- affected. proach. The extensive, protracted campaigns References to the disorder as early as 1841 had produced negligible results. The incidence have been found, but the first full description of hookworm infection in Puerto Rico, for ex- was by George Huntington in 1872. Discussing ample, was as high in 1920 as it had been in a large family on Long Island, Huntington dis- 1903, just before Ashford’s Anemia Commis- tinguished the condition from other known sion began its work. Not yet prepared to aban- choreiform movement disorders such as Syden- don hookworm work altogether, the Rockefeller ham’s chorea (“Saint Vitus’s dance”). The re- Foundation gradually withdrew from massive markable history of HD in the New World

16 8 72. Hypertension was recounted in 1932. Carriers of the mu- and/or greater than or equal to 95 mmHg tant gene responsible for nearly all known cases diastolic. of the disease sailed for Massachusetts from Normotensive: Less than or equal to 140 Suffolk in 1630. Upon arrival, these individu- mmHg systolic and less than or equal to 90 als founded family lines that included not only mmHg diastolic. the Long Island cases but also the celebrated Borderline hypertensive: Between hypertensive “Groton witch,” whose violent and uncontrol- and normotensive. lable movements were recorded in 1671 as ev- idence of possession. Pedigrees encompassing The condition is also divided etiologically into the various branches of the families demon- two types. Secondary hypertension, resulting strate a clear pattern of autosomal dominant from some known cause (such as kidney dis- transmission, meaning the disease will appear ease), represents less than 10 percent of total in one-half the offspring of an affected parent. hypertension incidence. Primary hypertension Since the first description of HD, numerous (also called essential hypertension), represent- biochemical and histological studies have been ing more than 90 percent of total incidence, undertaken, but the primary defect remains arises from unknown causes. unknown. A major breakthrough occurred in 1983, when researchers announced discov- Characteristics ery of an anonymous DNA sequence closely In most societies, average blood-pressure levels linked to the putative HD gene. This molecular and diseases associated with hypertension in- probe, which has been refined by subcloning, crease as people age; however, this is not the is now a tool for presymptomatic diagnosis of case in all populations. Indeed, hypertension HD. seems virtually nonexistent in “Stone Age” so- Eric J. Devor cieties. But surveys indicate that hypertension in developing countries is increasing. Many have hypothesized that environmental factors cause hypertension, principally because 72. Hypertension when members of unacculturated popula- tions – normally free of hypertension – migrate Hypertension is a condition of abnormally high to urban areas, their blood pressures rise. blood pressure. Blood pressure is measured by Some postulate that dietary changes (especially the force exerted against artery walls during salt intake) and/or weight gain occasion this each heartbeat or pulse. The peak of the pres- phenomenon. Others suggest that increased sure wave occurs when the heart contracts (sys- psychosocial stress is to blame. Still others tole) and is called systolic pressure. The valley surmise that those with the greatest rise in of the pressure wave occurs when the heart blood pressure have a genetic predisposition relaxes (diastole) and is termed diastolic pres- to the disease that is sparked by environmental sure. Blood pressure is recorded as systolic over phenomena such as salt or stress. diastolic. Dietary factors that may affect blood pressure Although even slight blood-pressure eleva- include salt (sodium chloride), potassium, mag- tions are associated with increased risk of pre- nesium, calcium, fat, and even licorice. Most in- mature death, the World Health Organization terest has centered around salt – specifically its has recommended the following categories for sodium component. The most compelling evi- classifying adults: dence for the influence of salt on blood pressure is that every low-salt-intake population ever Hypertensive: Greater than or equal to 160 studied has manifested low blood pressure with- millimeters of mercury (mmHg) systolic out age-linked increases. Some surveys have

16 9 72. Hypertension suggested that stressful societies have higher Over 4,000 years later, in 1827, British physi- mean blood-pressure levels than less stressful cian Richard Bright suggested that certain drop- ones. Unfortunately, stress is difficult to mea- sical swellings resulted from obstruction in the sure, and any association between stress and kidney’s circulatory system. Bright’s argument blood pressure has been difficult to demon- was so persuasive that throughout the nine- strate in humans. Heredity is an important teenth century most physicians considered a contributor to blood-pressure regulation, and strong or tense pulse a symptom of kidney hence to hypertension. Like many genetic traits, disease. high blood pressure tends to run in families. By the late nineteenth century, discoveries re- Genetic influence is also revealed by the con- lating to systolic blood pressure led to inven- cordance of hypertension in siblings, especially tion of the sphygmomanometer (blood-pressure identical twins. cuff). With the 1905 description of diastolic Some humans are “salt sensitive” and oth- blood pressure, this device effectively replaced ers are not, which may represent an interac- diagnosis by “pulse,” and its widespread use tive relationship between genes and environ- led observers to realize that most hyperten- ment. In former times, isolated populations mi- sion patients did not have kidney disorders. grated into different ecological systems and The newly discovered condition was given var- perhaps experienced different “selection pres- ious names: angiosclerosis, presclerosis, hy- sures” related to salt metabolism. These in- perpiesis, primary hypertensive cardiovascu- cluded different temperatures, salt intake, and lar disease, and essential hypertension. It was mortality from salt-depletive diseases such as soon recognized as among the most common diarrhea, possibly resulting in a new geno- cardiovascular disorders. type that enhanced survival in new environ- During the 1930s and 1940s, researchers ments by protecting against salt-depletive con- studied the influence of the sympathetic ner- ditions. If this genotype included enhanced vous system, the endocrine system, and the re- sodium-conserving ability, then such adapta- nal system on arterial pressure, noting several tions may predispose to salt-sensitive hyper- types of secondary hypertension. Pheochromo- tension today. This may have occurred when cytoma was first reported in 1929, Cushing’s many sub-Saharan Africans were forced to mi- syndrome in 1932, pyelonephritis in 1937, re- grate to the Western Hemisphere. Mortality nal artery stenosis in 1938, and Conn’s syn- from salt-depletive diseases was high, and those drome in 1955. In some cases, these “secondary” with superior salt-retaining ability may have causes of hypertension were cured through survived to pass their genes on to present- surgery, but in most cases – those with essential day African Americans. This enhanced salt- hypertension – the cause remained unknown. conserving ability may, therefore, be found One important breakthrough occurred among more among Western Hemisphere blacks than researchers in animal physiology. among West African blacks and may help ex- In the 1920s, Harry Goldblatt progressively plain why the former group has a higher preva- constricted blood flow to a dog’s kidney, lence of hypertension than the latter. producing rapidly developing hypertension that resulted in death from heart failure. The History experiment sparked a worldwide search for a For centuries, the only way to assess blood pres- renal-based pressor substance that produced sure was to feel the pulse and interpret its force hypertension. By the end of the 1930s, two and rhythm. About 2500 B.C., a Chinese physi- teams, one in the United States and one in cian remarked: “When the pulse is abundant but Argentina, simultaneously discovered that tense and hard like a cord, there are dropsical blood from “Goldblatt kidneys” contained a swellings.” substance that caused vasoconstriction. The

170 73. Infectious Hepatitis

North American group called the substance hepatitis usually refers to a small group of “angiotonin,” while the Argentine group chris- diseases caused by several unrelated viruses, tened the compound “hypertensin.” The two whose most obvious and consistent symptoms teams decided they were working on the same result from liver damage. substance and combined the names for it; the substance became “angiotensin.” These History discoveries led to extensive research into the Until the mid-1900s, hepatitis was frequently neural, cellular, and hemodynamic systems equated with jaundice, although jaundice is that control blood pressure, and eventually to only a sign of failure to clear normal breakdown the development of today’s antihypertensive products from the blood. Under this terminol- medications. These discoveries were extremely ogy, hepatitis and other liver diseases played an important, but researchers were still a long way important role in early medical writings, but it from finding the cause of the disease. is difficult to determine which references relate In the 1950s and 1960s, two British physicians to hepatitis as we now know it, and which refer debated the influence of heredity on hyperten- to various other causes of jaundice. It is even sion. Robert Platt argued that it was a “qualita- more difficult to distinguish one type of hep- tive” disease, controlled by a single gene, with a atitis from another in the early references. Hip- bimodal population distribution. George Picker- pocrates identified at least four kinds of jaun- ing reasoned that “hypertension” was only the dice, one of which he considered epidemic and upper end of a continuous unimodal distribu- thus, by implication, infectious. Another was tion of blood-pressure levels. He thought that “autumnal hepatitis”; this condition could have hypertension was a “quantitative” disease and been hepatitis A. An emphasis on the liver has was controlled by multiple genes in combina- persisted into modern times in French popular tion with environmental influences. The debate medicine, where the liver is commonly blamed was never resolved. Research since then has for ill-defined ailments. tended to favor Pickering’s quantitative defini- Postclassical writers continued to have dif- tion, but not entirely. ficulty in distinguishing infectious forms from Today, both environmental and genetic fac- noninfectious forms of jaundice because of the tors are under examination at the individ- variable incubation periods of infectious dis- ual and population levels, but the cause of eases. Clear recognition of the infectivity of hypertension remains unknown. Fortunately, hepatitis is usually ascribed to Pope Zacharias, blood pressure is successfully being lowered who in the eighth century advocated quaran- through diet, stress reduction, exercise, weight tine of cases. This had little effect on general control, and medication, in the hope that thinking, however, because of the variety of cir- premature deaths from hypertension will be cumstances associated with different outbreaks. reduced. Many cases seemed to be sporadic, but epi- Thomas W. Wilson and Clarence E. Grim demics of what must have been hepatitis A (or enterically transmitted non-A, non-B hepati- tis, known as ET-NANBH) were known from the early seventeenth century to be common 73. Infectious Hepatitis in troops under campaign conditions. An epi- demic of hepatitis B, associated with a single lot The term hepatitis literally means any inflam- of smallpox vaccine, was described in 1885. In mation of the liver. Even when restricted by spite of this, as late as 1908, the dominant med- the term “infectious,” it has many causes, in- ical opinion held that all hepatitis was due to cluding malaria, yellow fever, and numer- obstruction of the bile duct. The picture did not ous viruses. By convention, however, infectious begin to clear until the mid-twentieth century.

171 73. Infectious Hepatitis

Hepatitis A has the smallest DNA genome known. The pro- Hepatitis A is caused by an RNA virus 27 tein forming the external surface of the virus nanometers in diameter. It is very similar to is produced in such excess that the host im- poliovirus in general structure and also in its mune system cannot cope and becomes para- ability to spread through fecal contamination lyzed. The virus DNA can be integrated into hu- of food and water. The virus is fastidious in its man genetic material, to provide a secure resting host range. It is known to infect only humans, place for the virus and, perhaps, to interfere with apes, and marmosets. the host’s growth-control mechanism and cause The virus of hepatitis A is essentially world- cancer. wide in distribution but is much commoner The stability of hepatitis Bvirus means that it where drinking water is unsafe and sanita- can persist on any article that is contaminated tion inadequate. The prevalence of disease is with blood, most significantly used needles and often inversely related to the prevalence of surgical instruments. In developed countries, it virus. In less-developed countries, most peo- has usually been transmitted in this way. Pre- ple become immune through infection in child- cautions have reduced the incidence of this dis- hood, often with no apparent illness. Persons ease in most of the population, but it contin- from developed countries, however, especially ues to be a serious problem among intravenous when traveling in less-developed areas, are drug abusers. likely to become infected as adults with serious Hepatitis Bcan also be sexually transmitted. consequences. It is excreted in the semen and transmitted Hepatitis A is manifested by general malaise, from male to female and from male to male loss of appetite, and often jaundice. Specific in this way. Because the heterosexual transmis- diagnosis can be confirmed only by electron- sion does not form a complete cycle, this has microscopic examination of feces or, more prac- been less of a problem among heterosexuals tically, by demonstration of specific antibodies. than in the male homosexual communities of The disease is seldom fatal when uncomplicated Europe and North America. and rarely leaves sequelae. Recovery normally The ability of the virus to remain infectious occurs in 4–8 weeks. when dried means that it can persist on sharp Specific identification of hepatitis A was not stones and thorns along paths and, perhaps, also accomplished until the 1960s and afterward. on the proboscises of mosquitoes. This provides Then, the development of methods for recog- a particularly important mode of spread in prim- nizing hepatitis B, and the demonstration of itive societies. two distinct agents in studies of children, made The most serious pattern of hepatitis Bin- its existence apparent. The agent of this dis- fection is seen in South Asia and sub-Saharan ease remained enigmatic because it could not Africa, where transmission from mother to child be propagated, except in humans. The virus is common. Infection may occur during birth or was identified in 1973. An attenuated vaccine via mother’s milk. The significance of this pat- has been produced and successfully tested but tern of transmission is that persistent infection not marketed because of continuing production is particularly likely to follow infection in early problems. life, and liver cancer is a common sequela to persistent infection. In these parts of the world, Hepatitis B cancer of the liver is the most common of all The cause of hepatitis Bis a very unusual cancers and a major cause of death in middle virus. Most important, it is unusually stable and age. The situation is self-perpetuating, in that can withstand boiling temperatures and dry- persons infected in infancy are most likely to be- ing without inactivation. Although the virus is come carriers and, hence, most likely to transmit of moderate size, 45 nanometer in diameter, it to the next generation.

172 73. Infectious Hepatitis

Infection with hepatitis Bcan have a variety of gen was the surface protein of the hepatitis B outcomes. It may be inapparent, or it may cause virus. a disease indistinguishable from that caused by hepatitis A. It may also, however, cause chronic Hepatitis C active hepatitis with or without cirrhosis.Any The virus of hepatitis C has been neither seen of these forms may lead to a chronic carrier nor cultured. However, in 1989, a strand of state, which may damage the kidneys or lead RNA from the blood of an infected chimpanzee to cancer. Thus, although uncomplicated hep- was transcribed into DNA. Propagated into a atitis Bis not often fatal in the acute phase, the bacterial clone, this DNA codes for an antigen total mortality it causes can be great. that crossreacts with the agent of an important A good vaccine is available. It was proven transfusion-transmitted hepatitis virus. The dis- effective in an extraordinary trial carried out coverers suggested that this “hepatitis C virus” with the help of the New York male homo- might be structurally similar to the virus of yel- sexual community. Thousands participated, ei- low fever or equine encephalitis.This implies ther as vaccine recipients or as part of a that the virus genetic material was the orig- placebo group. Because of the high homosex- inal RNA strand, not DNA. Hepatitis C is in- ual transmission rate, the incidence of disease activated by chloroform, showing that, unlike in the unvaccinated group was high enough the viruses of hepatitis A and B, it has a lipid- to provide a good level of significance in the containing envelope. The agent of some other results. Bacterial clones have now been devel- transfusion-transmitted non-A, non-Bhepatitis oped that carry the gene for the virus antigen, is resistant to chloroform, indicating the exis- and the product of these clones has now re- tence of at least one more unidentified agent of placed blood as a source of antigen in the United this disease. States. This technology has been expensive, Wherever hepatitis A and Bhave been dis- however, and blood-derived vaccine is still used tinguished, a residuum of non-A, non-Bcases elsewhere. has remained. Some of these cases are asso- It must be remembered that the vaccine only ciated with blood transfusions, whereas oth- prevents infection. There is as yet no way to cure ers are not. Hepatitis C is the most common the disease or abort the carrier state. A person transfusion-transmitted non-A, non-Bin the who becomes a carrier is likely to remain so for United States, but its role in the rest of the many years. This means that many people al- world is unknown. Although it is important as ready infected are still doomed to liver cancer. a cause of posttransfusion hepatitis, this is not Although it had been clear for many years its main mode of transmission, and it is seen that blood products could transmit hepatitis, sporadically in untransfused persons. Trans- the full import of this fact did not register on mission by intravenous drug use is more fre- the medical profession. In 1942, a new yellow quent, and sexual transmission seems also to fever vaccine, mixed with human serum, was occur. administered to U.S. troops headed overseas: Of Hepatitis C is a serious disease in that a high those vaccinated, 28,000 developed hepatitis, proportion of cases develop permanent liver and many died. damage. In spite of the paucity of our knowl- The discovery of hepatitis Bvirus followed an edge about this disease, it is almost unique unusual course. In the early 1960s, an antigen among viral infections in being treatable. Alpha was found in the blood of Australian aborigines. interferon results in dramatic improvement of Later, a researcher who worked with the blood hepatitis C liver disease. Unfortunately, the dis- samples was discovered to have acquired the ease often recurs when treatment stops, and the “Australia antigen,” and it was recognized as in- treatment is both expensive and accompanied fectious. Ultimately, it turned out that this anti- by unpleasant side effects.

173 74. Infectious Mononucleosis

Delta Agent adults. It is caused by the Epstein-Barr virus A fourth hepatitis virus, the delta agent, is un- (EBV) and is followed by lifelong immunity. able to grow independently; it grows only in cells that are also infected with hepatitis B. Its Characteristics defect is an inability to make coat protein, and Based on populations investigated, it seems that it must, therefore, wrap itself in the surface pro- infectious mononucleosis occurs worldwide but tein of another virus to become infectious. En- attacks only people with no EBV antibodies. The velopment in the other’s coat also gives delta virus replicates in the salivary glands, is present the advantage of hepatitis Bvirus’s freedom in the oropharyngeal secretions of patients ill from immune attack, and the fact that hepati- with the disease, and continues to be shed for tis Bis commonly persistent in infected persons months following convalescence. As a lifelong gives delta a reasonably large field in which to inhabitant of the lymphoid tissues, it is excreted forage. Infection with delta virus has the high- intermittently into the oropharynx. est acute fatality rate of all the hepatitides. Out- In underdeveloped countries, it is a disease breaks of unusually severe hepatitis have often of childhood, and as it spreads via oral secre- proven to be caused by it. No vaccine is avail- tions, crowding and unhygienic surroundings able as yet. favor its transmission. In developed countries, it strikes especially among the 15- to 25-year ET-NANBH age group. In the United States, on college cam- Enterically transmitted non-A, non-Bhepati- puses, it is commonly known as the “kissing tis (ET-NANBH) is a virus structurally similar disease.” to but immunologically distinct from hepati- Children of low socioeconomic status almost tis A. It has recently been associated with a universally show antibodies to the virus. In number of previously inexplicable hepatitis epi- Ghana, for example, 84 percent of infants have demics. The virus has been identified by elec- such antibodies. In a worldwide study of 5,000 tron microscopy. Most ET-NANBH epidemics children and young adults without EBV anti- have occurred in less-developed countries at bodies, 29 percent developed antibodies within times when even normally limited sanitation 4–8 years. Among susceptible college students, procedures have broken down. All ages are com- annual incidence is about 15 percent. monly affected, but there may actually be a pre- Although pathological findings may be mul- ponderance of adult cases. These circumstances tivisceral, follicular hyperplasia of the lymph suggest that ET-NANBH virus is less infectious nodes predominates. Lymphoid tissues show than hepatitis A and that, even in conditions diffuse proliferation of atypical lymphocytes in of generally poor sanitation, most people re- the spleen, blood-vessel walls, liver, and periph- main only minimally susceptible. ET-NANBH is eral bloodstream. These monocytoid lympho- usually indistinguishable from hepatitis A or B. cytes (Downey cells) may constitute 10 percent However, infected pregnant women have an un- or more of white cells and are of diagnostic sig- usually high mortality rate, which may reach nificance. 20 percent. In childhood, the disease is subclinical or Francis L. Black masquerades as one of many episodes of up- per respiratory infection. In the typical youth- ful adult, after incubating 5–6 weeks, clinical disease presents with prodromes of malaise, 74. Infectious Mononucleosis fatigue, headache, and chilliness followed by high fever, sore throat, tender swollen cervi- Infectious mononucleosis is an acute infectious cal lymph nodes, and a transient maculopapu- disease of children, adolescents, and young lar rash. Palpebral edema and/or periorbital

174 75. Inflammatory Bowel Disease (Crohn’s Disease, Ulcerative Colitis) edema may develop. Mild jaundice appears in ulceration of the rectum and colon and the some 10 percent of patients. Rarely are symp- adjoining terminal ileum. Ulcerative colitis be- toms related to the central nervous system. gins in the inner bowel surface of the colon; In most patients the disease is mild, and re- in severe colitis the entire bowel wall may be covery occurs within several weeks. College stu- involved. The white blood cell count is usu- dents are generally up and about within a week ally normal except with complications. The or so. Complications in the nervous system may hemoglobin and red cell count are decreased in occasionally occur in adults, but death from the proportion to blood loss. Blood proteins includ- disease is extremely rare, splenic rupture being ing albumin are often diminished. The stools the most serious complication. contain blood. Complications are numerous. In the colon, they include perforation, peritoni- History tis, hemorrhage, obstruction, polyps, and carci- This disease was described in 1885 by Rus- noma. Systemic complications include anemia, sian pediatrician Nil Filatov as idiopathic protein loss, malnutrition, arthritis, skin prob- adenitis. Four years later, German physician lems, nephrolithiasis, and liver disease. Emil Pfeiffer also described a disease that The therapeutic emphasis in ulcerative col- was epidemic in children and characterized itis involves a general program of nutritional by glandular enlargement. He gave it the restoration, emotional support, medications, name Drusenfieber ¨ (“glandular fever”). In 1896, and various surgical alternatives in selected pa- J. West wrote of a similar epidemic in the tients. The prognosis of ulcerative colitis has United States, but only in 1920 did Thomas improved considerably, and mortality is less Sprunt give it the name infectious mononucleo- than 1 percent because of medical and surgical sis. The characteristic mononuclear leucocytes advances. were described in 1923. EBV was identified in Ulcerative colitis is common among young 1968. people, especially below the age of 40, but the R. H. Kampmeier number of older patients is increasing. The cir- cumstances of onset are not known; patients usually appear to be in good health. Occasion- ally, symptoms appear after visits to foreign countries, implicating an enteric infection. Ini- 75. Inflammatory Bowel Disease tial thoughts emphasized a microbial infection, (Crohn’s Disease, Ulcerative Colitis) and this possibility continues today. Many or- ganisms have been implicated and discarded. The inflammatory bowel diseases (IBD) are Immunologic mechanisms have been impli- disorders of the intestines that remain obscure. cated and may involve defective immunoregu- Their course is acute and chronic, with unpre- lation. dictable remissions and exacerbations and nu- Various circumstances may act as “trigger merous complications. The economic and emo- mechanisms,” precipitating the disease in vul- tional impact of these diseases is enormous. In nerable persons. Genetic influences may be ex- these contexts, IBD is one of the major contem- pressed through the immune response genes porary challenges in medicine. and the mucosal immune system of the bowel. Emotional disturbances are common in ul- Ulcerative Colitis cerative colitis patients but probably do not Symptoms of ulcerative colitis are rectal bleed- initiate the disease. Investigation of interac- ing, constipation, diarrhea, cramping, pain, tions among the nervous system, the gut, fever, anorexia, fatigue, and weight loss. and the endocrine and immune systems is Examinations demonstrate inflammation and ongoing.

175 75. Inflammatory Bowel Disease (Crohn’s Disease, Ulcerative Colitis)

Crohn’s Disease appears to be more prevalent in Britain, New Crohn’s disease is an acute and chronic inflam- Zealand, Australia, the United States, and north- matory disease of the small intestine, especially ern Europe. It is less frequent in central and the terminal ileum, but actually involving the southern Europe, infrequent in the Middle East, entire gastrointestinal tract. It occurs frequently uncommon in South America and Africa, but among children and young adults but is in- increasing in Japan. creasing in people over the age of 60. There is Similarly, Crohn’s disease is common in a slight female-to-male predominance. Clinical Britain, the United States, and Scandinavia, on manifestations include fever, diarrhea, cramp- the rise in Japan, but less frequent in cen- ing, pain, anemia, and weight loss. Symptoms tral and southern Europe and uncommon in may include arthritis, gynecological difficulties, Africa and South America. It has been increas- urinary symptoms, or a combination of severe ing throughout much of the world but appears appetite loss, weight loss, and depression. Occa- to have stabilized in some localities. The world- sionally, the initial presentation is indistinguish- wide prevalence of Crohn’s disease, especially able from an acute appendicitis. in industrialized areas, and the similarity of its Findings include a normal or elevated white features regardless of geographic and sociocul- blood cell count, anemia, decreased total pro- tural differences, are noteworthy. teins and serum albumin, and evidence of un- The IBD are more frequent among whites dernutrition. The intestinal lumen is ulcerated than blacks, but Crohn’s disease is increasing and narrowed, and fistulas are not uncommon. among black populations of the United States Complications of Crohn’s disease include most and Britain. Ulcerative colitis and especially of the problems enumerated for ulcerative coli- Crohn’s disease are much more common among tis along with abscesses, fistulas, and intestinal Jews of the United States, Britain, and Sweden obstruction and carcinoma. than among other groups. Ulcerative colitis and As in ulcerative colitis, medical treatment is Crohn’s disease occur among all ethnic groups, symptomatic and individualized, with emphasis including Maoris, Arabs, and probably the Chi- upon medication and restoration of nutrition. nese, albeit infrequently. There is a scarcity of Surgery is necessary for complications, es- cigarette smokers among ulcerative colitis pa- pecially abscesses and fistulas, unrelenting tients, and ex-smokers apparently have an in- intestinal obstruction, and uncontrollable hem- creased vulnerability to it. By contrast, there is orrhage. The recurrence rate is high. an excess of smokers in Crohn’s disease popula- Etiologic hypotheses vary widely, from exces- tions. This intriguing observation, however, has sive eating of cornflakes, sugars, or margarine to yet to be explained. bottle-feeding, pollutants, antibiotics, and oral Ulcerative colitis and Crohn’s disease are not contraceptives. A variety of bacteria and viruses “classic” genetic disorders. However, genetic in- have been implicated, and the “new” pathogens fluences are important in both, as reflected in have renewed interest in microbial possibilities. their familial clustering (20 percent for ulcera- Other suggested but unproven etiologies have tive colitis and up to 40 percent for Crohn’s dis- included blunt trauma to the abdominal wall, ease). In addition to the initial patient, one more ingestion of foreign material, and nutritional member of the family is usually affected, but up deficiencies. to 8 patients have been observed in a family. IBD occurs with a high degree of concordance General Characteristics among monozygotic twins. The nature of the Ulcerative colitis and Crohn’s disease share sim- genetic influence in IBD is not known. The occa- ilar demographic features. Ulcerative colitis ap- sional occurrence of IBD in the adopted child or parently has stabilized or diminished in many mate of an IBD patient supports an environmen- areas of the world, with several exceptions. It tal mechanism. Current studies focus upon an

176 75. Inflammatory Bowel Disease (Crohn’s Disease, Ulcerative Colitis) abnormality in immune response genes among from England, France, Germany, Italy, and other other possibilities. European countries. In 1895 W. Hale-White re- Both disorders have significant familial asso- ported the association of liver disease and ulcer- ciations. Approximately 25 percent of families ative colitis, and in 1920 R. F. Weir performed with multiple instances of IBD show both ulcer- appendicostomy to facilitate “colonic drainage” ative colitis and Crohn’s disease. Both share epi- in ulcerative colitis. J. P. Lockhart-Mummery demiological and demographic features. They in 1907 described colon carcinoma in patients also share many symptoms, local complications, with ulcerative colitis, and emphasized the di- and systemic complications. However, ulcera- agnostic value of sigmoidoscopy. In 1909 W. H. tive colitis is a continuous mucosal disease, at Allchin recorded perhaps the first “familial” ul- least initially, with diffuse involvement of the cerative colitis. Additional instances were noted colon. Crohn’s disease is a transmural process, at the Paris Congress of Medicine in 1913, and focal in distribution, penetrating through the in the same year, J. Y. Brown may have been the bowel wall, and producing abscesses and fistu- first to suggest ileostomy in the surgical man- las. Granulomas and prominent lymphoid ag- agement of ulcerative colitis. gregates are much more common in Crohn’s During the 1920s, the number of reports disease than in ulcerative colitis. increased steadily and included those by Ulcerative colitis is limited to the colon and H. Rolleston, C. E. Smith, J. M. Lynch and occasionally a short segment of terminal ileum; J. Felsen, A. F. Hurst, and E. Spriggs. Hermann Crohn’s disease may involve any segment of Strauss may have been the first to recommend the alimentary tract. Ulcerative colitis is a con- blood transfusions in the treatment of ulcera- tinuous inflammatory reaction; Crohn’s disease, tive colitis. In 1924, J. A. Bargen published his wherever located, is a discontinuous, focal pro- studies implicating the diplostreptococcus in ul- cess. Perianal suppuration and fistula formation cerative colitis – a notion later discarded. More characterize Crohn’s disease, but not ulcera- important was his 1946 study of the course, tive colitis. Immune-modulating drugs are more complications, and management of “thrombo- helpful in Crohn’s disease than in ulcerative col- ulcerative colitis.” C. D. Murray in 1930 drew itis. Surgery is often curative in ulcerative coli- attention to the psychogenic aspects, and this tis, but the same operations in Crohn’s disease initiated a period (1930s–60s) of intense psychi- carry a recurrence rate of 15–20 percent. atric interest in ulcerative colitis. Worldwide attention was directed to the dis- History of Ulcerative Colitis ease at the 1935 International Congress of Hippocrates recognized that diarrhea was not Gastroenterology, and the amount of literature a single disease entity, whereas Aretaeus de- increased rapidly after this. By the 1940s, ul- scribed many types, including one with “foul cerative colitis was recognized more often than evacuations,” chiefly in older children and Crohn’s disease. However, by the end of World adults. An apparent “ulcerative colitis” was de- War II, Crohn’s disease had become more fre- scribed by Roman physicians, including Eph- quent. Concurrently with an apparent stabiliza- esus in the eleventh century. “Noncontagious tion of ulcerative colitis in the United States, diarrhea” flourished for centuries under many Crohn’s disease has been the more prominent. labels, such as Thomas Sydenham’s “bloody flux” in 1666. In 1865, U.S. Army physicians de- History of Crohn’s Disease scribed the features of an “ulcerative colitis-like” The initial description of Crohn’s disease may process. (Several of these cases actually suggest date back to Giovanni Morgagni, who in 1761 Crohn’s disease more than ulcerative colitis.) described ileal ulceration and enlarged mesen- During the 1880s and 1890s, an ulcerative teric lymph nodes in a young man who died colitis was described by numerous physicians of an ileal perforation. More suggestive early

177 76. Influenza instances of Crohn’s disease include an 1806 until reports in 1959 and 1960 by Lockhart- report by H. Saunders and one in 1813 by Mummery and B. C. Morson that Crohn’s dis- C. Combe and Saunders. Nineteenth century ease of the colon was accepted as a valid en- descriptions of disease consistent with today’s tity. It is to the credit of Crohn, Ginzburg, and concept of Crohn’s disease were authored by Oppenheimer that their description stimulated J. deGroote, J. Abercrombie, J. S. Bristowe, worldwide interest in this disease. Certainly N. Moore, and S. Wilks. much credit belongs to Crohn for his long in- In 1913, T. Kennedy Dalziel described a terest in the illness, his many publications on group of patients with findings closely resem- the subject, and his encouragement of others in bling those recorded in 1932 by B. B. Crohn, its further investigation. L. Ginzburg, and G. D. Oppenheimer. Many re- Joseph B. Kirsner ports of a chronic inflammation of the last por- tion of the small bowel appeared subsequently. F. J. Nuboer in 1932 described two patients man- ifesting the same findings that Crohn described. 76. Influenza Soon after Crohn’s 1932 paper, A. D. Bissell re- ported on two patients. The first had symptoms Influenza, also known as “flu,” “grip,” and including cramps, diarrhea, and weight loss and “grippe,” is a disease of humans, pigs, horses, required resection of an ileocecal mass. The sec- and other mammals, as well as of a number of ond required resection of the terminal ileum species of birds. Among humans it is a conta- and cecum. These early case reports depicted gious respiratory disease characterized by sud- Crohn’s disease as a mass-producing, bowel- den onset and symptoms of sore throat, cough, narrowing process, virtually always requiring often a runny nose, fever, chills, headache, surgical intervention. The principal clinical dif- weakness, generalized muscle and joint pain, ferentiation in the early part of the twentieth and prostration. It is difficult to differentiate century included intestinal tuberculosis and between single cases of influenza and feverish granuloma formation simulating tumor in the colds, but when a sudden outbreak of symp- bowel. toms occurs among a number of people, the cor- In other notable articles, H. Mock in 1931 rect diagnosis is almost always influenza. and R. Colp in 1933 chronicled involvement of There is at present no specific cure effective the colon. C. Gotlieb and S. Alpert in 1937 de- against this viral disease. In mild cases, symp- scribed regional jejunitis, and J. R. Ross in 1949 toms disappear in 7–10 days, although physical identified “regional gastritis.” W. A. Jackman and or mental depression may occasionally persist. J. L. Kantor in 1934 and R. Marshak in 1951 Influenzal pneumonia is rare but often fatal. described the roentgenographic appearance of Bronchitis, sinusitis, and bacterial pneumonia Crohn’s disease, and in 1936 Harold Edwards are among the more common complications, described a resected terminal ileum with “the and the last can be fatal if untreated. Influenza is consistency of a hosepipe.” generally benign, and even in pandemic years, Authoritative descriptions of Crohn’s dis- mortality is usually low – 1 percent or less – the ease have been provided by S. Warren and disease being truly life-threatening for only the S. C. Sommers, G. Hadfield, and H. Rappaport. very young, the immunosuppressed, and the el- In 1952, Charles Wells distinguished between derly. However, this infection is so contagious ulcerative colitis and what he termed “segmen- that in most years multitudes contract it, and tal colitis” and suggested that this latter form thus the number of deaths in absolute terms is was a variant of Crohn’s disease. In 1955 Bryan usually quite high. The sequelae of influenza Brooke and W. Trevor Cooke recognized “right- are often difficult to define, but evidence in- sided colitis” as Crohn’s disease, but it was not dicates that the 1920s global pandemic of

178 76. Influenza encephalitis lethargica had its origin in the fection in a given locale. Several times a century, great pandemic of 1918–19. the virus has changed radically, rendering obso- lete the immunologic defenses of most humans. Characteristics In the mildest of these pandemics, millions fall In seemingly every year, there are at least some ill and thousands die. cases of influenza on every populated conti- The cause of the major changes in the virus nent and most large islands. During epidemics, that set off the pandemics is still a matter of which occur somewhere almost annually, the mystery. The three most plausible theories are malady sweeps large regions, even entire con- that the influenza A virus itself mutates into a tinents. During pandemics, a number of which new version of infection-producing organism; have occurred every century for several hun- that an animal influenza virus abruptly gains dred years, the disease infects a large percent- the ability to cause disease in humans; or that a age of the world’s population and, ever since the human virus and an animal virus “cross-breed,” 1889–90 pandemic, in all probability a major- producing a new infectious organism unfamil- ity of that population. Not everyone so infected iar to human immune systems. The first of these becomes clinically sick; nonetheless, influenza seems least likely and the last most likely. Noth- pandemics are among the most awesome of ing, however, is certain yet, and the cause of earthly phenomena. The disease strikes so many influenza pandemics remains unknown. so quickly and over such vast areas that eigh- teenth century Italians blamed it on the influ- History ence of heavenly bodies and called it influenza. Influenza’s origins, too, are unknown. It does The causative agents of influenza are three not afflict our primate relatives and so is proba- myxoviruses: influenza viruses A, B, and C. The bly not a very old human disease. It is unlikelyto Band C viruses are associated with sporadic have been common among our Paleolithic an- epidemics among children and young adults, cestors or their herd animals before the advent and do not cause pandemics. The A virus is of agriculture, cities, and concentrated popula- the cause of most cases during and between tions. In small populations, it would have burnt pandemics. It exists in a number of subtypes, itself out by killing or immunizing all available which usually do not induce cross-immunity. victims quickly. In most instances, influenza viruses pass from Although influenza could have been ac- person to person by breath-borne droplets, and quired from pigs or ducks or other animals from animal to animal by this and other routes. thousands of years ago, no clear evidence exists Its epidemics in temperate zones usually appear of its spread among humans until Europe’s in winter, when people gather together indoors Middle Ages, and no undeniable evidence until under conditions of poor ventilation. Geograph- the fifteenth and sixteenth centuries. Since that ically, the malady spreads as fast as its victims time, however, the malady has been our unfail- travel, which in our time can mean circumnav- ing companion, never absent for more than a igation of the globe in a few months, with the few decades, if that. Its associations and charac- pandemic veering to the north and south of the teristics suggest that it was restricted to the Old tropics with the changing seasons. World until the end of the fifteenth century, Influenza A virus is distinctive in its genetic after which it spread overseas with Europeans instability, which probably makes permanent and their livestock – and may account for much immunity to the disease impossible, no matter of the clinically undefined morbidity and mor- how many times it is contracted. This genetic in- tality among the indigenes of Europe’s empires. stability is the likeliest explanation of why even Large-scale epidemics rolled over Europe in during pandemics the virus seems to change 1510, 1557, and 1580. The latter – the first un- sufficiently to produce repeating waves of in- ambiguous pandemic of influenza – extended

179 76. Influenza into Africa and Asia as well. Further Euro- the very least two or three times greater. In- pean epidemics occurred in the seventeenth fluenza killed many more than cholera did in century, but seemingly of only a regional the nineteenth century, but much of the mor- nature. tality was restricted to the elderly, and thus its At least three pandemics of influenza oc- reputation as an unpleasant but not dangerous curred in Europe during the eighteenth century infection was preserved. (1729–30, 1732–33, and 1781–82), and several Its history for the first 17 years of the next epidemics, two of which (1761–62 and 1788– century reinforced this view. Although rarely 89) may have been extensive enough to be absent for long, influenza attracted little atten- termed pandemics. The pandemic of 1781–82 tion until the appearance of the unprecedent- was, in geographic spread and number of peo- edly virulent pandemic of 1918–19. What was ple infected, among the greatest manifestations probably its first wave rose in the spring of of disease of all history. 1918, perhaps first in the United States, attract- By the end of the eighteenth century, popula- ing little attention because its death rate was tion growth, urbanization, and improving trans- low. Its most ominous characteristic was that portation were changing the world in ways that many of the dead were young adults, in con- enhanced the transmission of microbes across tradistinction to the malady’s previous record. long distances. There were at least three in- That spring and summer, this new influenza fluenza pandemics in the nineteenth century circumnavigated the globe, infecting millions, (1830–31, 1833, and 1889–90) and several ma- killing hundreds of thousands, and hindering jor epidemics as well. Even so, one of the most the waging of war in Europe and the Middle intriguing aspects of the history of influenza in East. The name given this new disease was this century was the long hiatus between the the “Spanish flu,” not because Spain’s morbid- second and third pandemics. In fact, in Europe, ity and mortality were higher than elsewhere after the epidemic of 1847–48, only a few minor but because Spain was not a belligerent and upsurges occurred until 1889. thus the ravages of the malady in that coun- When influenza rose up again in 1889, med- try were not screened from world attention by ical science was making rapid advances, and censorship. As in previous pandemics, morbid- public health had become a matter of govern- ity was vastly greater than mortality, and the mental concern. The 1889–90 pandemic was latter, as a percentage of the former, was not the first for which we have detailed records. It impressive. reached Europe from the east (hence its nick- In August, that changed, as death rates dou- name, the “Russian flu”), and such was the ef- bled, tripled, and more. A second wave arose, ficiency of transatlantic shipping that it swept sending hundreds of millions to sickbeds and over western Europe and appeared in North killing millions. This wave tended to subside to- America in the same month, December of ward the end of the year but returned again in 1889. It struck Nebraska, Saskatchewan, Rio a third wave in the winter and spring. In both de Janeiro, Buenos Aires, Montevideo, and the fall and winter waves, about half the deaths Singapore in February, 1890, and Australia and were in the 20–40 age group. Fully 550,000 died New Zealand in March. By spring the pandemic in the United States, about 10 times the number was firmly established and widespread in Asia of battle deaths of Americans in World War I. In and Africa. Waves of the infection continued to remote parts of the world, where influenza had roll across large regions of the world for the rest never or rarely reached before, the death rate of the century, and although mortality in this was often extremely high. The total of deaths in pandemic was quite low, the total of deaths was the world was in excess of 21 million, a figure high. By conservative estimate, 250,000 died in estimated in the 1920s before historians and de- Europe, and the world total must have been at mographers sifted through the records of Latin

18 0 77. Japanese B Encephalitis

America, Africa, and Asia, adding many more – At present, a worldwide network of 100 or so millions, certainly – to the world total. centers, most of them national laboratories, co- It is possible that the 1918–19 pandemic was, operate under the direction of the World Health in terms of absolute numbers, the greatest sin- Organization to identify new strains of influenza gle demographic shock that the human species virus as quickly as they appear in order to min- has ever received. The Black Death and World imize the time between the beginning of epi- Wars I and II killed higher percentages of the demics and the production and distribution of populations at risk, but took years to do so and relevant vaccines. The efficiency of this orga- were not universal in their destruction. The so- nization has been impressive, and certainly has called Spanish flu did most of its killing in a saved many lives, but influenza is not yet under 6-month period and reached almost every hu- control. man population on Earth. Moreover, its impact Alfred W. Crosby was even greater than these numbers indicate because so many young adults died. To this day, we do not know what made the 1918–19 in- fluenza such a killer. Perhaps as has been sug- 77. Japanese B Encephalitis gested, a chance synergy of viral and bacte- rial infection produced an exceptionally deadly Japanese B encephalitis is a relatively uncom- pneumonia, or perhaps the 1918 virus was so mon disease even in areas where the infection distinctive antigenically that it provoked a mas- is endemic. The disease is one of several caused sive immune response, choking the victims with by arthropod-borne viruses (arboviruses) and is inflammation and edema. We have no way of carried by mosquitoes of the genus Culex.The proving or disproving such theories. virus belongs to the genus Flavivirus and is an In 1920, another wave of the disease rolled RNA virus. The most common insect vector for over the world, but morbidity and mortality the virus is Culex tritaeniorhyncus. soon shrank back to normal, and the disease lost The disease was recognized and described in most of its power to kill young adults. The med- 1871, and the virus was isolated in 1935. The in- ical profession, however, has subsequently wor- fection may appear in epidemic or sporadic out- ried about a resurgence of the killer virus and breaks and is carried particularly in swine but has devoted great energy to identifying it, learn- also has been isolated from a variety of birds and ing its secrets, and studying how to disarm it. equine animals. The virus is distributed princi- It is possible that more is now known about pally in East and Southeast Asia. the influenza virus than about any other, but its Epidemic outbreaks of Japanese Bencephali- changing nature has defeated all efforts thus far tis tend to occur in regions that are usually dry to make a vaccine against the disease that will and arid and therefore relatively free of viral be effective for more than a few years at most. activity; such areas may accumulate many in- Vaccines were produced in the 1940s to protect dividuals who are relatively susceptible. Then, the soldiers of World War II from a repetition of with rain and conditions favorable to the insect the pandemic that had killed so many of them in vector, epidemic outbreaks may occur, particu- World War I, and influenza vaccines developed larly among relatively dense populations of hu- since have enabled millions, particularly the el- man and animal hosts. In some arboviruses, a derly, to live through epidemics without illness change occurs in the relative virulence of the or with only minor illness. But the ability of the infecting strain, which may also account for an A virus to change – sometimes radically – and to epidemic outbreak. race around the globe faster than suitable vac- Why, given the presence of Japanese Ben- cines can be produced and delivered has so far cephalitis in birds with wide-ranging migratory frustrated all efforts to abort pandemics. patterns, the disease remains localized to certain

181 78. Lactose Intolerance and Malabsorption geographic areas is unclear but presumably has or there may be residual damage to the central to do with the specificity of the insect vector nervous system; Japanese Bencephalitis, in con- in carrying the infectious agent. The mosquito trast to other arboviral encephalitides, has rel- vector, C. tritaeniorhyncus, is found in rice fields atively high rates of complete recovery despite and feeds on pigs and birds as well as human high case-fatality rates. and other hosts. However, the Japanese custom There is no specific treatment, and support- of raising pigs in the fall, after the flooding of ive care is the major intervention that can be of- rice paddies is over, and of taking the pigs to fered. The protective effect of antibody suggests market early the following year may help ac- that convalescent serum or other sources of an- count for the general lack of large outbreaks tibody might have some therapeutic value, but as well as for the usual pattern of sporadic this has not been systematically investigated on cases. a suitable scale. Most information on the early stages of the Vaccines have been available for many years disease has been gained from studies in the for immunization of humans and livestock. mouse. Pathological features of fatal human Live attenuated vaccines have been available in cases have generally been consistent with ex- Japan since 1972, and in China more recently, perimental findings. Early in the disease, focal and their effectiveness is shown by serocon- hemorrhages, congestion, and edema are found version rates of up to 96 percent. Widespread in the brain. Microscopically widespread dam- immunization campaigns have been successful age to Purkinje cells of the cerebellum is noted, in Japan, Taiwan, and China. At present, vac- with perivascular inflammation and multiple cines are composed principally of the prototype foci of degeneration and necrosis. Extraneural Nakayama strain, and reasonable control of the evidence of spread of the virus is found in the disease has been achieved. form of hyperplasia of the germinal centers of Vector control has been investigated in some the lymph nodes and of the spleen; multiple detail. Larvicides and adulticides aimed at the foci of round-cell infiltration in many organs, chief mosquito vector have reduced attack rates including the heart, kidneys, and lungs; and, in test areas. Insect-control programs, clearing in pregnancy, infiltration of the placenta with irrigation channels, and spraying insecticides in corresponding abortion and stillbirth. Multiple livestock pens have had some success in China. lesions in the offspring indicate cross-placental Under epidemic conditions, spraying with ap- passage of the virus. propriate insecticides has sometimes been nec- The clinical disease consists of the usual essary. signs and symptoms of encephalitis, and no Edward H. Kass syndrome has been elicited that is specific for Japanese Bencephalitis. Within a few days to several weeks after an infective mosquito bite, the susceptible patient manifests fever and ev- 78. Lactose Intolerance and idence of damage to the central nervous sys- Malabsorption tem, which may include meningism, delirium, drowsiness, confusion, stupor, paralysis (espe- The inability to digest lactose (sometimes called cially of facial muscles), and – in the most se- “milk sugar”) is related to the enzyme lactase in vere cases – coma and death within a few days. the intestine. Lactose intolerance means that Definitive diagnosis is made only from studies the individual is unable to tolerate the lac- of the antibody status of the affected individual. tose in milk and other foods because of insuffi- The disease is among the most fatal ar- cient lactase activity. Such intolerance has been boviruses, with case-fatality rates of 50–70 per- recognized for some time. Early in the twen- cent in outbreaks. Recovery may be complete, tieth century, physicians began to realize that

182 78. Lactose Intolerance and Malabsorption much infantile diarrhea resulted from a lack of originated in the Euphrates Valley were no- “ferments” necessary for carbohydrate diges- madic, constantly in search of new pastures. tion. By the 1950s, attention was focused on lac- Presumably they migrated in two main direc- tose malabsorption. tions: northwest toward Europe and southwest toward Central Africa. When this occurred is un- Characteristics known, but the nomadic pastoralists of Africa Lactose is found in the milk of most mammals and Europe may have their origins in these in concentrations ranging up to 7 percent. It migrations. is digested in the small intestine by lactase, By contrast, in the Americas, no pastoral which is anchored to the membrane by amino groups existed, and no post-weaning ingestion acids. In most mammals, lactase activity is high of milk occurred until the Europeans arrived. during the perinatal period but declines by This was also the case in Australia, the Pacific about 90 percent after weaning. In certain hu- islands, Japan, and the rest of Asia. In these man groups, however, lactase activity remains regions, the weaned individual obtained cal- elevated throughout the lifetime of most in- cium from bones, limestone, vegetables, and dividuals. Examples of such groups include fermented or pressed dairy products (much re- northern Europeans, people of Magyar-Finnish duced in lactose). extraction, and two African tribes, the Fulani Thus the present-day geographic distribution and the Tussi. of lactose-tolerant and lactose-intolerant peo- Clinical manifestations of lactose intolerance ples matches historical knowledge of the dis- include abdominal discomfort, borborygmus, tribution of ancient pastoral groups and the flatulence, and fermentative diarrhea. These milking of animals. Data support the cultural symptoms primarily result from the level of lac- hypothesis of Frederick Simoons – first promul- tase activity relative to the quantity of dietary gated in 1970 – that ability to digest lactose lactose. The lower the activity, the less the ca- is associated only with populations that have pacity for hydrolysis of lactose, although other a history of pastoralism. The hereditary pat- factors – such as intestinal motility and the pres- tern for this ability appears to follow straightfor- ence of other nutrients – also play a role in this ward Mendelian genetics. Individuals who can phenomenon. When the capacity of the lactase digest lactose carry the mutated gene, which is is exceeded, the nonhydrolyzed lactose passes dominant; lactose nonabsorbers carry a reces- into the large bowel, where it is fermented by sive gene. Consequently, crosses between lac- myriad bacteria. This action yields propionic tose malabsorbers always yield progeny who acid, hydrogen, methane, and alcohols, result- are malabsorbers, thus perpetuating the lactose- ing in a watery diarrhea. intolerant population. Lactose malabsorption can be classified into Today, lactose malabsorbers who desire to three categories: congenital, documented only drink milk can purchase “lactase” preparations in rare cases; primary, encountered in most hu- that “digest” lactose before ingestion. Others mans after 5–7 years of age and in other ani- can overcome potential dietary calcium de- mals after weaning; and acquired malabsorption ficiency by consuming various calcium-rich from illness and other causes. foods. The worldwide distribution of lactose in- tolerance among human adults and all other History mammals argues that this condition is the nor- The ability to digest lactose is clearly associ- mal physiological state. It is only the bias of ated with evolutionary pressures. During the the milk-oriented societies of Europe and North Neolithic period, human adults began drink- America that casts lactose malabsorption as ing milk, probably in association with animal abnormal. domestication. The ancient pastoralists who Norman Kretchmer

183 79. Lassa Fever

79. Lassa Fever In early stages, the disease simulates many African illnesses, prominent among them Recognition of Africa’s major human diseases malaria. Sporadically occurring Lassa cases are was apparently well advanced by 1900. Malaria, infrequently diagnosed. When epidemics arise, trypanosomiasis, yellow fever, schistosomia- the clumping of cases of mysterious illness has sis, typhoid, brucellosis, and many others had attracted attention, leading to diagnosis. It has been characterized. But in 1969, a new member become recognized that there are many mild of the coterie was discovered: Lassa fever. Lassa cases. Mortality is directly associated with Events leading to the discovery were dra- level of viremia, although it must be noted that matic. A nurse at a mission hospital in Lassa, by the time viremia figures are received from Nigeria, became ill, progressed unfavorably, and the overseas laboratory, the patient is either re- died, despite thorough modern treatment. This covered or dead. Generally, fatalities in infec- death, as a statistic, would probably have been tions are estimated at 1–2 percent, a rate lower labeled “malaria” in national and international than estimates based on hospitalized patients. disease records. But another nurse, who at- How widely such findings can be extrapolated tended the first, also became ill. She was moved in West Africa is unknown. However, it is clear to the Evangel Hospital in Jos, Nigeria, where that prognosis is highly unfavorable for seri- she too died. Again, there was no firm diagno- ously ill patients, even when the best therapeu- sis, and then her nurse got sick. Doctors were tic regimes are applied. thoroughly alarmed; this third patient was evac- Diagnostic tests have been developed. uated to America and admitted at the medical Viremia is a constant feature, and the virus can college of Columbia University. be identified in cell culture. Progress has been The Yale Arbovirus Research Unit in New made in survey methodology. Serum specimens Haven, Connecticut, secured specimens from taken in samplings can be examined for the the patient (who ultimately recovered), and a presence of antibody to Lassa, using a special previously unknown virus was isolated and test plate developed in U.S. Army laboratories. named “Lassa” after the locale of the first This method has led to greater knowledge of outbreak. Two laboratory-acquired cases oc- several deadly African diseases and is a major curred in Yale personnel working on the virus: step toward understanding their geographic One died; the other was given plasma from distribution. All work with Lassa virus must the recovered nurse and was cured. In due be conducted under conditions of highest course, Lassa virus was designated an Are- security, because it can pass from human to navirus in the family Arenaviridae, a grouping human via blood, urine, feces, and saliva – of nearly worldwide distribution, including which, of course, slows down laboratory work. other entities such as lymphocytic chori- Several deaths have occurred among laboratory omeningitis, Tacaribe virus, Junin virus, and workers, nonetheless. Machupo virus. Several other outbreaks of The association with the Arenavirus group Lassa fever are known to have occurred in Africa helped determine the transmission cycle of since 1969. Lassa virus. Predictably, like its congeners, it is High fever associated with malaise, muscle an infection of small rodents, usually house- and joint pains, sore throat, retrosternal pain, frequenting. Praomys (Mastomys) natalensis in nausea, liver involvement, bleeding, protein- sub-Saharan Africa is the most common house- uria, and erythematous maculopapular rash frequenting rodent and has been found infected with petechiae are features of the illness but not in several African regions afflicted with Lassa. of themselves particularly diagnostic. Some con- The infection in the rodent is persistent, with sider an enanthem in the oropharynx to have virus in the urine a common feature. As epi- specific diagnostic importance. demics occurred in Nigeria, Liberia, and Sierra

18 4 80. Lead Poisoning

Leone over several years, it became apparent can poison kidney cells, eventually causing fa- that Lassa virus is widespread in West Africa and tal renal failure. may also be found in East Africa. At present, it The symptom of lead poisoning most com- is especially prevalent in eastern Sierra Leone monly encountered in historical literature is ab- and is also found in Senegal, Gambia, Guinea, dominal pain. It is usually attributed to intesti- Ghana, Mali, and Cote d’Ivoire. nal spasm, though the abdominal muscles may Wilbur G. Downs undergo the painful, uncontrolled contractions called “colic.” Similar pain is seen in diarrhea, but lead poisoning is instead accompanied by constipation; hence the abdominal pain of lead 80. Lead Poisoning intoxication is termed “dry bellyache.” Lead also has a destructive effect on the Lead poisoning or plumbism simply means nerves that transmit electrical impulses to the undesirable health effects induced by lead. muscles, producing muscle paralysis. Muscles Many are “nonspecific” and are similar to ef- raising the wrist or foot are especially affected, fects produced by other causes, and some are causing “wrist drop” (often termed “the dan- so subtle they require laboratory identification. gles”) and “foot drop.” Behavioral disturbances This chapter deals primarily with overt effects leading to convulsions, coma, and death are the apparent upon even casual observation. Princi- most severe of lead’s effects. Children are no- pal among these are abdominal colic, muscle toriously susceptible to such brain toxicity, and paralysis resulting from lead-damaged nerves, even a single episode of convulsions, when not and convulsions. fatal, often causes permanent cerebral damage. Finally, plumbism may cause gout because of Characteristics the reduced ability of lead-poisoned kidneys to Lead enters the body mainly through inhalation excrete uric acid. The full etiology of gout is ob- and ingestion. Residents of industrialized na- scure, but when the kidney injury is caused by tions acquire half of their “body burden” of lead lead, the condition is called saturnine gout. from polluted air. Healthy adults absorb 10 per- cent of ingested lead, but children may absorb History half the lead they ingest. Lead is also absorbed The prevalence of plumbism correlates with through the skin: Lead-containing cosmetics, practices and traditions of lead use. Because for example, may cause health-threatening ef- galena is the most abundant lead ore in Europe fects. The body’s ability to excrete lead is ex- and Asia, and because it produces little toxicity tremely limited, and 95 percent of unexcretable for its miners, lead poisoning probably was not lead is stored in bone, where it will remain for common before the popularization of smelting decades in an adult. If absorption ceases, such about 3500 B.C. The cupellation process, dis- lead is leached from the skeleton over many covered about 3000 B.C., permitted separation years and excreted. Lead may be transferred to of the small amounts of silver from the much the fetus via the placenta. larger quantities of lead. A substantial increase Lead interferes with almost every body func- in lead production was a byproduct of the pur- tion. At low blood concentration, it may impair suit of silver, and during this period, many in- intellectual development in children, an effect volved in lead production in the Middle East and of potentially greater significance than more Mediterranean regions must have been exposed overt symptoms. Intense exposure may cause to a toxigenic degree. Introduction of coinage temporary arrest of long bone growth. Lead pro- resulted in increased silver (and lead) produc- duces moderate anemia by poisoning enzymes tion, which eventually Rome exaggerated to the necessary for the formation of hemoglobin. It point of ore exhaustion and a marked reduction

185 80. Lead Poisoning in that form of mining. Not until the late Middle centrated fruit juice as a sweetening agent. Such Ages did lead production rise again in Europe. juice was concentrated by boiling in lead-lined But it was the Industrial Revolution, with its containers, and lead was leached from the con- enormous surge in lead production, that created tainers by the juice’s acids. Replications of orig- the recurrent endemics of plumbism in France, inal Roman juice recipes contain lead concen- Italy, Spain, Germany, and especially Britain, and trations up to 800 milligrams per liter, 16,000 later their colonies. Since Roman times, produc- times the upper limit for potable water defined tivity has expanded from 80,000 to more than by the U.S. Environmental Protection Agency! 3 million tons worldwide today. With this rise Eventually Romans became so addicted to the has come a staggering degree of lead exposure sweet flavor of lead acetate that it was employed in Western nations. as a seasoning in wine. The use of lead in prehistoric times is ev- Clearly, then, the majority of urban Romans idenced by various artifacts dating from the were exposed to lead. Roman customs, however, fifth through the second millennia B.C. in the probably resulted in unequal exposure. Poor Near and Middle East, South and Southeast Asia, and middle-class citizens shared ingestion of and China. By 2000 B.C., not only had lead lead-contaminated water from public water sys- smelting become common, but cupellation was tems. But wealthier people additionally contam- also widely practiced. Lead had broad utilitar- inated their wine and food through the use of ian applications and was widely traded. Such lead-lined containers, expensive pewter table- widespread use of the metal must have been ac- ware, and food additives. companied by lead intoxication, at least among By this time, contemporary writers were industrial workers and those using lead prod- aware of health problems associated with exces- ucts including foodware, but there is no evi- sive lead exposure. The Greek physician-poet dence of severe or widespread lead poisoning Nicander is credited with the first unequivocal in this era. description of plumbism in the second century Much of our knowledge about lead use in the B.C., and other early warnings came from Lu- Greco-Roman period is related to mines such as cretius and Vitruvius in the first century B.C. the one at Lavrion near Athens. The Athenians and Pliny and Celsus in the first century A.D. called Lavrion a “silver mine” even though they Moreover, the emperor Augustus prohibited the had to separate 100 to 200 ounces of lead for use of lead for water pipes, though there is little each ounce of silver. Similar mines were oper- evidence of the edict’s enforcement. ated in the Mediterranean islands, Asia Minor, Well-known historical arguments suggest Spain, France, Italy, and Britain. With the gener- that the lead poisoning endemic in Roman so- ation of huge quantities of lead as a byproduct ciety may have helped cause the decline of the of silver, the obvious utilitarian value of lead Roman aristocracy during the first and second was also exploited. Applications included table- centuries. It may also explain the bizarre be- ware, storage containers for oil and other flu- havior of many Roman emperors and their al- ids, construction materials, sheathing for ships’ leged afflictions of gout, and may even have hulls, coins, toys, statues, various alloys, coffins, been a major factor in the decline of the Roman tablets, solder, and many others. The most in- Empire. tensive Roman use of lead related to their water As already mentioned, only in the late me- systems: Lead sheets not only lined aqueducts dieval and early modern periods did lead pro- and cisterns but also were rolled and soldered duction return to levels approaching those of to make water pipes. Rome. Then the rapid production increase dur- Another dangerous application of lead was its ing the Industrial Revolution and its subse- use in food and beverage containers and, even quent explosive growth (including the modern worse, as a food additive. The Romans used con- era of lead fuel additives) shifted the scene of

18 6 80. Lead Poisoning lead poisoning. From the sixteenth to the eigh- included such a thorough description of the teenth centuries and even into the nineteenth, symptoms comprising plumbism that it can recurrent epidemics of tardily recognized lead be used as a medical teaching exercise even poisoning swept over Europe. Most of these today. were traced to either industrial exposure or in- Colics also appeared in the American gestion of lead-contaminated substances. The colonies. There, settlers had arrived with concept of industrial exposure as a cause of limited tools and machinery; malleable lead disease was crystallized in 1700 by Bernardino was employed to create many items normally Ramazzini. His studies established clear rela- manufactured out of steel, with consequent tionships between certain diseases and occupa- opportunities for lead exposure. One source tions – among them, lead poisoning in miners, of exposure was lead-contaminated liquor. potters, and painters. By 1685, epidemics of “dry bellyache” or “dry Epidemics of lead poisoning were even more gripes” were common in North Carolina and difficult to pin down. A French epidemic, called Virginia. Complaints of lead-contaminated the “colic of Poitou,” had begun in the late six- New England rum led to the enactment of the teenth century, but over 100 years passed be- Massachusetts Bay Law of 1723, prohibiting fore lead-contaminated wine was identified as the use of lead parts in stills. its cause. Similarly, a half-century-long colic en- Although the law is often hailed as the first demic, which began in Madrid about 1730, was public-health law in the colonies, it appears the not associated until 1797 with badly glazed lead legislators were motivated more by trade than food containers. In the mid-eighteenth century, by health concerns. Similar afflictions occurred the “colica pictonum” in Holland was traced to at Caribbean island plantations. Barbados was lead water pipes. especially affected, with literature from the lat- Interestingly, the eighteenth and nineteenth ter seventeenth and much of the eighteenth centuries were characterized by British impor- centuries replete with references to “dry belly- tation of port wine in prodigious quantities. ache.” Sufficient lead has been found in archae- The brandy used to fortify such wines was of- ologically excavated bones to suggest that at ten prepared in stills containing lead parts, and least one-third of Barbadian slaves had lead- fortified wines may have been responsible for poisoning symptoms of moderate or greater an epidemic of gout so widespread that the severity. period is called “the golden age of gout” in In 1745, Benjamin Franklin published England. In the same vein, “the colic of De- Thomas Cadawaler’s treatise that defined the vonshire” raged for decades in mid-eighteenth role of lead in dry gripes. Franklin may have century England, but in 1767 George Baker carried this knowledge to Europe, because published a milestone report in the history of Baker of Devonshire quoted Franklin in his plumbism, establishing that the epidemic was 1767 article. In 1788 John Hunter detailed dry caused by cider contaminated with lead during gripes symptoms in Jamaica and specifically the manufacturing process. Subsequent preven- attributed them to lead. The condition sub- tive practices led to a gradual subsidence of the sided in the West Indies toward the end of the epidemic. century. Similarly, for many decades in the eighteenth Another source of lead poisoning in colonial and early nineteenth centuries, Paris’s Charity America was pewter houseware. Plates and gob- Hospital had become famous for its treatment of lets were commonly of pewter in wealthier colo- patients with various “dry colic” syndromes. In nial homes, and perishables and beverages were 1839, L. Tanquerel des Planches demonstrated stored in lead-lined containers. Indeed, in such that most were engaged in occupations involv- a wealthy home almost everything the family ing lead exposure. His detailed observations ate or drank contained some lead. Colonists

187 80. Lead Poisoning were also exposed through their use of lead of the lead intoxication syndrome confused bottles, funnels, nipple shields, dram cups, can- earlier diagnosticians because other conditions dlesticks, lamps, pipes, roof gutters, and other can simulate some of lead’s toxic effects. Per- items. haps even more relevant is the fact that during Mining also claimed its New World victims. most of history the cause-and-effect relation- Eastern American mines were largely of poorly ship between specific agents (like lead) and spe- soluble galena ore and generated little morbid- cific symptoms was only vaguely appreciated ity. But in western mines, with predominantly by physicians whose theoretical concepts did lead carbonate ore, lead poisoning reached epi- not readily embrace such an association. Such demic proportions. Thousands of miners suf- physicians were apt to attribute a broad range fered from plumbism between 1870 and 1900. of symptoms to general environmental (often Even in modern times, the ongoing use of lead climatic) disturbances. Even nineteenth century provides new opportunities for exposure. Lead French naval surgeons, while accepting lead as encephalopathy acquired by infants nursing at the cause of the lead poisoning syndrome, re- the breasts of mothers using lead-containing jected it as the cause of an identical symptom cosmetics constituted the fourth most com- complex in tropical sailors. They attributed it mon, fatal, pediatric malady in Manchuria in instead to the effect of high tropical tempera- 1925. Poisoning from lead fumes occurred in tures, thus delaying recognition of its true ori- a Baltimore neighborhood in 1933 when poor gin in their custom of shipboard food storage in families burned battery casings as cheap fuel. lead containers. Even in the early 1980s, lead solder was still Lack of a system for regular publication and used to seal food cans. The common practice wide dissemination of medical knowledge also among children of pica (dirt eating) has be- contributed to delay in grasping the etiology come especially dangerous for those playing in of lead poisoning. As early as 1656, Samuel yards whose soils are badly contaminated by Stockhausen, a physician to the lead miners factory- and vehicle-exhausted lead and from of northern Germany, published his realization the chips of old, lead-laden paint peeling from that their affliction was the toxic effect of the aging inner-city houses. Many surviving victims lead ore they mined. Forty years later, that ob- of childhood lead poisoning in Australia suf- servation led his southern German colleague, fered failure of lead-poisoned kidneys several Eberhard Gockel, to recognize lead contamina- decades later. And in recent times plumbism tion of wine as the cause of an identical problem has been rampant among “moonshiners” us- in his clerical patients, and it was to be more ing lead-containing distillation units (automo- than another century (and many more “colic- bile radiators soldered with lead) in the United demics”) before the translation of Stockhausen’s States. report into French enabled Tanquerel to identify American lead production peaked about the same problem. 1975, with at least half converted into Serious and major efforts to reduce lead ex- automobile-fuel additive. Recent partial control posure, such as the 1971 Lead-Based Poison- of exhaust fumes has been accompanied by a ing Prevention Act in the United States and 37 percent reduction in average lead levels in more recent legislation involving lead air pollu- Americans. tion by automobiles, are phenomena primarily Humanity’s flirtation with lead frequently has since the 1970s. The history of the past two mil- been its undoing. No other metal is so easily ex- lennia, however, suggests that our knowledge tracted from the soil and so readily fashioned of lead’s potential hazards will not prevent at into needed items. In every age, however, writ- least some continuing problems with its health ers sounding the warning of its toxic hazards effects. were ignored. It may be that the nonspecificity Arthur C. Aufderheide

18 8 81. Legionnaires’ Disease (Legionellosis, Pontiac Fever, Legionella Pneumonia)

81. Legionnaires’ Disease (Legionellosis, colonization, direct inoculation, or ingestion is Pontiac Fever, Legionella Pneumonia) unknown. Many outbreaks have been recognized, but Legionnaires’ disease is an acute infection prin- most cases occur individually or sporadically. cipally manifested by pneumonia and caused The risk of Legionella pneumonia (including by bacteria of the genus Legionella. Typically, Legionnaires’ disease) increases with age and is the attack rate – the proportion of people ex- two to four times higher in men than in women. posed to the bacterium who become ill – is Nosocomial (hospital-acquired) legionellosis is less than 5 percent. Without specific antibiotic an important problem, probably because par- treatment, 15 percent or more of cases are fa- ticularly susceptible people are gathered in a tal, although that percentage rises sharply in im- building with water systems that Legionella can munosuppressed patients. contaminate. Legionnaires’ disease is one form of presen- Legionellosis occurs throughout the year tation of Legionella infections, which are gen- but is most common in summer. This pat- erally termed legionellosis. Another version of tern prevails even in outbreaks unrelated to legionellosis, Pontiac fever, affects 45–100 per- air-conditioning systems, but whether or not cent of those exposed; no pneumonia occurs, warmer weather causes the bacteria to flourish and all patients recover. More than 20 species is unknown. Most bacterial and viral pneumo- of Legionella have been identified, 10 of which nias are more prevalent in winter, making the are proven causes of legionellosis in humans. seasonality of legionellosis one clue in diagno- sis. Legionellosis does not seem to spread from Characteristics one person to another. The weak staining of Legionella and its failure to Legionnaires’ disease is multisystemic, char- grow on common bacterial media allowed it to acterized by pneumonia, high fever, chills, mus- be missed for many years in evaluation of pneu- cle aches, chest pain, headache, diarrhea, and monia patients. Once the right diagnostic pro- confusion. Pneumonia usually worsens over cedures were identified, Legionella was found the first week of illness and resolves gradually to cause 1–2 percent of the pneumonia in the thereafter. In the lungs, air sacs are filled with United States, perhaps 25,000–50,000 cases an- macrophages, other inflammatory cells, and fib- nually. rin. With the proper stain, large numbers of le- Legionellae live in unsalty warm water and gionellae can be seen, mostly in macrophages. are widely distributed. They thrive particularly The larger airways are generally spared, which well at or slightly above human-body temper- may explain the relative lack of sputum and of ature, and may be commonly found in various contagiousness. Pontiac fever is characterized hot-water systems, including heat-exchange de- by fever, chills, muscle aches, and headache. vices. The various ways in which legionellae can Cough and chest pain are much less common go from their watery environment to infect hu- than in Legionnaires’ disease. mans are not all worked out, but one method is clear. Aerosols created by some disturbance of History contaminated water, such as in a cooling tower, In July 1976, the Pennsylvania American Le- can on occasion infect people downwind. It is gion held its annual meeting in Philadelphia, likely that, after the aerosol is generated, the with headquarters in the Bellevue Stratford Ho- water droplets evaporate, leaving the bacteria tel. Within days of the convention, many con- airborne to travel a considerable distance and ventioneers sickened. A massive investigation be inhaled. Potable-water systems also originate uncovered 221 cases among legionnaires who legionellosis outbreaks, but whether this oc- had attended the convention and others who curs via aerosols, inhalation succeeding throat had been in or near the hotel. Ninety percent

18 9 81. Legionnaires’ Disease (Legionellosis, Pontiac Fever, Legionella Pneumonia) of those who became ill developed pneumonia, In 1968, a remarkable outbreak of a severe, and 16percent died. Diagnostic tests for known self-limited illness involved 95 of 100 employ- agents of pneumonia were negative. The epi- ees in a health-department building in Pontiac, demiological investigation suggested airborne Michigan. Some investigators from the CDC spread of the agent, because risk of “Legion- succumbed also, but only those who entered naires’ disease,” as the press dubbed it, in- the building when the air-conditioning was creased with the amount of time spent in the on. Inspection of the system showed that the hotel’s lobby and on the nearby sidewalk but exhaust from the evaporative condenser dis- was unrelated to contact with other people or charged on the roof just a few feet from the animals, eating, or participation in specific con- fresh air intake. In addition, the exhaust duct vention events. Those who drank water at the and an adjacent chilled-air duct had defects al- Bellevue Stratford had higher risk than others, lowing droplets from the former to puddle in the suggesting a waterborne agent, but 49 of the latter. cases had only been on the sidewalk outside When materials from the 1968 investigation and had drunk no water there. The outbreak of the “Pontiac fever” were used in the tests received considerable notoriety and prompted that succeeded for Legionnaires’ disease, sci- a congressional investigation. Failure to identify entists were intrigued to find positive results. the agent immediately led to much public spec- Not only did Pontiac-fever convalescents show ulation about toxic chemicals and sabotage. specific antibody to L. pneumophila, but also In August, Joseph McDade of the U.S. Public L. pneumophila was recovered from stored lung Health Service tested specimens from legion- tissue of exposed guinea pigs. Thus a very naires for evidence of rickettsiae. The experi- different disease – both epidemiologically and ments were complicated by an apparent bacte- clinically – was shown to result from a bac- rial contamination but overall yielded negative terium indistinguishable from that causing Le- results. In November, McDade noted that the gionnaires’ disease. liver was involved in many experimental guinea Investigations of legionellosis proceeded both pigs, a sign reminiscent of Qfever , the rickettsial forward and backward in time. In the sum- infection most commonly associated with pneu- mer of 1977, outbreaks of Legionnaires’ disease monia. Within a month, he discovered a cluster were quickly recognized in Vermont, Ohio, and of what seemed to be large rickettsiae or small Tennessee. In 1978 an outbreak at a Memphis bacteria in the liver section of a guinea pig that hospital started shortly after a flood knocked had been inoculated with a deceased legion- out the primary cooling tower, requiring oper- naire’s lung tissue. McDade was able to grow ation of an auxiliary that had been out of use these organisms (which have since become for 2 years. Cases clustered downwind from the known as Legionella pneumophila) and showed auxiliary cooling tower but stopped occurring them convincingly to be the causative agent. 10 days after it was shut off. L. pneumophila In previous years, the Centers for Disease was isolated from both patients and the cooling- Control and Prevention (CDC) had investigated tower water, confirming the epidemiological ev- other epidemics of mysterious respiratory dis- idence that Legionnaires’ disease, like Pontiac ease. One, in 1965, involved 81 patients at fever, could be caused by L. pneumophila con- St. Elizabeth’s Hospital in Washington, D.C. In tamination of cooling systems. autumn 1976, it was suggested that the same Other previously unsolved outbreaks were agent had caused both outbreaks. Fortunately, found to have been legionellosis. In 1973, specimens from the St. Elizabeth’s outbreak had 10 men cleaning a steam-turbine condenser at a been stored at the Centers, and tests in Jan- power plant in Virginia had developed what in uary 1977 unequivocally proved the suggestion retrospect seemed to have been Pontiac fever. correct. Testing of stored serum specimens confirmed

19 0 82. Leishmaniasis this. An outbreak of hospitalized cases of Somalia, Chad, Kenya, Gabon, Sudan, and Niger. pneumonia in Austin, Minnesota, in the sum- A variant mainly afflicting children inhabits mer of 1957 was further investigated in 1979, southern Europe, North Africa, the Middle East, confirming a diagnosis of Legionnaires’ disease Romania, and southern central Asia. in this earliest proven epidemic of legionellosis. In endemic areas, high levels of disease in As further studies were reported, the picture rodent and dog populations make leishmania- emerged of Legionella as a group of freshwater- sis so common that it marks every inhabitant. associated bacteria causing pneumonia in hu- Some 12 million individuals are estimated to mans when particularly susceptible people are suffer from this infection. Thus, leishmaniasis exposed by aerosols, or perhaps otherwise, to is second only to malaria among the protozoal contaminated water. The presence of running diseases. Although mortality is low for the skin hot water and other thermal pollution, often disease, the organ variant is almost always fatal. from industrial processes, favors its growth, All forms of leishmaniasis are zoonoses trans- suggesting that legionellosis may be particu- mitted to humans via the sandfly (usually Phle- larly common in developed countries. How- botomus). The leishmanial form of the parasite ever, the disease appears to be worldwide in its lives in reticuloendothelial cells of a mam- distribution. malian host, where it divides by binary fission David W. Fraser to destroy the host cell. The parasites are in- gested by the sandfly while feeding on the host’s skin and develop into leptomonad forms in the insect’s intestine. These reproduce enormously, 82. Leishmaniasis moving to the pharynx and buccal cavity. In- dividual leishmaniae are restricted to specific Leishmaniasis is primarily a skin disease pro- sandflies, even though many species may be duced by protozoa of the genus Leishmania. available. The disease takes three basic forms, within Cutaneous leishmaniasis is caused by mem- which are variants caused by different species, bers of Leishmania tropica, producing chronic subspecies, or strains of the pathogen. The in- skin lesions that mostly ulcerate. Some forms termediate host is the sandfly. tend to be “urban” and closely linked to dogs. Others are “rural,” with reservoirs in- Characteristics cluding rodents, marsupials, and foxes. In the Cutaneous leishmaniasis (“oriental sore”) is Americas, sandflies of the genus Lutzomyia found in Armenia, Azerbaijan, Turkmenistan, are often vectors. The initial lesion usually Uzbekistan, Afghanistan, India, Iran, much of heals spontaneously but leaves a disfiguring the Middle East and North Africa, the sa- scar. vanna states from Sudan to Senegal, Kenya, Mucocutaneous leishmaniasis is caused by and Ethiopia. In the New World, variants oc- Leishmania braziliensis. In the form called es- cur in Central America, the Amazon Basin, the pundia in Brazil, the initial lesion becomes an in- Guyanas, and the Andes, especially Venezuela fection of nasal and oral mucosal tissues, result- and Peru. In eastern South America, a vari- ing in gross deformities and sometimes death ant mainly afflicting children extends from Ar- from secondary infections. Lutzomyia flies are gentina to Venezuela and north to Mexico. the major vectors. Mucocutaneous leishmaniasis is restricted Visceral leishmaniasis, or kala-azar, is caused to the New World. It occurs in Brazil, Peru, by members of Leishmania donovani. In vis- Paraguay, Ecuador, Colombia, and Venezuela. ceral leishmaniasis, unlike other forms, the or- Visceral leishmaniasis (kala-azar ) is found ganisms parasitize cells beyond subcutaneous in India, Burma, Bangladesh, China, Thailand, and mucosal tissues. Internal organs may be

191 83. Leprosy (Hansen’s Disease) involved. Symptoms include liver and spleen Phlebotomus was suspected of being the vector swelling, fever, diarrhea, emaciation, anemia, as early as 1911, but this was not proven until skin darkening, and gross abdominal enlarge- 1941. ment. Mortality in untreated cases has reached Marvin J. Allison 95 percent.

History Leishmaniasis is an ancient disease of both 83. Leprosy (Hansen’s Disease) the Old and the New Worlds. Old World cu- taneous leishmaniasis was first described in Leprosy occurs only in humans and is caused English in the mid-eighteenth century. New by Mycobacterium leprae. Known since the nine- World pottery clearly depicts the disfiguring teenth century as Hansen’s disease after Nor- disease. Pre-Columbian Incas knew the dan- wegian microbiologist A. G. H. Hansen, who first gers of leishmaniasis in the lowlands, where isolated the microorganism in 1873, true lep- coca grew, and used captives to cultivate it. rosy is a chronic, debilitating, and disfiguring The Spaniards, who later took over the coca infection. The history of conditions attributed to trade, were less aware of the problem; their la- leprosy undoubtedly includes many afflictions bor policies resulted in much disfigurement and that only resembled leprosy symptoms. death. Nineteenth-century British physicians in Characteristics India knew visceral leishmaniasis as kala-azar The leprosy bacillus multiplies slowly, usually or “Dumdum fever,” its symptoms attributed in the sheaths of peripheral nerves. Losing sen- variously to malaria, Malta fever, and other sation in discrete, patchy areas of skin is often diseases. In 1900, W. B. Leishman noticed the the earliest symptom of infection. Lacking ad- similarity of the parasite to that of trypanoso- equate innervation, the affected dermis can be miasis, and soon it was revealed as the cause of damaged without evoking a pain response. Tis- kala-azar. Leishman published his findings in sue repair is then hindered by poor regulation 1903, yet Charles Donovan independently du- of local blood supply. Hence, secondary infec- plicated his work. Leishman’s name was given tion and inflammation are common, leading to to the genus, but the agent of kala-azar got its scarring and callusing of surviving tissues. This specific name from Donovan. process can result in loss of fingers, toes, nasal “Oriental sore” had long afflicted Africa and tissue, or other body parts frequently exposed. India, where it was known locally as “Delhi boil,” A “bear-claw” foot or hand is among the charac- “Aleppo boil,” and so forth. The first description teristic features of leprosy. Involvement of nasal of L. tropica was published in 1898 by Peter cartilage and vocal cords – common sites for the Borovsky in a Russian military journal; however, organism’s growth – leads to profound facial dis- his paper was unknown in the West, and discov- figuration and also to the raspy, honking voice ery of the organism is often credited to James described in historical accounts. Wright, who in 1903 found it in an Armenian Earlier physiological signs of leprosy have child’s ulcer. been noted consistently only since the nine- Cutaneous disease in the Americas was de- teenth century. The heavily innervated face scribed by A. Carini and V. Paranhos in Brazil loses “free play” of expression and affect. Eye- in 1909 – the same year that mucocutaneous lashes and part of the eyebrows disappear long leishmaniasis was described, also in Brazil. before grosser signs betray infection. Gasper Oliveira de Vianna named the agent Leprosy occurs commonly only in tropi- Leishmania braziliensis in 1911. The American cal and subtropical regions. At least 15 mil- visceral form was first seen in Paraguay in 1913. lion lepers reside mostly in Africa, South and

192 83. Leprosy (Hansen’s Disease)

Southeast Asia, and South America. However, berculosis, which may have contributed to a de- this geographic distribution more likely reflects cline in leprosy as large towns appeared. In West poverty than it does the possibility that elevated Africa today, leprosy in rural villages increases temperatures and humidity facilitate infection. with distance from a city, whereas tuberculosis Despite cheap, effective medication (dapsone), increases dramatically with population density. leprosy continues to spread in rural regions of There is little evidence that leprosy existed in Africa and South and Southeast Asia. Because the Western Hemisphere, Australia, or Oceania lepers are stigmatized socially, leading to loss of before it was introduced from the Old World. employment, alienation from family and com- This epidemiological relationship between tu- munity, and ultimately confinement in a lep- berculosis and leprosy, however, is obscured in rosarium, they often deny infection or evade individual patients. For despite cross-immunity, treatment as long as possible, thus ensuring the most common associated cause of death transmission of the disease to others. Leprosy among lepers is tuberculosis, illustrating how passes between individuals only with sustained long-suffering victims lose the ability to com- exposure, but the disease continues to spread bat other infections. Moreover, geographic de- even in areas with Western medicine, because terminants alone cannot explain the high preva- of the high social costs of early identification lence of leprosy in densely settled eastern India. and treatment. It could be that successful control of tubercu- In the past, leprosy probably extended north losis in the region permitted the persistence of to the Arctic Circle. Extensive investigations of leprosy and that stigmatization of lepers effec- medieval gravesites have produced evidence of tively delayed treatment of the illness. leprosy among thirteenth century Danes and Members of the family Mycobacteriaceae can Norwegians. Interestingly, the distribution of infect mammalian and avian hosts, and, as ex- leprosy in medieval Europe, like that of to- emplified by bovine tuberculosis and avian tu- day, appears to have been rural, and evidence berculosis, a pathogen dominant in one host of leprosy disappears with urbanization. The species can successfully infect another. Thus disappearance of leprosy in Europe historically humans have suffered from bovine tubercu- progressed northward from the urban Mediter- losis transmitted through contaminated milk ranean areas of Italy and Spain. Cases of leprosy and from atypical mycobacterial infections. But were still reported in Britain during the four- among these, only leprosy and tuberculosis can teenth and fifteenth centuries, and it persisted be transmitted from one human to another, and in Scandinavia until the late nineteenth century, M. leprae is the only one that cannot be trans- when Hansen discovered the leprosy bacillus. mitted naturally to nonhuman species. The or- One odd feature of leprotic distribution is in- ganism usually enters a new host via respira- creased prevalence on islands or near seacoasts. tion or the skin. Because the incubation pe- Early theorists attributed the cause of the dis- riod is lengthy, the microorganism’s growth and ease to a fish diet, an explanation now discred- dissemination through the body is poorly un- ited. Undoubtedly leprosy’s low infectivity and derstood. Early symptoms usually appear 3–5 association with poverty contribute to the slow years after infection, but clinical evidence may spread inland. appear in as few as 6months or as long as It is possible that Mycobacterium tuberculo- 20 years. sis, a related organism that also conveys limited As with other chronic infections, clinical fea- cross-immunity to M. leprae, has affected the tures of leprosy can vary. Indeed, leprosy is long-term distribution and incidence of leprosy. called a bipolar disease because of two differ- Other atypical mycobacterial infections, such ent forms of the illness, with “mixed” or “inter- as scrofula, may be involved as well. Increased mediate” reactions possible but infrequent. In population density facilitates the spread of tu- tuberculoid leprosy, one polar type, skin areas

193 83. Leprosy (Hansen’s Disease) of “patchy anesthesia” heal relatively quickly af- tribution of leprosy and failure to impede its ter injury, but new areas appear, more exten- spread has emerged as a historical problem of sive and severe, involving peripheral nerves to recent centuries. the extent that desensitized skin cannot be pro- In the biblical book of Leviticus, the disease tected from burns, exposure, or other insults. zara’ath or tsara’ath was identified by priests, Even though tuberculoid leprosy is considered and its victims cast “outside the camp” as un- milder than lepromatous leprosy – possibly be- clean and uncleansable. They were viewed as cause of a stronger immune response – infec- both chosen and rejected by God and, conse- tions secondary to skin injury make it a serious quently, not exiled altogether from the commu- disease. nity – as were criminals – but rather made to live In the “leonine facies” of lepromatous leprosy, apart. Thus, central problems posed by the dis- the other polar type, the skin reaction is severely ease involved on one hand the spiritual identity disfiguring: Intermediate healing produces of diseased individuals, who though probably thick, corrugated scar tissue. Lesions often teem morally “tainted” were not apparently responsi- with infective bacilli. Lepromatous leprosy and ble for their disease; and on the other hand the tuberculoid leprosy arise from morphologically delegation of diagnosis to religious, not medical, indistinguishable M. leprae bacilli. Thus, both authorities. strong and weak immunologic responses (if this The opprobrium attached to leprosy was han- difference is the “cause” of the two forms) pro- dled dramatically by Old Testament writers, and duce crippling and disfigurement. this Judaeo-Christian tradition was of central The leonine form is more distinctive and importance in European history for the next thus more frequent in historical accounts. How- 2,000 years. Stigmatization of the leper was ever, grossly disfiguring ulceration of face and derived from religious, medical, and social re- limbs is not necessarily caused by leprosy. sponses to individuals carrying the diagnosis. Syphilis, frostbite,ordiabetes could also ex- Thus, during the High Middle Ages (1100–1300 plain the descriptions in some reports. More- A.D.), lepers were identified by spiritual author- over, other illnesses such as psoriasis, pella- ities and then separated from the general com- gra, eczema, and lupus erythematosus could munity, often ritualistically. Considered “dead to easily lend themselves to the historical “diagno- society,” last rites might be said in the leper’s sis” of leprosy. Thus the more subtle changes presence, sometimes as the victim stood sym- of early leprosy provide more assurance of bolically in a grave. Thereafter access to his or a correct diagnosis than simply loathesome her city or village was severely limited. Italian appearance. cities, for example, posted guards to identify lepers and deny them entrance except under History carefully controlled circumstances. Leprosaria The history of leprosy has been dominated by (hospitals to isolate and house lepers) were con- three problems. One concerns stigmatization. structed at church or communal expense, al- Most ancient societies identified some individu- though medical services were limited. Where als as “lepers,” who were stigmatized, although public services were lacking, lepers depended surely “lepers” included many suffering from upon begging or alms. something besides Hansen’s disease. Stigmati- Laws in Western Europe illustrated the exag- zation of lepers has persisted into the present gerated fear of contagion lepers generated. Lep- despite advances in diagnosis and treatment. ers had to be identifiable at a distance, leading The second problem focuses on medical evi- to the creation of legendary symbols of leprosy: dence for leprosy’s changing prevalence over a yellow cross sewn to cape or vestment, a clap- time, particularly in Western Europe between per or bell to warn passersby, and a long pole the years 500 and 1500. Finally, the world dis- for indicating wanted items or for retrieving an

19 4 84. Leptospirosis alms cup placed closer to the road than lepers as exhumations of medieval remains have were allowed to go. illustrated. The stigmatization of lepers, however, was Knowledge of leprosy in modern terms not limited to Western tradition. Most past so- evolved during the nineteenth century, coinci- cieties denied lepers legal rights as well as so- dent with the germ theory of disease. During cially ostracizing them. In both East and South this period, the description of lepromatous lep- Asia, marriage to a leper or a leper’s offspring rosy by Danish physician Daniel Danielssen in was prohibited. As in Western tradition, the dis- the 1840s, the discovery of the microorganism ease was often attributed to sin as well as con- by Hansen in 1873, and widespread attention tagion. The stereotype of the leper as filthy, to leprosy in European colonies identified it as rotten, nauseating, and repulsive is so strong a contagious tropical infection. As such it was that most hansenologists today advocate rejec- believed eradicable by Western medicine and tion of “leprosy” in favor of “Hansen’s disease.” public-health intervention. The only exception to the pattern of stigmatiza- In the same year that Hansen found the tion seems to be in Islamic society, where lep- causal organism of leprosy, Catholic priest ers are neither exiled nor considered morally Damien de Veuster drew worldwide atten- repulsive. tion in attempting to humanize the treatment In contrast to ancient Chinese texts that de- of leprosy by going to live among lepers in scribe in detail leprosy’s destruction of the face, Hawaii. But he may have underscored the evidence for leprosy in the ancient Mediter- fear of contagion, because he eventually con- ranean is meager. Nowhere in the Biblical tra- tracted the disease. Thus in modern times, in- dition is there more than a general descrip- creasing medical knowledge of M. leprae may tion of the disease. Hippocratic texts provide have increased alarm as leprosy was “discov- no evidence that true leprosy existed in an- ered” to be the resilient global problem it cient Greece, but the Greek word lepra, prob- remains. ably describing psoriasis, gave origin to the Ann G. Carmichael disease’s name. Thus a coherent and power- ful Western tradition stigmatizing lepers appar- ently began in the absence of any organized, accurate medical description of the condition. 84. Leptospirosis Indeed, the earliest Western clinical descrip- tion of leprosy appears in the writings of tenth Leptospirosis manifested by severe jaundice century Persian physician Avicenna; his is the was first described in 1886by A. Weil. Named description upon which medieval Europeans “Weil’s disease,” it designated an infectious jaun- relied. dice. Not until later was it known that lep- The decline of leprosy in Europe coincided tospirosis was caused by leptospires triggering with increasing sophistication in diagnosis. This various syndromes. The first pathogens were decline may have resulted from several factors: discovered in 1915 among Japanese minework- an increase in another disease, such as tuber- ers and German soldiers. Leptospira, a genus of culosis; improvement of living standards; high family Treponemataceae, order Spirochaetales, catastrophic mortality from plague and other is a fine threadlike organism with hooked epidemics, reducing the number of lepers in the ends that is pathogenic for humans and other population; or the simple fact that medical au- mammals, producing meningitis, hepatitis, and thorities began to participate in diagnosis of lep- nephritis. Leptospirosis once killed up to 40 per- rosy. Surely other skin afflictions were better cent of those infected; modern treatment has re- recognized in the late Middle Ages. Nonethe- duced mortality to about 5 percent. Rodents are less, true leprosy certainly existed in Europe, the natural reservoir.

195 85. Leukemia

Characteristics accompanied by the appearance of specific an- Leptospires are obligate aerobes and are clas- tibodies. Frequently, the liver becomes enlarged sified serologically as bacteria, subdivided into and painful, and life-threatening complications two species. Leptospira biflexa includes various arise when renal damage is severe. Icterus water spirochetes; Leptospira interrogans em- can be intense and lasting. The most common braces parasitic strains. The species interrogans second-stage symptom is serosal meningitis, (so named because it appears like a question and less frequently encephalomyelitis or neu- mark) is subdivided into 187 serotypes. Human ritis. Other damage is rare. When death occurs, leptospirosis generally results from exposure to renal and hepatic failure is usually the cause. infected animal urine, although it is also trans- Hemorrhages can be found in almost any organ mitted via contact, animal bites, and ingestion and in muscles and subcutaneous tissue. Antibi- of contaminated food and water. Leptospires en- otics are effective against leptospires but only if ter the body through breaks in the skin as well employed within the first few days. After this, as through mouth, nose, and eye linings. efforts are directed at avoiding complications. Leptospirosis is mostly seen during warmer weather and heavy rainfall, and the presence History of the disease in mud and swamps has often Much of the history of leptospirosis appears placed soldiers at special risk. Usually, it causes as efforts to separate leptospiral jaundice and isolated cases, but small clusters and even large meningitis from other infections. Clinical his- outbreaks have occurred. tory began with Weil’s 1886description, fol- Leptospirosis is frequently an occupational lowed by isolation of the germs in 1915. disease. Fieldworkers and husbandmen are at In 1918, the newly discovered bacteria were risk, as are employees of slaughterhouses and named Leptospira. About the same time, re- poultry and fish processors, and workers in sew- searchers found cases without jaundice – the ers, mines, and other wet places infested with 7-day Nanukayami fever, carried by field mice. rodents. Infected wild rodents are the source In subsequent decades, numerous serotypes of infection in domesticated animals, especially were found throughout the world. After 1950, dogs, pigs, and cattle. a new classification grouped the serotypes into Localized leptospirosis infections produced malignant and benign human leptospires as by one or another strain occur worldwide. Pig- well as animal ones. raising areas of Europe, Australia, and Argentina After over a century of leptospirosis research, see one form called “swineherd’s disease.” Simi- it seems remarkable that widespread epidemics larly, sugarcane plantation regions of East Asia have been infrequent. Today, incidence of lep- and rice-growing regions of Spain and Italy har- tospirosis has been reduced in developed coun- bor other forms. Local names for various lep- tries, probably because of decreased rodent pop- tospiroses often reflect the circumstances of ulations and improved human hygiene in the contraction, as in “harvest” or “swamp” fever. In presence of domestic animals. Germany, agricultural workers contracted “field Otto R. Gsell fever”; in Silesia, “mud fever”; in Russia, “water fever”; and in Germany and Switzerland, “pea- pickers’ disease.” Leptospirosis can also be an urban disease carried by rats as well as by dogs. 85. Leukemia The first phase of leptospirosis involves acute onset of high fever, headache, malaise, conjunc- Leukemia, commonly known as cancer of the tival reddening, muscle pain, meningism, renal blood, denotes a group of malignant disor- irritation, hypotonia, and bradycardia. In the ders in the blood-forming cells. The bone mar- second stage, danger of organ involvement is row (where blood cells are made) malfunctions,

19 6 85. Leukemia producing abnormal white (leukemic) cells to abnormal growth of immature blast cells, the detriment of other essential blood cells. whereas in chronic leukemias, more mature Blood consists of plasma, the fluid compo- cells proliferate, although immature cells may nent; red blood cells (erythrocytes), which trans- be present. The following are the diseases that port oxygen; white blood cells (leukocytes, cat- mainly arise: egorized as monocytes, granulocytes, or lym- phocytes), which help defend the body against 1. Acute myeloid leukemia (AML) – also infection; and platelets, which control bleed- called acute myelogenous leukemia, ing. Blood-cell formation (hematopoiesis) starts acute myelocytic leukemia, acute in bone marrow, the spongy interior of the myeloblastic leukemia, and acute gran- large bones, with undifferentiated “pluripotent ulocytic leukemia – is synonymous with stem cells,” which contain characteristics of the group known as acute nonlympho- all blood cells. These cells divide, producing cytic leukemia (ANLL), which includes specialized cells. The production process is con- some of the rarer subtypes of the disease tinual, with cell characteristics becoming in- (e.g., monocytic leukemia). AML involves creasingly defined. Eventually, the cells are the neutrophils (one of the granulocytes) “committed” to evolution into one specific cell that stem from the myeloid progenitor cell type (red, white, or platelet) and are released line. into the bloodstream at a rate consistent with 2. Chronic myeloid leukemia (CML) – also the body’s needs and the death of old cells. In called chronic myelogenous leukemia, normal health, immature stem cells (“blasts”) are chronic myelocytic leukemia, and chronic present in the blood only in small numbers. granulocytic leukemia (CGL) – produces Every day at least 200 billion red cells, 10 bil- excessive numbers of granulocytes that ac- lion white cells, and over 400 billion platelets cumulate in the bone marrow and blood- are produced in the marrow. In normal cir- stream. culating blood there are approximately 1,000 3. Acute lymphoblastic leukemia (ALL) – red cells to each white cell. But in leukemia, also called acute lymphocytic leukemia normal production of blood cells fails. White and acute lymphatic leukemia – arises as a blood cells reproduce abnormally and create im- result of abnormal immature lymphocytes, mature blasts or poorly developed cells. These which proliferate in the bone marrow and leukemic cells overpopulate the bone marrow, bloodstream and affect the lymphocytes enter the bloodstream and lymph system, and (B cells and T cells) stemming from the lym- infiltrate organs and glands, causing them to phoid cell line. enlarge and malfunction. The bone marrow be- 4. Chronic lymphocytic leukemia (CLL) – comes unable to produce sufficient levels of red also called chronic lymphatic leukemia cells and platelets; consequently, the balance of and chronic lymphogenous leukemia – the blood cell population is seriously disturbed, produces an abnormal increase in lympho- and the body’s defenses based on white blood cytes that lack infection-fighting ability. It cells and platelets are rendered ineffective. is the major type of a group of diseases known as lymphoproliferative disorders, Characteristics which includes rarer forms of leukemia Leukemia is classified according to the type of such as hairy-cell leukemia and adult white cell affected. The two main types of the T-cell leukemia. disease are myeloid (affecting monocytes and granulocytes) and lymphatic (affecting lym- Leukemia occurs worldwide and represents phocytes). These are further subdivided into about 5 percent of all cancers. The disease has acute and chronic.Inacute leukemias, there is no regular pattern. Its comparative rarity helps

197 85. Leukemia explain its irregularity. Leukemia can strike any- common signs arising from the infiltration of one, at any time, at any age. Because of vari- the bone marrow. Lack of red cells causes fa- able medical standards, comparing the world- tigue and anemia, lack of normal white cells re- wide incidence of leukemia and other cancers sults in infections, and lack of platelets produces can present problems. The estimated incidence bleeding and bruising. Lymph nodes, spleen, of leukemia in the developed world is 10 per and liver may become enlarged with infiltrating 100,000 population, the most common being leukemic cells. Bone or joint pains are associated AML and its subgroups, followed by CLL includ- symptoms. Marked differences, however, exist ing its rarer forms, then CML, and lastly ALL. between acute and chronic leukemias in their Rates vary in some countries and among some presentation. In acute leukemias, influenza-like ethnic groups, but no variation is significant. symptoms signal the sudden and rapid progress The male/female ratio is about 1.7:1. of the disease. By contrast, symptoms of chronic What causes a healthy cell to become malig- leukemias are subtler. Often, the disease is dis- nant and to proliferate in that state? The con- covered accidentally during a routine blood test. sensus of opinion is that leukemia results from Common symptoms are weakness, tiredness, the interaction of several factors, and investi- fever, night sweats, and loss of appetite. gations are being pursued into genetic factors Remedies for leukemia in the nineteenth cen- (some studies indicate that certain individuals tury were few, and none helped control the dis- are more susceptible than others), disorders of ease for any length of time. Quinine was used the immune system, radiation, chemicals that for combating fever; morphine and opium, for suppress bone marrow function, and viral infec- diarrhea; iron, for anemia; iodine, for external tion (retroviruses are known to cause leukemia use as an antibacterial; and arsenic. In 1865, in certain animal species). a German physician prescribed arsenic trioxide Because of the occasional occurrence of “clus- for a woman with CML. The patient was tem- ters” of the disease, investigations are often porarily restored to health, and arsenic became launched to find a cause, and identification of the first beneficial agent against certain forms possible contributory factors within the envi- of leukemia. ronment is one approach. The most established The 1895 discovery of X-rays by Wilhelm cause of human leukemias is ionizing radia- Rontgen¨ soon led to X-ray therapy of leukemia tion. The atom bombs dropped on Hiroshima with results similar to those of arsenic. X-rays and Nagasaki in 1945, for example, increased seemed more advantageous because they could the incidence of leukemia beginning about prevent cell division and inhibit cell growth, 3 years after the attack, peaking at 6years, and but patients could become resistant to X-rays. then slowly declining to normal incidence at Nowadays, irradiation is used to attack leukemic 20 years. The greatest incidence was among cells that accumulate in certain areas of the those closest to the explosions, whereas from body where chemotherapy is less effective. 2,000 meters the risk of leukemia was no greater As late as 1938, one researcher wrote that than among the general population. Increased although chronic leukemia patients could be numbers of clusters of leukemia have been re- made more comfortable, acute leukemia did not ported in areas surrounding nuclear power sta- respond to any form of therapy. During the tions, and childhood cases appear to be more 1940s, however, some X-ray-resistant leukemia prominent than usual in these clusters. But if patients responded to treatment with chemi- nuclear power stations are emitting radiation, cal analogues of poisonous mustard gas. This relatively few people are affected – again rais- triggered intensive efforts to find less toxic and ing the question of individual susceptibility. more specific agents. The result was the begin- Early symptoms of leukemia are similar to ning of chemotherapy, in which various drugs, those of infectious illness. The leukemias share often given in combination, are used to attack

19 8 86. Lupus Erythematosus the leukemic cells. As these drugs can affect Thus began a new era in hematology, but both leukemic and normal cells, their use must nearly 70 years passed before any progress was be controlled with great care. made in the treatment of leukemia. Experiments In nearly all cases, modern therapy can ef- indicated that folic acid might stimulate the fect remission. The next stage is to keep the pa- growth of leukemic cells. This led to the de- tient in remission through “consolidation ther- velopment for trial of new drugs antagonistic apy,” followed by “maintenance therapy,” which to folic acid. Aminopterin was one of these and aims to destroy any remaining or undetected was used successfully against acute leukemia in leukemic cells. Complete remission, however, the late 1940s. Much research followed, with the does not always mean cure. A further form result that by the late 1980s there was an estab- of treatment in suitable cases is bone mar- lished armamentarium of drugs used mostly to row transplantation, although graft-versus-host achieve a remission and maintain it. disease may cause a major complication. This Leukemia is a disease of major interest in therapy, however, has controlled the disease in both hematology and cancer research. Much cases when other means would not have been progress has been made in terms of patient sur- successful. vival. Moreover, the outstanding “problem ar- eas” of research are now more clearly defined, History and research efforts within the fields of cell and Leukemia was identified as a disease entity in molecular biology, immunology, cytogenetics, 1845 by independent researchers John Hughes and virology are ongoing. Bennett and Rudolph Virchow. Virchow named Gordon J. Piller the disease leukemia, Greek for “white blood,” and Bennett called it leucocythemia, Greek for “white cell blood.” During the previous decade, there had already been reports of peculiar con- 86. Lupus Erythematosus ditions of the blood, pus in the blood, and “milky” blood, with some symptoms compatible Lupus erythematosus (LE) is a clinical syn- with leukemia. drome with multiple but largely unknown Microscopes were crude, and there was no causes. It exhibits a broad spectrum of symp- satisfactory means of illuminating specimens toms ranging in severity from potentially fatal being observed. In fact, it is remarkable that the to virtually undiagnosable. When limited to the disease was recognized at all. But after recog- skin, it is called discoid lupus erythematosus nition, reports of suspected or actual cases of (DLE); when viscera are affected, it is systemic leukemia began to appear, slowly revealing its lupus erythematosus (SLE). The inciting causes worldwide distribution. Case reports also indi- activate immunologic mechanisms that medi- cated the ineffectual nature of known therapies. ate the pathological, predominantly inflamma- The first breakthrough was the discovery tory, tissue responses. by Ernst Neumann in 1868 of the importance of the bone marrow in blood formation; he History also investigated changes in the bone mar- Medical use of the term “lupus” has been traced row in leukemia. Another breakthrough oc- to the fifteenth century, when it designated curred in 1877, when Paul Ehrlich developed a a cancer. The term was reintroduced in Eng- stain that permitted cells to be clearly defined. land in 1808 to designate cutaneous tubercu- By then, microscopes were improved, and the losis, particularly when it affected the face. Cu- new technique of staining enabled features of taneous tuberculosis was eventually designated the blood to be studied with unprecedented lupus vulgaris. In 1851, a French physician clarity. used the term lupus erythemateaux to describe

19 9 86. Lupus Erythematosus a condition later named discoid lupus erythe- at University Hospital in Prague, there were just matosus (DLE) by Moriz Kaposi in 1872. Ka- 8 cases from 1897 to 1908. At Johns Hopkins posi concluded that DLE was more common Hospital, only 3 cases were diagnosed between and more severe in women and further believed 1919 and 1923. In fact, among 7,500 autopsies that it was not related to tuberculosis. Such a of cases above 13 years of age reviewed at the causal relationship, however, was advocated by same hospital in 1936, there were just 5 in- other researchers ( particularly French derma- stances of SLE. Five cases were diagnosed at the tologists), and the question was debated until Mayo Clinic between 1918 and 1921, but as the the 1930s. disease became more familiar, 132 cases were Kaposi used the term disseminated lupus recognized during the decade 1938–47. erythematosus for cases with widespread skin In 1948, however, “LE cells” were reported lesions rather than visceral involvement. Never- in bone marrow, initiating numerous efforts to theless, he described some cases having fever, demonstrate these new entities more easily and pleuropneumonia, arthralgia, and arthritis. reliably. In 1954, researchers discovered that LE Slowly, recognition developed that various vis- cells result from reactions between a serum fac- ceral manifestations are attributes of the sys- tor and leukocyte nuclei, and in 1957,a quantifi- temic disease rather than coincidences. From able test for this reaction was developed. Such 1894 to 1903, William Osler saw 29 patients tests have greatly increased case findings and presenting an “erythema with visceral lesions”; brought about recognition that SLE exhibits a he provided the first clear descriptions of SLE. broad range of severity. Osler added kidney and central nervous system The next advance was standardization of involvement to Kaposi’s description, and it was the criteria for diagnosis. In 1971, American soon recognized that pneumonia also belongs rheumatologists published a battery of clini- to the syndrome. cal and laboratory findings of which a specified Before the 1940s, most publication on lupus number were required for acceptable diagnosis. erythematosus was by dermatologists; conse- This schema was well received, and a 1982 mod- quently, skin lesions were considered essential ification was adopted in many countries. to diagnosis. In 1923, a report described four In the 1940s, it was generally acknowl- cases of noninfectious endocarditis (heart in- edged that no effective treatment existed for flammation) of which three had the skin le- LE. The initial breakthrough occurred in 1949 sions. A 1932 review of 11 such cases found with the discovery that corticosteroids exert a that 5 lacked the skin eruption. In 1936, a study dramatic suppression of most SLE symptoms. concluded that this form of heart disease is a Prednisone, a synthetic derivative of cortisone manifestation of SLE. Leukopenia and sensitiv- introduced in 1955, has become the most com- ity to sunlight were convincingly related to SLE monly used oral corticosteroid. Only cutaneous in 1939, but only in the 1940s was it accepted and renal manifestations are frequently re- that skin eruption is not a necessary component fractory. In 1951, quinacrine, an antimalarial of SLE. Data indicate that only about 40 percent drug, was found effective against DLE. Soon, of patients ever have the “butterfly” facial rash other antimalarials were found similarly use- and that eruptions on the body occur in about ful, and hydroxychloroquine is now principally 75 percent of cases. That DLE and SLE are mani- employed. In SLE, antimalarials are most ef- festations of the same disease was first proposed fective against the rash but may also amelio- in 1937, but two decades passed before the con- rate some visceral symptoms. The third ma- cept achieved general acceptance. jor therapeutic category is immunosuppressive SLE was perceived to be rare and uniformly fa- drugs: The first was nitrogen mustard, in 1950; tal because only the most severe cases – identi- now the most common are azathioprine and fied by the rash – were diagnosed. For example, cyclophosphamide.

200 87. Lyme Borreliosis (Lyme Disease)

Modern therapy and the recognition of milder death rate for Oriental women in the United cases have not only improved the quality of life States (nearly three times that of white women) for SLE patients but also greatly prolonged their is similar to that of black women. Prevalence survival. Before corticosteroids, one-half of pa- of SLE among Polynesians also exceeds that of tients died within 3 years of diagnosis. Later, Caucasians. In the predominantly black pop- the mean survival of 15 years beyond diagnosis ulation of Jamaica, SLE constitutes a remark- reached 75 percent. ably large proportion of treated rheumatic dis- eases. In view of the prevalence of SLE among Characteristics nonwhite populations elsewhere, the apparent SLE mortality is influenced by race and sex. Ac- rarity of the disease among African blacks has cording to U.S. data, annual mortality – relative been perplexing. The possibility of differences in to 1.0 for white males – is 1.6for black males, susceptibility of various African ethnic groups 3.7 for white females, and 10.5 for black females. must be considered. The data from much of the The proportion of DLE cases in dermatol- world remain inadequate to draw firm conclu- ogy clinics has been reported since the early sions about ethnic and other possible variables twentieth century; incidence between 0.25 and related to SLE. 0.75 percent has consistently been found in var- Thomas G. Benedek ious parts of the world. The early belief that the disease is rare in the tropics and among black populations has been disproved. The only epidemiological conclusion about 87. Lyme Borreliosis (Lyme Disease) SLE until the 1950s was that it occurred pre- dominantly in young women. In 1952, an eth- Lyme borreliosis is a tick-borne spirochetal nic predisposition was postulated, based on the disease caused by Borrelia burgdorferi. This frequently deleterious effect of sun exposure: systemic illness potentially involves the derma- Redheaded, freckled persons – unable to tan – tologic, neurological, cardiac, and articular sys- were deemed most susceptible. This was con- tems. It can mimic various other diseases such tradicted, however, by a 1964 study indicat- as juvenile rheumatoid arthritis, multiple scle- ing that SLE is actually more common among rosis, and syphilis. blacks. More recent studies have substantiated an increased susceptibility of blacks, particu- Characteristics larly black women. Lyme disease is the most frequently diagnosed Unlike diseases such as rheumatic fever tick-transmitted illness in the United States, or tuberculosis, SLE appears unrelated to so- where its three major geographic loci are the cioeconomic factors. Annual incidence in the northeastern and Middle Atlantic coastal re- United States has been estimated at about 5 per gions, the upper Midwest, and the Pacific North- 100,000, with black females about three times west. The disease is also found in Europe, more susceptible and black males two times Australia, the former U.S.S.R., China, Japan, and more susceptible than their white counterparts. Africa. The vector of Lyme disease is a tick, The mean age of onset is 28–30 years, but the Ixodes dammini (or related Ixodes species such preponderance of female patients varies with as pacificus, scapularis, and ricinus ). age. About twice as many females as males are B. burgdorferi has also been found in other afflicted during the first decade of life and from ticks, horseflies, deerflies, and mosquitoes, but the seventh decade on. But between ages 20 and whether these insects are possible secondary 40, there are 8 female patients for every male. vectors has not been established. Reservoirs of Studies also indicate greater susceptibility of B. burgdorferi occur in animals parasitized by Chinese than other ethnic groups, and the SLE infected ticks. Ixodes is a three-host tick with a

201 87. Lyme Borreliosis (Lyme Disease) life cycle of 2 years. Adult ticks mate and feed may go undiagnosed. More than 20 percent of primarily on deer in late fall; the female deposits adults with Lyme borreliosis fail to remember eggs on the ground, which produce larvae that the rash, and the percentage is much higher in are active late the following summer. The tiny children. larvae obtain blood meals from infected rodents Stage II of Lyme borreliosis may involve the such as white-footed mice, shrews, chipmunks, neurological system. Of patients, 10–15 percent and squirrels, which are primary reservoirs for may present a meningitis-like picture or have B. burgdorferi. Ground-foraging birds are also cranial nerve palsies. The most commonly in- important hosts for the larvae and nymphs. Af- volved cranial nerve is the seventh, interfering ter a blood meal, the larva molts to a nymphal with proper control of facial musculature. In form, which is active the following spring and individuals with meningeal irritation, episodic into midsummer. It seeks an animal host, ob- headaches, neck pain, and stiffness may occur. tains a blood meal, and molts to the adult stage Occasionally, patients with stroke syndromes to complete the 2-year life cycle. Animal hosts including hemiparesis as well as cases mim- include humans, dogs, deer, cattle, horses, rac- icking multiple sclerosis or encephalitis have coons, cats, skunks, bears, and opossums. been reported. Individuals may have associated Each developmental stage of the tick re- confusion, agitation, disorientation, and mem- quires feeding once and may take several days. ory loss. The symptoms and signs may wax and B. burgdorferi is transmitted to the host during wane over weeks and months. Heart involve- the blood meal. The longer the time the infected ment in Stage II is rare. Cardiac manifestations tick is attached to the host, the greater proba- are commonly detected only as first-degree bility of transmission. heart block on electrocardiographic tracings, Lyme borreliosis is arbitrarily categorized in although some patients can have a more serious three stages: Stage I involves the dermato- second- or third-degree heart block and present logic system and is diagnosed by the clas- with episodic fainting spells. sic rash, erythema chronicum migrans (ECM); The most common late manifestation of Lyme Stage II involves the neurological or cardiac sys- borreliosis is arthritis, usually occurring several tem months to years after infection; Stage III months after the tick bite – but the range is involves the joints, also months to years after 1 week to over 10 years. It is usually oligoartic- infection. These three stages may overlap and ular arthritis (fewer than four joints) involving occasionally present simultaneously. Moreover, large joints such as the knee or ankle. Attacks any of these stages may occur in the absence of may last from a few days to several months. the others. Some individuals experience recurrence with The ECM rash is pathognomonic for variable periods of remission. The intensity of Stage I Lyme borreliosis and begins as a small articular involvement is variable: Some patients flat (macule) or swollen (papule) spot at the site complain only of aches (arthralgias), whereas of the tick bite. It then expands to a large oval others demonstrate joint swelling (arthritis). or round lesion with a red-to-pink outer border B. burgdorferi infection can be spread and a clear central area. Viable B. burgdorferi transplacentally in humans. Infections during occasionally can be cultured in the advancing pregnancy can result in spontaneous abortion, margins. Blood-borne spread of the spirochetes premature delivery, low birth weight, and con- may produce multiple secondary lesions days genital malformation – complications similar to to weeks later. The rash persists a few days or those caused by the spirochete Treponema pal- weeks, usually unaccompanied by systemic lidum, the causative agent of syphilis. symptoms, although occasional fever, chills, Lyme borreliosis is treated with antibiotics. and fatigue may occur. Because the rash can The best results are achieved with prompt ad- be asymptomatic or unobserved, many people ministration of oral antibiotics at the time of

202 88. Malaria initial infection (Stage I). The duration of the plied that the original 1941 description of 13 rash and associated symptoms is abbreviated patients provided by A. Bannwarth may have re- by a 3-week course of oral tetracycline, peni- sulted from the same organism. In 1984, Klaus cillin, or erythromycin therapy. In Stage III Lyme Weber and colleagues, also in West Germany, borreliosis, 3 weeks of parenteral medicine or noted an elevation of IgG antibodies in the ceftriaxone are the drugs of choice. The ear- blood of patients with the skin lesion acro- lier antibiotics are instituted, the more likely a dermatitis chronica atrophicans (ACA). ACA is cure may be achieved. A delay in starting antibi- an uncommon late dermatologic manifestation otics may result in lifelong residual symptoms – of Lyme borreliosis. German physician Alfred intermittent or even chronic – from the disease. Buchwald first described ACA in 1883, which may have been the first reported case of Lyme History borreliosis. In 1909, Swedish dermatologist Arvid Afzelius Robert D. Leff described a rash (which he labeled erythema migrans) that succeeded an Ixodes tick bite. In 1913, an Austrian physician described a simi- lar lesion and labeled it erythema chronicum 88. Malaria migrans. Recognition of ECM’s association with systemic symptoms occurred in France in 1922. Malaria results from infection by protozoans Investigators described tick-bite patients with of the genus Plasmodium. These parasites are subsequent erythema migrans and nervous- transmitted from one human host to the next system involvement. In 1934, a German den- by infected mosquitoes of the genus Anophe- tist described erythema migrans with associated les. Although malaria receded from many tem- joint symptoms. And in 1951, the beneficial ef- perate regions in the twentieth century, it con- fects of penicillin in treating a patient with ECM tinues to be a major cause of morbidity and and meningitis suggested a bacterial etiology. mortality in tropical and subtropical coun- In the United States, the first documented tries. Three of the species – Plasmodium vi- case of ECM occurred in Wisconsin in 1969. vax, Plasmodium falciparum, and Plasmodium In 1975, state health officials learned that sev- malariae – are widely distributed; the fourth, eral children living close together in Lyme, Con- Plasmodium ovale, is principally found in trop- necticut, had developed arthritis. An investiga- ical Africa. P. vivax (causing benign tertian tion by Allen Steere revealed ECM in 25 percent malaria) and P. falciparum (causing malig- of patients. He named the syndrome “Lyme dis- nant tertian malaria) are responsible for the ease” after the town. great majority of malaria cases throughout the In 1977, it was observed that an I. dammini world. tick bite preceded the ECM rash. Willy Burgdor- fer and colleagues isolated a spirochete from Characteristics the midgut of the tick; this spirochete was sub- Malaria is characteristically paroxysmal and pe- sequently named B. burgdorferi. The follow- riodic. The classical episode begins with chills, ing year, Steere isolated the spirochete from extends through a bout of fever, and ends with blood, skin, and spinal fluid of Lyme dis- sweating, subsiding fever, a sense of relief, and ease patients and concluded that it was the sleep. Between early paroxysms, infected per- causative agent. Also, in 1983 in West Germany, sons may feel quite well; as the disease pro- H. Pfister and colleagues concluded that B. gresses, however, patients are increasingly bur- burgdorferi isolated in spinal fluid from a dened by symptoms. P. falciparum infection is lymphocytic meningoradiculitis (“Bannwarth’s particularly dangerous because of associated syndrome”) patient was causative, and they im- complications.

203 88. Malaria

The term “malaria,” from the Italian mala and male and female gametocytes. These circulate aria (“bad air”), was in use by the seventeenth in erythrocytes and may eventually be ingested century and referred to the cause of intermit- by a female Anopheles mosquito to begin a new tent fevers (thought to result from exposure to sexual phase of the life cycle. marsh air). However, past writers used the term Following recovery, P. vivax and P. ovale can for the presumed cause rather than the disease. cause relapse even after several years, and re- Only after the pathogenic agents were identified crudescence of quartan malaria (P. malariae) did usage shift so that “malaria” came to mean may occur 30 or more years after infection. the disease rather than the agent. P. falciparum, however, has a much more lim- Protozoa of the genus Plasmodium are para- ited survival time; if it remains untreated and sitic in many vertebrate animals. Most primate is not fatal, the infection will terminate sponta- species are hosts for plasmodia. It is generally neously without relapse, usually in under a year. accepted that malaria parasites evolved in asso- Reported cases of malaria are increasing from ciation with early humans, perhaps differentiat- year to year, especially in areas of Asia and the ing into the four recognized species during the Americas undergoing agricultural colonization mid-Pleistocene. with forest clearing and pioneering of unex- All mammalian plasmodia have similar two- ploited lands. Eradication campaigns have given phase life cycles: an asexual (schizogonic) phase way to long-term control programs in most ar- in the vertebrate host and a sexual (sporogonic) eas where the disease remains endemic, and in phase in female Anopheles mosquitoes. These some countries control is now being linked to or cycles reflect ancient relationships that seem to integrated with systems of primary health care. date from at least the Oligocene. The United States, Canada, and most The sexual phase is initiated as the mosquito Caribbean islands are essentially free of malaria takes a blood meal. Parasites in ingested red transmission and report only small numbers blood cells are released as male and female ga- of imported cases. Costa Rica, Panama, and metes in the stomach of the mosquito. Fusion of several southern South American countries the gametes produces a zygote, which encysts in are also nearly free of local transmission. the stomach wall. After 10–20 days, this oocyst Haiti and the Dominican Republic report only releases thousands of sporozoites that migrate P. falciparum cases, although in substantial to the salivary glands. When the now infective numbers. P. vivax is the prevailing species in mosquito probes for blood, these sporozoites Mexico, Central America, and northern South are injected into the new host in saliva. America, although many P. falciparum cases are The sporozoites follow the bloodstream to also reported, especially from Brazil, Colombia, the liver and there reproduce by nuclear di- and Ecuador. vision into large numbers (10,000–20,000) of Malaria is no longer endemic in Europe and merozoites. These enter the bloodstream, in- the former Soviet Union, but Turkey still reports vade red blood cells (erythrocytes), and break some autochthonous cases. Only a few small down the hemoglobin contained therein. The foci of autochthonous transmission persist in parasite again divides, producing 8–24 mero- North Africa and western Asia. About 90 per- zoites. When it reaches maturity, the erythro- cent of the population in sub-Saharan Africa is cyte bursts and the merozoites are released. still at risk, and transmission is high in many ar- Again some invade uninfected red cells. The eas, especially in rural West Africa. P. falciparum process may continue through repeated cycles, is the predominant species. destroying more and more red cells. Immune re- Malaria remains endemic in most countries sponses or intervention can check the process of central and South Asia. P. vivax is predom- short of profound anemia, complications, and inant, but P. falciparum is also important and death. Some red-cell merozoites differentiate as appears to be increasing in relative prevalence.

204 88. Malaria

The northeastern area of Asia, including Japan, tertian malaria. The unfortunate consequences is free of transmission, as are many of the of sickle-cell disease (hemoglobin SS) are bal- smaller islands and groups in Oceania. En- anced by the substantial antimalarial advantage demic foci persist in some of the larger islands conferred by the heterozygous condition, but (e.g., Philippines, Solomons, New Guinea, In- only as long as P. falciparum remains endemic in donesia) and in Southeast Asia and China. P. the area. Another genetic condition, G6PD de- vivax prevails in China, where incidence is ficiency, also provides some protection against steadily declining. In Thailand (also experienc- falciparum malaria. ing a decline), P. falciparum is somewhat more Acquired immunity in malaria is species- prevalent. specific and also specific to stage, that is, to the Malaria transmission in any locale depends sporozoite, to the asexual forms in the blood, or upon the complex interactions of parasites; vec- to the sexual stages. In endemic areas, newborns tor mosquitoes; physical, socioeconomic, and may be protected for a few months by maternal environmental factors; and human biology, de- antibodies that have crossed the placenta. After mography, and behavior. In 1957, George Mac- this phase, however, infants and toddlers are es- donald attempted to fit many of these variables pecially vulnerable; most deaths from malaria into an epidemiological model, and his ideas in endemic regions occur in these early years. continue to be influential. Macdonald’s defini- Older children and adults gradually acquire im- tions of stable malaria and unstable malaria, munity with repeated exposure. for example, are still helpful in studies of epi- demiological patterns. Stable malaria is char- History acteristically endemic: There is little seasonal Since at least the mid-Pleistocene, thousands of change; transmission continues through most generations of humans have been parasitized or all of the year; epidemics of malaria are by the plasmodia. It is certain that human very unlikely to occur; and most individuals malaria originated in the Old World, but there have some immunity. Control under these cir- has been some debate about the timing of its cumstances is likely to be difficult. Malaria in appearance in the Western Hemisphere. Some much of tropical Africa corresponds to Macdon- have suggested that malaria was present in ald’s stable extreme. Unstable malaria may be the New World long before European contact, endemic, but transmission varies from year to but a strong case exists that the hemisphere year and may be strictly seasonal. Seasonal epi- was malaria-free until the end of the fifteenth demics may occur; collective immunity varies century. and may be low; and children as well as infants Malaria could have reached the New World may be nonimmune. Control is relatively easy; before 1492 only by traveling overland from indeed, many countries only recently freed from northeast Asia or via seaborne introductions. endemic malaria were in the unstable category. The possibility that humans brought malaria Acquired and innate immunity are important into North America from Siberia can almost cer- factors in the epidemiology of malaria. Innate tainly be discounted; conditions in the far north resistance has been recognized in some hu- for malaria transmission were and are unsuit- man populations. In parts of Central and West able. It is equally unlikely that the Vikings could Africa, for example, many individuals are genet- have introduced malaria in the centuries before ically resistant to P. vivax infection. Generally, Columbus. They came from northern regions in these areas, P. ovale replaces P. vivax as the presumably free of malaria at the time and seem prevailing cause of benign tertian malaria. In to have visited only coasts that were north of endemic P. falciparum areas of Africa, individ- any possible anopheline mosquito populations. uals heterozygous for hemoglobin AS (sickle- Similarly, voyagers from the central or eastern cell trait) are more likely to survive malignant Pacific could not have transported the parasites

205 88. Malaria because that region is free of anopheline vec- century, cinchona bark was an important medic- tors and thus of locally transmitted malaria. inal export product from Peru. Voyagers reaching American coasts from east- In the Old World, malaria was probably en- ern Asia could conceivably have introduced demic in Greece by the fourth century B.C.; malaria, but this possibility too is remote. Hippocrates described types of the intermittent Moreover, colonial records strongly indicate fevers and noted the enlarged spleens of peo- that malaria was unknown to indigenous ple who lived in low, marshy districts. In Italy, Americans, and some areas that had sup- too, intermittent fevers were well known, for ex- ported large populations soon became danger- ample, to Cicero, and well described by Celsus, ously malarious after European contact. The ab- Pliny, and Galen. sence in aboriginal American populations of any Malaria was of some importance in the cen- blood-genetic polymorphisms associated with turies of Roman domination of Europe and the malaria is another kind of evidence that the Mediterranean basin. However, it was probably Western Hemisphere remained free of the dis- much less destructive than it has been more ease until contact. recently, primarily because P. falciparum was After 1492, malaria parasites must have been absent or rare and the other species were less in- introduced many times from Europe and Africa. tensely transmitted. It is suggested that Anophe- Native American anopheline vectors were at les atroparvus, basically a zoophilic species, hand, and together with smallpox, measles, was a poor vector for the human parasites. and other infectious diseases from the Old By late classical times, however, two other World, malaria soon began to contribute to species, Anopheles labranchiae and Anopheles the depopulation of the indigenous peoples. sacharovi, were introduced and dispersed along From its early, usually coastal, sites of intro- the coasts of southern Europe. These anthro- duction, malaria spread widely in North, Cen- pophilic species were much more effective vec- tral, and South America, limited principally tors for the plasmodia. By the final centuries of by altitude and latitude – factors controlling the empire, malaria was a more lethal force and the distribution of vector mosquitoes. By the may have contributed to Rome’s decline. nineteenth century in North America, the dis- After the fall of the Roman Empire, the his- ease was prevalent in much of the Mississippi tory of malaria in Europe and the Mediterranean Valley, even in the northernmost areas. Malaria is obscure for many centuries. With few excep- transmission extended into the northeastern tions, medieval writers provide only sketchy ac- United States, well north in California, and far to counts of outbreaks that may have been malar- the south in South America. By the eighteenth ial. During the Renaissance, malaria appears not and nineteenth centuries, malaria had also be- to have represented a major problem. Not until come established in the American subtropics the seventeenth and eighteenth centuries did and tropics. malaria become resurgent in Europe, not only The Old World gave malaria to the New; the in the south but periodically as far north as New World, however, provided the first effective the Netherlands, Germany, Scandinavia, Poland, remedy for the disease. Cuttings of cinchona and Russia. bark, taken from a Peruvian tree, were carried to Through all of these centuries the record of Europe in 1632. The bark was soon discovered malaria’s impact in Asia and Africa is fragmen- to provide relief from certain intermittent fevers. tary. With European colonization, however, it This therapeutic action allowed Richard Mor- soon became obvious that endemic malaria was ton and Thomas Sydenham in England in 1666, a threat almost everywhere in the Old World and Francesco Torti in Italy in 1712, to begin tropics, especially to the colonizers. to define malaria as a clinical entity separable The modern era in malariology began in from other fevers. By the end of the seventeenth the last decades of the nineteenth century

206 89. Marburg Virus Disease with the identification of the causal parasites 89. Marburg Virus Disease and the recognition of the role of anopheline mosquitoes as vectors. These discoveries pro- The so-called Marburg virus, presumed to be vided the rationale for new strategies in malaria African in origin, remains among the more mys- control. Malaria control itself was not a new terious of disease-causing organisms. concept; nor was the control of mosquitoes a new idea. Humankind had sought from ancient History times to control mosquitoes. The new ratio- In 1967, a disease outbreak occurred at a nale, however, provided for more specific con- laboratory in Marburg, Germany, where mon- trol directed principally at the anophelines that key kidneys were being prepared for cell cul- were important in transmission. Malaria con- tures. Twenty-seven laboratory workers (in- trol was further strengthened in the 1930s with cluding one in Yugoslavia) fell gravely ill; the introduction of synthetic antimalarials. The seven died. Four secondary cases occurred (in- 1940s brought further advances in chemother- cluding a laboratory worker’s wife), but none apy together with the first of the residual were fatal. Early suspicion focused on yellow insecticides. fever, but subsequently investigators isolated By the late 1940s and early 1950s, attempts an unknown virus. Electron micrographs re- at national eradication in a few countries (e.g., vealed a bizarre morphology of a type never Venezuela, Italy, United States) seemed justified. seen before: Photographs resembled a mass Early successes in local eradication, together of spaghetti. The agent was named Marburg with concerns about the emergence of anophe- virus. Strict monkey quarantines were initi- line resistance to insecticides, led to a 1955 ated. No further cases were seen in laboratory decision to commit the World Health Organiza- workers. tion (WHO) to malaria eradication. This commit- Field studies were initiated in East Africa, ment pushed many countries into supposedly the monkeys’ homeland. No virus was recov- time-limited eradication campaigns, often with ered from any monkeys examined. Later, sero- considerable financial and advisory support. logic studies involving humans, primates, and Some of these campaigns were successful, but rodents were undertaken in many regions. others faltered after dramatic initial results. By The first Marburg cases seen in Africa oc- the end of the eradication era in the early 1970s, curred in 1975. A young Australian couple tour- some hundreds of millions of people were living ing Rhodesia (now Zimbabwe) became ill by the in areas where campaigns had eliminated en- time they reached South Africa. They were ad- demic malaria, but in other areas it continued mitted to a Johannesburg hospital, where the to prevail, forcing a return to long-term control man died and the woman recovered. A nurse strategies. also sickened and recovered. After the disease In 1980 the WHO began to recommend that was determined to be Marburg, a thorough epi- malaria control be coordinated with primary demiological inquest investigated the victims’ health care. Malaria control and therapy con- travel route, concentrating particularly on ev- tinue to be complicated by mosquito resis- ery locale where they spent a night. Animal, in- tance to insecticides and parasite resistance to sect, and human populations were sampled. No drugs. Vaccine development proceeds, although evidence of endemic disease was found. slowly. The problems posed by malaria persist, In 1980, a man from western Kenya entered but they are not insoluble. Malaria remains en- a Nairobi hospital. He died 6hours after admis- demic in many countries in the twenty-first sion, and a physician attending him also became century, but steady improvement in control is ill but recovered. Marburg virus was isolated expected. from his blood. Subsequent epidemiological FrederickL. Dunn investigations produced a positive finding:

207 90. Mastoiditis antibodies against Marburg virus in two vervet agnosis is imperative to abort possible develop- monkeys among many examined. ing epidemics. Another episode, in 1987, involved a boy who Ebola virus is considerably more fatal in hu- became infected while visiting a park in western mans than is Marburg virus. In secondary Mar- Kenya. The boy died. No secondary cases were burg cases studied, the clinical course was less reported. Since that time, there have been many severe than in primary cases, with no mortal- isolated cases as well as outbreaks – such as that ity. No effective therapy has been found. In one of 1998–99 in civil-war-torn eastern Congo – case, therapy employed interferon in conjunc- suspected of being Marburg virus disease.In tion with immune plasma. The patient (a sec- the latter case, this was confirmed by the World ondary case) recovered. Further clinical trials Health Organization only after Ebola virus was await further cases. ruled out as the cause of some 50 deaths. Mar- Basic methods of managing patients with sus- burg virus disease, however, continues to elude pected viral hemorrhagic fever include strict easy diagnosis. isolation and precaution in examination, in tak- ing specimens, and in handling material in Characteristics the laboratory. Such procedures are not read- Marburg virus is unrelated to many arboviruses ily applicable in African bush clinics. Medicine against which it was tested. It most closely re- awaits further epidemiological information on sembles Ebola virus. Both Marburg and Ebola animal reservoirs, modes of transmission, and have been placed in a new family, Filoviridae, the persistence of the virus in nature. For which includes but the two members thus far. like Ebola, Marburg is the only other disease- A cytopathic effect was observed in Cercopithe- causing human virus for which the host cus kidney cells and human amnion cells. and the natural transmission cycle remain Incubation following exposure varied from unknown. 5–7 days. In six cases with available data, death Wilbur G. Downs occurred between days 7 and 16. Onset involved malaise, myalgia, and often prostration. Vomit- ing frequently occurred by the third day, and conjunctivitis by the fourth, by which time the 90. Mastoiditis ◦ temperature had reached 40 C. Rash, beginning on the fifth day, progressed to a maculopapular Infections of the middle ear and mastoid encom- rash that later became more diffuse. In severe pass a spectrum of potentially serious medical cases, a diffuse dark livid erythema developed conditions. Decreased hearing from ear infec- on face, trunk, and extremities. An enanthem of tions may have a lifelong impact and is a major the soft palate developed along with the rash. health concern. Because of the anatomic rela- Lymph node enlargement was noted. A diar- tionship of the middle ear and mastoid to the rhea appeared, often with blood. The South middle and posterior cranial compartments, life- African cases differed only in having no enan- threatening complications may occur. them and no lymph node enlargement. Diagnosis may be easy with a clustering of Characteristics cases and when epidemiologists are alerted; Acute suppurative otitis media (AOM) is however, the occurrence of single cases is not characterized by obstruction of the eustachian likely to arouse suspicion. Moreover, during the tube, allowing retention and suppuration of first several days, the symptoms could be mis- secretions. AOM is the term associated with the taken for many other diseases. None of the acute ear infection of childhood. Generally the methods of laboratory diagnosis is readily ac- course of this infection is self-limited, and in- cessible in the usual field situation; yet early di- fected secretions are discharged through either

208 90. Mastoiditis the eustachian tube or a ruptured tympanic plicated AOM in approximately 20 percent of membrane. cases. By the 1950s, acute mastoiditis resulting Acute coalescent mastoiditis can result from from AOM had declined to 3 percent. failure of these processes to evacuate the ab- AOM occurs most commonly between 6and scess. Coalescence of disease within the mas- 24 months of age. Subsequently, incidence de- toid leads to pus under pressure and ultimately clines with age except between 5 and 6years, dissolution of surrounding bone. This condition the age of entrance into school. The incidence of may require urgent surgical evacuation because uncomplicated AOM in boys is not significantly the infection is capable of spreading to other different from that in girls. Mastoiditis, however, structures. appears to be more common among males. Otitis media with effusion (OME) is an The severity of otitic infections is related inflammatory condition of the middle ear to factors such as extremes of climate and in which fluid accumulates. Both AOM and poverty. During winter months, outpatient visits OME are precursor conditions to tympanic for AOM are approximately fourfold higher than membrane retractions and perforations. Ongo- in summer months. Intake of mother’s milk and ing eustachian tube dysfunction predisposes to avoidance of cigarette smoke appear to confer persistent secretions in the ear and recurrent some protection against OME, but no effect on attacks of otitis media. Some patients develop complications is known. a chronic tympanic membrane perforation that Eustachian tube dysfunction is the most im- may allow eventual aeration of the middle ear portant factor engendering middle ear infec- and mastoid air-cell spaces and resolution of the tions. It commonly occurs in young children; underlying disease. adolescent growth improves the eustachian Chronic suppurative otitis media (CSOM) is tube opening. However, poor tubal function defined as an ear with a tympanic membrane may persist for many reasons and induces a rel- perforation. Benign CSOM is characterized by ative negative pressure in the middle-ear space. a dry tympanic membrane perforation unas- Lack of aeration and accumulation of effusions sociated with infection. Active CSOM results conduce to the development of OME or AOM. from intermittent infection often associated When AOM continues beyond 2 weeks, pro- with ingrown skin (cholesteatoma) in the mid- gressive thickening of middle-ear mucosa ob- dle ear and mastoid cavities. Primary acquired structs free drainage of purulent secretions, cholesteatoma occurs through tympanic mem- permitting bone destruction and extension of brane retraction into the attic of the middle-ear infection. This process may eventuate in mas- space with subsequent potential for extension toiditis and possibly other extensions of suppu- into the middle ear and mastoid air-cell systems. ration. Secondary acquired cholesteatoma is defined The onset of AOM in childhood is often as- as skin growth through a tympanic membrane sociated with fever, lethargy, and irritability. perforation into the ear. Older children may experience earaches and de- Some 80 percent of all children experience creased hearing. However, there is considerable one or more episodes of AOM by the age of 6. variability in the symptoms. OME is often char- Together AOM, OME, and CSOM comprise one acterized by hearing loss and a history of re- of the most common disease entities affecting current episodes of AOM. CSOM in its active humans. Indeed, AOM may be the most com- form often presents with foul-smelling drainage mon disease treated with antibiotics. and longstanding hearing loss. Development of Complicated infections producing mastoidi- pain in such an ear is a foreboding sign, as it of- tis have dramatically declined since the advent ten represents obstruction of drainage and pus of antibiotics in the 1930s and 1940s. Prior under pressure. Local complications of CSOM to that time, acute coalescent mastoiditis com- include bone erosion, facial nerve dysfunction,

209 90. Mastoiditis hearing loss, and “ringing” in the ear. Infection mary source of lethal, intracranial abscesses.) may extend into the bony skull or the soft tis- Also in the early eighteenth century, Jean Petit sues of the neck and scalp. of Paris performed probably the first successful operation on the mastoid for the evacuation of History pus. He stressed the need for early drainage of Studies of 2,600-year-old Egyptian mummies mastoid abscesses because of the potential for reveal perforations of the tympanic membrane further damage. and destruction of mastoid air cells. Suppura- Unfortunately, the advancement of otological tive destruction of the mastoid is also evident surgery suffered a setback when a mastoidec- in skeletons from Persian populations of the sec- tomy was performed on Baron von Berger (per- ond and first millennia B.C. sonal physician to the King of Denmark), who Hippocrates appreciated the potential seri- had heard of Petit’s achievement. He persuaded ousness of otitic complications and noted that a surgeon to operate upon his mastoid to re- delirium and death could result; later, Roman lieve tinnitus and hearing loss. The operation physician Celsus agreed. Later still, the Per- took place but resulted in a wound infection. sian Avicenna reasoned incorrectly that ear dis- The baron died of meningitis 12 days later, and charge was caused by brain disease. For cen- the mastoidectomy operation fell into disrepute turies, infections producing discharges from the until the middle of the nineteenth century. ear were considered virtually normal conditions One of the first to specialize in otology was because they occurred so frequently. Jean Marie Gaspard Itard, a military surgeon Although the seriousness of ear suppuration in Paris. In 1821, he exposed many errors of was appreciated much earlier, the idea of open- his predecessors, particularly the opening of the ing the mastoid to relieve infection awaited the mastoid cavity as a cure for deafness. Like Itard, sixteenth century. Medieval surgeon Ambroise Jean Antoine Saissy, another Parisian surgeon, Pare´ was summoned to treat Francis II of France. was opposed to puncturing the tympanic mem- Pare´ found the boy-king febrile and delirious brane for aural suppuration. Instead, he treated with a discharging ear. He proposed to drain the suppuration by rinsing through a eustachian infection through an opening in the skull. Fran- catheter, describing the technique in 1829. cis’s wife, Mary “Queen of Scots,” consented, but In 1853, William Wilde of Dublin (Oscar the king’s mother, Catherine de Medici,´ refused Wilde’s father) recommended incision of the to permit the operation, and Francis died. mastoid for mastoiditis when symptoms were Notable advances were made in the seven- life-threatening. The mid-century also saw the teenth century. In 1683, Joseph DuVerney pub- beginning of advances in anesthesiology, bacte- lished an account of the structure, function, and riology, surgical practice, and other fields that diseases of the ear, including infectious aural mean so much to modern medicine. pathology and the mechanisms producing ear- London surgeon James Hinton and Hermann ache, otorrhea, and hearing loss. He was the Schwartze of Halle are credited with establish- first to describe extension of tympanic cavity ing the specific method of simple mastoidec- infection to the mastoid air cells as a cause of tomy. This operation involved removal of the mastoiditis. bony cortex overlying the mastoid air cells. In 1704, Antonio Valsalva suggested a method Schwartze’s work led to the first account of the of removing purulence from the ear, consist- operation as a systematic procedure performed ing of exhaling strongly with mouth and nose according to a definite plan to correct a specific firmly closed, forcing air to pass into the mid- condition. By the end of the nineteenth cen- dle ear through the eustachian tube. (In 1761, tury, the operation had attained widespread ac- Valsalva’s student Giovanni Morgagni would ceptance, overcoming more than a century of demonstrate that aural suppuration was the pri- prejudice.

210 91. Measles

In 1861, German surgeon Anton von Troltsch coalescences were established, fewer complica- reported successful treatment of mastoiditis tions requiring surgical intervention would re- with a postauricular incision and wound ex- sult. Nonetheless, modern-day physicians have ploration. He recognized that failure to address recognized that too low a dose given for too little disease deeper within the middle ear and mas- time may indeed mask a developing mastoiditis. toid invariably resulted in disease recurrence, Interest in hearing preservation in surgical and in 1873 proposed extensions of Schwartze’s treatment of chronic ear infections continued. procedure to treat these areas. In 1889, Ernst German surgeons F. Zollner¨ and H. Wullstein von Kuster¨ and Ernst von Bergmann recom- share credit for performing the first successful mended extending Schwartze’s mastoidectomy repair of the tympanic membrane using skin- to include removal of the posterior wall of the grafting techniques in 1951. Since the 1950s, external canal and middle ear structures. This emphasis on preservation and restoration of extended procedure became known as the rad- hearing has fostered the development of meth- ical mastoidectomy. Properly performed, mas- ods of ossicular reconstruction designed to sim- toidectomy for well-localized infections proved ulate the middle-ear sound-conducting mecha- to be extremely effective in removing the risk nism. Prostheses made of polyethylene, Teflon, of serious complication within the mastoid. The and bioceramic materials have produced mixed addition of new techniques, as well as earlier results with respect to long-term hearing, stabil- diagnosis of mastoiditis, capped this important ity, and acceptance. phase of otologic surgery. In 1954, B. W. Armstrong reintroduced a pro- In many cases of radical mastoidectomy, pre- cedure (first suggested by Adam Politzer in vious infection had destroyed the middle-ear 1869) to reverse the effects of eustachian tube sound-conducting system. Removal of the tym- dysfunction, entailing a limited incision of the panic membrane and ossicular remnants was tympanic membrane and insertion of a tym- necessary in order to extirpate the infection. In panostomy tube. Tympanostomy tubes appear 1899, however, Otto Korner¨ demonstrated that to be beneficial in restoring hearing and pre- the majority of the tympanic membrane and os- venting middle-ear infections and structural sicular chain could be left intact, thus maintain- deterioration. ing the preoperative hearing level. The historical development of otology consti- In 1910 Gustav Bondy devised the modified tuted an evolution in the management of au- radical mastoidectomy. He demonstrated that ral infections. The lessons learned by otologists removal of the superior bone overlying infected underscore the importance of adequate surgical tissue adequately exteriorized and exposed dis- exposure, removal of irreversibly infected tis- ease while preserving hearing. Despite the suc- sue, and regular postoperative follow-up in or- cess of this less radical approach, otologic sur- der to maintain a safe, dry ear. geons were slow to accept it, but it finally gained John L. Kemink, John K. Niparko, widespread acceptance by the 1930s. and Steven A. Telian A marked decline in the need for mastoid op- erations followed the use of sulfanilamide and penicillin. The favorable results achieved with these antibiotics encouraged their application 91. Measles at earlier stages of severe infections. At first, otologic surgeons were hesitant to abandon es- Measles (rubeola, “hard measles,” “red measles,” tablished surgical procedures, fearing that an- “9-day measles,” morbilli) is a common in- tibiotics would mask the clinical picture and fectious disease, principally of children, with lead to late complications. It became evident, worldwide distribution, and characterized by however, that if antibiotics were given before fever and a red, blotchy rash. Measles is a

211 91. Measles vaccine-preventable disease, and its vaccine is Because of underreporting, worldwide reported among those included in the Expanded Pro- incidence represents only a small fraction of gramme on Immunization of the World Health the estimated annual 50 million cases and Organization. The disease is known by many lo- 1.5 million deaths caused by measles in devel- cal names throughout the world. oping countries. Vaccination – with global cov- erage estimated at 55 percent for children un- Characteristics der 1 year old – currently averts over 40 million Measles is caused by a species of Morbillivirus cases and 1 million deaths each year in devel- (family Paramyxoviridae). Although this virus oping countries. A single dose of live attenuated does not survive drying on a surface, it can sur- measles virus vaccine confers long-term, prob- vive drying in microdroplets in the air. ably lifelong, immunity in over 95 percent of Measles is one of the most communicable dis- susceptible individuals. eases, transmitted via contact of susceptible in- The prodromal phase of measles typically dividuals with nose and throat secretions from presents fever, cough, coryza, and conjunctivi- infected persons, primarily by droplet spread. tis. During this stage, small whitish specks on Measles has no reservoir other than humans, reddened areas of the mucosal lining of the meaning that a continuous chain of suscepti- mouth (Koplik’s spots) are diagnostic. Symp- ble contacts is necessary to sustain transmis- toms continue 3–7 days until the characteris- sion. The period of communicability lasts up to tic blotchy reddish rash appears, usually first 4 days after the start of the rash. There is no car- on the head and then spreading down the body rier state. The incubation period from exposure over 4–7 days. After its peak, in uncomplicated to rash onset is about 14 days. cases, all symptoms recede and the rash fades In populated areas with no or low vaccination in the same order it appeared. coverage, measles is primarily an endemic dis- Complications from secondary infection may ease, with epidemics occurring every few years. occur, however, possibly resulting in otitis, en- In such areas, the greatest incidence is in chil- cephalitis,orpneumonia. Diarrhea may also dren under 2 years of age. In more remote and complicate measles and is one of the most im- isolated populations, measles is not endemic, portant causes of measles-associated mortality and disease is dependent upon introduction in developing countries. Measles is uncommon from the outside, at which time an epidemic during pregnancy, and limited available data fail may occur, affecting all persons born since the to demonstrate clearly any increased risk of fetal last epidemic. No evidence indicates any gender mortality or congenital malformations. difference with respect to incidence or sever- ity, or any racial difference with respect to in- History cidence. Differences in severity among certain The origin of measles is unknown. Francis populations are most likely the result of nutri- Black notes that populations of sufficient size tional and environmental factors. to sustain measles transmission would not have Measles mortality is highest in the very young developed until sometime after 2500 B.C. He and the very old. In malnourished children in suggests that measles may be an adaptation the developing world, the case-fatality rate may of another virus of the same genus (which in- be as high as 10 percent or more. Some stud- cludes rinderpest and canine distemper). Hip- ies have indicated that multiple cases within a pocrates, writing in the fourth century B.C., family group may lead to higher mortality rates. described no rash illness consistent with The Expanded Programme on Immuniza- measles, even though his case histories docu- tion of the World Health Organization main- ment many other infections in ancient Greece. tains information on reported measles cases The history of measles is confused with and vaccination coverage in member countries. that of smallpox in much early literature.

212 91. Measles

Although records are scanty, major unidentified demics were reported in the seventeenth and epidemics with high mortality spread through eighteenth centuries. the Roman Empire in 165–80 A.D. and again in The most famous epidemiological study of 251–66 – epidemics that may have signaled the measles was conducted by Peter Panum in 1846. arrival of measles and smallpox. In China, Measles attacked about 6,100 Faroe islanders two major epidemics with high mortality during that year and was associated with the were recorded in 161–2 and 310–12 A.D., but deaths of 102 of the 7,864 inhabitants, who had again we cannot be certain about the identity been completely free of the disease for 65 years. of the diseases. Panum confirmed the respiratory route of trans- Persian physician Rhazes is generally credited mission, the incubation period, and the lifelong with the first written record of measles by differ- immunity acquired from previous infection. Au- entiating it from smallpox in approximately 910. gust Hirsch built on Panum’s work, recording Rhazes, however, quoted previous writers, in- the universal geographic distribution of measles cluding Hebrew physician El Yahudi, who lived and noting epidemics from most parts of the 300 years earlier. Around the year 1000, Avi- world. He noted too that measles reached the cenna also wrote about measles, and translators Western Hemisphere soon after the arrival of of his writings may have introduced the term Europeans and followed the westward move- rubeola for the disease. ment of settlers. He suggested that introduction During medieval times, measles was desig- of the disease into Australia occurred in 1854, nated by the Latin morbilli (“little disease”). after it first appeared in Hawaii in 1848. Measles was also called rossalia and rosagia, Measles was especially dramatic when it as well as fersa or sofersa (Milanese), mesles struck “virgin-soil” populations with no prior or (English), maal and masern (German), and ma- recent exposure, and thus the outbreak affected sura (Sanskrit). The derivation of the English most individuals. The disease played an impor- “measles” is in some doubt. One suggestion tant role in thinning the ranks of Native Amer- is that it arose from the Latin miscellus or icans after 1492, and later high mortality also misella, a diminutive of the Latin miser, mean- occurred in epidemics among several Pacific ing “miserable” – a term given to those suf- virgin-soil populations during the nineteenth fering from leprosy. Leprotic sores were called century: 40,000 deaths (out of a population of mesles, and John of Gaddesden in the early 150,000) in Hawaii in 1848; 20,000 deaths, com- fourteenth century unjustifiably coupled these prising 20–25 percent of the Fijian population mesles with the disease morbilli. Eventually in 1874; and 645 deaths out of 8,845 cases in the term “measles” lost its connection with Samoa in 1911. Such high case-fatality rates in leprosy. these settings likely resulted from some of the Measles, smallpox, and other rash illnesses same factors that cause high mortality among continued to be confused in medieval Europe. unvaccinated individuals in developing coun- Physician and epidemiologist Thomas Syden- tries today, including lack of supportive care, ham studied measles epidemics in 1670 and lack of treatment for complications, and mal- 1674 and discussed clinical features of the ill- nutrition. In virgin-soil settings where popula- ness and its complications. He is generally cred- tions were well nourished and had better med- ited with differentiating and describing measles ical care, mortality was much lower, as seen in in northern Europe. The first clear demonstra- the measles outbreak in southern Greenland in tion that measles was infectious is attributed to 1951. In one district, 4,257 persons out of a pop- Francis Home, who in 1758 attempted to cre- ulation of about 4,400 contracted measles, but ate immunity by placing blood from measles only 77 deaths occurred. patients beneath the skin or into the noses Not until 1896did Henry Koplik pub- of susceptible persons. Numerous measles epi- lish a description of Koplik’s spots, although

213 92. Meningitis apparently their significance was independently in the past as “spotted fever,” “cerebrospinal recognized about a century earlier by John fever,” typhus cerebralis, and meningitis epidem- Quier in Jamaica and Richard Hazeltine in ica. Aseptic meningitis means inflammation of Maine. the meninges without detectable bacterial in- Research leading to current measles vaccines volvement. The most common causes are any began about the early twentieth century. In of a number of viruses. 1911, investigators demonstrated that the ill- ness was caused by a virus. By the 1940s, the Characteristics virus had been cultured, and in 1954 it was Many bacteria can cause meningitis, but in isolated. Subsequent research resulted in an at- developed countries over 80 percent of cases tenuated strain of measles vaccine, which was in recent years have resulted from only three produced in 1958. In 1963, after field trials, the species: N. meningitidis, Hemophilus influen- attenuated (“live”) vaccine was licensed for use zae, and Streptococcus (Diplococcus ) pneumo- in the United States. An inactivated (“killed”) niae. Other common members of the human measles vaccine was also developed, but was bacterial flora such as Escherichia coli and vari- shown to be inferior and is no longer available. ous streptococci and staphylococci can also pro- With the 1974 establishment of the World duce meningitis under special circumstances, as Health Organization Expanded Programme on can members of genera Listeria, Pseudomonas, Immunization, measles vaccine has been in- and Proteus. Meningitis sometimes develops as troduced into the national immunization pro- a complication of tuberculosis. grams of most countries, and geographic oc- Aseptic meningitis is usually the result of vi- currence in endemic regions is related to ral infection. Among the many types of viruses the immunization coverage with measles vac- that can be involved are mumps, echovirus, cine. In countries with sustained, large-scale polio, coxsackievirus, herpes simplex, herpes immunization programs and reliable disease zoster, hepatitis, measles, rubella, and several surveillance, the impact of control efforts has mosquito-borne agents of encephalitis. Fungi, been documented through decreasing num- most commonly Cryptococcus, are other possi- bers of reported cases. Global measles eradi- ble agents. cation is considered technically possible, but Laboratory study is necessary to determine experts increasingly recognize that extremely the cause of any particular case of meningi- high immunization-coverage levels are neces- tis, so it is generally difficult to be certain of sary to achieve such a goal. the exact etiology of past meningitis cases or Robert J. Kim-Farley epidemics. However, despite the current rela- tive significance of Hemophilus and Streptococ- cus, Neisseria is the most important pathogen for meningococcal meningitis; it is the only type 92. Meningitis that commonly occurs in major epidemics and is the most likely to attack adults. Meningitis means inflammation of the me- N. meningitidis is closely related to the or- ninges, the membranes covering the brain ganism that causes gonorrhea. Humans are its and spinal cord. It usually results from bacterial only natural host. It is a common inhabitant of infection but can also be caused by other the mucosal membranes of the nose and throat, microbial agents and noninfectious conditions. where it normally causes no harm. Up to 50 per- Meningococcal meningitis, caused by a bac- cent of a population may be asymptomatic car- terium, Neisseria meningitidis, is the form oc- riers without any cases of meningitis develop- curring in major epidemics. Also called cere- ing, but such carriers are crucial to the spread brospinal meningitis (CSM), it has been known of the disease. The organism is transmitted via

214 92. Meningitis droplets sneezed or coughed from the nose and History throat. It is very susceptible to desiccation and Meningitis was not described definitively until sunlight. after 1800, so the antiquity of the disease is un- The majority of victims, especially in sporadic known, but it is unlikely that it is a “new” in- cases and small outbreaks, are children under fection in humans. Mention of “epidemic con- age 5. Among adults, military recruits crowded vulsion” in tenth century China and a descrip- into barracks have traditionally been prime tar- tion by T. Willis in England in 1684 could indi- gets. Throughout the nineteenth and twenti- cate earlier recognition. From the sixteenth cen- eth centuries, wartime mobilization was always tury onward, many possible references occur in accompanied by sharp increases in meningitis European literature. cases. In 1805, an epidemic of CSM occurred in Meningitis is highly seasonal. In temperate re- Geneva. Most victims were infants and children. gions, a large preponderance of cases develop Clinical accounts by Gaspard Vieusseux and au- in the winter and early spring. The reasons for topsy studies by A. Matthey identified the dis- this are unclear, but indoor crowding, cold tem- ease. In 1806, a cluster of cases developed in perature, and low humidity may all play a role. Massachusetts. As in Switzerland, the victims Epidemics in sub-Saharan Africa develop during were infants and children; most died despite the cool, dry season – when people travel more frantic application of an array of therapies. Case and sleep indoors to keep warm – and tend to descriptions and autopsies confirmed a diagno- end abruptly when the rains come. sis of CSM. An epidemic of apparent meningitis In most cases, bacteria are carried in the nose afflicted British troops in Sicily in 1808, and gar- and pharynx without any symptoms or perhaps risons in France were struck in 1814. In North a sore throat. Serious disease develops only if America, meningitis epidemics were reported the bacteria reach the bloodstream. This can in Canada in 1807; in Virginia, Kentucky, and produce fulminating blood infection, charac- Ohio in 1808; in New York and Pennsylvania in terized by sudden prostration, high fever, skin 1809; and among U.S. troops during the War of blotches, and collapse. Most cases are fatal un- 1812. They were described as “sinking typhus” less promptly treated, and death may ensue or “spotted fever” in New England from 1814 to in only hours, before the meninges become 1816. involved. Little more was heard about the apparently Meningitis, however, is the more common re- new disease until the years 1837–42, when sult, occurring when bacteria travel through the a series of outbreaks occurred in French gar- blood to infect the meninges. Fever, headache, risons and among nearby civilians. Epidemics stiffness, and vomiting are typical symptoms, in Algeria (1840–47) began among French and many victims show a rash from blockage of troops but killed many among the indige- small blood vessels. A thick, purulent exudate nous Moslem population as well. Meningitis covers the brain, and arthritis, cardiac damage, was also widespread in Italy in 1839–45 and and shock may develop. Coma, convulsions, was reported in Corfu, Ireland, and especially and delirium are frequent, and death rates for Denmark from 1845 to 1848. There was also a untreated cases range up to 90 percent. Even series of small epidemics in the United States in in epidemic conditions, however, only a small the 1840s, primarily in the South. minority of carriers develop clinical disease. It The first recorded major epidemic of CSM be- is unknown why most people remain healthy gan in Sweden in 1854, starting in late winter whereas others become desperately ill. Indi- and slowly spreading during the next 5 years. It vidual susceptibility, damage to mucous mem- died out in the summers and resumed a slow, branes, and concomitant infections may all play irregular progress during winters. The epidemic a role. declined in 1859, with scattered cases reported

215 92. Meningitis in the next several years and a small flare-up in the past. For example, China has experienced 1865–67. Government returns showed a total of three major epidemics of serogroup-A meningi- 4,158 meningitis deaths in 1854–60 and 419 in tis since 1949, with rates of 50–400 per 100,000. 1865–67. During the 1963-69 epidemic, there were more During the 1860s, small but deadly epidemics than 3 million cases and 166,000 deaths. occurred in Germany, the Netherlands, England, Africa has had two kinds of experience with France, Italy, Portugal, Austria, Hungary, Greece, the disease. In most of the continent, meningi- Turkey, Poland, and Russia. There were numer- tis is a sporadic disease, behaving much as it ous outbreaks in the United States during the does in the West, although often with higher same decade, with both sides suffering dur- incidence and fatality rates. However, one ter- ing the Civil War. Everywhere, troops and small rible epidemic occurred in 1913 in Kenya and children were the most common victims. Scat- Tanganyika, lingering in Tanganyika until 1919. tered cases and sporadic outbreaks continued Both territories, as well as neighboring Uganda, for the rest of the century, with flurries of ac- had dramatic surges during World War II. In tivity in the mid-1880s and at the end of the North Africa, Algeria and Egypt experienced epi- century. demics in the nineteenth century, and Morocco A new burst of meningitis occurred in the had over 6,000 cases in 1967. first decade of the twentieth century. The first The classic area for epidemic CSM, however, cases from Australia were recorded in 1900–01. has been the savanna zone south of the Sahara Portugal had more than 5,000 cases from 1901 from Sudan to Senegal. This “CSM belt” was to 1905; a series of North American epidemics swept by a series of epidemics during the twen- in 1904–47 involved much of the United States tieth century. Indeed, there the disease has be- and Canada, with 2,755 patients in New York haved differently, advancing on regular fronts alone in 1905. A severe epidemic in Silesia and killing tens of thousands each season. Only caused almost 10,000 cases from 1905 to 1908. the Swedish epidemic of the 1850s seems to For most of the twentieth century, menin- have displayed a similar broad geographic pat- gitis in the developed countries followed a tern. In both places, the disease advanced reg- pattern of small, local epidemics and scat- ularly from season to season, but cases were tered cases, mostly among children. The two scattered widely and unpredictably within the world wars caused major spurts as military au- afflicted zone. The epidemics hopped about, thorities crammed recruits into crowded bar- skipping some communities and striking hard racks. For example, there were 5,839 cases at others. Areas struck in one CSM season were and 2,279 deaths among U.S. soldiers during usually spared the next. World War I. In 1942 and 1943, however, al- The antiquity of meningitis in the savanna is though there were 13,922 military cases, thanks unknown, but evidence exists that it had oc- to new therapy there were only 559 deaths. curred in Sudan and Nigeria by the 1880s. Small Moreover, except for a spurt to about 14 cases outbreaks struck in Senegal in the 1890s and per 100,000 people in 1942, civilian case rates in Ghana in 1900. The first of the great West in the United States have remained under 4 per African epidemics began in Nigeria in 1905. It 100,000 since the late 1930s. Total meningococ- spread westward to Mali and Ghana in 1906, cal infections have rarely exceeded 3,000 a year, lingering there until 1908. British authorities but reported cases of aseptic meningitis have guessed the death toll in Ghana at some 34,000; risen steadily. case mortality was estimated at 80 percent. Total The situation in non-Western countries is deaths in the epidemic are unknown but were quite different. Incidence rates tend to be much clearly disastrous. higher, and there are still major epidemics The second CSM cycle began in Ghana in like those that afflicted Sweden and Silesia in 1919, spread to Upper Volta in 1920, and swept

216 92. Meningitis

Nigeria and Niger from 1921 to 1924. The death serologic differences existed among strains. toll in one Nigerian province was put at over Four serogroups were identified by the end of 45,000 in 1921 alone, and French officials as- World War I. Vaccine therapy remained of lim- sumed at least 15,000 deaths in Niger over the ited value but – in the absence of anything 4-year period. else – was frequently tried. In the 1930s, French The third cycle began in 1935, when Chad efforts to protect Africans against serogroup A was attacked by an epidemic that had raged by vaccination had inconclusive results, and the previous year in Sudan – the first and similar British trials in Sudan were unsuccessful. only time that an east-west spread pattern from The development of sulfa drugs in the 1930s Sudan was demonstrated. Infection moved revolutionized meningitis therapy. Clinical tri- westward into Chad, Nigeria, and Niger, with als showed the almost miraculous impact of sul- epidemics developing in 1937. CSM hit Upper fanilamide on meningococcal infections in 1937. Volta in 1938 and Mali and Ghana in 1939. Local This drug reduced case-fatality rates to 20 per- outbreaks continued through 1941. Even with cent and less and saved thousands of lives dur- sulfa drugs, tens of thousands died. CSM was ing the epidemics of World War II. Sulfa drugs again epidemic in the years 1943–47, with out- were successfully used for prophylaxis by the breaks reported from Chad to Senegal. U.S. Army beginning in 1943, and the technique Another cycle developed in 1949 from foci was widely adopted. in northern Ghana, northern Nigeria, and Up- The “wonder drugs” had an especially dra- per Volta, spreading eastward to Sudan by 1952. matic impact in the CSM belt of Africa, where By this time, meningitis had become well estab- they were introduced in 1938. Africans had lished, and geographic patterns were less dis- been well aware that prior European therapies tinct. At least 250,000 and perhaps a million were useless. Preventive measures seemed fu- or more people died of CSM in West Africa be- tile, arbitrary, and even harsh. Victims were tween 1905 and 1960. The disease remains a se- quarantined, and cordons thrown around en- rious public-health problem in the entire CSM tire districts. Such efforts disrupted trade and belt. other activities but did nothing to impede the The late identification of meningitis did not spread of the disease. Annoying procedures like delay study of its etiology. By 1860, researchers “nasopharyngeal disinfection” of travelers or de- widely assumed that a specific poison or agent struction of houses discouraged African coop- was involved. In 1887, Austrian pathologist An- eration with medical authorities. Sulfa drugs ton Weichselbaum described the meningococ- were, however, extremely effective. Africans re- cus. This organism was suspected of being sponded pragmatically and eagerly began to re- the meningitis pathogen, but its role was not port cases and seek treatment. proven until the early twentieth century. By In 1963, sulfa-resistant strains of N. menin- 1910, researchers recognized that the meningo- gitidis were detected, and their spread has coccus was responsible for epidemics and that halted sulfa prophylaxis. Penicillin therapy is other bacteria could cause sporadic cases. Lum- still effective but has no preventive value. Vac- bar puncture, introduced in 1891 by Heinrich cines against serogroups C and A were intro- Quincke, made cerebrospinal fluid available for duced in the early 1970s, and improved vaccines study and sometimes relieved the headaches have been developed since, although protection caused by CSM. The crucial epidemiological against serogroup B is still unavailable. Meningi- role of asymptomatic carriers was appreciated tis remains a public-health problem, especially by the turn of the twentieth century. in underdeveloped countries. Death occurs in After 1905, attempts were made to develop about 5 percent of all cases, even with prompt a therapeutic serum. Some early successes treatment. were reported, but by 1909 it was clear that K. David Patterson

217 93. Milk Sickness (Tremetol Poisoning)

93. Milk Sickness (Tremetol Poisoning) to be abandoned. Physicians in Kentucky and Tennessee described milk sickness as being so Milk sickness, usually called “milksick” by early widespread that the Kentucky legislature ap- nineteenth-century American pioneers, denotes pointed a committee in 1827 to investigate its what we now know to be poisoning by milk from cause. A few years later, the state medical so- cows that have eaten either the white snake- ciety of Indiana also attempted a similar inves- root or the rayless goldenrod plants. The white tigation. It is said that Evansville, Indiana, be- snakeroot (Eupatorium urticaefolium) is com- came a prominent city only because an early mon in the Midwest and upper South and also rival, Darlington, was abandoned as a result of known as “white sanicle,” “squaw weed,” “snake- milk sickness. weed,” “pool wort,” and “deer wort.” The rayless In 1811, an anonymous author wrote that goldenrod (Haplopappus heterophyllus) is found milk sickness was a true poisoning because it in southwestern states such as Arizona and involved no fever. He also believed that it was New Mexico. caused by poisonous milk that had a peculiar Milk sickness has been called variously “al- taste and smell. The source of the poison, he kali poisoning,” “puking disease,” “sick stom- wrote, was vegetation eaten by the cows. He ach,” the “slows” or “sloes,” “stiff joints,” “swamp further advised that finding the offending plant sickness,” the “tires,” and (in animals) the trem- would remove a major stumbling block to emi- bles. It is now known as tremetol poisoning af- gration westward. ter a toxic ingredient of white snakeroot and In subsequent years, theories as to the cause rayless goldenrod. Tremetol is an unsaturated of milk sickness were numerous. One suggested alcohol that in consistency and odor resembles that the cause was arsenic; another claimed it turpentine. was a soil organism, whereas another attributed the disease to a mysterious exhalation from soil. Characteristics Still others incriminated various poisonous min- Milk sickness was unknown in Europe or erals and springs. However, no specific toxic any other region of the world except North plant was identified during the nineteenth cen- America. It appeared in North Carolina as early tury. In the 1880s, the medical revolution fol- as the American Revolution near a mountain lowing the discoveries of Louis Pasteur and ridge named Milk Sick. Its highest incidence was Robert Koch led to the expectation that many in dry years when cows wandered from their obscure diseases such as milk sickness would brown pastures into the woods in search of for- prove to be of bacterial etiology. This expecta- age. As more forests were cleared so that cattle tion was apparently realized when researchers had more adequate pasture, and as fences were reported in 1909 that Bacillus lactimorbi was built, the incidence of milk sickness decreased the cause of milk sickness in humans and trem- rapidly. bles in cattle. Needless to say, they were wrong. The disease wrought havoc in the Midwest, Beginning in 1905, Edwin Moseley of what is especially in Illinois, Indiana, and Ohio, and in now Bowling Green State University in Ohio be- the upper southern states of Kentucky, North gan a study of the white snakeroot that lasted Carolina, Tennessee, and Virginia. Milk sick- more than three decades. He established the ness was, in some years and some localities, toxic dose for animals at 6–10 percent body the most important obstacle to settlement by weight. He also found that the stems were less the pioneers. Beginning about 1815, a flood of poisonous than the leaves and that neither pioneers moved west. As they penetrated the freezing nor drying destroyed the poison. His forest wilderness of the Midwest, epidemics of book, published in 1941, is the definitive work the disease all too frequently caused villages on milk sickness.

218 93. Milk Sickness (Tremetol Poisoning)

Finally, in 1928 James Couch reported the once tartly remarked that General McClellan isolation of three poisonous substances from “seemed to have the slows.” the white snakeroot: a volatile oil and a resin acid that did not produce trembles, and an oily History liquid that did. The last had the characteris- Milk sickness has vanished from the list of ma- tics of a secondary alcohol and was identified jor concerns of modern Americans. Although as C16H22O3.Drawing on the Latin (tremere )for endemic in the Midwest and upper South, it “tremble,” Couch named it “tremetol.” had never been seen elsewhere in the United Heating reduces somewhat the toxicity of poi- States, Europe, or any other continent. The set- soned milk, and oxidation destroys the toxic tlers along the Atlantic seaboard knew nothing properties of tremetol. Because only a small of it, and if the Indians or their cattle suffered number of cows are likely to be secreting toxic from the disease, they did not inform the early milk at one time, human illness is seen chiefly settlers. Not until the pioneers began to push when milk from a single animal or herd is con- westward beyond the Alleghenies did the dis- sumed. It is now thought that dilution (from col- ease attract attention. lection and distribution at a large milk source) The first sporadic cases of milk sickness were rather than pasteurization is the reason that recognized in North Carolina in the years pre- milk sickness has failed to develop in urban ar- ceding the Revolution. It was generally known eas and has become extremely rare. Moreover, that on the western side of the Allegheny Moun- in rural areas, farmers are now well aware that tains from Georgia to the Great Lakes a disorder to avoid trembles or milk sickness, they need called trembles prevailed among cattle, and that only abandon woodland grazing, for the white wherever it appeared, the settlers were likely to snakeroot is a woodland plant and almost never get a disease, which from its most prominent found in bright and open pastures. symptom received at first the name “sick stom- Animal trembles (occurring chiefly in cat- ach” and from a theory concerning its cause that tle) causes anorexia, weakness, falling, stiff- of “milk sickness.” ness, and trembling. In humans, symptoms of In 1811, the Medical Repository of New York milk sickness include anorexia, listlessness, se- contained an anonymous report entitled “Dis- vere constipation, and – most important of all, ease in Ohio, Ascribed to Some Deleterious and underlying most other symptoms – pro- Quality in the Milk of Cows.” This appears to be found acidosis. The latter, if untreated, leads the earliest surviving reference to a disease that to coma and death. Because of the acidosis, became a frequent cause of death and a major the breath smells of acetone, described in the source of misery and mystification in the rural past as overpowering. The weakness is thought South and Midwest through a large part of the to arise chiefly from hypoglycemia, and death nineteenth century. from ketoacidosis and marked fatty degener- In 1834, Anna Pierce Hobbs, a pioneer doc- ation of liver, kidneys, and muscles. The dis- tor in Illinois, learned from a Shawnee medicine ease can be chronic or latent and is likely woman that white snakeroot caused trembles to recur if the patient is subjected to fatigue, and milk sickness. Hobbs fed a calf several starvation, intercurrent infection, or vigorous bunches of the root. The calf developed typical exercise. trembles, enforcing her conviction that she had The lethargy that characterizes a milk- found the cause of milk sickness. John Rowe, a sickness convalescent helped give it the name farmer of Fayette County, Ohio, wrote in 1838 of slows (or sloes). Abraham Lincoln knew it that he had discovered through similar exper- by that name, and, annoyed by the desultory imentation that trembles was caused by inges- progress of the army early in the Civil War, he tion of white snakeroot.

219 94. Multiple Sclerosis

During the second half of the nineteenth cen- the United States averaging $15,000 per annum tury, milk sickness occurred sporadically, which per affected family. made sequential observations difficult, and its cause was lost in the widely held medical belief History in miasmas and exhalations from the ground. Multiple sclerosis is a remarkable disease. It was Moreover, because milk sickness was limited to first clearly described more than 130 years ago the Midwest, upper South, and Southwest, in- in a way that we would recognize as a modern, fluential eastern physicians tended to ignore it pathologically based account that discusses the or even discount its existence as a disease sui clinical features of the illness and their possi- generis. ble pathophysiology. But only since the 1970s Nonetheless, the solution was eventually has real progress been made in understanding found when attention returned to the poi- its nature, course, and pathogenesis. It was dis- sonous plant theory. Although many plants cussed in pathological treatises of the 1830s and were suspected, such as poison ivy, water hem- 1840s, and more knowledge was added in 1873. lock, Virginia creeper, coralberry, spurge, mush- The “French school” did most to delineate the rooms, and march marigold, scrutiny finally disease. Good descriptions appeared in neurol- centered once again on white snakeroot. Yet ogy textbooks before the end of the nineteenth not until 1928 was white snakeroot established century, and an exhaustive 1916account of the with certainty as the cause of milk sickness – pathology of MS remains a standard reference. over a century after the anonymous 1811 arti- The geography of multiple sclerosis is inter- cle appeared. In 1956, an article in the Journal esting because it is strange and because under- of the American Medical Association by William standing it may provide a crucial clue to the Snively and Louanna Furbee asked the ques- nature of the disease. Geographic peculiarities tion: “How could a disease, perhaps the leading were first noted around a century ago when By- cause of death and disability in the Midwest and ron Bramwell argued that the higher incidence Upper South for over two centuries, go unrec- of multiple sclerosis in his practice in Edinburgh ognized by the medical profession at large until than that of neurologists in New York reflected 1928?” a real difference in frequency between the two Thomas E. Cone, Jr. cities. Fifty years ago, the notion of the relevance of genetic background as well as latitude was pointed out by Geoffrey Dean on the basis of the 94. Multiple Sclerosis lower prevalence of multiple sclerosis among Boers than among British descendants in South Multiple sclerosis (MS) is a disease of the cen- Africa; in both groups, the prevalence of the dis- tral nervous system characterized by recur- ease in Africa was the same as in their countries ring episodes of neurological disturbance. The of origin. The idea that genetic background was course of the disease is quite variable, at one important also received support from the dis- extreme lasting 50 years without significant dis- covery of the rarity of multiple sclerosis among ability and at the other terminating fatally in a the Japanese. In recent decades, strenuous ef- matter of months. Overall, about one-quarter of forts have been made to determine the conse- patients remain able to work up to 15 years af- quences of migration at different ages from ar- ter the first recognized manifestation, and mean eas of high to low prevalence, and vice versa. duration of life is approximately 25 years from These studies support the general idea of an in- that time. Nevertheless, because MS commonly teraction between latitude and genetic factors affects young adults, producing disability in the determining the geographic distribution of the prime of life, the economic burden is heavy, in disease.

220 94. Multiple Sclerosis

Characteristics the frequency in siblings. The difference in con- The characteristic lesion of multiple sclerosis cordance rates between identical and noniden- is the plaque of demyelination – patches of tical twins strongly implicates a genetic factor; varying size in which the myelin sheathing of however, the rather low concordance of identi- nerve fibers is destroyed, leaving the axons rel- cal twins suggests that an environmental factor atively intact. Small plaques are oriented around is also involved. small veins (venules), though this orientation is Among Caucasoids, the prevalence of MS often obscured in large lesions. Venules in ar- generally increases with latitude. MS is more eas of active demyelination are surrounded by common in the northern United States and cells derived from the immune system. Such Canada than in the southern United States, and cells are also present in the substance of the in southern New Zealand and Australia than brain – in the lesions, especially at the edges, in the north. The influence of migration on where they may help limit the spread of dam- risk has been studied in several populations. age. The plaques are distributed asymmetrically Migration from high-prevalence (e.g., northern throughout the brain and spinal cord, but cer- Europe and the northern United States) to low- tain sites of predilection determine the char- prevalence areas (e.g., Israel, South Africa, or the acteristic pattern of the disease. The impor- southern United States) before puberty appears tant functional consequence of demyelination to decrease risk of developing MS, whereas such is block of electrical conduction in the nerve migration after puberty does not. These and fibers, which causes many of the symptoms. related studies provide further – albeit rather In at least 80 percent of patients, the disease weak – evidence for the operation of an envi- follows a relapsing and remitting course, often ronmental factor in MS. in the later stages entering a steadily progres- On the face of it, stronger evidence comes sive phase. Fully 10–20 percent experience a from apparent clusters of cases in the Faroe steadily progressive course from onset. The typ- Islands. No cases were identified in the Faroes ical episode of neurological disturbance devel- before World War II. But between 1943 and ops in up to 2 weeks, persists for a few weeks, 1973, 32 cases occurred, with no new cases then resolves over a month or two. Common since. Some investigators have suggested that manifestations include reversible episodes of vi- the pattern of presentation suggests a point- sual loss (optic neuritis), sensory disturbance or source epidemic. Noting that patients’ resi- weakness in trunk or limbs, vertigo, and blad- dences were close to the location of 1940s army der disturbance. Obvious disturbance of intel- camps, analysts further proposed that an infec- lectual function is uncommon – except in se- tion was introduced by British troops occupy- vere cases – although subtle defects have been ing the islands during that period. Other re- demonstrated early in the course of the disease. searchers have challenged these conclusions. Multiple sclerosis principally affects individu- Nonetheless, the overall clustering of cases is als of northern European Caucasoid origin liv- striking and probably a phenomenon of biolog- ing in temperate zones, though it does occur ical significance, indicating exposure to a newly infrequently in the tropics and in other racial introduced environmental agent in the early groups. Females are affected about twice as 1940s. Other examples of clustering have been commonly as men. The average age of onset is reported but are less convincing. 30 years, and it rarely starts over the age of 60 MS is much less frequent in non-Caucasoid or before puberty. In Caucasoid populations, ap- populations. No proven case has yet been de- proximately 10 percent of patients have an af- scribed in African blacks, and prevalence is fected relative. The concordance rate in twins is lower in American blacks than in whites in about 30 percent for identical twins and 2 per- the same areas. The disease is similarly rare cent for nonidentical twins, the latter similar to among American Indians, New Zealand Maoris,

221 95. Mumps

Hungarian gypsies, and Orientals on the U.S. epidemiology indicates that an environmental west coast, but not in the larger populations trigger, probably infective, is required in the ge- they live among. MS is also rare among the netically susceptible individual. The most likely Japanese, Chinese, and (Asian) Indians in their infective agent is a virus, though interest in homelands. It is unreported in Eskimos. Real dif- spirochetes has revived as well. ferences in the frequency of MS in different eth- In conclusion, knowledge of the nature and nic groups again suggest the operation of a ge- cause of MS seems to be within sight. When we netic factor in determining susceptibility. understand the reasons for the peculiar distri- The most intensively studied genetic associa- bution of the disease, we are also likely to un- tions of multiple sclerosis are those within the derstand its etiology and pathogenesis. human leukocyte antigen (HLA) region of the W. I. McDonald sixth chromosome. The most frequent associa- tion in Caucasoid populations is with HLA-DR2, though others have been reported. There are fewer data for non-Caucasoid populations, al- 95. Mumps though it should be noted that MS is rare in two populations in which DR2 is common: the Mumps (also infectious parotitis or epidemic Hungarian gypsies (of whom 56percent of con- parotitis) is a common viral infectious disease, trols are DR2 positive) and the Maoris – raising principally of children, with worldwide distri- the possibility of an overriding genetic protec- bution. It is frequently characterized by fever tive effect. The frequency of association with the and painful enlargement of one or more sali- HLA system suggests that the observations are vary glands. Inapparent infection is common, significant, yet no identified factor alone seems occurring in about one-third of cases. Some- to confer susceptibility to the disease. The sim- times, postpubertal males with mumps may de- plest explanation is that DR2 acts as a marker for velop painful swelling of the testicles, usually another gene (or genes) conferring susceptibil- only on one side, with sterility an extremely rare ity, and that other genetic factors are involved as complication. Mumps is a vaccine-preventable well. What is common to all the genetic associa- disease, but the vaccine is not yet widely used tions so far identified is that they are concerned on a global basis. in one way or another with control of the im- mune response. Characteristics Much evidence suggests an immunologic ba- Mumps is caused by the mumps virus, of the sis for MS: abnormal synthesis of antibodies, genus Paramyxovirus. Mumps virus has an ir- both inside and outside the brain; changes regular spherical shape and contains a single- in the number and activity of peripheral- stranded RNA genome. blood lymphocyte subsets; and the presence Mumps is a contagious disease, only slightly of immune-competent cells around the venules less contagious than rubella and measles, in the lesions and in the brain itself. The oc- transmitted from infected persons to suscepti- currence of such changes in the retina (where ble individuals by droplet spread and by direct there is no myelin) is evidence that the vascular saliva contact. Mumps virus can also be trans- events are not secondary to myelin breakdown, mitted across the placenta to the fetus. There indicating that vascular change is a critical early is no natural reservoir for mumps other than event in development of the new lesion. humans, which means that a continuous chain These processes provide a plausible though of susceptible contacts is necessary to sustain incomplete explanation for the development of transmission. Although the duration of commu- the lesions in established MS. But what of its ini- nicability may be as much as 15 days, the period tiation? Good evidence from family studies and of greatest infectivity is about 48 hours before

222 95. Mumps salivary-gland involvement. There is no carrier A single dose of live attenuated mumps virus state. Mumps incubates about 18 days with a vaccine confers long-term, probably lifelong, range of 2–3 weeks. immunity in more than 90 percent of suscep- In populated areas with no or low vaccina- tible individuals. tion coverage, mumps is primarily an endemic The prodromal phase of mumps disease may disease of children, with epidemics occurring in be absent or include symptoms of low-grade closely associated groups such as schools. Its fever, loss of appetite, malaise, and headache. peak incidence is found in the 6–10 age group, Salivary-gland swelling often follows the pro- and mumps is rare before 2 years of age. Out- dromal period within a day, although some- breaks may occur at intervals ranging from 2 to times not for a week or more. The salivary-gland 7 years. Cases concentrate in the cooler seasons swelling progresses to a maximum in 1–3 days. in temperate climates, but no apparent season- The gland is painful and tender to the touch. ality prevails in tropical areas. In remote isolated Typically, both parotid salivary glands are af- populations, mumps is not endemic, and dis- fected, usually with one enlarging a few days ease depends upon introduction from outside, after the other; hence the name “parotitis.” One- at which time epidemics may occur, affecting all sided parotid-gland involvement occurs in ap- persons born since the previous epidemic. No proximately one-fourth of patients who have evidence exists for a sex or racial difference in such swelling. The fever lasts for a variable pe- mumps incidence, although clinically apparent riod (1–6days), and parotid gland enlargement mumps may be more common in males than in for 6–10 days. females. A common manifestation of mumps in 20– Mumps is not a reportable disease in most 30 percent of postpubertal males is painful tes- countries and is underreported even where it ticular swelling (orchitis), usually one-sided. is notifiable. In populated areas where mumps Sterility is an extremely rare outcome of testicu- is both endemic and epidemic, more than lar involvement on both sides, occurring in ap- 80 percent of the adult population evidences proximately 2 percent of cases. The next most prior infection. In remote or island populations common manifestation of mumps is central ner- where mumps is not endemic, a significant pro- vous system involvement in the form of menin- portion of the population can be susceptible, gitis – usually benign – occurring in about which may lead to large outbreaks when the 10 percent of infections. Uncommon manifesta- virus is introduced from outside. In some coun- tions of mumps include involvement and some- tries, such as the United States, where mumps times painful swelling of other glands such as is a reportable disease and mumps vaccine has ovaries, breasts, thyroid, and pancreas. Mumps- been extensively used (often in combination associated complications are rare but include with measles and rubella vaccine), impressive encephalitis, neuritis, arthritis, nephritis, hep- declines in reported cases have occurred. atitis, pericarditis, and hematologic compli- Infants usually have a passive immunity to cations. Deafness, usually one-sided and of- mumps because of maternal antibodies ac- ten permanent, is reported to occur once per quired transplacentally from immune mothers. 20,000 cases. Although increased fetal mortal- This passive immunity protects an infant from ity has been reported in women who contracted infection for about 6months, depending on the mumps during the first trimester, there is no ev- amount of maternal antibody acquired. Mumps idence that mumps in pregnancy increases the infection in both clinically apparent and in- risk of fetal malformations. apparent cases induces lifelong immunity. Be- cause a significant percentage of infections History are inapparent, persons may develop immunity Hippocrates (fifth century B.C.) is believed to without realizing they have been infected. have first recognized mumps as a distinct

223 96. Muscular Dystrophy clinical entity. He described an outbreak on used in the former U.S.S.R. since the early 1960s. the island of Thasus. Other ancient Greek and In 1966, researchers reported development of a Roman medical writers as well as medieval live attenuated mumps virus vaccine, and suc- practitioners at various times recorded cases cessful trials led to its licensure in 1967 in the of mumps-like illnesses, but the disease was United States. relatively little studied. In the sixteenth cen- Robert J. Kim-Farley tury, Guillaume de Baillou recorded outbreaks of mumps in Paris. In 1755, Richard Russell de- scribed mumps and opined that the disease was communicable. 96. Muscular Dystrophy Mumps is called Ziegenpeter or Bauerwetzel in German and oreillons in French. The origin of The muscular dystrophies are genetically de- the term “mumps” is unclear although it may termined, almost exclusively pediatric diseases. come from the English noun mump, meaning Generally, the earlier the age at which symp- a “lump,” or the English verb mump, meaning toms begin, the poorer the prognosis. Because “to be sulky,” or even perhaps from the pattern of a considerable overlap of manifestations and of mumbling speech in individuals with signifi- rates of progression and, until recently, the lack cant salivary gland swelling. of any biochemical test, their classification is In 1790, Robert Hamilton presented a full de- still unsettled. As a group, the principal differ- scription of mumps, emphasizing that orchitis ential diagnosis of muscular dystrophies is from was a manifestation of mumps and suggest- muscular atrophies. In the former, the primary ing that some mumps patients had symptoms defect is in voluntary muscle fibers; in the latter, of central nervous system involvement. Study it is in the innervation of muscles. of epidemics helped establish the communi- The most common of the dystrophies and cability and wide distribution of the disease. the first to be described was that delineated Some 150 epidemics occurred between 1714 by French neurologist Guillaume Duchenne in and 1859 in temperate, cold, subtropical, and 1868. Duchenne muscular dystrophy (DMD) is equatorial regions in both hemispheres. a sex-linked recessive disorder. Consequently, it Data have demonstrated the occurrence of affects only males and is inherited through fe- epidemic mumps in the closely associated male carriers of the gene. Affected boys have populations of prisons, orphanages, boarding abnormally elevated concentrations of muscle- schools, armies, and ships. Indeed, mumps was cell enzymes such as creatine phosphokinase the most important disease in terms of days lost in their blood; this abnormality is also found from active duty in the American Expeditionary in about three-fourths of female carriers. DMD Force in France during World War I, and in 1940 appears to have a rather uniform incidence the disease was one of the most disabling acute worldwide of 15–33 cases per 100,000. A family infections among U.S. armed forces recruits, ex- history of DMD is identified in only about one- ceeded only by venereal diseases. third of cases. Others are attributed to either a Despite earlier animal experiments suggest- previously unexpressed carrier state or a new ing that salivary-gland fluid was infective, the mutation. viral etiology of mumps was not conclusively Cases can be identified during the first proved until 1934. In 1945, mumps virus was week of life by excessive concentration of cre- successfully cultivated in chick embryos. In atine phosphokinase in the blood, although 1948, the significant percentage of clinically in- the infant appears normal. The boy learns to apparent infections was confirmed. In 1951, an walk somewhat late, falls easily, and has diffi- experimental killed-virus vaccine was used in culty getting up again. The gait gradually be- humans. A live mumps virus vaccine has been comes broad-based and waddling. Nevertheless,

224 97. Myasthenia Gravis diagnosis usually is not made before age 5. downward to the pelvic girdle and legs but may Without intervention, the parents’ risk of pro- become arrested at any time. Reproduction is ducing additional dystrophic children remains not impaired. Death from sudden heart failure high. occurs in some cases. So far there is no effective The child’s physique may be perplexing in treatment for the underlying abnormality of any that, despite his weakness, his muscles may ap- of the muscular dystrophies. pear unusually well developed, a pseudohyper- Thomas G. Benedek trophy resulting from infiltration and replace- ment of muscle fibers by fat and connective tissue. As the disease progresses, muscle fibers increasingly appear abnormal microscopically, 97. Myasthenia Gravis and others disappear. The upper extremities are affected later but in the same fashion as the Myasthenia gravis is a disorder of skeletal mus- pelvic girdle and lower limbs. Smooth muscle cle characterized by weakness and easy fatiga- (e.g., intestinal tract, bladder) is not affected. bility resulting from autoimmune destruction of Subnormal stress on the developing skeleton the acetylcholine receptor in the postsynaptic from the weak musculature delays ossification membrane of the neuromuscular junction. of long bones, and the mineral content of bones is deficient. Once weakness has resulted in con- Characteristics finement to wheelchair or bed, contractures of The disease has a worldwide distribution and extremity joints and kyphoscoliosis (deformity is the primary cause of death in 1.5 cases per of the vertebral column) supervene. A moder- million annually in the United States. It at- ate degree of mental retardation frequently is tacks whites and nonwhites equally and seems an associated problem. Death generally results to be uniformly distributed around the globe. from respiratory failure before age 20. There appears to be a twin-peaked incidence, The defective gene of DMD was identified in with females peaking between ages 15 and 24, 1986. Researchers discovered that this genetic and males peaking between 40 and 60. The abnormality causes a deficiency of a protein – death rate is slightly higher for women than for dystrophin – in the membrane of muscle fibers. men. Morbidity data in surveys of the United Although this substance constitutes only 0.002 States, Canada, England, Norway, and Iceland percent of total muscle protein, its deficiency is over a 10-year period using retrospective anal- detectable and can serve as a specific diagnostic ysis show that the incidence of myasthenia test. is probably 0.2–0.5 per 100,000, with preva- At the other extreme of severity from DMD is lence being 3–6per 100,000. In other words, facio-scapulo-humeral dystrophy (FSHD), de- the prevalence is approximately 10 times the scribed by French neurologists Louis Landouzy incidence. and Joseph Dejerine´ in 1884. Onset usually The overwhelming evidence is that myas- occurs during adolescence but can be much thenia gravis results from an immune sys- later. Incidence has been estimated as from 5 to tem dysfunction that produces an autodirected 50 percent of the incidence of DMD. Inheri- antibody against the acetylcholine receptor in tance is autosomal dominant, and FSHD oc- the postsynaptic membrane of the neuromus- curs equally in both sexes. As the name indi- cular junction. The evidence is clinical, labo- cates, muscles of the face and shoulder girdle ratory, serologic, and therapeutic. The clinical are affected first. Sometimes only facial mus- evidence that myasthenia is an autoimmune cles are involved. An affected person may be disease is based on the association of myasthe- unable to close the eyelids completely or to nia with vaccination, insect sting, infection, and purse the lips. Muscular involvement progresses trauma and its association with autoimmune

225 97. Myasthenia Gravis diseases such as hypothyroidism, systemic lu- seemingly unrelated to the neuromuscular pus, and polymyositis. Laboratory abnormali- system – for instance, burning eyes from expo- ties pointing to an immune-system dysfunction sure to keratitis, from incomplete eye closure include serologic abnormalities, increased inci- during sleep, or a sore throat on awakening from dence of a specific human leukocyte antigen mouth breathing during sleep. The disease may (HLA-B8) in certain types of disease, histologic affect people of any age and either sex and varies abnormalities of thymus and skeletal muscle, in severity from mild nonprogressive disease in- and abnormal responsiveness of lymphocytes volving the eyes only (ocular form) to severe to mitogens. Antinuclear antibodies are posi- cases that may be rapidly fatal such as acute tive in uncomplicated myasthenia in about 18 myasthenia gravis afflicting older men. percent of cases and in 54 percent of myas- No two myasthenic patients look alike or have thenic patients who have thymoma, a tumor the same signs and symptoms. The classical ap- derived from elements of the thymus. Antistri- pearance is unmistakable and is usually associ- ated muscle antibodies are present in about 11 ated with bilateral ptosis, weakness of the face, percent of patients with uncomplicated myas- and difficulty in smiling, chewing, and talking. thenia and in all patients who have myasthe- The consistent pathology found in every patient nia associated with thymoma. Perhaps the most is autoimmune destruction of the postsynap- important serologic test in myasthenia is the tic receptor, simplification of the postsynaptic IgG antibody directed against the acetylcholine membrane, widening of the synaptic gap, and receptor. This antibody is probably positive in reduction in the acetylcholine receptor num- 70–95 percent of clinically diagnosed myas- bers and efficiency. Thymic pathology is also thenic patients and is the cause of the weakness present; approximately 80 percent of patients and easy fatigability in the disease. have germinal centers and enlarged thymus, The single most important feature of myas- and about 10 percent have a thymoma. thenia gravis is weakness of skeletal muscle worsened by exercise and relieved by rest. History Weakness with easy fatigability is the only con- Although myasthenia gravis was not described stant in this disease; all other features are vari- as a clinical entity until the late nineteenth cen- able. For instance, the weakness is usually worse tury, a mention by seventeenth century English in the afternoon and evening, although some clinician Thomas Willis indicates that he knew patients are weaker in the morning when they the disease and recognized its chief symptom. first awaken. Usually the muscles supplied by His description of strangely weakened patients the cranial nerves are the first and most severely occurs in his 1672 work on the physiology and affected, with resultant diplopia, ophthalmo- pathology of disease. Willis noted that such pa- plegia, dysphagia, dysphonia, dyspnea, and tients developed general albeit partial paralysis dysmimia. The disease may involve proximal and that they were unable to move their mem- lower- and upper-extremity muscles. In rare bers strongly or bear any weight. This seems to instances, however, proximal muscles weaken be a description of myasthenia gravis, although, first. Involvement of individual muscles may of course, we will never really know. be symmetrical but is often asymmetrical with Nearly 200 years passed before myasthenia a dominant leg and arm usually weaker than gravis was again mentioned in medical litera- a nondominant counterpart. Myasthenia gravis ture. The next recorded observation appears to can also present as weakness of a single mus- have been made by English physician Samuel cle (for example, the external rectus or supe- Wilks in 1877. He discussed a woman who rior oblique in one eye) or as a single complaint could scarcely walk and had defective extraoc- (for instance, jaw ptosis from inability to close ular movement. Her speech was slow and de- the mouth). It can also present as a symptom liberate, and she fatigued easily. Subsequently,

226 98. Nematode Infection she developed trouble swallowing, was unable reaction of muscles in myasthenia gravis to elec- to cough, and died of respiratory paralysis. This trical stimulation and to name the disease. He incomplete discussion is the first fatal case of also suggested physostigmine as drug treatment myasthenia gravis ever described. Wilks’s report but does not seem to have pursued this impor- was of some importance because the patient tant point; 40 years later, the therapeutic value was autopsied and no nervous system abnor- of physostigmine was demonstrated. mality found, indicating that the trouble was Modern studies of the pathological physiol- caused by some functional defect. ogy of myasthenia gravis started in the 1940s The first really complete report of myasthe- with a series of illustrious researchers, who rec- nia gravis was by Wilhelm Erb in 1879. His first ognized the characteristic response of evoked patient’s illness developed over 4 months, and muscle action potential to repetitive stimula- the first principal symptoms, which were clearly tion of nerve, thereby localizing the defect of described, included ptosis, neck weakness, and myasthenia gravis to the neuromuscular junc- dysphagia. Some atrophy was noticed in the tion. Evidence accumulated of an immunologic neck muscles. The patient, who seemed to re- disorder in myasthenia. This was first suggested spond to induced current (he was probably one in 1959 by recognition of the histological par- of the first to be treated by Erb with electricity), allel between the thymus in myasthenia and went into remission, and it was natural for Erb the thyroid gland in thyroiditis. The following to attribute the improvement to his electrical year, attention was drawn to the increased fre- treatment. Erb’s second case had symptoms of quency, in myasthenia gravis, of other diseases double vision, ptosis, dysphagia, and weakness. regarded as autoimmune, especially rheuma- She died suddenly at night, and no autopsy was toid arthritis. But the major advance occurred done. She had clear-cut exacerbations and re- in 1973, when rabbits were injected with acetyl- missions. The third patient reported by Erb had choline receptors. The process induced experi- difficulty holding his head up, and showed bi- mental autoimmune myasthenia gravis in the lateral ptosis and facial weakness. animals, which led to experiments indicating Subsequently, a score more cases were re- the nature of the human disease. We now know ported by 1893, when Samuel Goldflam pro- that the disease is caused by a circulating anti- vided a detailed study of myasthenia gravis, body directed against the acetylcholine receptor mentioning all the currently accepted signs of and that treatments directed against the abnor- the disease: (1) The disease occurs in early life; mal antibody are effective in modifying myas- (2) both sexes are equally affected; (3) it at- thenia gravis. tacks the motor system; (4) chewing, swallow- Bernard M. Patten ing, and eye movements are most affected at first, followed by involvement of trunk extrem- ity; (5) trunk involvement is usually but not al- ways symmetrical; (6) most patients are worse 98. Nematode Infection in the afternoon and evening and are improved by rest. The thousands of species in the phylum Ne- Goldflam also mentioned that daily exacerba- mathelminthes, the nematodes or “round- tions and remissions may occur, and that death worms,” include both free-living forms and im- may suddenly occur from respiratory impair- portant parasites of plants and animals. Many ment. His article in many ways is the most im- species of nematodes parasitize humans, and portant ever written in the history of myasthe- several of them are major public-health prob- nia gravis. lems in poor countries, especially in the trop- The next major advance occurred in an 1894 ics. Some species reside as adults in the intes- paper by F. Galle. He was first to analyze the tine; others are found in the blood and tissues.

227 99. Onchocerciasis

See: Ascariasis, Dracunculiasis, Enterobia- have been observed. Conversely, dermatologic sis, Filariasis, Onchocerciasis, Strongyloidia- symptoms predominate in Arabia, and ocular in- sis, Trichinosis, and Trichuriasis. volvement is rare. K. David Patterson O. volvulus, one of several filarial worms that are important human parasites, lives in the cu- taneous and subcutaneous tissues. Humans are the only definitive host; there is no animal reser- 99. Onchocerciasis voir. Numbers of adult worms, the females of which may reach a length of 50 centimeters, Onchocerciasis is caused by a filarial nema- live in large coiled masses, which usually be- tode, the roundworm Onchocerca volvulus. Hu- come surrounded by fibrotic tissue generated mans are infected by larval microfilariae trans- by the host. In these nodules, which may reach mitted by blood-feeding female flies of the the size of a walnut and are often easily visible genus Simulium. Symptoms include skin dam- on head, trunk, hips, or legs, the adults live and age, extreme itching, and ocular lesions that can breed for as long as 16years. Thousands of lar- lead to permanent blindness. Synonyms include vae, the microfilariae, emerge from the nodules “river blindness” in West Africa, sowda in Yemen, and migrate in the tissues of the skin. and enfermedad de Robles in Latin America. Host immune reactions to dead or dying mi- crofilariae cause various forms of dermatologic Characteristics destruction, including loss of elasticity, depig- Onchocerciasis is widely distributed in sub- mentation, and thickening of the skin. These Saharan Africa, especially in the savanna grass- changes are complicated by the host’s reaction lands from Senegal to Sudan. Its range extends to the extreme pruritis caused by allergic reac- southward into Kenya, Zaire, and Malawi. The tions to worm proteins; the victim may scratch region encompassing the headwaters of the incessantly in a vain attempt to relieve the tor- Volta River system in northern Ghana, north- menting itch. This condition is sometimes called eastern Ivory Coast, southern Burkina Faso (Up- craw-craw in West Africa. Wandering microfi- per Volta), and adjacent territories has been lariae can also cause damage to the lymphatic a major center for the disease. Onchocerciasis system. Microfilariae that reach the eye cause was almost certainly indigenous to Africa, but it the most damage. Larvae dying in various ocu- has been transmitted to the Arabian Peninsula lar tissues cause cumulative lesions that, over a (Saudi Arabia and Yemen) and to the Caribbean period of one to several years, can lead to pro- basin, where scattered foci exist in Mexico, gressive loss of sight and total blindness. Dis- Guatemala, Colombia, Venezuela, Ecuador, and tinct geographic strains appear to exist, which Brazil. helps explain different pathological pictures in The disease has a patchy distribution within parts of the parasite’s range. its range; infection rates in particular villages Diagnosis is by detection of nodules, by may range from zero to virtually 100 percent. demonstration of microfilariae in skin snips, In the Volta Basin alone, the World Health Or- and, in recent years, by immunologic tests. ganization estimated in the 1970s that 1 million Therapy includes surgical removal of nodules, of 10 million inhabitants were infected, with which has been widely practiced in Latin Amer- about 70,000 classified as “economically blind.” ica to combat eye damage, and various drugs to In northern Ghana, surveys in the early 1950s kill microfilariae. A number of such drugs, how- determined that about 30,000 people, roughly ever, may cause serious side effects in heavily 3 percent of the population, were totally blind infected people. because of onchocerciasis. In some West African The vectors and intermediate hosts of the villages, adult blindness rates of 10–30 percent pathogen are flies of the genus Simulium,

228 99. Onchocerciasis especially Simulium damnosum. These annoy- It is possible that a cycle of colonization and ing and appropriately named insects, sometimes retreat, with farmers caught between malnu- called “buffalo gnats,” are close relatives of the trition and land shortages on one hand and “black flies” of the northern United States and the perils of onchocerciasis on the other, has southern Canada. The females bite people, cat- been going on for centuries in parts of the tle, goats, wild animals, and birds to obtain Volta basin. blood meals. Flies feeding on infected humans may ingest microfilariae. These undergo about a History 1-week developmental process before migrating Onchocerciasis is almost certainly a disease that to the salivary glands. Here, as infective larvae, originated in Africa and has spread to Ara- they await the opportunity to enter a new host bia and the New World as an unintended by- when the fly feeds again. Once this happens, the product of the slave trade. Skin lesions caused larvae wander briefly in the skin before settling by onchocerciasis were first described in the down in clumps to mature, breed, and produce Gold Coast (modern Ghana). The organism was microfilariae. first described in 1893 by eminent German par- Simulium females lay eggs on rocks and veg- asitologist Friedrich Rudolf Leuckart. In 1916, etation in swiftly flowing, richly oxygenated the disease was first recognized in the Ameri- water. Ripples around rocks, bridge abutments, cas by Guatemalan investigator Rodolfo Robles. and dam spillways provide favorable conditions Robles linked nodules to eye disease and sug- for the larval development of the vector. There is gested that the distribution of infection im- no transovarial transmission, so newly emerged plicated two species of Simulium as vectors. adults must acquire onchocerca in a blood meal. D. Blacklock, working in Sierra Leone, showed Adult flies have extensive flight ranges: Infected in 1926that S. damnosum was the vector. females aided by winds and weather fronts can In 1931, J. Hissette, working in Congo, linked move hundreds of kilometers to establish new onchocerciasis with blindness for the first time foci of disease. However, because of the vector’s in Africa, but despite confirmation in the breeding preferences, most flies and hence most Sudan a year later, colonial doctors generally onchocerciasis cases are found within a few kilo- considered onchocerciasis only a skin disease. meters of a stream with suitable breeding sites. Just before World War II, French doctors in what The term “river blindness” accurately reflects is now Burkina Faso began to link the disease the geographic distribution of the disease. with mass blindness and river valley abandon- Onchocerciasis often has dramatic effects on ment. Their colleagues across the frontier in the human activities and settlement patterns. In British Gold Coast did not make a similar discov- many heavily infested areas, notably in the ery until 1949. headwaters of the Volta River, swarming flies, Although British physicians and administra- tormenting skin infestation, and progressive tors were aware of river valley depopulation, blindness among a significant proportion of the onchocerciasis, and substantial blindness in the population have resulted in progressive aban- northern part of the colony, they did not link donment of rich, well-watered farmlands near these phenomena, partly because doctors who the rivers. Depopulation of river valleys be- became interested in the problem in the 1930s cause of onchocerciasis has transpired for some were repeatedly distracted by other duties or time in northern Ghana, with people forced transferred. After the war, the association was to cultivate crowded and eroding lands away finally made. A series of investigations in the from the streams. In many areas, land-hungry 1950s confirmed the widespread incidence and people were settling river valleys in the early serious consequences of the disease in a num- twentieth century, but in recent decades the ber of African countries, and Latin American foci line of settlement has retreated from the rivers. were delimited.

229 100. Ophthalmia (Trachoma, Conjunctivitis)

In 1975 the World Health Organization be- The term derives from the Greek ophthalmos gan the Onchocerciasis Control Programme, an (“eye”), and almost any eye disease was called ambitious and expensive 20-year effort to elim- ophthalmia until the twentieth century. The inate onchocerciasis in the entire Volta Basin. problem for historians of past disease is that The basic strategy was to kill fly larvae by aeri- “ophthalmia” meant any of a number of eye ally spraying temephos (an organophosphate) ailments and that blindness from “ophthalmia” over breeding sites throughout a huge and re- had many possible causes. Historically, two of peatedly extended portion of West Africa. The the most important “ophthalmias” were tra- absence of an effective agent to kill adult flies choma and conjunctivitis. has not prevented tremendous success in re- ducing and sometimes eliminating Simulium Trachoma populations. Trachoma (also called granular conjunctivi- Although treatment of victims was less suc- tis and “Egyptian ophthalmia”) is caused by cessful until recently because existing drugs Chlamydia trachomatis. It is characterized by were too dangerous for mass use, the vector inflammatory granulations on the inner eyelid control program, though costly and constantly that severely scar the eye, eventually causing faced with the problem of reintroduction of blindness (but not in all cases). It was a leading adult flies from places beyond its limits, has re- cause of blindness in the past and still blinds sulted in dramatic declines in biting rates, in- millions in Asia, the Middle East, and Africa. Two fection, and blindness in most of the region. Re- estimates place the number of victims world- cently, treatment of thousands of victims with wide at between 400 and 500 million, with per- ivermectin, a safe and effective microfilaricide, haps 2 million totally blinded. has helped to reduce blindness among infected Because a dry climate seems to affect inci- persons and has reduced the chances that a dence, some of the highest rates of infection feeding fly would ingest infective microfilariae. are found in the countries of North Africa and The absence of an agent to kill adult worms the Middle East, from Morocco to Egypt and and the logistical and financial difficulties of the Sudan and from the Red Sea to Turkey and Iran. massive larviciding campaign make total erad- It is also widespread in Asia, with 20–50 per- ication unlikely, but vector control and micro- cent of the population infected in Burma, Pak- filaricidal treatment can reduce the number of istan, India, China, Indonesia, and Borneo. Such infected persons and lessen or eliminate severe rates also occur in sub-Saharan Africa (except- clinical symptoms. Success at this level could ing West Africa, where incidence falls below help make thousands of square kilometers of 20 percent). Similar trachoma rates continue valuable farmland safe for use in many regions along the Mediterranean coast of Europe, in of Africa. It is, however, clear that there must be Eastern Europe, Russia, Korea, Japan, Australia, a long-term commitment to the campaign for New Zealand, and Oceania. In the Western many years into the future, or river blindness Hemisphere, Brazil and Mexico have the high- will reconquer its old haunts. est incidences, but trachoma also infects Indians K. David Patterson and Mexican-Americans in the U.S. Southwest. Sporadic cases appear in Europe, the Philip- pines, and some Central and South Ameri- can countries. Trachoma is practically extinct 100. Ophthalmia (Trachoma, in Canada, Switzerland, Austria, and northern Conjunctivitis) Europe – areas with high standards of liv- ing and sanitary conditions and without ex- In its broadest sense, ophthalmia is an inflam- treme poverty. Where living conditions have im- mation of the eye, especially of the conjunctiva. proved, trachoma has declined or disappeared.

230 100. Ophthalmia (Trachoma, Conjunctivitis)

Trachoma generally requires prolonged con- dersurface of the eyelids. A new infection of tact in filthy and overcrowded conditions for C. trachomatis may occur at this stage and start transmission. In endemic areas, infection first the process all over again. Thus Stages 2 and occurs in childhood as a result of close family 3 may coexist for many years and may be fur- contact. Transmission may be from mother to ther complicated by repeated infections. Each baby, from eye to eye, by fingers, and by eye- new attack forms more scar tissue, and an ever- seeking flies. In urban slums and poor villages increasing pannus covers the cornea. This phase where people live crowded together in unsani- may be several years in duration. tary conditions, garbage and raw sewage attract Stage 4 (healed trachoma) is the final stage flies that breed copiously. As the insects swarm in which healing has been completed without on the faces of infants and children, they feed inflammation, and the disease is no longer in- on the infected eye discharges of those with tra- fectious. Trachomatous scarring remains, how- choma and carry it to the eyes of other victims. ever, and may deform the upper lid and cause Most children in endemic areas have trachoma opaqueness in the cornea. When the eyelid in- at an early age, but hosting the disease in child- turns, the lashes rub on the cornea (trichiasis), hood does not provide a lifelong immunity. irritating, tearing, and scarring the corneal sur- Trachoma transmission may also occur by di- face. Ulcers may develop, and bacterial infec- rect touch, by contamination of clothing or bed- tion of the ulcers can lead to blindness. Another ding, possibly by bathing in communal pools, complication may be drying of the conjunc- and by sexual means. Factors contributing to tiva and cornea. Many combinations of com- trachoma are ocular irritants and bacterial con- plications may account for impaired vision and junctivitis. It is most prevalent in hot, dry cli- blindness. mates – low humidity can excessively dry the conjunctiva. Wind, dust, and smoke further ir- Conjunctivitis ritate the eyes. Bacterial infections often cause Simple acute conjunctivitis is a common eye in- the worst cases. fection, caused by a variety of microorganisms The clinical features of trachoma are usually and characterized by a red or bloodshot eye. divided into four stages: Stage 1 (incipient tra- Mild cases may present with feelings of “rough- choma) is characterized by increasing redness ness or sand” in the eye, but serious cases pro- of the conjunctiva lining the upper lids. As the duce pain and photophobia. After some days, organism proliferates, pale follicles appear. Both discharges may become so purulent that they features spread across the conjunctival surface. gum the lids together. The infection often be- Minimal exudate occurs but may be more pro- gins in one eye before spreading to the other. fuse with secondary bacterial infection. The up- An acute conjunctivitis may last up to 2 weeks. per part of the cornea becomes edematous and Bacteria often infect the conjunctiva simul- infiltrated with inflammatory cells, and pannus taneously with trachoma (causing acute bac- appears. Stage 1 lasts several weeks to months. terial conjunctivitis), and the two in combi- Stage 2 (established trachoma) marks the in- nation may blind many individuals. Viruses crease of all Stage 1 symptoms and is often can also cause conjunctivitis; historical descrip- termed the “florid stage.” The pannus increases tions of mild ophthalmia may indicate bacte- toward the apex of the cornea, and the red ves- rial or viral conjunctivitis. By contrast, more se- sels in the cornea are visible to the naked eye. vere ophthalmias – producing eye-scarring or In severe cases, a secondary bacterial infection permanent blindness – were often trachoma. may worsen the appearance of the eye. Duration Even today, forms of bacterial and viral con- is 6months to several years. junctivitis are still confused with trachoma. Se- Stage 3 (cicatrizing trachoma) is the scarring vere forms of conjunctivitis include ophthalmia and healing stage. Scar tissue forms on the un- neonatorum, from infection in the birth canal;

231 100. Ophthalmia (Trachoma, Conjunctivitis) follicular conjunctivitis, often confused with porary of Celsus wrote a book of remedies for early trachoma; phlyctenular conjunctivitis; many diseases, including several for trachoma. and hemorrhagic conjunctivitis. The Romans were also well acquainted with Gonococcal conjunctivitis, caused by Neis- trachoma. Troop movements must have dis- seria gonorrhea, infects newborns as well as persed the disease throughout the Mediter- children and adults but is now transmitted ranean region and beyond. In France, England, mainly by sexual intercourse. Ocular gonorrhea and Germany, the stone-seals of Roman oculists infection was one of the principal causes of name remedies used for trachoma. Roman med- blindness in Europe until the 1880s, when a ical books also include remedies for the ailment. silver nitrate solution came into use in new- In the fourth century, Theodorus Priscianus borns. The consequent decrease in blindness used garlic juice to anoint the conjunctiva. has been described as “one of the great victo- In the sixth century, Aetius of Amida in ries of scientific medicine.” In contrast to gono- Asia Minor distinguished four stages of tra- coccal conjunctivitis, which has declined in the choma, whereas in the seventh century, Paul developed world, chronic follicular conjunctivi- of Aegina, an Alexandrian physician, provided tis and acute conjunctivitis in newborns have descriptions of trachoma treatments as well as been on the increase along with other sexually different phases of the disease. Like his pre- transmitted diseases. decessors, Paul recommended eyelid scraping. Trichiasis patients were operated on with needle History and thread, a procedure “reinvented” in 1844. Trachoma was known in China in the third mil- To prevent eye inflammation, he recommended lennium B.C. and in Egypt in the second. The burning the forehead and temples – a treatment Ebers Papyrus clearly described a chronic oph- later used on Saint Francis of Assisi in Italy. Paul thalmia with discharge, leukoma of the cornea, and Aetius were also familiar with eye diseases and trichiasis – all suggestive of trachoma. in newborns. By the time of the ancient Greeks, eye inflam- Later Arabic authors continued to study tra- mations were frequently described, and about choma. In the ninth century, Ibn Masawaih 60 A.D. the term trachoma (“roughness”) was mentioned pannus and trichiasis. His pupil, first used by Dioscorides. Although the Hip- Hunain ibn Is-haq, distinguished the four forms pocratic books do not define ophthalmia pre- of trachoma. In the eleventh century, a Christian cisely, Galen defines it as “an inflammation of oculist in Baghdad, Ali ibn Isa, distinguished the conjunctiva.” An important Hippocratic ref- 13 diseases of the conjunctiva and 13 of the erence to trachoma describes not the disease cornea. He clearly described trachoma and was but its treatment: scraping the eyelids, cutting the first to make the connection between trichi- away the fleshy granulations, and cauterization asis and trachoma. His is the best description with a hot iron. Another Hippocratic text de- of trachoma and its treatment written in antiq- scribes an operation for trichiasis. The concern uity, and probably the best until the work of with trachoma in the Hippocratic corpus may J. N. Fischer of Prague in 1832. Most subsequent have arisen from an apparent outbreak of the works in Arabic copied Ali ibn Isa’s chapters disease among the Athenians during the Pelo- on trachoma. One exception is by Cairo oculist ponnesian War (431–404 B.C.). Sadaqa ibn Ibrahim al-Sadhili in the fourteenth For treatment of trachoma, Greek physicians century, who meticulously noted his own in- stressed scraping thickened eyelids with fig formed observations of the disease, including leaves or the rough skins of sea animals such (for the first time) its high incidence in Egypt. as sharks. In the first century A.D., Celsus de- Thus the Greeks and Arabs knew far more scribed trachoma and recommended treatment about trachoma than did their counterparts for trichiasis. About 45 A.D., a younger contem- in Europe until the nineteenth century. They

232 100. Ophthalmia (Trachoma, Conjunctivitis) recognized the stages of trachoma, the scars, the Egypt as the “land of the blind.” It has been sug- contagiousness, and the danger of reinfection. gested that eye disease there had increased un- The Arabs also knew the connection of trichia- der Turkish rule, with 2 million peasants living sis and pannus with trachoma, and their treat- in misery. Perhaps poverty combined with the ments were superior to those in the West. arrival of foreign armies to trigger the terrible In contrast, medieval Europe was poorly pre- epidemics of “ophthalmia” that tormented Eu- pared to confront trachoma when it appeared, rope for half a century. often accompanying returning Crusaders. How- When Napoleon’s troops invaded Egypt in ever, frequent mercantile and military traffic 1798, they suffered from a contagious oph- between Italy and the Middle East meant that thalmia, probably the conjunctivitis preva- Italy (especially Salerno) became a center of lent in Egypt during the summer months. By eye-disease knowledge. Arabic and Greek writ- September, few soldiers had escaped. Some were ers, translated into Latin, influenced Italian con- suffering from gonorrheal conjunctivitis and cepts of trachoma and its treatment. (Latin trachoma; many were completely blinded by translators, garbling the Arabic, called trachoma swollen eyelids. Of one group of 3,000 men, “scabies.”) A possible trachoma victim was Saint 1,400 were unable to fight because of “oph- Francis of Assisi, who certainly had some kind thalmia.”Thousands suffered, and those blinded of ophthalmia acquired on a trip to Egypt. He re- were hospitalized, sent home, or massacred in turned to Italy in the early stages of the disease battle. Many veterans suffered from eye prob- and sought treatment at an ophthalmia center lems for years after their return to Europe. in Rieti. He later underwent the ancient temple- Turkish and British troops in Egypt also cauterization treatment and was finally blinded contracted ophthalmia. British surgeon George shortly before his death. Power described the disease as a purulent con- In the fourteenth century, French surgeon junctivitis that had been prevalent in Ireland Guy de Chauliac provided a description of tra- about 1790. He regarded it as infectious and choma, whereas in England, one medical tract related to Egyptian ophthalmia. “Egyptian oph- on eye disease (by John of Arderne in 1377) sur- thalmia” accompanied British troops on their re- vives from the period. Some of its references turn home. As early as 1802, Patrick MacGre- suggest trachoma, although a form of conjunc- gor described granulations on the conjunctivae tivitis is more likely. Trachoma usually was of 56veterans who had returned from Egypt. poorly identified, but possibly remained estab- Reaching grave proportions by 1806, this epi- lished in Europe until the sixteenth century on- demic may have been gonorrheal ophthalmia ward, when notable epidemics of “ophthalmia” rather than trachoma. When British troops at- coincided with troop movements. A well-known tacked Egypt in 1807, they again contracted epidemic, described by Forestus, occurred in “ophthalmia,” then spread it when they moved 1556. A little later, Jean Costoeus mentioned the on to Sicily. Ophthalmia continued to ravage treatment of trachoma by cautery. Epidemics the British army for another decade. By 1818, similar to that of 1556occurred at Breslau in over 5,000 men had been invalided out for 1699 and 1700 and at Westphalia in 1762. In the blindness. later 1700s, trachoma epidemics swept through Probably the eye diseases that afflicted the Sweden and Finland. French, Turkish, and British forces were the Trachoma was again imported after Napoleon same two forms of conjunctivitis that prevail in Bonaparte’s campaign in Egypt (1798–1801). An Egypt, sometimes complicated by genuine tra- ophthalmia epidemic swept Europe, and many choma in its various stages. When trachoma oc- returning French troops lost their sight. Tra- curs along with acute conjunctivitis, it tends choma and conjunctivitis were still endemic in to be more severe and contagious. Lack of Egypt; indeed, European travelers referred to sanitation in the armies and among the local

233 101. Osteoarthritis population would have facilitated the rapid junctivitis, other eye-affecting diseases such spread of the ophthalmias. as smallpox, measles, leprosy, tuberculosis, The epidemics, of course, had spread to other syphilis, and onchocerciasis doubtless also armies. In 1801, Italian troops were infected at blinded slaves. Elba and Leghorn by the French. This epidemic By the nineteenth century, the term oph- lasted until 1826. The Italians carried the thalmia had come to cover an extraordinary disease to the Hungarian (1809) and Austrian variety of eye diseases. Hence, qualifiers such (1814) armies. A severe epidemic struck the as cachectic, senile, menopausal, abdominal, Prussian army from 1813 to 1817, with 20,000– and scrofulous were attached to the word oph- 25,000 men affected. From there it passed to thalmia. Only in the twentieth century were the Swedish troops in 1814 and to the Dutch in actual causes of eye diseases isolated and accu- 1815. More than 17,000 suffered in the Russian rate descriptions of trachoma and conjunctivitis army between 1816and 1839, and by 1834, made possible. 4,000 Belgian troops had become completely Mary C. Karasch blind. In fact, in 1840 one in five Belgian sol- diers still suffered from “ophthalmia.” When the epidemic hit Portugal in 1849, it affected 10,000 soldiers over an 8-year period. In 1813, it even 101. Osteoarthritis reached Cuba, where it devastated 7,000 sol- diers; reports claimed that “most” were blinded. Osteoarthritis (OA) is the most common But although the Napoleonic Wars had doubt- rheumatic disorder afflicting humankind and less furthered the transmission of endemic vertebrates in general. The most common al- Egyptian and European ophthalmias, other epi- ternative terms, osteoarthrosis and degenera- demics may have had different points of ori- tive joint disease, are used because of divergent gin. As the nineteenth century progressed, “oph- concepts of the nature and cause of the disor- thalmias” continued to afflict European troops der. One school maintains that OA is a family around the world. By the end of the nineteenth of systemic inflammatory disorders with similar century, the disease had become known as mil- clinical and pathological results. Another sup- itary ophthalmia. ports the use of the term “osteoarthrosis” be- Yet civilians carried the disease as well. Im- cause inflammation is not present. Still another migrants and slaves brought ophthalmia to uses the term “degenerative joint disease” be- the Americas, and British reports identified tra- cause it is held that aging and “wear-and-tear” choma among immigrants from Ireland, Poland, are responsible for its occurrence. Finland, Russia, and Armenia. The United States OA is a multifactorial systemic inflamma- and Canada declared trachoma dangerous and tory disorder with clinical symptoms of pain prohibited entry to those infected, but many es- and stiffness in movable joints, showing ra- caped detection. “Ophthalmia” also was among diographic evidence of cartilage loss and bony the most feared diseases of the slave trade, as overgrowth. The anatomic changes – carti- it could spread quickly through a slave ship, lage loss and a kind of bony overgrowth and blinding the entire cargo and crew. Such ships spurs – may occur physiologically without clin- were occasionally discovered drifting helplessly ical symptoms. The disease is classified as pri- on the open sea. In the 1830s and 1840s, mary osteoarthritis when there is no known slave ships from Angola and Benguela repeat- predisposing factor,orsecondary osteoarthri- edly introduced the disease into Brazilian port tis when there is a clearly defined, underly- cities, from where it spread to the surround- ing condition contributing to its etiology, such ing plantations. But historians cannot attribute as trauma, metabolic diseases, or gout. Sev- all ophthalmias to trachoma. Along with con- eral symptom complexes are grouped as variant

234 101. Osteoarthritis subsets such as generalized osteoarthritis or ease was difficult. Later, use of roentgenograms erosive inflammatory osteoarthritis. to detect changes allowed for the classifica- tion of OA ranging from mild to severe, de- Characteristics pending on the loss of cartilage and the pres- Osteoarthritis spares no race or geographic area. ence of bony overgrowth. The cartilage loss is In most – especially younger – patients, the dis- seen as joint space narrowing, whereas bony ease is mild and causes no significant disability. overgrowth can be one or more of the follow- However, in older patients, it is more severe, of- ing: osteophytes, bony eburnation, or increased ten producing disability, loss of time from work, bone density. Early physical findings such as and thus economic loss. The disease occurs with Heberden’s nodes may precede radiographic increased severity and frequency in older pop- changes. ulations as a result of prolonged exposure to Surveys of skeletal remains of contemporary pathophysiological processes responsible for its white and black Americans, twelfth-century development. Native Americans, and protohistoric Alaskan OA occurs with more frequency and severity Eskimos showed that those who underwent the in women than in men. There is a sex differ- heaviest mechanical stresses suffered the most ence in distribution of the joints involved. Lower severe joint involvement. Climate does not in- spine and hip disease are more common in men, fluence the prevalence of OA. Hereditary predis- whereas cervical spine and finger arthritis are position to Heberden’s nodes has been found in more common in women. The most commonly half of observed cases. Remaining cases are con- affected joints are the distal interphalangeal sidered traumatic. joints (Heberden’s nodes); the proximal inter- Differences in patterns of affected joints occur phalangeal joints of the fingers (Bouchard’s in different ethnic groups. Heberden’s nodes, nodes); the first metatarsophalangeal joints of for example, are rare in blacks, as is nonnodal the feet (“bunions”); and the spine, hips, and generalized osteoarthritis. Occupational factors knees. may play a role in incidence, especially in males. Studies of the incidence of osteoarthritis pro- Studies from Britain, the United States, and duce divergent data because of differences in France show osteoarthritis to be a major cause definition and diagnostic techniques. For exam- of incapacity, economic loss, and social disad- ple, when the definition includes only patholog- vantage in persons over age 50. Hip disease ical anatomic changes (cartilage loss and bony is more common in white populations than in growth), investigators find evidence for the dis- blacks and Native Americans. Asian populations order in 90 percent of persons over age 40. Only have a low incidence of hip disease, but inci- about 30 percent of persons with radiographic dence of OA of the fingers in Asia is high, as in changes of degenerative joint disease complain Europeans. Knee disease shows less difference of pain in relevant joints. The frequency and among ethnic groups, being similarly preva- severity of symptoms of the illness increase with lent in whites and blacks in South Africa and age so that osteoarthritis is a major cause of Jamaica. symptomatic arthritis in the middle-aged and The popular concept that osteoarthritis is a elderly population. single disease resulting from attrition of carti- The first epidemiological studies on os- lage due to age and wear-and-tear is not tenable teoarthritis were reported during the first half in light of modern experimental studies. Os- of the twentieth century in England, using only teoarthritis can be regarded as the result of aber- questionnaires and clinical examination to eval- rations in a complex pattern of biological reac- uate incapacity and invalidism caused by the tions whose failure leads to anatomic changes in disease. These methods, however, lacked diag- joint structure and function. One or more bio- nostic reliability, and classification of the dis- logical feedback loops may lead to malfunction

235 102. Osteoporosis of the complex system. Biological modifiers in- ing arthrosis, was found in a Scythian skeleton duce variable effects, depending on the tar- derived from the Hippocratic period. Evidently, get mechanism. One hypothesis proposes that shoulder OA was common among the Scythians OA is a multifactorial metabolic inflammatory despite treatment. disorder in which too little cartilage and too Over the centuries, the names of disorders much bone are synthesized because of impaired encompassing OA have changed and have in- liver function in processing growth hormone cluded terms such as rheumatism and lum- and insulin. Hepatic dysfunction results in al- bago, which are no longer scientifically used. tered neuropeptide levels: too little insulin-like Today we recognize dozens of forms and sub- growth factor 1, which is required for cartilage sets of OA. growth, and too much insulin, which acceler- The prevalence of OA and the pattern of joint ates bony growth and osteophyte formation. involvement show wide geographic differences. Osteoarthritis usually has an insidious onset In a worldwide study, OA was most prevalent depending on the specific joints afflicted and in the north of England, where 67 percent of the patient’s tolerance to pain. The character- men and 73 percent of women had OA. The low- istic symptoms are pain and stiffness localized est incidence was in Nigeria and Liberia. Preva- to the involved joints. In early disease the pain lence of OA was also low in Soweto, South Africa, occurs with use of the joint; later pain occurs and in Piestany, Czechoslovakia. The incidence during rest. Morning stiffness is usually of short of OA also varied with the specific joint be- duration, less than 30 minutes. Frequently it is ing studied. Data on Heberden’s nodes revealed related to changes in the weather. The affected the highest frequency (32 percent) in the pop- joint creaks on movement, and its motion is ulation of Watford, England; 30 percent in the reduced. Blackfeet Indians of Montana; and 26percent The affected joint is enlarged, owing to bony in the people of Azmoos, Switzerland. All black overgrowth and to synovitis with accumula- populations had low prevalence, as did inhab- tion of fluid. It is tender and painful. Late in itants of Oberholen, Germany. The Pima Indi- the disease, subluxation and muscle atrophy ans of Arizona had an 11 percent incidence in occur. Rarely is there ankylosis or fusion with women, whereas in men 20 percent were af- complete loss of motion. Radiographic exami- fected, a reversal of the normal sex distribution. nation shows cartilage loss, causing joint-space Factors influencing osteoarthritis prevalence narrowing with bony overgrowth. in populations include heredity, occupation, and possibly diet and resultant body build. History Comparison of populations living in different Since prehistory, vertebrates have presumably parts of the world indicates no correlation with suffered from osteoarthritis. Dinosaur bones latitude, longitude, or any type of climate. No show bony spurs and ankylosed spinal seg- significant differences are found among differ- ments that mark the disease. The same changes ent groups in the prevalence of osteoarthritis. occurred in prehistoric humankind as well Charles W. Denko as in animals, modern and ancient, such as horses and dogs. Clinical descriptions of arthri- tis date back to the fifth century B.C., to Hip- pocrates, who described the Scythians as hav- 102. Osteoporosis ing markedly lax or hypermobile joints. The disorder was attributed to divine retribution Osteoporosis is defined as a proportional de- for the destruction of the Temple of Ashkelon, crease of both bone mineral and bone ma- which the Scythians wrought during an inva- trix, leading to fracture after minimal trauma. sion of Palestine. Severe shoulder OA, deform- It differs from osteomalacia, which presents a

236 102. Osteoporosis normal amount of bone matrix (osteoid) but Osteoporosis in the elderly is exceedingly com- decreased mineralization. There are two clin- mon and involves multiple factors of age, sex, ical syndromes of osteoporosis. Type I (post- endocrine system, genetics, environment, nu- menopausal osteoporosis) occurs in women trition, and physical activity. Age-related fac- aged 51–75, involves primarily trabecular bone tors include decreased osteoblast function, loss, and presents as vertebral crush fracture decreased intestinal calcium absorption, de- or distal radius fracture. Type II (senile osteo- creased renal activation of vitamin D, and porosis) occurs in both men and women, par- increased parathyroid hormone secretion com- ticularly after age 60, involves trabecular and bined with decreased clearance of the hormone cortical bone loss, and commonly presents with by the kidney. hip fracture and vertebral wedge fracture. In women, decreased estrogen production in Postmenopausal osteoporosis is associated with menopause accounts for 10–20 percent loss of decreased serum levels of parathyroid hormone total bone mass. Although men have no equiv- and a secondary decrease in activation of vita- alent of menopause, gonadal function declines min D, whereas senile osteoporosis is associated in many elderly men and contributes to os- with a primary decrease in activation of vita- teoporosis. Multiple pregnancies and extended min D and increased parathyroid hormone. breastfeeding in premenopausal females may also produce negative calcium balance and Characteristics subsequent bone loss. Underlying medical Osteoporosis is an enormous public-health conditions or medications can contribute to problem, responsible for at least 1.2 million frac- osteoporosis, particularly hyperthryoidism, tures annually in the United States. Fractures hemiplegia or paralysis, alcoholism, use of of the vertebral bodies and hip comprise the glucocorticoid steroids, and smoking. majority, and complications of hip fracture are Population and familial studies implicate both fatal in 12–20 percent of cases. Nearly 30 per- genetic and environmental factors in causing cent require long-term nursing home care. The or inhibiting osteoporosis. Blacks, for example, direct and indirect costs of osteoporosis in the tend to have greater initial bone mass or bone United States are estimated in billions of dollars density than whites. Even with similar bone annually. loss, osteoporosis begins at a later age in blacks. Age-related bone loss or involutional osteo- Among whites, women of British ancestry had a porosis begins about age 40 in both sexes at higher incidence of osteoporosis than those of an initial rate of about 0.5 percent per year. other national origins. The bone loss increases with age until slowing Nutrition, particularly calcium intake, plays very late in life. In women, accelerated post- a role in inhibiting osteoporosis. Long-term tri- menopausal loss of bone occurs at a rate of als of calcium supplementation, however, have 2–3 percent per year for about 10 years. Over had mixed results in postmenopausal women. their lifetime, women lose about 35 percent of Such supplementation may be more effective cortical bone and 50 percent of trabecular bone, if initiated years before onset of menopause. A whereas men lose about two-thirds of these high-protein diet increases urinary excretion of amounts. The skeletal bone mass is comprised calcium and may induce a negative calcium bal- of 80 percent cortical and 20 percent trabecu- ance. Decreased renal activation of vitamin D lar bone. Trabecular or spongy bone has much with age may also be a factor in populations higher turnover – nearly eight times that of cor- without vitamin D supplementation or with the tical or compact bone. elderly confined indoors. The process of age-related osteoporosis is Physical activity decreases the rate of bone universal, although certain populations are af- loss in the elderly. Skeletal stresses from weight fected to a greater degree or at an earlier age. bearing and muscle contraction stimulate

237 103. Paget’s Disease of Bone osteoblast function, and muscle mass and bone to modern Western samples, perhaps secondary mass are directly related. to inadequate calcium intake or extended Osteoporosis was defined as a clinical entity in lactation. 1941. Since then, many studies have attempted R. Ted Steinbock to evaluate the varying rates of osteoporosis and osteoporosis-related fractures in different pop- ulations. The process of age-related and post- menopausal bone loss occurs in all populations. 103. Paget’s Disease of Bone It appears to start earlier for women in Japan and India compared to women in Britain and the Paget’s disease of bone was described as os- United States. It occurs later in Finnish women, teitis deformans, a “chronic inflammation of and age-related rates of bone loss in women bone” by Sir James Paget in 1876. His original between 35 and 64 are lower in Jamaica and description was masterful and thus has with- the four African countries studied than in other stood the test of time. Paget’s disease of bone countries examined. describes an abnormal osseous (bony) struc- Relating the differing rates to calcium in- ture whereby isolated and sometimes contigu- take correlates well with populations in Japan, ous areas of the skeleton undergo changes India, and Finland but not Jamaica or the African leading to clinical deformity for some of those countries. Other factors such as genetically de- affected. Clinically affected people may have termined initial bone density or increased phys- the appearance of enlarged bone, bowed ex- ical activity may also be involved. The rate of tremities, shortened stature, and simian pos- hip fracture varies according to the age distribu- turing because the body’s usual system for tion of osteoporosis in all countries. Incidence of maintaining strong and healthy bone malfunc- hip fracture is higher in white populations in all tions. Normal bone turnover is altered in the geographic areas, compared to indigenous pop- affected areas. The resorption process acceler- ulations. For example, low incidence is noted ates, and the repair process responds by build- among Maoris in New Zealand and the Bantu in ing a heavy, thickened, and enlarged bone. South Africa compared to white populations in Although the new bone contains normal or in- both areas. In the United States, over 90 percent creased amounts of calcium, the material of the of all hip fractures occur in individuals over 70. bone is disorganized, and the bone is struc- By age 90, a third of all women have sustained turally weak. The result may be pain, deformity, a hip fracture. Vertebral fractures occur in fracture, and arthritis. 25 percent of women over 70. Characteristics History The disease apparently has its greatest preva- Age-related bone loss has been examined in lence in Europe and the neo-Europes, such prehistoric skeletal populations. Skeletons of as Australia, New Zealand, and areas of South hunting-and-gathering archaic Indians (c. 2500 America. For no apparent reason, it is un- B.C.) showed differential rates between females common in African blacks, Orientals, and and males as well as overall rates of osteoporo- inhabitants of India and Scandinavia. Where sis quite similar to those of a modern hospital studied, incidence ranges between 3.5 and population. A more recent Hopewell Indian pop- 4.5 percent of the population in high prevalence ulation showed greater age-related bone loss, regions, with a high of 8.3 percent in Lancashire, probably resulting from genetic or nutritional England, and a low of 0.4 percent in Sweden. factors. Study of three ancient Nubian popu- In a U.S. survey, incidence was 3.9 percent lations found that osteoporosis occurred ear- among Caucasians residing in Brooklyn and lier in life among these women as compared 0.9 percent among Caucasians residing in

238 103. Paget’s Disease of Bone

Atlanta. Similarly, another study revealed no following: frontal bossing, scalp-vein dilatation, Paget’s disease in Lexington, Kentucky, and 1.1 angioid streaks, simian posture, short stature, percent Paget’s disease in Providence, Rhode flexion contractures at hips and knees, anterior Island. and lateral bowing of long bones, warmth of Males are more at risk than females by a involved extremity, periosteal tenderness, and 3:2 ratio. There is evidence of heritability: A compressive neuropathy. Pagetic bone pain is survey, for example, revealed that 13.8 percent uncommon, but when present it is aching, deep, of Pagetic patients had relatives with Paget’s and often aggravated by pressure or weight disease. Approximately half were from succes- bearing. sive generations and half from siblings. Familial The following deformities may develop: cases had earlier onset than others. An autoso- (1) The involved skull may become soft, thick- mal dominant pattern was suggested. ened, and enlarged; (2) femora tend to migrate, The etiology remains unknown. Paget named deforming the softened pelvis; (3) enlargement the disease “osteitis deformans” believing that it of vertebrae alters the spine; and (4) affected was inflammatory and of infectious origin. Re- long bones soften and bow from weight-bearing cent ultrastructural studies have revealed nu- or from the force of surrounding muscles. clear and cytoplasmic inclusions – found in no Pathological fractures can also occur. Low- other skeletal disorders except giant-cell tu- back pain is the most common clinical presen- mor of bone. Morphologically, the nuclei resem- tation of Paget’s disease and is often related to ble ones infected with paramyxoviruses such secondary osteoarthritis. Sarcomatous degen- as parainfluenza, mumps, and measles, and eration, although uncommon, occurs in 1 per- the cells resemble ones infected with respira- cent of Pagetic patients – a fortyfold greater risk tory syncytial virus (RSV). This finding sug- than that of the general population. gests the possibility that Paget’s disease is a slow virus infection of bone. Other such infections History have similarly demonstrated long latent peri- Paget’s disease is not a new disease, having been ods, a lack of acute inflammatory responses, a suspected in a Neanderthal skull. Although iso- slowly progressive course, restriction to a single lated reports in the mid-nineteenth century de- organ system, patchy distribution, and genetic scribed it, the classical clinical description by predisposition. Paget and a pathological description by Henry Studies have demonstrated both measles and Butlin clarified the entity in 1876. Paget was a RSV antigens in Pagetic bone. The suggestion of major figure in the medical community, having different RNA viruses (measles is genus Morbil- been knighted at 43. He is also credited with livirus; RSV is genus Pneumovirus) seems incom- defining diseases such as Paget’s disease of the patible. It has been proposed that Paget’s disease breast, rectum, and skin; carpal tunnel syn- stems from a previously uncharacterized virus, drome; and trichinosis. Paget’s disease of bone perhaps a Pneumovirus. According to this hy- affects only adult humans; reports of it in ani- pothesis, Pagetic patients are infected at an early mals are not convincing. A childhood osseous age, probably under 30. The slow virus isolates condition called juvenile Paget’s disease ap- to particular skeletal areas, and as the metabolic pears to be a separate entity. activity of the skeleton decreases with age, the It is difficult to reconcile the geographic infested osteoclasts increase their metabolic ac- isolation of the disease to Europeans (exclu- tivity, eventually producing diseased bone some sive of Scandinavians) and their descendants. decades after initial infection. Theories of a slow virus infection in suscep- Estimates indicate that 80 percent of people tible individuals seem dubious, for theoreti- with Paget’s disease are asymptomatic. When cally the disease would then have a more symptomatic, findings may include any of the widespread distribution. Temperature cannot

239 104. Paragonimiasis be implicated, as high-prevalence areas in- Treatment of the lung form of the disease clude disparate climatic regions of Italy, Spain, is usually effective but may be prolonged. The Germany, and Russia. Similarly, occupation and disease can be prevented by avoidance of raw, physical activity seem unrelated, as the ge- poorly cooked, pickled, or marinated freshwater ographic areas involve all types of lifestyles. crabs and crayfish. Interestingly, U.S. blacks apparently sustain K. David Patterson a higher frequency of Paget’s disease than might be expected. An explanation partly in- volves intermarriage with those of European ancestry. 105. Parkinson’s Disease (Parkinsonism) Roy D. Altman Parkinson’s disease,orparkinsonism,isa syndrome with four cardinal features: rest- ing tremor, bradykinesia (physical and mental 104. Paragonimiasis sluggishness), rigidity, and impaired postural re- flexes. Diagnosis is based on finding any three Several species of the genus Paragonimus, the of the four. lung flukes, can parasitize humans. The most important, Paragonimus westermani, is found Characteristics in China, Japan, Korea, Southeast Asia, New Parkinsonism occurs throughout the world; no Guinea, and parts of India and Africa. It was first population is protected. Most studies have in- discovered in the lungs of tigers in European vestigated Caucasian populations of northern zoos in 1878. Other species occur in Asia, Africa, European or Anglo Saxon descent. Prevalence Central America, and South America. Wild and exhibits no geographic patterns and no clus- domestic members of the cat and dog families ters of increased incidence. Two studies seem to and other carnivorous animals are hosts, and indicate a lower prevalence in blacks; this has in many places humans are accidental hosts of been the clinical experience as well, probably worms that normally reside in other mammals. indicating decreased risk for blacks. Annual in- Adult worms produce eggs in the lungs; these cidence varies from 5 to 24 per 100,000 of the reach fresh water either in the sputum or by be- white population. ing coughed up, swallowed, and passed in the Parkinsonism usually occurs in late middle feces. life or beyond. The mean age of onset is 58–62. Motile larvae hatch, penetrate an appropri- Onset before 30 is rare, but a juvenile form also ate snail, undergo two reproductive cycles, and exists. The greatest incidence is in the 70–79 age emerge to seek their second intermediate host, group, with 1–2 cases per 1,000 annually. Later, a crab or crayfish. Here they penetrate between incidence of parkinsonism seems to decline, a the joints of the crustacean’s exoskeleton and finding that – if true – suggests the disease is encyst to await ingestion by humans or other not simply a result of an aging nervous system. definitive hosts. They then burrow through the No apparent difference prevails between the intestinal wall and the diaphragm and enter the sexes in regard to risk. Parkinsonism was lungs, where they may survive for many years. known before 1817, when James Parkinson Slow, chronic lung damage may become seri- published his famous manuscript, but preva- ous in heavy infestations. Lost migrating flukes lence studies have been possible only since the sometimes wander widely and reach atypical 1960s; they indicate no substantial change in (ectopic) sites like the brain, where they cause incidence. a variety of neurological symptoms and may In 1917, an encephalitis lethargica epidemic prove fatal. started in Vienna and spread throughout the

240 105. Parkinson’s Disease (Parkinsonism) world. Following this illness, about half the By modern standards, Parkinson’s essay was victims developed parkinsonism with tremor, scientifically slipshod. The information he con- bradykinesia, and rigidity, often associated with veyed was drawn from visual inspection, not oculogyric crises, parkinsonian crises (sudden examination. However, his paper was well re- episodic worsening of symptoms), behavioral ceived, and subsequent clinicians have added abnormalities, cranial nerve palsies, and a host to his description. of other central nervous system abnormalities. In 1859, Armand Trousseau lectured on The age of onset of postencephalitic parkin- parkinsonism, discussing rigidity and bradyki- sonism is early compared to other types of nesia. The great French neurologist Jean Char- Parkinson’s disease. cot considered parkinsonism a neurosis be- Parkinsonism mortality varies from 0.5 to cause no causative central nervous system 3.8 per 100,000 population, and duration aver- lesion could be identified, and the condition ages about 10 years depending on age of onset, worsened with stress or emotion. Charcot fre- rate of progression, the patient’s general health, quently commented that everything possible and treatment. Treatment with levodopa in- was employed to treat parkinsonism but with creases the quality of life, decreases symptoms, little effect. He recommended belladonna al- and reduces excess mortality. Genetic studies kaloids, especially hyoscyamine, now called have failed to show significant familial risks scopolamine. Modern biochemical understand- of parkinsonism, and analysis of monozygotic ing of parkinsonism indicates that this agent twins indicates a lack of concordance for the should partially improve the symptoms. disease. In 1893, Paul Blocq reported a case of hemi- Symptoms of parkinsonism are caused by de- parkinsonism. Autopsy revealed a lesion in the creased striatal dopamine from loss of dopamin- inferior peduncle with complete destruction of ergic neurons in the substantia nigra of the the substantia nigra. This suggested that the midbrain. Environmental agents are the pri- neuroanatomic substrate of parkinsonism was mary known cause of parkinsonism: exposure the substantia nigra and probably is the first to manganese, carbon disulfide, carbon monox- description of a lesion producing parkinson- ide, and other substances can produce the dis- ism. Many other descriptions merely added to order. Drugs that interfere with dopaminergic the fundamental and original observations of pathways or receptors can also produce the syn- Parkinson. drome, and the same may be true of multiple The road to effective therapy was paved in the head traumas. 1960s by A. Carlsson, who showed that bradyki- nesia could be reversed by administration of History L-dopa, a dopamine precursor. Further stud- Tremor was mentioned in the writings of ies reported a marked decrease in dopamine Hippocrates, Celsus, and Galen, but the real his- in parkinsonism patients. Small doses of tory of parkinsonism started in 1817 with pub- L-dopa were tried, both orally and intravenously, lication of Parkinson’s essay on what he called with possible temporary benefits. Other stud- the “shaking palsy.” He provided a Latin name ies, however, failed to confirm any major ef- as well: paralysis agitans. He reported on six fect until George Cotzias and colleagues showed patients. The first was personally observed; two that much larger oral doses of L-dopa resulted others were noticed casually in the street; case in dramatic improvement in many patients – 4 had an abscess on the chest wall but was lost so dramatic that the efficacy of levodopa treat- to followup; case 5 was evidently seen at a dis- ment was established beyond doubt, and a tance, and no details of that patient are avail- new era in the management of parkinsonism able; case 6was a 72-year-old man who was vi- began. sually inspected but evidently not examined. Bernard M. Patten

241 106. Pellagra

10 6. P ellagra is chemically bound and is released only after the grain is treated with an alkali. In Central Pellagra is a nutritional disease principally America, pellagra has seldom been a problem – caused by dietary deficiency of niacin, a B com- even though corn is the dietary staple – be- plex vitamin. The disease is usually associated cause the grain is soaked in lime and heated with deficiencies of other B vitamins and nearly before being baked, thus releasing the niacin always with poverty and diets based on maize. content. Pellagra is characterized by dermatitis, diar- Pellagra usually appears in winter or spring rhea, and dementia and is nicknamed the “dis- and seems to disappear a few months later, only ease of 3 Ds.” If untreated, a fourth “D” – death – to recur the following year. In the early stages, may ensue. In the past, mortality sometimes patients feel weak, lose appetite, and cannot reached 70 percent, but as knowledge about the sleep. Dermatitis is the classic symptom of pel- disease increased, mortality rates were substan- lagra. Reddened skin (sometimes confused with tially reduced. sunburn) is an early sign. Symmetrical lesions During the early twentieth century, the U.S. appear on the hands, arms, feet, ankles, neck, Public Health Service, working in the South, and face. Later the skin crusts and peels. Le- linked pellagra to the inadequate “3-M” (meat, sions usually (but not always) occur on parts of meal, and molasses) diet of the region’s poor. the body exposed to the sun and in acute cases Cornmeal bread constituted the bulk of di- may blister and rupture. etary intake, although occasionally flavored Pellagra also affects the gastrointestinal tract. with “meat” (usually only fat back) and molasses Symptoms include nausea, excessive salivation, (cane syrup). Widespread pellagra was found a reddened tongue, and burning sensations. Di- among agricultural laborers, mill workers, and arrhea, sometimes intense, is characteristic. institutionalized individuals. The diet of pella- Particularly distressing are neurological grins was always both monotonous and cheap, symptoms, including insomnia, apprehension, and systematic analysis of diet in relation to in- and peripheral neuritis. Mental aberrations come showed that pellagra appeared wherever are varied. Some patients suffer only mild income was marginal and variety in diet was depression, confusion, or memory loss. Others limited. manifest severe psychotic changes. Some are Even the realization that pellagra was a di- suicidal. All these symptoms are caused by bio- etary deficiency disease – and the discovery chemical changes still imperfectly understood. of niacin as the pellagra-preventive (or “P-P”) Electrical rhythms of the brain also change, factor – failed to explain everything about pella- even if mental symptoms are not present. These gra. For example, why does milk (a poor source changes may be related to altered metabolism of niacin) prevent pellagra? Why does a diet of serotonin (synthesized from tryptophan), a based on corn (with more niacin than milk) substance that modulates behavior. cause pellagra? The first question was answered by the discovery that the liver converts tryp- History tophan, of which milk is a rich source, into Pellagra has always been associated with maize, niacin. The answer to the second question lies the staple food of American Indians. Carried to in the chemical form of niacin contained in Europe by Christopher Columbus, maize was maize. at first of interest chiefly to herbalists, and one Niacin is found in many foods, but its pres- of these, in the middle of the seventeenth cen- ence does not mean that it is available to tury, observed that the grain might have a dele- the body. It may appear in a chemically “free” terious effect if consumed in quantity. Despite form (ready to be absorbed) or in a biologi- this caveat, the advantages (ease of cultivation cally unavailable “bound” form. In maize, niacin and prolific yields) of maize ensured its spread

242 106. Pellagra beyond the botanical garden and into the field. researchers searched for a toxin. Lodovico By the end of the eighteenth century, maize Balardini thought he had found it in certain was widely grown in Italy and spreading into corn-grown molds, and Cesare Lombroso spent Yugoslavia, France, Austria, and Hungary. a quarter of a century studying these. The Pellagra was first identified by Gaspar Casal, a spoiled-corn theory was advanced when pella- royal physician of Spain. In 1735 in the town gra broke out in Yucatan in 1882 and later; crop of Oviedo in Asturias, he first noticed a skin failures meant corn had to be imported from disease that the peasants called mal de la rosa. New York. The grain spoiled en route, but the He described the disease and noted that its vic- poorer classes ate it anyway, and pellagra fol- tims lived primarily on maize. Casal emphasized lowed. Not everyone was convinced that corn that the “rose” could be treated by consuming caused pellagra. Some thought that heredity, milk or cheese, foods seldom seen by the poor. bad air, or an unseen organism was responsi- French physician Franc¸ois Thiery` read Casal’s ble. But when governments were persuaded to manuscript and wrote a brief description of the curtail maize consumption, as in France, success disease for a French journal, published in 1755, was possible. although Casal’s own work was not published For a century and a half after pellagra was first until 1762. Within 10 years, the disease was described, the magnitude of the problem out- noted in Italy and named “pellagra” (“rough” or side Europe was not appreciated. Not until the “dry skin”) by Francesco Frapolli. 1890s, with reports by British epidemiologist By the nineteenth century, pellagra was ram- Fleming Sandwith, was anything written about pant in northern Italy. An estimated 5 percent of pellagra in English. In Egypt, Sandwith found the population of Lombardy was affected, and many patients with pellagra. He noted the dis- 20 percent in the worst areas. In Milan in 1817, ease as “country-bred” and associated it with a 66 percent of inmates in a mental institution maize diet. Later, during the Boer War, he found were pellagrins. pellagra among poor Bantus living on maize in French physician Theophile´ Roussel, visit- South Africa. ing Spain in the 1840s, determined that pella- In the United States, pellagra suddenly drew gra was endemic but often misdiagnosed. The attention in 1907 as an epidemic ravaged an French benefited from the work of Roussel, Alabama hospital with 64 percent mortality. In who strongly believed that pellagra was caused succeeding months, thousands of cases were by eating maize. He encouraged improvement identified. Some researchers thought the cause of diets and the living conditions of peasants. might have an insect vector, like the recently He wrote two books on pellagra, the second discovered vectors of malaria, yellow fever, appearing in 1866, stating that the problem and Rocky Mountain spotted fever. Others would be solved not by scientific discovery but blamed foodstuffs other than corn, notably cane through social progress. His arguments were sugar and cottonseed oil. sufficiently persuasive that the French govern- The U.S. Public Health Service began work on ment decreased maize cultivation for food and pellagra soon after the first Alabama cases were encouraged animal husbandry. By the twenti- diagnosed, but not until 1914 was real progress eth century, pellagra had virtually disappeared made: Joseph Goldberger identified the cause of from France. the disease as a dietary deficiency of some es- Few people wanted to believe that pella- sential substance. He introduced a new diet into gra was caused by economic conditions, but selected institutions to see if the disease would many associated it with maize. Italian physician disappear. Succeeding in that experiment, he Giovanni Marzari suggested that the grain then induced pellagra with a poor diet in a molded in storage. He also believed that population of volunteer prisoners. Goldberger corn lacked a nutritive element. For years, next attempted to infect several colleagues,

243 107. Periodontal Disease (Pyorrhea) including himself. Neither he nor anyone else has certainly helped to eliminate the disease, got pellagra, which strongly indicated that the but so has burgeoning prosperity. The exam- cause was not a contagious infection. ple of France in the nineteenth century showed Goldberger also studied the relationship of that government encouragement of varied agri- pellagra to economics. He noted that rural vic- culture resulted in important benefits. Pellagra tims were sharecroppers and laborers caught was brought under control in Italy by the 1930s, in a cycle of poverty tied to one-crop agricul- probably because of a rising standard of living. ture. Few grew foodstuffs or kept a cow, and At the end of the twentieth century, the dis- diet was restricted to the inadequate but afford- ease appeared in only isolated pockets in Egypt, able “3-M” items mentioned previously. Most Lesotho, and India. were chronically in debt. Millworkers suffered Elizabeth W. Etheridge similar poverty. In South Carolina mill villages, Goldberger demonstrated that poverty begets disease. His multiyear epidemiological study conclusively proved that pellagrins were sick 107. Periodontal Disease (Pyorrhea) because they were poor. The study itself became a model in epidemiology. The word pyorrhea comes from the Greek pyon In the 1920s, Goldberger began to search for (“pus”) and rhoia (“to flow”), a graphic descrip- the specific element missing in the pellagrin’s tion of the disease in which an outflowing of diet. Almost accidentally, his team found a rich pus proceeds from the gingival (gum) tissues of source of the unknown P-P factor. They added the oral cavity. The term “pyorrhea” has been yeast to the daily ration of their experimental used in Europe since the mid-1500s and in animals, and the results were magical. Four days America since the late 1800s. In 1937, however, after a pellagrous dog was given yeast, its con- the term was abandoned in favor of periodontal dition had markedly improved. Distribution of disease. yeast became a standard feature of emergency Periodontal disease means any ailment of and economic aid to people. Goldberger was the supporting structures of the teeth, includ- studying liver extracts at the time of his death in ing gingiva, periodontal ligament, and alveo- 1929, and it was from yeast and liver (another lar bone. In simplest terms, periodontal disease effective pellagra preventive) that the missing can be divided into two distinct, but not mu- dietary element was finally isolated. tually exclusive, disease processes. The first in- After Goldberger’s death, the next break- volves inflammation of gingival tissues, called through in conquering pellagra occurred in gingivitis, and the second, a destructive loss of 1937, when Conrad A. Elvehjem isolated nico- bone and connective tissue attachment termed tinic acid (later named niacin). It was found to periodontitis. be the pellagra-preventive factor, and subse- quently Tom Spies used nicotinic acid to treat Characteristics pellagra patients with considerable success at Epidemiological research during the past various hospitals. Commenting on the work 25 years indicates that periodontal disease is of Elvehjem, Spies, and others, the New York one of the most common diseases affecting Times noted that “an ailment which has baffled humankind. There is a direct cause-and-effect medicine for centuries has at last been relegated relationship between the bacterial colonization to the curable diseases.” on the surface of the tooth and the inflam- The disappearance of pellagra from large ar- mation (and often consequential destruction) eas of the world is due as much to social factors of the tooth’s supporting structures. The rate as to medical advances. In the U.S. South and of destruction varies and depends on the elsewhere, enrichment of staples with vitamins individual’s response to the bacterial irritation.

244 107. Periodontal Disease (Pyorrhea)

Periodontal disease is a widespread chronic microorganisms in plaque produce metabolic disease and remains the primary reason for products and cellular constituents that affect teeth loss in the adult population throughout underlying periodontal tissues. These include the world. In fact, virtually all individuals in any exotoxins, endotoxins, antigens, and enzymes. population exhibit manifestations of the dis- Any microbial plaque within the gingival ease. The prevalence and severity of periodon- crevice causes at least gingivitis. In some ar- tal disease increase with advancing age, tend to eas of the mouth, plaque and gingivitis lead to be greater in nonwhites than whites, and are a destructive periodontitis. Periodontal disease greater for males in both groups. There appears is not caused by the intraoral invasion of for- to be an increasing trend in the prevalence and eign pathogens, but rather by colonization of severity of periodontal disease in the over-35 microorganisms of the normal oral flora that age group. This increase is most pronounced in exists even in the absence of disease. Certain lower socioeconomic groups and is highly cor- species of this bacterial plaque play a more sig- related with differing levels of personal and pro- nificant part in the development and progress fessional oral hygiene. of disease because they increase in relative pro- Many individuals in the older population portions as well as in absolute numbers. These have had fewer teeth extracted as a conse- species are also relevant in that their virulent quence of lower caries (“cavities”) incidence, mechanisms act to disrupt the host’s defenses. which results from fluoride use, improvements Inadequate or improper oral hygiene tech- in dental care, and better public-health educa- niques must be considered one of the etio- tion. Paradoxically, this increase in the reten- logic factors in the development of periodon- tion rate of teeth in the aging population pro- tal disease. Other causative influences include vides an increase in the number of teeth at risk food impaction between teeth, defective den- of periodontitis. The only improvement noted tal restorations, malposed teeth, physiological since the 1970s has been a slight reduction in gingival stress due to high frenum attachment, the incidence and severity of gingivitis among effects of dry mouth, and, to a minor extent, the under-35 age group. heredity. Of course, there is a strong relation- Numerous studies have firmly established the ship between all of the etiologic factors and the primary etiologic agent in periodontal disease host’s resistance. The capacity to resist or repair as plaque. Plaque is a colorless, soft, sticky depends on many factors such as adequate nu- film of bacteria that constantly forms on the trition and assimilation, antibody production, teeth. Plaque is composed primarily of different hormonal influences, white cell defenses, and and numerous types of microorganisms as well formative cell capabilities. as adherent mucin (a protein and polysaccha- The pathogenesis of periodontal disease must ride combination), foodstuffs, and cellular de- be considered in four stages: colonization, in- bris. One gram of dental plaque contains more vasion, destruction, and healing. During col- than 1011 bacteria. Plaque can calcify to form a onization, plaque accumulates on the teeth local tissue irritant – calculus (“tartar”) – to and microbial growth ensues. If the plaque is which new colonies of plaque can readily ad- not removed through adequate oral hygiene, here. The microbial population of plaque is vari- the formation of calculus may begin, and the able and is determined by its location on the early stages of microbial invasion into the adja- tooth surface, the intraoral environment at the cent gingival tissues commence. Clinical signs time of the plaque formation, and the length may consist of gingival tissues that are ten- of time the colony has been present in the der, swollen, and red. This tissue may bleed mouth. When plaque is removed, a new plaque upon probing or during brushing. However, pe- may form, having different characteristics in its riodontal disease usually progresses over the quantity, quality, and spatial arrangement. The course of many years, and discomfort is a

245 107. Periodontal Disease (Pyorrhea) rarity. It is because of this asymptomatic evo- “deposits” from the teeth with a cloth-covered lution that persistent bacterial invasion and lo- index finger. More aggressive periodontal ther- cal irritation can progress into the destructive apy appeared when first century A.D. Roman phase of the disease in which loss of connec- physician Celsus treated gums and loose teeth tive tissue and loss of alveolar bone take place. with gold wire and seared the gingiva with red- Signs and symptoms of the destructive stage can hot iron. Oral hygiene techniques can also be include pocketing around the tooth within the traced to the Mayan culture and others in Cen- gingival crevice, gingival recession, suppurative tral America between 200 B.C. and 800 A.D. exudate (pus) from the gingiva, and looseness or Roman writer Pliny in the first century A.D. separation of the permanent teeth. described the prevalence of periodontal dis- The healing phase is the least understood of ease among the Romans as well as various the four stages of the disease. However, studies remedies for its prevention and care. The most reveal that periodontal disease is episodic, and notable prescriptions were dentifrices, mouth- undergoes periods of remission and exacerba- washes, and toothpicks. The first mention of tion. Although colonization, invasion, and de- “toothbrushing” seems to have been by Roman struction are interrelated and overlapping, this poet Ovid in the same century. The siwak,afi- fourth stage, healing, is clearly distinct in that it brous wood product that preceded the tooth- is characterized by reduction of inflammation, brush, was used by the Arabians since the ninth repair of gingival tissues, and sclerosis and re- century and is still in use in some areas today. modeling of the alveolar bone. The modern toothbrush, however, was invented in China only in 1498. History In 1530, Zene Artzney wrote about dental Although periodontology began being prac- therapeutics, discussing the formation and pre- ticed as a specialty only during the twentieth vention of calculus. In 1575, Ambroise Pare´ century, the recognition of periodontal disease coined the term pyorrhea alveolaris and de- in various forms has persisted for millennia. The scribed the attachment of teeth to the jaw by dental structures of teeth and bone of our ances- their roots. tors have been revealed through examination of Pierre Fauchard, the founder of modern den- skulls discovered in archaeological excavations, tistry, in 1728 suggested that teeth and gums evidencing that periodontal disease existed in might suffer from the same diseases. In 1820, some of the earliest members of humankind. Eleazar Parmly recommended that all deposits Egyptian mummies show signs of dental on teeth be removed. He later became known caries and periodontal disease as well as primi- as the “apostle of dental hygiene.” In the latter tive, yet valiant, attempts at repairing these den- half of the nineteenth century, John Riggs, who tal pathoses. Indeed, it is believed that the Ebers was to become the “father of periodontology,” Papyrus, written around 1550 B.C. by Egyptians, described periodontal disease as a “progressive contains the earliest written record of dentistry process from marginal gingivitis to the final ex- as a distinctive branch of the healing arts. The foliation of the teeth.” He developed preventive Greek historian Herodotus described Egypt as as well as surgical treatments for what he called being the home of medical specialties, includ- “scurvy of the gums.”For decades, any such con- ing dentistry. dition was called Riggs’ disease. About 1300 B.C., Aesculapius, the mythi- Our understanding of periodontal disease, cal physician, supposedly recognized the im- including its etiology and pathogenesis, grew portance of dental hygiene by recommending enormously during the 1900s. Periodontal dis- cleaning of the mouth and teeth. The physician ease is currently under attack on several fronts, to the king of Babylon, Arad-Nana, in the sixth through preventive care, improvements in oral century B.C. suggested removing “film” and hygiene techniques, mechanical and chemical

246 108. Pica plaque inhibitors, nutrition, surgical interven- clay consumption, with its practitioners later tion, drugs, and immunology. Much work, how- switching to starch. Although the flavors of clay ever, remains ahead, especially in the relation- and starch are different, the texture is similar. ship of the disease to the host’s immune system. Research indicates that pregnant women eat Jeffrey Levin starch because it relieves nausea, vomiting, and morning sickness. Trichophagia is the ingestion of hair and is al- most always associated with young females who 108. Pica habitually chew their long hair. Trichophagia is closely related to other “mouthing” behaviors. Pica usually means a pathological craving for Over time, ingested hair can form “hairballs” in nonfoods, although it can mean a craving for the stomach, causing gastrointestinal problems. foodstuffs as well. Although pica is not a dis- Other harmful forms of pica include ease, it is often a symptom of disease and is lithophagia (eating rocks or pebbles). Indeed, frequently associated with nutritional deficien- many picas are dangerous; consumption of cies – especially of minerals. In addition, psychi- paint chips by children, for example, can result atry and psychology find that pica is often con- in lead poisoning. nected with mental problems. Anthropologists Pica has been closely associated with women study it as a cultural phenomenon, as it has been and pregnancy since classical times. It was long associated with some religions and also perhaps believed that pregnancy caused mental insta- because the use of nonfoods is indicative of food bility, provoking the mother’s craving for both shortages in the distant past. foods and nonfoods. Recent studies, however, The word “pica” comes from the Latin for indicate that changes in taste are not a constant “magpie,” a bird that eats practically anything. in pregnancy, despite a desire for sharp-flavored Ambroise Pare´ first employed the term in the foods. 1500s, although references to the practice can Most medical investigations of pica are con- be found in many ancient and medieval writ- cerned with children. The practice is usually as- ings. In 1638, M. Boezo distinguished between sociated with those in poverty, especially black pica, an appetite for “absurd things,” and mala- children in rural areas and urban slums. Re- cia, a voracious desire for normal foods. ports conflict as to whether pica in this group is Probably the type of pica that has received nutritionally motivated. No difference in preva- the most scrutiny is the consumption of earth, lence has been found between males and fe- called geophagy (“dirt eating”). Unlike other males. However, during adolescence, girls are types of pica, geophagy has occurred on nearly more likely than boys to begin or continue the all continents, and at nearly all times. Through- practice. out history, various humans have consumed Babies put many things in their mouths. The dirt, clay, mud, chalk, and other earths for nu- ingestion of nonfood substances may begin at tritional, cultural, and psychological reasons. 6 months of age, but declines with a devel- Another form of pica – although that is de- opmental increase in hand/mouth activity and batable – is papophagia (ice eating). Chewing drops sharply after 3 years of age. After that age, or sucking ice is sometimes recommended as the possibility of mental disturbance is often a method of appetite control, or as a smoking explored. substitute. Pica is usually described as rare among adult Amylophagia means consumption of laun- males, although some claim that it is merely un- dry starch and is almost exclusively associ- derreported. The most common picalike prac- ated with women. It was first observed in the tice among men – chewing tobacco – is not gen- American South and may have originated as erally viewed as pica.

247 10 8. P ica

Causes of pica are unclear and have been History the subject of medical speculation since antiq- Pica was well known to the ancients. Aristotle uity. Most modern physicians view pica chiefly discussed earth eating, and as early as 40 B.C. as a means of alleviating nutritional deficiency. in Greece, the sacred “sealed earth” was used as Similarly, past scholars stressed good nutrition a “cure-all.” Clays from Samos, Chios, and Seli- and recommended fresh fruits and vegetables nos were said to be especially effective. Galen as a remedy. However, no definite connec- transported 20,000 clay lozenges from Lemnos tion has been established between pica and di- to Rome to treat victims of poisoning. Pliny de- etary imbalance. Nutrients in which pica prac- scribed how residents of Campania mixed chalk titioners may be deficient include vitamins C with their porridge, adding color and texture. and D, phosphorus, calcium, zinc, and espe- He also noted a region in northern Africa, where cially iron. Investigation into the relationship a similar porridge was made with gypsum mixed between iron deficiency and pica continues in. today. Many early researchers concentrated on the Mental specialists suggest that nutritional pica habits of pregnant women. In the sixth cen- deficiencies and psychological disorders are tury, Aetius of Amida claimed that the urge to linked in pica patients. A 1971 study of consume nonfoods was caused by suppression 90 children demonstrated that those who prac- of menstrual flow. He recommended exercise ticed pica after infancy generally were slower and fresh fruits and vegetables. Avicenna de- to develop than the others. Other studies have scribed pica (although not by that name) and found that black children are more likely than employed various iron preparations in treat- white children to exhibit pica, which has been ment, among them iron dross steeped in fine linked to lower income levels rather than to wine and strained through a plant known as any racial cause. Numerous studies indicate “Hippocrates’-sleeve.” Avicenna believed that that the pattern of pica in youngsters is very pica in pregnant women was treatable, but if close to that of addiction. Often, pica seems the children of that pregnancy began practic- an emotional or psychological defense mecha- ing pica, they could not be cured of it. This nism. Most children who practice pica exhibit disorder must have been fairly widespread, be- other oral activities, such as thumbsucking or cause Avicenna wrote of the need to control it nailbiting. in young boys, recommending imprisonment if There is also a “cultural” etiology for pica. An- necessary. Pregnant women, however, were to thropologists have long sought to explain why be treated more gently, for fear of damaging certain cultures require consumption of non- their infants. food items. Symbolic geophagy was practiced Medical writers of medieval Europe tended to in ancient times in Europe, the Middle East, view mental instability and food as important and even among early Christians. In parts of causes of pica. J. Ledelius, for example, stated Africa, belief holds that clay eating promotes fe- that leftover food in the stomach rotted, emit- male fertility and lactation. Pregnant women in ting humors that ruined an individual’s sense of Nigeria consume clay as “loaves” purchased in taste and caused cravings for odd substances. the marketplace, gaining needed calcium and H. Betten, by contrast, argued that the cause magnesium. of pica was not foul humors in the stomach A last reason for pica is pharmacological. In- but weakness of the mind. He concluded that dividuals engaged in pica may be attempting this was why women exhibited pica more of- to medicate themselves for real or imagined ill- ten than men. He recommended that nonpreg- ness. Physiological causes of pica might include nant women receive stern lectures to strengthen gastrointestinal malaise, stress, hunger, parasitic their will and prescriptions to strengthen their infestations, and toxicosis. stomachs.

248 108. Pica

Famine was often a cause of pica, as in China, Plantation managers in all slaveholding areas where starving people consumed varicolored of the New World were concerned about pica clays instead of rice. Usually, grass, foliage, because slaves who consumed earth appeared weeds, and tree bark became famine food, but in to become addicted to it, and the addiction was truly desperate times, such as the 1640 famine thought to be fatal. Planters referred to pica in Hunan, people ate not only clay but also as a disease, calling it mal d’estomac, cachexia shoes, leather, and wood. Similarly, in Europe Africana, or “stomach evil.” Contemporary au- during the Thirty Years’ War, with armies plun- thors described the practice as widespread in dering village and countryside, the peasants of the West Indies. The dirt eaters usually became Pomerania baked bread of dough mixed with sick, with stomach pains and difficult breath- powdered earth. The practice was repeated in ing, often followed by nausea, diarrhea, de- Germany during the War of the Austrian Suc- pression, and listlessness. Death followed within cession, not only in peasant villages but also in months. Slaveholders tried every means at their the castle of Wittenberg. disposal to break the habit but were generally As Europeans explored Africa, Asia, and the unsuccessful. Americas, they discovered that pica existed In 1843, physician John Imray in Dominica on almost every continent of the globe. The wrote that pica became much rarer in the West Otomac Indians, living along the Orinoco River Indies after emancipation. He noted that slaves in South America, were particularly fond of an had been expected to feed themselves from iron-rich clay in the neighborhood. Pica was their provision grounds, but had been over- also observed among natives of Peru, where worked by the planters; thus, they had little powdered lime mixed with coca leaves was sold energy left for their own crops. In desperation, in the marketplaces. The Indians of the Rio de they turned to earth eating. Freedom gave them la Hacha, however, preferred to consume lime more time to grow their food. without additives, usually carrying it about in Iron deficiency and earth eating, associated small boxes. since ancient times, remain so today. Over time, In Central Africa, David Livingstone re- physicians have increasingly believed that ane- ported that some tribes were clay eaters. mia causes geophagy. Moreover, during the Africans called the practice safura; it was most twentieth century, pica in its various forms was prevalent among pregnant women but was more systematically studied than previously, also practiced by males. Availability of food leading to a greater appreciation of its myster- seemed unrelated to the prevalence of clay ies – and its dangers. consumption. In 1924, it was suggested that lead poisoning The literature of India indicates that arose from pica, specifically the consumption of geophagy was practiced in ancient times, paint chips by children. In the early 1940s, the yet no early European accounts mention it. By U.S. government limited lead content in paints the end of the nineteenth century, however, and plasters. Unfortunately, pica continued to British colonial physicians believed that earth be a major cause of lead poisoning in children. eating was universal in India. At the beginning In New York City alone, there were about 52 re- of the twentieth century, a native-born Indian ported cases every year, with mortality ranging physician thought it was a racial characteristic. from 13 to 27 percent. He wrote that although clay eating was prac- In the late 1940s and early 1950s, the prac- ticed in many areas of the world, the Aryan tice of clay eating in the United States was ex- and Dravidian races were unique in using clay amined in articles by a number of physicians for food on a regular basis, whereas other races and nutritionists. A 1942 survey of black chil- ate it only occasionally for sustenance, or for dren in rural Mississippi found that of 209 chil- pharmacological reasons. dren, 25 percent of the girls and 26 percent of

249 10 9. P inta the boys had eaten either dirt or clay in the 109. Pinta previous 2 weeks. In 1947, the practice was ob- served among pregnant black women in North Pinta (meaning “spotted”) is also called mal de Carolina. There were no reports of clay eating pinto and carate. It is the least destructive of the by males, and it was concluded that the prac- human treponematoses. Although the taxon- tice was related to gender. The same year, an- omy of the treponemes is by no means resolved, other study examined the types of clays con- pinta is sufficiently distinctive to argue for a sumed and among them identified soot from separate causal species, Treponema carateum. stovepipes. (Subjects did not eat the soot directly As a specific treponemal variety, it was not de- but placed it in bags that were subsequently scribed until 1938. The disease is chronic, pre- soaked in water, making a sort of tea.) dominantly affects the skin, and is now found In the 1950s, questionnaires to 47 health only among isolated rural groups in Central and agencies and 91 individual health workers in South America and Mexico, where it is endemic. the southeastern United States revealed that su- Local names for the illness are tina, empeines, perstition and oral tradition played a large role and vitiligo. in the selection of pica materials. A subsequent study discovered that women who ate clay and Characteristics cornstarch had diets that were otherwise low According to one historian, pinta may have had in calories, calcium, iron, thiamine, and niacin. a considerable world distribution at the end of In 1957, a book-length study appeared, which the Paleolithic period, some 10,000 years ago. included the history of pica and its associa- However, its past geographic distribution is in tion with mental and physical illness and nu- some doubt, and an alternative view suggests trition. It argued that pica becomes established that it evolved purely in Amerindian communi- in children because they lack an understanding ties of the New World as a final microevolution of dietary taboos. Poor nutrition leads them to in the treponematoses there. It is not greatly de- practice pica with any number of substances. structive and remains untreated in many Latin Another major work appeared the following Americans. As many as a million individuals year, which focused on the geography of the dis- may have the disease. order, scrutinizing geophagy in Indonesia and Pinta is caused by T. carateum, which can- Oceania as well as among blacks in Africa and not be distinguished from Treponema pallidum America. (the causative agent of endemic syphilis and Throughout the twentieth century, most venereal syphilis). These treponemes are found studies assumed that nutritional deficiency mainly in the lower Malpighian layers of the epi- leads to pica. Although iron deficiency is as- dermis and may be present for years before the sumed to be the major cause, other elements, skin lesions eventually become inactive and de- especially zinc, have also been investigated. Yet, pigmented. Large areas may be infected, and the despite the fact that iron-deficiency anemia disease may remain infectious for a long period. and pica have been associated for centuries, the It is unusual for other areas of the body, such as question of whether pica is a cause or an ef- the genitals, to be involved. In contrast to the fect of the anemia is still debated. Moreover, other human treponematoses, the skeleton is although both children and pregnant women never affected. practice pica, there is no clear understanding of This chronic clinical condition usually begins the mechanisms causing the behavior. Pica has in childhood and lasts into adulthood, if not for been recognized by physicians since the begin- most of the infected individual’s lifetime. Social ning of history, but medicine has yet to under- and hygienic factors result in differential inci- stand its causes. dence of the disease in varying components of Brian T. Higgins Latin American societies, with native Indians,

250 110. Plague of Athens mestizos, and blacks being most affected. In- It appears, however, that the earliest recog- fection seems most likely to be by skin con- nizable description of pinta as a separate dis- tact. Insect vectors have also been suggested ease was not recorded until 1757 in Mexico. as a means of transmission, but this has not Because of the possible similarities to leprosy been substantiated. Serologic reactions are pos- in regard to skin changes, it is not so surpris- itive early, then increase in degree. Experiments ing that a medical commission in 1811 reported show that there is cross-immunity to a varying on it as leprosy. In 1889, pinta was viewed as extent in individuals infected with T. carateum, perhaps linked to syphilis and was thought to T. pallidum, and Treponema pertenue. be transmitted by venereal contact. Indeed, this There is no chancre. The condition begins as hypothesis seemed to support accounts that re- an extragenital papule, usually situated in the ported the efficacy of mercury in the treatment lower extremity (and perhaps associated with of pinta and the fact that infected individu- damage to the skin surface). Within 3 weeks, als who worked in mercury mines felt better. the papule has expanded into a reactive patch of The positive Wassermann reaction was demon- circinate form, termed a pintid. In the next few strated in 1925, but the true nature of this dis- months, a more general rash occurs on the face tinctive treponemal condition was not recog- and limbs, which can be similar in appearance nized until 1938. to diseases such as psoriasis, ringworm, and Don R. Brothwell eczema. Histologically, hyperkeratosis and intercellu- lar edema are evident, with an increase of lym- phocytes and plasma cells. In adults, there are 110. Plague of Athens usually pigmentary changes in the later stages. Bluish patches are perhaps most characteristic, The Greek historian Thucydides interrupts his but lesions may be white. Pigmentary function history of the Peloponnesian War between is clearly disturbed, and in the white patches Athens and Sparta to describe a virulent epi- pigment is absent. It should be emphasized that demic in 430 B.C. Expanding rapidly in early other treponematoses can start out to some ex- summer, it was far more lethal than other epi- tent like pinta, but the others progress beyond demics Thucydides had known, and he claimed purely skin changes. The disease is not trans- that the novelty of the disease left Greek physi- mitted to the fetus. cians powerless to deal with it. The epidemic was said to have begun in Africa, south of History Ethiopia, spreading first to Egypt and Libya, then Pinta is believed to be most prevalent in Mexico, Persia, then Greece. Venezuela, Colombia, Peru, and Ecuador. It is an “old” disease in the Americas, clearly Characteristics present before the arrival of Europeans. Al- The stricken initially complained of “violent though relatively mild, it has tended histori- heat in the head,” coryza, swollen and inflamed cally to evoke a variety of social responses. In eyes, throat, and tongue, proceeding to violent some instances the pintados or “spotted ones” coughing. Then the victims usually began to have been shunned, much like lepers in the Old vomit, the disease bringing on “all the vom- World. Yet in other circumstances their distinc- its of bile to which physicians have ever given tive appearance brought them high status. For names.” Death claimed many of the sufferers in example, Montezuma, the Aztec emperor, se- 7–9 days, a merciful end to wrenching convul- lected such individuals to bear his litter, and sions, intense internal heat, and extreme thirst. they were apparently frequently formed into Thucydides described an exanthem character- special elite battalions in Mexican history. izing many cases: The skin, not hot to the touch,

251 110. Plague of Athens took on a livid color, inclining to red, and break- most recently, tularemia have found scholarly ing out in pustules and ulcers. However, he did proponents. not offer clear comment about the distribution The facts that (1) the Plague of Athens oc- of the rash, thus permitting much disagreement curred during wartime; (2) the severe clinical in the literature. course lasted 7–10 days; and (3) the fever was Causing almost equal difficulty for medical accompanied by first respiratory, then gastroin- observers today is Thucydides’ description of testinal complaints, and finally delirium associ- the behavior of sufferers, hurling themselves ated with a rash – all have led several physician- into wells and cisterns in order to assuage the historians to a diagnosis of epidemic typhus. “inner heat” and satisfy their thirst. Thucydides Typhus is a louse-borne disease, and severe does not identify any age group, sex, or socioe- cases could lead to circulatory collapse, ac- conomic category among those most at risk, counting for the loss of distal extremities (fin- rather emphasizing that the previously healthy gers and toes) as well as damage to the optic were as likely to suffer and die as those pre- nerve. viously debilitated by illness. He claims that Insofar as Thucydides mentions vision loss as 1,050 of 4,000 adult male soldiers perished well as crippling of the extremities among some in the epidemic – a high mortality rate even survivors, William MacArthur and Harry Keil, if all were afflicted. Pericles, the great orator writing in the 1950s, both found more support and leader of Athens, apparently perished from for this diagnosis of the clinical symptoms than the sickness, but Thucydides and Socrates did for that of smallpox. By contrast, Hans Zinsser not. Thucydides assumes that the disease was – author of the 1935 work, Rats, Lice, and His- contagious, and no one has questioned that tory – was not persuaded that the description assumption. Thucydides offered bore any resemblance to the The epidemic lingered for 4 years in south- typhus that cost many lives in the two world ern Greece, killing up to 25 percent of the wars. Yet other clinicians, citing their clinical population (if one accepts the highest mortal- experiences in wartime, have been equally per- ity estimates). No subsequent epidemics in the suaded that the description of Thucydides does Hellenic and Hellenistic Greek hegemony are suggest typhus. comparable to this epidemic in magnitude. Be- J. F. D. Shrewsbury, however, has argued cause the epidemic, according to Thucydides against a diagnosis of typhus, pointing out that and to many later historians of ancient Greece, Thucydides made no mention of either cloudy was responsible for Athenian military losses to mental state or depression, both among the ty- Sparta, many have judged the Plague of Athens phus symptoms most frequently reported over to be a “turning point” in the history of Western the last 500 years. Shrewsbury emphasizes the civilization. generally good personal and domestic cleanli- ness of the ancient Greeks, in order to argue that Historiography they were not lousy and thus could not have Although many have speculated on causal transmitted typhus with ease. Yet Keil has pro- questions surrounding the Plague of Athens vided an extensive survey of the words for lice and are convinced of their retrospective diag- found in Greek texts of the fifth century B.C., noses, no consensus is likely to emerge. Fairly which indicates that they were hardly uncom- well-supported arguments have advanced mon. Even so, Shrewsbury argues that typhus epidemic typhus, measles, and smallpox as is too mild a disease to have killed a quarter of candidates because all produce some of the those who fell ill, and consequently, he holds clinical and epidemiological features of Thucy- that some virgin-soil epidemic of a viral nature dides’ description. Less frequently, bubonic was the more probable cause of the Plague of plague, ergotism, streptococcal infection, and, Athens.

252 110. Plague of Athens

Indeed, Shrewsbury favored a diagnosis of Edna Hooker and many predecessors inclined measles, as did classicist D. L. Page. Shrewsbury toward a diagnosis of bubonic plague. Littman points to similar levels of mortality in the se- and Littman, however, argue against bubonic vere virgin-soil epidemic of measles in the Fiji plague, dismissing any possibility that the Islands in 1876, where more than 25 percent of terms Thucydides chose could refer to buboes the native population died. He considered the (lymphadenopathy associated with plague). most significant passage in Thucydides to be Another hypothesis suggests that ergotism, the description of sufferers plunging themselves caused by fungal toxins in grain, explains the into cool water for relief. The Fiji Islanders dis- Plague of Athens, even though Athenians rarely played identical behavior. Because even in the ate rye, the grain on which ergot usually grows. twentieth century, measles in adults could be The occurrence of gangrene in extremities of malignant, causing severe diarrhea and pneu- victims who survived is, supporters maintain, monia, he argued that the Plague of Athens an important symptom, which does not sup- might have been measles in an early virulent port other diagnoses but does support one of form, not the “emasculated” modern virus. Page ergotism. agrees that the Plague of Athens was measles, John Wylie and Hugh Stubbs have provided feeling that the clarity of Thucydides’ account a review of those infections with a wide host was such that little support can be found in the range that might have caused this level of hu- text for other diagnoses; that is to say, Thucy- man mortality 2,400 years ago, and thus they dides, although a layman, was not guilty of consider zoonoses other than plague and ty- omitting crucial diagnostic details that medical phus. Alexander Langmuir and colleagues have contemporaries would have noted. revived a pre-twentieth century diagnosis of in- Robert J. Littman and M. L. Littman, however, fluenza, but emphasize that concurrent or sub- have more recently argued for smallpox as the sequent staphylococcal infection could easily disease called the Plague of Athens, on the ba- have created a toxic-shock syndrome, with se- sis of the specific terms used by Thucydides to vere respiratory symptoms, bullous (or vesicu- describe the exanthem or rash of the infection lar) skin infections, and violent gastrointestinal in question. Using Page’s careful retranslation, symptoms. As staphylococcal infection height- the Littmans emphasize terms meaning “small ened the mortality from influenza in 1918, so blister” or “pustule” and “ulcer” or “sore,” con- a similar combination of viral and bacterial in- tending that the description could refer only fection could explain the great Plague. On the to a vesicle-forming eruption. In other words, other hand, Holladay takes issue with this latter Thucydides’ description suggests a diagnosis explanation. of smallpox, because neither measles nor ty- Study of the epidemic briefly described by phus typically forms vesicles in the exanthem. Thucydides has inspired discussions of how dis- Moreover, the description hints strongly at the eases in the distant past can be identified, and centrifugal spread of the rash, from face and thus discussions of the methods of historical trunk to extremities, again confirming a diagno- epidemiology. Three difficulties emerge in the sis of smallpox. The fact that Thucydides does literature of the Plague of Athens that are il- not mention pockmarks among the survivors lustrative of problems in retrospective diagnos- is found by the Littmans to be without import tic efforts. The first has to do with virgin-soil because they believed he was more concerned epidemics. Although Thucydides only implies with the military impact of the disease than that all members of society were at risk of con- long-term effects on the survivors. In addition, tracting the sickness, that no one was immune, the Littmans point to the absence of reference and that immunity was conferred on the sur- to pockmarking even in some modern medical vivors of infection, he does specifically state accounts of smallpox. that the disease was previously unknown to lay

253 111. Pneumocystis Pneumonia (Interstitial Plasma Cell Pneumonia, Pneumocystosis) and medical Athenians. Some scholars hold that vived (the account claims that most died early a new disease among a population immuno- in the epidemic), individuals tended to believe logically virgin to the microorganism in ques- that their own experience with an infection was tion need display neither the expected seasonal characteristic of all those who suffered from it. onset characterizing the disease nor the case- Most assume, however, that Thucydides’ ac- fatality rates usually seen. Those who oppose count of events lacks some crucial details from a this methodological stance hold that this prin- modern point of view but is otherwise accurate. ciple of retrospective analysis calls into ques- Since Page’s review, which offers abundant de- tion all diagnostic precepts. Many assume that tail that Thucydides was particularly well versed supramortality would cause a breakdown in in medical terms and ideas, most have come to normal nursing care and hygienic services, lead- believe that the account was informed by con- ing to excess mortality; therefore, they stress the temporary medical knowledge. Longrigg agrees, need for distinguishing the socioeconomic ef- but skeptically. Jody Pinault, however, tracing fects of a virgin-soil epidemic from discussions an ancient legend that Hippocrates himself de- of the virulence of the disease or the immuno- vised the successful remedy of building fires logic vulnerability of the population. to combat the epidemic at Athens, argues that The second difficulty pertains to the chang- Thucydides’s failure to mention Hippocrates’s ing epidemiology (or even clinical presentation) achievement is compelling evidence that he was of diseases over time and thus is a variation not at all well versed about the Plague. of what is called “virgin-soil epidemics argu- Clearly, discussions of the cause of the Plague ment”: that infections of the past may have been of Athens form an important and instructive ex- caused by an organism known today but that ample of the study of the history of human in- the organism behaved quite differently in past fectious diseases. In addition, such a study re- individuals and populations. From a historical veals the many pitfalls connected with this type standpoint, this can be a particularly pessimistic of integration and points to the need for still argument, and in fact James Longrigg has dis- more sophisticated methods and techniques. allowed the possibility of ever discovering the Ann G. Carmichael cause of the Plague on much these grounds. Poole and Holladay go even further in deny- ing any possible resemblance of the Plague of Athens to an infectious disease known in more 111. Pneumocystis Pneumonia (Interstitial recent times, whereas Langmuir and colleagues Plasma Cell Pneumonia, Pneumocystosis) suggest that the discussion abandon altogether the hope for a one-to-one correspondence with This form of pneumonia is caused by Pneumo- a modern infectious disease and look instead to cystis carinii,aprotozoan in the class Sporo- a physiological understanding of the processes zoa. An extracellular parasite of the lungs involved. of humans, dogs, rodents, and other mam- The third difficulty focuses on the intent and mals, the organism occurs worldwide. It ap- fidelity of Thucydides’ account to actual events. pears to have low virulence and almost never Of the authors discussed here, only Watson causes disease except in weak or immunosup- Williams argues that Thucydides himself might pressed individuals. P. carinii was discovered in not have been terribly well informed about the guinea pigs in 1909, but human disease was epidemic, because he did not write his history first recognized in the 1940s in malnourished until after 404 B.C., approximately 25 years af- and premature infants. Victims of leukemia, ter the epidemic occurred. Williams further sug- Hodgkin’s disease, and other immunosuppres- gests that even if Thucydides wrote from notes sive diseases, or organ-transplant recipients and or consulted one of the few physicians who sur- others whose treatment requires suppression of

254 112. Pneumonia immune responses, are also vulnerable to infec- ticularly contagious condition usually localized tion. In the early 1980s, pneumocystis pneu- to part or all of one of the five lobes of the lungs, monia achieved prominence as the most com- and caused by a pneumococcus, Streptococcus mon opportunistic infection afflicting patients pneumoniae (formerly Diplococcus pneumoniae). with acquired immune deficiency syndrome Untreated lobar pneumonia has a mortality of (AIDS). Over half of AIDS victims suffer from about 30 percent, but the advent of antibiotic the disease, and it frequently is the proximate treatment has improved survival rates. cause of death. Several other pathogens (bacterial, viral, fun- Transmission is usually by airborne droplets, gal, and parasitic), chemical irritation, expo- although transplacental passage resulting in fe- sure to or aspiration of noxious substances, tal death has been reported. Latent infection and hypersensitivity are also recognized causes. may be common, with clinical disease and In many cases, pneumonia is only one man- droplet transmission developing only in weak- ifestation of another specific disease such as ened hosts. The parasite damages the alveolar the acquired immune deficiency syndrome walls and induces an abundant foamy exudate (AIDS), ascariasis, cytomegalovirus, influenza, and fibrosis. Death results from asphyxiation by Legionnaire’s disease, plague, pneumocystis, the exudate. Although initial response to chem- Q fever, rickettsial diseases, tuberculosis, tu- ical therapy is common, treatment is difficult laremia, and varicella. because of drugs’ side effects and patients’ de- bilitated state. Characteristics K. David Patterson Many pathogens have been associated with in- fectious pneumonia. However, despite the large number of possible pathogens, pneumonia de- velops only if other host or environmental con- 112. Pneumonia ditions are met. Normally the airways and lung tissue distal to the throat are sterile. Occasion- Pneumonia is an acute inflammatory condi- ally, organisms that are always present in the tion of lung parenchyma (lung tissue exclud- upper airway, in the digestive tract, or on the ing the airways) caused by a variety of infec- skin enter the lung. Ordinarily they are rapidly tious agents and toxins and favored by aspects eliminated either by mechanical means, such as of the environment and/or the general physical coughing and the microscopic action of cilia, or status of the patient. The term “pneumonia” is by immune mechanisms. Infection and the re- derived from a Greek word meaning “condition sultant inflammation of pneumonia can occur about the lung” and refers to a clinicopatholog- in healthy individuals but are often associated ical state that arises in several different yet spe- with a breakdown in one or more of the usual cific disease patterns. All of these are character- defense mechanisms – or, more rarely, with ex- ized by some degree of fever, cough, chest pain, posure to a particularly virulent pathogen or and difficulty in breathing. Technically speak- an unusually high aerosol dose of organism (as ing, pneumonitis (“inflammation of the lung”) in Legionnaire’s disease). Occasionally, bacterial is a synonym for pneumonia, but the former pneumonia will occur as a result of septicemic is usually reserved for benign, localized, and spread from an infectious focus elsewhere in the sometimes chronic inflammation without major body. toxemia (generalized effects). Many modifiers Immune defenses are altered by underlying are applied to the term pneumonia to reflect debility, be it nutritional (starvation and alco- cause (e.g., embolic pneumonia) and localiza- holism), infectious (tuberculosis and AIDS), neo- tion (e.g., bronchopneumonia). The classic form plastic (cancer or lymphoma), or iatrogenic. is lobar pneumonia, an infectious but not par- Iatrogenic causes of immune depression are

255 112. Pneumonia becoming more important with the increas- United States, where mortality is estimated to ingly frequent use of immunosuppressive or cy- be approximately 0.3 per 1,000. totoxic drugs in the treatment of cancer, au- The incubation period for pneumonia is vari- toimmunity, and organ transplantation. One able, depending on the causative organism, but special form of immune deficiency resulting pneumococcal pneumonia has a fairly uniform from absent splenic function leads to an ex- pattern. A brief prodrome of cold-like symp- aggerated susceptibility to S. pneumoniae in- toms may occur, but usually onset is sudden, fection and lobar pneumonia. This condition, with shaking chills and rapid rise in temper- called functional asplenia, can arise following ature, followed by a rise in heart and respira- splenectomy or as a complication of sickle-cell tory rates. Cough productive of “rusty” blood- anemia. Thus a relative predisposition to pneu- tinged sputum and dyspnea are usual. Most mococcal infection can be found in the geo- patients experience pleuritic chest pain. In se- graphic regions containing a high frequency of vere cases, there can be inadequate oxygena- hemoglobin S. tion of blood, leading to cyanosis. If untreated, Controversy surrounds the ancient etiologic the fever and other symptoms persist for at least theory about cold temperatures, but two fac- 7–10 days, when a “crisis” may occur consist- tors do tend to support an indirect correlation ing of sweating with defervescence and spon- between cold and pneumonia: Predisposing vi- taneous resolution. With antibiotic treatment, ral infections are more common in winter, and the fever usually falls within 48 hours. Un- some evidence suggests that the mechanical ac- treated, or inadequately treated, the disease may tion of cilia is slowed on prolonged exposure to progress to dyspnea, shock, abscess formation, cold. empyema, and disseminated infection. When Lobar pneumonia appears in all populations. empyema occurs, surgical drainage is essential. Incidence and mortality are higher in individ- uals or groups predisposed to one or more of History the factors described above. Elderly patients Lobar pneumonia has probably always afflicted frequently develop pneumonia as the terminal humans. Pneumococcal organisms have been complication of other debilitating illness, hence found in prehistoric remains, and evidence of the famous metaphor “friend of the aged.” illness has been observed in Egyptian mum- Mortality rates for pneumonia are difficult mies from 1200 B.C. Epidemics of this disease to estimate because of its multifactorial nature have probably been less common than pre- and complication of other diseases. With antibi- viously thought. Pre-germ-theory observations otics, fatalities are reduced to a varying extent cited sixteenth to late-nineteenth century re- depending on the underlying condition of the ports of epidemic outbreaks of “pneumonia” patient, but in persons over age 12, mortality in numerous places on six continents, empha- is at least 18 percent, and in immunocompro- sizing “malignant” and typhoid-like symptoms. mised persons much higher. Atmospheric pol- But these qualifiers raise doubts about whether lution may have contributed to the apparent such outbreaks were truly pneumonia. It is rise in pneumonia mortality in Britain during probable that most, if not all, were caused by or- the last half of the nineteenth century. Toward ganisms other than pneumococcus. Conditions the end of that century, William Osler saw pneu- now called by other names and known to have monia as one of the most important problems of pneumonic manifestations, like plague and in- his era and applied to it John Bunyan’s metaphor fluenza, are far more likely candidates for retro- (originally intended for tuberculosis): “captain spective diagnosis. of all these men of death.” Contemporary pneu- Pneumonia is not only an old disease but also monia mortality combined with influenza is still one of the oldest diagnosed diseases. Hippo- the sixth most common cause of death in the cratic accounts of a highly lethal illness called

256 112. Pneumonia peripleumonin give a readily identifiable de- terms for pathological lung sounds – including scription of the symptoms, progression, and “rale,” “rhoncus,” “crepitation,” “bronchophony,” suppurative complications of classic pneumo- “egophony” – some of which became pathog- nia and localize it in the lung. This disease nomonic for disease states. Percussion and aus- was a paradigmatic example of the Greek the- cultation changed the concept of pneumonia ory that all illness progressed from coction (ap- from a definition based on classic symptoms to proximately, incubation and early illness) to cri- one based on physical findings. This conceptual sis and lysis (“breaking up”), while certain days shift was endorsed by the advent of the chest in the sequence were “critical” to the outcome. X-ray at the turn of the twentieth century. Auscultation was recommended to confirm the The Italians Giovanni Rasori and Giacomo presence of pus in the chest. Variant pneumonic Thommasini had recommended high-dose an- conditions of the lung were also described, in- timony potassium tartrate (tartar emetic) as a cluding lethargy, moist pneumonia, and dry treatment for pneumonia, and Laennec used the pneumonia (also called erysipelas of the lung). new method of statistical analysis with histori- Therapy included bleeding, fluids, expectorants, cal controls to suggest that this was an effec- and, only if absolutely necessary, surgical evac- tive remedy. Yet in spite of its potential utility, uation of empyemic pus. the extreme toxicity of the drug guaranteed its In the first century A.D., Aretaeus of Cappado- unpopularity. Benjamin Rush, an American, and cia distinguished this disease from pleurisy, Laennec’s contemporary, Jean Baptiste Bouil- and four centuries later Caelius Aurelianus rec- laud, were proponents of copious phlebotomy. ognized that it could be confined to only certain Until the late nineteenth century, when sal- parts of the lung. Except for a few subtle mod- icylates became available for fever, pneumo- ifications, little change occurred in the clinical nia therapy consisted of the ancient remedies: diagnosis and treatment of pneumonia until the emetics, mercury, and especially bleeding. early nineteenth century. Germ theory had a major impact on the con- Eighteenth century anatomists drew atten- cept of pneumonia, but it was rapidly appar- tion to the microscopic appearance of the ent that despite its fairly homogeneous clini- lung in fatal cases of lobar pneumonia. This cal manifestations this disease was associated work, however, had little impact until 1808, not with a single germ but with a variety when Jean-Nicolas Corvisart at the Paris Clinical of pathogens. This situation cast some doubt School translated and revised the 1761 treatise on the imputed role of each new pathogen. on percussion by Leopold Auenbrugger. This In December 1880, Louis Pasteur isolated the technique made it possible to detect and local- organism that would later become the pneu- ize fluid or consolidation in the lung and to mococcus. Carl Friedlander discovered the first follow its evolution. Eight years later, Corvis- lung-derived pneumonia organism, Klebsiella art’s student, Rene´ Laennec, carried this one step pneumoniae (Friedlander’s bacillus) in 1883. further by inventing the stethoscope. In call- Albert Frankel identified the pneumococcus (D. ing his technique m´ediate auscultation, Laennec pneumoniae) in 1884, and Anton Weichselbaum readily gave priority to Hippocrates for hav- confirmed his findings in 1886. Klebsiella was ing practiced the “immediate” variety by direct found to be quite rare and seemed to favor application of the ear to the chest. Laennec the upper lobes, whereas the pneumococcus fa- recommended both percussion and ausculta- vored the lower lobes; however, there was some tion of the breath sounds and voice to confirm overlap between the pneumonic states induced the physical diagnosis of pneumonia. With this by these organisms. Specific diagnoses could be combination he was able to distinguish consol- made only by isolation of the pathogen. idated lung from pleural fluid or pus in the liv- Gradually many other organisms and viruses ing patient. He introduced most of the technical came to be associated with pneumonia, usually

257 113. Poliomyelitis in clinical settings that deviated more or less 113. Poliomyelitis from classic lobar pneumonia. Moreover, it is likely that new pathogens will be recognized as Poliomyelitis is a disease of inflammation and antibiotics and vaccination alter the ecology of destruction of motor neurons caused by a po- the lung. liovirus. Sensory functions are not affected. Al- Knowledge of the pneumococcus led to im- though frequently asymptomatic, the infection provement in treatment and reduction in mor- may cause fever and a number of other general tality from pneumonia, but it also had a major symptoms, described as abortive polio or mi- impact on the broad fields of immunology, bac- nor illness. Occasionally, however, these prodro- teriology, and molecular genetics. Study of the mal symptoms are followed by a central nervous capsule – its antigenic properties and capacity system infection and fever, with meningitis,or to transform – provided key information about paresis (weakness) or paralysis of one or more drug resistance in bacteria. muscles. Many patients recover use of affected Treatment and prevention of pneumonia muscles in subsequent months, although some have been dramatically improved in the twen- have permanent paralysis or paresis. When res- tieth century. Oxygen therapy was introduced piratory muscles are affected, death may follow. during the 1918 New York influenza epidemic. In the past, cases of abortive polio and tempo- Typing of pneumococci led to the 1912 intro- rary paralysis were often included in polio statis- duction of antisera; it was claimed that, by 1929, tics. Today, only cases with paralysis or pare- this therapy dramatically reduced mortality in sis after 3 months are recorded as paralytic some populations. Antisera, however, were ef- polio. fective only when the exact type of pneumococ- Poliomyelitis was known by different names cus was known. Pronotosil (sulfanilamide) was (such as infantile paralysis and “Heine-Medin not particularly effective against pneumococcus disease”) until the 1870s, when it became but did control other predisposing conditions. known as acute anterior poliomyelitis.Po- Its successor, sulfapyridine, was more effective. liomyelitis – inflammation of the gray marrow – The advent of penicillin in the mid-1940s led eventually became the name of choice and is of- to further reduction in mortality; however, it ten shortened to polio. also led to the evolution of penicillin-resistant strains of pneumococci and the now seemingly Characteristics endless chase after effective derivatives against There are three immunologic types of po- so-called new organisms. liovirus, with strain differences in each. Each Pneumonia-control programs relied at first on type has a wide range of ability to cause paraly- antipneumococcal serum therapy, but as early sis, from the highly virulent type 1 Mahoney as 1911, vaccination trials were conducted on strain to avirulent wild and vaccine strains. thousands of black South African gold min- Wild strains may paralyze only a few individuals ers. These trials (conducted before the diver- while immunizing others. The introduction of a sity of capsular types was fully appreciated), new virulent strain, however, may cause an epi- were inconclusive. Not until 1945 was unequiv- demic, as in Malta in 1942. Strains differ widely ocal protection against type-specific pneumo- in their transmissibility: In Malta, the pattern coccal infection in humans demonstrated using of cases suggests that everyone was rapidly in- a tetravalent vaccine. Contemporary vaccines fected. But many small epidemics have spread contain at least 23 capsular antigens and are no further than those initially afflicted. 80–90 percent effective in immunocompetent The virus spreads from person to person via persons but may be useless in some forms of the fecal-oral route, although a few epidemics immunodeficiency. may have resulted from contaminated milk. In- Jacalyn Duffin gested virus replicates in the gut and lymphoid

258 113. Poliomyelitis tissue. The level of viremia correlates with vir- potential problems of the cold chain. On the day ulence; there is little viremia with avirulent of immunization (which is heavily advertised), strains. Animal experiments indicate that the all available children 2 years and younger re- protecting antibody level is below the detection ceive OPV. The flood of virus shed by vaccinees threshold. Exposure leads to lifelong immunity then vaccinates any who did not receive OPV. against viruses of the same type. People who Inactivated polio vaccine is more stable and are immune may still be infected but have no may be combined with other vaccines, thus sim- viremia. Humans are the only natural host and plifying immunization schedules and reducing reservoir. cost. The latest IPV is very safe, highly purified, Since 1910 it seemed that immunization and antigenic. might be feasible, but first attempts in 1935 Epidemics of polio are difficult to assess be- ended with deaths attributed to the vaccines. cause several polioviruses of different virulence Many vaccines were made for experimental use, and type may be circulating. Thus the extent of but a human vaccine was not possible until the circulation of virulent viruses will not be known, virus could be grown in quantity, the number of and cases will not necessarily correspond to types established, and cheap methods of test- the geographic boundaries used for reporting. ing for viruses and antibodies developed. J. F. Consequently, our epidemiological knowledge Enders, T. H. Weller, and F. C. Robbins grew po- of the disease depends on the study of virgin- liovirus in 1948 and solved all three problems. soil epidemics in islands and isolated commu- In 1954, Jonas Salk’s inactivated polio vaccine nities with definite boundaries. (IPV) was given to 400,000 children in a success- Until the early twentieth century, most polio ful field trial involving 1.8 million children. The cases occurred in young children. Beginning in 1980s produced a purified and more antigenic the 1930s, however, there was a shift to older IPV that required two doses instead of three. children and adolescents, first in Scandinavia In the 1950s, A. B. Sabin produced an oral and the United States, and then in Europe. Older polio vaccine (OPV), which has been used ex- children suffered less paralysis, and fatality rates tensively throughout the world. The Sabin vac- were low. By contrast, young adults had paraly- cine has many advantages: (1) It can be ad- sis and fatality rates like those of small children. ministered by nonmedical staff; (2) it induces In many severe epidemics, case rates for 2-year- gut immunity; (3) it is inexpensive; and (4) im- olds have been about 2 percent, with increasing munity spreads to nonvaccinated individuals. rates up to 10 years of age, when the rate stabi- Yet it also has disadvantages: (1) Three doses lizes at 25 percent. are required; (2) it is inactivated by heat; and Early epidemiological surveys included all (3) it causes some vaccine-associated cases cases whether there was residual paralysis or (VAC). Purely as a precaution, the Sabin vac- not. From the late 1930s, however, statistics cine is not given to pregnant women. About one were increasingly restricted to those with paral- child in a million given OPV develops paraly- ysis, and later only those with residual paral- sis. A very small number of contact VACs oc- ysis. In countries with universal immunization cur, mainly among mothers of OPV-vaccinated and very few cases, every suspected case is children. investigated. Oral polio vaccine is successful in temperate For reasons unknown, there are more male climates but less so in many warmer developing than female cases of polio at any age; however, countries, largely because cold-chain facilities pregnant females have higher incidence than and organization are lacking. The most effec- nonpregnant females of the same age. Fatality tive method of immunization is the semiannual rates of males and females are similar. Studies “polio day.” Vaccine is distributed to local immu- of afflicted pregnant women show no increase nization posts a few days in advance, reducing in miscarriages and no affected births. Yet when

259 113. Poliomyelitis mothers suffered paralysis between 7 days be- animal experiments, however, it was observed fore and 10 days after birth, 40 percent of babies that 75 percent of infected neurons recover. Sec- suffered concurrent paralysis, with a 56 percent ond attacks by another poliovirus presumably fatality rate. By contrast, babies born of moth- should occur; yet only 44 have been reported – ers who had experienced paralysis earlier in far less than expected. This does suggest, how- the pregnancy (nonconcurrent) had a less than ever, that second attacks are not blocked by 0.01 percent chance of polio in the month after antibodies. birth and only a 10 percent case-fatality rate. There are two theories as to how virus reaches History the central nervous system (CNS). The first sug- Polio may be as old as humankind, but few gests that virus crosses the blood-brain bar- early indicators of the disease exist. An Egyp- rier and travels along neuronal pathways in the tian stele (c. 1400 B.C.) shows a priest with a CNS. However, postmortems reveal that lesions deformed foot in the typical equinus position of in the CNS can be discrete and separate, sug- polio. During the 1830s, three small epidemics gesting that virus enters at motor neurons in were reported from England, the United States, the muscles and reaches the CNS at many dif- and St. Helena. In the 1890s and early 1900s, ferent places. The time taken to reach the CNS greater epidemics were reported in Scandinavia, from any muscle depends on the length of the Massachusetts, and Vermont, and then the nerve to be traveled, during which time the New York epidemic of 1916 occurred, with over virus would be shielded from antibody. 9,000 cases in the city itself. Almost all pa- Leg muscles are more often affected than tients in the New York epidemic were under arms. In general, the larger the muscle, the 5 years of age. After this, polio cases in the greater the chance of paralysis; the smaller the United States fell to a low level, then exhibited muscle, the greater the chance of paresis. Mus- peaks and troughs, and then rose again to some cles are not affected at random. The neurons 40,000 cases annually in 1951–55. serving them lie in adjacent and overlapping After 1955, with widespread use of IPV in the bundles in the CNS: Damage in one bundle of- United States, Canada, South Africa, Australia, ten spills over into the next, so there is a high and some countries in Europe, cases fell dra- probability that both muscles will be affected. matically. Not all children were immunized, and Up to 60 percent of the neurons serving a small epidemics still occurred among the poor- muscle may be destroyed before loss of func- est classes. But soon almost all countries in tem- tion occurs; thus patients with past nonparalytic perate climates were using vaccine, and vaccine CNS infection can have considerable damage. potency was improved. Nonetheless, by 1960 Many survivors suffer late effects of polio (LEP) many doubted that IPV would eliminate polio. more than 30 years later. Previously unaffected By the end of 1960, however, Sabin’s OPV, muscles become weak; already affected mus- given to more than 115 million people in Russia cles become weaker; generalized fatigue occurs. and eastern Europe, had practically eliminated Most commonly affected are those muscles that polio there. Gradually, opinion favored routine recovered well from the initial attack and have use of OPV instead of IPV, although Scandi- been used strenuously ever since. Loss of mo- navia and Holland continued to use IPV. With tor neurons continues with age, and LEP may these exceptions, beginning in 1961, OPV was indicate normal aging superimposed on previ- increasingly used in temperate countries, and ous polio loss. the number of cases fell even lower. But small In the acute stage, the condition resembles epidemics still struck communities that refused a host-versus-graft reaction. Infected neurons immunization or lacked primary health care. are destroyed, although the inflammation does The United States now has about 10 cases a year, not correspond with the location of virus. In roughly half of which are vaccine-associated.

260 114. Protein-Energy Malnutrition

By contrast, in Holland there is a large com- annually, immunizes fewer than half, and lame- munity that rejects immunization on religious ness surveys show rising prevalence among grounds and has suffered eight epidemics since older children despite increased use of vaccine. 1960. Polio has not, however, spread to the Indeed, in India, surveys of all kinds reveal a immunized population. The epidemic that oc- steady increase in prevalence since 1945. This curred in 1978 produced 110 cases with 79 par- increase, however, may merely reflect better re- alytic (one baby died). During that outbreak, porting and investigation. the virus was carried to Canada. Cases occurred H. V. Wyatt in Alberta, British Columbia, and Ontario, after which polio reached Pennsylvania, then Iowa, Wisconsin, and Missouri, and then returned to Canada, causing 21 cases and three nonpar- 114. Protein-Energy Malnutrition alytic attacks in North America. Genomic se- quencing confirmed that the same virus was Protein-energy malnutrition (PEM) – or, as involved for over 15 months on both conti- it is still sometimes called, protein-calorie nents. It may well have originally come from malnutrition – is a term of convenience that Turkey. refers to a range of syndromes among infants Polio was previously thought to have low in- and children of preschool age in whom man- cidence in developing countries, although it oc- ifestations of growth failure occur because curred in such diverse and remote places as of protein and energy deficiencies. In most St. Helena, Greenland, and Nauru, which instances, this condition besets those in the suffered severe epidemics. Despite outbreaks less-developed world of Asia, Africa, and Latin among Allied troops in the Middle and Far East America, where dietary factors are thought to and India during World War II, little attention be a crucial part of the etiology. PEM thereby was paid to the disease, epidemics in Singapore, tends to exclude what is conventionally known the Andamans, and Bombay notwithstanding. as “failure to thrive” in Europe and North Early data from developing countries were America, in which the vast majority of cases based on hospital admissions and seriously un- result from organic disorders such as cystic derestimated the true number of cases. Even in fibrosis and congenital heart disease and are the 1980s, country statistics sent to the World not so directly associated with diet as such. Health Organization represented perhaps only 10 percent of the true number. By way of il- Characteristics lustration, in Nigeria in 1977 more children at- PEM is best described in its two clinical ver- tended one clinic than the official number of po- sions of kwashiorkor and marasmus. In the lio cases for the entire country. Truer estimates former, edema is always present, whereas ex- are yielded by lameness surveys of schoolchil- treme wasting (below 60 percent of normal dren and seeking out disabled children who do weight for height) identifies the latter. However, not attend school. Unfortunately, such investi- cases purely of one or the other are the ex- gations always produce outdated data and do ception rather than the rule; most display both not include deaths. edema and extreme wasting, plus a variable mix Very promising immunization programs are of other symptoms, and are designated by the under way in Central and South America, which term marasmic kwashiorkor. Far more com- reach more than 80 percent of children be- mon than these three clinical entities are nu- low 1 year of age. By contrast, in central Africa merous subclinical syndromes usually referred few countries achieve even a 50 percent immu- to as mild-to-moderate PEM. A frequent anal- nization rate of children under 1 year of age. ogy for PEM, therefore, is an iceberg; only a Similarly, India, with 22 million children born small proportion of the total is clearly visible.

261 114. Protein-Energy Malnutrition

Most cases remain below the surface and go This portrayal has proved not so much erro- undetected except under close analysis. neous as somewhat oversimplified. Clinical re- Numerous attempts have been made to de- search has verified that kwashiorkor is always velop a logically ordered, comprehensive clas- associated with low serum proteins, but consid- sification of PEM, but several problems have erable variation has been found in energy in- prevented the achievement of one satisfactory take. Some cases show deficits, whereas others to both clinicians and field workers. A partic- have adequate and occasionally even excessive ular dilemma is that the various syndromes energy levels. Protein deficiency is clearly sec- are not static. Mild-to-moderate cases fluctu- ondary to energy deficiency in marasmus and ate considerably and can move in the direction probably marasmic kwashiorkor. Indeed, if en- of kwashiorkor, marasmus, or marasmic kwash- ergy were not so severely restricted, it is un- iorkor. Moreover, clinical conditions may not re- likely that signs of protein shortages would be main constant: Kwashiorkor can become maras- observable. mus, and vice versa. An extremely important finding is that diet Traditional interpretations have stressed the does not seem to play quite the overarching role predominant role of diet in the etiology of PEM, in PEM that was initially believed. What is crit- with protein singled out as the most important ical is availability of nutrients to the cells, and missing ingredient. Critical shortages of pro- thus infections can act as an equal if not more tein alone, it was believed, led to kwashiorkor – important limiting factor. Included in these and when combined with severe energy deficits, infections are not only the various diarrhea- to marasmus or marasmic kwashiorkor. Mild- producing gastrointestinal disorders but also to-moderate syndromes simply reflected lesser widespread childhood diseases such as pneu- shortages of the two essential dietary require- monia, measles, tuberculosis, and malaria. All ments, protein and calories. can imitate symptoms of PEM by inducing The behavioral variables deemed most criti- anorexia and lowering amino acid levels, and cal in the past were duration of breast-feeding it is clear that malnourished children are more and subsequent food habits. Too-early wean- susceptible to serious episodes of infection. The ing onto poor-quality substitutes for mother’s various syndromes of PEM, therefore, are best milk such as rice water, sugar water, diluted construed as resulting from complex nutrition- milk or formula, and cornstarch was asso- infection interactions. Based on current knowl- ciated with marasmus. These substances are edge, it would appear that how they develop de- often contaminated with bacteria because of pends on how the life history of a child unfolds polluted water supplies and unsanitary uten- within a particular environmental context. sils; consequently, repeated bouts of diarrhea Many cases undoubtedly begin in the uterus. were seen to accentuate nutritional shortages. Because of widespread maternal malnutrition, Later-age weaning onto predominantly bulky low birthweights are common throughout Asia, carbohydrate/low amino acid foodstuffs, no- Africa, and Latin America. Breast-feeding on de- tably cassava and plantains, was seen as the mand during the first 4–6 months of life tends to pathway to kwashiorkor. Abrupt weaning was compensate for any fetal growth deficit and pro- believed especially hazardous, particularly if vides important disease immunities, but infants children had to compete for food from a “com- who are not breast-fed are well along a path- mon pot” with older siblings and adult males way to PEM. If a serious infection should ensue, who often monopolize high-quality protein then marasmus may very likely develop. If not, foods such as meat, fish, eggs, and milk. With then – at the least – growth failure continues, kwashiorkor, the problem was the balance of and the child remains at risk. protein and energy, not the quantity of food After about the first 6 months of life, breast- consumed, which generally appeared ample. feeding alone no longer provides adequate

262 114. Protein-Energy Malnutrition nutrition, and at this point many children begin The edema that defines all cases of kwashiorkor to show signs of mild-to-moderate PEM. Food varies. It can be mild and localized on the ex- supplies might be limited generally, or perhaps tremities and sacrum or more severe and gen- there is little knowledge of proper supplements. eral. Although muscle wasting is discernible, In any event, the course of PEM depends on subcutaneous fat is usually retained, and con- the severity of the food shortage – a “hungry sequently the child takes on a bloated appear- season” seems especially dangerous – and once ance, called the “sugar-baby” look in the West again on infections to which the child is ex- Indies. Some growth retardation in head length posed. When nutrition-infection stress is ex- and circumference may also occur. treme, then overt clinical symptoms of PEM can More often than not, the skin develops ulcer- be expected. ating areas, open and healed sores, scabies,or Weaning is frequently a time of stress, and “flaky-paint” dermatosis, in which removal of when it occurs at 18–24 months of age, symp- the flakes reveals lighter patches of skin. When toms of kwashiorkor tend to predominate over kwashiorkor persists, the hair is affected; it loses marasmus, assuming no gross deficiency of en- its luster, and dark hair becomes lighter. Curly ergy in the new diet. However, weaning by it- hair straightens, and eventually the hair be- self does not appear to produce kwashiorkor; comes brittle and falls out, leaving bare areas this is true even if staple foods are overwhelm- of scalp clearly visible. ingly starchy. The child must already be nu- Upon examination, the liver and spleen fre- tritionally disadvantaged or otherwise in poor quently are found to be enlarged, and a range of health before discernible symptoms of kwash- other symptoms includes anemia and vitamin- iorkor emerge. A deficiency, with some vision impairment; a The overriding etiologic issue, of course, is range of micronutrient deficiencies; plus ten- poverty, and PEM is a problem only where dencies to hypothermia, higher bilirubin, hy- poverty is pervasive. Poverty means that local ponatremia, hypoglycemia, and low plasma food shortages cannot be overcome by pur- albumin. chases, that living conditions foster recurring Behavioral changes are marked. Vomiting and infections, that education for effective inter- diarrhea become persistent; without resolution, vention is inadequate, that proper parental su- anorexia usually sets in. As the child’s strength pervision of the feeding of infants and young wanes, motor skills regress, and eventually he children is likely to be lacking, and that preven- or she becomes almost totally apathetic to ex- tive and curative health services are not readily ternal stimuli. This withdrawal makes treatment available. In a real sense, then, PEM is the out- difficult outside of a clinical setting where the come of “total deprivation.” Acceptance of this child can be fed intravenously. has led to recent shifts in policies designed to The overt symptoms of marasmus are far combat it. For many years, officials emphasized fewer and less medically unusual. Wasting of providing protein-fortified and energy-rich food both muscle and subcutaneous tissue, along substitutes or developing meat and dairy in- with stunting, is marked. Because the victim dustries, but these approaches have proven too is so emaciated, the head appears abnormally costly for most people in need and address only large, especially the eyes. The skin tends to be part of the problem. PEM must be attacked on dry and patchy, but neither dermatosis nor any a broad front, including economic and political significant hair changes appear. Anorexia is un- as well as nutritional intervention. common, and in fact appetite is usually good, In the earliest stages of PEM, the child simply which helps simplify therapy. As in kwashiorkor, appears smaller than he or she should be for there is likely to be hypothermia and a tendency that age. If the condition deteriorates further, to hypoglycemia. Dehydration is a problem as however, clinical symptoms begin to emerge. marasmus worsens, and behavior changes from

263 114. Protein-Energy Malnutrition fretfulness and irritability to a semicomatose History state immediately preceding death. PEM is undoubtedly as old as humankind. The With severe PEM, mortality is high – over term marasmus has referred to starvation for 20 percent. Seldom, however, is starvation the fi- centuries. However, medical literature fails to nal cause of death; rather it is one or more of the mention PEM specifically until about the mid- infections that brought on the condition, and nineteenth century, when concepts of mal- these usually run their fatal course in just a few nutrition were developing, especially among days. Onset of hypothermia and hypoglycemia pediatric specialists in France and Germany, probably signals the need for immediate who treated numerous childhood illnesses. One treatment. disorder, in particular, received considerable at- For those who have recovered, the question tention. Called mehlnahrschaden ¨ , it was at- of long-term effects remains. Available evidence tributed to diets based excessively on flour, supports a relationship between chronic PEM usually breads or thin gruels, with little milk or and some permanent stunting. But much more meat included. importantly, areas of chronic-PEM prevalence At the same time, in the wake of colonial also have a high incidence of cephalopelvic expansion, doctors began to report similar dis- disproportion among women, leading to mis- orders in many tropical areas. Although such carriages, stillbirths, and heightened maternal diseases were initially blamed on parasites, by mortality. Investigators suspect that PEM inter- the 1920s a dietary etiology gained some ac- feres with calcium metabolism, producing in- ceptance. A proliferation of terms ensued, such complete pelvic development, but this has not as “infantile pellagra,” “nutritional edema,” “in- been conclusively proven. There is also some fantile edema,” “starchy dystrophy,” and “fatty- suggestion that later-age cardiovascular dis- liver disease” – all describing, of course, what is ease, hepatic ailments, and pancreatic condi- now designated kwashiorkor, a term first used tions may be connected with childhood PEM. in the 1931–32 Annual Medical Report of the The issue that has stimulated the most in- Gold Coast (now Ghana). The term was taken terest and controversy, however, is the effect from the local Ga language and refers to an ill of PEM on the brain. Research has shown that child who has been “deposed” from the breast subnormal mental and psychomotor function- because of a new pregnancy. ing tends to follow PEM, and during the 1960s Although terminological and etiologic argu- and 1970s, direct causal connections were com- ments continued, by the 1950s the concept of monly made. Some investigators even hypoth- kwashiorkor was firmly entrenched in nutrition esized that severe PEM resulted in permanent literature and accepted by the medical com- mental disabilities. But once again important munity as a certifiable human disease result- reassessments have been forthcoming: Earlier ing from a deficiency of protein. Continuing tests generally failed to control for the learn- research led to discovery of other syndromes ing environment of their subjects. Currently, the and to formulation of the more general concept prevailing view is that neither mild-to-moderate of protein-calorie malnutrition. The word “calo- nor acute clinical PEM seems to be associ- rie,” however, was subsequently replaced by “en- ated with long-term intellectual and psycholog- ergy” in the 1970s, when the international sys- ical disabilities. The matter of permanent injury tem of unit measures was adopted by the United caused by chronic PEM, notably of the maras- Nations. mic variety during the first year of life, however, A rough regional patterning of PEM has been remains unresolved. Irreversible brain damage attempted by two studies using both weight-for- may well occur in more serious cases, as is age information and weight-for-height (wast- strongly suggested by research on laboratory ing) calculations. What emerges from these animals. efforts is a focus of PEM in Southeast Asia. Some

264 116. Puerperal Fever

52 percent of preschool children are estimated or classes of Protozoa have species pathogenic to fall below 80 percent of the weight-for-age for humankind. The Sarcomastigophora (the standard, led by Bangladesh with 91 percent flagellates and amebas) include trypanosomes, and India with 75 percent. No country in the leishmanias, and parasitic amebas. The Cil- region shows a prevalence of wasting among iophora (the ciliates) have only one human 12- to 23-month-olds under 10 percent. Once pathogen, Balantidium coli, an intestinal para- again, Bangladesh and India are at the upper site of wide distribution but, usually, little clin- extreme, with 53 percent and 43 percent, ical significance. The Apicomplexa (the sporo- respectively. zoans) include many pathogens, including the Both African and eastern Mediterranean re- four species of Plasmodium that cause malaria. gions show 35 percent deficient by weight-for- K. David Patterson age criteria. Of the countries included, only Yemen and Mali stand above 50 percent. Wast- ing totals are generally in the vicinity of 10 per- cent, but there are two countries that register 116. Puerperal Fever exceptionally high totals: Malawi (36 percent) and Somalia (66 percent). Historically, the terms puerperal fever and On both measurement scales, the less- childbed fever meant any acute fever occurring developed countries in the Americas fare much in puerperae during the first few days after de- better. The regional below-weight-for-age av- livery. Less frequently, the terms were also ap- erage is 21 percent, and all countries except plied to similar diseases occurring during preg- one show a less than 10 percent incidence of nancy or even in the newborn. From a mod- wasting. That lone exception is Haiti, where the ern point of view, what was formerly called figure is calculated at 18 percent, still far lower puerperal fever includes a range of disorders, than figures for many places in Asia and Africa. most of which are now called puerperal sep- Limited trend data suggest some lessening of sis. Typically, puerperal sepsis involves postpar- the incidence of PEM since the 1960s, an obser- tum infection in the pelvic region, but it can vation supported by declining infant and child mean disorders in other areas, such as masti- mortality rates. This is true even in Africa, where tis. In modern usage, the term puerperal fever scenes of famine have created the image of occurs mainly in discussing the great fever epi- spreading malnutrition. Still, there is little room demics that afflicted maternity clinics in earlier for complacency, given the magnitude of the centuries. problem that remains and the fact that poverty has proved to be intractable in many areas. Characteristics James L. Newman A wide range of microorganisms have been as- sociated with acute pelvic inflammation and other postpartum inflammations identified as puerperal fever, but a principal cause is strep- 115. Protozoan Infection tococcal infection. Group A streptococci (pyo- genes) were probably the leading agents in Protozoa are one-celled animals or animal-like most puerperal fever epidemics during earlier eukaryotic (having an organized nucleus) or- centuries. However, since the 1970s, group B ganisms. Older classifications treated the Pro- streptococci (agalactiae) have become the most tozoa as a phylum in the animal kingdom, but prevalent causal agents. modern taxonomists generally consider them Among puerperae, the clinical manifestations members of a distinct kingdom, the Protista, of puerperal sepsis include acute fever, pro- along with other simple eukaryotes. Three phyla fuse lochial flow, and an enlarged and tender

265 116. Puerperal Fever uterus. Onset is generally 2–5 days after deliv- clinic consisted of two divisions, one for obste- ery. Normally there is inflammation of the en- tricians and the other for midwives; the former dometrium and surrounding structures as well consistently had a mortality rate three to five as the lymphatic and vascular systems. One times greater than the latter. After months of also finds pelvic cellulitis, septic pelvic throm- investigation, Semmelweis concluded that the bophlebitis, peritonitis, and pelvic abscesses. difference was caused by decaying organic mat- Among neonates, infection usually becomes ap- ter (usually from autopsied corpses) conveyed parent in the first 5 days after birth, but onset to patients in the first division on the hands is sometimes delayed by several weeks. Symp- of medical personnel. He introduced washing toms include lethargy, poor feeding, and abnor- in a chlorine solution for decontamination, and mal temperature. Infection by group B strepto- mortality in the first clinic dropped below that cocci is often clinically indistinguishable from in the second. However, incidence of the dis- other bacterial infections. ease had always been seasonal, and most obste- tricians were unpersuaded. History By 1850, Semmelweis was convinced that de- The Hippocratic corpus contains case histo- caying organic matter caused all cases of puer- ries of puerperal fever. Various epidemics were peral fever – even the relatively few occur- recorded in the sixteenth and seventeenth cen- ring in the second clinic. Indeed, he provided turies. The disease was first characterized and an etiologic characterization of puerperal fever named in the eighteenth century when seri- in which it became true by definition that all ous epidemics began appearing with regular- cases of the disease resulted from contamina- ity in the large public maternity clinics of Eu- tion. Given Semmelweis’s definition, it also fol- rope. In the late eighteenth and early nineteenth lowed that puerperal fever was not a unique centuries, various English and American ob- disease but only a form of sepsis. Semmelweis stetricians concluded that puerperal fever was had virtually no evidence for this position. His sometimes contagious. Alexander Gordon and critics cited cases of women dying from puer- Oliver Wendell Holmes argued that physicians peral fever without any exposure to decaying transmitted the disease from one patient to an- organic matter. Semmelweis responded that in other, and they recommended measures to limit such cases the decaying matter was produced such accidents. By the early nineteenth century, internally, perhaps by decomposition of blood the disease was responsible for mortality of 5– or placental fragments. Even physicians who ac- 20 percent of maternity patients in most ma- cepted his initial results rejected this bold and jor European hospitals. Smaller hospitals had apparently unwarranted claim. outbreaks in which, over several months, 70– By the 1860s, Louis Pasteur’s work on fermen- 100 percent of maternity patients died. The eti- tation and putrefaction heralded the possible ology of puerperal fever was unclear, although significance of microorganisms in disease pro- seasonal patterns and high incidence in mater- cesses. Building on Pasteur’s work, and certainly nity clinics suggested that it resulted from a lo- aware of Semmelweis’s theories, Carl Mayrhofer cal poison conveyed through the atmosphere. examined vaginal discharges from more than By the middle of the nineteenth century, the 100 patients at the Vienna maternity clinic. disease attracted much attention in medical lit- In 1865, he described various microorganisms erature, and cases were reported worldwide. that appeared only in discharges from puerperal In 1847, Ignaz Semmelweis became assistant fever victims. Using the techniques he had avail- in the Vienna maternity clinic. Incidence of able, Mayrhofer isolated these organisms, cul- puerperal fever in the Vienna hospital was about tured them in solutions of sugar, ammonia, and 7 percent, which compared favorably with other water, and then reproduced the disease by intro- hospitals around Europe. However, the Vienna ducing the organisms into healthy test animals.

266 117. Q Fever

Mayrhofer’s work was unimpressive to his 117. Q Fever Vienna colleagues but received considerable attention in Berlin. Within a few years, many The “Q” in Qfeverstands for “query,” the des- investigators pursued the discoveries of Sem- ignation applied by E. H. Derrick to an acute melweis and Mayrhofer, studying the microor- illness with fever and severe headache of un- ganisms identified in puerperal fever and other known cause occurring in abattoir workers and forms of sepsis. Through the middle decades dairy farmers in Queensland, Australia, in 1935. of the nineteenth century, most of those who Despite the discovery of the causative agent, wrote about wound infections, including Edwin a rickettsia-like organism, this unenlightening Klebs, Robert Koch, and Pasteur, gave promi- name has remained current, although an al- nence to puerperal fever. In 1879, Pasteur iden- ternative is abattoir fever. Q fever, occurring tified the streptococci that principally caused in epidemics in military personnel stationed in the disease. By this time, it was apparent that the Balkans and Italy during World War II, was puerperal fever was actually a form of sepsis. In known as “Balkan influenza” or “Balkan grippe.” this sense, therefore, puerperal fever ceased to Q fever is caused by infection with Coxiella exist as a diagnostic or theoretical entity. burnetii, the sole member of genus Coxiella, Studies in the early twentieth century led to family Rickettsiaceae. It was initially confused serologic classification of streptococci and to with viruses, but though C. burnetii is an intra- recognition that group A strains were the most cellular parasite, it has a true bacterial cell wall. prevalent agents in puerperal fever. Group B Q fever is a zoonosis of worldwide distribu- streptococci were first reported in puerperal sep- tion. Many animals, birds, ticks, and other in- sis in 1935 and in recent decades have displaced sects are natural hosts. In animals, naturally ac- group A strains as the most prominent agents in quired infection appears to be asymptomatic. puerperal sepsis in the United States and Britain. Transmission to humans occurs via inhalation Infections of group A streptococci are gener- of contaminated dust while infected animals, ally exogenous and affect puerperae, whereas carcasses, or animal products are being han- infections of group B pathogens are usually en- dled; via laboratory accidents; and sometimes dogenous and, although the mother may be via tick bite or consumption of unpasteurized affected, generally strike the fetus or neonate. milk. Asymptomatic infection is common. Ill- The change has had important ramifications in ness may take two forms. Acute Q fever is usu- clinical manifestations, prophylaxis, and ther- ally a self-limiting febrile flu-like illness or atypi- apy. Development of antibacterial agents has cal pneumonia lasting up to 4 weeks. Untreated, obviously revolutionized the management of mortality is less than 1 percent. Chronic Q fever puerperal sepsis. Improved care for delivering presents as endocarditis and/or hepatitis. En- mothers has also had an important impact, and docarditis usually occurs in those with preexist- liberalization of abortion laws has reduced in- ing heart-valve disease; untreated, it is usually cidence of puerperal sepsis associated with ille- fatal. gal abortions. However, control of sepsis is now recognized as more difficult and complex than Characteristics previously believed; it remains particularly dif- The distribution of acute Q fever is worldwide, ficult in Third World countries, where medical but chronic Q fever appears more limited, most care is not readily available. Therefore, although cases being reported from Britain, Australia, and incidence of puerperal sepsis has been dramati- Ireland. Surveys of British livestock suggest that cally reduced, the various forms of this disorder 3–5 percent of dairy cattle and 2–6 percent of continue to be a leading cause of maternal and sheep are infected. In other countries, it is still neonatal death throughout the world. rare, which may result from underdiagnosis or K. Codell Carter perhaps differences in strain virulence. Acute

267 117. Q Fever

Q fever affects predominantly adult men, and because it places coxiellae at the border of re- association with farmers, abattoir workers, and sistance to high-temperature/brief-interval milk veterinarians is well recognized. Q fever often pasteurization. However, some experts dispute occurs in seasonal spring and autumn peaks as- whether symptomatic Q fever can be acquired sociated with lambing and calving. from drinking contaminated milk, although an- In the United States, Q fever was recognized as tibody prevalence is raised in raw milk drinkers. endemic in dairy herds throughout the country Person-to-person spread has been documented by 1960. Reports of human cases were uncom- but is unusual. mon but increased steadily from 1948 to 1977. The vast number of organisms excreted by Over this period, 1,164 cases were reported to infected animals, their dissemination in dust by the Centers for Disease Control and Prevention. wind, their hardy nature, and the low infective Fully 67 percent of cases occurred in California, dose for humans (said to be one organism) ex- which has a high prevalence of infection in cat- plain a characteristic feature of Q fever – the oc- tle and consequently a high proportion of cattle currence of explosive, localized outbreaks often excreting organisms in milk. without an obvious source of infection. More- Coxiellae differ from other rickettsiae in not over, even when the source of infection is iden- needing an arthropod vector for transmission. tified, such as sheep used in medical research Two cycles of natural infection have been rec- institutions, human cases occur in people only ognized. In the wildlife cycle, transmission be- indirectly exposed by being in the vicinity of the tween wild animals and birds occurs from tick animals. bites, from inhalation of dust, and possibly (in Subclinical infection is common. Only 191 of carnivores) from ingestion of infected placen- 415 newly infected persons were symptomatic tas and meat. Ticks are infected from the blood in an outbreak in Switzerland in 1983, caused of an infected host, but transovarial spread has when infected sheep were driven from moun- also been documented. Coxiellae multiply in the tain pastures through several villages on the tick gut and salivary gland, and transmission way to market. The clinical features of acute occurs by biting or when tick feces contami- Q fever are similar to other infectious agents. nate broken skin. In the domestic animal cycle Illness begins 2–4 weeks after exposure, with in- and in human infection, tick-borne infection is cubation possibly varying with the dose. There less important, and transmission occurs usually is sudden onset of fever, sweating, shivering, from inhalation of contaminated dust and pos- rigors, malaise, joint and limb pains, severe sibly from direct contact with infected animals. frontal headache, retro-orbital pain and photo- Cows, sheep, and goats are the main reservoirs phobia, and a mild nonproductive cough. Rash for human infection. In these animals, coxiel- is uncommon. Untreated fever usually lasts lae localize in the genital tract and udder and 1–2 weeks, but pneumonia may persist consid- are excreted in vast numbers in milk, birth flu- erably longer. Jaundice is less common, and se- ids, and placentas without usually causing dis- vere respiratory symptoms are unusual. Rarer ease or decreased milk yields in cows, although complications of acute Q fever are meningoen- abortion may occur in sheep and goats. Investi- cephalitis, cerebellar ataxia, coma, myocardi- gations have also implicated rabbits and parturi- tis, pericarditis, infiltration of bone marrow by ent cats as possible sources of human infection. granulomas leading to marrow failure, orchitis, Coxiellae are very resistant to environmen- and placentitis. There may be splenomegaly tal conditions, surviving for months or years and lymphocytosis. in dust and animal litter. Experiments have Chronic Q fever is usually considered a rare shown that they can survive – among other occurrence, particularly but not exclusively af- ◦ harsh conditions – temperatures of 63 C for up fecting patients with preexisting aortic or mitral to 30 minutes, an observation of importance valve malformations or disease and occurring

268 117. Q Fever months to years after acute infection. However, cycle has not proved a significant source of hu- the lack of a history of acute illness or preex- man infection. The domestic animal cycle is far isting heart-valve disease or exposure to infec- more important and explained the epidemic of tion does not exclude the possibility of chronic Q fever during and after World War II, when Q fever. Illness begins as a low-grade fever thousands of troops in the Balkans and Italy with night sweats, anemia, joint pains, finger were infected. clubbing, heart murmur, and developing heart The epidemic began in Yugoslavia in 1941 failure. There is usually hepatosplenomegaly. and involved more than 600 troops. Further out- Coxiellae can be isolated from vegetations on breaks occurred in Yugoslavia, Crimea, Greece, damaged or prosthetic heart valves. Abnor- Ukraine, and Corsica. Risk of illness was asso- mal liver function tests are usual, and chronic ciated with sleeping on hay or straw. Further Q fever may sometimes present as chronic liver outbreaks in 1942, 1943, and 1944 were noted disease. in German troops exposed to sheep and goat Acute Q fever can be treated successfully, but flocks. Following the Allied invasion of Italy, Al- chronic Q fever is difficult to treat. Eventually, lied troops shared the Q fever epidemic. In 1945, heart-valve replacement may be unavoidable. other outbreaks occurred in Italy, Greece, and Reinfection of prosthetic valves has been de- Corsica. scribed, possibly occurring as a result of persis- The epidemics of Q fever were militarily sig- tent extracardiac infection. nificant. The attack rate among exposed troops was very high and illness was prolonged. For History example, of 160 men billeting in a hay barn, 53 In 1935, E. H. Derrick investigated an out- (33 percent) developed Q fever. Of 900 men on break of a febrile illness among meat workers in a training exercise, which included sitting in a Australia. In 1937, he published the first report barn loft to watch training films, 267 (30 per- of a new disease that he called Q fever. He went cent) became ill. After the war, outbreaks oc- on to show that guinea pigs could be infected curred from 1946 to 1956 among Greek and by inoculating blood or urine from febrile pa- Swiss troops, in 1951 among U.S. servicemen in tients and that extracts of guinea pig liver and Libya, and in 1955 among French soldiers in spleen could transmit infection to other guinea Algeria. Factors contributing to epidemics pigs. In collaboration with Derrick, F. Burnet among troops were the sudden exposure of and Mavis Freeman searched for a virus in ex- susceptible people to infection, particularly by tracts of guinea pig liver using animal inocu- sleeping on straw and hay (the local indige- lation experiments and identified a rickettsia- nous population was apparently unaffected), like agent that was named Rickettsia burnetii.In the rapid movement of flocks during wartime, 1938 in the United States, G. Davis and H. Cox and the mixing of infected and uninfected reported an organism isolated from ticks col- flocks. This was well illustrated in 1974–75 on lected in Montana, which they called Rickettsia Cyprus. An outbreak of abortion affected sheep diaporica. It was later proved to be identical to R. and goats herded together to escape the Turkish burnetii, and its infectivity for humans was un- invasion. In a nearby camp, 78 British soldiers happily demonstrated by laboratory-acquired developed Q fever. infections. Cox showed that the Q fever agent The importance of domestic animals as the differed significantly from other rickettsias, and reservoir for human infection was further em- it has been placed in a separate genus, Coxiella. phasized by outbreaks in the United States, Derrick had speculated that transmission was where the first naturally acquired cases were via blood-sucking insects and that the organism reported in 1941 in Montana. In March 1946, had an animal reservoir; he identified the bandi- 55 of 132 livestock and meat handlers in a coot as such a reservoir. However, the wildlife plant in Texas developed Q fever, and 2 died.

269 118. Rabies

In August of the same year, a similar outbreak there is good evidence that infection was in- occurred in Chicago. Further studies revealed troduced through importation of infected sheep sporadic cases, particularly in California. During from England in the 1960s, with the first indige- outbreaks that occurred in 1947, city residents nous cases being identified, retrospectively, in living near dairy farms were infected, probably 1962. Today Q fever is known to be global in by dust carried in the wind. distribution, and it is likely that any patchiness Laboratory-acquired infection was one of the in distribution reflects as much the differing lev- earliest problems caused by Q fever. During els of awareness of the disease as differences in 1938–55, 22 incidents involving more than disease incidence. 250 cases were recorded. In one military institu- S. R. Palmer tion, 50 cases were recorded during 1950–65. In 1940, an outbreak occurred in the U.S. National Institutes of Health in which 15 workers were infected. In this and other laboratory-associated 118. Rabies incidents, infections occurred not only in those directly handling the organism but also in those Rabies is a viral inflammation of the brain and who worked near or walked through the labora- spinal cord of humans and other mammals. The tory buildings, an observation that emphasized disease is nearly always transmitted to humans the importance of the respiratory route of infec- in the saliva of biting animals and is almost in- tion. In the 1970s, attention was drawn to the variably fatal. The terms “hydrophobia” and la serious risk of working on infected animals in rage illustrate two common symptoms. research institutions, and interest in developing a safer and more effective vaccine was restimu- Characteristics lated in the United States. In the 1980s, in both Rabies occurs in Africa, Asia, the Americas, and the United States and Britain, large outbreaks most of Europe. It has never occurred in, or has were associated with operative procedures on been eliminated from, Britain, Ireland, Sweden, pregnant sheep. Norway, Japan, Australia, New Zealand, Hawaii, The first vaccines for Q fever were devel- and many islands in the Pacific and Caribbean. oped principally to protect laboratory workers Rabies is a disease of wild carnivores, particu- from infection. Used in the late 1940s and early larly canids such as foxes, wolves, jackals, and 1950s, they had the drawback of provoking se- coyotes. Skunks and raccoons are also common vere skin reactions. In 1956, the unique phe- hosts, as are bats. Virtually any mammal can nomenon of C. burnetii’s phase variation was contract the disease when bitten by an infected reported, which has proved of great value not animal. Domestic dogs are the major threat to only in diagnosing chronic Q fever but also in humans; cats are a growing danger in North developing an effective vaccine. In the 1970s America. Cattle, horses, sheep, and other live- in Australia, an upsurge of infection in abattoir stock may also be affected, but bovine rabies workers led to renewed efforts in vaccine devel- and equine rabies usually pose little danger for opment. humans. Following the original work in Australia, the Rabies is relatively uncommon in humans, oc- United States, and the Mediterranean area, curring sporadically as isolated cases or in small many other countries quickly identified cases. clusters. Persons working alone in remote ar- Surveys by the World Health Organization re- eas are vulnerable to attack by infected animals. vealed that by 1956, 51 countries on all conti- Wolves are especially dangerous because their nents were infected. Only Scandinavia, Ireland, size and strength allow them to inflict multiple New Zealand, and the Netherlands were said bites. Most human cases result from the bites to be free of infection. Since then, in Ireland of “mad dogs,” which were themselves victims

270 118. Rabies of such attacks by feral animals. Vampire bats dog” (foaming at the mouth and wandering the in parts of South America are a source of ra- streets) does exist, but not all sick dogs display bies in cattle and occasionally humans. Other such dramatic symptoms. In northern Canada, bats can infect people and animals, but this is rabid foxes and wolves may become “crazy,” uncommon. invading settlements, mingling with sled dogs, Human rabies has become a rare disease in and attacking dogs or their owners. Nocturnal developed countries. There were 236 cases in animals like skunks and raccoons may wander the United States in 1946–65. No cases at all through inhabited areas in daytime and exhibit have been reported in many of the subsequent little fear of people or other animals. Unfortu- years. Canada reported only 21 cases in 1924– nately, such abnormal behavior can deceive; 86, but Mexico recorded 157 fatalities in 1985– many people have undergone a series of rabies 86. In Africa, Ghana had 102 cases in 1977–81, shots after handling “friendly” raccoons. whereas Ethiopia had 412 in 1982. In the early Although people commonly contract rabies 1980s, India reported the highest annual num- via virus-laden saliva, two other mechanisms ber of cases (20,000) as well as the highest rate have been reported: inhalation of virus in dust of infection – 28.8 per million individuals. and contamination in surgery. High concen- Rabies is caused by a virus of the rhabdovirus trations of virus may occur in dust in bat- group. Large concentrations of virus are present populated caves, and spelunkers have died of in the saliva of sick animals. The virus is neu- rabies after inhaling the virus. Laboratory in- rotrophic; it migrates along nerves to the brain, halation of virus-laden aerosols has also caused where it multiplies, causing grave damage man- infections. Cornea transplants from undiag- ifested in part by behavioral changes. nosed rabies victims have caused at least two Rabies circulates primarily in wild carnivores deaths, but immunologic testing of donors and only incidentally attacks domestic ones. should prevent future incidents. Humans are accidental and terminal hosts. The If infected saliva enters a break in the skin, spread of rabies in skunks and raccoons, two viruses are carried from the wound through species that have adapted with great success to the nerves to the brain. Incubation takes up to suburban habitats, has caused concern in the 16 weeks, depending on severity and location United States, but thus far no human cases have of the wound and the size of the viral inocula- occurred. tion. Severe bites on the face and head are the In the wild, rabies tends to occur in irregu- most dangerous and have the shortest incuba- lar waves and may spread over thousands of tion periods, because the virus does not have miles in a few decades. Control of rabies by far to travel. Infection results in destruction of population reduction is generally unsuccess- cells in the brain and spinal cord and damage to ful, and vaccines for wild mammals are still the myelin sheaths of nerves. Clumps of viruses experimental. Monitoring reservoir hosts can (called “Negri bodies”) are often seen on micro- alert public-health authorities to possible cases scopic examination. among dogs and cats and provide warning of Rabies patients show restless, agitated be- wild animals. In the United States, where ca- havior and hypersensitivity, becoming appre- nine rabies steadily declined for decades, cases hensive or aggressive shortly after onset. in cats began to exceed cases in dogs in 1980, Convulsions and excessive salivation are com- resulting in widespread campaigns to vaccinate mon. Patients often suffer intense thirst but felines. have severe muscle spasms in the throat when Animals exhibit either furious rabies, with they attempt to drink. This frequently devel- agitated, aggressive behavior preceding paral- ops into extreme hydrophobia, with the sight ysis and death, or dumb rabies, with lethargy or even mention of liquids inducing terror and and progressive immobility. The classic “mad spasms. Within days, this “furious” phase is

271 118. Rabies followed by depression, paralysis, and death. Roman writers of the first and second cen- The gruesome symptoms and inevitability of turies, such as Dioscorides, Pliny, Galen, and death make rabies one of the most frightening especially Celsus, wrote extensively on rabies diseases. and established ideas about the disease that There have been a handful of reports of sur- remained influential in European and Islamic vivors, but even the most intensive supportive medicine well into the eighteenth century. In care is generally futile, and there are no specific accordance with prevailing humoral doctrines, drugs or other therapies. Prevention is the only it was believed that animals developed rabies solution. Vaccinating dogs and cats, controlling from a “corruption of the humors” caused by strays, monitoring wildlife populations, and ed- factors such as stress, cold, heat, or poisoning. ucation are all essential. A preexposure human Their saliva became poisonous, and bites car- vaccine is available for persons at special risk, ried the “virus” to others. Like his contempo- such as game wardens, veterinarians, and labo- raries, Celsus described a wide array of internal ratory workers. and external remedies, none of which (based on Fortunately, persons bitten by a rabid animal modern knowledge) could have done any good can be effectively vaccinated before the disease but which lasted into the nineteenth century. completes its long incubation period. If the bit- Pliny’s unfounded belief that a canine “tongue- ing animal is rabid, or if grounds exist to suspect worm” caused rabies lasted as long as the ideas it is rabid, prompt treatment is essential. Cleans- of Celsus. ing of the wound to remove as much virus as Rabies interested many writers after the fall of possible is followed by injections of a serum con- Rome and into medieval times. Jewish author- taining preformed antibodies to the virus. The ities wrote about rabies in the Talmud. Chris- key measure, a series of shots with a specific tian writers in the West and the Byzantine Em- vaccine, is then begun. pire followed the humoral theories of classi- In the 1880s, Louis Pasteur developed the cal times. Islamic authorities such as Rhazes in earliest vaccines using rabbit spinal-cord tissue. the tenth century and Avicenna in the eleventh Brain tissue of sheep, goats, or mice is used in also worked in the humoral tradition and were some developing countries but is being replaced strongly influenced by Celsus. Avicenna gave because it can cause allergic reactions. Duck- good accounts of rabies in dogs, wolves, foxes, embryo cultures were used until human diploid and jackals. cell vaccine was developed in the late 1970s. As in most medical matters, commentators in This vaccine is cheaper, safer, and requires fewer medieval Europe had little to add to ancient injections. An improved vaccine was released in and Islamic writers. In the thirteenth century, the United States in 1988. Arnold of Villanova wrote wrongly that dogs be- came rabid after eating corpses, but he rightly History stressed the thorough washing of bite wounds. Rabies possibly was described in Mesopotamian Once symptoms appeared, many persons re- texts as early as 2300 B.C., and it was well sorted to religious healing. In Western Europe, known to ancient writers from China to Rome. pilgrimages and prayers were directed toward The first certain reference in Chinese texts dates Saint Hubert, patron of hunters. Other saints from the sixth century B.C., and the disease were invoked elsewhere in Europe and among is described in a first century Indian text. Ra- the Coptic Christians of Egypt. bies is also mentioned in ancient Greek litera- Early modern medical authorities had little to ture including works by Euripides, Xenophon, add. Girolamo Fracastoro, sometimes hailed as a and perhaps Homer. Aristotle described rabies sixteenth-century forerunner of germ theorists, in dogs and other animals in his History of considered rabies one of many diseases caused Animals. by “seminaria,” something more like a seed or

272 118. Rabies a self-replicating poison than a microorganism. enough to be a major public-health hazard, Sixteenth-century French surgeon Ambroise but it was spectacular enough to attract a fair Pare´ gave a good clinical description and rec- amount of research. The work of French veteri- ognized central nervous system involvement. narian Pierre-Victor Galtier was especially im- Perhaps because the disease was more com- portant. In 1879 he published experiments in mon or because of the growing volume of which he maintained rabies in rabbits. The de- medical research, literature on rabies became velopment of a vaccine was the climax of the much more abundant in the eighteenth cen- career of another investigator, Louis Pasteur. tury. Autopsy studies were performed (although Pasteur published his first paper on rabies without results, as the lesions are microscopic) in 1881. Working with rabbits as advocated by and many case reports published. The growth Galtier, Pasteur used dried spinal-cord material of literature was especially notable in France, as a source of infection. By 1884 he had devel- where considerable interest in rabies existed. oped a method of attenuating the still unknown About 1750, many physicians believed in “spon- agent in the material. The weakened infective taneous” rabies. But within a few decades it was agent was injected into dogs. Unlike fresh prepa- recognized that rabies resulted only from bites rations, it did not cause sickness, but instead of rabid animals and that not all such bites trans- provided protection against injections of viru- mitted the disease. Joseph-Ignace Guillotin, in- lent virus. ventor of the guillotine, proposed an experi- The first human trials were conducted in mental approach: Condemned criminals would 1885. Pasteur and his associates could not inject be bitten by mad dogs, whereupon trials of var- a human with the virus to test the vaccine, but ious remedies would be conducted on them. rather had to treat a recent bite victim, hoping This scheme was not adopted, but some that the weakened virus in the vaccine would important experiments occurred around the convey immunity before the virulent virus from turn of the nineteenth century. English physi- the bite could cause disease. In July 1885, a 9- cian John Hunter proposed saliva inoculation year-old boy – badly bitten by a rabid dog – was experiments in the 1790s. Italian investigator brought to Paris within 2 days of exposure. Doc- Eusebio Valli claimed that gastric juice from tors were convinced that he was infected, and frogs rendered the “virus” in saliva less viru- Pasteur knew that death would supervene un- lent. The first saliva inoculation experiments less the new vaccine was effective. The boy was are credited to German investigator Georg given serial injections of progressively fresher Gottfried Zinke, who was aware of Hunter’s rabbit spinal-cord vaccine. He lived – and even- work and may have been inspired by it. In tually became concierge at the Institut Pasteur. 1813, French researchers Franc¸ois Magendie A second victim was treated successfully in Oc- and Gilbert Breschet infected dogs and other an- tober, and 350 others were inoculated over the imals with saliva from a human rabies victim. next several months. Only one died – a girl who Nineteenth-century therapy, however, re- received vaccine over a month after exposure. mained a hopeless melange of useless reme- The treatment was a major breakthrough, dies, many inherited from ancient times. Doc- causing a public sensation, and people bitten by tors tried everything possible from drugs and rabid or suspicious animals flocked to Pasteur’s purges to electric shock and immersion in the laboratory from all over Europe. Success rates sea. Sedatives were often employed, and eu- were consistently high, especially if vaccine was thanasia may have been practiced. promptly administered and if wounds were not Modern knowledge of rabies dates from the on the head. Even with a long train ride to de- last half of the nineteenth century and is closely lay treatment, 35 of 38 Russians who had been linked to the rise of experimental methodol- bitten by rabid wolves were saved. The French ogy and germ theory. Rabies was not common government promptly began to fund Pasteur’s

273 118. Rabies work, and his institute was expanded. His as- Rabies declined in the twentieth century in sociates, notably Emile Roux, and others devel- wild and domestic animals as well as in humans. oped methods of vaccine production and treat- The disease was exterminated in Britain in 1922 ment. Research suggested a route from the bite and became rare throughout Western Europe. through the nerves to the brain, but this was not In the early 1940s, however, a fox epizootic de- proven until well into the twentieth century. veloped in Poland and spread westward at a rate In 1903, Adelchi Negri in Italy discovered mi- of 30–60 kilometers a year, reaching France in croscopic bodies in nerve cells of rabid dogs. 1968. Denmark defended itself by intensive fox He thought they were protozoans. Although control in a belt of territory near the German this proved erroneous, the “Negri bodies” be- border; Britain is still protected by the Channel. came a useful sign. However, inoculation tests The history of rabies on other continents is introduced in 1935 and serologic methods have little known. Sporadic cases and scattered epi- largely replaced histological examination for demics occurred in Ethiopia prior to the twenti- Negri bodies as tests for rabies. The virus was eth century, a pattern that must have been com- first seen in 1962; electron microscope stud- mon in other African and Asian countries. Ra- ies in 1965 showed that the Negri bodies were bies did not exist in Australia or New Zealand clumps of viruses and antibodies. prior to English colonization in 1788 and seems Rabies epidemics and epizootics are diffi- to have been absent from the Pacific islands cult to trace before the twentieth century. In as well. Europe, most descriptions are of isolated cases The antiquity of rabies in the New World is or small outbreaks. In 1271, rabid wolves in- unclear. It is possible that bat rabies existed vaded towns in Franconia, attacking herds and in pre-Columbian times, and Arctic foxes and flocks and killing 30 persons. There was a fox wolves could have carried the virus from Siberia epizootic in Frankfurt in 1563. Rabies became to Alaska millennia ago. Oral traditions suggest more widespread in Western Europe during the that the Eskimos were aware of rabies long eighteenth and nineteenth centuries, possibly before European contact. However, early Euro- because population growth caused greater con- pean sources do not mention rabies among the tact between feral mammals and domestic dogs. American fauna, and a 1579 Spanish work In 1701 Nancy, France, was beset by rabies specifically denied its existence in the “Indies.” and enacted laws against stray dogs. Paris re- The first accounts of the disease are from sponded to rabies cases in 1725 with a leash Mexico in 1709, Cuba in 1719, Barbados in law, and other European cities followed with 1741, Virginia in 1753, North Carolina in 1762, similar ordinances. Such restraints, as well as New England in 1768, Jamaica and Hispaniola campaigns to rid the streets of strays, were sel- in 1783, and Peru in 1803. Because rabies is dom strictly enforced until there was a rabies such an obvious disease, at least when it afflicts scare. domestic animals and people, and because it A widespread epizootic in 1719–28 involved was so well known to both lay and medical France, Germany, Silesia, and Hungary, and observers, the absence of early reports could many cases occurred in Britain in 1734–35. indicate that rabies, at least in temperate Rabies was common in greater London in and tropical America, was a late biological 1759–62 and in France, Italy, and Spain in 1763. importation from Europe. A major epizootic in French foxes in 1803 appar- Foxrabies was known in the eighteenth cen- ently lasted until the late 1830s and spread over tury, and the disease was widespread in North Switzerland and much of Germany and Austria. American wildlife populations in the nineteenth Outbreaks among wolves, foxes, and dogs con- century. Rabid skunks were described in the tinued throughout the century and caused hun- Great Plains in the 1830s and in California in the dreds of human deaths. 1850s. Most U.S. cases in the twentieth century

274 119. Relapsing Fever were in dogs, but as canine rabies is in decline, mortality is about 5 percent, but in times of dis- greater attention has been given to wild ani- tress, as in war or famine, it can reach 60–70 mals. percent. Raccoon rabies was first described in 1936, It is also known as famine fever and tick and bat rabies, now recognized in 47 states, was fever, and in the past as “yellow fever” (which detected in 1953. An epizootic among raccoons it is not) because of associated jaundice.The in Florida in 1955 spread northward into Geor- term “relapsing fever” was first used by David gia and South Carolina in the 1960s and 1970s. Craigie in 1843. The disease often was, and is Sportsmen transported infected raccoons from still, confused with malaria and epidemic ty- this focus to the Virginia-West Virginia border in phus, whose symptoms are similar. the mid-1970s; rabies has spread in both states and into Pennsylvania, Maryland, and Washing- Characteristics ton, DC. Tick-borne relapsing fever is normally con- Skunk rabies has been spreading slowly from tained between tick and rodent host; humans two foci in the Midwest for several decades. Fox become affected only when they accidentally rabies is widespread in Appalachia. In Canada, become involved in that relationship. For exam- an epizootic was recognized in the far north in ple, if human shelters such as log cabins attract 1947 but probably began in the 1930s or ear- rodents, they may in turn become tick habitats. lier. Foxes and wolves are the primary victims, Transmission of relapsing fever is through the and the epizootic has spread south into Ontario, infected saliva or coxal fluid of the tick, making Quebec, and the United States. it essentially a disease of locality. In the case of Wildlife rabies represents a potential threat to louse-borne relapsing fever, the only reservoir Europeans and North Americans, but vaccina- of B. recurrentis is humans, despite the fact that tion of pets should prevent more than an oc- the disease is spread by lice, either in the bite, casional human case. In developing countries or by contact with the body fluids of the louse such as Mexico and India, canine rabies is a real through scratching. The louse is infected by in- danger, and little attention has been given to gesting infected human blood; once infected, it wildlife reservoirs of the virus. remains so for the rest of its life, which is about K. David Patterson 3 weeks. The infection is not congenital in the offspring. As in typhus fever, the febrile con- dition of the patient encourages the departure of lice because they are sensitive to tempera- 119. Relapsing Fever ture and, consequently, prefer the temperature of healthy persons. Relapsing fever is a disease characterized by Tick-borne relapsing fever tends to be more one or more relapses after the primary febrile severe than the louse-borne variety, but both paroxysm has subsided. Various types of relaps- types vary greatly in severity and fatality. In ing fever are caused by blood parasites of the 1912, for example, louse-borne relapsing fever Borrelia group. There are two chief forms of was very severe in Indochina and India but very the disease: endemic relapsing fever, transmit- mild in Turkey and Egypt. There are also indica- ted to humans by various ticks of the genus tions that levels of individual and residual im- Ornithodoros and maintained among a vari- munity are important. Illustrative are Borrelia ety of rodents; and epidemic relapsing fever, infections that are severe in European popula- caused by a parasitic spirochete, Borrelia recur- tions in North and East Africa but mild in the rentis, which is transmitted by human head and local populations. In West Africa, however, the body lice. B. recurrentis is less virulent than the disease is equally severe among Europeans and tick-borne forms. Under favorable conditions, locals. Case fatality depends not only on the

275 119. Relapsing Fever type of infection and availability of treatment and in some epidemics no more than 50 percent but also on the individual’s nutritional status of patients suffer relapse. Death results from and resilience. Thus, after World War II, adult liver damage, lobar pneumonia, subarachnoid fatalities from the disease averaged 8.5 per- hemorrhage, or rupture of the spleen. cent among poorer classes but only 3.6 per- The causal organisms are present in the blood cent among the well-to-do. Children suffered during febrile attacks but absent in intermis- the most, with death the outcome in 65 percent sions. After one or more relapses, the active im- of cases. munity produced by the patient is sufficient to Because mortality varies inversely with liv- prevent further invasion of the blood by the ing conditions, louse-borne relapsing fever is spirochetes. It is doubtful, however, that this a true famine fever, generally manifesting it- represents a true end of the disease for the pa- self in times of distress, when overcrowding, di- tient. Rather it would seem that equilibrium is minished hygiene, and undernutrition encour- established between host and parasite, and like age its spread and increase its deadliness. It is all equilibria is liable to disturbance. called “the most epidemic of the epidemic dis- eases,” and it rarely occurs except as an epi- History demic. The factors involved in the survival of The louse-borne form of relapsing fever was the disease between epidemics are still not fully clinically distinguished from typhus and ty- understood. phoid by William Jenner in 1849. Louse-borne Endemic foci of tick-borne relapsing fever relapsing fever was the first of the communica- exist in most parts of the world, but not Aus- ble diseases to have its causal organism identi- tralia, New Zealand, and the Pacific islands. fied, when Otto Obermeier made his observa- Louse-borne relapsing fever has been reported tions of spirelli during the Berlin epidemic of worldwide, but, since 1964, Ethiopia is the 1867–68. The louse was identified as the vec- only country that has continuously reported tor in 1907 by F. Mackie, then working in India, large numbers of cases. Foci of the disease and the epidemiology of the disease was finally appear, however, to be present in other African worked out by Charles Nicolle and colleagues countries. at the Institut Pasteur in Tunis between 1912 As with tyhpus fever, there is a marked and 1932. seasonal incidence coinciding with the winter Moving back in time, Hippocrates described months. Warm winter clothes (and in the past, an apparent outbreak of relapsing fever on deficient winter hygiene) favor the growth of the island of Thassus, off Thrace, and it is possi- louse populations, whereas rising heat and hu- ble that the yellow fever of seventh-century midity in spring and summer cause lice to die. Europe may have been relapsing fever. The After incubating some 5–8 days, the dis- disease may also have been among those con- ease manifests itself suddenly, with shivering, stituting the epidemics of sweating sickness headache, body pains, and high temperature. that affected England in 1485–1551. There were Nausea and vomiting are occasionally present. probably a series of relapsing-fever epidemics The spleen and liver are enlarged and tender; in late eighteenth-century Gloucestershire, bronchitis is present in 40–60 percent of cases and the first reliable observation of the illness and jaundice in 20–60 percent. In cases with a was recorded in Dublin by John Rutty in 1739. favorable outcome, there is a crisis of 1–2 hours The disease was observed principally in Britain or longer within 3–9 days, followed by a fall in and Ireland before the mid-nineteenth century, temperature. Relapse, shorter and less severe when it became more active. An outbreak in than the primary attack, follows in 11–15 days. Scotland in 1841 spread south into England, and A diminishing proportion of patients suffer up from there to the United States. The disease was to four relapses. Not all cases relapse, however, present, with typhus, in Ireland during the Great

276 120. Rheumatic Fever and Rheumatic Heart Disease

Famine of 1846–50. Epidemics also occurred in ple occupying tick-infested log cabins. The first Prussia (1846–48) and Russia (1864–65), which took place at Browne Mountain in 1968; of presaged repeated outbreaks in Germany and 42 people, 11 became ill. The second – and Russia during the remainder of the century. the largest outbreak known in the Western Relapsing fever was reintroduced into the Hemisphere – resulted in 62 cases on the north United States by Irish immigrants, resulting in rim of the Grand Canyon in 1973. outbreaks in Philadelphia in 1844 and 1869, Anne Hardy and in New York in 1847 and 1871. There was an extensive epidemic in Finland in 1876–77. Egypt, Russia, central Europe, and Poland all suf- fered great epidemics during World War I, and 120. Rheumatic Fever and Rheumatic widespread outbreaks occurred in Russia and Heart Disease central Europe in 1919–23. There were further outbreaks in the Middle East, notably in Egypt, Rheumatic fever is a noncontagious disease after World War II. The disease was shown to be characterized by febrile inflammation, primarily endemic in China along the Yangtse River in the of articular and cardiac tissues, less frequently 1930s, and its appearance in Korea after the Ko- affecting the skin and brain. The cerebral mani- rean War suggests that a Chinese focus persists. festation (Sydenham’s chorea) and the superfi- Since the 1950s, however, the major contin- cial manifestations (subcutaneous nodules and uing focus of louse-borne relapsing fever has erythema marginatum) are limited to children been in Africa. In 1910, it was present in Tunisia and young adults. Rheumatic fever is caused by and Algeria; in 1921, a virulent outbreak ap- streptococcal infection, usually of the throat. peared in North equatorial Africa and spread Fever, joint pains, and tachycardia typically be- across the continent as far as Sudan. In 1943, gin 1–3 weeks after onset of untreated strepto- a serious epidemic in North Africa spread into coccal pharyngitis. However, only 0.1 to 3.0 per- the eastern Mediterranean and Europe. From cent of untreated bouts of this infection result in the 1950s, at least, the disease has had an en- a first attack of rheumatic fever. Consequently, demic focus in Ethiopia, making excursions into various largely unidentified factors must partici- neighboring Sudan. pate in initiating the immunologic pathogenesis Conditions in Ethiopia and Sudan during the of the disease. past 10 years have not been conducive to the First attacks of rheumatic fever can be pre- collection of satisfactory statistical information. vented by timely treatment of the infection with Reports from the field, however, suggest a con- antibiotics, but such treatment does not affect tinuing low endemic prevalence of relapsing the disease once it has begun. Rheumatic fever fever, while at the same time indicating confu- recurs only as a result of a new infection with sion of the disease with malaria and typhus by a pathogenic strain. Antibiotics diminish but do fieldworkers. It seems likely, however, that any not eradicate recurrences. The shorter the in- major epidemic escalation would have received terval since the previous bout, the greater is attention, and thus fears of an epidemic escala- the likelihood that a new attack will occur. An tion in Sudan have so far proved unfounded. infection occuring within 2 years of an attack The history of tick-borne relapsing fever is has a 20–25 percent chance of inducing recur- less well documented, probably because of the rence. If the first attack spares the heart, a re- local, nonepidemic character of the disease. It currence usually spares it too, but if the heart was first recognized in Africa in 1847, and in has been involved, a second bout will likely re- the United States soon after the West had been sult in greater damage. Attacks of rheumatic settled. Among recent recorded outbreaks are fever usually last several weeks but are rarely two from the western United States among peo- fatal. Death usually results from chronic heart

277 120. Rheumatic Fever and Rheumatic Heart Disease failure caused by heart-valve damage. In about in the extension of Swift’s conclusions and iden- half the cases, rheumatic heart disease de- tified the pathogen as the hemolytic strepto- velops in the absence of any history of acute coccus, serologic type A. The hypothesis that rheumatic fever, the infection having slightly the disease is mediated immunologically was initiated the pathogenic immunologic mecha- supported by the discovery by E. W. Todd in nism in the heart. London of antibodies to streptococci in the blood of rheumatic fever patients. History In the 1880s, it was estimated in London that The symptoms of rheumatic fever were first de- about 20 percent of patients without symptoms scribed separately, their relationships not be- or history of rheumatic fever who were admit- ing recognized until the ninteenth century. ted to a hospital for any reason had a sibling Thomas Sydenham in 1685 distinguished an or parent who had had rheumatic fever; such acute, febrile polyarthritis from gout. One year familial cases were present in about 35 per- later, he described as “Saint Vitus’ dance” the cent of the patients who were hospitalized be- neurological disorder now called Sydenham’s cause of rheumatic fever. It was also noted in a chorea. In 1839, Richard Bright connected the medical survey that rheumatic fever’s greatest condition with rheumatic fever. prevalence was among the lower classes. The In 1797, Matthew Baillie of London noted occurrence of multiple cases in a family was thickened heart valves in patients with acute at first attributed to inheritance. But as bacte- rheumatism. In 1809, David Dundas, surgeon riologic studies expanded, researchers realized to George III, described nine cases of “a peculiar that both familial occurrence and the associa- disease of the heart.” Four years later, William C. tion with poverty could best be explained by the Wells published 16 cases of “rheumatism of the easier spread of an infectious agent in crowded heart” (median age 15 years). living conditions. (Several modern investiga- Before the introduction of auscultation by tions, however, have suggested that there is a Rene´ T. Laennec in 1818, rheumatic heart heritable factor that influences susceptibility to disease was recognized from abnormal pulse rheumatic fever.) and respiration, with fever and joint pain. During World War I, crowded living condi- Laennec described murmurs caused by heart- tions gained further attention because of the valve deformities. In 1835, James Hope also de- prevalence of the disease in military encamp- scribed heart-valve murmurs and concluded ments. Between April 1917 and December 1919, that rheumatic fever is the most frequent cause. for example, 24,770 U.S. soldiers, representing In the 1870s, bacteriologic studies were made 27 percent of all rheumatologic cases, were di- on blood and joint fluid aspirates. This approach agnosed with rheumatic fever. was justified in 1883 by demonstration of the The development of epidemiological data cause of gonococcal arthritis. The normal bac- about rheumatic fever has been difficult be- terial flora of the throat was not understood, cause the acute phase of the disease may be yet contrary to most investigators of the time, a brief or actually imperceptible, so that it may be Berlin physician concluded that rheumatic fever recognized only from findings of valvular heart must be caused not by a specific microbe but by disease, perhaps years later in an uncertain pro- a peculiar reactivity of susceptible individuals. portion of the cases. This problem began to be In 1916, Homer F. Swift of New York be- addressed in 1943 by the Cardiovascular Dis- gan investigating rheumatic fever. By 1928, he eases Subcommittee of the National Research had concluded that an allergic response to re- Council. Boston cardiologist T. Duckett Jones peated streptococcal infections was the most devised a set of five “major” and seven “minor” likely cause. Investigations begun by Alvin F. criteria for diagnosis. These criteria received in- Coburn in New York in the mid-1920s resulted ternational acceptance quite rapidly.

278 120. Rheumatic Fever and Rheumatic Heart Disease

Greater understanding of the causes and ef- whether its acute manifestations differ in the fects of rheumatic fever did not immediately tropics has long been debated. If one consid- affect its treatment because there was no way ers, however, the wide variation in acute mani- to eradicate streptococcal infection. Eventually, festations of the disease in temperate regions, it sulfanilamide was found to prevent recurrences. seems doubtful that there are consistent biolog- Penicillin became available in 1945 and quickly ical differences in the presentation of rheumatic proved to be safer and more reliable. fever in the tropics. Some reported inconsisten- London physician G. B. Longstaff may have cies reflect selection biases, whereas others re- been the first to suggest (in 1905) that the flect over- or underdiagnosis. For example, the prevalence of rheumatic fever was decreasing. fact that virtually all patients in a series of cases Numerous studies over more than a century from Nigeria and Uganda had carditis probably of data (beginning in the 1880s) in Britain indicates that cases of lesser severity were sim- and the United States have confirmed this de- ply not seen, rather than nonexistent. cline but not explained it. Interestingly, the ma- The wide range of occurrence of arthritis in jor declines in morbidity and mortality from rheumatic fever cases may be attributed in part rheumatic fever took place before the advent to the differentiation by some authors between of antibiotics. In the latter half of the twen- objective signs of joint inflammation and mere tieth century, such decreases continued at a arthralgia. Nevertheless, there can be striking lesser – albeit still impressive – rate. In the differences in the occurrence of “arthritis,” even United States, for example, reported incidence when rigorous diagnostic criteria may be as- of rheumatic fever declined from 10,470 cases sumed. But the extreme variations in the occur- in 1961 to 2,793 cases in 1971 and 264 cases in rence of chorea – ranging from 2 to 52 percent – 1981. are the most inexplicable. The relationship of subcutaneous nodules Characteristics to carditis may indicate real geographic dif- Rheumatic fever was at first thought to be rare ferences in disease expression. Nodules have in the tropics, as judged by English observa- occurred in 8–12 percent of several series of tions from India and Malaya in the nineteenth cases from temperate regions, whereas they century. But these observations are somewhat have been less common in others and have con- perplexing, for beginning in 1925 many cases sistently been rare in the tropics. In temperate of rheumatic heart disease were reported from climates, nodules are almost always associated tropical India. Nevertheless, rheumatic fever with acute carditis and may be predictive of se- has been found to occur less frequently in vere valve damage. In tropical areas there is a tropical than in temperate regions despite the weaker association between the occurrence of fact that poverty is in general more prevalent nodules and carditis and a difference in valvular in the tropics. Climate may be a factor, as a involvement, or at least this seems to be the case north-to-south declining gradient of rheumatic of India. There, carditis not only results in per- fever within the United States, suggested dur- manent valve injury more rapidly and is more ing the 1920s, has been confirmed by numer- likely to be acutely fatal, but it also has a pe- ous studies. Moreover, a similar gradient has culiar tendency to cause pure mitral stenosis. been reported from China, and an altitude gra- Reports from other countries do not resolve the dient has been demonstrated in Kenya and question of whether this finding represents an in Mexico. In both countries, there was sig- ethnic difference or is a result of delayed medi- nificantly more disease in the more temperate cal care. highlands. The surgical treatment of rheumatically dam- The “classical” manifestations of rheumatic aged heart valves began in the late 1940s when fever were described in northern Europe, and Dwight E. Harken in Boston performed the first

279 121. Rickets and Osteomalacia successful mitral commissurotomy, a procedure ses, and its manifestations are often much less improved by Charles P. Bailey of Philadelphia prominent. a year later. This was “closed” heart surgery. No attempt to repair a damaged valve was History possible until an oxygenating system to by- Historically, rickets was among the earliest dis- pass blood around the heart was developed. eases to be described. As early as 300 B.C., The first practical apparatus was employed by Lu-pu-wei described crooked legs and hunch- John W. Kirklin. The first valve operations to back; however, these can occur with other dis- ameliorate aortic insufficiency and to correct orders. More specifc references are found in the aortic stenosis were performed in 1959, re- separate writings of three Chinese physicians of spectively, by Bailey and Donald G. Mulder of the seventh and eighth centuries A.D., including Los Angeles. The next technical phase was the enlarged head, body wasting, pigeon breast, and replacement of an active valve. This began delayed walking. In the tenth century, Chien-i, with the ball valve devised by Albert Starr and the father of Chinese pediatrics, described many Lowell Edwards. Such plastic valves, however, cases of rickets. tend to destroy red blood cells, and thus valves In the second century A.D., Soranus of were developed with leaflets of pig, cattle, or Ephesus mentioned characteristic deformities sheep tissue. This type of prosthesis was first of the legs and spine in young children and inserted to replace an aortic valve in 1965, and remarked on the higher frequency in urban a mitral valve in 1967, both by A. Carpentier in Rome compared to Greece. Slightly later, Galen’s Paris. work included a description of skeletal deformi- By 1983, tens of thousands of valve replace- ties in infants and young children, particularly ments were performed annually in the United the knock-knee, bow leg, funnel-shaped chest, States. However, the cause of the injury, partic- and pigeon breast seen in rickets. Sporadic and ularly of the aortic valve, has gradually shifted somewhat ambiguous references to the disease from rheumatic to other varieties of heart were made until the mid-seventeenth century, disease. when the classic descriptions of Daniel Whistler Thomas G. Benedek and Francis Glisson appeared. In 1645, Whistler published his medical the- sis on rickets. Five years later, Glisson wrote the classic text on the subject, still unsurpassed as 121. Rickets and Osteomalacia a clinical description of rickets. Both physicians considered the disorder of recent origin, and in- Rickets and osteomalacia are diseases with deed the northern climate, crowded living con- multiple etiologies primarily related to abnor- ditions, and socioeconomic changes may have mal metabolism of vitamin D and secondar- influenced its prevalence at that time. Glisson ily to calcium and phosphate metabolism. Of noted a number of cases affecting wealthy fam- the many causes, by far the most important re- ilies, perhaps related to the use of swaddling late to dietary vitamin D deficiency and the clothes and the vitamin D-deficient diet of pap activation of vitamin D precursors by the kid- and starch. ney and sunlight. Rickets and osteomalacia are The word “rickets” was first used in the characterized by a failure of normal mineraliza- London Bill of Mortality report for 1634. The tion of bone and epiphyseal cartilage resulting derivation of the word has been a source in skeletal deformity. Rickets occurs in grow- of contention since that time. Possibilities in- ing infants and children, and both bone and clude rucket in Dorset dialect, meaning “short epiphyseal cartilage are affected. Osteomalacia of breath”; the verb rucken, meaning “to rock occurs in adults after closure of the epiphy- or reel”; the Middle English word wricken,

280 121. Rickets and Osteomalacia denoting “to twist”; the Saxon word rick, mean- Characteristics ing “heap” or “hump”; or the Norman word As early as 1890, Theobald Palm gathered data riquets, for hunchback. Glisson suggested the worldwide and concluded that the main etio- term rachitis, derived from the Greek word for logic factor in rickets is lack of sunlight. It was “spine,” and this term remains in use in many much later before scientists linked the variable countries today. pigmentation in races of humans with the reg- Nearly 250 years passed before the specific ulation of vitamin D synthesis. The processes role of vitamin D and its active metabolites of pigmentation and keratinization of the outer was elucidated via biochemical studies. In 1908, layer of skin (stratum corneum) directly affect L. Findlay reported inducing the disease in pup- the amount of solar ultraviolet radiation reach- pies raised in a confined, darkened space. A year ing the deeper stratum granulosum, where later, Georg Schmorl demonstrated the strik- vitamin D is synthesized. White or depigmented ing seasonal variation of the disease by autopsy skin of the northern latitudes allows maximum findings. In 1917, Alfred Hess and L. Unger de- ultraviolet penetration. Black or heavily pig- scribed the prevention of rickets by cod liver oil mented skin and Oriental or keratinized skin or by ultraviolet irradiation. Shortly thereafter, minimize ultraviolet penetration in southern a number of researchers, particularly Elmer latitudes to maintain vitamin D synthesis within McCollum’s group, isolated vitamin D and re- physiological limits. Skin pigmentation or kera- lated compounds. A better understanding of the tinization also plays a role in preventing sun- exact mechanisms and conversion of vitamin D induced skin cancer, a problem among light- metabolism into more active forms was gained skinned people who move to sunnier climates. only since the mid-1960s. Historically, rickets incidence increased with Vitamin D is more accurately classified as a the rise of sunless, crowded urban centers as prohormone rather than a vitamin. It is formed part of the Industrial Revolution. Indeed, rickets by interaction of ultraviolet light with a choles- may, among other things, be considered an air- terol derivative in deep layers of the skin, but pollution disease, because factory-produced small amounts of vitamin D may also be derived smog filters and decreases available ultraviolet from dietary sources such as dairy products and light. In 1899, Theodor Escherich reported that fish liver oils. Vitamin D is then hydroxylated – in Vienna 97 percent of infants 9–15 months first in the liver and then again in the kidney. It old had clinical evidence of rickets. An au- acts upon the target organs, intestine, and bone topsy analysis in Dresden by Schmorl showed to regulate serum calcium and phosphate levels that 89 percent of children between 2 months and the mineralization of bone. and 4 years exhibited evidence of active or As a disease producing characteristic skeletal healed rickets. Similar high numbers were re- deformities, rickets can be traced back to antiq- ported near the turn of the twentieth century for uity by direct examination of the skeletal evi- Oslo, Bergen, Berlin, Glasgow, Dublin, Belfast, dence. As expected, the disease was extremely Edinburgh, Paris, Florence, and Moscow. Some rare in ancient Egypt. Only one or two possi- authorities noted a general decrease in rickets at ble cases have been described in skeletal re- higher altitudes in the Scottish Highlands and mains from North and South America. Most re- Swiss Alps, related to the increased ultraviolet ported examples of ancient rickets come from component of solar radiation. However, cases Europe. A few date back to Neolithic times in became more numerous and severe at the high- Norway, Sweden, and Denmark. Examples be- est altitudes, presumably related to the practice come more plentiful during the Middle Ages in of keeping infants heavily bundled or indoors cities across northern and central Europe, con- nearly year-round. firming the central role of inadequate sunlight Large American cities also had a high preva- in causing the disease. lence of rickets. In 1900, John Morse estimated

281 122. Rickettsial Diseases that 80 percent of all infants under 2 years old in decreased hydroxylation of vitamin D in liver Boston had rickets. Hess reported in 1921 that and kidneys. Osteomalacia in combination with 75 percent of New York City children had clini- osteoporosis is an important factor in the oc- cal evidence of rickets. Martha Eliot found that currence of hip fracture among the elderly. 83 percent of infants under 8 months in New R. Ted Steinbock Haven had radiographic findings of mild rickets. L. Du Buys noted that rickets was widespread in New Orleans and that clinical manifes- tations were more marked in blacks than 122. Rickettsial Diseases whites. As deficiency diseases involving sunlight and The rickettsial diseases have common char- diet, rickets and osteomalacia involve cultural acteristics and similar symptoms. The proto- and socioeconomic factors interacting with cli- type is classic, louse-borne, epidemic typhus mate. In general, rickets is uncommon in sunny fever. Most other rickettsial diseases, originally climates; however, even sun-rich areas may described as “typhus-like,” were differentiated have rickets. For example, nearly 30 percent of from the classic disease during the twentieth children seen at an Ethiopian clinic had clinical century. Those in the genus Rickettsia are epi- evidence of rickets, primarily related to reduced demic typhus, murine typhus, Rocky Moun- breast-feeding and swaddling of infants to avoid tain spotted fever and others of the spotted- the “evil eye.” In many Muslim countries, the fever group, and scrub typhus (tsutsugamushi ). custom of purdah – the complete shielding of Trench fever and Qfeverare also designated women and young children indoors or with rickettsial diseases, but in recent decades, key veils – is a major factor in rickets and osteo- differences between the rickettsiae and these malacia. A study of 1,482 Muslim girls aged two diseases have prompted their classification 5–17 showed that 40 percent had evidence of in separate genera. rickets. Pathological rickettsiae were discovered early Among many Asian groups, the use of chu- in the twentieth century and named after patti flour as a dietary staple also contributes Howard Taylor Ricketts, who lost his life inves- to rickets prevalence. The high phytate con- tigating typhus in Mexico after several years of tent binds calcium and zinc, resulting in de- fruitful research into Rocky Mountain spotted creased intestinal absorption of these minerals. fever. Although smaller than most bacteria, rick- Moreover, the lignin component binds to bile ettsiae are visible under the light microscope. salts and ingested vitamin D, decreasing their Unlike common bacteria, they are obligate in- absorption. The use of raghif, an unleavened tracellular parasites – that is, they metabolize bread rich in phytates, is also a factor in osteo- and multiply only inside living cells, a charac- malacia among Bedouin women of childbearing teristic shared with viruses. For several decades, age. this combination of traits caused rickettsiae to With the addition of synthetic vitamin D to be classified as organisms midway between bac- dairy products and bread in the United States, teria and viruses. By the late 1960s, however, there has been a dramatic decline in the inci- research revealed that they were true, if highly dence of rickets. Vitamin D supplementation is fastidious, bacteria. not practiced in Britain, and 9 percent of young Most rickettsial maladies are “diseases of na- children in Glasgow still had radiographic evi- ture,” normally existing as infections of arthro- dence of rickets in 1968. Osteomalacia among pods (insects, ticks, and mites) and their mam- the elderly remains a significant public-health malian hosts. Humans are accidental intruders problem related to decreased sunlight expo- into the natural cycle. Like bubonic plague and sure, intestinal malabsorption, poor diet, and yellow fever, the manifestations of infection

282 123. Rocky Mountain Spotted Fever and Related Diseases are often more severe in humans than in the Characteristics arthropods and mammals to which the organ- The severity with which Rocky Mountain spot- isms have adapted over eons. The geographic ted fever treats its victims underscores its nat- distribution of rickettsial diseases is linked to ural existence as an infection of ticks and their environments favorable to host arthropods, and mammalian hosts. The microbe causing the dis- the diseases tend to occupy “islands of infec- ease, Rickettsia rickettsii, inhabits ixodid (“hard- tion” within favorable environments. This phe- shell”) ticks, apparently causing little harm to nomenon has been attributed to ecological con- the host. Small mammals are susceptible to mild ditions (in the case of scrub typhus) and to infection and may transmit it, but the principal antigenic incompatibility between pathogenic way the organism is maintained in nature is in and nonpathogenic rickettsiae residing in the the eggs of ticks. ovaries of female ticks (in the case of Rocky The Rocky Mountain wood tick (Derma- Mountain spotted fever). centor andersoni) and the American dog tick The common clinical manifestations of these (Dermacentor variabilis) are the most com- diseases reflect their pathological physiology mon vectors in the United States, although as infections of the human circulatory system. the Lone Star tick (Amblyomma americanum) The agents multiply inside endothelial cells lin- also transmits the disease in the south cen- ing small blood vessels. Affected cells become tral and southeastern parts of the United swollen and may impede blood flow. Electrolyte States. Two other ticks (Rhipicephalus san- imbalance and capillary permeability establish a guineus and Amblyomma cajennense) carry the vicious circle that progresses to circulatory col- disease in Mexico, Central America, and South lapse in fatal cases. Blood seeping from capil- America. Usually, less than 5 percent of ticks are laries into the skin causes the typical rash, and infective. capillary blockage in the brain contributes to In the western United States, hikers and the neurological symptoms. Since the introduction like may become subjected to infection when of broad-spectrum antibiotics in 1948, the rick- traveling in tick-infested areas, especially dur- ettsial diseases are curable if diagnosed before ing spring. In the East, where most cases now progressing too far. occur, changing land-use patterns have brought Victoria A. Harden humans into the ticks’ habitat. Suburban hous- ing developments and the transformation of agricultural land into recreation areas are two examples. Rocky Mountain spotted fever characteris- 123. Rocky Mountain Spotted Fever and tically appears in “islands” of infection. Dur- Related Diseases ing early research on a particularly virulent form in Montana’s Bitterroot Valley, for ex- Rocky Mountain spotted fever is an acute rick- ample, investigators were baffled by the fact ettsial disease transmitted by ticks and limited that Rocky Mountain spotted fever appeared to the Western Hemisphere. Its major symptoms on the west side of the Bitterroot River but are similar to epidemic typhus, but its rash cov- not on the east side. Recently, Rocky Moun- ers the entire body, including face, palms, and tain Laboratory investigator Willy Burgdorfer soles of the feet. Between 20 and 25 percent of has shown that this peculiar epidemiological oc- untreated victims die, making it the most se- currence is related to an antigenic “interference vere rickettsial infection in the Americas. First phenomenon.” Nonpathogenic rickettsiae in the identified in the U.S. Rockies, its earliest name ovaries of ticks on the east side of the river “in- has remained even though it is inaccurate and terfere” with the establishment of pathogenic even misleading. rickettsiae in these tissues, thus preventing the

283 123. Rocky Mountain Spotted Fever and Related Diseases pathogenic R. rickettsii from being passed on to tered a disease in the spring variously known as the next generation of ticks. “trail typhus,” “spotted fever,” “spotted typhus,” Rocky Mountain spotted fever has been iden- and other names. Mortality varied from under tified in Canada, the United States, Mexico, 5 percent in Idaho to approximately 70 percent Costa Rica, Panama, Brazil, and Colombia. Be- in the Bitterroot Valley of western Montana. fore 1940, most cases were reported in the In 1901, public outcry against the deadly Rocky Mountains, but since then, cases in the disease in the Bitterroot Valley stimulated the U.S. Southeast and Southwest (sometimes called newly created Montana State Board of Health the “tick belt”) have far outstripped those in to launch a scientific investigation. In 1902, the West. In the 1970s, incidence in the United pathologists suggested that the wood tick might States began rising, peaking with 1,192 cases in be the vector of the disease, possibly caused by 1981. Oklahoma has the highest infection rate, a protozoan. In 1906, Howard Ricketts of the whereas North Carolina reports the most cases. University of Chicago and Walter King of the A few cases continue to occur in Canada. In U.S. Public Health Service confirmed the tick Mexico and Central and South America, the dis- as the vector. Ricketts continued the investiga- ease is poorly reported. tion, seeking a vaccine. In 1909, when Ricketts’s After an incubation period of 3–12 days, ty- funding was delayed in the Montana legislature, phus-like symptoms appear abruptly: headache, he began studying tabardillo (Mexican typhus). joint and back pains, prostration, and high fever. Tragically, he contracted typhus in Mexico and About the fourth day, the characteristic skin died in 1910. rash appears. Usually beginning on wrists and Between 1910 and 1920, efforts focused on ankles, it spreads to cover the entire body. The tick-eradication programs. Modeled on the pro- fever continues 2–3 weeks, usually subsiding gram that had eliminated Texas cattle fever gradually. In fatal cases, neurological symptoms throughout the South, the campaign failed of deafness, delirium, and coma are accompa- against Rocky Mountain spotted fever for two nied by circulatory collapse and kidney failure. reasons. The Texas-cattle-fever tick was a one- The rash may darken and spread, becoming host vector, whereas the Rocky Mountain wood almost black, and confluent in cases. These tick chose different hosts for each stage in its characteristics contributed to two early names: life cycle, making control difficult. Second, cold “black measles” and “blue disease.” spring weather in Montana interfered with live- If diagnosed early, Rocky Mountain spotted stock dipping when ticks emerged. In 1916, fever may be treated effectively with antibiotics. Burt Wolbach at Harvard University described Patients at risk of dying are usually those not the agent of Rocky Mountain spotted fever. diagnosed in time for this treatment. At spe- Wolbach originally named it Dermacentroxenus cial risk are people who suffer from glucose-6- rickettsi, the genus name after its vector and phosphate-dehydrogenase (G6PD) deficiency, the species name after Ricketts. Taxonomists a genetic disorder especially frequent in black later classified it in the same genus with typhus males. Thus Rocky Mountain spotted fever mor- germs, changing its name to Rickettsia rickettsii. tality is significantly higher for black males than In 1921, the U.S. Public Health Service re- for the general population. newed efforts to prepare a vaccine against Rocky Mountain spotted fever. In 1924, Roscoe History Spencer and Ralph Parker produced the first Rocky Mountain spotted fever as a specific dis- successful vaccine made from arthropod vec- ease entity is essentially twentieth century in tors. From 1925 through 1948, when effective origin. The first reports differentiating it from antibiotics were introduced, the Spencer-Parker other fevers were published in the late 1890s. vaccine was the chief weapon against Rocky Travelers in western North America encoun- Mountain spotted fever.

284 124. Rubella

In 1931, the disease was discovered in the fever.” Its usual agent is Rickettsia conorii. Sev- eastern United States, and shortly thereafter, eral ticks transmit it; R. sanguineus is most pockets of infection were identified in Brazil, common. Many Africans apparently gain immu- Colombia, Mexico, Canada, and other areas of nity from childhood infection, for the disease the Western Hemisphere. The original names of is primarily seen in tourists and new residents. the disease underscored its “local” character. For Boutonneuse fever is known from Africa example, it was called febre maculosa brasiliera throughout the Mediterranean basin and into but also “Sao Paulo typhus” in Brazil, “To- India. bia petechial fever” in Colombia, and fiebre de Siberian tick-typhus was first documented Choix as well as fiebre manchada in Mexico. In- during the 1930s, when exploitation of Siberia’s vestigators suggested more appropriate names, forests and steppes brought humans into the such as tick-borne typhus, tick spotted typhus, habitat of its vector ticks. Transmitted by sev- American spotted fever,orspotted fever. None eral species of ixodid ticks, it may be far more successfully supplanted “Rocky Mountain spot- widespread than reported statistics indicate. ted fever.” The agent is Rickettsia siberica. Known also as After introduction of broad-spectrum antibi- “North Asian tick-typhus,” it is found in China otics in 1948, Rocky Mountain spotted fever in- and elsewhere in north Asia as well. cidence in the United States dropped to about Queensland tick-typhus, caused by Rickettsia 250 cases per year, with only about 24 deaths. australis, was reported in North Queensland, But beginning in 1969 and continuing through Australia, in 1946. Its vector tick, Ixodes holo- the 1970s, incidence rose inexorably. Although cyclus, parasitizes marsupials and rodents. For- this phenomenon was not reported from other est and scrub areas in Queensland are risk ar- countries of the hemisphere, it was reported in eas, and in 1979 an urban focus was reported in the Mediterranean basin for boutonneuse fever, Sydney. a related but milder spotted-fever disease. The A final member of the spotted-fever group, increase in U.S. cases and deaths stimulated new rickettsialpox, is unique in not being trans- research into diagnosis and prevention. mitted by ticks. In 1946, a disease resembling Unlike epidemic typhus, Rocky Mountain chickenpox and exhibiting an eschar was re- spotted fever poses no threat of epidemics; how- ported in a New York apartment building. New ever, it is unlikely to be eradicated. If patients York investigators collaborated with the U.S. and physicians are alert to the possibility of in- Public Health Service, and within 8 months the fection during “tick season,” effective therapy entire picture of the disease had been eluci- can avert unnecessary loss of life. dated. The agent was a hitherto unknown rick- ettsia that inhabited the mite Allodermanyssus Other Diseases of the Spotted-Fever Group sanguineus (a parasite of the house mouse) and Three other major tick-borne rickettsioses are was named Rickettsia akari. In 1949–50, the ill- known. These “spotted-fever group” maladies ness was also identified in the Soviet Union and are usually mild and fatal only to aged or debil- there called vesicular rickettsiosis. itated patients. All exhibit a distinctive eschar, Victoria A. Harden or dark scab, that forms over the initial tick bite. Boutonneuse fever, named for the button-like eschar, was the earliest to be identified. De- 124. Rubella scribed in North Africa in 1910, it has had many local names, including “Mediterranean spot- Rubella (“German measles,” “3-day measles”) is ted fever,” fi`evre boutonneuse, “Marseilles ex- a common viral infectious disease, principally anthematic fever,” “Indian tick-typhus,” “South of children and young adults, with worldwide African tick-bite fever,” and “Italian eruptive distribution, frequently characterized as a mild

285 124. Rubella rash illness. Inapparent infection is common, oc- in 1964–65 and produced 20,000 infants with curring in as many as half the cases. Rubella has CRS, showed that the risk of defects was about special significance when a woman contracts it 50 percent when mothers were infected during in early pregnancy because fetal infection can the first month of pregnancy, 22 percent dur- ensue and result in congenital rubella syn- ing the second, 6 percent during the third, and drome (CRS). Rubella is a vaccine-preventable about 1 percent during the fourth. Infection in disease, but the vaccine is not yet widely used the first 8 weeks of pregnancy also produces on a global basis. high rates of abortion and stillbirth. Rubella has a global distribution. In popu- Characteristics lated areas where it is both endemic and epi- Rubella is caused by the rubella virus, of demic, 80–90 percent of adults show evidence the genus Rubivirus, which contains a single- of prior infection. In remote populations where stranded RNA genome. It is highly contagious, rubella is not endemic, a significant proportion transmitted by contact with nose and throat of the population can be susceptible. In some secretions of infected persons, primarily by countries, such as the United States and Britain, droplet spread. Infection also occurs by direct extensive vaccination and notification policies contact, indirect contact through freshly soiled have caused impressive declines in reported articles, and airborne transmission. No reser- cases of rubella and CRS. voir other than humans exists, meaning that a Infants usually have a passive immunity continuous chain of susceptible contacts is nec- to rubella because of maternal antibodies ac- essary to sustain transmission. Communicabil- quired transplacentally from immune moth- ity lasts from about 1 week before rash onset ers. This protects the infant from infection for to at least 4 days after. Infants with congenital 6–9 months, depending on the amount of ma- rubella, who may shed virus for many months ternal antibody acquired. after birth, are the only carriers. Rubella’s incu- Rubella infection in both clinically apparent bation period from time of exposure to onset of and inapparent cases induces lifelong immu- rash is 16–18 days, with a range of 14–23 days. nity. Because a significant percentage of rubella In populated areas with no or low vaccina- infections are inapparent, persons may develop tion coverage, rubella is primarily an endemic immunity without recognizing that they have disease of children with periodic epidemics. been infected. A single dose of live attenuated However, a significant proportion of adults re- rubella virus vaccine confers long-term, proba- main susceptible. In remote isolated popula- bly lifelong, immunity in approximately 95 per- tions, rubella is not endemic and disease de- cent of susceptible individuals. pends on introduction from outside, at which The prodromal phase of postnatally acquired time epidemics may occur, affecting all persons rubella usually occurs 1–5 days prior to rash born since the last epidemic. No evidence exists onset but may be completely lacking, espe- for a sex difference in incidence or severity, al- cially in children. Prodromal symptoms may in- though more female cases may be reported be- clude headache, low fever, malaise, conjunc- cause of concern about congenital rubella. No tivitis, mild rhinitis, and lymphadenopathy evidence exists for any racial difference in inci- (most commonly tender swelling of the lymph dence or severity. nodes behind the ears and at the base of the The risk of congenital rubella is related to ges- skull). Next, a reddish, discrete rash, sometimes tational age at the time of maternal infection. itchy, usually appears first on the face and then Fetal or placental infection accompanies 85 per- spreads to hands and feet. Although the pro- cent of maternal infections during the first gression, duration, and extent of the rash vary 8 weeks of pregnancy. Data from the last major greatly, it typically covers the whole body within epidemic in the United States, which occurred 24 hours and disappears completely by the

286 125. Saint Anthony’s Fire end of the third day – hence the name 3-day 1881 reached a general consensus that rubella measles. was an independent entity. During the next Complications in postnatally acquired illness 60 years, medicine focused on the character- may include arthritis and arthralgia, which are istics, symptomatology, and course of rubella, more common in adults and women than in which was considered an inconsequential infec- prepubertal children and men. Neurological in- tion of childhood. In 1938, Y. Hiro and S. Tasaka volvement, including encephalitis, is rare. established that rubella was caused by a trans- In congenitally acquired rubella, the fetal in- missible virus. fection may result in abortion, stillbirth, con- Then, in 1941, Norman Gregg published his genital malformations, or growth retardation. landmark observations of an epidemic of con- CRS results from inhibition of cell multiplica- genital cataracts and other ocular and cardiac tion in the developing fetus and a chronic in- abnormalities in infants whose mothers had fective state that may persist many months af- contracted rubella in the first trimester of preg- ter birth. Some consequences of fetal infection nancy. Although skepticism at first prevailed, may not become apparent until years after birth. Gregg was confirmed, and other congenital Common congenital abnormalities and active abnormalities associated with rubella in preg- infective processes at birth include cataracts, nancy were described. In 1953, researchers doc- deafness, central nervous system defects lead- umented that rubella infection can occur with- ing to mental retardation, structural defects of out rash. the heart and myocarditis, bone lesions, pneu- The rubella virus was isolated in 1962, lead- monitis, and hepatitis. ing to the hemagglutination-inhibition test in- troduced in 1967 and subsequent research and History development of vaccines. In 1969, a live atten- Although it has been suggested that early Ara- uated rubella virus vaccine was licensed for use bian physicians differentiated rubella as a form in the United States, and shortly thereafter other of measles known as Hhamikah, the disease strains were adopted for use in the United States appears to have been first described in 1619 and several European countries. by Daniel Sennert, who used the term Rotheln Robert J. Kim-Farley (r¨oteln), attributing the name, which seems to have been popular in origin, to the red color of the rash. Two German physicians are cred- ited with clinically describing rubella as a sepa- 125. Saint Anthony’s Fire rate entity during the 1750s, and it continued to be called Rotheln by German investigators This disease is associated with ergotism, which from the mid-eighteenth to the mid-nineteenth results from ingesting the ergot fungus that century. The early interest in the disease by grows on rye. Most authorities assume that German physicians apparently led to use of the the name Saint Anthony’s fire refers to Saint term “German measles” in other countries. It Anthony the Great, third-century hermit and has, however, also been suggested that the word founder of Christian ascetic monasticism, who may have actually been “germane” rather than renounced the world for the deserts of Egypt. “German,” with derivations meaning “closely However, Saint Anthony of Padua, born in the akin to.” In other words, “germane measles” late twelfth century, may also be connected was intended to indicate a disease similiar to with the name of the disease. He was a noted measles. preacher, popular for exorcising demons and In 1866, Henry Veale proposed the name restoring the insane to health. “rubella” for its ease of use in speech and writ- Supposedly, the “fire” part of the name refers ing. The International Congress of Medicine in to the painful skin infections, gangrene, and

287 126. Scarlet Fever neurological disturbances that occur with ergot 126. Scarlet Fever poisoning. Thus, in French areas where rye was a staple, historians have attributed most cases of Scarlet fever is an acute infectious disease, mal des ardents to ergotism. Sufferers reportedly caused by certain types of group A hemolytic lost limbs, attributable to gangrenous ergotism, streptococci. The disease is characterized by if they survived both the initial inflammation sore throat, fever, headache, and a rash. The and the generalized famine that accompanied term “scarlet fever” was supposedly first used such epidemics. Possibly, however, erysipelas by Thomas Sydenham in 1683, but it appeared and other bacterial skin infections caused the in a diary of Samuel Pepys from 1664. From symptoms mentioned, for these diseases also the seventeenth century to the early twentieth, flourish during famines. scarlatina popularly denoted a mild form of the Saint Anthony’s fire was commonly described disease. in Western Europe from 900 to 1700. During the eleventh century, recurrences of the “sa- Characteristics cred fire” (usually associated with erysipelas in Like streptococcal sore throat – to which it is classical medicine) resulted in creation of hos- closely related – scarlet fever is a disease of tem- pitals and also appeals to interceding saints, perate climates, prevailing generally in winter of whom Anthony was only one. In France, months. It occurs principally in young children, however, Count Gerlin II acquired the relics of although adults may suffer sore throats as a re- Saint Anthony the Great and in 1070 installed sult of the same infection. them in Vienne. By 1090, healing miracles were Group A hemolytic streptococci are respon- attributed to them, and local nobles and lay sible for a range of afflictions other than scar- hospitalers formed a pilgrimage site for “fire” let fever, including erysipelas, rheumatic fever, sufferers. By the twelfth century, this hospice and the sore throats known as tonsillitis in was run by regular clergy called “friars of the Britain and pharyngitis in the United States. blue Tau” after the Greek letter symbolizing An- Scarlet fever is caused only by certain strains thony iconographically. Wine or water steeped that release a soluble toxin, whose absorption with the saint’s bones was the miraculous cure, causes the disease’s characteristic rash. Dif- but food supplements at the hospice of Saint ferent strains of streptococci produce differ- Anthony may have arrested ergot intoxication. ent amounts of toxin. Epidemics vary greatly During the later Middle Ages, the cult of in severity, with mortality ranging from 0 to Saint Anthony spread beyond the regions of 30 percent. Transmission of infection is by in- southern France and Savoy, where it had gained timate contact, such as in overcrowded homes rapid popularity, through central Europe and and classrooms. Evidence of airborne or droplet into Russia. There, people commemorated cures nuclei infection is slight. In the past, scarlet fever with votive art that has come to symbolize the occasionally occurred as a hospital infection disease to posterity. The earliest unambiguous and was also transmitted in contaminated milk. references to ergot fungus occur in the late six- Susceptibility to the skin rash differs accord- teenth century; by the late seventeenth, ergo- ing to the immune and hypersensitivity status tism was described independently. The older of the individual. Those who experience scar- name – perhaps the older “disease” as well – let fever once are unlikely to do so again but rapidly disappeared from learned descriptions, remain vulnerable to streptococcal sore throats partly because of the association of ergot fungus when exposed to a new serologic type. Re- with epidemics of neurological disorders rather search into susceptibility of different popula- than the skin infections and gangrene that char- tion groups suggests that more than half of acterized “Saint Anthony’s fire.” young infants are immune to the disease, but Ann G. Carmichael by age 2 only some 20 percent remain so.

288 126. Scarlet Fever

Thereafter the proportion of immune individ- Schultes in 1665 that the scarlatinal manifesta- uals rises steadily, reaching 77 percent at 10– tions of desquamation, nephritis, and dropsy 15 years and 86 percent in adults. Rare second were well known before the disease received attacks of scarlet fever with rash probably result its modern name. Although in 1683 Sydenham from a new antigenic erythrogenic toxin. Evi- wrote of the disease as having a mild character, dence suggests that the geographic dominance he nevertheless established its autonomy, dis- of particular strains of scarlet fever streptococci tinguishing it from other acute exanthema.By is long-term, varying from country to country the end of the seventeenth century, the identity and from time to time. With all types, the disease of scarlet fever was well recognized, although appears to follow a general pattern of alternate much epidemiological confusion remained – severity and mildness. and still remains – over the respective roles Initial symptoms of scarlet fever are similar to of scarlet fever, streptococcal sore throat, and those of streptococcal sore throat: sudden onset diphtheria (cynanche maligna) in contempora- of soreness on swallowing, fever, and headache. neous epidemics. Vomiting and nausea are often early symptoms During the seventeenth and eighteenth cen- in young children. The characteristically ery- turies, scarlet fever was epidemic throughout thematous and punctuate rash appears within Europe and the United States. It appeared in 2 days, at first on the upper chest and back, then Copenhagen in 1677, in Scotland in 1684, in the spreading to the rest of the body. In white pa- United States in 1735, and in Sweden in 1744. tients, the rash does not commonly appear on In general, however, evidence suggests that the the face, but in about half of black patients it disease made irregular epidemic appearances, does. The rash is accompanied by the charac- and its mortality varied considerably. During teristic “raspberry tongue.” In general, the rash the early 1700s, it seems to have been fairly is variable in its manifestations. Desquamation mild, but by midcentury a quite virulent strain usually occurs, beginning sometimes as early as also appears to have been present. the fifth day, sometimes as late as 4–5 weeks af- Scarlet fever’s character as a relatively new ter disease onset. A range of complications, prin- disease may be reflected in age incidences re- cipally affecting young children, add to the dan- ported during this period. Sydenham noted that gers of the disease. These include anemia, otitis it attacked whole families, though especially in- media, rheumatic fever, and meningitis. In rare fants. Nils von Rosenstein observed in 1744 the cases, scarlet fever appears in severe septic or simultaneous occurrence of sore throat with- toxic forms. out rash in children in infected households, a pattern observed in adults by Maxmilian Stoll History in 1786. In the last years of the century, scar- It is possible that outbreaks of scarlet fever were let fever was extensive and virulent in Europe, observed by Near Eastern practitioners of the with severe outbreaks in Denmark and Finland Arabian school, but the first undoubted account in 1776–78, and in central Germany in 1795– of a disease with a characteristic fiery rash was 1805. By 1814 it was again very mild, but con- provided by Giovanni Ingrassia in 1553. The dis- tinued its global spread, appearing in Greenland ease was apparently present in Germany and in 1847, in Australia and New Zealand in 1848, Italy in the early seventeenth century, and we and in South America in 1892. know of a severe outbreak in Poland in 1625. At During the 1820s and 1830s, however, a more that time, the disease was variously known as virulent form reappeared, and consequently, the rossalia, purpurea epidemica maligna, and febris disease was the leading cause of death among miliaria rubra. infectious childhood maladies until 1875. Dur- It is clear from observations by Daniel Sennert ing the 1880s, scarlet fever continued as widely in 1619, Michael During¨ in 1625, and Johann prevalent but declined as a cause of death, and

289 127. Schistosomiasis by the 1890s its character was again relatively japonicum inhabit the mesenteric veins supply- mild, although not as mild as it has become to- ing the intestines. Their eggs are discharged in day. The decline in severity was first apparent feces. However, the worms may also be found in in Britain and Western Europe, although a ma- the liver and portal system. A few other species lignant form was still present in Poland, Russia, also parasitize humans. Another name for the and Romania during the 1930s. Observations by disease is bilharzia (or even bilharziasis, a tech- Edward Goodall showed that as fatality dwin- nically unacceptable term) to honor Theodor dled, so did the more serious clinical forms. Bilharz, discoverer of the trematodes causing Streptococci were first isolated from the blood it. But it is more accurately known – especially of scarlet fever patients by Edward Klein in 1887, in America – as schistosomiasis, after its generic but he failed to reproduce the disease in an- name Schistosoma. imals. In 1911, Karl Landsteiner produced a similar disease in monkeys with material from Characteristics scarlet fever patients, but until about 1922 Schistosomiasis has an almost worldwide trop- the streptococci were generally considered sec- ical distribution but is absent from the Indian ondary invaders. subcontinent. S. haematobium is endemic in the In the early 1920s, seminal work by George Nile Valley and is distributed about the Mid- Dick and Gladys Dick proved scarlet fever to be dle East and North Africa, West and central primarily a local throat infection caused by type Africa, and along the East African coast from A hemolytic streptococci. In 1923, the Dicks Somalia to Natal. S. mansoni is endemic in the successfully inoculated volunteers, and in 1924 Nile Delta and possibly spreading into the Nile they developed the Dick test: intradermal injec- Valley. In Africa, it has a similar (although ir- tion of a diluted filtrate of a scarlatinal strain of regular) distribution to that of S. haematobium, streptococcus, which by the resultant appear- but S. mansoni also occurs in South America ance or not of a local erythematous reaction, and the Caribbean. It was transported to the determines the subject’s susceptibility to scar- New World via the slave trade. S. japonicum let fever. In other words, a negative Dick test is is endemic to the Yangtze Valley and coastal an indication of antitoxic immunity. mainland China; it also occurs in Sulawesi and Anne Hardy the Philippines, with smaller foci in Malaysia, Thailand, and Japan. Over 200 million people may be infected with the disease, although data are extremely unreliable. However, in the Nile 127. Schistosomiasis Delta and other areas, prevalence can approach 100 percent. Surveys of 42 affected coun- Schistosomiasis (also bilharzia), with many tries indicated an overall infection rate of local names such as “red-water fever,” “snail 21 percent. fever,” “big-belly,” and “Katayama disease,” is The worm eggs are shed by a human host an immunologic disease caused by eggs of and hatch, producing a minute larva called a blood-vessel-inhabiting worms of the genus miracidium. The miracidium invades a specific Schistosoma. The eggs induce an immunologic snail host, where it reproduces asexually, even- response after being trapped in body organs, tually producing the final larval stage, the cer- especially the liver, gut wall, and urogenital caria. These are released from the snail, swim tract. freely, and then bore into the skin of a human Three major human schistosome species ex- host. In the human, the parasite migrates via ist. Schistosoma haematobium inhabits veins of heart and lungs, eventually maturing in veins of the bladder area, and its eggs are discharged in the liver, gut, or bladder. Eggs appear in urine or the urine. Schistosoma mansoni and Schistosoma feces 30–40 days after infection. The disease has

290 127. Schistosomiasis a complex epidemiology, partly because of the deposition of fibrous connective tissue. The intricate relationship between parasite and snail resulting venous obstruction causes compen- intermediate host. Not only are there strains satory increased arterial flow, leading to portal of each schistosome species, but also there hypertension and the classical enlargement of are multiple genera of snails, varying in sus- liver and spleen (hepatosplenomegaly). More- ceptibility, with a taxonomy undergoing con- over, eggs of all three species may be trapped in stant revision. Historically, this has long created the lungs, and with S. japonicum, nervous dis- confusion. orders or cerebral schistosomiasis can occur if Schistosomiasis can be a serious chronic dis- eggs collect in the brain. ease in poor rural areas, where humans are reg- ularly in contact with fresh water contaminated History by schistosome cercariae. In most endemic ar- Human schistosome worms were first described eas, prevalence and intensity of infection (i.e., in Egypt by Bilharz in 1851 and related to dis- the number of eggs released – an indication ease symptoms by Wilhelm Griesinger shortly of the number of worms carried) peaks in the thereafter. Both men assumed the worm was teenage years. But even in highly endemic ar- a single species, occurring in blood vessels of eas, the transmission rate is low, partly because the gut or bladder. That two Egyptian species of patchy distribution of the surprisingly few in- existed was suggested in 1907 by Louis Sam- fected snails. bon, who named the second species S. mansoni. Reservoir hosts play an important role A year later, Piraja da Silva in Brazil gave the first in Oriental schistosomiasis. Rodents may be description of S. mansoni but assumed it was a significant reservoirs of S. mansoni in South third distinct species. A long controversy over America. Human schistosomes belong to a large the existence of two Egyptian species was finally family of trematodes (Schistosomatidae) that resolved by Robert Leiper in 1915. Meanwhile, parasitize birds and mammals. In many regions, in 1905 Fujiro Katsurada had described eggs particularly the lake country of the central and worms from patients in Japan and named and western United States and Canada, non- them japonicum. human schistosome cercariae penetrate human The worms’ life cycles long remained mys- skin accidentally. Although they are destroyed terious, although researchers usually assumed in the skin, this causes a harmless but irri- involvement by an intermediate host. In 1894, tating rash – “swimmer’s itch” or schistosome Arthur Looss, then the foremost authority, ar- dermatitis. gued against any intermediate host, claiming Embolized trematode eggs induce inflamma- that the miracidia bored directly back into hu- tory reactions in various body organs, caus- mans. This bizarre theory likewise generated ing symptoms of chronic schistosomiasis. controversy, finally resolved in 1913. Keinosuke The pathology is quite variable and gener- Miyairi and Masatsuga Suzuki discovered the ally related to the intensity of infection. With snail host entered by the miracidia and de- S. haematobium, lesions occur in the bladder scribed the schistosome cercariae emerging and ureter around the entrapped, calcifying from the snails later. Leiper, sent to China to eggs, with eventual development of fibrous con- uncover the mysterious life cycle of the worm, nective tissue. Symptoms include blood in the hurried to Japan to confirm the breakthrough. urine (hematuria), painful and excessive uri- In 1914, he was posted to Egypt and quickly nation (dysuria), distension of the ureters (hy- resolved the life-cycle problem in that coun- droureter), and distension and atrophy of the try, distinguishing the two species by their mor- kidneys through blockage of the urethras (hy- phologies, egg types, and different snail hosts. dronephrosis). With intestinal schistosomes, With such problems resolved, interest in schis- gut wall and liver lesions occur, also with tosomiasis subsided. It was thought curable by

291 128. Scrofula the drug antimony tartrate and preventable by of latrines, drugs, and mollusc-killing chemi- the snail-killing chemical copper sulfate. cals. Utilizing a host of methods including mass Between the two world wars, campaigns us- reclamation of swampland, the Chinese eradi- ing these chemicals were undertaken in Egypt, cated schistosomiasis from many areas of their Sudan, Rhodesia, and South Africa, particularly country. after schistosomiasis was found among children The threat posed by irrigation schemes of “poor whites” in Transvaal. In addition, high led to development of better molluscicides. prevalence among African mineworkers gener- Chemotherapy has now become the favored ated interest by the South African Institute for weapon, particularly after a 15-year experimen- Medical Research. The International Health Di- tal control campaign in St. Lucia sponsored by vision of the Rockefeller Foundation financed the Rockefeller Foundation. Oral oxamniquine an eradication campaign against hookworm proved effective against S. mansoni, and met- and schistosomiasis in Egypt between 1929 and rifonate against S. haematobium, whereas prazi- 1940. quantel is emerging as a “wonder drug” effective After World War II, interest in the disease dra- against all schistosome species. Today, with sup- matically increased, especially in British, French, port from the McConnnell Clark Foundation, and Belgian colonies in Africa. By 1950, schis- emphasis is on problems of schistosome immu- tosomiasis, previously considered unimportant nity and development of vaccines. outside Egypt, Sudan, South Africa, and China, John Farley was recognized as the most important tropi- cal disease after malaria. In America, interest followed from an outbreak among Americans in the Philippines, where in 1944 over 1,000 128. Scrofula combat-engineering troops involved in bridge building and road construction came down with Scrofula can be defined only historically. It was the disease. Scientists and physicians posted to a term about which there was some measure of Leyte to deal with the problem brought the dis- consensus in the past but has now largely been ease to American attention immediately after superseded by terms indicating some form of tu- the war and initiated the growth in schistoso- berculosis. Scrofula is not, however, simply an miasis research. old name for tuberculosis. Our ontology of dis- In British Africa, a helminth subcommittee of ease centers on the tubercle bacillus, and we the Medical Research Advisory Committee be- would commit a grave historical error if we as- gan to stress the danger of schistosomiasis, par- sume that with its aid we can know what under- ticularly as new irrigation schemes threatened lay old discussions of scrofula. To understand to spread the disease. The subcommittee initi- such discussions, we must learn how and why ated testing of a new drug, Miracil D, discov- the concept of scrofula was constructed. ered by the British after occupying the Bayer The distribution of scrofula (or “scrophula”) laboratories toward the end of World War II. resulted more from the religious and political The first major British work on the epidemiol- convictions of those who saw it than from phys- ogy of the disease in Africa occurred between ical geography, economic conditions, or other 1955 and 1965, when the East Africa Medical circumstances normally considered conducive Survey was conducted and the South African to disease. In regard to its clinical manifesta- government initiated surveys and supported tions, we note, first, that the term itself implies research into experimental schistosomiasis in an underlying entity that becomes manifest. But animals. second, scrofula historically was its collection of The 1950s also witnessed the first mass cam- symptoms and signs. We must understand what paign involving more than the introduction went into that collection, and why.

292 128. Scrofula

History Charles I, his opponents saw it as a justification “Scrophula,” like scurvy and syphilis, was not a of absolute rule by a king who claimed to be term used by the ancients. Whereas there may God’s representative. The Stuarts, whether on be special reasons why the latter two were un- the throne or in temporary or permanent exile, known (a distribution to the north of the ancient continued to touch for the King’s Evil, and their Mediterranean and a possible Columbian ori- supporters claimed that their success in curing gin, respectively), there seems no reason to sus- scrofula was a sure sign of their status as the pect that scrofula was a new disease – or at least only legitimate monarchs. The Puritans and Par- so it seemed to Renaissance humanist doctors liamentarians saw the Touch as politically dan- trying to reconstitute Greek medicine. In fact, gerous and tried to suppress it. Queen Anne was the best they could do in the case of scrofula was the last British monarch to use the Touch. The to claim that one of its chief symptoms, neck tu- Hanoverians made no attempt to practice it, and mor, was the struma of the classical physicians. their Whig supporters professed horror at the But strumae in the ancient descriptions were not superstitious medieval ritual. associated with other features that Renaissance Conflicts surrounding the issue aroused physicians knew were part of scrofula. But how the strongest passions. Crowds of thousands did they “know” this? Where did their picture of pressed around the Stuart kings to receive the scrofula come from? Touch. Because the King’s Evil was intimately The answer is that medieval descriptions of bound up with the king’s person, if we look for scrofula existed. Partly these came from a surgi- a “distribution” of scrofula – in seventeenth- cal tradition, which was less Hellenizing than century medical literature, for example – we Renaissance physicians’ medicine. Partly they find abundant references to it in Britain and came from popular tradition, in which scrofula France. But elsewhere, texts may not mention it was identified as the “King’s Evil” and was be- at all. Thus in Holland, recently freed from ab- lieved curable by a king’s touch. solutist Catholic rule, scrofula had no place in The essence of the medieval ceremony of medical consciousness. Nor did Italian or Ger- touching in order to dispel evil was demonstra- man physicians – with no national attachment tion of the quasi-sacerdotal nature of kingship. to a “true” royal dynasty – emphasize scrofula as The political advantages were clear, for a king, a disease entity, rather viewing its various symp- in performing the cure, showed he was king in toms discretely. accordance with God’s will. This was the impor- By the eighteenth century, some medical tant point in the seventeenth and eighteenth works betray Enlightenment embarrassment centuries, when scrofula’s nature was energet- in identifying scrofula as having a nonmed- ically explored: The power of curing by Royal ical cure, the Touch. In discussing the dis- Touch was vouchsafed by God only to true ease, British writers followed a tradition based kings. It could be used to legitimate claim and on the works of Richard Wiseman, surgeon to accession. French kings continued to touch un- Charles II. In the nineteenth century, after the til the Revolution and were emulated by other disappearance of the French kings, scrofula was monarchs. still identified, although perhaps more usually In France and pre-Reformation England, the in adjectival form applied to a symptom. The no- ceremony’s religious nature cemented the re- tion underlying the name failed to survive germ lationships and mutual stability of church and theory, when attention turned from symptom throne. The ceremony was too miraculous for clusters to causative microorganisms. some Protestants, although English Puritans at first tolerated it, and James I, although of Characteristics Calvinist background, found it increasingly ex- We have seen something of the geography pedient to use the Touch. But by the time of and history of scrofula. We next examine what

293 128. Scrofula observers saw when describing the disease. The pital; other times, scrofulous patients were re- classical description was by Wiseman, a passion- jected as incurable or infectious. Often a physi- ate royalist to whom the Restoration seemed an cian admitted a patient to test for “scrofulous” expression of God’s will, which had placed the symptoms, and sometimes admittedly scrofu- rightful line of kings back on the throne. The lous patients were taken into hospitals in the be- king’s power to cure by Touch was again tri- lief that a course of mercury sweats would cure umphantly demonstrated, and if it was good to them. show that the king cured, it was better to show From the records, we can see that the physi- that he cured where medicine or surgery could cian sought several signs to establish a scrofu- not. Thus Wiseman selected only the most dif- lous condition: an itch and tumors in the glands, ficult cases for the Touch. joints, and other tissues. As the disease pro- Wiseman rejected the identification of scro- gressed, the physician saw these tumors change fula with struma, insisting that scrofula in- into ulcers, which deepened and ultimately pro- cluded more than struma’s tumors-in-their- duced caries in the bones. Exploratory surgery own-membranes. There was bifurcated swelling attempted to discover the stage of disease and of the upper lip; tumors of muscles, ligaments, what, accordingly, the prognosis was. Some- tendons, and bones; fistulae of the tonsils and times patients were released as incurable, some- the lachrymal region; and ophthalmia. Cases times they were treated with mercury sweats for the king had characteristic tumors near the to unblock glands and vessels from the imped- mastoid muscle and eye protrusion (lipitudo). imenta held to cause scrofula. Which of these Wiseman assembled his description of scro- many alternatives was used probably depended fula partly from descriptions by others, and on where the doctor had been trained. there must have been some consensus of what The politics of early nineteenth-century the disease was. There would not otherwise Europe no longer supported the idea of the “true have been any perception of the disease or the line of kings.” Without true kings, there was no king’s role in its cure among ordinary people, King’s Evil, and scrofula was seen as a disease or among their parsons or squires who, we may entity less often than in the preceding century. suppose, encouraged them to go to London for William Cullen’s influential system retained the the Touch. disease entity, but in fact even he helped de- The term “scrofula” remained in use in mainly stroy the unity of scrofula as a concept by subdi- British and French texts through the eighteenth viding it into differing conditions: “scrofula vul- century, and we can gather more information garis,” “scrofula mesenterica,” “scrofula fugax,” from medical practice in hospitals. The volun- and “scrofula Americana.” tary hospitals of the time were charitable insti- The term “scrofula” survived largely in adjec- tutions. Demand for effective use of funds (and tival form, so that “scrofulous” tumors or ul- the utility of recovered patients for advertising cers could be described independently without purposes) often meant pressure for rapid pa- necessarily referencing other “defining” char- tient turnover. As a result, chronic or infectious acteristics of the seventeenth-century disease. cases were generally not admitted. So when we With new emphasis on postmortem patholog- see scrofulous patients admitted to an eigh- ical anatomy in the nineteenth century, inter- teenth century hospital, we can assume that nal scrofula was often associated with tuber- the physician permitting the admissions did not cles in the lungs. Discovery of the causative consider the disease chronic or infectious. In bacillus created an ontology of disease around practice, hospital admissions show the same tuberculosis, thus rendering “scrofula” periph- ambivalence about scrofula as the eighteenth eral to medicine and accessible only to the century medical world at large. Sometimes the historian. term simply did not exist for physician or hos- Roger K. French

294 129. Scurvy

129. Scurvy 26 weeks, and two others suffered apparent cardiac hemorrhages at 36 and 38 weeks. Scurvy is a dietary deficiency disease, arising They were clearly near that stage of the dis- from lack of vitamin C (ascorbic acid). It usu- ease that killed an eighteenth-century self- ally occurs in the absence of fruit and vegeta- experimenter, not to mention many thousands bles. Scurvy appears in no regularly recogniz- of sailors. (When volunteers were given large able way in ancient literature. Its name, derived doses of ascorbic acid, all made complete re- from northern European vernaculars (for ex- coveries.) Historical reports of symptoms, in- ample, schverbaujck in Dutch and scorbuck in volving far more severe cases, add flaccidity of Danish), was Latinized as scorbutus in 1541 by flesh, loosening of teeth, and reopening of old Dutch physician Johannes Echthius. wounds.

Characteristics History Humans, unlike many other animals, do not No doubt scurvy appeared in ancient times and synthesize vitamin C, and scurvy has histori- was treated by physicians. The ancients, how- cally appeared under circumstances where di- ever, do not seem to have had a name for it. ets are circumscribed, especially on long sea In any event, scurvy could not be found in the voyages. In modern times, infantile scurvy has writings of Hippocrates or Galen by individu- been a problem, occurring mostly in lower so- als of the late fifteenth and sixteenth centuries, cioeconomic groups. Such outbreaks are associ- to whom the disease was so obvious, and for ated with trends away from breast-feeding, com- whom medicine was founded on Hippocrates bined with maternal ignorance about substitute and Galen. As with the other apparently new foods. disease of the Renaissance – syphilis – it was im- Scurvy occurs in followers of fad diets, and portant for humanist physicians to believe that, in single, middle-aged men. It is not widely re- notwithstanding name changes, ancient writers ported from the Third World, perhaps because had known the disease. Only then could it be fit- of comparatively greater availability of fresh ted into “classical” theory and practice and effec- plant foods but doubtless also because of a lack tive treatment sought. Attempts were made to of medical services to report the disease. show that Hippocrates knew of scurvy, but prac- Generally, scurvy is a disease of northern tical persons, such as ships’ surgeons, treated it countries, although the traditional Eskimo diet as a new disease. of uncooked meat is sufficient to prevent it Of course, the circumstances surrounding (meat has vitamin C, but heat – as in cooking scurvy’s appearance during the Renaissance – destroys the vitamin content). Until recent were very different from those surrounding times, adult scurvy was endemic in Russia, but diseases discussed by Galen and Hippocrates. not infantile scurvy, for suckling infants do bet- European economic power was growing ter than adults when the diet is scorbutic. rapidly, and the desire to trade was matched The characteristic features of scurvy have by technical developments of shipbuilding and been experimentally monitored. At 12 weeks navigation. The Europeans’ theater of action without vitamin C, a feeling of lethargy ap- was the Atlantic, not merely the enclosed pears. At 19 weeks, the skin becomes dry and Mediterranean, and all these factors meant that rough, and hair follicles form lumps. Small hem- ships stayed at sea long enough for scurvy orrhages in the legs begin at 23 weeks; a bit to develop. In 1498, Vasco da Gama, reaching later, fresh wounds will not heal. A classic symp- the east coast of Africa, reported many of his tom – swollen, soft, purple gums – appears after men suffering from what was probably scurvy. 30 weeks. In a mid-twentieth century study, Twelve weeks at sea on the return journey one volunteer developed a tubercular lesion at renewed the disease. Fernando Magellan, too,

295 129. Scurvy saw much scurvy among his crew when at sea Naval warfare involved not only long- for 15 weeks in 1519. distance operations but also blockades of long Spain and Portugal established control over duration. The citrus fruit supply was simply not southern routes to the Far East but were quickly adequate for such operations: A complement followed by the French and English, who tried of 500 men for a large warship was not un- to find a northern route. A French expedition of usual. Some physicians even advised against cit- 1534, overwintering on the St. Lawrence River rus juice, and generally substitutes were sought. in North America, suffered greatly from scurvy. One was cider, to which tradition attributed an- The seventeenth century saw expeditions by tiscorbutic properties. In the early 1740s, ship’s big trading firms like the East India Company, surgeon Edward Ives was losing the usual large and the establishment of more colonies by more number of men to scurvy when he persuaded countries. It also witnessed more sea voyages of his admiral to provision with cider. While it long duration. The East India Company, for ex- lasted, he lost no crewmen: Scurvy came only ample, sent an expedition to Sumatra in 1601; it afterwards, all other conditions remaining the was 29 weeks at sea before reaching the Cape, same. and scurvy was widespread. The only ship ex- This was essentially a forced clinical exper- empted was that of Sir James Lancaster, who iment, a technique used more elaborately by provided lemon juice for his sailors. James Lind. Lind divided scurvy patients into Observers noted the rapid recovery of scorbu- those taking citrus fruit, those taking cider, and tic sailors on reaching a port where fresh food those taking other remedies. The first group was available. Experience showed in particular improved rapidly, followed by the second; the the value of citrus fruits. But general acceptance remainder did not improve. Lind has been of this knowledge was long delayed. Part of the much celebrated for this early clinical trial, but problem lay in provisioning the ever larger ships doubt has recently been cast on his results on and squadrons: Citrus fruits are not native to the grounds that modern research shows no the countries where merchant fleets were based; vitamin C in cider. Yet cider made in the these fruits might spoil over long voyages; and eighteenth-century manner was high in vita- attempts to concentrate or preserve the juice min C. By 1753, Lind had published his results must have often reduced its effectiveness. The in the most authoritative argument yet made for Dutch East India Company tried to ensure reg- the use of citrus to prevent scurvy. But not un- ular supplies by planting orchards at Mauritius til the end of the century did administrator Sir and St. Helena, and even experimented with Gilbert Blane obtain regular issue of lime juice shipboard gardens. Review of company records to British sailors. indicates that, at least in regular trading voy- Lessons learned at sea enabled control of ages with known landfalls and provisions for the occasional outbreaks of scurvy in early nine- crews including fruit juice, scurvy was not very teenth-century prisons. But there was no ade- deadly. quate remedy for the scurvy produced by the This did not hold, however, for European great failure of the potato crop in 1845–46. Pota- navies, particularly during the eighteenth cen- toes are rich in vitamin C, and the population of tury. Their operations were far from regular. Ireland depended upon them as food. Scot- In any such operation, it was expected that land also suffered. Later in the century, when lives would be lost, and experience showed conditions precluded access to fresh fruit and that disease would take many. Fully 855 of vegetables, scurvy appeared: in the California 1,000 men succumbed – most to scurvy – Gold Rush of 1848 and later; in the Crimean when Commodore George Anson fulfilled his War (1854–56); during an American blockade of 1740 commission to capture Spanish treasure Mexico in 1846; and during the U.S. Civil War, shipments. particularly in prisoner-of-war camps.

296 129. Scurvy

Scurvy was a special danger in Arctic regions. numerous disputes arose about the nature of Where regular commerce obtained – in Hudson the disease. Bay Company territory, for example – scurvy Over time, the theory of the disease had was only a minor threat, and since the seven- changed with theories of medicine. In the six- teenth century the company had shipped lime teenth century, humoral theories attributed juice. Fresh meat was also recognized as valu- scurvy to spleen damage from a dietary cause – able, a truth learned the hard way in early over- the salt meat, stale water, and preserved food of wintering disasters. Explorers, however, gen- long sea voyages. In the seventeenth century, erally encountered scurvy, particularly when when chemical notions of the body were attrac- small parties left their ships for exploration on tive, some writers distinguished between acid foot. scurvy and alkaline scurvy. When mechanism Perhaps the least expected occurrence was was employed in the medicine of the eighteenth that of infantile scurvy in Europe and America century, physicians discussed corrosive parti- between the 1870s and World War I. The odd cles in the blood. These were still humoral the- feature was that infantile scurvy occurred in the ories, and the humors’ vices still derived from higher social classes, where no economic reason diet. for vitamin C deficiency obtained. The reason Hermann Boerhaave, the most authoritative was that upper-class mothers tended to avoid eighteenth-century voice, blamed salt; dried breast-feeding, and newly available preserved- and smoked meats, including fish and seabirds; milk products contained no vitamin C. Scurvy ships’ biscuits; dried peas and beans; and old, often occurred before children began consum- sharp, salty cheese. Such a diet, he argued, ing adult food. Upper-class mothers had also led to the proximate cause of the disease: The avoided breast-feeding in previous eras, but blood became thin and sharp. From this all the then infants were breast-fed by wet nurses. symptoms could be deduced, and all treatment Before the discovery of vitamin C, etiologi- should be directed to restoring the blood. (The cal theories of scurvy were more destructive theory of the time held that “disturbance” of the than helpful overall. Many government offi- blood caused many diseases.) cials, trading-company surgeons and officers, Boerhaave mentioned citrus fruits, but only in and eventually naval and military administra- a list of other remedies, and without explaining tors, were convinced that certain fruits pre- how such remedies worked. The value of cit- vented and cured the disease. But advice from rus juice was after all merely an empirical dis- educated physicians was sometimes bad: Medi- covery. Boerhaave’s rationalist view attributed cal theory had its impact on practice. scurvy not to a lack in the diet but to an excess The rise of the germ theory of disease in the of things undesirable. His student Gerard van second half of the nineteenth century, which Swieten, however, believed that the cause of the changed medicine more than anything else had disease was a dietary lack. Scurvy, he argued, done in the preceding 2,000 years, had an enor- appeared more often in besieged cities than mous effect on the study of scurvy. Disease was in besieging armies, which had access to fresh now seen as caused by living microorganisms, provisions. and clinical symptoms as secondary. By the end In 1795, Sir Gilbert Blane became commis- of the century, the new medicine proved spec- sioner of the Board of Sick and Wounded Sailors. tacularly successful in combatting infectious Supported by recent experiments with lemon diseases. For scurvy, the effect of this revolu- juice, he persuaded the Admiralty to authorize a tion was to encourage a search for a causal or- daily dose to each sailor. Over the next 20 years, ganism, or at least a poison. In other words, the this totaled more than 1.5 million gallons. new research ran counter to the previous con- Although scurvy virtually disappeared from sensus that incomplete diets caused scurvy, and the British fleet (but not from other fleets), on

297 130. Sickle-Cell Anemia land the theories of physicians continued to Despite these opposing doctrines, the results threaten practice. The Siege of Paris (1870–71) obtained by Holst and Frolich¨ prompted efforts produced an outbreak of scurvy, focusing atten- to isolate the active component. McCollum had tion on its cause at a time when ideas about con- already identified a fat-soluble factor “A” and tagion and germs were becoming widespread. a water-soluble factor “B” in experimental rats, In 1874, the French Academy of Medicine aired and it was natural to look for a “vitamine C.” the view that scurvy was a contagious miasma From 1918, S. S. Zilva and others attempted to and no more caused by lack of fresh fruit than isolate vitamin C, a feat achieved by Hungarian malaria was caused by lack of quinine. A British Albert Szent-Gyorgyi,¨ who was actually work- expedition of 1894 spent three winters in the ing on a different problem involving the sugars Arctic, remaining healthy on a diet including in lemon juice. In 1932, Glen King in Pittsburgh fresh meat but little lime juice. Physicians ex- published results that combined Szent- plaining the absence of scurvy stated that the Gyorgyi’s¨ findings with his own. Vitamin C had disease was caused by bacterial action in spoiled been discovered, and scurvy was vanquished. meat. They realized that no one had studied Roger K. French scurvy in the light of germ theory; such a study was undertaken and seemed to support a germ theory of scurvy. So thoroughly was scurvy as- sociated with germ theory that one physician 130. Sickle-Cell Anemia explained lime juice as simply an antibacterial mouthwash. Sickle-cell disease is an inherited disorder re- The final recognition of scurvy as a de- sulting from an abnormality in the structure of a ficiency disease is a twentieth-century story. protein in the red blood cell called hemoglobin. From the last years of the nineteenth century, It represents a spectrum of disorders ranging there had been concern about the incidence from the full-blown form, sickle-cell anemia, of ship beriberi. Axel Holst knew about the to the carrier state called sickle-cell trait or sim- use of chickens in previous studies of beriberi ply sickle trait. Also included in this spectrum but chose guinea pigs (which, like humans, are several other variant hemoglobin disorders, do not synthesize their own vitamin C) as his which all have the sickle hemoglobin. Sickle-cell experimental animals. Under a restricted diet, anemia is the prototype for most molecular dis- the animals developed symptoms of scurvy. eases and was the first disease to have its cause By 1913, Holst and his collaborator Theodor isolated to a single molecular change in the hu- Frolich¨ showed that scurvy indeed resulted man genetic structure. This single change is re- from a deficient diet. sponsible for all of the dramatic physiological Meanwhile, in 1912, Casimir Funk in changes and clinical events that occur in this London proposed that scurvy was one of four disease. diseases (along with beriberi, rickets, and Sickle-cell trait occurs when the individual is pellagra) caused by dietary deficiency. Each heterozygous for the sickle-cell gene and re- missing factor, he believed, was a nitrogenous sults in abnormal hemoglobin (hemoglobin S) base, for which he coined the name “vitamine.” concentrations of less than 50 percent. It The deficiency thesis met opposition from generally causes no serious illness, although bacteriologists, and in 1916 and 1917 cultured this has been disputed. Other sickle-cell syn- bacteria from scorbutic animals were inocu- dromes occur when hemoglobin S is present lated into healthy animals, producing signs in a heterozygous state with other hemoglobin of scurvy. Related to the bacterial theory was variants – some with similar properties. Com- E. V. McCollum’s notion that scurvy was caused mon examples of these include hemoglobin C by bacteria-developed poisons. and hemoglobin E.

298 130. Sickle-Cell Anemia

Characteristics lature of the capillary bed; vascular occlusion Sickle-cell anemia is found in up to 4 percent and tissue destruction result. Cell lifespan is of Africans and 1 percent of black Americans. also decreased and is manifested as a hemolytic Upward of 40 percent of Africans carry the anemia. sickle-cell trait, as compared to 9 percent of Indeed, sickle-cell anemia is characterized by black Americans. The trait is also present in chronic hemolytic anemia and recurrent states some Mediterranean cultures. Experts believe called “crises,” divided into three types: “pain,” that sickle-cell gene mutation occurred inde- “sequestration,” and “aplastic.” Pain crisis (the pendently in several areas of Africa, explaining most common) occurs an average of three times its presence in different peoples. annually. It first presents after 6 months of life, Hemoglobin S is transmitted as an autosomal when fetal hemoglobin reaches low levels. At recessive gene. So if both parents have sickle- this age, early signs often include painful in- cell trait, the chances are 1 in 4 that their child flammation of extremity bones (hand-foot syn- will have hemoglobin SS and thus sickle-cell drome). Older patients develop recurrent joint, anemia; 1 in 4 that it will have hemoglobin AA back, abdominal, or long-bone pain lasting ap- and be normal; and 2 in 4 that it will have proximately 7 days. hemoglobin AS and have sickle-cell trait. Sequestration crisis occurs when a large pro- The pattern of death in persons who have portion of red cells become trapped in the sickle-cell anemia is bimodal, with the first peak spleen, resulting in shock. With age, recurrent occurring in childhood and the second occur- vascular occlusion in the spleen causes its func- ring among people in their late 30s. Deaths tional destruction. Because the spleen elimi- during childhood are related to infectious nates certain bacteria, sickle-cell patients are at causes, whereas those during adulthood result increased risk of infection. from organ failure caused by repeated tissue In rare aplastic crises, the blood-forming destruction. bone marrow becomes suppressed for short pe- Hemoglobin carries oxygen in the blood- riods, resulting in acute reduction of red cells. stream and is found inside red blood cells. Along Known as red-cell aplasia, this temporary con- with iron, it is composed of amino acids that dition may require blood transfusions until the in turn are built from deoxyribonucleic acid bone marrow recovers. (DNA). In sickle-cell anemia, the DNA molecule By contrast, sickle-cell-trait carriers are phe- is changed through a single genetic mutation, notypically normal in most respects, although thus changing the amino acid composition of sickling is occasionally reported in such individ- the hemoglobin, which alters its solubility and uals at high altitudes or low oxygen, resulting interactive properties. Under appropriate condi- in splenic infarction. Kidney bleeding and de- tions, this results in a conformational change in creased renal concentrating ability occur more the red cell from a flexible biconcaved disk to frequently in people with sickle-cell trait. The an inflexible sickled cell. Thus, recurrent sick- condition is almost always benign; nevertheless, ling can cause the cellular membrane to be- claims have arisen that sickle-cell-trait carriers come permanently calcified, resulting in rigid, are at increased risk for acute muscle destruc- irreversibly sickled cells. These cells are found tion and sudden death. These reports are con- in all persons afflicted with sickle-cell disease troversial and require confirmation. and may represent from 5 to 50 percent of the red cell mass. History Hemoglobin S has a lower affinity for oxy- Sickle-cell anemia has been traced back to at gen, resulting in early release of oxygen and in- least 1670, when it was noted to be present in ability to oxygenate tissues adequately. Sickled the Krobo tribe of Ghana. It was first described cells have difficulty traversing the small vascu- clinically by Chicago physician James Herrick

299 131. Smallpox in 1910. Thirteen years later, J. Huck reported cowpox and monkeypox, but smallpox proba- on 14 patients and first noted the reversibility bly was an exclusively human infection. Virolo- of sickling. In 1939, J. Bibb and L. Diggs de- gists recognized two kinds of smallpox: Variola scribed irreversibly sickled cells, and in 1946, major, with a mortality rate of 25–30 percent; M. Sherman demonstrated the ordered struc- and Variola minor, with mild symptoms and a ture of hemoglobin S. Linus Pauling investigated death rate of 1 percent or less. The characteris- hemoglobin S by electrophoresis and reasoned tics of smallpox viruses varied, and strains inter- that the sickling resulted from a single gene. mediate between V. major and V. minor proba- V. Ingram then demonstrated that the condition bly existed. The history of smallpox is mostly a resulted from the amino acid substitution of va- history of V. major. line for glutamic acid. In 1949, A. Raper noted the high incidence of sickle-cell trait in malaria- Characteristics endemic areas and suggested that it protected As far as we know, the source of smallpox was against infestation. In 1954, A. Allison correlated always an infected human. No animal reser- sickle trait with regions of past and present fal- voir existed. Laundry workers occasionally con- ciparum malaria endemicity. tracted smallpox from clothing and bedding of Further analysis showed that the mutation il- smallpox patients, but most transmissions were lustrated a genetic principle termed balanced airborne over distances of no more than a few polymorphism. Generally, a gene such as sickle meters. Quarantine was effective, as long as it cell – causing severe morbidity and mortality – was applied early (even before the appearance dies out unless circumstances create a more fa- of symptoms) and strictly enforced. vorable survival. Africa and the Mediterranean Incubation lasted about 12 days. Onset was have areas that are (or were) endemic for abrupt and prostrating: high fever, headache, Plasmodium falciparum, which causes malig- back and muscle pain, and in children some- nant malaria. But when persons with sickle- times vomiting and convulsions. In the severest cell hemoglobin are infected with malaria, the infections, extreme toxemia and massive hem- infected cells tend to sickle and are selec- orrhaging into skin, lungs, and other organs tively destroyed. Therefore, the sickle-cell gene could cause death swiftly. In most cases, victims – itself potentially fatal – helps defend against experienced the characteristic rash 2–5 days af- a potentially fatal disease and, paradoxically, ter onset. Generally, it appeared more densely prolongs survival. In regions where P. falci- on face, palms, and soles than on the trunk. In parum is not endemic, the sickle-cell gene be- another few days, the rash turned to pustules comes the sole determinant of morbidity and that in extreme cases were confluent, usually does not prolong life. This explains why sickle- indicating a lethal infection. William Bradford cell frequency has decreased in much of the observed cases like this among Amerindians in Americas. 1633–34. Complications may have been com- Georges C. Benjamin mon in these peoples. Drying and crusting of the pustules began on the eighth or ninth day after the first erup- tions. The scabs fell off 3 or 4 weeks after onset, 131. Smallpox and the victim was well again, barring complica- tions. Among possible sequelae were blindness Smallpox, now existing only in laboratories, is and male infertility. The probable sequel was a no longer an active infection. It was a viral dis- pocked and scarred face, appalling to others as ease usually transmitted by airborne droplets well as the survivor. Literature is full of refer- and entering the body through the respiratory ences to women thus robbed of their smooth tract. There never was a cure. Closely related are skins.

300 131. Smallpox

Except in the rarest instances, smallpox infec- Though widespread, smallpox seems not to tion ended in one of two ways: death or long- have been among humanity’s chief curses lasting immunity. Lacking an animal reservoir in those centuries. It ranked behind plague and the ability to remain latent within the body, and tuberculosis in the Middle Ages and be- smallpox existed only as an active infection. came a major demographic check in Europe It was a classic epidemic disease, surviving in only during the sixteenth and seventeenth many eras and parts of the world only as rolling centuries. waves of infection. It achieved endemicity only Smallpox historically acted as a solvent ex- in large and cosmopolitan populations, where it uded by dense populations. For example, it was could infect nonimmune visitors, infants, and an important ally of the Russian invaders of children. Where it was endemic, it was usu- Siberia and of the Hollanders in South Africa. ally a childhood disease; trial by smallpox was But it was a merciless enemy of barbarians try- a prerequisite of adulthood for all but a small ing to penetrate such populations. The Manchus minority. were obliged to excuse dignitaries from the thinly populated steppes from coming to History Beijing to make obeisance to the Emperor. For Because it persisted only by passing from one their safety, special audiences were provided in human to another, smallpox could not have Jehol, north of the Great Wall. existed among the sparse populations of the No later than 1519, smallpox crossed Paleolithic Age. It may have first appeared spo- the Atlantic to a New World still free from radically among village dwellers of the Neolithic the disease. It decimated the Arawaks of the Age. West Indies; accompanied the Spaniards to Smallpox may well have afflicted ancient Mexico; and rolled on ahead of them into the Egyptians. The face, neck, and shoulders of the Incan Empire. Amerindians had at best no more mummy of Pharoah Ramses V, who died in 1157 resistance than did Europeans, and they must B.C., is disfigured by a rash of elevated pustules, have suffered similar morbidity rates. Spanish but researchers cannot be sure of the infection estimates of Amerindian death rates in this first that caused them. Dreadful epidemics rolled of many pandemics of smallpox ranged from through the Old World in ancient times, but about one-fourth to one-half – rates compa- rarely were symptoms described clearly enough rable to those of afflicted European children. for researchers to make diagnoses. In the sec- The psychological effect was considerable. The ond and third centuries A.D., two pandemics Amerindians quaked in confusion and terror; devastated the Roman Empire, but we know and the Europeans preened themselves as the very little about them. There is some indication chosen people. of smallpox in China by the fourth century, and In 1789, smallpox appeared among Australian stronger evidence of it in Japan in the 730s. aborigines neighboring the newly arrived With Rhazes, a ninth-century Baghdad English settlers at Sydney Harbor. It destroyed physician, we are finally on solid ground. He half the indigenes, by English estimate, and differentiated between smallpox and measles spread into the interior. This epidemic was prob- and revealed smallpox to be a common child- ably the single greatest demographic shock ever hood disease in southwest Asia. The density dealt the aborigines. of population centers suggests strongly that By the eighteenth century, smallpox ac- smallpox was prevalent throughout advanced counted for 10–15 percent of all deaths in Old World civilizations before the end of the some European countries, 80 percent of the first Christian millennium. In the same period, victims being under 10 years of age. Similar smallpox may have invaded sub-Saharan rates were probably common in major cities of Africa, northern Europe, and Indonesia. North Africa and Eurasia. Outside these densely

301 131. Smallpox populated areas, smallpox was epidemic, killing amazingly – it may have been the first example high percentages of adults. of careful quantitative analysis of the effects of Modern techniques of inoculation and a medical procedure. Of Boston’s population of vaccination began – no one knows when or around 11,000, 5,980 caught the disease, and where – with variolation (artificial infection 844 – or 14 percent – died. But only 6 – or just with smallpox of healthy people), an effort to 2.4 percent – of the 244 variolated by Boylston produce immunity through mild cases of the died. disease. In China, smallpox scabs were blown Variolation, however, was not adopted rapidly. up the nostril, seemingly a dangerous method After an initial flurry among the upper classes because it might infect the respiratory tract, but and their domestics in the 1720s, the spread the scabs were apparently aged first, attenuat- of the new procedure slowed. British North ing the virus. Elsewhere, variolation generally Americans resorted to it only during epi- involved scratching infected matter into the demics, when contracting the disease naturally skin. If variolation was expert, the infection was seemed more dangerous than embracing it via mild and death rates no more than 4 percent. variolation. Variolation was practiced for a long time, Acceptance of variolation was contingent on not by trained physicians but by folk healers. several developments: increased fear of small- For example, Cotton Mather in Massachusetts pox, which a surge of the disease around 1750 first heard of it about 1706 from his African stimulated; reduction of fees for variolation; slave, who told him that smallpox and vario- and improvement of the technique to reduce lation were both common in Africa. Peasants in the chances of death. These changes were ac- Scotland, Wales, Greece, the Middle East, and complished by, among others, American James elsewhere were “buying the smallpox” long be- Kirkpatrick and the British Sutton family. The fore the rich and wellborn learned of variolation. Suttons reduced variolation to a slight pricking Lady Mary Wortley Montagu, whose brother of the skin rather than deep incisions. Small- died of the disease, was herself attacked as an pox hospitals, where variolated patients could adult, losing her beauty, even her eyebrows. be isolated, helped quell fears of artificially trig- While in Constantinople, she learned about “in- gered epidemics. grafting” the disease, which usually led to a mild From the 1760s onward, variolation became infection and yet stout immunity. She had her increasingly common in the British Empire and son variolated in Constantinople in 1717, and Europe. The smallpox death of Louis XV in May her daughter in London in 1721. and the variolation of Louis XVI in June of 1774 The same year, smallpox broke out in Boston, spurred the practice everywhere. By the end where the people, too few to maintain the of the century, many thousands had been var- disease endemically, periodically suffered epi- iolated in Europe and America. Some experts demic waves of it. Mather knew nothing of Lady claim that the spread of variolation was among Montagu’s experiments, but he had heard of the causes of the population explosion that be- variolation from his slave and other sources. gan in the eighteenth century, but it is impossi- He persuaded Zabdiel Boylston to experiment ble to separate this factor from others, such as with the new technique in Boston. Despite fierce improved nutrition. Yet we can be sure that in opposition from those who viewed the practice the long run variolation stimulated population as dangerous (which it certainly was), Boylston growth, at least indirectly. scratched pus from a smallpox pustule into the The greatest windfall of variolation (indeed, skins of his son and two slaves. In all, he vari- the greatest in the history of medicine) oc- olated 244 people, while other physicians var- curred in the last decades of the eighteenth iolated 36 more. This was the first large-scale century. English variolator and scientist Edward test of the practice, at least in the West. Also – Jenner noticed that variolation failed to produce

302 131. Smallpox symptoms in people who had previously con- zero by the end of the century. Elsewhere, suc- tracted a mild pox from cattle. He “vaccinated” cess was equivocal, even though the effect of (a new word derived from the Latin for “cow”) vaccination was supplemented by the appear- several people with cowpox matter and then at- ance of V. minor toward the end of the cen- tempted variolation. Inoculation with smallpox tury, displacing the more virulent form in some matter uniformly failed to produce illness. regions. Jenner published his results in 1798. Vaccina- Jenner realized that his discovery could mean tion may have been practiced before by com- “the annihilation of smallpox,” but not until the mon folk, like variolation, but now one of the mid-twentieth century did this seem a prac- elite had printed an account of the technique tical possibility. By 1950, wealthy societies in for the whole world to read, and that made all the temperate zones with strong governments, the difference. England led the way – more than skilled medical personnel, and scientifically so- 100,000 were vaccinated there by 1801 – and phisticated populations were nearly free of the the rest of the world followed. Within 3 years disease. But most of the world’s smallpox raged of Jenner’s publication, his work was translated in the tropics, where few of these factors existed into German, French, Spanish, Dutch, Italian, and where vaccine lost potency quickly in the and Latin. In France, 1.7 million were vacci- heat. Freeze-drying, invented in the 1940s and nated between 1808 and 1811; in Russia about adapted for vaccine production in the 1950s, 2 million in the decade ending 1814; and so on. solved that problem. Getting potent vaccine across oceans as scabs In 1966, the World Health Assembly called or bits of thread soaked in infected matter was for eradication of smallpox from the Earth. An problematical. Often, the virus proved useless. officer of the World Health Organization, Don- The surest way of preserving cowpox virus over ald Henderson, led the Smallpox Eradication great distances was by serial infection: Recruit Programme. In 1967, smallpox existed in every several unimmunized people and vaccinate one. continent except North America and Europe, When his pustules are ripe, transfer the disease and it was estimated that from 10 million to to another, and so on in sequence until the des- 15 million people contracted the disease annu- tination is reached. This technique was used by ally. By 1972, it was gone from South America. Francisco Xavier Balmis, who from 1804 to 1806 By 1974, it was restricted to India, Ethiopia, and led a Spanish-government-backed expedition to Somalia. In October 1975, the last case of small- the Americas and then on to the Philippines and pox in Asia occurred, and in October 1977 in China, vaccinating thousands as he went. He Somalia came the last case of naturally occur- used young boys – usually orphans – as cow- ring smallpox in the world. In 1978, smallpox pox reservoirs, the first set obtained in Spain and virus somehow escaped from a laboratory in others as required. Birmingham, England, infecting a mother and During the 1800s, humanity began to win its daughter. The daughter died; the mother sur- battle with smallpox. Vaccination continued to vived; and the laboratory’s director commit- spread, and in some countries was made com- ted suicide while in quarantine. These were pulsory for infants. Its benign effect on death the last deaths associated with the ancient rates, unlike variolation, was obvious. Literally scourge of smallpox. In 1979 came the of- millions of children, who would have died with- ficial announcement of the demise of the out Jenner’s discovery, lived to enrich their so- disease. As of 1980, stocks of vaccine suffi- cieties and to fuel the population explosion. In cient for 200 million vaccinations were be- a few advanced and disciplined societies, such ing maintained in case smallpox should arise as England and Prussia, where doctors, officials, again. and the public cooperated to smother smallpox, Humanity won the victory against the small- deaths from the disease had declined to near pox virus by displacing it with the vaccine virus.

303 132. Streptococcal Diseases

Almost everyone for more than a century be- green hemolysis; beta: complete or clear hemol- lieved that virus to be cowpox, but in 1939 care- ysis). Thus, for example, the streptococcus re- ful comparison of vaccinia virus (which does sponsible for pharyngitis is known as a “group-A not exist naturally), cowpox virus, and smallpox beta-hemolytic streptococcus.” virus showed them to be related but clearly dis- The streptococcus has several biological pe- tinct. One expert claims that the Jenner strain culiarities that influence its infectiousness. The of vaccinia virus was early contaminated with genetic insertion of a bacteriophage produces a mild strain of smallpox and that vaccination a toxin responsible for the rash of scarlet fever. was thus actually a continuation of variolation. A group of proteins renders the streptococcus Decades of variolation, according to this the- impervious to the normal bodily defense of ory, produced attenuated strains of smallpox, phagocytosis. Hemolysins and enzymes, when and vaccinia virus is one of these tamed vari- present, help the streptococcus to invade the eties. Other experts suggest that Jenner’s strain host. This potential biological variability may was not cowpox but horsepox, which cattle oc- be responsible for abrupt changes undergone casionally contracted. Horsepox died out early by streptococcal illnesses in the past. in the twentieth century, so this hypothesis re- Streptococcal illness is extremely common. mains untested. Still others suggest that vac- Few have escaped streptococcal pharyngitis or cinia virus resulted from hybridization of other superficial impetigo of the skin. Some forms pox viruses. Careful analysis, however, has un- of streptococcal illness, however, are rare, such covered little indication of this. The stuff of as streptococcal endocarditis. Most strepto- smallpox vaccination, although a mystery, is coccal diseases are spread through respiratory perhaps the greatest happy accident in the his- droplets. Other means include bacterial con- tory of the relationship between humans and tamination of food or milk, soiled hands or in- pathogens. struments touching open wounds, or invasion Alfred W. Crosby of the bloodstream by normal resident bacteria. Group A streptococci produce several common illnesses. Streptococcal pharyngitis presents with fever, headache, sore throat, 132. Streptococcal Diseases and abdominal discomfort. Before penicillin, the disease was often self-limited, but the Microorganisms of the genus Streptococcus are streptococci could disseminate to other sites, responsible for many common and not so com- producing otitis media, mastoiditis, tonsillar mon human and animal diseases. Streptococ- abscesses, or osteomyelitis. Puerperal sepsis, cal pharyngitis and pneumonia, scarlet fever, or childbed fever, occurs when streptococci, impetigo, erysipelas, neonatal meningitis and introduced at delivery, invade the internal sepsis, puerperal sepsis, and bacterial endo- lining of the uterus. Group A streptococci can carditis all follow infection with streptococci. In cause impetigo (a superficial skin infection), addition, some streptococci provoke two postin- cellulitis, and erysipelas (a life-threatening, fectious conditions: acute rheumatic fever and rapidly progressing soft-tissue infection). acute glomerulonephritis. Group A streptococci are responsible for two striking postinfectious conditions. The first, Characteristics rheumatic fever, can include one or more Streptococci are classified into distinct serologic of the following: carditis (pericarditis, my- groups – labeled alphabetically – each with dis- ocarditis, and/or endocarditis); migratory, crete subgroups. Microbiologists further clas- nondeforming arthritis; chorea; subcutaneous, sify streptococci on whether and how they fibrous nodules; and erythema marginatum. hemolyze red blood cells (alpha: incomplete or The second postinfectious condition is acute

304 132. Streptococcal Diseases glomerulonephritis, a usually temporary form or surgical. Any deep cut through uncleansed of renal failure. skin risked injecting streptococci into suscep- Group B streptococci form part of the normal tible tissue. Erysipelas also accompanied other flora of the vagina and usually do not produce streptococcal-related illnesses, such as childbed illness in adult women but can infect babies fever. Scarlet fever crosses medical history in a during delivery, producing meningitis and sep- number of places. In the latter part of the nine- sis. Group C streptococci are usually pathogenic teenth century during the early years of bacte- only for animals. Group D streptococci, normal riology, Friedrich Loffler¨ had to sort out scarlet residents of the human body, can produce en- fever cocci from diphtheria bacilli (both pro- docarditis in people with deformed heart valves. duced sore throats). Scarlet fever often occurred Some streptococci cannot be readily grouped, in epidemics passed both in the usual droplet such as Streptococcus viridans. These can also fashion and in contaminated foods – especially cause endocarditis and play a role in the forma- milk. tion of dental caries. Streptococcal pharyngitis, with or without rash, provoked postinfectious acute rheumatic History fever. For about a century, rheumatic fever in- Women have suffered from puerperal fever, pre- jured more hearts than any other disease. It sumably caused by streptococci, since ancient struck children and young adults (usually un- times. Many case studies in the Hippocratic cor- der 25) in temperate climates. Although men- pus indicate that women suffered from post- tioned by prominent seventeenth-century writ- partum fever, debility, and death. But childbed ers, such as Thomas Sydenham, rheumatic fever was probably never common. Oliver fever apparently was not a major problem un- Wendell Holmes wrote in the early 1840s that it til the late eighteenth and early nineteenth was rare. When it occurred, it clustered around centuries, when carditis emerged as its ma- the practice of an individual physician. Holmes jor component. This may have resulted from pointed to the need for cleanliness to prevent a biological change in the body’s response further victims. to the streptococcus (rheumatic fever is not Similarly, in 1861 Ignaz Semmelweis demon- an infection in the usual sense, but rather strated that physicians who followed dead pa- an immunologic response) coupled with intro- tients to the autopsy room and then returned to duction of the stethoscope, which facilitated the lying-in room to deliver babies had more pa- diagnosis. tients die of puerperal fever than did midwives All streptococcal diseases except neonatal who did not perform autopsies. The observa- sepsis and meningitis have become less viru- tions of Holmes and Semmelweis illustrate the lent since the end of the nineteenth century, a tremendous gulf in personal cleanliness that ex- phenomenon yet to be explained. Incidence was isted between pre- and post-germ-theory prac- clearly declining before the arrival of specific titioners. Holmes, for example, tells of distin- measures to treat these illnesses. The possibil- guished obstetricians who carried pelvic organs ity exists that streptococci, with their biological removed at autopsy in their street coat pock- variability, became less invasive in natural fash- ets. Both accounts also underscore the irony ion. But they did so at the precise time in history in the fact that the most scientifically oriented (at least in Europe and the United States) when physicians, the ones who performed autopsies, nutrition, housing, and living standards sub- were responsible for spreading illness! Those ac- stantially improved. Today, streptococci are usu- counts, however, treat with silence the plight of ally sensitive to sulfonamides and penicillins; infants born of infected mothers. thus most infections are curable with appropri- Erysipelas’s role in history was an inevitable ate antibiotics. accompaniment of wounds, whether accidental Peter C. English

305 133. Strongyloidiasis

133. Strongyloidiasis pain, nausea, alternating diarrhea and constipa- tion, anemia, weight loss, and low fever. Au- Strongyloidiasis,orCochin-China diarrhea,is toinfection can produce an enormous number caused by a minute nematode, the threadworm of worms and can be fatal. Persons with im- Strongyloides stercoralis. The organism was dis- mune deficiencies from diseases such as can- covered in 1876 in French troops with severe cer or acquired immune deficiency syndrome, diarrhea in what is now Vietnam. Strongyloides or whose therapy requires immune suppres- occurs around the world, with a range similar sion, may develop devastating hyperinfections to that of hookworms. Millions of people harbor from mild or inapparent strongyloidiasis. Ther- the organism. Because poor sanitation and bare apy is usually effective, although side effects feet favor transmission, it is especially prevalent from drugs are common. Prevention is largely in poor tropical countries. Like hookworm dis- a matter of education and improved living ease, strongyloidiasis prevalence has declined conditions. greatly in the southern United States since the Strongyloides fulleborni ¨ , a parasite of mon- early twentieth century but still has foci in Ken- keys, has been found in many people in Zaire, tucky and other states. Zambia, and other central African countries; lar- The worm has a complex life cycle. Parasitic vae may possibly be transmitted in mother’s males may not exist, but if they do, they are milk. The same or a similar species has been eliminated from the body shortly after infec- found in 80–100 percent of infants in a region tion. Females burrow in the mucosa of the in- of New Guinea. testine, where they feed and lay eggs, apparently K. David Patterson by parthenogenesis. The eggs pass into the lu- men of the intestine, where they hatch into a rhabditiform larval stage. In most cases, these larvae are voided in the feces and either trans- 134. Sudden Infant Death Syndrome form themselves directly into an infective filari- form larval stage, or, if conditions are favorable, Sudden infant death syndrome (SIDS) is diffi- undergo one or more generations of sexual re- cult to define because medical scientists do not production before filariform larvae appear. Like yet fully understand its nature. In the typical hookworms, the filariform Strongyloides larvae SIDS case, an apparently healthy infant, who penetrate human skin, often on an unshod foot, may recently have suffered some minor respira- enter the venous circulation, and are carried tory ailment, is put to bed in the evening and is through the heart to the lungs. Here they bur- found dead in the crib next morning. The baby row through the walls of the air sacs, ascend to shows no signs of having been distressed; au- the throat, and are swallowed. Autoinfection is topsy reveals no significant findings to explain also possible and can maintain the parasite for the cause of death. Physicians diagnose SIDS by years after the host has left endemic areas. In excluding other causes of death in infants be- this variation of the life cycle, rhabditiform lar- tween one month and one year. vae develop into infective filariforms while still in the intestine. These larvae penetrate the mu- Characteristics cosa, enter the bloodstream, and are eventually The vast majority of reported and published swallowed to continue the cycle. SIDS cases come from countries and continents Migrating larvae may produce itching when in the Earth’s temperate zones (e.g., the United they penetrate the skin, and cough and chest States, Canada, Europe, Australia, New Zealand, pain when they are active in the lungs. Light Japan, Hong Kong, and Israel). But SIDS oc- intestinal infections are often asymptomatic, curs worldwide, in countries in tropical and but heavier worm loads may cause abdominal frigid zones, in the mountains and at sea level.

306 134. Sudden Infant Death Syndrome

SIDS tends to receive less attention in coun- groups generally suffer a higher incidence tries with high infant-death rates from problems of SIDS than do others. The distribution of such as infections and malnutrition. Autopsies SIDS also seems to follow racial lines in the are rarely performed on adults, much less on United States: Afro-Americans (blacks) show the children, in these countries, making it almost highest incidence, followed by Euro-Americans impossible scientifically to label a sudden infant (whites), followed by Asian-Americans. That death as SIDS. SIDS becomes a significant fac- racial distribution may be deceptive, as it prob- tor in a country when the infant-death rate ap- ably reflects the generally lower socioeconomic proaches approximately 15 per 1,000 live births. status (SES) of blacks compared to other groups. The lower the death rate from other causes of Low SES does not always translate into high risk infant mortality, the higher the proportion of for SIDS, however. Studies show that Hispanics deaths from SIDS. of low SES have a SIDS rate comparable to or The occurrence of SIDS has probably not lower than that for whites. changed much over the centuries. Generally, Certain other characteristics of babies, moth- rates range from 1.5 to 3.5 cases per 1,000 ers, and families appear to be risk factors as- live births per year, though incidence varies sociated with a higher incidence of SIDS in in- from country to country. SIDS accounts for fants. None of these factors is predictive of SIDS 6,000–7,000infant deaths per year in the United and none are found in all SIDS cases, but all States. It is the greatest killer of infants between increase the risk in a child vulnerable to SIDS. 1 month and 1 year old. All can be related to low SES. Both prematurity SIDS’ outstanding characteristic is the age at and low birthweight are important risk factors in which it strikes children. Most deaths occur SIDS. SIDS occurs more frequently in children of between 1 and 6 months of age, peaking be- the following: multiple births, younger mothers, tween 2 and 3 months. Very few cases occur be- mothers who smoke, mothers of greater parity, fore 1 month; incidence drops significantly after higher birth rank in the family, single mothers, 6 months. SIDS deaths thus occur when babies mothers who abuse drugs, mothers with poor are undergoing their most rapid systemic de- prenatal care, and families in which a SIDS death velopment, and when their needs for efficient has previously occurred (slightly increased risk). bodily processes and outside sources of energy At present, the etiology of SIDS remains a to fuel them are greatest. Infants at this time mystery. It is not even clear whether SIDS has a are adjusting, for example, their sleep patterns single cause, has several causes, or is the result to changing internal needs and to the outside of a combination of factors working together. environment, their gastrointestinal systems to Before medicine took an interest in the sud- changing foods, their immune systems to new den, unexplained deaths of infants in the eigh- antigens and pathogens, and their nervous sys- teenth century, they were attributed to acci- tems to a variety of new motor and sensory stim- dental suffocation in bedclothes or acciden- uli. Life outside the womb is very different from tal smothering and overlaying by sleeping par- life inside the womb. ents. Less charitable people accused parents or SIDS strikes children of both sexes, of all so- nursemaids of infanticide. These theories per- cial, economic, ethnic, and racial groups, and at sisted throughout the nineteenth and early to all times of year. The distribution of SIDS within mid-twentieth centuries concomitantly with these groups and seasons is not equal, however. medical theories ascribing the deaths to an en- About 60 percent of SIDS victims are boys. SIDS larged thymus or a thymic condition. Since the occurs more commonly, but by no means ex- 1940s, when researchers took a renewed inter- clusively, during the colder months of the year est in the etiology of sudden unexplained infant (autumn and winter), in both northern and deaths, medicine has proposed numerous theo- southern hemispheres. Lower socioeconomic ries to explain why these children die.

307 134. Sudden Infant Death Syndrome

When medical examiners in the 1940s and The very definition of SIDS incorporates this 1950s tested the blood of infants who had died fact, stating that negative postmortem findings suddenly and inexplicably, they often found ful- help to classify an infant’s cause of death as minant infections that could easily have caused SIDS. Pathologists studying large numbers of death. For some years, bacterial and viral in- SIDS cases have, over the years, noted only a few fections were considered a major cause of sud- consistent postmortem findings that might at den infant deaths. But when deaths from in- some time help explain the nature of SIDS. The fection were weeded out, there still remained a pathological changes so far discovered fail to large number for which pathologists could find provide enough information for medical scien- no infectious agents. Researchers then found tists to understand the etiology or mechanism other possible causes of death, including the behind SIDS deaths. following: powerful allergic reactions to cow’s milk, dust mites, or an unidentified allergen; bo- History tulism (beginning in 1976 when a number of in- The medical profession and society did not rec- fants infected with Clostridium botulinum were ognize SIDS until the late twentieth century. discovered in California); severe undetected res- And yet people from Biblical times onward de- piratory viral infection; response to vaccination; scribed sudden unexplained infant deaths that overheating; hypothermia; high blood sodium; matched the typical history of a SIDS death to- deficiency of a trace element such as magne- day. Because the deaths almost always occurred sium, zinc, copper, calcium, selenium, or man- at home or in private situations, and to seem- ganese; vitamin deficiency; and high or low ingly healthy children, most people, including levels of thyroid hormones. Some physicians re- parents and caregivers, generally ascribed the iterated the old view that a proportion of parents cause of death to accidential or intentional committed infanticide. Further research into smothering or suffocation. When discovering these and other proposed etiologies continues. their infants, with whom they regularly slept, Most current research relates the “final path- dead next to them after a night’s sleep, with no way” of SIDS to malfunction or immaturity of signs of any disease or disturbance, and no cries the respiratory or cardiovascular system. Etio- during the night, parents believed that they logic theories under consideration include pre- had unknowingly overlaid and smothered their existing hypoxia, heart conduction problems children. (arrhythmias), and apnea. Evidence indicates Or, if they had not slept with their infant, but that children who die of SIDS possess physical found it lifeless where they had put it down risk factors such as small size, slower growth for the night or for a nap, parents assumed the rate, fatty changes in the liver, and thymic child had suffocated in its bedclothes. In ei- changes compatible with previous infection. ther circumstance, parents blamed themselves These risk factors are not specific to SIDS but re- for the tragedy. Worse, others suspected not flect increased risk for all infant deaths. When a just parental negligence but overt infanticide. young patient possesses enough of these physi- Because SIDS leaves no telltale marks on its cal and social factors, all that is needed is a trig- victims, no one could determine if the infant’s ger to cause SIDS to occur. Presumably, the trig- demise was truly accidental or intentional. As a ger is activated during sleep, because virtually result, society assumed parental negligence and all SIDS deaths occur during sleep. The nature punished the parents or whoever was responsi- of that trigger is the mystery of SIDS. ble for the child’s care. Medical people were not SIDS leaves few pathological footprints in its consulted in these situations except perhaps to young victims’ bodies. Postmortem examina- confirm the death. It was purely a societal mat- tion reveals little for the physician to use in ter dealt with by religious, and later by secular, understanding the pathology of the condition. authorities.

308 135. Sudden Unexplained Death Syndrome (Asian SUDS)

Perhaps the first recorded Western case of explained infant deaths. For example, a Scottish SIDS is found in the Bible story of the two police surgeon in 1892 openly accused parents women who went before King Solomon with of neglect, ignorance, carelessness, and drunk- claims to motherhood of an infant boy. One enness in overlaying their children, whereas of the women had awakened, found her son William Osler still discussed thymic enlarge- dead, thought she had overlaid him, and se- ment as a cause of sudden infant death in the cretly switched the child with another. 1904 edition of his influential and widely used Medieval church rules enunciated specific medical textbook. punishments for those who overlaid their chil- Recognition of the condition now known as dren, and forbade parents from taking infants SIDS began to occur in the 1940s and 1950s to bed with them. As early as the sixteenth cen- with studies demonstrating the extreme diffi- tury, Florentine craftsmen designed a wooden culty of overlaying a child or smothering a child arch that fit over, and kept blankets away from, in bedclothes, and the importance of perform- the child, thus preventing potential suffocation ing full autopsies on these children. As medical with bedclothes. scientists and epidemiologists gathered infor- The power of ecclesiastical courts began to mation during the 1960s and 1970s, they better wane in the Renaissance. As secular authorities characterized SIDS. Public awareness and polit- gained power during subsequent centuries, ical campaigns since the 1970s have succeeded civil courts investigated cases of overlaying in removing much of the parental stigma asso- and smothering to determine causes of death. ciated with sudden infant deaths. At the same time, medicine was learning more Todd L. Savitt about human anatomy and physiology. In 1761, Italian physician Giovanni Morgagni published his treatise correlating specific autopsy findings with disease signs and symptoms during a 135. Sudden Unexplained Death patient’s illness. The resultant development of Syndrome (Asian SUDS) pathological anatomy in the early nineteenth century helped medicalize the previously Sudden unexplained death syndrome (SUDS) nonmedical conditions of sudden unexplained occurs when a relatively young healthy person, infant death. As autopsies of these children usually male and Asian, dies unexpectedly while revealed large thymuses (actually a normal sleeping. The victim has no known antecedent finding), physicians explained death on the illnesses and no factors that might precipitate basis that the thymus gland cut off the tra- cardiac arrest. At autopsy, no cause of death cheal airway or overly reduced the size of can be identified in heart, lungs, or brain. Post- the thoracic cavity in which the heart and mortem toxicologic screening tests reveal no lungs had to function. Such explanations poisons. relieved parents of blame for their children’s deaths. Characteristics Despite evidence presented by other physi- SUDS has occurred among Southeast Asians cians during the nineteenth and early twenti- in the United States, mainly Laotians, Hmong, eth centuries that neither an enlarged thymus Kampucheans, and Filipinos. In Asia, SUDS is nor a similar but more complex condition called described in Japanese and Filipino medical lit- status thymico-lymphaticus could cause sud- erature and has been observed in Thailand. In- den infant death, many people, including judges cidence of SUDS has decreased since 1983, and in courts, used thymic death to absolve parents evidence indicates that the longer an immigrant of guilt. By the end of the nineteenth century, has been in the United States, the lower the medical people were divided over sudden un- risk.

309 135. Sudden Unexplained Death Syndrome (Asian SUDS)

The first comprehensive report of SUDS in or resulting from such stress may have been the United States was published in 1981; it de- involved. scribed 38 victims, all Southeast Asian refugees. All but one of the cases were male. Median pe- History riod of time in the United States was 5 months Sudden death in healthy individuals is a phe- (range, 5 days to 52 months) before death. Ge- nomenon that has occurred throughout his- ographic distribution of the deaths reflected tory and in many cultures. Because of their the distribution of Southeast Asians in the unexpected nature, many such deaths have United States. The deaths occurred between been attributed to supernatural or psycholog- 9:30 P.M. and 7:00 A.M. The victims whose deaths ical causes. Some have speculated that SUDS were witnessed appeared to be asleep prior to among Southeast Asians in the United States death or were just falling asleep. None of them may be triggered by stress, night terror, evil spir- complained of illness or symptoms before go- its, or culture shock. ing to bed, and all were considered in good Yet a number of reports in past Filipino med- health. ical literature identified a sudden nocturnal Witnesses of SUDS deaths become aware death syndrome known as Bangungut. Pre- of abnormal breathing sounds, in some cases viously healthy males die during the night, preceded by a brief groan. Victims cannot be making moaning, snoring, or choking noises. aroused. Terminal respirations are said to be la- Bangungut means “to rise and moan in sleep” bored and deep, irregular and without wheez- in Tagalog, reflecting folk beliefs that the ing or stridor. The victims remain flaccid dur- deaths are caused by terror from nightmares. ing these events, although a few are described The victims are men 20–50 years old. No as having tonic rigidity. Some victims are in- consistent cause has been found despite ex- continent of urine or feces. Witnesses recall tensive autopsy evaluation. The main post- no signs of pain or terrifying dreams. A few mortem finding is hemorrhagic pancreatitis, victims who are still alive when paramedics which most observers believe is not a cause reach them are found to be in ventricular of the syndrome but, rather, an effect after fibrillation. death. The etiology of SUDS remains unknown. Be- Filipino physicians claim to see numerous cause of differences between these cases and cases of SUDS every year. The typical victim is other victims of sudden death, SUDS may in- a young male adult with a stocky build, usu- volve a new syndrome. The quickness of the ally a poorly educated construction worker who deaths is unusual, and extensive postmortem migrated from the Visayan Islands to work in investigation reveals no ascribed cause. A case- Manila and who had either been on a drinking control study yielded meager results. No sin- spree shortly before sleeping or just eaten a fatty gle variable differentiated cases from controls. meal prior to retiring for the night. The victim is Victims tended to have been in the coun- brought to the hospital by fellow workers who try less than 6 months, to have left Laos are unable to wake him, but who remember his less than 3 years earlier, to have spent a moaning and groaning in sleep. greater proportion of their income on hous- Similar episodes of sudden death among ing, and to have acquired fewer possessions in Filipinos living in Hawaii were described in the United States than other immigrants. Al- medical and popular literature during 1930– though cases had similar amounts of English 60. Nearly universally, Filipinos have heard training, they had less job training. Cases had about Bangungut and believe in its authentic- gained weight less frequently than controls and ity. Many describe experiences as children being lost weight more frequently. Researchers con- assigned to watch over their fathers’ afternoon cluded that factors enhancing emotional stress naps.

310 136. Sweating Sickness

In Japan, a disease called pokkuri involves 136. Sweating Sickness sudden death similar to those previously de- scribed. A study of autopsies found cardiac The sweating sickness,orsudor anglicus,is death of unknown etiology in some cases. Al- one of the great puzzles of historical epidemi- most all such deaths occurred in young men ology because no modern disease easily corre- who were considered healthy and died sud- sponds to its principal features. Thus it has gen- denly during sleep. Some Japanese pathologists erated much speculation and debate over what believe that the cause of death is a fulminant caused the five English epidemics attributed to deletion of myoglobin from myocardial fibers the “Sweat.” during a state of acute cardiac failure. In refugee The first description, written in 1486, indi- camps in Thailand, certain deaths were quite cated that the earliest epidemic occurred (north- similar to SUDS deaths occurring among sim- ern England) during June of 1485. Strictly con- ilar refugees in the United States. temporary accounts use the words “plague” and Emotional trauma, voodoo, spirits, and magic “pestilence” to describe the local mortality cri- have all been suggested as important factors sis. However, most modern authors agree that for sudden unexplained death in folk cultures. the initial outbreak began later, in London, on Modern biomedical beliefs prescribe that psy- September 19, 1485, brought with Henry VII’s chological factors cannot cause death per se but mercenaries from France and Flanders. may trigger a fatal event. A different emphasis Once in London, the epidemic displayed occurs in cultures where the concept of psycho- some of its most characteristic and consis- logical sudden death has greater currency than tent features: higher mortality among men in scientific Westernized cultures. For example, than women, peaking during middle adulthood in Australia the aborigines believed that a per- among the economically advantaged, and a son pointed at with a bone would die as a re- sudden, acute fever accompanied by profuse sult. A government surgeon in 1897 reported sweating. Its victims generally lapsed into coma witnessing several such cases. A phenomenon and died within 48 hours. Similar outbreaks of wishful dying has been described among ru- have been identified: in 1508, 1517, 1528, and ral Bantus in South Africa. 1551. Oddly, the disease preferred Englishmen Several studies of the Hmong, the group hard- at home and abroad. In the British Isles, Scots, est hit by SUDS in the United States, have pro- Welsh, and Irish were spared. posed psychological triggers as explanations for The “Sweat” had no important demographic their deaths. An extensive cultural study of repercussions, as the numbers affected were al- SUDS focused on Hmong religion and health ways small in comparison to other epidemics concepts, but no correlation was found between of this period. Nonetheless, each recurrence of the deaths and religious preference, degree of the disease produced widespread fear. In 1528– belief in traditional religion, or anxiety over re- 29, the Sweat uncharacteristically extended to ligious questions. Again, it was concluded that Calais and many German regions but was one possible triggering mechanism for SUDS clearly associated with severe famine as well might be overwhelming and inescapable stress. as epidemics of typhus (“petechial fever”) and Another study also considered stress as a po- plague. As might be expected, a body of liter- tential trigger in SUDS, specifically that night ature on the disease accumulated at the time terror might have contributed to the deaths. as well as later, which has fueled interest in the Researchers speculated that such terror was Sweat’s identity. brought on by exhaustion, culture shock, fam- In 1508, Sir Thomas More informed Cardinal ily quarrels, or even violent images found on Wolsey of the Sweat’s progress among young television. scholars at Oxford and Cambridge, but little dis- Neal R. Holtan cussion was generated. In fact, the 1517 and

311 137. Syphilis

1551 epidemics are the only two epidemics ances dictated by variations in weather condi- for which we have substantial contemporary tions. He contrasted the ability of the French to accounts. host the disease and survive, and the partial im- Court historian Polydore Vergil’s graphic de- munity many Africans displayed when exposed scription of the disease was based on his to yellow fever, with the susceptibility of the experience during the Sweat’s 1508 and 1517 English and drew a parallel with the effect, on appearances and written from memory. In ad- unprotected flocks of cattle, of bringing an an- dition, some speculate that Vergil had access to imal infected with Texas cattle fever into the reports contemporary with the 1485 outbreak. fold. The earliest description by a physician was not Most recent authorities concur with written until 1552. His advice, however timely Creighton that whatever caused the Sweat, or expert, was to no avail, for the disease never it was a disease that found “virgin soil” in recurred. England or among the English. In so doing, Early nineteenth-century epidemiologist they follow Hans Zinsser’s assessment that the J. Hecker was fascinated by the Sweat’s abrupt Sweat was caused by a viral illness to which appearances and disappearances and felt the uniquely susceptible English population that English methods of therapy were partly gradually acquired immunity. Zinsser departed responsible for the high case-fatality rates. from earlier twentieth-century physicians in Writing over a century later, Maurice Strauss ascribing the cause of the Sweat to influenza, concurred, arguing that efforts to encourage although today there seems to be agreement perspiration and to stimulate vigorous purging that the Sweat was not an influenza virus, of the bowels would have exacerbated fluid although it spread in a similar manner. and salt losses associated with a high fever and Finally, John Wylie and Leslie Collier specu- led to circulatory collapse. Hecker, however, late that a novel arbovirus infection, transmit- also blamed the English climate and gluttonous ted by an insect vector, accords with most of the habits of Englishmen of the period. clinical and epidemiological information. By the Building on the suggestion that peculiarities mid-sixteenth century, the disease was becom- of the sixteenth-century English diet might ac- ing endemic in England, affecting children more count for the disease, Adam Patrick argued that than adults and in the process losing some of its the Sweat resembled a shock reaction, with its terror. hyperacute pyrexia (fever) and sweating, oc- Ann G. Carmichael casionally associated with evidence of circula- tory collapse. Among the most likely toxins, he passed over bacterial endotoxins and exotoxins in favor of fungal toxins associated with food 137. Syphilis poisoning. Ultimately, he felt that the sweating sickness was a form of ergotism. Venereal syphilis was long the most serious Writing in 1891, Charles Creighton, by con- and dreaded of the sexually transmitted trast, denied the possibility that local condi- diseases (STD). Caused by Treponema pallidum tions could alone explain the appearances of subspecies pallidum, a spirochetal bacterium, the Sweat, and he was loath to identify it with the only known natural hosts of which are any one known infection. He was, however, con- humans, venereal syphilis is one of the human vinced that it was introduced by Flemish mer- treponematoses – along with pinta, yaws, and cenaries hired by Henry Tudor. An opponent of endemic syphilis. Predominantly transferred the germ theory of disease, Creighton believed by sexual contact, T. pallidum may also be that the soil of the Seine’s lower basin perenni- transmitted through other physical contact, ally harbored the disease, its epidemic appear- intravenously (as in contaminated blood

312 137. Syphilis transfusions), and by infected mothers to these areas. Congenital syphilis is considerable fetuses during pregnancy (congenital syphilis). in many developing countries. Syphilis develops naturally through three The Treponema genus includes several clinical stages (primary, secondary, and tertiary pathogens responsible for four human diseases: or late), separated by subclinical periods. Of the (1) pinta, a Central and South American dis- latter, that between the secondary and tertiary ease affecting the skin, caused by Treponema stages is most pronounced (latent syphilis). carateum; (2) yaws, a disease of skin and bones Clinical manifestations of syphilis are extremely occurring in rural populations of the humid protean and capable, at the tertiary stage, of af- tropics, caused by T. pallidum subspecies fecting any system of the human body. pertenue; (3) endemic syphilis, similar to yaws Syphilis was named from Girolamo Fracas- but found only in warm, arid climates, caused toro’s 1530 poem, Syphilis, sive morbus gallicus, by T. pallidum subspecies endemicum; and (4) in which the Italian physician discussed the dis- venereal syphilis, with no climatic restrictions, ease then known throughout Europe as morbus affecting any bodily tissue, and caused by gallicus (the “French disease”). However, the T. pallidum subspecies pallidum. Surprisingly, term syphilis was not widely used until the late in spite of the differentiated diseases they eighteenth century, and that usage was vague produce, the four treponemes cannot be mor- and applied to many other symptoms besides phologically distinguished. Moreover, they those of venereal syphilis until the development elicit the same immunologic reactions, and all of the germ theory in the late nineteenth and are susceptible to penicillin. early twentieth centuries. Almost from the time of Columbus’s arrival in America, but particularly from the European En- Characteristics lightenment, the uncertain geographic and his- Unlike the nonvenereal treponematoses (pinta, torical origins of syphilis have been the object yaws, and endemic syphilis), venereal syphilis of scholarly controversy. Since the 1950s, how- has established a worldwide distribution, al- ever, the rise of molecular biology has pushed though its incidence patterns are somewhat dif- anthropologists and historical epidemiologists ferent in developed and developing countries. to frame this problem progressively in terms For example, it has declined in the West since of the evolutionary origins of all the human the 1860s, although major wars have momen- treponematoses. At present, two major theo- tarily interrupted this trend. After World War II, ries – the unitarian and the nonunitarian – congenital syphilis and late syphilis almost dis- contend with each other in providing an expla- appeared, mainly because of public-health mea- nation for the surprising similarities of the hu- sures and penicillin. Since the 1950s, however, man treponematoses. both primary syphilis and secondary syphilis For E. H. Hudson, the most outstanding de- have increased, with peak incidence in the fender of unitarian theory, there is only one 15–34 age group. A high male/female ratio re- treponematosis, although it assumes different sults from considerable incidence of syphilis in clinical patterns under different epidemiological male homosexuals. conditions. Thus, the changing physical and so- In developing countries, the disease remains ciocultural environment of humans has caused widespread, although interpretative problems treponematosis to change into one or another of of serologic tests for syphilis make it difficult those four different clinical syndromes already to estimate the numbers of infected people in mentioned: pinta, yaws, endemic syphilis, and those regions. Syphilis is increasing where yaws syphilis. From the unitarian viewpoint, then, it was previously endemic, as in tropical America does not make sense to talk about transmission and Africa and Southeast Asia. Infected prosti- of syphilis from the New World to the Old, or tutes are important to the spread of syphilis in vice versa.

313 137. Syphilis

By contrast, C. J. Hackett, the main upholder ditions in congested European cities at that of nonunitarian theory, maintains that the clin- time – produced a more serious disease. Ini- ical variety of human treponematoses proba- tially extremely virulent, this form of syphilis is bly resulted from mutational changes in the supposed to have progressively weakened since treponemal strains themselves. His thesis is around the 1530s. Still other scholars, however, that successive mutations have been respon- trace the sudden epidemic of venereal syphilis sible for the different human treponematoses to a post-Columbian importation of an Ameri- starting from a lost ancestral animal trepone- can parasite to Europe. matosis. The earliest of the treponematoses As noted previously, the natural course of seems to have been pinta, which might have syphilis includes three clinical stages separated extended from Africa and Asia into America by latent periods with no visible symptoms. In about 15,000 B.C.; that is, during the last part primary syphilis, T. pallidum penetrates mucous of the last glaciation and before the subsequent membranes and skin. After incubating over a melting of the polar icecaps that formed the period of 2–6 weeks (average 3 weeks), the pri- Bering Strait. mary lesion (chancre) appears. It is a small, pain- By about 10,000 B.C., a warm humid environ- less ulcer, usually appearing in the genitalia and ment caused either the pinta treponemes them- less frequently in other regions. The chancre selves (hypothesis A) or the lost ancestral an- heals spontaneously in 2–6 weeks. imal treponemes (hypothesis B) to mutate in In most patients, after a brief latent period, Afro-Asia, bringing forth yaws, a disease that there is a secondary stage characterized by the extended through Africa, Southeast Asia, and appearance of disseminated lesions on the skin eventually Australia and the Pacific islands, but and in the internal organs. In women, these are that did not reach the Americas. often the first sign of syphilis. Secondary le- Around 7000 B.C., in the warm arid climates sions consist of a painless rash, variable in ap- that developed after the last glaciation, another pearance and localization, and usually accom- mutation occurred, this time from yaws to en- panied by fever, malaise, and bone aches. After demic syphilis. The latter appeared in northern a few weeks, secondary lesions and symptoms and Saharan Africa, southwestern and central disappear. In about 25 percent of patients, how- Asia, and central Australia, whereas yaws itself ever, secondary lesions recur during the first remained unchanged in the warm and more hu- 2 years. mid climates. The tertiary (late) stage develops only in about Finally, about 3000 B.C., the development one-third of untreated cases, and only after an- of large urban areas and the increasing use other latent period lasting from 1 to 20 years or of clothing in the eastern Mediterranean and even longer. Tertiary syphilis involves progres- southwestern Asia became selective agents for sive destruction of skin, mucous membranes, still another mutation as syphilis changed from bones, and internal organs. The typical lesion a nonvenereal disease of rural children (en- is the gumma, a small, rubbery, benign tu- demic syphilis) to a venereal disease of urban mor, developing anywhere in the body. Serious adults (venereal syphilis). forms of late syphilis attack the cardiovascu- According to Hackett, by the first cen- lar and central nervous systems. Cardiovascu- tury B.C., syphilis had spread throughout the lar syphilis may cause aneurism and dilatation Mediterranean. He suggests, however, that this of valves. Neurosyphilis includes a loss of po- early venereal syphilis was a “mild” form of sitional sense and sensation (tabes dorsalis, lo- the disease – a possible explanation for the comotor ataxia) or a form of insanity (general lack of evidence of it before the end of the paresis [GPI], dementia paralytica). Since the fifteenth century. Then, a new successful tre- introduction of antibiotics, tertiary syphilis has poneme mutation – probably favored by con- almost disappeared.

314 137. Syphilis

History The term morbus gallicus became dominant in Historians usually identify today’s venereal designating a disease generally considered new syphilis with morbus gallicus, first mentioned in in 1490s Europe. It was incurable and loath- European writings of the late fifteenth century. some, consisting of sores – usually beginning in The disease erupted in Europe in the 1490s, the genitals but eventually covering most or all although neither its geographic origins nor its of the body – and other symptoms. Contempo- precise date of appearance is certain. These is- raries included it among the numerous calami- sues have been the object of a continuous and ties that befell Europeans at this time. Sources unresolved controversy between defenders of indicate that the “French pox” spread in Italy in an American origin of syphilis and those who 1494–95, after the armies of France and Spain claim that syphilis existed in the Old World clashed over the question of the kingdom of long before Columbus’s voyages. The most var- Naples. The notoriety the phrase morbus galli- ied documental proofs (medical and lay writ- cus achieved throughout Italy was closely asso- ings, iconography) and – increasingly since the ciated with the tragic impact of the French inva- late nineteenth century – material proofs (pa- sion on the fragile Italian political equilibrium. leopathological remains) have been wielded in Similarly, the acceptance in early sixteenth cen- this debate. It is an unfinished debate, how- tury Italy of morbus gallicus’s reputed Ameri- ever, for in claiming that present-day venereal can origins may be explained by the fact that syphilis was already known and had been de- Spaniards were regarded as the newest barbari scribed under several names before or after the stranieri to devastate Italy. The prestige of Re- Europeans’ arrival in America, historians have naissance Italy and its cultural hegemony were produced the kind of contradictory conclusions important in ensuring the rapid popularization that serve only to keep it alive. of both the term morbus gallicus and the theory Another approach to the history of syphilis by of its American origin. studying it in the context of the development of Through the sixteenth century, “French pox” human treponematoses has already been men- achieved overwhelming dominance over other tioned. It has yielded some promising hypothe- names for the disease. Only French physicians ses but no definitive conclusions. seem – understandably – to have rejected this Thus, a third approach – examining the his- name and offered others. For example, in 1552, tory of the concept of syphilis rather than the Thierry de Hery´ of Paris suggested maladie history of the disease itself – seems appro- ven´ erienne´ or grosse vairolle; in 1553, Auger Fer- priate. This third way requires contemplating rier of Toulouse proposed pudendagra or lues the disease entity called syphilis within the hispanica; in 1560, Antoine Chaumette of Paris strict historicocultural context it occupies, and tried morbus venereus; and in 1563, Leonardo from which it receives its true significance. Put Botallo of Paris used lues venerea, as did Jean plainly, every disease entity is an intellectual Fernel’s 1579 publication. construction that is peculiar to some form of During the seventeenth century, the term lues medicine; and every form of medicine is noth- venerea (“venereal infection”) was adopted all ing but a historical variable in any human com- over Europe, sharing leadership with morbus munity. Venereal syphilis took shape in Western gallicus. In the eighteenth century, lues venerea medicine only because of intellectual and so- eventually superseded morbus gallicus, and use cial changes in the latter nineteenth and early of the latter declined dramatically. twentieth centuries, foremost among them the Two points may be raised about the expres- formulation of germ theory. Let us consider the sion lues venerea. The adjective venerea stressed development of the concept of syphilis in this the direct relationship between the French light. Our departure point is an epidemic in late pox and the pleasures of Venus, and thus the fifteenth century Europe. individual’s responsibility for contracting the

315 137. Syphilis disease. Applied to morbus gallicus, this ad- ment controversy over lues venerea eventually jective seems to have appeared for the first concentrated on whether blennorrhagic dis- time in 1527 in a work by French physician charge (usually called gonorrhea) constituted a Jacques de Bethencourt, entitled Nova poeni- different disease entity or was just a peculiar tentialis Quadragesima, nec non Purgatorium in clinical stage of lues venerea. The beginning of Morbum Gallicum sive Venereum. Both the ti- this process of disease differentiation may be tle and contents of this book evoke the cli- found in the work of Giovanni Battista Mor- mate of religious exaltation and of moral rear- gagni, published in 1761. He found that patients mament present in Reformation Europe. The with blennorrhagic discharge and no evidence second point has to do with the name lues, of chancre rarely had hidden chancre, which which underscores the perception of the dis- was supposed to provoke the discharge in the ease, at that time, as a contagious and calami- first place. tous one from a physical, and even from a moral, During the following decades, physicians ar- viewpoint. gued the single or dual nature of lues venerea. The dominance exerted by the expression This controversy lasted well into the nine- lues venerea on eighteenth century medicine teenth century, in part because tremendous is exemplified by French royal physician Jean ambiguity existed in the vocabulary of vene- Astruc’s 1736 work, De Morbis Veneris, reis- real complaints. The term “syphilis” became al- sued several times and translated into many most dominant after the 1820s but nonetheless European languages. It argued that lues venerea sometimes appeared as alternative or comple- was caused by a specific virus – venereum – and mentary to “venereal disease.” attempted to classify all supposed “venereal” in- The controversy over whether venereal dis- fections under this general rubric. ease was a single disease entity or several Until the mid-eighteenth century, most Eu- illnesses was ended in the 1830s by French ropean medical thought defended the unity of venereologist Philippe Ricord, who had devel- lues venerea on the basis of a specific virus. oped a vast clinical and experimental program However, after 1750 the unified concept was in Paris and in 1838 published his experiments challenged by pathologists, who began to ques- demonstrating the existence of the virus syphili- tion whether lues venerea was a single dis- tique, so that chancre and blennorrhagia could ease entity after all. This challenge resulted in be definitely separated. Moreover, he distin- the progressive disappearance of the expres- guished primary lesions from others, and pri- sion lues venerea from the literature. Although mary symptoms from secondary symptoms. Ri- it entirely disappeared only in the nineteenth cord proposed the division of syphilis symptoms century, it was increasingly replaced by the into primary, successive, secondary, transitional, plural expression morbi venerei (“venereal dis- and tertiary. eases”). Around the same time, specific denom- Ricord’s concept of syphilis was gradually re- inations for each of the morbi venerei (chancre, shaped as other sexually transmitted disease gonorrhea, bubo, and syphilis, among others) entities (gonorrhea, chancroid, lymphogran- appeared with increasing frequency. From the uloma venereum, genital herpes, venereal early nineteenth century, medical works specif- warts, and others) emerged. If most of these ically devoted to certain among these diseases were first shaped according to clinical criteria, – mainly gonorrhea and syphilis – began to each eventually got its definitive “identity card” proliferate. when the relevant germ was isolated. During the period 1750–1850, specialized Gonorrhea and chancroid are two illustra- hospitals emerged, including those for the treat- tive examples. Ricord had definitely separated ment of venereal disease, and dermatovenerol- chancre and blennorrhagia, but the clinical pic- ogy was born as a medical specialty. Enlighten- ture of gonorrhea was completed only in 1879,

316 138. Syphilis, Nonvenereal when Albert Neisser discovered the gonococcus difficulties in establishing scientific criteria that germ. Chancroid or “soft-sore” emerged as a dis- delimit precisely the so-called venereal syphilis ease entity in 1852, when Ricord’s pupil Leon´ from the remaining human treponematoses. Bassereau demonstrated that the two kinds of Jon Arrizabalaga luetic chancre – one hard, painless, and unique; the other soft, painful, and frequently multiple – resulted from exposure to a like lesion. In 1889, August Ducrey identified the bacillus responsi- 138. Syphilis, Nonvenereal ble for it. As for the concept of syphilis, it changed Nonvenereal syphilis has apparently occurred profoundly during the second half of the in many forms and places, and one interpre- nineteenth century as the disease became tation of this phenomenon is that venereal a major research area in Western medicine. syphilis can revert to nonvenereal transmis- French venereologist Jean-Alfred Fournier per- sion. Others see it as a discrete disease with haps contributed most in developing the con- its own etiologic epidemiology. The most com- cept of syphilis during this period. Fournier pro- mon and enduring form of the disease is called pounded the idea of latency in both acquired bejel; it occurs in the arid regions of North and congenital syphilis, established the rela- Africa, the Middle East, and the eastern Mediter- tionship between syphilis and parasyphilitic af- ranean, and seems to have antedated venereal fections, and began a social campaign against syphilis by a considerable period of time. It is the disease. one of the treponematoses caused by spiro- The syphilis germ, however, was not discov- chetes, bacteria belonging to the genus Tre- ered until 1905, when Fritz Schaudinn and Erich ponema. Other diseases in this group are yaws Hoffmann isolated it from a secondary lesion. In and pinta. Like yaws, bejel is essentially a dis- 1906, August von Wassermann, Albert Neisser, ease of children, although those who escape Carl Bruck, and others made possible the first the illness as children are likely to acquire it as serologic procedure to diagnose syphilis: the adults, often from their own children. Its spe- complement-fixation test, later known as the cific cause seems to be Treponema pallidum, Wassermann reaction. In subsequent years, the same agent as that of syphilis, although it T. pallidum was also found in tertiary lesions, may be an intermediary form between T. pal- verifying Fournier’s theory. Karl Reuter, for ex- lidum and Treponema pertenue, the agent of ample, in 1906 found the germ in a syphilitic yaws. Although treponemal disease has been aorta, whereas Hideyo Noguchi in 1913 proved transferred experimentally to animals, humans its presence in brain tissue from paretics. appear to be the only natural reservoir. By way of conclusion it should be emphasized that, as has been the case with many other dis- Characteristics ease entities, a crisis of a disease-entity concept Because the treponemas that cause yaws, non- based on its specific biological cause has also venereal syphilis, pinta (an American disease), ensnared venereal syphilis. In 1935, as most re- and syphilis are morphologically and serolog- searchers still claimed specificity of a causal mi- ically indistinguishable, it is believed that at croorganism to be the definitive criterion for an least the Old World diseases may represent an infectious disease, Ludwik Fleck lucidly stressed evolutionary continuum running from south to the essential incompleteness of the concept of north. Yaws, thought to be the oldest, spreads by syphilis. skin-to-skin contact and flourishes in the hot, Time has confirmed Fleck’s insight. Put moist regions of sub-Saharan Africa where in- plainly, it should be obvious from the forego- dividuals have historically worn little clothing. ing that Western medicine has had enormous Syphilis, by contrast, seems to be the newest of

317 138. Syphilis, Nonvenereal the treponematoses. Venereal transmission al- much of the pathology stems from the immune lows it to spread among peoples of colder cli- response of the host. Nonvenereal syphilis or mates whose clothing would frustrate skin-to- bejel is similar to yaws in some respects, among skin transmission. them, juvenile acquisition, absence of chan- Bejel or nonvenereal syphilis seems to be in- cre, and congenital transmission. Moreover, termediate between the two both bacteriologi- both diseases rarely involve the cardiovascular cally and geographically. It has been conceived and central nervous systems. Yet nonvenereal of as yaws modified by a desert environment, syphilis resembles syphilis in its affinity for the and as juvenile, nonvenereal syphilis. It is not mucous membranes and in many of its patho- transmitted congenitally. The disease spreads logical aspects. And, like syphilis, it occurs out- from child to child in dry, mostly rural areas side the tropics. Finally, the usual serologic tests where lack of cleanliness facilitates transmis- for syphilis are positive in nonvenereal syphilis. sion. The spirochetes of nonvenereal syphilis, like those of yaws and syphilis, perish in the History presence of atmospheric oxygen, soaps, deter- The story of bejel is intimately bound up with gents, and antiseptics, and are sensitive to dry- the work of physician and medical historian Ellis ing. T. pallidum can penetrate mucous mem- Hudson. He described the disease in 1928, after branes, but intact skin is a formidable barrier. observing it among Bedouins. In 1937, he sum- The primary lesion is often in the region of the marized all available information on the disease mouth, probably from sharing drinking vessels and stated that the Arab word bejel had been in- or utensils or direct mouth-to-mouth contact. troduced into the literature to distinguish this It can also spread via direct nonsexual contact. nonvenereal and endemic form of syphilis from Flies, lice, and fleas may also have a role in the venereal variety. In 1946, he emphasized transmission. the intermediary nature of bejel between yaws The stages of the disease – primary, sec- and syphilis and presented a unitarian concept ondary, and late or tertiary – are not so pro- of treponematosis, which stressed an evolution- nounced as those of syphilis. In the case of bejel, ary relationship among yaws, endemic syphilis, the primary lesion is soon followed by the ap- pinta, and venereal syphilis, and held that they pearance of moist papules in skin folds and by were all varieties of a single disease caused by drier lesions on the trunk and extremities. Late one parasite, T. pallidum. lesions, when they occur, can be ugly. Huge ul- Not all agree. Some, for example, argue cers may form, and ulceration of the palatal and that the various treponemal infections arise nasal bones can cause them to erode. Other pos- from changes in the treponemal strains them- sible physical symptoms are changes in pigment selves – mutations. Others feel that the trepone- distribution and the deformity of other bones, mal infections are essentially different diseases, especially long bones such as the tibia. caused by different parasites. One hypothesis Although pinta has been given experimen- argues that venereal syphilis has reached vil- tally to syphilitics, a high degree of cross- lages (in the Sudan at least) from towns, only immunity between T. pallidum and T. pertenue to become endemic (i.e., nonvenereal) in a rural seems to exist. Thus, one who has suffered non- environment. venereal syphilis is not only safe from another There is, however, general agreement that attack but is also at least partially protected nonvenereal syphilis is an old disease. Hudson against syphilis and yaws. argued that it flourished in villages during the The pathogenic mechanisms in this and other early Neolithic period and that it was the “vene- treponemal infections are not fully understood. real leprosy” of the Middle Ages, the “sibbens” The pathogens kill no cells and produce no of Scotland, the “button-scurvy” of Ireland, the known toxic substances. Thus it seems that radesyge of the Scandinavian countries, and the

318 139. Tapeworm Infection skerljevo of the Balkans. Apparently, it never and the Mediterranean world. Encysted larvae – took root in the Americas. bladderworms or cysticerci – have been known Because endemic syphilis fades in the face in beef and pork for millennia, but their rela- of the cleanliness associated with civilization, tionship to adult worms was not suspected un- and because of the high efficacy of penicillin til the eighteenth century and not proved until as a cure, the disease has withdrawn from most 1855, when F. Kuchenmeister¨ fed larval tape- of Europe. But the bejel of the Middle East has worms concealed in food to condemned crimi- its counterparts in the njovera of Rhodesia, the nals and recovered adult worms on autopsy. The dichuchwa that plagues the Bushmen, and the three large species that infect humans were not irkintia of the Australian aborigines. clearly differentiated until 1782. The notion of Kenneth F. Kiple spontaneous generation of adult tapeworms in the human intestine – a theory consistent with the then known facts – was widely accepted un- til about 1820. 139. Tapeworm Infection Characteristics Tapeworms are flatworms in the class Cestoda Intestinal infections are discovered when of the phylum Platyhelminthes. The body of an proglottids are passed or when eggs are found adult worm consists of a small head or scolex, by microscopic examination of feces. Diagnosis usually armed with hooks or suckers to attach of larval infections is more difficult and depends the animal to the wall of its host’s small in- on serologic tests or surgery. Drugs are effec- testine, and a chain of segments or proglot- tive against adult tapeworms, but larval infec- tids. New proglottids arise by budding from tions are more difficult to treat and may require the scolex region. As they mature, they are surgery. pushed away from the head by formation of new Five species are important parasites of proglottids and develop both male and female humans: Echinococcus granulosis and Taenia sex organs. After fertilization, eggs or gravid solium are dangerous as larvae; Taenia saginata, proglottids are excreted with the host’s feces. T. solium, Hymenolepsis nana, and Diphylloboth- Tapeworm life cycles are complex. In general, rium latum live as adults in the intestine. Sev- the eggs must be ingested by an intermediate eral other species can infect humans but usually host, where they typically become saclike lar- have other hosts. For example, Dipylidium ca- vae in the tissues. When the host of the adult nium, the dog tapeworm, can spread to children form (the definitive host) eats an infected in- who accidentally eat fleas. Larval stages of sev- termediate host, adult worms develop in its in- eral species of Spirometra, normally parasitic in testine. Some species have two or more inter- other vertebrates, can cause a dangerous con- mediate hosts and can use several species as dition called sparaganosis if a person swallows the definitive host. Serious clinical disease of- them in their copepod hosts. The Oriental cus- ten occurs when a parasite becomes established tom of treating wounds or inflamed eyes with a in an atypical host or when larval forms are poultice of fresh frog flesh can permit larvae to able to develop in what is normally a definitive become established in the patient. host. T. saginata, the beef tapeworm, inhabits hu- man intestines around the world, although it History is no longer common in developed countries. Because tapeworms can exceed 30 feet in length Cattle and other bovids are the intermediate and strings of segments are often passed in hosts. If a cow or water buffalo eats grass con- the feces, it is not surprising that they were taminated with feces and eggs, the eggs hatch in described by ancient writers in China, India, the animal’s intestine into a larva that migrates

319 140. Tay-Sachs Disease through the intestinal wall and forms a blad- covered in pre-Christian archaeological sites in derlike sac, a cysticercus, in the muscles. Hu- Germany. This large tapeworm is found in the mans acquire the worm by eating raw or poorly Baltics, the Alps, the lower Danube, European cooked beef, as in steak tartare. Infections are Russia, Central Asia, the Far East, Africa, Alaska, sometimes asymptomatic, but many people ex- and the Great Lakes area of North America. The perience mild to severe abdominal discomfort worm was probably introduced into the United and a few have convulsions and develop prob- States and Canada by Scandinavian immigrants. lems of malnutrition. As with many other par- D. latum has a complex life cycle, with the first asites, higher prices for fuels in poor countries larval stage in small freshwater crustaceans and are often accompanied by increasing incidence the second stage, the pleurocercoid, in the mus- because of undercooking. cles of fish of the trout, pike, and perch families. T. solium, the pork tapeworm, is much less People become infected by eating raw or under- common than the beef tapeworm but poten- cooked or undersalted fish. Adult worms pro- tially considerably more dangerous. It occurs duce as many as a million eggs a day. If the host around the world, except where Islamic or defecates in or near water, motile larvae emerge Jewish customs restrict pork consumption. The that seek a crustacean to complete the cycle. A life cycle resembles T. saginata, except that wild related species with a life cycle involving ma- and domestic swine are the intermediate hosts. rine fish and sea lions has afflicted inhabitants Human infection usually results from eating of coastal Peru and Chile since pre-Columbian poorly cooked pork; sausages can be especially times. dangerous. People can also serve as intermedi- D. latum may exceed 35 feet in length and, ate hosts if they ingest eggs in food or water like the beef and pork tapeworms, can thrive or from soiled hands. The resulting larval infec- for many years in its host’s gut. Symptoms are tion, cysticercosis, can be serious and even fatal, similar to those of other tapeworms, but in rare especially if cysticercoids develop in the brain. cases this worm can produce a form of anemia

Adults cause symptoms like those of the beef by robbing the host of vitamin B12. There seems tapeworm. Inspection and thorough cooking or to be a genetic component to this complica- freezing of pork are important for prevention, tion, with Finnish populations most vulnerable. and adult infections should be treated to avoid Treatment is effective. Better sanitation and ap- the danger of cysticercosis. propriate cooking of fish – to kill pleurocercoid 1 H. nana, the dwarf tapeworm, is only 1–1 /4 larvae – are preventive. inches long. It occurs around the world, includ- K. David Patterson ing the southern United States, and is a common parasite of domestic mice was well as humans. Infection results from eating larvae in fleas or in the grain beetle Tenebrio. Autoinfection is 140. Tay-Sachs Disease also common. In this direct life cycle, eggs hatch in a person’s intestine, and the larvae attach to Tay-Sachs disease (TSD) is the best known the intestinal wall to mature. Heavy infection of the sphingolipidoses, a group of genetic can cause severe diarrhea, abdominal pain, and disorders including Niemann-Pick disease, convulsions, especially in young children. Gaucher’s disease, and others. Specifically, TSD

D. latum, the broad fish tapeworm, was de- is GM2(beta) gangliosidosis. Affected individu- scribed in 1602 and recognized as a distinct als (recessive homozygotes) produce virtually species in 1758, but its complex life cycle was no hexosaminidase A (hex A), an enzyme nec- not fully explained until 1917. D. latum is an essary for normal neurological development. old parasite of humankind; eggs have been dis- TSD is rare in most populations but is about

320 140. Tay-Sachs Disease

100 times more prevalent among Ashkenazi convulsions. Between 18 and 24 months, mega- Jews. This indicates that TSD gene frequency is cephaly, cortical blindness, and quadriplegia about 10 times higher in the Ashkenazi pop- commonly occur. After age 2, victims are in a ulation. Persons with TSD usually show symp- vegetative state, and most die sometime dur- toms of neurological degeneration by 6 months ing the next 2 years. Until then their condition of age. Their condition steadily deteriorates, and steadily worsens. they seldom live beyond age 4. There is no Though the role of gangliosides in neural cure, but heterozygous “carriers” of the defec- physicology is not completely understood, tive gene can be identified, and amniocentesis the basic biochemical cause of TSD remains can detect an affected fetus. straightforward. In persons with TSD, unusually

large amounts of GM2 ganglioside accumulate History in brain tissues, disrupting normal develop- In 1881, British ophthalmologist Warren Tay ment and function. This accumulation results first reported some early clinical signs of TSD. from lack of a functional specific enzyme,

In 1887, the American Bernard Sachs further hex A, that breaks down the GM2 ganglioside. documented the disease he later called amau- Heterozygous carriers of the TSD gene have rotic family idiocy. Sachs first noted the familial roughly only half the hex A activity of individ- nature of TSD and its seemingly exclusive oc- uals homozygous for the normal allele. This currence in Jewish families. However, reports of is apparently enough, however, for normal non-Jewish cases soon appeared. In the 1930s, catabolism of the GM2 ganglioside. D. Slome surveyed population characteristics TSD and other genetic disorders present an of TSD and confirmed the disease’s autoso- enigma. How can a lethal gene reach a high fre- mal recessive mode of transmission as well as quency in a population? How is that frequency the gene’s higher frequency among Jews. E. maintained? Why is that gene found at a rela- Klenk discovered that nerve cells of TSD vic- tively high level in a particular population? In tims contained what he called “ganglioside.” L. addressing such questions, one examines the

Svennerholm later described the specific GM2 basic evolutionary forces that change gene fre- ganglioside. In the 1960s, D. Robinson and quencies: mutation, gene flow, genetic drift, and J. L. Stirling discovered that the hexosaminidase natural selection. enzyme had two components (A and B), and Mutations are the original source of all ge- S. Okada and J. S. O’Brien found that hex Ade- netic variability, occurring at generally low but

ficiency was associated with high GM2 ganglio- constant rates. Mutation created the TSD gene side in TSD patients. More recently, the hex A variants found among both Ashkenazim and gene has been mapped to chromosome 15, and non-Ashkenazim, but it cannot explain the high different variants (alleles) of the gene, each of frequency of the TSD genes in the Ashkenazim. which causes TSD, have been discovered. No evidence of an unprecedentedly high mu- tation rate of this gene in Ashkenazi Jews has Characteristics been found. Between birth and age 6 months, children with Gene flow, the movement of genes from TSD may display apathy, hypotonia, and ex- one population to another, plays a greater or aggerated startlement at noise. Between 6 and lesser role in various explanations of high TSD 12 months, the characteristic cherry-red spot gene frequency. One intriguing scenario sug- in the eye appears; psychomotor retardation, gests that the Ashkenazim are descended from spasticity, and rigidity are displayed. From 12 to members of the Khazar Empire, which existed 18 months, children may drool excessively and north of the Caucasus from the seventh to the undergo bouts of unmotivated laughter, and tenth centuries. During that time, some Khazars

321 140. Tay-Sachs Disease converted to Judaism. After the empire’s fall, less susceptible to tuberculosis – especially such converts could have moved into central common in urban centers during the nine- Europe, where Jews from Western Europe were teenth century. However, a negative associa- also immigrating. If the Khazars carried the TSD tion found between TSD estimates and tuber- gene, they may have delivered it as part of their culosis prevalence was too small to be statisti- contribution to the Ashkenazi gene pool. Lit- cally significant. Furthermore, no physiological tle evidence of this exists, however, and as with basis was offered to explain why heterozygote mutation, gene flow by itself cannot account for TSD carriers might have such an advantage in the high frequency of TSD genes among Ashke- the face of tuberculosis. The nature of the hy- nazi Jews. Natural selection and genetic drift are pothesized selective forces has yet to be fully more likely causes. elucidated. In 1962, it was suggested that heterozygote It has also been suggested, however, that carriers of the TSD gene may have a selective founder effect and genetic drift (rather than het- advantage over the normal homozygote. Re- erozygote advantage and natural selection) bet- searchers calculated that a selective advantage ter explain high Ashkenazi TSD gene frequen- of about 1.25 percent on the part of the het- cies. Genetic drift refers specifically to random erozygous carrier of the TSD allele would be changes in gene frequencies from one genera- sufficient to maintain the allele at its present tion to the next (“sampling errors”). Sampling er- frequency of approximately 1.3 percent among ror is most pronounced in small populations in the Ashkenazim, despite the loss of TSD genes which, simply because of chance combination through the deaths of recessive homozygotes of a relatively small number of gametes, the off- afflicted with TSD. They then showed that spring generation’s gene pool may not exhibit over the course of 50 generations (roughly the same frequencies as the parental genera- from the time of the Diaspora to the present), tion. Thus, gene frequencies “drift” up or down a heterozygote-selective advantage of about through time. 4.5 percent would increase the TSD allele fre- Founder effect, related to genetic drift, is the quency from 0.13 percent to 1.3 percent, again random genetic impact of one or a few individu- despite losses of TSD alleles through the deaths als on the genetic structure of a new population of recessive homozygotes. In order to provide after either migration or population decline. Be- support for their hypothesis, they compared sib- cause of the chance factor, founder effect is usu- ship sizes of the parents of TSD offspring to the ally considered in the context of genetic drift. sibship sizes of a control group. They found One investigation of the population history of the former to be slightly larger than the lat- Ashkenazi Jewry finds that the conditions most ter. Although the differences were not statisti- conducive to genetic drift may well have been cally significant, they indicated a heterozygote present throughout much of Europe for hun- advantage sufficient to result in the observed dreds of years. However, others have calculated present-day TSD gene frequency in the Ashke- that even in such a situation, the probability nazi population (assuming that the heterozy- of occurrence of present discrepancies in TSD gote advantage had remained more or less con- gene frequencies between the Ashkenazim and stant over time). non-Ashkenazim is low. Two conditions are essential for a natural Up to now the difference between Ashke- selection explanation: (1) a selective agent of nazi and non-Ashkenazi Jews (and non-Jews) sufficient magnitude to affect negatively the in TSD prevalence and gene frequencies has reproductive success of individuals; and (2) a been emphasized. However, considerable ge- physiological basis for the advantage one geno- ographic disparity in TSD prevalence exists type has over the others. In 1972, it was sug- among Ashkenazi groups as well. These differ- gested that heterozygous carriers of TSD were ences are also important in assessing reasons

322 141. Tetanus for the overall high frequency of TSD genes 141. Tetanus among the Ashkenazim. Studies have found that the ancestors of the majority of Jewish Tetanus is an acute disease caused by a neu- TSD cases in the United States came from the rotoxin produced by the bacterium Clostrid- northeastern provinces of Poland and the Baltic ium tetani when its spores enter a wound and states. develop into their toxin-producing vegetative Such findings can be incorporated into both form. The case-fatality rate averages 50 percent the natural selection hypothesis and the ge- in adults and is higher in neonates (especially in netic drift hypothesis. The former is facilitated developing nations) and patients over 60 years because a selective agent favoring heterozy- old. gotes needs only to be shown to exist in a delimited geographic area. TSD genes spread Characteristics out from there via gene flow, and it would C. tetani is an obligate anaerobe, a spore- be some time before their removal in appre- forming, motile rod. The terminal spore caused ciable numbers through the deaths of reces- the organism to be called the “drumstick” rod. sive homozygotes; by then the carrier frequency The protein toxin, tetanospasmin, blocks acetyl- may become rather high. The case for genetic choline release at motor end-plates. The toxin drift is strengthened because the Ashkenazim travels up the nerve trunks, as well as fix- no longer need to be viewed as a large inter- ing directly on nerve cells. The spinal cord is breeding population, but instead can be viewed the primary target organ, with chromatolysis as a subdivided population made up of semi- of the motor neurons and inhibition of an- isolated groups, in each of which genetic drift tagonists accounting for the spasm and rigid- is more likely. The TSD genes spread from ar- ity that characterize the disease. Toxin fixa- eas of high frequency to those of low frequency tion to central nervous system neurons may through gene flow. lead to seizures; involvement of the sympa- In the absence of much substantive data, and thetic nervous system may evoke vascular given that evolutionary forces usually work in irregularities. concert, some experts have concluded that a Humans are accidental interveners in the life combination of heterozygote advantage and ge- cycle of the organism, which is a soil saprophyte netic drift is the most probable explanation of and a harmless inhabitant of the intestines high Ashkenazi TSD gene frequencies. Other of many herbivores. The organism requires a possible explanations include inbreeding, ge- wound to invade mammals. Traumatic, surgical, netic “hitchhiking,” epistasis, or a wider com- dental, umbilical, burn, and cosmetic wounds bination of factors acting together. are the most common causes of infection in hu- In recent decades, there has been some de- mans. “Skin popping” of drugs, insect bites, and bate about whether the incidence of TSD is in- nonmedical abortions are less common causes. creasing. Despite various arguments attempt- The organism can reproduce and produce toxin ing to verify or deny such an increase, it only when local oxidation-reduction processes must be remembered that modern “high” lev- reduce tissue oxygen to near zero; deep, in- els of TSD may result from better diagnosis fected wounds are thus ideal culture media. and case reporting. Aside from continuing study There may be 300,000–500,000 cases of tetanus and debate, more immediate concerns exist. At a year worldwide, of which perhaps 120,000 present, there is no cure for TSD. However, are neonates whose umbilical wounds become because heterozygote carriers and affected fe- infected. tuses can be identified, individuals have avail- There is no special characteristic or di- able some important options. agnostic pathology. Incubation ranges from Bradford Towne 2 to 14 days after wounding. Cases of “dormant”

323 141. Tetanus tetanus have been reported after several History months, probably because spores remained in Hippocrates recorded tetanus cases and dis- a closed wound as a silent abscess. Diagnosis is cussed the condition in general terms as well, based entirely on history and clinical findings; providing details of symptoms, the course of there are no specific laboratory findings. Clin- the disease, and treatment. Treatment regimens ical manifestations are usually classified into were many and varied, and largely ineffective. four forms: Aretaeus, writing some 700 years later, believed that onlookers’ prayers for the death of the pa- tient were useful; he pitied the attending physi- 1. Localized tetanus presents with spasm cian’s inability to afford relief. After an excellent near the site of injury, usually in an extrem- clinical description of the disease, Aretaeus too ity. The fatality rate is 1 percent or less. urged a wide variety of therapeutic maneuvers. 2. Generalized tetanus, the more common Ancient clinical descriptions have not been form, is marked by the classic tris- bettered. Therapy has changed, but it is possi- mus (“lockjaw”), fixed grin (risus sardon- ble that the number of survivors “after the four- icus), and backward arching of the trunk teenth day” may not have improved markedly. (opisthotonos). Tonic seizures of muscle William Osler, writing in 1892, found 80 percent groups occur in spasms, lead to rigidity, mortality within 4 days. Therapy had improved: and are very painful. Pneumonia may fol- The nasogastric tube enabled feeding and hy- low respiratory muscle involvement or la- dration; morphine provided sedation, and chlo- ryngeal spasm with aspiration. Cardiovas- roform provided muscle relaxation. Osler em- cular disturbances are common, especially phasized antiseptic care of the wound. It is fair vasoconstriction and a labile blood pres- to say that from Hippocrates to Osler – and to sure. Severe spasms may cause vertebral today – there have been no changes in diagnos- fractures. The course of this form, in sur- tic techniques, and there has been only a small vivors, is 1–2 weeks. reduction in mortality rates in established cases. 3. Cephalic tetanus, an uncommon form of Tetanus is a disease that must be prevented, and the disease, follows facial wounds, involves prevention had to begin with isolation of the or- the facial nerves, and may be followed by ganism and advances in immunology. generalized tetanus. The discovery of the tetanus organism was 4. Neonatal tetanus following infection of part of the microbiological revolution that the umbilical cord (discussed in another proved the theory that specific organisms chapter) usually begins 3–10 days after caused specific diseases. In 1884, Arthur Nico- birth and then progresses to generalized laier produced tetanus-like symptoms and tetanus. death by injecting soil samples into animals. He isolated a rod-shaped bacillus and suggested Death usually results from respiratory failure that it secreted a toxin resembling strychnine with hypoxia or pneumonia, and occasionally in its action. He did not isolate the organism from circulatory collapse, especially in patients in pure culture. Neither did D. Rosenbach in over 60 years old. Treatment involves measures 1886, although he was able to produce classic to decrease the organism’s presence: debride- tetanus in guinea pigs by injecting tissue from a ment of the wound; antibiotics; neutralization fatal human case. He described the “drumstick” of the toxin by antitoxin; and control of toxic shapes and correctly deduced that these were effects by drugs with specific neuropharmaco- terminal spores. It remained for Shibasaburo logical effects. Curarization and artificial respi- Kitasato to isolate the organism in pure culture, ration have been used in severe cases. Careful in 1889, from a fatal case in Berlin. He described continuous nursing care is essential. the anaerobic culture requirements, confirmed

324 141. Tetanus

Nicolaier’s observations, and concluded that the improved wound management and routine an- clinical effects were caused by a toxin. The study titoxin use developed, the rate fell to 1.5 per of tetanus toxin and antitoxin followed directly 1,000 wounded. World War I patients, perhaps and in parallel with the research of Emil Behring because the antitoxin produced a forme fruste, and Kitasato on diphtheria toxin, a much more had a syndrome of “local tetanus” – not fa- important disease. tal, and usually confined to one extremity. U.S. Tetanus and diphtheria investigations pro- forces, entering the war in 1917, had the ad- vided the framework on which Behring built vantage of the experience of their allies and his understanding of the principles of serum thus had an incidence of only 0.16 per 1,000 therapy. In an 1892 paper, he argued that the wounded. Allergic reactions to horse serum oc- serum of a patient should contain material pro- curred, more commonly after repeated doses of tective and curative for another individual with antitoxin. the disease. In a series of studies, he and others The practical use of formaldehyde to produce proved this point in animals but did not recom- a toxoid (a formalin-inactivated antitoxin) was mend serum use in humans until its mechanism introduced for tetanus in 1927. As opposed to was better understood. They noted that even the passive immunity conferred by antitoxin, if treatment of the animal began very early, at the toxoid produced an active immunity that least 1,000 times as much antitoxin was needed would protect against tetanus. Later, the dura- to cure as to protect before infection, and that, tion of immunity and the timing and effect of as the symptoms became general, the antitoxin booster doses was worked out. was useless in any amount. A fluid toxoid was in use because of its The availability of horse antitoxin soon led to harmlessness and efficacy (although it caused clinical trials, with widely varying results. Anal- more local reactions than does the modern alu- ysis eventually showed that antitoxin had to be minum phosphate absorbed vaccine). This tox- given very early in the disease; that dosage – oid, a combined diphtheria-tetanus toxoid vac- empirical at first – was critical; and that it was es- cine, was given to infants in parts of France in sentially useless once the toxin was fixed to neu- the late 1920s and, by regulation, to French sol- rons and the patient was symptomatic. Better diers in 1931. understanding of wound care and more aseptic Immunization with the much more epidemi- surgery accompanied the rising rate of success- ologically important diphtheria toxoid began in ful use of antitoxin and a decreased death rate, the 1920s in parts of the United States and just especially in selected populations like soldiers. before World War II in Britain. The absorbed Given that soldiers often have fought in well- tetanus toxoid was used by the armies of Britain, manured farmland and do not have clean skins, France, and Canada by 1939; the United States and that until very recently armies lived in close began its use in 1941. During World War II, the proximity to horses used for transport and cav- American army had 5 fatal tetanus cases (2 in alry, it is not surprising that tetanus was a com- nonimmunized patients) and 7 nonfatal cases mon problem in wounded soldiers. In 1808, for (all in immunized patients) in over 500,000 example, the rate of tetanus before immuniza- wounded soldiers. The reaction rate to the im- tion was 12.5 per 1,000; by contrast, the rate was munization series of three doses was 21 per only 0.04 per 1,000 in World War II. 100,000, none fatal. World War I saw the general introduction of After World War II, routine use of a combined early, near-universal use of antitoxin, accom- vaccine of diphtheria and tetanus toxoids (DT) panied by meticulous debridement of wounds. was urged for childhood immunization. Soon The effect of these measures may be seen in the triple vaccine, with pertussis added (DPT), the British army. Incidence was 8 per 1,000 became legally required for school admission wounded from August to October 1914. As in the United States. Childhood immunization

325 142. Tetanus, Neonatal programs in Europe vary but tend to be on before the twentieth century, it was global in similar schedules and under similar laws. Non- occurrence. The bacillus, found in soil, water, in- fatal anaphylactic reactions occur at a rate of testines, and the feces of animals and humans 1–1.5 per 2 million doses. The benefit/risk ratio (where it can survive for years if not exposed for tetanus immunization is thus extraordinarily to sunlight) is ubiquitous. Although it was once good. A worldwide infant and child immuniza- common in rural areas like much of Ireland and tion campaign, coupled with a booster upon in- the southern United States, the disease is virtu- jury, would essentially eliminate the disease as ally unknown anywhere in North America and a clinical entity. Western Europe today. Its incidence depends on Robert J. T. Joy soil conditions, type of agriculture, level of eco- nomic development, available health services, and quality of obstetrical procedures. The most important reasons for the decline 142. Tetanus, Neonatal of neonatal tetanus in the twentieth century were improved standards of living, urbaniza- Neonatal tetanus is a form of tetanus confined tion, and an understanding of sepsis. Efforts to newborns. It is characterized as a neurolog- are being made by the World Health Organi- ical disease resulting in severe muscle spasms, zation to educate women and birth attendants which can persist for at least a week, and com- on preventive measures and to bring obstetri- monly results in death. The agent is Clostrid- cal procedures and concepts of cleanliness to ium tetani, which usually enters the blood- areas where the disease still exists. Statistics stream or motor nerves through an infected have shown that higher standards of obstetri- umbilicus. cal hygiene significantly decrease the chance of infection. Characteristics Neonatal tetanus occurs when C. tetani enters C. tetani produces two toxins, one of which is the body as a result of a dirty dressing or poor tetanospasmin, the extremely potent neurotoxic care of the umbilicus. Where the disease is com- component causing spasms. This toxin reaches mon, the umbilicus is often cut with an unclean the nervous system and eventually becomes instrument such as a knife, razor, sickle, or piece fixed in the ganglion cells of the spinal cord of sharpened rock or bamboo. Often the umbili- or cranial nerves. Neonatal tetanus differs from cus stump is covered with ashes, charcoal pow- numerous other bacterial diseases in that it is der, cow dung poultices, ghee, powdered pep- not transferred from person to person; instead, per, snail saliva, turmeric, or other contaminated C. tetani is found in soil and is introduced into substances, and is dressed with leaves or dirty the body through an exposed area. The disease rags, or is left exposed. Rural tribes might blame has had various names, including tetani neona- evil spirits for the disease, but efforts to keep toria, trismus nascentium, “lockjaw,” and the spirits away from a new baby often increase un- “9-day illness” or “fits” because it normally oc- hygienic postnatal procedures. curs during the first 9 days of life. Its associa- Observers have found the disease to be more tion with filth and rural conditions means that common among male newborns than among neonatal tetanus is still common in Third World females, although this reported difference may nations and is one of their greatest public- reflect greater parental concern for the health health problems. Mortality rates are high, even of sons than daughters in some cultures. There with modern treatment, and preventive mea- is a question of whether race affects the fre- sures are essential to avoid the disease. quency of neonatal tetanus, but unclean habits Neonatal tetanus today is confined primarily and living conditions of certain populations are to Africa, Asia, and the West Indies, although probably much more important reasons why

326 142. Tetanus, Neonatal some peoples seem to suffer more than others. The disease develops if the spores are converted It seems to occur more often in warm months, to vegetative organisms, producing the potent perhaps because during these times babies are toxin, tetanospasmin. The toxin reaches the ner- more exposed to soil and possible infection. All vous system via the bloodstream or by travel- infants are susceptible unless they receive pas- ing along the axon cylinders of motor nerves, sive immunity from mothers who have been eventually becoming fixed in the spinal cord previously immunized. and cranial nerves. Reflex convulsive activity Next to prematurity, neonatal tetanus is the follows. most frequent cause of infant death in poor A baby with neonatal tetanus is beset with communities where traditional birth attendants symptoms that are easy to recognize and usu- serve mothers. Current estimates are that it kills ally appear 3–10 days after birth. Signs include some 10 percent of those born alive in such ar- difficulty with feeding and swallowing, gener- eas. It has taken an enormous toll in developing alized stiffness, spasms, and convulsions. The nations and, during the first half of the nine- newborn can develop special problems relating teenth century, accounted for many infant slave to ventilation, hydration, and sedation. The first deaths in the southern United States. and most distinctive sign of neonatal tetanus is Mortality rates from the disease vary up to trismus, or a stiffening of the jaw, resembling 80 percent of infants in Third World nations, al- a smile. The mouth will not open fully, result- though accurate statistics are difficult to obtain ing in a condition that has become known as because many infants are delivered outside hos- risus sardonicus. Patients often have legs and pitals or clinics, and numerous deaths are never arms partially flexed, arms crossed over the ab- registered. Current estimates are that 750,000 domen, hands clenched, excessive flexion of the newborns die annually from neonatal tetanus. toes, stifled cry, and wrinkled face. ◦ Mortality is often as high as 90 percent if it is Body temperatures can reach 100 F or higher. contracted by newborns during the first week Sucking is impaired, thus making regular nurs- after birth, and 50 percent if contracted during ing impossible. That and general fussiness are the second. the first symptoms most mothers notice. Res- One of the paradoxes concerning neonatal piratory complications commonly arise. Infants tetanus, and a major problem in eradicating the who die within 48 hours generally succumb to disease, is that immunization is more difficult in uncontrolled spasms or intense congestion of areas where the illness is most common. Such liver, lungs, or brain. Newborns who die from populations are often suspicious of modern ob- the disease after 2 days generally die from bron- stetrical procedures or are located far from clin- chopneumonia. Other complications include ical care. Yet the actual cost of preventing the aspiration pneumonia, acute gastroenteritis, disease is minimal. and umbilical hernia. Because neonatal tetanus is usually caused by The best means of controlling the disease an infection of the umbilicus (though circumci- are those that prevent the organism from sion leads to a few cases), it does not occur as an entering – namely ensuring sterile conditions epidemic. It strikes individuals rather than com- for the birth. The umbilicus should be treated munities and, therefore, is difficult to study and conservatively and cleaned with hydrogen per- does not generate the public interest that epi- oxide; foreign objects should be removed, and demics do. Consequently, the disease has not thimerosal (Merthiolate) applied. The transfer yet received the attention it deserves. of maternal tetanus antibodies across the pla- C. tetani is an obligate anaerobe (i.e., it grows centa has been found to be effective in confer- only in the complete absence of molecular oxy- ring passive immunity to the neonate for several gen), a nonencapsulated slender, motile rod. It months, though it is better if the mother is im- is introduced into an injured area as spores. munized before, rather than during, pregnancy.

327 143. Tetany

History The bacterial theories of Louis Pasteur and The term “tetanus” is from the Greek verb tano Robert Koch were important in eradicating (“to stretch”). Hippocrates described three vari- the disease in the twentieth century. In 1884, eties of the infant disease. Aristotle noted infant Arthur Nicolaier found the bacillus in soil and convulsions that occurred before the seventh produced the disease in animals. He found the day. Moschion (Muscio), writing about three same bacillus in human wounds. Shibasaburo centuries after Galen, claimed that it was caused Kitasato obtained the germ in pure culture. The by stagnant blood in the umbilical cord, as did tetanus toxoid was first used effectively dur- Andre´ Levret and others some 1,500 years after ing World War II. Immunization, along with the Galen. Indeed, in the early nineteenth century, benefits of urbanization and industrialization, doctors were still attributing neonatal tetanus to and a rise in the standard of living, have helped this cause as well as a variety of others, includ- eradicate the disease from developed nations. ing irritation within the intestinal canal, poverty, In 1923, another preventive measure evolved filth, poor diet, falls, impure atmosphere, rough when investigators showed that tetanus an- handling, a vaginal disease, cold or sea air, cos- titoxin could cross the placenta. Some sug- tiveness, smoke from chimneys, and misman- gested that this could protect the newborn from agement by midwives. tetanus by providing passive immunity. Later, it In 1793, M. Bartram ascribed the disease to was proved that immunizing a pregnant woman the umbilicus, and his theory generated much with two or three injections of tetanus toxoid debate. Some physicians urged cleanliness and would decrease incidence of the disease. Unfor- washing the umbilicus with a weak solution of tunately, it is difficult to provide such medical silver nitrate and dressing the area with an oint- services to the people who need it most. ment formed of lard and lead acetate. But atten- The World Health Organization continues to tion strayed again from the umbilicus. A 1782 monitor the incidence of neonatal tetanus, to study at a Dublin hospital noted that of 17,650 survey mortality rates of home and clinic de- infants born, 2,944 died within a fortnight from liveries, and to hold worldwide conferences to neonatal tetanus. The institution’s impure at- discuss means for improving the care of new- mosphere and poorly ventilated chambers were borns. Its goal is to eradicate neonatal tetanus. blamed for the high rate. In 1846, Marion Sims concluded that a depression of the occipital Sally McMillen bone during birth caused the disease and urged colleagues to observe bone formation closely in newborns. In 1818, however, Abraham Colles first noted 143. Tetany the similarity between neonatal tetanus and tetanus and attributed its incidence to inflam- Tetany is a symptom complex characterized mation and ulceration of the umbilicus. He sug- by painful and prolonged contractions of the gested that air be purified, that the umbilicus (generally smooth) muscles. These often appear be dressed with spirits of turpentine, and that as convulsions and are usually triggered by the baby be plunged into cold water. Efforts hypocalcemia. Adult varieties of the condition were made to bleed patients to remove the nox- include maternal tetany, parathyroid tetany, ious influences and produce relaxation. During osteomalacic tetany, magnesium tetany, gas- the nineteenth century, accounts demonstrate a tric tetany, and hyperventilation tetany. An- 99 percent fatality for those who were affected. other form of the disease – grass tetany, caused No disease of infancy was more fatal, and few by magnesium deficiency – is found in cattle. parents saw any reason to call a doctor. Despite these many forms, however, the disease

328 143. Tetany occurs chiefly in infants (neonatal tetany) and At greatest risk are infants born prematurely, young children (infantile tetany), in whom it is born with low birthweights, and born of multi- normally associated with rickets. It affects males parous or diabetic mothers as well as those who far more than females and, in the absence of are products of difficult labor. The greater sus- proper treatment, frequently proves deadly. ceptibility of males suggests the involvement of an androgen. The peak incidence of neona- Characteristics tal tetany for full-term infants occurs about the Tetany has often been confused with tetanus.It sixth day of life, and the disease seldom appears probably occurs worldwide in temperate zones, before the third day. In those born prematurely with the highest frequency of neonatal tetany or whose mothers suffered a difficult birth, the among bottle-fed, black, and prematurely born condition frequently develops within the first infants. Abundant vitamin D from year-round 24 hours. sunshine may reduce the incidence of infantile Infantile tetany, the most common form, oc- tetany in the tropics. curs chiefly between 6 months and 2 years Tetany’s etiology is incompletely understood. of age and is most prevalent between 4 and It was originally associated with calcium defi- 8 months. Males again predominate among vic- ciency and more recently with magnesium de- tims, and bottle-fed babies are at substantially ficiency, although it can also be produced by greater risk than their breast-fed counterparts. alkalosis. The disease can follow the removal In neonatal tetany, vitamin D has the paradox- or incapacity of the parathyroid glands and can ical effect of raising the incidence of hypocal- be a complication of alcoholism and a conse- cemia, perhaps because of its suppressive effect quence of prolonged diarrhea and vomiting. on the parathyroid glands. But a deficiency of Protein-energy malnutrition may also precipi- vitamin D to promote absorption of calcium is tate the disease. strongly implicated in the etiology of infantile As a rule, neonatal tetany strikes during the tetany, and indeed, rickets is nearly always evi- first 14 days of life, producing spasms, twitches, dent. The disease is much more frequent during rigid body, and turned-down mouth corners winter months when sunlight and, thus, vitamin (“carp mouth”) nearly identical to the symp- D are in shortest supply. Because of pigment, toms of neonatal tetanus. Full-term newborn black children in temperate zones have in the infants generally have significantly higher lev- past proved the most susceptible to rickets dur- els of serum calcium than their mothers. How- ing these months. Doubtless they are also more ever, these levels fall rapidly during the first susceptible to infantile tetany than their white days of life, and perhaps the high phospho- counterparts. rus content of cow’s milk places the bottle- Tetany is often signaled by a tingling sen- fed baby at special risk from tetany because it sation in the fingers, and it may become impairs alimentary absorption of calcium. An- impossible to open and close the hands. other contributing factor is, doubtless, parathy- Carpopedal spasms are common, as are roid immaturity, whereas still another can be stiffness, pain, and spasms in other muscles. the poor nutritional status of the mother. Ma- Vomiting is also common. Infants in particular ternal tetany can develop in malnourished and may develop a rigid face and body. Mental multiparous mothers whose serum calcium falls symptoms include hallucinations, dullness, with each succeeding pregnancy. Thus, fre- and distortion. Cardiac spasms may develop, quent pregnancy, maternal dietary deficiency, and coma, along with respiratory failure (fol- and hypocalcemic convulsions or hypomag- lowing asthma-like attacks), leads to death. nesemic convulsions in infants have a positive Mortality from neonatal tetany is low today in correlation. developed countries because of treatment with

329 144. Toxoplasmosis calcium. However, in the 1950s and previously, 144. Toxoplasmosis it has been suggested that over half of victims died. The agent of this disease, the sporozoan proto- zoan Toxoplasma gondii, is a common parasite History of many birds and mammals. The organism was It is probable that tetany caused by mineral first seen in 1908 in the tissues of a Tunisian ro- (and perhaps vitamin D) deficiencies has always dent, the gundi, and described in 1909. Human plagued humankind to some limited extent. In disease was first described in 1923, and congen- children, the convulsions of tetany in the past ital neonatal disease reported in 1939, but the were often attributed to “teething.” Not until parasite’s complex life cycle was not elucidated the nineteenth century, with increased bottle- until 1970. Serologic tests show that humans feeding, was a syndrome resembling tetany around the world harbor T. gondii, but almost described in England. Franc¸ois Corvisart gave all infections are asymptomatic. The protozoan the syndrome its name in 1852, and in 1854 is an intracellular parasite of a variety of tis- Armand Trousseau described tetany in lactat- sues in warm-blooded vertebrates. It multiplies ing women. In 1881, H. Weiss observed that by binary fission in a host cell, eventually rup- tetany appeared occasionally in patients af- turing the cell and releasing parasites to attack ter goiter removal, and in the 1880s the dis- other cells. Sexual reproduction occurs only in ease appeared in near-epidemic proportions in felines. These definitive hosts release oocysts, Vienna. the stage infective for herbivores, in their fe- In 1913, E. Kehrer described neonatal tetany ces. Asexual intracellular replication takes place and suggested treatment with calcium salts. in the herbivore, and, if the tissues containing However, the first satisfactory chemical study T. gondii are eaten by a carnivore, asexual repro- may have been that by J. Howland and duction may also occur in its tissues. Humans W. Marriott in 1918. It distinguished rickets become infected by eating poorly cooked or raw from tetany and reported a substantial reduc- flesh, by ingesting oocytes from cat feces, or tion of serum calcium in infantile tetany pa- congenitally. tients. It also reported that calcium salts relieved Human infections are usually inapparent, the symptoms. although they sometimes lie dormant for years In 1929, Alfred Hess pointed out that inci- and flare up in weakened or immunodeficient dence of tetany peaked in early spring, that hosts. Most cases in otherwise healthy people cases seldom developed in summer, and that are mild and cause vague symptoms like fever black youngsters were highly susceptible. This and weakness. The disease often mimics infec- suggested a role for vitamin D, given its short- tious mononucleosis. Chronic cases can cause age during winter months in temperate climates diarrhea, headache, and eye damage. Rare ful- and the difficulties blacks have had histori- minating infections cause severe symptoms and cally with vitamin D while wintering in those may affect the brain. Uterine transmission of climates. toxoplasmosis often has grave consequences: During the 1950s and 1960s, much attention 5–15 percent of cases result in fetal death; was focused on the disease. Subsequently, how- 18–23 percent result in brain and eye ever, as more has been learned about mineral abnormalities. Some apparently normal infants metabolism and as the disease has declined, so later develop severe retinal disease or mental has the name “tetany.” Although it is still in the retardation. Cerebral toxoplasmosis is a fairly literature, since the 1960s experts tend to write common and serious complication of AIDS. of hypocalcemic and hypomagnesemic, rather The highest known prevalence rate, 93 per- than tetanic, convulsions. cent, was found in Parisian women who en- Kenneth F. Kiple joy eating raw beef. By age 25, roughly

330 147. The Treponematoses

70 percent of El Salvadorans and 30 percent during World War I than any other malady ex- of white residents of New York City harbor an- cept influenza. tibodies against Toxoplasma. Estimates suggest Also known as “Wolhynian fever” and “His- that about 3,000 babies with congenitally ac- Werner disease,” trench fever occurred in quired toxoplasmosis are born annuallyinthe Russia, England, France, the Middle East, Italy, United States. Germany, and Austria. It is carried by body lice; K. David Patterson hence it follows the pattern of its more deadly relative, epidemic typhus, in plaguing armies where hygiene is substandard. The disease be- came quiescent after World War I but reap- 145. Trematode Infection peared on the eastern European front during World War II. Trematodes or flukes are flatworms of the class The etiological agent of the disease, Rochal- Trematoda of the phylum Platyhelminthes. ima quintana, was first studied during World They have complex life cycles that usually War I by a commission of the American Red involve a snail as an intermediate host. The Cross, which reported that the organism, un- definitive host of the adult worms, generally a like other rickettsiae, passed through porcelain mammal, acquires the parasite by ingesting an filters. Later, in another departure from typi- encysted form in a second intermediate host or cal rickettsial characteristics, the trench fever on vegetation. Many species can infect humans, organism was cultivated on lifeless blood-agar but most normally parasitize other mammals, media. Such differences prompted its removal and humans are accidental hosts. from the genus Rickettsia to a separate genus, K. David Patterson Rochalima, in 1961. Victoria A. Harden

146. Trench Fever 147. The Treponematoses Trench fever is a nonfatal acute disease first de- scribed in 1915 during World War I, when it af- According to most medical texts, the members flicted at least 1 million soldiers on both sides of genus Treponema – family Treponemataceae, of the conflict. Although initially known by order Spirochaetales – include Treponema pal- several names, including “Polish fever,” “Meuse lidum, which causes syphilis and nonvene- fever,” and “Russian intermittent fever,” the term real syphilis; Treponema pertenue, which causes “trench fever” – assigned by British troops in yaws; and Treponema carateum, which causes France – has endured. pinta. The three pathogens, however, may ac- After incubating 14–30 days, trench fever tually be only one, for although they produce elicits typical typhus-like symptoms: sudden different pathological processes, the pathogens onset, chills, headache, dizziness, and aches and themselves are virtually indistinguishable un- pains. Two of its descriptive names, “shin fever” der the microscope, and the diseases they cause and “shank fever,” recall characteristic leg pains. respond to the same treatment. The origin Although also known as “5-day fever” or “quin- of this infamous family and the relationships tan fever,” the disease usually disables its vic- among its members have been considerably de- tims for 5–6 weeks. About half of those afflicted bated since the 1970s, largely because such suffer only one bout of fever, but others may questions bear directly on the centuries-old have several relapses. Although trench fever is debate about whether the Americas bestowed never fatal, it caused greater loss of manpower syphilis on the rest of the world.

331 147. The Treponematoses

Many agree that the treponemes probably it spreads mostly from mouth to mouth. Both evolved from microorganisms that originally of these illnesses are normally rural, fostered parasitized decaying organic matter, and which by unsanitary conditions, and are usually en- later – perhaps hundreds of thousands of years demic and thus diseases of children. Vene- ago – came to specialize in human hosts, but real syphilis, however, is a disease of adults, probably only after first parasitizing another an- seems to have first become manifest in urban imal host. Few disagree that the first treponemes areas of temperate climates, and has been por- to parasitize humans did so by entering their trayed by Hudson, Cockburn, and others as a bodies through traumatized skin and were sub- consequence of improving hygienic conditions. sequently passed on to other humans by skin- Put succinctly, in colder climates where peo- to-skin transmission. Real disagreement begins, ple were better clothed and washed, the tre- however, over questions of where the first hu- ponemes were denied their established patterns mans were infected, and the identity of the dis- of skin-to-skin or mouth-to-mouth transmis- ease that infected them. sion among youngsters. Consequently, persons E. H. Hudson argued that the first of the tre- reached sexual maturity without exposure to ponemal infections was yaws and that it proba- them, and sexual intercourse became another bly emerged in central Africa, where it quickly means of transmission for the treponemes, par- became endemic. Then, about 100,000 years ticularly in urban areas where promiscuity and ago, it accompanied humans migrating from prostitution were common. Africa and spread around the globe. C. J. Hack- The historical gradation of treponemal infec- ett, however, portrays pinta as the first trepone- tions – from the yaws of warm, moist sub- mal disease, arising only about 20,000 years Saharan Africa, through nonvenereal syphilis in ago in Eurasia to spread throughout the world. hot and dry North Africa, to venereal syphilis At issue here are two different concepts of in cooler, urbanizing Europe – has consti- treponematosis. Hudson feels that the distinc- tuted a compelling geographic model for both tions among the treponematoses are artificial. Hudson and Hackett and their followers. They In this so-called “unitarian” view, all of the point out nonetheless that yaws and both non- human treponematoses actually constitute a venereal and venereal syphilis may all prevail single disease, but one that has different man- in a relatively small geographic area, with yaws ifestations depending on climate and culture. and perhaps nonvenereal syphilis dominating Hackett, however, argues that the distinctions the rural area surrounding a city, which har- are quite real – the consequence of muta- bors syphilis. Moreover, both views hold that tions of the treponemal strains themselves. T. A. venereal syphilis was present in Eurasia long be- Cockburn has shown along Darwinian lines fore the voyages of Columbus, but its symptoms how human geographic isolation, especially af- were lumped with other disfiguring illnesses ter the Ice Age, could have led to treponemal (including yaws and nonvenereal syphilis), usu- speciation. Similarly, Don Brothwell has also ally under the rubric of leprosy. speculated on the evolution of the treponemes Needless to say, this challenge to the long- and suggests that there may have been six lines held notion that syphilis was introduced from of Treponema, which underwent separate mi- the Americas has encountered some heavy op- croevolutionary development to reach the four position. Yet we know that pinta was present in existence today. in the Americas when Columbus arrived, and Historically, yaws has been prevalent in hot both the unitarian and the mutation hypothe- and moist regions of Asia and Africa where little ses accommodate the notion that other tre- clothing is worn, facilitating transmission from ponemal diseases could have developed there skin to skin. By contrast, nonvenereal syphilis as well. In fact, Brothwell has argued that Asia has flourished in hot but dry regions, where was probably the cradle for the evolution of

332 148. Trichinosis human treponemes and that they diffused from on the treponematoses, have also provided the there to the Americas via the Bering Straits latest hypothesis as to their origin and antiq- land bridge to the New World, as well as uity. Given the scarcity of skeletal evidence of throughout the Old World. In other words, treponematosis in the Old World, and its abun- it is conceivable that all the pathogenic hu- dance in the Americas, they suggest that tre- man treponemes were present in each of the ponematosis is a relatively new disease that major landmasses of the globe by 1492. Yet arose in the Americas as a nonvenereal infec- Hudson believes that endemic syphilis and tion that spread by “casual contact.” However, yaws reached the Americas via the slave trade after the men of the Columbian voyages con- and there evolved into syphilis; Francisco tracted the illness and carried it back to Europe, Guerra holds that all four treponemal infections the circumstances of urban environments trans- were present in the New World, but only en- formed the nonvenereal American disease into demic and venereal syphilis resided in the Old the venereal syphilis that raged across Europe World until yaws, not syphilis, was imported and much of the globe for the next century or from the Americas; whereas Corinne Wood, af- so before subsiding into the considerably more ter reviewing the arguments and evidence, finds tame disease we know today. the Columbian hypothesis for the origin of Clearly, then, despite decades of debate about syphilis the most plausible. the nature of the treponematoses, there is still Much evidence underlying this last conclu- no agreement on their locational origin or their sion is skeletal in nature, embracing both nega- antiquity. It seems to be generally accepted that tive and positive findings. Most negative find- a transition in methods of transmission of tre- ings have to do with the Old World, where ponemal syndromes can be, and was, rather it appears that those buried in leper cemeter- swiftly brought on by changing environmen- ies were mostly lepers and not syphilitics, as tal and social circumstances, and thus, that those who placed syphilis in Europe prior to syphilis is the youngest of these syndromes. But the Columbian voyages felt would be the case. like other surveys of the treponematoses, this Moreover, there is a dearth of evidence in Old one, too, must end with the hope that more World skeletal remains that would testify to the evidence will be uncovered to shed light on presence of syphilis in Eurasia prior to 1493, the many paradoxes posed by this fascinating although the presence of yaws and endemic family. syphilis has been occasionally reported. Kenneth F. Kiple In the New World, by contrast, there is a great deal of positive skeletal evidence of pre- Columbian treponematosis. This evidence is not, however, of pinta, which causes changes 148. Trichinosis in pigmentation but does not affect the bones as the other treponemal illnesses are capa- Trichinosis, also known as trichinellosis, ble of doing. Thus yaws, endemic nonvenereal trichiniasis,ortrichinelliasis, is a disease of syphilis, and syphilis are all possibilities for the humans and other mammals infected with American infection in question, as is perhaps the nematode worm Trichinella spiralis.The some other treponemal infection now extinct. pathological changes and symptomatology of Of these candidates, however, venereal syphilis Trichinella infection are manifestations of three seems least promising, because of an apparent successive stages in the life history of the worm: absence of congenital syphilis in the skeletal (1) penetration of adult female worms into material. the intestinal mucosa; (2) migration of juvenile Brenda Baker and George Armelagos, in pro- worms; and (3) penetration of juvenile worms viding us with an extensive review of literature and subsequent encystment in muscle cells.

333 148. Trichinosis

Characteristics fied, although they may remain viable for sev- Although trichinosis occurs worldwide, in hu- eral years prior to calcification. mans it is found principally in the United Not all striated muscles are parasitized to the States, Canada, and Eastern Europe. It is same degree. Among muscles most heavily af- also well known in Mexico, parts of South fected are the diaphragm, tongue, and mastica- America, Africa, southern Asia, and the Mid- tory muscles, intercostals, and muscles of the dle East. People acquire trichinae by ingest- arms and legs. ing uncooked or poorly cooked meat, especially Most mammals are susceptible to Trichinella pork. Homemade sausages have caused many infections. Infections are maintained in nature recent outbreaks in the United States. Hence, by flesh-eating animals. Humans are regarded the prevalence of trichinosis is less in the tropics as accidental hosts because, barring cannibal- and subtropics, where less meat is consumed. ism or the consumption of cadavers by other Trichinosis does not occur among Hindus, Jews, mammals, the infection reaches a dead end. and Moslems, for whom there are religious bans Most human infections result from eating pork on eating pork. or pork products, but numerous fatal cases Although the prevalence of trichinosis in of trichinosis have been recorded among peo- human populations is low (probably 2.2 per- ple eating undercooked or underfrozen bear or cent or less in the United States, based on au- walrus meat. topsy surveys), epidemic outbreaks are not in- Cooking meat is of importance in prevent- frequent. Incidence of infection is likely to be ing trichinosis. Pork should be cooked until the higher than suspected because of the vague- pink color turns to gray. Alternatively, freez- ◦ ness of symptoms, which usually suggest other ing of meat at −15 F for 20 days destroys all conditions. parasites. T. spiralis is unusual in that a single individual Trichinella infection results in development animal serves as both intermediate and defini- of serum antibodies and cell-mediated im- tive (final) host, with the juvenile and adult mune responses. Resistance to reinfection has worms located in different organs. been demonstrated by an allergic inflamma- Humans acquire infections by ingesting in- tory response that expels adult worms from the fective juveniles, which are encysted in striated intestine. Eosinophils may also play a role in im- muscle of swine or other animals. The worms munity to Trichinella because experimental de- are freed from their cysts by gastric juices and pletion of eosinophils has been shown to result invade the intestinal mucosa where they cop- in increased numbers of larvae recovered from ulate. Males die shortly after copulation, and infected animals. females migrate through the intestinal epithe- The first symptoms of Trichinella infection lium, each giving birth to as many as 1,500 live occur 1–2 days after ingestion of infected meat. young over 4–16 weeks. Spent females eventu- Initial symptoms are vague and often misdiag- ally die and are absorbed by the host. nosed, if apparent at all. As a host reacts to Young juveniles are carried throughout the waste produced by the worms, lesions develop body via the arterial system. They finally reach and enteric bacteria are introduced into them. skeletal muscle, where they penetrate indi- Nausea, toxic diarrhea, sweating, and vomiting vidual fibers and grow in a spiral fashion, may occur, mimicking an acute food-poisoning eventually becoming encysted by a blunt, ellip- syndrome. Respiratory symptoms may follow soidal capsule of host origin. The time required between the second and sixth day and last for for complete encapsulation is about 3 months. 6 days. In addition, there may be red blotches Calcification of the capsule begins as early as erupting on the skin. 6 months and may take up to 2 years to com- During the period of migration of juve- plete. Eventually the worms also become calci- niles, there are muscular pains as inflammatory

334 148. Trichinosis processes develop in the muscles. Difficulty in blunted the scalpel. Others had seen these breathing, chewing, and swallowing develops. gritty particles previously, but Paget had natural Edema around the face and hands results from history training and the intense desire to ob- endovascular and perivascular inflammation. serve new things, and thus was the first to note Edema around the eyes is a common early sign. that the particle was a worm in its capsule. Paget Lymph nodes become enlarged and tender. En- did not have a microscope but eventually se- larged parotid or sublingual glands often lead cured the use of one. Specimens of the worm to misdiagnosis of mumps. Eosinophilia may were taken to Richard Owen, who would be- be present but often does not occur, even in come England’s greatest comparative anatomist. the most extreme cases. Myocarditis, peritoni- Owen subsequently presented a paper on the tis, pneumonia, encephalitis, pleurisy, menin- worm and named it. gitis, and eye damage may result from migrating Although Paget’s discovery was overshad- juveniles. Death from myocarditis may occur at owed by Owen’s detailed and complete report, this stage. Paget retained his intense spirit of scientific Penetration by juveniles into muscle cells, inquiry and published many papers on medi- and subsequent encystment, may result in toxic cal subjects. Later, he became Sir James Paget, edema, cachexia, or dehydration. Blood pres- one of the most distinguished surgeons of his sure drops rapidly, and the patient may dis- time. play nervous disorders such as defects of vision, Trichinae in animals other than humans were altered or lost reflexes, hallucinations, delir- first noted in 1846. Joseph Leidy in Philadel- ium, and encephalitis. Severe cases can result in phia found worms in the extensor muscles of death 4–6 weeks after infection. Death may oc- a hog’s thigh. Leidy had previously seen trichi- cur as a result of toxemia, myocarditis, nephri- nae in human bodies in a dissection room, and tis, peritonitis, or other complications. he perceived no distinction in the worms from Most cases of trichinosis, however, go unde- the two hosts. In 1850, Ernst Herbst, working in tected, and in milder cases no special symptoms Gottingen,¨ established that trichinae from meat may be present. There is no thoroughly effective eaten by an animal may invade its muscles. The treatment. significance of Herbst’s experiments, as well as Leidy’s observations, was not appreciated at the History time because leading authorities believed that Although knowledge of the parasite causing the trichinae from nonhumans were of a dif- trichinosis dates from 1835, knowledge of the ferent species than those from humans. Herbst disease goes back to antiquity. Dietary laws himself believed that trichinae were actually the prohibiting consumption of swine may have larvae of filarial worms. been engendered by the observation that hu- The problem of determining the life cycle of man illness sometimes followed the eating trichinae soon caught the attention of two of of such flesh. Historians have surmised that the leading researchers of their time, Rudolf Muhammad – recognizing the possible cause Virchow of Berlin and Rudolph Leuckart of of certain epidemics as ingestion of pork – fol- Giessen. Leuckart, in 1850, observed that lowed the example of Moses in prohibiting pork female intestinal trichinae are viviparous, consumption. but he believed that the trichinae were de- The first person to actually see trichinae rived from the intestinal nematode Trichuris was James Paget, a 21-year-old freshman med- trichiura. Virchow, in 1859, fed encapsulated ical student in London. In 1835, Paget noted trichinae from a human to a dog, where the a curious pathological condition in a cadaver worms reached sexual maturity. Virchow thus brought in for study. The cadaver had “spicules refuted Leuckart’s claim that the trichinae were of bone” in the muscles – so hard that they identical with Trichuris.

335 149. Trichuriasis

Verification of the life cycle of trichinae and that occurs worldwide but is most abundant the discovery of the pathogenesis of trichinous in warm, moist climates. It still exists in the infections represent monumental contributions southern United States but in recent decades by Friedrich Zenker in 1860. Zenker autopsied has declined there and in other developed a 20-year-old servant girl in Dresden whose countries with improved sanitation; it is now illness had been diagnosed as typhoid fever. found mostly in poor tropical countries. Adult He examined muscle fibers from the arm and worms range up to 2 inches long, so whipworms was startled to see “dozens” of live trichinae. were probably seen by ancient observers, but Other skeletal muscles were likewise inhabited they were first clearly recognized by an early by the worms. Upon examining intestinal con- Portuguese writer on tropical medicine, Aleixo tents, Zenker saw sexually mature worms. It was de Abreu, in 1623. Several scientists described apparent to him that the parasite underwent its the species in the mid-eighteenth century. Ar- entire life cycle in one and the same host. chaeological evidence shows that the worm in- Zenker subsequently investigated the ser- fected people in the Americas prior to the voy- vant’s household and found the parasite in age of Columbus. sausage prepared just prior to the girl’s illness. Trichuris attaches itself to the wall of the large Furthermore, other members of the household intestine and passes its eggs in the host’s feces. who had eaten the meat had become seriously Eggs require 10–14 days in the soil to mature or ill with the same symptoms. “embryonate.” Embryonation is most successful Following establishment of the life cycle and in warm, moist soils in shady places. Like As- pathogenesis of trichinae, several outbreaks caris, which has a similar range, Trichuris infects were recorded. Some 140 epidemics of trichi- people who have swallowed embryonated eggs nosis were noted in Europe in 1860–77. In in soil or in contaminated food or water. Un- 1863, examination of pork for trichinae began like Ascaris, however, the whipworm does not in parts of Germany, and in 1879 a Prussian require an elaborate period of larval migration law required such examination for all pork. In in the host. The eggs hatch in the small intes- the same year, ordinances were passed in Italy, tine, where the larvae spend some time before Austria, and Hungary forbidding importation of moving to their home in the cecum. swine or pork products from the United States, Trichuriasis rarely causes much harm unless and other countries followed with similar bans. there is a heavy worm load. Severe infections Subsequently, the U.S. Department of Agricul- can cause abdominal discomfort, bloody or mu- ture, although not requiring specific examina- coid diarrhea, weight loss, weakness, and ane- tion for trichinae, did specify methods of pro- mia. Masses of worms can cause appendicitis, cessing pork products customarily eaten raw. and prolapse of the rectum can occur in chil- Such procedures destroy the infectivity of any dren. Symptoms, including anemia, tend to be trichinae present. Public education and heat more severe in children. Drug treatment is ef- treatment of garbage used to feed hogs have fective, and improved sanitation is preventative. also helped to reduce the incidence of the dis- K. David Patterson ease in North America and Europe. Donald E. Gilbertson

150. Tuberculosis

149. Trichuriasis Tuberculosis is most commonly associated with the lungs but can affect almost any bodily The nematode Trichuris trichiura, the whip- tissue or organ. Caused by a bacillus (My- worm or threadworm, is a common parasite cobacterium tuberculosis), it is usually a chronic

336 150. Tuberculosis infection, lingering for months and sometimes clusively in Europe and North America. Type I years, although acute forms, which most com- is the least virulent of the three, making Indi- monly strike infants and young children, can ans more susceptible to disease when infected prove fatal in weeks or days. One acute form with type AorB.These differences probably is called miliary tuberculosis because of the result from the evolution of widely separated small grain-like tubercles it creates simultane- organisms over long periods of time. However, ously in almost every organ of the body. Since all forms of M. tuberculosis show a strong resis- ancient times, tuberculosis was endemic in most tance to mutation, and thus it is unlikely that populations of Eurasia, North Africa, and pos- an increase in virulence caused the disease to sibly the Americas, affecting relatively small become epidemic, or that a decrease in viru- numbers and maintaining low prevalence rates. lence prompted the decline in tuberculosis mor- But with modern urban and industrial develop- tality rates that occurred in England, the United ment it became epidemic in much of the globe. States, and other Western nations before the in- In some places, tuberculosis prevalence rates troduction of streptomycin and other specifics. have approached 100 percent of the population. Except for bovine forms, tubercle bacilli reach Tuberculosis killed millions over the centuries, human hosts almost exclusively through aerial placing it on a historical par with other great epi- transmission. Talking, coughing, sneezing, spit- demic diseases: plague, cholera, smallpox, and ting, singing, and other respiratory actions pro- the like. In 1944, researchers discovered strep- duce airborne particles called droplet nuclei; tomycin, which effectively inhibited the disease. these, when emitted by tubercular individu- In combination with streptomycin, two newer als, can contain up to three bacilli – one is drugs – para-aminosalicylic acid and isoniazid – enough to establish an infection if inhaled. provided further potent therapy. Today, all but Once airborne in a closed space, droplets dis- the most advanced cases are curable. perse, and some remain suspended, like smoke. Larger ones fall, presenting little threat, al- Characteristics though dry tubercle bacilli can remain viable Over 30 species of genus Mycobacterium have for months. Bovine bacilli are ingested in milk been identified, more than 15 of which can and usually cause intestinal disease but in- cause disorders similar, but not identical, to tu- frequently pulmonary tuberculosis or miliary berculosis. Human disease typically is caused tuberculosis. by members of the species M. tuberculosis.In After entering the body, tubercle bacilli are addition, mycobacteria can cause disease in a remarkably durable. They can remain viable wide variety of animals, including birds, fish, throughout the host’s lifetime, dormant until re- rodents, elephants, and cattle. Of its animal sistance fails, whereupon they can cause disease forms, only bovine tuberculosis can infect peo- even if they never did so when first entering the ple. Some bacteriologists consider the bovine body. Whether or not tubercle bacilli cause im- form a separate species of the tubercle bacillus, mediate disease upon infection depends on sev- whereas others group it with several variants eral factors: age, gender, and immunogenetics that they classify together as the “M. tuberculosis (“host-dependent” factors), along with environ- complex.” mental factors such as crowding, nutrition, and The human bacillus has also been divided working conditions. A population’s genetic pool into three types according to immunologic re- is important as well. For example, long inhabita- sponses (phage types), which show marked vari- tion of urban environments has apparently in- ations in virulence. Type I tuberculosis is found creased Jews’ resistance to the disease. By con- in India; type Atuberculosis is found in Africa, trast, lack of prior exposure can lead to acute China, and Japan as well as in Europe and North epidemics, such as among the New Zealand America; and type B tuberculosis is found ex- Maori and Alaskan Eskimos.

337 150. Tuberculosis

Some epidemiologists assert that natural se- The tubercle bacillus does not itself damage lection determines the course of tuberculosis the body. Rather, cellular and tissue damage epidemics, based on the idea that genetic back- arises from an allergic reaction or hypersensitiv- ground and resistance to the disease are of ity to the bacillus. In other words, after the body paramount importance. Mortality rates drop, has become allergic to invading tubercle bacilli, they say, as the susceptible are weeded out. the immune system destroys them. This pro- Others oppose this theory, noting that although cess, however, releases proteins and fatty sub- natural selection has doubtless reinforced re- stances that in turn cause inflammation and sistance to tuberculosis, it has not strongly af- can damage surrounding tissue and cells. The fected the decline in epidemics. Rather, eco- same process also creates the illness’s distinc- nomic and social changes seem to constitute the tive tubercles. Individual resistance to tubercu- most important factors in declining tuberculosis losis fluctuates markedly: Quiescent infections mortality rates until the 1940s, when cures be- rekindle with depressed resistance only to ca- came available. Numerous studies indicate that pitulate when resistance returns. Acquired resis- lowest-income groups suffer most from the dis- tance to the tubercle bacillus confers no durable ease and also that rising incomes greatly re- protection (such as in measles and smallpox). To duce tuberculosis mortality. This means that the contrary, it can assist the development of ac- industrialization alternatively exacerbates and tive disease. Antituberculosis vaccination usu- improves tuberculosis rates. An early-stage in- ally consists of BCG (bacillus Calmette-Guerin),´ dustrial economy subjects many to crowded an attenuated strain of bovine bacillus first iso- and impoverished living conditions. Eventu- lated in 1921. Tests indicate that it offers some ally, however, material benefits improve hous- degree of immunity to uninfected recipients. ing and nutrition, reducing risks of infection and lowering disease rates. History Tuberculosis frequently causes disease in the Archaeological evidence of tuberculosis af- meninges, intestines, bones, lymph system, skin, flicting prehistoric humans dates at least from spine, kidneys, and genitals. Most of these forms the Neolithic period. Stone Age skeletons (excepting tubercular meningitis) are chronic, with apparently tubercular lesions have been sometimes lasting years before either recovery unearthed in Europe, and spinal tuberculosis or death. Miliary tuberculosis affects most vi- has been found in Egyptian mummies dating tal organs concurrently. Pulmonary tuberculo- from the third millennium B.C. In China, a sis, however, is the most common form, its most mummified body from the second century B.C. familiar symptom a frequent, violent cough pro- has tuberculosis scars on the lungs. Trade and ducing purulent sputum and sometimes blood. migration ensured dissemination of China’s But symptoms are not universal. Indeed, un- diseases throughout East Asia during the til the disease becomes advanced, many vic- first three centuries A.D. Skeletal evidence tims are completely free of symptoms or expe- strongly suggests that native Americans suf- rience only mild respiratory symptoms. In the fered from tuberculosis as early as 800 B.C., past, many developed mild, asymptomatic cases and pulmonary lesions have been discovered and recovered unknowingly, as autopsies and in Chilean mummies from 290 A.D. X-rays later revealed. In early stages, the un- This evidence suggests two important points alarming symptoms and myriad manifestations concerning the prehistory of tuberculosis. First, of tuberculosis make diagnosis difficult even to- the disease quite possibly evolved with hu- day. A tuberculin test usually indicates whether mans from earliest times. Second, tuberculosis a person has become infected. But although tu- afflicted most people worldwide from prehis- berculin testing is highly reliable today, false- toric times, save for small groups such as the positive responses do occur. Maori, who lived in isolation for centuries. Most

338 150. Tuberculosis epidemics therefore resulted not from the intro- that is, as scrofula. This was because of the duction of foreign pathogens into virgin popula- custom of the “king’s touch”: French and tions but from changes in host populations and English kings were believed to cure scrofula their environments. simply by touching its victims. The custom orig- Until the present concept of tuberculosis – inated in the twelfth century and continued as a single disease caused by the tubercle through the eighteenth. bacillus – emerged during the nineteenth cen- Chinese texts providing detailed treatments tury, its various forms were often considered dif- of tuberculosis were written during the Sui ferent diseases. For example, pulmonary forms (581–617) and Tang (618–907) dynasties. were commonly called phthisis or consump- Japanese physicians, using the Chinese texts, tion; lymph infections were termed scrofula, clearly described symptoms of tubercular dis- and skin infections lupus vulgaris. This confu- eases in their own country. By the twelfth cen- sion makes identification of tuberculosis from tury, Taoist priests attributed phthisis both to historical texts difficult. Consequently, conclu- evil airs and to animalculae, which attacked ex- sions concerning tuberculosis based on most hausted individuals. In positing a systematic sources up to the nineteenth century necessar- “germ theory,” the Chinese anticipated West- ily engender some skepticism. ern medicine by centuries. In the sixteenth cen- Nevertheless, classical Hindu, Babylonian, tury, Girolamo Fracastoro became the first West- Assyrian, Chinese, Greek, and Roman sources ern physician to propose such ideas. Unlike the all describe symptoms of tuberculosis. Hindu Chinese, however, Fracastoro believed that ph- texts dating from 1200 B.C. and perhaps ear- thisis was only one of many diseases caused by lier, along with Mesopotamian texts from the animalculae. seventh century B.C., described treatments for During the sixteenth century, tuberculosis pulmonary tuberculosis and scrofula. The first mortality increased noticeably among urban description of tuberculosis in Chinese may populations. In England, for example, it caused date from 2700 B.C., and texts from around about 20 percent of all deaths, with the great- 400 B.C. clearly describe the symptoms. The est concentrations in London. A similar phe- first Greek mention of what was probably tu- nomenon occurred in Japan: Observers in the berculosis is by Homer (c. 800 B.C.). Hippo- early seventeenth century noted that phthisis cratic writings from approximately 400 B.C. dis- was widespread in the rapidly growing cap- cuss phthisis (the Greek term for consumption), ital of Edo. During the eighteenth century, which was attributed to evil airs. “Phthisis” be- however, the great epidemics of tuberculosis came the standard European term signifying a began and were well under way by the be- symptom-cluster similar to pulmonary tuber- ginning of the nineteenth. The nations that culosis. Other Greek and Roman writers used suffered most severely from tuberculosis were the term extensively, including Galen, who dur- experiencing intense urbanization and industri- ing the second century A.D. recommended a alization. Thus reports of phthisis were common change of climate as therapy for consumption. in England, the United States, Italy, and France. Researchers have noted that the ancient cul- Autopsies showed that close to 100 percent tures that described the signs and symptoms of some urban populations, such as those of of the disease were primarily urban, whereas London and Paris, developed tuberculosis pastoral cultures make scarce mention of the sometime during their lives, even if they disease. Biblical literature, for example, makes died from another cause. Tuberculosis mortal- scant reference to it. ity rates in American cities during the early Medieval Europeans suffered from tubercu- nineteenth century ranged from 400–500 per losis, although contemporary documents men- 100,000. Women textile workers generally led tion it more often in its glandular form – other groups in tuberculosis mortality in every

339 150. Tuberculosis country where textile factories appeared. When of tuberculosis. A leading theoretician of this statistics became available for most industrial school, Karl Wunderlich, asserted the impossi- countries after 1860, they showed that tuber- bility of drawing a meaningful distinction be- culosis epidemics were declining. In developing tween, for example, dysentery and enteric di- countries (including Japan), however, epidemics arrhea. Wunderlich thought of disease names were just starting at the end of the century. only as conveniences, not as linguistic symbols Beginning in the seventeenth century, for specific entities. In his views of tuberculosis, European physicians gave increasing attention Wunderlich echoed his contemporary, Rudolph to tuberculosis, partly because of major changes Virchow, one of the greatest medical theoreti- in medical theory and partly because of growing cians of the nineteenth century. He also repu- mortality from phthisis and scrofula. In 1685, diated Laennec’s idea that all tubercular phe- Richard Morton became the first Westerner to nomena manifested a single, specific disease. publish a monograph on phthisis, a term he Rather, he divided them into separate categories used to embrace several diseases, including of inflammatory and neoplastic phenomena and pulmonary consumption and scrofula. By thought that some forms fundamentally resem- the eighteenth century, however, physicians bled cancer. were redefining their concepts of disease and Despite Virchow, the tradition of combining seeking new explanations of causes, and the clinical and pathological investigation contin- nineteenth century became a period of intense ued in France, most notably by Jean-Antoine research into tubercular diseases. In Europe Villemin, who followed Laennec’s principles and and the United States, investigators sought to demonstrated in practice what Laennec had identify lifestyle and environmental factors that postulated. In 1865, Villemin caused tubercu- made people “susceptible.” Among such factors losis in rabbits by injecting them with matter were dissolute living, alcohol and tobacco con- from human tubercles. Although his work had a sumption, and developmental life crises such as negligible impact on German ideas, tuberculosis puberty and childbirth. In addition, damp soil was established as a specific disease by Prussian and filth could make an individual susceptible bacteriologist Robert Koch. to consumption. Others, however, believed Using clearly defined bacteriologic methods, that pulmonary consumption was a hereditary Koch proved in 1882 that animals contracted affliction – a belief that became a powerful tuberculosis from inoculations of bacteria (not social stigma. Indeed, throughout the nine- simply tubercular matter) isolated from human teenth century, popular (and some medical) tubercles. Although many problems remained concepts of tuberculosis held that it expressed (such as the identity of scrofula, which some a person’s inherent nature, instead of just being still maintained was a separate disease), Koch’s something one had. work finally showed tuberculosis to be a sin- A major break with previous theories oc- gle disease entity. For several years, some cir- curred in the early nineteenth century, which cles disputed Koch’s methods and conclusions. transformed the tubercular diseases’ classifica- Nonetheless, his discovery of the tubercle bacil- tion by the 1880s. From the early 1800s, the lus changed the way most people viewed the French “clinical school” compared the course of disease. disease symptoms with autopsy observations. Koch’s discovery had little effect on treat- Eventually, Rene´ Laennec, a leading physician of ment but important implications for prophy- this school, postulated that all tubercular phe- laxis. Observers concluded that dry tuber- nomena including phthisis, scrofula, and mil- cle bacilli in dried sputum presented the iary tubercles constituted a single disease. greatest threat. They recommended general German physicians of the “physiological removal of dust from all buildings, restric- school” vigorously attacked Laennec’s theory tions on spitting and the use of spittoons

340 150. Tuberculosis everywhere, and disinfection or destruction of As diagnostic techniques improved but the belongings and surroundings of tubercu- medicinal cures remained ineffective, thera- losis victims. In some places, such procedures pies based on climate and regimen evolved. were already “on the books.” Not until the 1930s From the mid-nineteenth century, open-air did researchers demonstrate that tuberculosis and rest therapies became increasingly popu- mainly resulted from airborne infection and lar throughout Europe and the United States. that other forms of contact played little role in Systematic integration of these therapies with transmission. other forms of treatment culminated in the san- Most practicing physicians, however, were itorium. From the 1880s, luxury sanitoria for the primarily interested not in ascertaining the wealthy drew patients from around the world. etiology of tuberculosis but in treating it. About 1900, state-sponsored sanitoria began Hundreds of thousands of victims created an to appear throughout Western Europe, North unbounded demand for remedies, creating America, and Japan. Where sanitoria were not opportunity for both physicians and quacks. feasible, such as in inner cities, public-health of- Popular cures for tuberculosis included cre- ficials developed alternatives that offered open- osote, carbolic acid, gold, iodoform, arsenic, and air treatment as well as preventive regimens. menthol – administered orally, inhaled, or in- Many sanitoria and prevention programs jected directly into lungs. More unusual were sponsored by antituberculosis organiza- treatments ranged from drinking papaya juice tions, established in most of Western Europe to enemas of sulfur gases. Starting during the and North America from the 1890s and in late nineteenth century and continuing well much of the rest of the world during the into the twentieth, physicians practiced surgical next few decades. Their educational programs, therapies, including collapsed-lung treatments which became a mainstay of tuberculosis and surgical removal of ribs to diminish the control, informed the public about disease thoracic cavity. transmission and encouraged people to se- The search for a remedy (rather than his dis- cure frequent checkups and early treatment. covery of the tubercle bacillus) brought Koch However, the most commonly afflicted groups – international fame. In 1890, under pressure industrial workers and the urban poor – rarely from the German government, he announced could afford treatment even if they received an a cure for tuberculosis, which attracted thou- early diagnosis. sands to his Berlin laboratory. Soon, however, Tuberculosis declined dramatically from the many questioned the efficacy of “Koch’s lymph” late nineteenth century onward, and re- (a tubercle extract); indeed, it proved harm- searchers, officials, and volunteers understand- ful in advanced cases. But it soon became the ably concluded that the decline was the di- extremely important diagnostic tool known as rect result of their efforts, especially in Britain, tuberculin – the primary means of determining Germany, and the United States. Yet other ex- tuberculosis infection. perience contradicted such claims. For exam- After 1895, the X-ray too helped change the ple, during the early twentieth century, the way people thought about tuberculosis. It dis- Japanese implemented Western tuberculosis played tubercular lesions long before symptoms control measures including extensive legisla- became noticeable, allowing physicians to start tion, state-sponsored sanitoria, intensive ed- treatment much earlier in the disease than be- ucation programs, and mass screenings and fore. X-ray photographs together with tuber- BCG immunizations. However, Japan’s tubercu- culin became the basic tools of mass screen- losis mortality rate, initially hovering around ing programs implemented by governments and 200 per 100,000, actually increased from the antituberculosis associations from the 1920s to early 1930s. Not until the late 1940s did rates the 1950s. begin a sustained fall. In Japan’s case, the

341 151. Tularemia prevention movement was much less important tion has continued to deteriorate. The year 1998 than later improvements in living standards and was declared to be the worst TB year in human working conditions, and even later nationwide history, and it was expected that between 1995 treatment with modern drugs. and 2005 some 300 million new TB cases would Since the 1950s, the countries with the high- occur, almost exclusively in developing coun- est tuberculosis mortality have been those with tries, most of which are ravaged by poverty, and low standards of living, poor working con- many of which are under siege from AIDS. ditions, and inadequate treatment programs. A good share of the new TB cases has been at- Medicine has learned that the mere availability tributed to the simultaneous rise and diffusion of specifics is insufficient to stem the disease; of AIDS, which cripples the immune systems of their administration must be coordinated with its victims (indeed, TB and HIV form a lethal reforms that raise living standards and improve combination, with each hastening the progress working conditions. As late as the 1970s, over of the other). But it has also been the case that 20 developing countries had new-case tubercu- poorly supervised drug therapy for the disease losis rates over 150 per 100,000 per year. has helped to create drug-resistant strains that Thus although many have long envisioned facilitate the spread of TB. Tourism, migration, the eradication of tuberculosis, it remains a ma- and international travel do the same, and the jor health problem in many countries. Even WHO has called attention to developing coun- in developed nations, when social conditions tries that act as facilitators. These include those deteriorate, the incidence of tuberculosis rises of the former Soviet Union, whose health sys- quickly. Clearly, tuberculosis remains far from tems are in shambles. eradicated and can be a significant health prob- But developed countries are not blameless lem during times of depression, war, and unrest. in this regard. Made complacent by the steady William D. Johnston reduction in TB rates since the 1950s, their health systems have been slow to react. It was a complacency rooted in the notion that mod- ern medicine had conquered all of the impor- Postscript tant infectious diseases and therefore could and The 1990s saw a sharp increase in tuberculo- should turn its attention to the chronic illnesses. sis (TB) cases in the United States and in the Forgotten was that TB had not been subdued world. The number of U.S cases, which had in the developing world (meaning most of the been falling at around 5 percent annually since world), that pathogens can develop defenses 1953, suddenly rose from fewer than 23,000 in against drugs (as well as vice versa), and that 1988 to peak at some 27,000 cases in 1992, be- it was possible for new diseases – like AIDS – fore falling to around half that number by the to emerge that would act in concert with TB. end of the century. In the larger world, how- For Western medicine, then, tuberculosis has ever, where there was no such reversal, the become “the disease that never went away.” picture was much bleaker. In the mid-1990s, Kenneth F. Kiple the World Health Organization (WHO) declared TB a global emergency, with the magnitude of that emergency made clear in 1996 estimates indicating that (1) one in every three of the 151. Tularemia world’s citizens was infected with M. tuberculosis (although the majority had not developed ac- Tularemia is primarily a specific infectious dis- tive cases); (2) eight million new cases were de- ease of rodents and lagomorphs. The causative veloping each year; and (3) some three million organism, however, has been isolated from over persons were dying of TB annually. The situa- 100 species of mammals, 9 species of domestic

342 151. Tularemia animals, 25 species of birds, 70 species of in- ing and handling infected animals. Human-to- sects, and several species of fish and amphib- human transmission is extremely rare, and the ians. In humankind, tularemia is an acute, in- disease is largely confined to rural areas. It may fectious, moderately severe, febrile disease, with occur in any season but is least prevalent in win- mortality of approximately 7 percent in un- ter when insect vectors are least abundant and treated cases. The causative agent, Francisella small animals are not much hunted. (Pasteurella) tularensis, is a tiny pleomorphic The fatality rate in North America, prior to coccobacillus. Tularemia is also known as “deer- widespread use of streptomycin in the late fly fever,” “Pahvant Valley plague,” “rabbit fever,” 1940s, ranged up to 9 percent. Today that fig- Ohara’s disease, yatobyo, and “lemming fever.” ure has been reduced to less than 1 percent. In Europe, the mortality rate has always been Characteristics much lower – in the realm of 1 percent – Two variants (biovars) of the causative or- because of lower virulence there. An attack con- ganism are recognized. F. tularensis biovar tu- fers relatively solid lifelong immunity. A live larensis (type A) has been isolated in nature attenuated vaccine is now available that re- only in North America and is the most viru- duces the severity of the ulceroglandular in- lent in humans. The second, F. tularensis bio- fection and reduces incidence of typhoid-type var palaearctica (type B), is found in all areas tularemia. However, the vaccine is still being where tularemia is endemic in the Northern investigated and used primarily for laboratory Hemisphere. workers who are always at high risk in working Tularemia is unique in the number of ways with the tularemia organism. humans can become infected, and the clini- Tularemia in humans is confined to the cal picture of the disease depends on the in- Northern Hemisphere with three main areas fection route. The most common route is via of epidemicity: North America, Europe (espe- the skin, either by insect bite or by direct pas- cially Eastern Europe and Russia), and to a sage through intact skin by contact with in- lesser extent Japan. It is not found in nature fected carcasses or a scratch from an infected in the British Isles. Tularemia has been re- animal. Of numerous insects that transmit the ported everywhere in the United States except disease, the tick is most important. The wood Hawaii. In Canada, the disease is endemic in tick (Dermacentor andersoni ) and three species the central and western provinces as well as of rabbit tick are especially important in the the Northwest Territories but seldom is reported United States. Biting insects such as the deer fly from the eastern provinces. Other countries (Chrysops discalis) and the stable fly (Stomoxys that have reported the disease include Mex- calcitrans) also carry the disease to humans. Of ico, Norway, Sweden, Belgium, France, Germany, several species of mosquitoes that harbor the Poland, Czechoslovakia, Austria, Yugoslavia, organism, only two act as human vectors: Aedes Turkey, and Tunisia. Sporadic cases have been cinereus and Aedes excrucians in Sweden and the reported from northern South America includ- former U.S.S.R. Infection of the intestinal canal ing Venezuela, Ecuador, and Colombia, but follows ingestion of contaminated water and un- these have not been confirmed. dercooked meat. Humans can also contract in- In the United States, tularemia became a fection via the respiratory route by inhaling the reportable disease in 1927 and rose to peak organism from sources such as contaminated incidence in 1939 with 2,291 reported cases hay and wool. (17.5 per million population). Since the 1950s, Susceptibility to tularemia is independent of the disease has undergone a dramatic decline. age, sex, race, and health status. That men are In 1984 in the United States, only 291 cases were more often infected is related to their intru- reported (1.2 per million). Since 1931 in Canada, sion into the transmission cycle through hunt- nearly 400 cases have been reported but with a

343 151. Tularemia steady decline over the years. In Russia, a sim- accompanied by acute abdominal symp- ilar decrease has been observed. In the mid- toms such as pain, vomiting, and diarrhea 1940s, 100,000 cases per year were reported; with ulcerative lesions in the intestinal yet these were reduced to a few hundred cases mucosa. per year by the mid-1960s. The reasons for this 5. Glandular tularemia develops without a worldwide decline are controversial. The rea- primary lesion but with enlargement of re- sons advanced range from ecologically induced gional lymph nodes. selection against the more virulent strains of 6. Septicemic typhoidal tularemia develops F. tularensis and reduction of the organism without a primary lesion and without en- circulating in wild reservoirs, to an increased largement of the regional nodes. Infection awareness of the disease through mass educa- arises via the respiratory route or is the late tion, to a failure to detect and report cases. result of local infection. Tularemia manifests an extremely variable 7. Meningitic tularemia is rare in North clinical picture depending on the inoculation America but not infrequent in Asia, under site and the extent of spread. In general, incu- certain conditions of insect transmission. bation averages about 3 days. The disease be- gins with headache, chills, vomiting, and fever, In all these types, subclinical infections may with generalized aches and pains. An ulcer de- be more common than previously supposed. velops at the site of initial entry, while associ- ated lymph nodes become enlarged and ten- History der. The disease lasts 3–4 weeks, with sweating, Tularemia enjoys a unique place in medical weight loss, and general debility. Convalescence history as it is the first disease to be iden- requires 2–3 months. Several clinical types of tified and entirely described by American in- the disease have been described: vestigators. In 1910, G. McCoy, while studying plague in California ground squirrels, reported a “plague-like disease of rodents” in these an- 1. In ulceroglandular cutaneous tularemia, imals. The following year, he and C. Chapin, an inflamed papule develops at the inocu- using a special nutrient medium, succeeded in lation site, which soon breaks down, leav- culturing the causative organism and named ing a punched-out ulcer. Associated lymph it Bacterium tularense after Tulare County, nodes painfully enlarge, which may last California, where infected squirrels were first 2–3 months. The usual signs of infection, discovered. W. Wherry and B. Lamb were first fever, and prostration are common. to diagnose a human case of the disease in 2. Oculoglandular ophthalmic tularemia oc- 1914. The infected patient showed ulcerative curs when the bacterium enters via the conjunctivitis and lymphadenitis. conjunctival sac. Local inflammation oc- Earlier, in 1911, R. Pearse had described sev- curs with enlargement of neck lymph eral cases of deer fly fever and suggested that nodes. Permanent impairment of vision the disease was caused by the bite of Chrysops may occur. discalis, the common deer fly. Edward Francis 3. Pleuropulmonary tularemia develops pieced together the complicated etiologic con- secondary to other forms. Milder forms nection among deer fly fever in humans, the resemble atypical pneumonia and may plague-like disease of rodents in California, and include shortness of breath, malaise, chills, similar illnesses in small mammals of Utah and and pleuritic pain. Indiana. Francis isolated the organism in 1921 4. Oropharyngeal gastrointestinal tulare- and proved that it was indeed spread by the mia is contracted from the ingestion of bite of the deer fly as well as by direct contact contaminated food and water and may be with infected meat. The role of the tick in the

344 152. Typhoid Fever spread of tularemia was determined in 1924. complex interactions among hosts, vectors, and It was also Francis who coined the term “tu- varied environments. Such complexity makes laremia” after finding the organism in the blood eradication of tularemia unlikely. of infected individuals. In the late 1950s, the Patrick D. Horne genus name of the organism was changed to Pasteurella because of a supposed relationship to the causative organism of plague.In1974, the genus name was changed to Francisella to 152. Typhoid Fever honor Francis who, through more than 30 years of investigation into tularemia, was the man Typhoid fever is a systemic infection caused by most responsible for sorting out its complexities the bacterium Salmonella typhi, usually mani- and many manifestations. fested by slow onset of a sustained fever and Beginning in 1925, Hachiro Ohara, a Japanese other symptoms including headache, cough, di- scientist, published studies of a disease of wild gestive disturbances, and profound weakness. rabbits and described how an illness that would In a minority of sufferers, specific diagnostic become known as Ohara’s disease was suc- symptoms such as spleen or liver enlargement cessfully transmitted to humans. Other papers or a characteristic “rose-spot” rash are found. by Japanese scientists soon followed, but none Untreated, the illness lasts 3–4 weeks; it kills made reference to American investigations of about 10 percent of victims and leaves 2 per- tularemia. Francis and a colleague, recognizing cent as permanent carriers of the organism. that Ohara’s disease seemed similar to tularemia Three-quarters of the world’s population live in every way, requested sera from convalescent in typhoid-endemic areas; 1 in 300 contracts Japanese patients, examination of which quickly the disease annually. Each year, typhoid kills confirmed that Ohara’s disease and tularemia 1 million people, mostly children. A variant, were actually the same illness. paratyphoid fever, has similar features but Although tularemia is often described as a is caused by different Salmonella species. Ty- “new disease,” it is perhaps new only in terms of phoid and paratyphoid are sometimes lumped discovery. Evidence suggests that tularemia was together under the term enteric fever. endemic in the United States, Scandinavia, and Russia in the eighteenth and nineteenth cen- Characteristics turies. Travelers in Russia as early as 1741 noted The microorganism responsible for typhoid a disease with all the characteristics of tularemia fever belongs to one of the largest and most and termed “Siberian ulcer.” widespread families of bacteria on Earth, with In the United States at least three written over 1,700 serotypes recognized. Salmonellae records survive describing the disease, includ- are rod-shaped bacteria that have a cell wall and ing one from California in 1904 and another flagella, which provide motility. from Arizona in 1907. In fact, the wide distribu- Salmonellae can colonize the gastrointesti- tion of the disease and its adaptation to a wide nal tracts of a broad range of animal hosts, in- variety of animals suggest that the disease is an- cluding mammals, birds, reptiles, amphibians, cient, perhaps dating from the latter Miocene or fish, and insects. Some types of salmonellae are early Pliocene periods. highly adapted to specific animals; others have Despite the dramatic decline in the incidence a wide range of hosts. Because of this versatility of tularemia since the 1950s, it appears that and the consequent enormous animal reservoir, tularemia will remain a hazard to humans for the eradication of all salmonellosis would be many years to come. In spite of the great amount essentially impossible. of research over the past 70 years, numerous Salmonellosis is generally a mild disease in questions remain unanswered because of the humans, characterized by a few hours or days

345 152. Typhoid Fever of vomiting and diarrhea followed by weeks to ingested. In experiments using human volun- months of shedding the organism in feces. The teers, illness was produced in about 25 per- disease is usually acquired by ingestion of con- cent of those ingesting 100,000 bacilli each; in- taminated foods, but other means are possible. gestion of 10 million bacilli caused illness in In the 1970s in the United States, more than 50 percent; and ingestion of 1 billion organ- 10 percent of salmonellosis was acquired from isms virtually guaranteed the development of baby turtles, then a favored children’s pet. typhoid fever. However, some strains can pro- By contrast, and almost unique among the duce disease at very low numbers, and most salmonellae, typhoid bacilli are adapted to hu- epidemics in the developed world appear to be mans alone. They possess a protective enve- initiated by exposure to only a few hundred or lope that helps resist the host’s immunologic thousand organisms. defenses. Fortunately, S. typhi’s adaptation to A distinctive feature of the epidemiology of humans permits control through public-health typhoid is the existence of a large number of measures. asymptomatic carriers. Normally, fecal excretion Typhoid spreads via the fecal-oral route: Bac- of the organism persists for some weeks, but teria shed by infected persons are ingested by about 2 percent of infected persons never clear others, usually through contaminated food or the bacillus from their stools. In such persons, water. Control depends on separating sewage the organism appears to colonize the biliary and drinking water. In certain regions, as many tract; S. typhi seems to have a particular affin- as 3 percent of adults may be shedding S. typhi. ity for bile and gallstones. Once a stone is in- Thus the population is continuously exposed, fected, it forms a focus of infection sheltered and the disease constantly present. Many less- from antibiotics and the host’s immune system. developed areas are highly endemic for typhoid The likelihood of becoming a carrier increases fever. with age, peaking at age 55, with female carri- In contrast, where effective sanitation barriers ers outnumbering males 3 to 1 – a pattern sim- are suddenly breached, transmission becomes ilar to that of biliary disease but contrasting epidemic. For example, typhoid is almost un- sharply with acute typhoid fever, which is a dis- known in Switzerland; yet in 1963, water con- ease of the young and affects both sexes equally. tamination caused 280 cases in a brief period. The lack of symptoms often makes carriers diffi- Ten years later, a similar problem in Florida sud- cult to identify, and sequestration of the bacillus denly produced 222 cases, apparently originat- on gallstones makes its eradication difficult or ing with a single carrier. impossible. Though denied another animal host, S. ty- Since the beginning of the twentieth century, phi also grows well on foods, which has been typhoid fever has been largely a disease of the responsible for large-scale outbreaks. In 1964, developing world. Estimates suggest that global 500 cases of typhoid fever in Scotland were incidence averages 300 cases per 100,000 per- traced to imported canned beef that – after pro- sons annually or 15 million cases each year. In cessing under sterile conditions in Argentina – endemic areas, 75 percent of cases occur in per- had been cooled in a sewage-laden river, where sons 3–18 years old. Typhoid is only rarely de- microscopic cracks in the seams of the cans per- scribed in children younger than 2 years, al- mitted contamination. though studies indicate that it can be present The percentage of persons who develop ty- yet unsuspected clinically. No susceptibility by phoid fever after exposure depends on several race has been identified, but poverty, usually as- factors, including the virulence and number of sociated with poor sanitation and health care, organisms ingested, and the host’s health and does constitute a risk factor for typhoid. For ex- immune status. The attack rate of the disease ample, blacks in South Africa have four times depends directly on the number of organisms the incidence of typhoid – with eight times the

346 152. Typhoid Fever mortality rate – of whites. In Israel, the rate diagnose typhoid fever, although it is not always for the Jewish population is similar to that for reliable. Persons with typhoid fever may never Europe; for the non-Jewish population, it is sim- show a rise in antibody levels, and past exposure ilar to that for the Middle East. to S. typhi (which is common among adults in In endemic areas, typhoid tends to peak in the endemic areas) can mean a positive Widal test, summer months. Whether this pattern results whatever the patient’s current ailment. In unim- from greater consumption of water or enhanced munized children in endemic areas, however, proliferation of the bacteria in food is unknown. the Widal test may be of value. In the developed world, to judge by the United Until 1948, little other than supportive treat- States, seasonality reflects foreign-travel pat- ment was possible, but with discovery of terns, with peaks in January and February and the antibiotic chloramphenicol, mortality was again in the summer months. markedly reduced. For 20 years, chloram- Most ingested typhoid bacilli are killed by phenicol was entirely effective, but resistance stomach acid. Surviving bacilli enter the small emerged in the 1970s. Soon, 75 percent of intestine, penetrate the mucosal lining, and are all S. typhi isolates in Vietnam, for example, ingested by white cells located in gut lymph were resistant. In developed areas, the per- nodes. Perhaps because of its protective enve- centage of resistant strains remained below lope, S. typhi resists digestion and multiplies 5 percent. Trimethoprim, sulfamethoxazole, within the cells that normally destroy bacteria. and ampicillin are now among the drugs of As bacteria multiply and pass into the blood- choice for typhoid fever. stream, they are absorbed by white cells located Exposure to the typhoid bacillus appears to in the liver and spleen, but there, too, the bacilli confer some degree of immunity. However, the multiply and reenter the bloodstream. During immunity is relative, seeming to decay after this second period of bacteremia, the symptoms some years, and can be overcome by adminis- of typhoid begin. Lymph nodes in the small in- tration of sufficient bacilli. Nevertheless, a rel- testine become laden with bacilli, occasionally ative immunity is better than none, and at- to the extent that the tissues die, leading to in- tempts to induce it began almost as soon as testinal hemorrhage or perforation – the major the bacillus was isolated in the last decades of causes of mortality in typhoid. Delirium, heart the nineteenth century. Most vaccine trials in- inflammation, and shock may occur and are dicate a protective effect of about 75 percent. caused not by direct infection, but rather by tox- Although control of typhoid fever is best ac- ins released by the bacilli or by the white cells. complished with improvement of sanitary con- Over several weeks, the immune system rec- ditions, immunization may play an important ognizes the bacillus, and the host destroys the public-health role in developing countries. invader. If the disease is untreated, mortality ranges History between 10 and 20 percent; 1 in 5 persons ex- Typhoid fever has surely been a human dis- periences gastrointestinal hemorrhage, and 1 in ease since prehistory, but for ancient physicians 50 suffers perforation of the gut. Relapse occurs its nonspecific symptoms did not distinguish in about 10 percent of patients, usually after it from other illnesses. Hippocrates described a week free of illness, but symptoms are fre- a possible case of typhoid, and Augustus was quently milder and duration shorter than dur- cured of a typhoid-like fever by cold baths, a ing the original attack. remedy that persisted well into the twentieth In 1896, Fernand Widal determined that century. most persons develop O and H antibodies to Meaningful reports from ancient and me- S. typhi. Since then, the Widal test for antibod- dieval times are lacking. However, early ies in the blood has been used extensively to European mercantile and colonial enterprises

347 152. Typhoid Fever were clearly affected by typhoid epidemics. In thereafter it was isolated from blood and the early seventeenth century, 6,500 colonists stool. at Jamestown, Virginia, died most likely from Despite these rapid advances, therapeutic in- typhoid fever. About the same time, Belgian terventions against typhoid were lacking. Dur- anatomist Adriaan van den Spieghel (Spigelius) ing the Spanish-American War of 1898, one- described lesions in lymphoid tissue of the small fifth of the American army contracted typhoid intestine, the first report of the characteris- fever, with a mortality rate six times the num- tic findings of typhoid. Later, British physician ber of combat deaths. About this time in Thomas Willis cataloged the course of what England, Almroth Wright developed a vaccine he called “putrid malignant fever,” which was that reduced attacks among Indian soldiers by clearly typhoid. 75 percent. Despite these impressive results, the In the eighteenth century, Franc¸ois Boissier vaccine was little used 2 years later in the Boer de Sauvages of France consolidated several War, and the disastrous experience of the Amer- ailments (including Willis’s putrid malignant ican army was virtually repeated among British fever) under the rubric typhus. In the 1830s, troops in South Africa. Pierre Louis, dissatisfied with the “typhus” con- Early in the twentieth century, both British cept, proposed isolating a particular symptom and American forces ordered mandatory ty- cluster under the name “typhoid” (typhus-like) phoid immunization and better sanitation. The fever. Later, William Gerhard in Philadelphia es- effect a decade later was dramatic: During World tablished typhoid fever as an entity indepen- War I, the typhoid rate was reduced from 1:5 to dent of typhus. In the 1840s, the Englishman 1:2,000. Since then, typhoid has been insignifi- William Budd virtually inaugurated the science cant in armed conflicts. of epidemiology by demonstrating that typhoid In 1906, New York sanitary engineer George spread from infected individuals to new hosts Soper investigated an outbreak of typhoid in through water and food. Unfortunately, Budd Oyster Bay, a well-to-do town where the disease was actively opposed, and little came of his was unknown. Yet 6 of 11 people in one house public-health recommendations. As a result, the had become ill. Soper determined that 3 weeks annual incidence in Europe at that time re- earlier a new cook had been hired but had left mained as high as 1 per 200 persons. after the first persons began falling ill. Her name, Finally, however, in 1875, the British Public Mary Mallon, was destined to become inextrica- Health Act was passed, radically improving san- bly linked with typhoid fever. itary practices. Within a decade, typhoid mor- Koch had proposed that a person might tality was cut in half. Other developed nations chronically shed the typhoid bacillus and thus enacted sanitary laws of their own. Since then, infect others yet remain unaffected by the typhoid incidence in the developed world has disease–ahypothesis doubted by many. Soper, steadily declined. however, realized that the perplexing cases in This profound revolution in public health be- Oyster Bay might be explained if the cook were gan before the microbial etiologies of any dis- a carrier. He discovered that over 10 years, in- eases were established. Yet just 2 years after explicable typhoid outbreaks had occurred in the Public Health Act was passed in England, seven of the eight families for whom Mary the German Robert Koch demonstrated that a Mallon had worked. A year later, Soper located microorganism caused anthrax, and 3 years her working once again in a house stricken later his countrymen Carl Eberth and Edwin with typhoid fever. Mallon was removed against Klebs identified the typhoid bacillus. The next her will to a hospital, where culture of her 2 decades saw an explosion of knowledge about stool proved that she was indeed shedding the organism, and in 1884 Georg Gaffky cul- S. typhi in great numbers. After a 3-year de- tured the bacillus from lymph nodes. Shortly tention on North Brother Island in Long Island

348 153. Typhomalarial Fever

Sound (which raised many civil-liberty ques- Midwest, and western regions of the country tions), she was released with the proviso that as well as in the minds of military and other she never again handle food. Five years later, European physicians practicing in unsanitary, however, she was identified as the source of malarious regions of the globe, particularly the an epidemic at Women’s Hospital in Manhattan. Mediterranean, British India, and some areas She was arrested and spent the rest of her life of China. It was primarily an Anglo-American on North Brother Island. “Typhoid Mary” had es- phenomenon, although some reports from tablished beyond scientific doubt that a carrier southern Europe indicate that the possibility of state existed in typhoid. the diagnosis was at least considered. The 1948 discovery of antibiotics against Typhomalarial fever was generally regarded S. typhi converted typhoid from a rare but as a noncontagious, infectious disease resulting dreaded disease to just a rare one in the devel- from exposure to atmospheric or environmental oped world. Despite the advances of the past infections or toxins that caused malarial fevers century, however, on a global scale little evi- and typhoid fevers. Most commonly, patients dence indicates that typhoid is fading into ob- were previously debilitated, or their vital pow- scurity. Although inexpensive vaccines make ers were depressed in some way. In Woodward’s typhoid control affordable for nations with lim- classic formulation, this was the result of the ited resources, the huge reservoir of carriers and depression produced by army camp life and the continuation of poor sanitation in endemic malnutrition – particularly incipient scurvy. areas suggest that some time must pass before The disease required an area of endemic developing nations can significantly reduce ty- malarial fever, frequently a marsh, into which phoid fever. the animal causes of typhoid fevers – crowd- Charles W. LeBaron and David N. Taylor ing and improper sanitation – intruded. The debilitated individual in such an environment was almost sure to contract typhomalarial fever. 153. Typhomalarial Fever The clinical course of the disease was ex- tremely varied, depending on whether the Typhomalarial fever as a specific disease is malarial or typhoid elements predominated. not recognized by medical authorities today, When the malarial element was dominant, but in the last half of the nineteenth cen- the symptoms were those of periodic fever – tury it was a frequently useful diagnostic cat- usually of the remittent rather than the in- egory of diverse and often imprecise meaning. termittent variety. It was frequently quotidian Joseph Woodward defined the term during but could be tertian, quartan, or irregularly the American Civil War for those camp dis- remittent. However, the patient was more than eases “in which the malarial and typhoid ele- usually depressed; there were frequent central ments are variously combined with each other nervous system symptoms, commonly stupor and with the scorbutic taint.” Woodward con- or coma, as well as gastrointestinal complaints, sidered the disease distinct, both clinically most commonly diarrhea. The disease had and at postmortem, from malarial fevers and more rapid onset than classic typhoid fever, but typhoid fevers. if the typhoid elements dominated, the disease would clinically resemble typhoid fever except Characteristics for a definite periodicity, frequent hepatic ten- William Osler once wrote that typhomalarial derness, and a greater degree of splenomegaly, fever existed “in the minds of doctors but not often with pain on palpitation. Convales- in the bodies of patients.” If so, it existed in the cence was more rapid than typical typhoid minds of many American doctors in the South, fever.

349 153. Typhomalarial Fever

History tinued fevers were more variable: Some were of Woodward’s concept was born of the frus- short duration and only an inconvenience to the trations of mid-nineteenth century medicine, patient, whereas others were long and grave of particularly in America. At the beginning of the prognosis. Continued fevers with coma or stu- nineteenth century, diagnosis was based almost por and of severe aspect were frequently called entirely on patient descriptions of complaints – typhus by the Anglo-American medical world that is, the perceived functional derangements of the late eighteenth century. The adjective “ty- that resulted in consultation with the physi- phoid” was applied to fevers that were typhus- cian. The physicians placed these complaints in like but not true typhus. the context of their own experience and knowl- During the first half of the nineteenth cen- edge, made diagnoses, and offered patients their tury, a group of research-oriented, urban- professional advice. Diseases were collections of hospital-based physicians began to define symptoms appearing in known orders in partic- disease on the basis of the postmortem find- ular locations; adjectives were frequently part ings as correlated with the clinical course. This of a diagnosis, providing further refinement to hospital-based medicine was most strongly as- a relatively limited array of disease nouns. sociated with the pathologists of Paris, particu- The most common disease was “fever,” of larly Rene´ Laennec, Jean Corvisart, and Pierre which fever was the chief symptom. The fever Louis. In Britain, Irish clinicians William Stokes symptom was essentially the subjective sensa- and Robert Graves and London physicians tion of chill and heat and was related by the Richard Bright, Thomas Addison, and Thomas medical profession to a quickened pulse. Ele- Hodgkins were part of the same movement. This vated body temperature was related to fever approach to medicine spread through the world but was not objectively measured by most but did not fully replace the purely clinical ap- physicians until the last third of the nine- proach, particularly among those whose chief teenth century. If a cause of fever was ob- interests were in medical practice. In 1829, Louis served – particularly an inflammation – then the described a specific fever with lesions of “Peyer’s fever was symptomatic. Both pneumonia and patches” of the small bowel and named it “ty- erysipelas were associated with symptomatic phoid” because he thought it was the disease fevers. Without an observed cause of fever, then British authorities of the previous generation the fever was essential – that is, a disease itself. had called “typhus.” This is, of course, the dis- Essential fevers were categorized by symptom ease known today as typhoid fever. variation, severity, location, pathological associ- All of this nosographic confusion was re- ations, and so forth. flected in North American medical literature. The two main categories were periodic fever Daniel Drake, the great medical geographer and continued fever, but they were also cat- of the interior valley of North America, wrote egorized by terms such as malignant, perni- about the typhoid stage of “autumnal fever,” cious, epidemic, putrid, spotted, and bilious, by which he probably meant what we might based on the understandings of the physician call pernicious malaria. Louis’s American stu- observing a particular case. Periodic fevers – dents brought his view of typhoid to Amer- intermittent and remittent fevers, which had ica, and one of them, James Jackson, demon- a classic periodicity – were believed to be strated that what was commonly called “autum- caused by atmospheric contamination of veg- nal fever” in New England was the same disease etable decomposition associated with marshes Louis called typhoid. Another student of Louis, and other well-recognized areas of periodic William Gerhard, proved that the disease his fever endemicity. During the nineteenth cen- mentor had termed typhoid was distinct from tury, this poison came to be called malaria, and the disease usually called “autumnal fever” in the fevers it caused were “malarial” fevers. Con- Philadelphia.

350 153. Typhomalarial Fever

Based largely on his New England practice these doubts increased, but so did the utiliza- and experience, Elisha Bartlett described ty- tion of the diagnosis. By the late 1870s, the phoid fever as the most common disease in the specificity, in pathological terms, of typhomalar- United States. By 1847,however, he realized that ial fever was an idea of the past, but the clinical malarial fevers were the dominant concern of reality remained, and the name seemed to ex- physicians in the South and Midwest, but not plain the etiology of the symptom complexities enough people learned of the revised opinion. so described. Support for almost any interpretation could be For the same reasons, physicians in other found in the medical literature of the period. parts of the world began seriously to con- In the 1850s, as the American South became sider the American diagnosis in the 1870s. In increasingly isolated culturally, there arose a the 1860s, British army surgeons stationed on campaign for a distinctively southern medicine. Malta had identified a new disease originally In part, this desire reflected real geographic dif- called gastric remittent fever and later “Malta ferences in disease, but in part it was a result fever.” We know it today as brucellosis.In1875, of the increasingly strident southern national- W. Maclean suggested that Malta fever might ism that led to the Civil War. As a result of this be typhomalarial fever. James Donaldson, on the campaign and the preexisting nosological con- other hand, suggested the name “faeco-malarial fusion, there was, by 1860, a belief in a “south- fever” to reflect more accurately the current un- ern typhoid fever” that was occasionally peri- derstanding of dual causes. By the 1870s, the odic and frequently cured by quinine therapy. special role of human fecal matter in the propa- Etiologic theories of the mid-nineteenth cen- gation of typhoid fever was becoming accepted tury also contributed to the confusion. Urban in Britain, largely because of the work of Charles diseases, like typhus and typhoid, were believed Murchison and William Budd. Similar new dis- to be the result of the unsanitary conditions of eases reported by British doctors overseas were life in the early industrial city. Crowding, gen- also considered typhomalarial fever by some eral lack of cleanliness, and a combination of an- authorities. imal and human waste gave rise to a distinct and In the 1880s, miasmatic etiologic specula- unpleasant odor in the cities. Where the smell tions began to give way to the new germ was worst was also frequently the area of great- theory of disease based in medical microbiol- est morbidity, and it was believed that some an- ogy. Alphonse Laveran observed the malaria imal miasmas caused urban fevers, much like plasmodium; Georg Gaffky isolated Salmonella the marsh miasmas (malaria) that caused ru- typhi. David Bruce discovered an organism that ral fevers. If the two causes were simultane- caused Malta fever; he called it Micrococcus ously present, a combined or composite disease melitensis, but the genus was subsequently state should be expected. In the camps of the named Brucella. However, germ theory and Civil War, that is exactly what was experienced, medical microbiology were not immediately ac- and typhomalarial fever was the name officially cepted by all or even most practitioners. De- sanctioned for the camp disease that was not bate on typhomalaria remained lively, partic- obviously a malarial or typhoid fever. ularly in American medical literature. Leading During and immediately after the war, an era physicians saw etiologic research and eventual when disease theory was changing and the di- etiologic definition of disease as the way to agnostic precision of the profession was limited, resolve clinical difficulties, but microbiological physicians found the concept of typhomalarial techniques remained largely in the realm of ex- fever to be very useful and flexible in diagnosis. perimental pathology, not yet overly useful to There were, however, serious doubts on the part practitioners. The possibility of specific diseases of leading medical theorists concerning the spe- similar to typhoid and malaria yet etiologically cific nature of typhomalarial fever. In the 1870s, unique remained viable, but the profession was

351 154. Typhus, Epidemic divided on how prevalent such diseases might ing “spotted fever,” Fleckfieber and typhus ex- be. “Periodic typhoid” and “severe malaria” were anthematicus in German, typhus exanthematique´ clinically real and needed names. Debate con- in French, tifo exantematico´ and tabardillo in tinued, but the terms were changing. Spanish, and typhus-esantematico in Italian. In the 1890s, progress in medical microbiol- Hippocrates applied the word “typhus” (from ogy and the development of serum diagnostic Greek “smoky” or “hazy”) to confused or stu- tests for typhoid and Malta fevers made etio- porous states of mind associated with high logic definitions of disease more useful to prac- fevers, but the word was not associated with the titioners, and doubts increased about the utility disease under discussion until the eighteenth of typhomalarial fever as a diagnosis. century. After murine typhus was identified, When America mobilized volunteers for the the appellation typhus historique was some- war with Spain in 1898, sanitation in the camps times applied to the classic epidemic disease. was very bad. Disease was widespread and Army Surgeon General George Sternberg appointed Characteristics a commission of experts composed of Walter Occurring naturally only in humans, epidemic Reed, Victor Vaughan, and E. Shakespeare to in- typhus is caused by Rickettsia prowazekii.Itis vestigate. Using modern techniques, the com- spread by the human body louse (Pediculus hu- mission proved that most of the cases diagnosed manus corporis) and less often by the human as typhomalarial fever were typhoid. Because head louse (P. humanus capitis). The body louse the conditions, particularly in camps in the spends its entire existence in the clothes of hu- Deep South, approximated those under which mans. Eggs laid in the seams of the undergar- Woodward had originally postulated the exis- ments hatch after about 8 days, and the nymphs tence of typhomalarial fever, these results were become adults in about 2 weeks, going through particularly significant. By the early twentieth three molts. Each louse takes 4–6 blood meals a century, the diagnosis of typhomalarial fever day from its host under natural conditions. Hu- was widely regarded as an admission of diag- man blood constitutes its only food. nostic failure, and slowly it vanished from the Typhus organisms in blood ingested by a medical literature. louse multiply rapidly in the louse’s intestines Dale Smith and are secreted in the feces of infected lice. Rickettsiae are transmitted to new hosts me- chanically, usually by contact of infected louse feces with skin abrasions incurred when the 154. Typhus, Epidemic human scratches the unpleasant itch caused by feeding lice. The disease spreads when lice Epidemic typhus is an acute rickettsial disease leave feverish or dead victims for new hosts with transmitted by lice. Characteristic symptoms in- normal temperatures. Unlike other rickettsiae, clude fever, prostration, aches, and a widespread R. prowazekii is not passed from generation to rash covering trunk and limbs. Mortality in un- generation in the eggs of its host arthropod. treated cases varies widely. Broad-spectrum an- Typhus is widely known as a disease of cold tibiotics provide effective therapy. climates, with epidemics that peak in late winter Associated with poor conditions, typhus has and taper off in spring. This pattern clearly re- had many names. “Jail distemper,” morbus flects favorable conditions for lice multiplica- carcerum, and “gaol fever” indicate its preva- tion and transmission. Typhus flourishes when lence in prisons. “Ship fever,” “camp fever,” and people crowd together in unsanitary surround- “famine fever” reflect the poor hygiene charac- ings and lack fuel, circumstances predisposing teristic of such circumstances. Typhus’s charac- them to wear the same garments day and night teristic rash has elicited other names, includ- for months. Persons of all ages are susceptible.

352 154. Typhus, Epidemic

Mortality in untreated cases varies between recrudescence of typhus in persons who had 5 and 25 percent, occasionally reaching 40 per- earlier suffered an attack. During the 1950s, in- cent. In children under 15, however, the dis- vestigations confirmed this, and the condition ease is generally mild. As age increases, so does was renamed Brill-Zinsser disease. mortality. After incubating from 5 to 15 days, onset of History typhus is abrupt. Many patients can state the ex- Although some have speculated that certain an- act hour their illness began. Headache, loss of cient plagues were probably typhus, the first appetite, and malaise are followed by rapidly ris- contemporary accounts of such a disease ap- ing fever. Chills, nausea, and prostration charac- peared during the late fifteenth century. In terize the first week. A widespread rash appears 1489–90 during the wars of Granada, physi- 4–6 days after onset. After recovery, the rash cians described a typhus-like disease that killed usually fades but in rare cases leaves a brown- 17,000 Spanish soldiers – six times the number ish stain that persists for several months. killed in combat with the Moors. During the first 2 or 3 days, the fever reaches In the early sixteenth century, a similar mal- ◦ ◦ its maximum, between 102 and 105 F, and ady appeared in Italy. During the French siege persists another 5 days, after which it falls of Naples in 1528, an apparent typhus epidemic rapidly. In fatal cases, however, prostration be- may have altered subsequent European history. comes more progressive, with increasing neu- The French were at the point of decisive victory rological symptoms including deafness, stupor, when the disease struck down 30,000 French delirium, and eventually coma preceding death. soldiers, forcing the remnants to withdraw. In Since broad-spectrum antibiotics were intro- 1546, Girolamo Fracastoro (Fracastorius), who duced, however, no one need die of typhus with had observed the epidemics in Italy, published timely diagnosis. the first clear description of what he termed a An attack of typhus confers long immunity. “lenticular or punctate or petechial” fever, also Many children in endemic regions may contract characterized by headache and general malaise. mild cases that protect them somewhat from In the Balkans, where European troops assem- later infection. Because R. prowazekii persists in bled to combat the Turks, many were struck its victims even after recovery, symptoms may by typhus even before they reached the battle- reappear years later, especially under condi- field. As it was disseminated across Europe by tions of stress, when a victim’s immune system forces returning from Hungary, typhus became is depressed. This phenomenon was noted in known as morbus hungaricus. Toward the end of 1898, when Nathan Brill described a disease fre- the sixteenth century, typhus was also recorded quently diagnosed as typhoid but having symp- in Mexico, where it killed over 2 million toms more closely related to typhus. In 1910, Amerindians. Whether the disease was brought Brill published an exhaustive study, which led to the New World by Spanish explorers or, as to the designation of Brill’s disease as a catchall some evidence indicates, was known to pre- for unknown, typhus-like symptoms. Two years Columbian Mexicans is unclear. later, U.S. Public Health Service investigators Typhus increased dramatically in the early John Anderson and Joseph Goldberger demon- nineteenth century. In 1812, Napoleon’s catas- strated reciprocal cross-immunity in monkeys trophic Russian expedition was plagued by ty- between Brill’s disease and epidemic typhus. phus. Between 1816 and 1819, a great epi- For the next two decades, because of igno- demic struck 700,000 people in Ireland. For rance surrounding rickettsial diseases, illnesses several decades, however, confusion character- exhibiting typhus-like symptoms were often ized medical understanding. By the late eigh- classified as Brill’s disease. But in 1934, Hans teenth century, medical nosologist Boissier de Zinsser hypothesized that Brill’s disease was a Sauvages had begun using the word “typhus”

353 154. Typhus, Epidemic to describe its neurological symptoms, but few Lima’s assertion that R. prowazekii caused attempted to distinguish between typhus and typhus. typhoid fever, which also produced a rash. Even During the 1920s and 1930s, research on into the twentieth century, confusion between a typhus vaccine was hampered because typhoid and typhus was perpetuated in the rickettsiae could not be grown in necessary nomenclature. quantities outside of living cells. Then in In 1837, William Gerhard, who had studied 1937, U.S. Public Health Service investigator the intestinal lesions of typhoid, noted their ab- Herald Cox discovered that rickettsiae grew in sence in typhus victims. Gerhard’s work, how- fertile egg yolksacs. This method made vaccine ever, was not immediately accepted. Not un- production commercially feasible just as the til mid-century were most American physicians onset of World War II again raised concern convinced that typhus and typhoid were dis- about large-scale epidemics. tinct disease entities. The threat of typhus was a key factor in Allied The European revolutions of 1848 spawned military plans, and in 1942 President Roosevelt typhus epidemics, as did warfare in Ethiopia. created the U.S. Typhus Commission to com- During a particularly severe outbreak in Sile- bat typhus wherever it might threaten military sia, German physician Rudolph Virchow ob- efforts. The so-called Cox vaccine was adminis- served that the disease afflicted the poor, tered to all Allied personnel and, although fail- the uneducated, and the unclean, and he ing to prevent the disease, clearly ameliorated called for democracy, education, and public- its course. Intensive research demonstrated that health measures as proper “treatment” for the lice could be controlled with dichlorodiphenyl- epidemic. trichloroethane (DDT), applied with a “blowing Although typhus subsided during the later machine” to puff it under clothes without the nineteenth century, the advent of the germ the- wearer having to remove them. DDT proved ory of disease spurred bacteriologists to search highly effective in the 1943–44 epidemic in for a microbial cause. In 1909, Charles Nicolle, Naples, where a nascent outbreak collapsed director of the Institut Pasteur in Tunis, demon- with astonishing rapidity. Within two decades, strated that the body louse was the vector. The however, adaptive resistance of lice to DDT was following year, Howard Ricketts described bac- documented. Moreover, its ecological hazards teria in the blood of typhus victims, in infected were found unacceptable, and it is no longer lice, and in lice feces. Before he could con- widely used. firm his observations, however, Ricketts con- Prophylaxis and control during World War II tracted and died of typhus. In 1916, Brazilian reduced typhus from a major threat to a mere Henrique da Rocha Lima described similar or- nuisance. Only 104 cases occurred among U.S. ganisms, which he named Rickettsia prowazekii military personnel, with no deaths. In contrast, after Ricketts and Stanislaus von Prowazek, who severe epidemics occurred in North Africa, had also died from a laboratory-acquired typhus Yugoslavia, German concentration camps, infection. Japan, and Korea. During World War I, the military on both In 1948, the broad-spectrum antibiotics were sides acted on Nicolle’s discovery, instituting discovered to be effective treatments for rick- delousing procedures including bathing and ettsial diseases. Since then, efforts against steam-treating clothing. Among poor Eastern typhus have depended on them almost ex- European populations, with no such preventive clusively. In 1980, concern about the lim- measures, the disease exacted high mortality. ited efficacy and side effects of the Cox In 1915, Serbia was particularly hard hit, and vaccine halted its production, and for now, Russia and Poland after 1918. Research in at least, no typhus vaccine is commercially Poland after World War I confirmed Rocha available.

354 156. Typhus, Scrub (Tsutsugamushi)

Since 1950, typhus has been reported most In guinea pigs, R. typhi causes a characteris- frequently from the horn of Africa, from tic reaction in scrotal cells useful for distin- the high plains of the Andes, and from the guishing between murine and epidemic typhus. Himalayan region – all areas characterized by First noticed in 1917 by Mather Neill and con- rural poverty and cold weather. Since identifi- firmed nearly two decades later by Mooser, the cation of the vector, the slogan of public-health reaction became known as the Neill-Mooser efforts against typhus has been “no lice, no phenomenon. typhus.” But as Zinsser has noted, typhus re- mains a threat, ready to break out whenever History war, famine, and other catastrophes remove the Although murine typhus was identified only barriers against it. during the twentieth century, it may be even Victoria A. Harden older than classic epidemic typhus. Neither the rat nor the rat flea suffers ill effects from the infection, whereas R. prowazekii inevitably kills 155. Typhus, Murine its vector louse and causes serious illness in its human host. Murine typhus is an acute illness characterized Sporadic cases of typhus-like fevers in ar- by symptoms similar to those of epidemic ty- eas free from lice were reported early in the phus but milder in character. Unlike its epi- twentieth century in the United States, Malaya, demic relative, it is a natural infection of rats and Australia. Often these infections were desig- and transmitted sporadically to humans by the nated by local names, such as “urban” or “shop” rat flea, Xenopsylla cheopis. Its relation to the rat typhus. Not until 1926, however, was the dis- is reflected in the name “murine” typhus. The tinctiveness of this disease recognized. Investi- etiologic agent is Rickettsia typhi. gating such cases in the southeastern United States, Kenneth Maxcy described an endemic Characteristics form of typhus fever and postulated that some Symptoms and course of illness in murine ty- ectoparasite of the rat was its vector. By 1931, phus are similar to those in epidemic, louse- infected fleas had been found in nature, con- borne typhus; thus, distinguishing the two has firming Maxcy’s hypothesis. Although the name been difficult. The flea-borne illness, however, endemic typhus was used for some time, it was is almost never fatal, with about 2 percent mor- observed that the disease could occur in epi- tality in persons over 50. demics as well as sporadically. In 1932, Mooser Murine typhus is found worldwide. Peo- proposed the name “murine typhus” to indicate ple living or working in areas where rats are its relationship to rats. abundant are most susceptible. Like epidemic Although broad-spectrum antibiotics provide typhus, murine typhus is transmitted mechani- effective treatment against the disease, its mild cally, through rubbing infected flea feces into a course and low fatality rate make these mea- skin abrasion, through the eye, or through mu- sures almost unnecessary. By the time it is diag- cous membranes of the respiratory tract. Follow- nosed, the patient is usually in convalescence. ing World War II, campaigns against rats and Victoria A. Harden their fleas with DDT and rodenticides sharply reduced the incidence of murine typhus in the United States. Some investigators prefer the name Rickettsia 156. Typhus, Scrub (Tsutsugamushi) mooseri (over R. typhi ) to honor Swiss pathol- ogist Herman Mooser, who differentiated be- In 1810, Hakuju Hashimoto described a tsut- tween this organism and Rickettsia prowazekii. suga (disease) along the Shinano River. A similar

355 156. Typhus, Scrub (Tsutsugamushi) disease, thought to be carried by mites (mushi ) toms. Those who die usually do so by the end had been known at least since the sixteenth of the second week from circulatory failure, century in China. Sometimes called “Japanese secondary pneumonia, or encephalitis. Even flood fever,” tsutsugamushi is more commonly in recovered patients, neurological effects may known in the United States as scrub typhus – continue, and convalescence is usually long. a name widely used during World War II. The Fortunately, broad-spectrum antibiotics have disease exhibits typhus-like symptoms of fever, reduced mortality in treated patients to nearly headache, and rash. zero.

Characteristics History The geography of tsutsugamushi is defined by Bacteriologic investigations of tsutsugamushi the range of its vectors, which extend from India began in Japan in the 1890s. Various researchers and Pakistan to Japan and northern Australia, studied the disease through the first three including all of Southeast Asia, southern China, decades of the twentieth century, identifying its Korea, the Philippines, and Indonesia, as well causative microbe as a rickettsia. as additional islands. During World War II, inci- Renewed investigation was stimulated by dence of scrub typhus among troops was high, outbreaks in the Pacific and East Asia during reaching 900 per 1,000 in some areas. It remains World War II. With Allied countermoves to a problem in isolated rural areas. stem the Japanese advance, the occupation of The agent of scrub typhus, Rickettsia tsutsuga- islands often took place in haste, and troops mushi, is a natural infection of its several vector would shortly become quite ill. From 1943 mites, most commonly Leototrombidium delien- until war’s end, scrub typhus disabled some sis. Maintained in nature by generational trans- 18,000 Allied troops, including 6,685 American mission in mite eggs, the disease is communi- servicemen. Mortality varied from a low of cated to humans only during the larval stage 0.6 percent in some regions to as high as 35 of the mite’s life cycle. The six-legged larva, of- percent in others; 234 deaths occurred among ten called a “chigger,” seeks to feed on tissue U.S. troops. juices or lymph, usually from mice, rats, shrews, Throughout the 1920s and 1930s, British re- and other small mammals, but humans are sat- searchers had observed that tsutsugamushi was isfactory if they happen into the mite’s envi- distinguished from other typhus-like diseases ronment. Ground-frequenting birds may also by its reaction to a particular bacterial strain in become infected and transport mites to a new the Weil-Felix test. When the U.S. Typhus Com- location. mission began to study scrub typhus, this test Scrub typhus incubates 10–12 days, after was virtually the only laboratory tool available. which it manifests itself suddenly, with chills The army launched education efforts, including and fever, headache, and other typhus-like posters describing the mite, where it was likely symptoms. During the first week, fever increases to be found, and how soldiers should prepare ◦ to about 105 F. Between the fifth and eighth their campsites to avoid it. In addition, chemi- days, a macular rash appears on the trunk cals were developed to impregnate clothing that and may extend to arms and legs. During the would repel the tsutsugamushi mite. Benzyl ben- second week, the pulse may increase, blood zoate proved to be effective and lasted 2 weeks pressure falls, and neurological symptoms such before reapplication was necessary. Researchers as deafness, stupor, delirium, and twitching also focused on developing a vaccine against may appear in untreated patients. Pneumonia tsutsugamushi. Then, in 1948, broad-spectrum and signs of circulatory failure may also oc- antibiotics were found to be highly effective as cur, but by the beginning of the third week, treatment. those who recover experience reduced symp- Victoria A. Harden

356 157. Urolithiasis

157. Urolithiasis creased intake of refined sugar plus decreased intake of fiber increase intestinal absorption The major forms of urolithiasis consist of of calcium. Increased protein and sucrose in- upper-tract stones within kidneys or ureters (re- take cause increased urinary-calcium excretion. nal stones) or lower-tract stones formed within This sets the stage for calcium-phosphate- or the bladder. These two forms of urolithiasis calcium-oxalate-stone formation in the kidneys. have distinct differences and are considered Other less common renal stones have spe- separately. cific etiologies, and a multitude of other fac- Historical evidence exhibits a striking in- tors also operate in renal-stone formation or crease in renal-stone disease in developed prevention. countries over the past century. A simultane- Ancient physicians observed the frequent oc- ous decrease in bladder-stone disease has oc- currence of bladder stone in young boys, and it curred, demonstrating an inverse relationship still primarily affects boys under 10 years. Nu- between them. Changes in environment af- merous studies confirm the early age of occur- fect disease epidemiology, which is exempli- rence and the marked predominance of male pa- fied by the role of dietary change in the shift- tients. Anatomic differences between males and ing pattern from bladder-stone to renal-stone females probably account for the infrequency disease. of bladder stone in females. The female urethra is short, wide, and straight, allowing stronger Characteristics flow of urine and passage of gravel before large Most bladder stones occur in young boys from stones are formed. rural or impoverished areas, where the disor- Bladder-stone disease occurs in agricultural der is termed endemic bladder-stone disease. regions, particularly among lower economic A nutritional deficiency during infancy or pos- classes. Historical accounts from the 1500s to sibly in utero appears to be the major factor. the mid-1800s document the disease through- Other causes are schistosomiasis and, in el- out Europe, Asia, and the Americas. Bladder derly males, obstruction from benign prostatic stone remains common in Egypt, India, China, hypertrophy. Thailand, Afghanistan, Iraq, Turkey, and Mada- Although deficiencies of vitamin A, vita- gascar. Prior to 1940, it was also common in min B6, or magnesium have been suggested portions of Iceland, Russia, Hungary, Indonesia, in endemic bladder-stone disease, low intake Tunisia, and Sicily. of animal protein combined with high intake Renal-stone disease has mainly afflicted the of grain carbohydrate is more important. In- industrialized, affluent countries of Europe, deed, it seems that whereas low animal-protein North America, and Japan and has been uncom- intake in infancy may cause bladder stone, a mon or unknown in impoverished regions and high animal-protein diet provokes renal stones. primitive societies. However, people in such ar- This probably explains the enigma of disappear- eas have developed similar prevalence with im- ing endemic bladder stone as areas improved provement in living conditions and subsequent economically, with concomitant increasing in- dietary changes. cidence of renal stone. Studies in North America and Europe show Low intake of animal protein and high in- prevalence rates of renal stone up to 13 per- take of grain carbohydrate produce more acidic cent. Nearly 75 percent of people with so-called urine and decreased urinary phosphate. These idiopathic calcium-stone disease have recur- in turn decrease the solubility of calcium ox- rences, implying a continuous exposure to risk alate and uric acid, leading to bladder-stone factors such as diet. Incidence has risen con- formation. Conversely, greater animal-protein tinuously since the turn of the twentieth cen- intake produces more urinary phosphate. In- tury except for brief declines during both world

357 157. Urolithiasis wars – again suggesting dietary changes as a fac- numerous prescriptions are two for flushing out tor. Unlike bladder-stone disease, renal stones or dissolving renal stones; one contains 50 in- occur predominantly in adults. Men are affected gredients with particular emphasis on camphor slightly more often than women. and vinegar. Other Assyrian works include di- rections for infusing various preparations into the bladder through a bronze tube to dissolve History bladder stones. Bladder stone is a disease of communities where In Alexandria around 100 B.C., Ammonios diets are high in grain and low in animal protein. developed an instrument for crushing stones With dietary changes resulting from technol- within the bladder. In the first century A.D., ogy, migration, or cultural shift, bladder-stone Rufus gave detailed instructions for removing disease is replaced by renal-stone disease. This bladder stones through a transverse perineal is well demonstrated over the past two centuries incision. in Europe, Russia, China, and Turkey. It is there- In Rome during the same century, Celsus fore not surprising that ancient references are performed numerous operations for bladder almost entirely to bladder stone, with rare men- stone in boys 9–14 years of age. His writ- tion of upper-tract stones. ings contain a description of transverse per- Bladder stone was common in ancient Per- ineal lithotomy followed almost without mod- sia, particularly in infants, and was consid- ification until the sixteenth century. Galen de- ered a result of ingesting sour milk, fruits, or scribed lateral perineal lithotomy and noted the acidic drinks. The Babylonian Talmud refers to frequent occurrence of bladder stone in young bladder-stone disease and includes the sugges- boys. He also administered stone solvents (litho- tion that patients urinate on the doorstep in or- tryptics). der to see the stone. In Arabic medicine, Rhazes at about the turn In India, the Rig Veda and Atharva Veda (c. of the tenth century described both renal and 1500 B.C.) consist of incantations against dis- bladder stones and implicated salt intake and ease, including bladder stone. The Ayur Veda, hot weather as factors in renal stone forma- composed about the first century A.D., de- tion. Around a century later, Avicenna thought scribed suprapubic incision for removing blad- that bladder stones formed when the urine con- der stones. In the second century, Charaka de- tained excess matter. scribed four types of stones almost certainly By the eighteenth century, surgeons were in- from the bladder. creasingly attempting the dangerous lateral per- In China, case histories of 25 patients treated ineal lithotomy. Special hospitals for bladder- by Shunyu¨ I in the second century B.C. stone patients opened in England, France, have been preserved, including one afflicted Holland, and elsewhere. In 1753, Frere` Come with hematuria, urinary retention, and bladder opened such a hospital in Paris, operating on stones. This may represent a case of either schis- more than 1,000 patients. The Norfolk and Nor- tosomiasis or endemic stone disease. wich Hospital was founded in 1771, and one of In Greece, Hippocrates recognized both renal every 55 admissions was for removal of bladder and bladder stone and recommended diuret- stone. ics and large quantities of water. He considered Through paleopathology and careful archae- wounds of the bladder wall as invariably fatal ological techniques, renal and bladder stones and specifically forbade his followers to cut for have been recovered from skeletal and mummi- the stone. fied remains, testimony to the antiquity of these The Assyrian Book of Medicine (c. 300 B.C.) in- diseases. cludes much of Hippocrates’s teaching. Among R. Ted Steinbock

358 158. Varicella-Zoster Virus Disease (Chickenpox)

158. Varicella-Zoster Virus Disease sions on the extremities. Vesicles may appear (Chickenpox) in the mouth, and laryngeal involvement may cause dyspnea. Chickenpox is a benign disease Varicella or chickenpox is an acute infection in children unless they suffer from leukemia of short duration caused by varicella-zoster or are taking corticosteroids. Other than acute virus (VZV), spread in early stages by droplets encephalitis, an occasional circumstance late in from the nasopharynx. It is followed by lifetime the disease, complications have rarely been re- latency – broken in occasional patients by re- ported. In adults, varicella tends to be less be- activation of virus in sensory ganglia, which is nign, and pulmonary infiltrates are commonly manifested as herpes zoster or shingles. noted. An attack of herpes zoster may begin with Characteristics fever, chills, malaise, and gastrointestinal symp- Chickenpox is endemic worldwide, highly toms. With or without prodromal symptoms, communicable, and commonly appears as the patient becomes aware of pain, at times epidemics among children, who are usually at- with itching, in the area of the affected seg- tacked between ages 2 and 8. Infants are pro- mental nerves. After several days, crops of vesi- tected by transplacental maternal antibodies. cles on an erythematous base appear in the dis- Few escape infection until adulthood, and these tribution of nerves of one or several posterior usually live in isolated communities. Probably root ganglia, usually accompanied by hyperes- most of those who have seemed to escape the thesia and pain. The vesicles dry and become disease had subclinical infections. crusted in about a week, although the course Sporadic reactivation of the virus as shingles may be slower in aged persons. Hyperesthesia is unrelated to exposure to exogenous infection or pain may last for weeks and months, espe- and, in general, is uncommon even in popula- cially in patients with malignant disease. In an tions in which practically all have had chicken- occasional aged patient, these residua never dis- pox. Its peak incidence is after age 50. Of those appear. Herpes of the ophthalmic branch of the who develop shingles, only 1 percent have two trigeminal nerve is not uncommon and may attacks. Patients with impaired cellular immu- be accompanied by keratoconjunctivitis, which nity are at risk, and herpes zoster is not uncom- may be followed by serious corneal scarring and mon in those suffering from malignant disease. glaucoma. Zoster of the geniculate ganglion Although immunity is lifelong, it has been sug- produces Ramsey Hunt’s syndrome. The char- gested that a waning of immunity in older age acteristic pain syndrome of zoster may run its explains shingles. course without skin eruption. After an incubation period of 10–20 days, and some 24 hours before the varicella rash appears, History the prodromes of mild headache, malaise, and Italian physician Giovanni Ingrassia is cred- moderate fever appear. Because these are com- ited with differentiating chickenpox from scar- monly unrecognized in children, the rash seem- let fever in 1553, and English physician William ingly is the initial evidence of disease. It appears Heberden gave the earliest clear description of as a cutaneous blush, with the development of varicella and distinguished it from smallpox successive crops of macules, papules, and super- in 1768. Jean Alibert in 1832 included vari- ficial vesicles surrounded by a red areola, which cella in his Group II category of exanthema- begin crusting within 24 hours. The acute phase tous dermatoses – acute febrile contagious dis- lasts about a week. eases. In the early twentieth century, American Although the rash may be generalized, it usu- researchers described cellular inclusion bodies ally involves the trunk and face, with fewer le- and isolated the virus.

359 159. Whooping Cough

P. Rayer in 1845 described the microscopic Although among the more important child- contents of zoster vesicles and the underlying hood diseases, whooping cough has been skin. In the 1860s, F. von Barensprung¨ con- relatively neglected, and various aspects of its cluded that zoster was a disease of the poste- epidemiology are not fully understood. Trans- rior roots. In subsequent years, several reports mission seems to be mainly airborne, appar- described herpes zoster with postmortem find- ently by droplet infection. Humans are the only ings of inflammation of posterior root ganglia. reservoir of the disease; B. pertussis cannot sur- Barensprung’s¨ suspicion that the Gasserian gan- vive long outside the host, and quickly suc- glion was affected in herpes zoster of the face cumbs to drying, ultraviolet light, and temper- ◦ ◦ was confirmed by O. Wyss in 1872. A. Camp- atures above 120 –130 F. It spreads primarily bell and Henry Head in 1900 established that through household and schoolroom contact, al- herpes zoster results from hemorrhagic inflam- though mild subclinical cases, perhaps in ado- mation of the posterior nerve roots and homol- lescents and adults, may play a further role in ogous cranial ganglia. In 1925, Karl Kundratitz transmission. One attack confers immunity, and described inoculation of susceptible children rare second attacks are probably explained by with zoster vesicle fluid, resulting in varicella. infection with the milder and rarer Bordetella R. H. Kampmeier parapertussis. An incubation period of 7–10 days is followed by an initial catarrhal stage lasting 1–2 weeks. During this phase, the disease is highly commu- 159. Whooping Cough nicable, but the symptoms are nonspecific and resemble many other infectious diseases and Whooping cough, otherwise known as pertus- minor respiratory ailments. An increasingly per- sis, after the causative bacillus Bordetella pertus- sistent cough develops, which in the third stage sis, is an infectious disease of childhood. Affect- becomes more severe and spasmodic, terminat- ing the respiratory tract, it is characterized by ing in the characteristic whoop. In acute cases, paroxysms of coughing, culminating in the pro- paroxysms may occur 40–50 times in 24 hours. longed inspiration that provided its name. Be- The whoop is frequently followed by vomit- fore the twentieth century, the popular name ing. In young infants, who are unable to pro- was generally spelled without the initial “w”; in- duce the whoop and resume effective breathing deed, it was not in general use until the end quickly, episodes of cyanosis follow paroxysms. of the eighteenth century. Until the early nine- The acute stage lasts up to 4 weeks, but parox- teenth century, the commonest appellation was ysms may continue for 3 months or longer. chincough. The term “pertussis” was first used The patient is considered convalescent when by Thomas Sydenham in the latter seventeenth vomiting ceases and severity of the paroxysms century. diminishes. Complications include collapsed lungs, anoxic convulsions, and exhaustion; sec- Characteristics ondary bacterial infections may cause otitis me- The distribution of whooping cough is world- dia or pneumonia. Bronchiectasis has become wide. It is generally an endemic disease that rare since the introduction of antimicrobial erupts in sporadic epidemics but in most devel- agents. oped countries has been controlled by immu- nization programs. Of clinical cases, 80 percent History occur in the under-10 age group, and unlike The history of whooping cough before the twen- most communicable diseases, whooping cough tieth century is obscure. It cannot with certainty develops in females more often than males. be traced back further than the mid-sixteenth

360 159. Whooping Cough century and was almost certainly unknown to oped countries today, hospital case-fatality rates the ancient world. Although the term “chin- are about 15 percent. cough” was current in the early sixteenth cen- Although the infectious character of whoop- tury, the first medical description of the dis- ing cough was appreciated from at least the ease dates from 1578, when Guillaume Baillou early eighteenth century, the nature of the clin- observed a severe epidemic in Paris. He wrote ical disease was a matter of debate. Both Willis of it as a familiar affliction, for which there and Sydenham, for example, thought the dis- seemed to be several names already. More- ease seated chiefly in the chest, whereas William over, it was apparently the subject of medical Harvey and his followers held it to be in the discussion. stomach and the alimentary canal. Not until Nonetheless, the prevalence of the disease re- Robert Watt, stimulated by the deaths of two of mains largely obscure until the mid-eighteenth his children from the disease, undertook a se- century. August Hirsch in 1886 suggested that ries of dissections in 1812–13 did the involve- the native habitat of the disease was originally ment of the respiratory tract become clear. Med- northern Europe. But widespread folklore re- ical interest in the disease during the nineteenth garding its treatment may indicate a more an- century was minimal until discussion about pre- cient existence in places such as southern India vention began in the 1880s. and Malabar. In London during the nineteenth century, the Thomas Willis in 1675 described chincough highest whooping cough mortality was among as an epidemic disease of infants and children, children of the working classes; death generally usually occurring during summer and autumn. resulted from complications involving the respi- In his view, the cough, although difficult to cure, ratory organs. The disease was made notifiable was rarely fatal or dangerous. in the United States in 1922, but not until some- By contrast, his contemporary, Sydenham, what later in Britain. thought it so formidable as to require the most Mortality and morbidity from whooping rigorous treatment. The earliest statistics re- cough declined greatly in developed countries garded as in any way reliable come from mid- during the twentieth century. The causative or- eighteenth century Sweden, where Nils von ganism was first isolated by Jules Bordet and Rosenstein described it as a familiar epidemic Octave Gengou in 1900 but was not grown in disease of variable fatality. The terms “whoop- vitro until 1906, when its morphology and cul- ing cough” and “chincough” first appear as tural characteristics were established. Vaccines causes of death in London in 1701, and an in- against the disease were first introduced in the creasing number of deaths were attributed to 1930s and were in widespread use by the latter them. 1940s. With the introduction of civil registration In the latter twentieth century, increasing of deaths in 1838, English mortality figures public awareness of possible complications became more reliable. Deaths from whooping from whooping cough vaccine was stimulated cough peaked at some 1,500 per million popu- by a relatively small number of cases in which lation under age 15 annually around 1870, after the vaccine supposedly caused brain damage which the rate began to decline. This was first in children. Consequently, during the 1970s manifest in agricultural regions, whereas in ur- vaccination rates fell off in both Britain and ban and industrial areas the death rates were Japan, where immunization was voluntary. In slower to fall. During the 1880s, case fatality, so both countries, the disease began to increase in far as can be ascertained, stood at 10 percent, prevalence, and epidemic outbreaks in 1978 and compared to 1.1 percent during World War II, 1982 were similar in scale to those of the 1950s, and 0.1 percent in recent years. In underdevel- when the immunization program was new.

361 160. Yaws

Afterward, intensive publicity concerning the present in many populations where previously benefits of vaccination caused immunization it was a serious health threat. Before the mid- rates to rise again. twentieth century, however, there were proba- Anne Hardy bly some 50 million yaws cases in the world. In the 1940s and early 1950s, estimates of yaws prevalence were made in various ar- eas of the world, partly for use by yaws- 160. Yaws eradication programs. Although regional fig- ures have dropped radically, it is pertinent to This disease has suffered from confusing de- the history of the subject to note the extent of scriptions. It is now generally called yaws, al- the previous evidence, and the variation found. though the term framboesia is still in use. In most of the New World, although yaws was Primary, secondary, and tertiary stages of the probably introduced by slaves centuries ago, no condition are recognized, and further subdivi- significant incidence continued into this cen- sions have been made that are associated with tury. However, in the Caribbean area, which various alternative terminology. had been varyingly affected by the slave trade, yaws displayed some contrasts. Thus, Cuba was Characteristics reported as having a low frequency of yaws, Yaws is considered a highly contagious disease whereas in Haiti, 60–80 percent of the rural in tropical areas and in populations with lim- population were estimated to have had yaws. ited hygiene. It is characterized in early stages Similarly, Jamaica registered 70–80 percent fre- by variable cutaneous changes and eventually quency figures in some districts. In South affects joints and bones. The causal organism is America, Brazil was known to have many considered to be Treponema pertenue, although cases, especially in the northern regions, where the taxonomy of the pathogenic treponemes is 350,000 cases were at one time noted. In Colom- in some doubt, and some reclassification may bia, there was also regional variation, with the well take place in the near future. An incuba- Pacific coast regions reporting 80,000 cases tion period of up to 28 days is followed by the (with a general rate of 43.5 per 100,000). In con- appearance of the primary lesion, 2–5 centime- trast to these two countries, yaws appears to ters in diameter, which develops into granular have been only a modest health problem in Peru excrescences at times with lymph node enlarge- and Venezuela. ment. Further eruptions take place, which can In the Old World, the disease was endemic be characterized by “waxing and waning” of suc- in parts of Africa, Asia, and the Pacific. In cessive lesions. Single or multiple lesions can Africa, high frequencies were found in some ar- eventually develop on the feet (“crab yaws” or eas, although possibly the highest incidences ulcerative plantar papules) and are some of the occurred in Asia and the Pacific. For exam- most painful and disabling lesions of all. Eventu- ple, Congo, India, Indonesia, Samoa, and the ally, in what some would see as a tertiary stage, Marianas appear to have suffered greatly from there can be patchy depigmentation, deep de- yaws; Tanganyika, Niger, Chad, and Laos were struction and remodeling of bones, and gan- much less afflicted. gosa (damage of nasopharyngeal structures). In- Yaws is one of four chronic infectious tre- ternal organs are not normally involved, and in ponemal diseases that affect humans, and in this respect the disease contrasts markedly with contrast to pinta, endemic syphilis, and vene- its relative venereal syphilis. real syphilis, it appears to be especially adapted As a result of the intensive campaign against to hot and humid tropical and subtropical en- yaws carried out in the 1950s by the World vironments. Rural populations were probably Health Organization, the disease is no longer more affected than urban groups. The causal

362 160. Yaws organism has been given separate species sta- ters in size, which may ulcerate or become sec- tus, Treponema pertenue, but the taxonomy ondarily infected. The ulceration crusts, and of the treponematoses deserves reevaluation. eventually a raspberry-like granuloma develops The microorganism was discovered by Aldo beneath. Bleeding may occur, and there can be Castellani in 1905, and since then its morphol- a yellowish discharge. ogy has been to some extent revealed, especially Within 3–6 weeks after the initial lesion, sec- by electron microscopy. Differences between ondary eruptions occur, extending all over the the pathogenic treponemes have not, however, body. These can continue up to 2 years. Annular been resolved at this level, and it now seems un- lesions encircle an area of skin; macular erup- likely that significant morphological differences tions may occur as well. These disappear within will appear between T. pertenue and Treponema a few weeks or months. The “lichenous” rash can pallidum (which causes syphilis). be regional or cover the whole body with small Humans appear to be the only natural hosts papules, usually for not more than a few weeks. of all the pathogenic human treponemes. There Plantar and palmar lesions can be ulcerative or is variable cross-protection once an individual nonulcerative. In the case of painful ulcerating has one variety of treponeme and comes into soles, the individual tends to walk on the outer contact with another form. border of the foot in a crablike fashion (“crab The site of entry for yaws treponemes is yaws”). often the legs, and large numbers of tre- In later stages of yaws, usually after 5 years, ponemes are probably unnecessary to instigate further lesions may occur in individuals whose the disease. Transmission by flies is consid- condition has not become fully latent. In partic- ered unimportant. Like endemic syphilis, yaws ular, there can be nodular “lupoid” involvement characteristically develops during childhood by of the skin, with formation of granulation tissue, nonvenereal contact. Eventually, after chronic ulceration, and scars. One or a few large ulcers progress of the disease, over 8 months or more, (“gummatous ulceration”) may develop, lasting individuals commonly undergo spontaneous for years. Possibly the most significant of the cure, although some cases continue to a tertiary late stages of yaws are significant changes in the stage. bones. Parts of the skeleton, especially the long There appears to be no significant natu- bones, may show a range of changes from pe- ral resistance to infection by yaws or other riostitis to deep cavitation and shaft swelling. In pathogenic treponemes. However, there is clear children there can also be dactylitis, which can evidence that some individuals can develop spe- produce remodeling and expansion of one or cific resistance or immunity following infection more phalanges, especially of the fingers. Also, with these treponemes. The plasma cells and the vault of the skull may be affected, causing lymphocytes present in treponemal lesions indi- localized cratering or more widespread osteitis cate local antibody formation and some degree and eventual stellate scarring. Most destructive of immunologic response. Sera from yaws and of all is gangosa (rhinopharyngitis mutilans), the other pathogenic treponemes react to the which is characterized by massive destruction same antigens. of the nose, palate, turbinates, and vomer. The progress of yaws seems best described in two major stages: an early phase with initial History and secondary lesions; then a late stage, which The history of yaws has been, to some extent, usually develops after some years. In the region confused with that of syphilis. Early physicians of entry of the treponemes, primary lesions de- and writers could easily mistake one condition velop within the first 8 weeks, with the legs usu- for the other, or were vague about the actual ally involved first. The lesion is a large, rounded, nature of the disease under study. This does itching papule, usually less than 5–6 centime- not mean that all earlier medical writers were

363 160. Yaws wrong, and Robert Koch, in a 1900 report to the travels in the East Indies. In the Moluccas, the German government, perceptively wrote that in frequency of yaws led Bontius to call it a “com- the Bismarck Archipelago he had seen places mon plague.” where practically all children were infected with From the mid-seventeenth century to the end yaws, and that framboesia was frequently mis- of the eighteenth, a view of yaws as a distinct taken for syphilis by both laypersons and med- disease was consolidated. A 1720 “epidemic” in ical practitioners. Koch went on to say that the Scotland of “sibbens” offered symptoms sugges- alleged great epidemics of syphilis in the South tive of intruded yaws. John Brickell of North Seas were in large part the result of this same Carolina, writing in the 1730s, distinguished misdiagnosis. yaws from syphilis, noting that the former was Although it has been suggested that the bibli- of African origin. In the West Indies, physicians cal condition blains could have been yaws, and attending slaves came to know the condition similarly that a reference by Pliny (first century well; they, too, believed it came from Africa. As A.D.) to a yaws-like eruption of the face may in Africa, yaws was a disease mostly of children indicate early treponemal disease, no ancient in the Caribbean, and many plantations erected written records can be taken seriously as evi- yaws houses. Edward Bancroft, a physician who dence. However, the archaeological record does experienced yaws in South America, concluded appear to provide clear proof of the antiquity of that it could be transmitted by flies, a sugges- treponemal diseases. tion generally accepted in subsequent decades. In 1367, Marco Pizziani explored along the During the late eighteenth century and African coast, and by 1470 others had sailed the first decades of the next, the stages of south as far as the Equator. Portuguese set- yaws development were slowly being under- tlements were established, linked to the slave stood. Vaccination was also attempted to pre- trade, and these intimate contacts between vent the disease, and positive results were widely different peoples and environments pro- claimed. Somewhat more alarming in human- vided opportunities for the movement of dis- itarian terms, experimental injection of slaves ease as well as people. Although the estimated was practiced, at times with “success.” Of special figure of between 300,000 and 400,000 slaves value were experiments on humans known to arriving in Portugal by the end of the fifteenth have already been infected, the negative results century may well be too high, there is no showing that immunity to secondary infection doubt that this was a significant corridor for the was possible. potential shunting of disease, including yaws, Gangosa (“nasal voice”) was first discussed to other areas, including Europe. Moreover, by a Spanish medical committee in 1828, and slaves did not simply move toward Europe and by 1891 J. Numa Rat had discussed these le- western Asia. sions in rhinopharyngitis mutilans and viewed At the beginning of the sixteenth century, the them as an indication of tertiary yaws. Simi- first consignment of slaves from Africa arrived larly, “boomerang leg” (also called “sabre tibia”), in Hispaniola and, following this, millions more a later-stage yaws feature in Australian aborig- reached the New World. It was thus that yaws ines, was first noted in 1894 by E. C. Stirling. became established to varying degrees in vari- The question of the taxonomy of the ous parts of the Americas. In 1648, Willem Piso, pathogenic treponemes was opened up for de- a doctor with the Dutch West India Company in bate in 1900 with the suggestion that, con- Brazil, wrote of treponematosis in that country, trary to growing opinion, yaws and syphilis were mentioning a condition called “bubas” which he simply different patterns of the same disease – distinguished from the “Spanish pocks.” Earlier, an argument still strongly disputed 100 years in 1642, Jacobus Bontius, another Dutch doc- later. But during the past century, researchers tor, had written of witnessing yaws during his have tended to study the treponemal diseases

364 161. Yellow Fever singly. Thus, one might concentrate not only on transmit the disease among them – but not yaws but specifically on parangi, a form that mosquitoes that ordinarily bite humans. This in the 1920s had some prevalence on Ceylon. form of the disease is jungle yellow fever or syl- Field work in the 1930s among Australian and van yellow fever; it is enzootic, meaning that African tribal communities and contributions transmission is from monkey to mosquito to dealing with bone changes in yaws and syphilis monkey. have been especially significant. Such findings When the disease leaves the treetops, and in turn are helping physical anthropologists mosquitoes (such as Aedes africanus and Aedes trace the history of these diseases in human simpsoni in Africa, and species of Haemogogus skeletal remains. It is hoped that such efforts in the Americas) begin transmission from non- will soon produce major breakthroughs in our human primate to mosquito to human, the dis- knowledge of the treponematoses. ease is called endemic yellow fever. When the Don R. Brothwell virus is carried by an infected human to popu- lated areas, where transmission is from human to A. aegypti mosquito to human, the disease is termed epidemic yellow fever or urban yellow 161. Yellow Fever fever. The habits of the female A. aegypti have much Yellow fever is an acute viral disease transmit- to do with shaping the characteristics of an epi- ted to humans by various mosquitoes, espe- demic. She is a domestic mosquito, living close cially Aedes aegypti (formerly Stegomyia fasci- to humans, depending on them for blood meals, ata). The disease remains endemic in tropical and breeding in nearby loci of water. Her range regions of Africa and the Americas in a sylvan is short, at most a few hundred yards, meaning or jungle form, but historically its greatest im- that she requires a fairly dense human popula- pact on humans has been in an epidemic or ur- tion. Because A. aegypti can survive only days ban form. It presents symptoms ranging from without water (although her eggs can survive mild to malignant, classically including fever, for years in dehydrated form) and requires water headache, jaundice, and gastrointestinal hem- in which to breed, adequate rainfall is a prereq- orrhage. High mortality rates were recorded uisite for epidemic yellow fever. Warm weather during epidemics (20–70 percent), although to- is another prerequisite: A. aegypti will not bite ◦ day we know that yellow fever mortality is ac- in temperatures under 62 F and hibernates in tually relatively low, suggesting that many cases extended chilly weather. were mild and undiagnosed. The virus also has some distinctive require- The jaundice has prompted the appellation ments, especially for transmission – a process in “yellow fever” and other designations such as which humans are best thought of as the site mal de Siam, fievre` jaune, gelbfieber, and virus where the virus changes mosquitoes. This ex- amaril, whereas the hemorrhaging of black change can take place only during the first 3–6 blood underlies the name vomito negro (“black days of infection of the yellow fever victim while vomit”). Known early in the New World as “Bar- the virus still remains in the blood (viremia); bados distemper,” “bleeding fever,” maladie de after the virus has entered the mosquito, it Siam, el peste, and “yellow jack” (from ships’ must incubate for another 9–18 days before quarantine flags), the disease has had some 150 the mosquito can infect another human. After names. this period of extrinsic incubation, however, the mosquito remains infective for the remainder Characteristics of its life, which could be upward of 180 days, Yellow fever is normally a disease of nonhuman although generally the lifespan of the female primates, particularly monkeys. Mosquitoes A. aegypti is closer to a month or two.

365 161. Yellow Fever

In the Americas, epidemic yellow fever de- Many in the New World came to believe clined during the twentieth century, essentially that blacks possessed a special ability to re- because of efforts to eradicate A. aegypti in sist yellow fever. Most slaves reaching the population centers. The last outbreak occurred Americas originated within the African endemic in Trinidad in 1954. Nonetheless, the virus re- zone and would have acquired immunity before mains alive in the monkeys of Central and South ever stepping aboard ship. Thus it is possible to America; consequently, some human cases are explain blacks’ refractoriness to yellow fever as still reported among people who work or live acquired immunity. close to the forests. Most cases occur in re- On the other hand, genetic selection for yel- gions of Brazil, Ecuador, Venezuela, Colombia, low fever resistance as a result of prolonged ex- and Peru that are drained by river networks posure cannot be discounted, for many of the contributing to the Orinoco, Magdalena, and West African descendants of those first arrivals Amazon systems. Earlier in the twentieth cen- to the Americas lived for generations in areas tury, human cases were also reported fairly reg- untouched by yellow fever, yet, without any op- ularly in Central America, Bolivia, Argentina, portunity to acquire immunity in advance, suf- and Paraguay. fered much less than whites when the disease In Africa, severe yellow fever epidemics still finally did make an appearance. It has been sug- occur; a notable example, in Ethiopia in 1961, gested that related arboviruses or flaviviruses cost thousands of lives. Still more recently, a (dengue or Japanese encephalitis, for example) major outbreak in Nigeria claimed thousands may confer some cross-protection against yel- more, and yet another was ongoing at the turn low fever, whereas others believe that certain of the twenty-first century. A vast belt of en- strains of the illness may vary in mildness or demic yellow fever stretches across Africa, but severity, depending on the groups of individuals isolated cases are only irregulary reported. under attack. In this latter connection, it may be One mystery surrounding yellow fever is its significant that Chinese in the New World were lack of incidence in Asia, despite the pres- reputed to be almost as resistant to the illness as ence of Aedes mosquitoes. Some think that the blacks, because although yellow fever has never mosquitoes themselves are resistant to infec- invaded Asia, dengue and Japanese encephalitis tion. Others suspect that a population may sup- are endemic to much of the region. port only so many arboviruses and that en- trenched ones such as dengue and Japanese History encephalitis may have forestalled the advance Much historical interest in yellow fever has of yellow fever. focused on its place of origin: Africa or the A yellow fever attack confers lifetime immu- Americas? Those favoring the latter emphasize nity on the host. Because the disease gener- that the disease was described in the Western ally reserves severe symptoms for young adults Hemisphere over a century before it was rec- and treats children more gently, whole popu- ognized in Africa. The first recognizable epi- lations in endemic or frequently visited areas demic struck Barbados in 1647 and spread dur- can become more or less immune, with yel- ing the next 2 years to Guadeloupe, St. Kitts, low fever just another childhood ailment. Un- Cuba, and Yucatan. Moreover, Amerindian ac- der such circumstances, epidemics never oc- counts and early Spanish records mention dis- cur unless groups of newcomers arrive, as was eases that could have been yellow fever, such the case with immigrants, soldiers, and sailors as a 1454 epidemic on the Mexican plateau, a reaching the Americas. It was this phenomenon 1477–97 outbreak in Yucatan, and a disease that that gave rise to yellow fever nicknames such as assaulted Columbus’s men in 1493. “strangers’ fever,” the “disease of acclimation,” By contrast, protagonists of an African ori- and “patriotic fever.” gin dismiss these outbreaks as diseases other

366 161. Yellow Fever than yellow fever, largely because of immuno- may have been present all along – in jungle logic evidence. Whatever the illnesses were, form – quietly immunizing the population by they argue, the Indians were quite susceptible; periodically producing mild cases in the young. however, any endemic yellow fever should have Significantly, in the years immediately prior to engendered its own immunity. Moreover, Amer- the 1849 epidemic, Brazil had been the recipi- ican monkeys are susceptible to yellow fever, ent of a sizable influx of European immigrants; whereas West African monkeys – and humans – in addition, the population of Rio de Janeiro still are resistant, suggesting long exposure. included a number of individuals on their way Certainly the timing of yellow fever’s recorded to California. Thus in this epidemic, as in count- appearance in the New World detracts noth- less ones to follow, newcomers were the chief ing from the case for an African origin, for the sufferers. 1640s saw an accelerated slave trade to Barba- Yellow fever sought out Europeans in their dos as it converted to a slave-labor-based sugar- homelands as well, apparently reaching there plantation economy. The same slave ships that from the Caribbean. The Iberian Peninsula could have delivered the virus in black bodies was the most common target, with epidemics doubtless carried the mosquito in water casks. throughout the eighteenth and nineteenth cen- Many of the outbreaks to follow also seem to be turies. Coastal cities such as Oporto, Lisbon, and traceable directly to Africa via the slave trade. Barcelona bore the brunt of these attacks, al- It does seem, however, that Yucatan and the re- though the disease did penetrate inland on oc- gion around Vera Cruz became endemic foci at casion, even reaching Madrid in 1878. Small out- an early date. breaks also occurred in France, England, and Having reached the Caribbean, yellow fever Italy. moved northward, striking New York in 1668, Without doubt, however, yellow fever gained Philadelphia and Charleston in 1690, and its most fearsome reputation in the Caribbean Boston in 1691. To the south, the disease regu- because Europeans, often military personnel, larly visited the port cities of Colombia, Ecuador, provided the disease with a stream of nonim- and Peru. Interestingly, it disappeared from munes. In 1655, of 1,500 French soldiers oc- Cuba after 1649–55 and, save for an oubreak cupying Saint Lucia, only 89 survived an on- in 1695, did not return until 1761. A similar slaught of disease led by yellow fever. The 1690s phenomenon occurred in Brazil. There seems saw yellow fever sweep much of the region. no doubt that the epidemic that struck in 1685 In 1693, the English attack on Martinique col- was yellow fever, killing thousands before wan- lapsed in face of yellow fever, whereas in 1741, ing about 5 years later. As in the Caribbean, the Admiral Edward Vernon’s abortive attack on Brazilian outbreak has been attributed to ships Cartagena saw the loss of nearly half his force arriving from Africa. However, despite a thriving of 19,000 to yellow fever. slave trade that presumably could have brought Prisoners sent as workmen from Vera Cruz the disease, and a monkey population that some to Havana in 1761 are credited with reintro- believe already harbored the virus, Brazil reput- ducing yellow fever in Cuba, where it proved edly was free of yellow fever for the next cen- a formidable Spanish ally in an unsuccessful tury and a half; the next outbreak was not until effort to deny Havana to the English. But yel- 1849. low fever deaths really peaked in the Caribbean Equally perplexing is the selectivity yellow around the turn of the century. In 1793–96, the fever demonstrated in seeking out victims as it British army lost 80,000 men, with over half the spread from Bahia to other coastal cities, for, al- deaths attributed to yellow fever. The disease though the disease afflicted European newcom- also decimated the French during their 1802 in- ers with considerable fury, it treated local blacks vasion of Hispaniola and accounted for many and whites far more gently, suggesting that it of the 40,000 men lost. After their retreat to

367 161. Yellow Fever

Martinique and Guadeloupe, yellow fever raged trading and the decline of the sugar industry among the survivors for another 3 years. The turned them into economic backwaters seldom tremendous loss of life to yellow fever (and visited by outsiders. malaria) prompted the English to fill West In- The blockade of southern ports during the dies regiments with black troops thought to American Civil War, rather ironically, freed the be immune to the diseases, who demonstrated South of yellow fever for the duration by cur- over and over again that, indeed, many were. tailing West Indian shipping traffic. However, Because of Philadelphia’s brisk trade with the the disease returned to New Orleans in 1867, Caribbean, yellow fever appeared frequently in Montgomery in 1873, and Savannah in 1876, be- that port city during the eighteenth century, fore ascending the Mississippi in 1878 to leave with epidemics in 1741, 1747, 1762, 1793, 1794, countless dead – 5,000 in Memphis alone. and 1797. The epidemic of 1793 was carried to This 1878 epidemic almost certainly reached the city by French refugees from revolution- the United States from Cuba, where the influx torn San Domingue. With the turn of the nine- of Spanish soldiers sent since 1876 to end the teenth century, however, the U.S. South began Ten Years’ War had provided the tinder for an to receive yellow fever’s attention, with New epidemic that raged on that island from 1876 Orleans, Savannah, Mobile, and Charleston the until 1879. Whether the Cuban epidemic also most frequent ports of call. reached out to slaughter French workers ar- Chief among the victims of these epidemics riving in Panama from 1878 onward to work were Northerners, foreigners (especially the on Ferdinand de Lesseps’ abortive attempt to Irish), and white Southerners from the inte- build a canal across the isthmus, or whether rior. Permanent white residents, however, sel- that outbreak came from an endemic jungle dom died from yellow fever. Physicians reported source, is a matter of speculation. But like their that mulattoes were the most susceptible blacks predecessors, who between 1851 and 1855 lost (about the same as local whites). “Pure” blacks thousands of their numbers to yellow fever in were believed to be totally immune, yet in the building the Panamanian railroad for Ameri- years just before the Civil War, physicians noted can financiers, the French canal workers died in that blacks did contract mild yellow fever dur- droves, many even bringing their own caskets ing epidemics – so mild that it had heretofore with them to the isthmus. escaped notice. Just 3 years after the yellow fever disas- In Brazil, the almost continual epidemic on- ter of 1878, Carlos Finlay y Barres of Cuba slaught of yellow fever on coastal cities for the postulated that the A. aegypti mosquito trans- remainder of the century makes it reasonable mitted the disease. The theory was confirmed to suppose that the disease was endemically es- in 1900 using human volunteers (three of tablished there. Cuba, like Brazil, was a nine- whom died) by the U.S. Army Commission on teenth century destination of European labor- Yellow Fever in Havana headed by Walter Reed. ers, and these, along with numerous refugees With this knowledge, William Gorgas rid Ha- from Spanish America and Spanish soldiers, as- vana of the disease by eradicating A. aegypti.He sured yellow fever a plenitude of hosts. More- later applied his methods in Panama, enabling over, a contraband slave trade maintained con- workers on the American canal to avoid the tact with the yellow fever reservoir in Africa, and fate of their French predecessors. These mea- trade with Vera Cruz kept Cuba in touch with sures were applied elsewhere, so that the 1905 another endemic focus of the disease. Thus it New Orleans outbreak and the 1908–9 Bar- is not surprising that Cuba became the yellow bados epidemic represented, respectively, the fever capital of the Caribbean. By contrast, the last of yellow fever on North American soil, disease began to wane in most of the rest of the and its last appearance in the Caribbean for islands as the end of British and French slave decades.

368 161. Yellow Fever

Gorgas suggested eradicating yellow fever used in laboratory experiments, efforts to iso- from the entire globe, and in 1915 the Rocke- late the yellow fever virus were begun. Shortly feller Foundation launched this effort by creat- afterward, Max Theiler discovered that the virus ing its Yellow Fever Commission. Initially, the could also be transmitted to mice, which were commission concentrated on Latin America but less expensive and easier to handle than mon- in 1920 turned its attention to Africa. In 1925, keys. Soon, he showed that if the virus was the Second Commission to West Africa estab- transmitted among several mice, it weakened lished itself in Nigeria, soon discovering that the sufficiently to use in immunizing monkeys. By rhesus monkey was susceptible to yellow fever, the late 1930s, a further attenuated strain called which permitted use of monkeys rather than 17D Valline was developed. It is harmless to hu- humans for experiments. Nonetheless, yellow mans but immunizes them against yellow fever. fever research remained dangerous – Adrian The development of a vaccine was crucial, for Stokes, Hideyo Noguchi, William Young, and the discovery of jungle yellow fever meant that Theodore Hayne all perished from the disease in yellow fever could not be wiped out after all. The Africa during these “heroic days” of yellow fever virus is always present in monkeys and perhaps research, which by 1929 had demonstrated be- other wild creatures of the forest as well. yond doubt that yellow fever was the result of For this reason, epidemiologists are partic- infection by a virus. ularly alarmed at the relaxation of mosquito- In Brazil, Oswaldo Cruz began a mosquito- control measures in the Western Hemisphere, eradication campaign that freed coastal cities where few have been vaccinated. In the U.S. from yellow fever for the first time in more South, the Caribbean, and Central America, than 50 years. But the disease failed to disap- A. aegypti has reestablished itself, and Brazil, pear. Sporadic outbreaks continued in Brazil, once apparently free of the mosquito, has reim- Peru, Ecuador, Venezuela, and Colombia. In ported it from North America. With modern 1923, Brazil invited the International Health air travel, an infected individual – or even Division of the Rockefeller Foundation to ad- mosquito – could easily be whisked from the minister the Brazilian Yellow Fever Service. Sur- South American or African forests to any num- veys conducted under Fred Soper showed that ber of large cities where A. aegypti again resides many Brazilians residing near forests had hosted in large numbers and stands ready to spread the yellow fever. In 1928, an epidemic triggered in- disease throughout nonimmune populations. vestigations revealing that yellow fever could Moreover, Aedes albopictus has recently been in- spread without A. aegypti and that the dis- troduced into the United States from its native ease was very much alive in the monkeys Asian habitat. This close relative of A. aegypti is of the South American rain forest. Jungle fully susceptible to the yellow fever virus and yellow fever had been discovered, and thus capable of transmitting it to vertebrates. The most riddles of yellow fever transmission were newcomer is more tolerant of cold weather and resolved. has spread widely in the United States. Its spread Meanwhile, by the late 1920s, the rhesus to the Caribbean and Central and South Amer- monkey was found to be susceptible to yel- ica is feared. low fever; thus with an animal that could be Donald B. Cooper and Kenneth F. Kiple

369 Name Index

A Baillie, Matthew, 80, 113–14, 278 Abercrombie, John, 32, 178 Baillou, Guillaume de, 83, 224, 361 Abreu, Aleixo de, 336 Baker, Brenda, 333 Adams, Joseph, 140–41 Baker, George, 187 Adams, Robert, 157 Balardini, Lodovico, 243 Addison, Thomas, 22, 350 Balfour, Francis, 152 Aesculapius, 246 Balmis, Francisco Xavier, 303 Aetius of Amida, 82, 232, 248 Bancroft, Edward, 364 Afzelius, Arvid, 203 Bancroft, Joseph, 128 Ainsworth, Geoffrey C., 128–32, 132–34 Bancroft, Thomas, 87, 128 Albert, Jose, 48 Bang, Bernhard, 60 Alexander of Tralles, 135 Bannwarth, A., 203 Alibert, Jean Louis, 147, 162, 359 Bard, Samuel, 83 Ali ibn Isa, 232 Barensprung,¨ F. von, 360 Allchin, W. H., 177 Bargen, J. A., 177 Allison, A. C., 25, 300 Barker, William H., 57–58 Allison, Marvin J., 70–71, 191–92 Barthelemy,´ Eloy, 31 Alpert, S., 178 Bartlett, Elisha, 351 Altman, Roy D., 238–40 Bartoletti, Fabrizio, 103 Alzheimer, Alois, 14, 17 Barton, Alberto, 69 Ammonios, 358 Bartram, M., 328 Amos, H. L., 162 Bassereau, Leon,´ 317 Andersen, Dorothy, 84 Bateman, Thomas, 145, 162 Anderson, John, 353 Bateson, William, 141 Andral, Gabriel, 80 Battistine, T., 69 Annesley, James, 21 Baumann, Eugen, 149 Arad-Nana, 246 Beard, George, 106 Archibald, R. G., 131 Beet, E. A., 24, 25 Aretaeus the Cappadocian, 80, 82, 88, 177, 257, 324 Behring, Emil, 95–96, 325 Aristotle, 135, 248, 272, 328 Bell, Benjamin, 152 Armelagos, George, 333 Bell, J., 31 Armstrong, B. W., 211 Bell, John, 138 Armstrong, C., 38 Benedek, Thomas G., 63–67, 83–84, 153–56, Arnold of Villanova, 272 199–201, 224–25, 277–80 Arrizabalaga, Jon, 312–17 Benivieni, Antonio, 136 Artzney, Zene, 246 Benjamin, Georges C., 298–300 Aselli, Gasparro, 64 Bennett, John Hughes, 130, 199 Ashford, Bailey K., 167 Berg, F. T., 130 Astruc, Jean, 162, 316 Bergh, R., 162 Auenbrugger, Leopold, 103–4, 156–57, 257 Bergmann, Ernst von, 210 Aufderheide, Arthur C., 185–88 Berkeley, M. J., 131 Avicenna, 99, 102, 145, 195, 210, 213, 248, 272 Bernard, Claude, 88 Bethencourt, Jacques de, 316 B Betten, H., 248 Baglivi, Giorgio, 103 Beurmann, Charles Lucien de, 131 Bailey, Charles P., 280 Bibb, J., 300

371 Name Index

Bichat, Marie Franc¸ois, 69 C Bilharz, Theodor, 290–91 Cadawaler, Thomas, 187 Bissell, A. D., 178 Cailius Aurelianus, 257 Black, Francis L., 171–74, 212 Campbell, A., 360 Blackall, John, 104–5, 146 Capivaccio, Girlamo, 102 Blacklock, D., 229 Carini, A., 192 Blane, Sir Gilbert, 296–97 Carlsson, A., 241 Blaud, P., 23 Carmichael, Ann G., 60–63, 94–96, 121–22, Blessed, Gary, 17 192–95, 251–54, 287–88, 311–12 Blocq, Paul, 241 Carpentier, A., 280 Boe,¨ Franc¸ois de la, 69 Carrion,´ Daniel, 69 Boerhaave, Hermann, 69, 103, 297 Carson, Paul E., 24 Boezo, M., 247 Carswell, Robert, 80 Bollet, Alfred Jay, 21–26 Carter, H. Vandyke, 131 Bondy, Gustav, 211 Carter, K. Codell, 265–67 Bontius, Jacobus, 75, 364 Casal, Gaspar, 243 Bordet, Jules, 361 Casserio, Giulio, 147 Borovsky, Peter, 192 Castellani, Aldo, 363 Boswell, James, 152 Castle, William B., 22 Botallo, Leonardo, 315 Celsus, Aulus Cornelius, 102, 122, 129, 186, 232, Bouchardat, Apollinaire, 88 246, 272, 358 Bouchut, E., 83 Chagas, Carlos, 71 Bouillaud, Jean Baptiste, 257 Chalmers, A. J., 131 Boussingault, Jean Baptiste, 148 Chapin, C., 344 Bowman, William, 146 Charaka, 358 Boylston, Zabdiel, 302 Charcot, Jean, 32, 119, 241 Bozzolo, Camillo, 167 Chatin, Adolphe, 148 Bradford, William, 300 Chauliac, Guy de, 233 Brain, P., 25 Chaumette, Antoine, 315 Bramwell, Byron, 220 Chen, Peter S. Y., 79–81 Brandt, Allan M., 1–5 Chen, Thomas S. N., 79–81 Breschet, Gilbert, 273 Cherry, James D., 81–83 Bretonneau, Pierre, 83, 95 Chevreul, M. D. Eugene,` 88 Brickell, John, 364 Cheyne, John, 32 Bright, Richard, 32, 104, 145–46, 170, 278, Chien-i, 280 350 Chipley, William Stout, 27 Brill, Nathan, 353 Christie, A., 164 Bristowe, J. S., 178 Clossey, Samuel, 104 Brooke, Bryan, 178 Cobbold, T. Spencer, 127–28 Brothwell, Don, 250–51, 332, 362–65 Coburn, Alvin F., 278 Brown, Audrey K., 21–26 Cockburn, T. A., 332 Brown, J. Y., 177 Coindet, J.-F., 148 Brown, Peter J., 123–25 Colles, Abraham, 328 Browne, John, 80 Collier, Leslie, 312 Bruce, David, 58, 60, 351 Colombo, Realdo, 147 Bruch, Hilde, 28–29 Colp, R., 178 Bruck, Carl, 317 Combe, C., 178 Brumpt, E., 131 Come, Frere,` 358 Buchwald, Alfred, 203 Cone, Thomas E., Jr., 218–20 Budd, William, 78, 348, 351 Cooke, John, 32 Bumm, Ernst von, 152 Cooke, W. Trevor, 178 Burgdorfer, Willy, 203, 283 Cooper, Donald B., 14, 365–69 Burnet, F., 269 Correia, Gaspar, 75 Burns, Allan, 104 Correns, Carl, 140–41 Butlin, Henry, 239 Corvisart, Franc¸ois, 330 Bylon, David, 87 Corvisart, Jean-Nicholas, 104, 257, 350

372 Name Index

Costoeus, Jean, 233 Dubini, Angelo, 167 Cotugno, Domenico, 145 Du Buys, L., 282 Cotzias, George, 241 Duchenne, Guillaume, 224 Couch, James, 219 Ducrey, August, 317 Councilman, William, 21 Duffin, Jacalyn, 255–58 Cournand, Andre,´ 158 Dumas, Jean-Baptiste, 148 Courtois, Bernard, 148 Duncan, Howard, 39–42 Cox, H., 269 Dundas, David, 278 Cox, Herald, 354 Dunn, Frederick L., 203–7 Cox, L. B., 132 DuPont, Herbert L., 92–94 Crede,´ Karl Siegmund, 152 During,¨ Michael, 289 Creighton, Charles, 312 DuVerney, Joseph, 210 Crohn, B. B., 178 Cronk, Christine E., 96–98 E Crosby, Alfred W., 178–81, 300–4 Eberth, Carl, 348 Cruveilhier, Jean, 32 Echthius, Johannes, 295 Cruz, Oswaldo, 369 Edwards, Harold, 178 Cullen, William, 294 Edwards, Lowell, 280 Ehrlich, Paul, 13, 22, 81, 199 D Eijkman, Christian, 48 Dalziel, T. Kennedy, 178 Einthoven, Willem, 157 Dampier, William, 129 Eliot, Martha, 282 Danielssen, Daniel, 195 Elvehjem, Conrad A., 244 Darling, Samuel, 164 El Yahudi, 213 Darwin, Charles, 71 Emmel, V. E., 142 Davaine, Casimir, 29, 31 Emmons, C. W., 129 Davies, Scott F., 163–65 Empedocles, 139 Davis, G., 269 Enders, J. F., 259 Davison, Francis, 83 English, Peter C., 304–5 Dean, Geoffrey, 220 Ephesus, 177 deGroote, J., 178 Erasistratus, 80 Dejerine,´ Joseph, 225 Erb, Wilhelm, 227 Dekkers, Frederick, 145 Ermengem, Emile Pierre Marie van, 58 Demarquay, Jean-Nicolas, 127 Escherich, Theodor, 281 Denko, Charles W., 234–36 Esquirol, J., 17 Denman, Thomas, 112 Estes, J. Worth, 100–5 Derouesne, Christian, 31–34 Etheridge, Elizabeth W., 242–44 Derrick, E. H., 267, 269 Ettling, John, 165–68 Desault, Pierre-Joseph, 138 Euripides, 132 Devor, Eric J., 138–44, 168–69 Eustachi, Bartolomeo, 147 Dick, George, 290 Evans, Alice, 59 Dick, Gladys, 290 Evans, R. Winston, 24 Dickson, E., 130 Dieffenback, J. F., 78 F Diggs, L. W., 142, 300 Fabricius, Hieronymus, 147 Dioscorides, 232 Fabricius, Wilhelm, 64, 140 Dobson, Matthew, 88 Fanconi, Guido, 84 Donaldson, James, 351 Farley, John, 290–92 Donath, W. F., 48 Fauchard, Pierre, 246 Donovan, Charles, 192 Fedchenko, Aleksei, 100 Dowdle, W. R., 162 Fehleisen, Friedrich, 122 Down, J. Langdon, 97–98, 143 Felsen, J., 177 Downs, Wilbur G., 34–38, 38–39, 107–9, 184–85, Fernel, Jean, 102, 152, 315 207–8 Ferrier, Auger, 315 Dozy, A. M., 142–43 Filatov, Nil, 175 Drake, Daniel, 350 Findlay, L., 281

373 Name Index

Finlay y Barres, Carlos, 368 Gougerot, H., 131 Fischer, J. N., 232 Graham, Thomas, 146 Fleck, Ludwik, 317 Grassi, B., 128 Flexner, S., 162 Graves, Robert, 350 Flint, Austin, 22 Greenfield, W., 31 Floyer, John, 113, 157 Greenough, F. B., 162 Folin, Otto, 154 Gregg, Norman, 287 Ford, John, 12 Griesinger, Wilhelm, 17, 291 Forest, Peter, 83 Grifford, Myrnie A., 130 Forestus, 233 Grijns, Gerrit, 48 Forssmann, Werner, 158 Grim, Clarence E., 169–71 Fourcroy, Antoine F. de, 154 Gruby, David, 129–30 Fournier, Jean-Alfred, 31, 317 Gsell, Otto R., 195–96 Fox, Daniel M., 52–54 Guerra, Francisco, 333 Fracastoro, Girolamo, 272, 313, 339, 353 Guillimeau, Jacques, 112 Francis, Edward, 344–45 Guillotin, Joseph-Ignace, 273 Francis of Assisi, Saint, 233 Gull, William Withey, 27–28 Frankel, Albert, 257 Guthrie, C. G., 24 Franklin, Benjamin, 187 Frapolli, Francesco, 243 H Fraser, David W., 189–91 Hackett, C. J., 314, 332 Freeman, Mavis, 269 Hadfield, G., 178 French, Roger K., 69–70, 292–94, 295–98 Hales, Stephen, 104 Fresenius, J., 132 Hale-White, W., 177 Freud, Sigmund, 28 Haller, John S., Jr., 120–21 Friedlander, Carl, 257 Hallier, Ernst, 78 Frolich,¨ Theodor, 298 Haly Abbas (Ali ibn al-Abbas al-Majusi), 135 Funk, Casimir, 48, 298 Hamilton, Robert, 224 Furbee, Louanna, 220 Hanau, Arthur, 64 Hansen, A. G. H., 192, 195 G Harden, Victoria A., 282–83, 283–85, 331, 352–55, Gaffky, Georg, 348, 351 355–56 Galen, 63, 69, 80, 82, 102–3, 112, 120, 130, 135, Hardy, Anne, 275–77, 288–90, 360–62 152, 232, 248, 280, 295, 339, 358 Harken, Dwight E., 279 Galle, F., 227 Harrison, Tinsley R., 104 Galtier, Pierre-Victor, 273 Harvey, William, 80, 103, 140, 156, 158, 361 Gama, Vasco da, 295 Hashimoto, Hakuju, 355 Garrod, A. B., 40 Hayem, George, 22 Garrod, Alfred B., 154 Hayne, Theodore, 369 Garrod, Archibald, 141 Hazeltine, Richard, 214 Gengou, Octave, 361 Head, Henry, 360 Gentile da Foligno, 135 Heberden, William, 157, 359 Gerhard, William, 348, 350, 354 Hecker, J., 312 Gilbertson, Donald E., 333–36 Helwich, Christianus, 104 Gilchrist, T. C., 130–31 Henderson, Donald, 303 Ginzburg, L., 178 Herbst, Ernst, 335 Glisson, Francis, 280–81 Hermann, R., 78 Gluge, Gottlieb, 80 Herodotus, 246 Gockel, Eberhard, 188 Herrick, J. B., 142 Goldberger, Joseph, 243–44, 353 Herrick, James, 24, 157, 299 Goldblatt, Harry, 170 Hertig, M., 69 Goldflam, Samuel, 227 Hess, Alfred, 281, 330 Goodall, Edward, 290 Higgins, Brian T., 247–50 Gordon, Alexander, 122, 266 Hinton, James, 210 Gorgas, William, 368–69 Hippocrates, 63, 69, 122, 135, 139, 152, 167, 171, Gotlieb, C., 178 177, 206, 210, 212, 223–24, 232, 254, 256–57,

374 Name Index

276, 295, 305, 324, 328, 339, 347, Joy, Robert J. T., 323–26 358 Judah, Rabbi, 54 Hiro, Y., 287 Hirsch, August, 47–48, 148, 213, 361 K Hissette, J., 229 Kampmeier, R. H., 84–85, 161–62, 174–75, Hobbs, Anna Pierce, 219 359–60 Hodgkins, Thomas, 350 Kan, Y. W., 142–43 Hoffman, Friedrich, 71 Kantor, J. L., 178 Hoffmann, Erich, 317 Kaposi, Moriz, 200 Holmes, Oliver Wendell, 122, 266, 305 Karasch, Mary C., 230–34 Holst, Axel, 298 Kartulis, Stephanos, 21 Holtan, Neal R., 309–11 Kass, Edward H., 181–82 Home, Francis, 82–83, 213 Katsurada, Fujiro, 291 Homer, 82, 339 Kay, D. K., 14 Hooke, Robert, 64 Kehrer, E., 330 Hooker, Edna, 253 Keil, Harry, 252 Hooper, R., 70 Kemink, John L., 208–11 Hope, James, 104 Kendall, Edward C., 149 Hopkins, Donald R., 98–100 Kerner, Justinius, 58 Horne, Patrick, D., 342–45 Kim-Farley, Robert J., 211–14, 222–24, 285–87 Howell, Joel D., 156–61 King, Glen, 298 Howland, J., 330 King, Walter, 284 Huck, John G., 24, 142, 300 Kiple, Kenneth F., 5–7, 18–19, 63–67, 109–10, Hudson, Ellis H., 313, 318, 332–33 317–19, 328–30, 331–33, 342, 365–69 Hudson, Robert P., 71–74 Kirklin, John W., 280 Hughes, Matthew Louis, 60 Kirkpatrick, James, 302 Hunain ibn Is-haq, 232 Kirsner, Joseph B., 175–78 Hunter, John, 64, 152, 157, 187, 273 Kitasato, Shibasaburo, 95, 324–25, 328 Huntington, George, 168 Kiyoshi Shiga, 44 Hurst, A. F., 177 Klebs, Edwin, 64, 83, 95, 146, 148, 267, 348 Klein, Edward, 290 I Klenk, E., 321 Ibn Masawaih, 232 Knudson, Ronald J., 112–14 Imray, John, 249 Koch, Robert, 31, 77–78, 95, 218, 267, 340–41, 348, Ingram, V. M., 142, 300 364 Ingrassia, Giovanni, 359 Kocher, E. Theodor, 147 Itard, Jean Marie Gaspard, 210 Koplik, Henry, 213 Ives, Edward, 296 Korner,¨ Otto, 211 Kraepelin, Emil, 17 J Kretchmer, Norman, 182–83 Jackman, W. A., 178 Kuchenmeister,¨ F., 319 Jackson, James, 350 Kundratitz, Karl, 360 Jackson, John, 119 Kuster,¨ Ernst von, 210 Jackson, Robert, 136–38 Kwentus, Joseph A., 14–18 James, Robert, 104 Jamot, Eugene,` 13 L Janet, Pierre, 28 Ladd, W. S., 22 Jansen, B. C. P., 48 Laennec, Rene,80,157,257,278,340,350´ Jenner, Edward, 302–4 Lafleur, Henri, 21 Jenner, William, 276 Lamb, B., 344 Jensen, Carl, 64 Lambotte-Legrand, J. and C., 24 John of Arderne, 233 Lancaster, Sir James, 296 John of Gaddesden, 213 Lancisi, Giovanni Maria, 103 Johnston, William D., 336–42 Landouzy, Louis, 225 Jones, Alfred Lewis, 11 Landsteiner, Karl, 290 Jones, T. Duckett, 278 Lange, Johann, 71, 73

375 Name Index

Langenbeck, B., 130 Lutz, Adolfo, 131 Langerhans, Paul, 89 Lynch, J. M., 177 Langmuir, Alexander, 253–54 Lyons, Maryinez, 7–13 Larson, Donald M., 144–46 Lasegue,` Charles, 28 M Latta, Thomas, 78 MacArthur, William, 252 Laveran, Alphonse, 351 Macdonald, George, 205 Lawn, R. M., 142 Macdowall, Patrick, 87 LeBaron, Charles W., 345–49 Macewen, William, 119 Ledelius, J., 248 MacGregor, Patrick, 233 Leeuwenhoek, Anton van, 144, 153 Mackenzie, James, 157 Leff, Robert D., 201–3 Mackey, J. P., 25 Legendre, F. L., 162 Mackie, F., 276 Legg, J. M., 80 Mackinnon, J. E., 131 Lehmann, Hermann, 25 Maclean, W., 351 Leidy, Joseph, 335 Magellan, Fernando, 295–96 Leiper, Robert, 291 Magendie, Franc¸ois, 273 Leisen, James C. C., 39–42 Mallon, Mary, 348–49 Leishman, W. B., 192 Mallory, Frank B., 80 Leonardo da Vinci, 138, 147 Malpighi, Marcello, 103, 146 Lereboullet, Dominique, 80 Manson, Patrick, 10, 21, 127–28 Leuckart, Friedrich Rudolf, 229, 335 Marey, Etienne-Jules, 157–58 Lever, John, 112 Marine, David, 149 Levin, Jeffrey, 244–47 Marriott, W., 330 Levine, P., 22 Marshak, R., 178 Levret, Andre,´ 328 Marston, J. A., 60 Levy, Jerrold E., 116–19 Marzari, Giovanni, 243 Lewis, Thomas, 104, 157 Mason, Verne R., 24 Lewis, Timothy R., 78, 127 Mather, Cotton, 302 Lhermitte, J., 32 Matthey, A., 215 Lieber, Charles S., 81 Maupertuis, Pierre Louis Moreau de, 140 Lieberman, Leslie Sue, 88–92 Mauriceau, Franc¸ois, 112 Liebermeister, Karl von, 80 Maxcy, Kenneth, 355 Lillie, R. D., 38 Mayrhofer, Carl, 266–67 Lincoln, Abraham, 219 McClendon, J. F., 149 Lind, James, 75, 296 McCollum, Elmer, 281, 298 Lipschutz,¨ B., 162 McCoy, G., 344 Lister, Joseph J., 64, 138 McDade, Joseph, 190 Littman, M. L., 132, 253 McDonald, W. I., 220–22 Littman, Robert J., 253 McGinn, Sylvester, 104 Lockhart-Mummery, J. P., 177–78 McMichael, John, 105 Loeb, Leo, 64 McMillen, Sally, 110–12, 326–28 Loffler,¨ Friedrich, 83, 95, 305 McSherry, James, 85–88 Lombroso, Cesare, 243 Meade, Melinda S., 44–49 Longrigg, James, 254 Mendel, Gregor, 140–41 Longstaff, G. B., 279 Mercatus, Ludovicus, 102 Looss, Arthur, 167, 291 Mezeray,´ Franc¸ois Eudes de, 121 Losch,¨ Fedor, 21 Minot, George Richards, 22 Louis, Pierre, 348, 350 Miyairi, Keinosuke, 291 Low, George C., 128 Mock, H., 178 Lower, Richard, 103 Monro, Donald, 104 Lucretius, 186 Montagu, Lady Mary Wortley, 302 Ludwig, Carl, 146 Moore, N., 178 Lu-pu-wei, 280 Mooser, Herman, 355 Lusitanus, Zacutus, 64 More, Sir Thomas, 311

376 Name Index

Morgagni, Giovanni Battista, 31, 80, 136, 177, 210, Pare,´ Ambroise, 64, 71, 102, 138, 210, 246, 247, 309, 316 273 Morgan, T. H., 143 Park, Katharine, 49–52 Morse, John, 281–82 Parker, Ralph, 284 Morson, B. C., 178 Parkinson, James, 240–41 Morton, Richard, 27, 206, 340 Parmly, Eleazar, 246 Moschion (Muscio), 328 Pasteur, Louis, 31, 138, 218, 257, 266–67, 273–74 Mosely, Edwin, 218 Patrick, Adam, 312 Mueller, Johannes Peter, 146 Patten, Bernard M., 225–27, 240–41 Mulder, Donald G., 280 Patterson, K. David, 19–21, 42, 43–44, 70, 81, 105, Mundinus (Mondino de’Luzzi), 135 110, 116, 123, 144, 214–17, 227–28, 228–30, 240, Murchison, Charles, 351 254–55, 265, 270–75, 306, 319–20, 330–31, Murray, C. D., 177 336 Murray, George R., 149 Pauling, Linus, 142, 300 Paul of Aegina, 232 N Pearse, R., 344 Nahmias, A. I., 162 Penrose, L. S., 143 Nasse, Christian, 140 Perroncito, Edoardo, 167 Negri, Adelchi, 274 Peterson, J., 164 Neill, Mather, 355 Petit, Jean, 210 Neisser, Albert, 152, 317 Pfeiffer, Emil, 175 Neumann, Ernst, 199 Pfister, H., 203 Newman, James L., 261–65 Pickering, George, 171 Nicander, 186 Piller, Gordon J., 196–99 Nicolaier, Arthur, 324–25, 328 Pinault, Jody, 254 Nicolle, Charles, 276, 354 Piso, Carolus, 102 Niparko, John K., 208–11 Piso, Willem, 364 Noe, G., 128 Pizziani, Marco, 364 Noguchi, Hideyo, 69, 317, 369 Platt, Robert, 171 Nuboer, F. J., 178 Platter, Felix, 147 Pliny, 129, 139, 186, 246, 272, 364 O Poirier, Jacques, 31–34 Obermeier, Otto, 276 Politzer, Adam, 211 O’Brien, J. S., 321 Pollender, Aloys, 31 Ohara, Hachiro, 345 Posadas, Alejandro, 130 Okada, S., 321 Pott, Percival, 64 Oppenheimer, G. D., 178 Power, George, 233 Opuls, W., 130 Prescott, Heather Munro, 26–29 O’Shaughnessy, W. B., 78 Prevost,´ Jean-Louis, 148 Osler, William, 72, 200, 256, 309, 324, Priscianus, Theodorus, 232 349 Procopius, 62 Otto, John, 57 Prowazek, Stanislaus von, 354 Owen, Richard, 335 Q P Quier, John, 214 Pacini, Filippo, 74, 78 Quincke, Heinrich, 21, 217 Page, D. L., 253 Quintal, Diane, 136–38 Paget, Sir James, 238, 335 Painter, T. S., 143 R Palm, Theobald, 281 Rabe, Edward, 83 Palmer, C., 164 Ramazzini, Bernardino, 187 Palmer, S. R., 267–70 Ramses V, Pharoah, 301 Panum, Peter, 213 Raper, A., 300 Paracelsus, 102, 147 Rappaport, H., 178 Paranhos, V., 192 Rasori, Giovanni, 257

377 Name Index

Rat, J. Numa, 364 Saliceto of Bologna, Guglielmo de, 145 Ratnoff, Oscar D., 54–57 Salk, Jonas, 259 Ravenholt, R. T., 114–16 Sambon, Louis, 291 Rayer, Pierre, 31, 360 Sandwith, Fleming, 243 Raynaud, Maurice, 138 Sanne,´ A., 83 Reed, Walter, 35, 352, 368 Sant’Agnese, Paul di, 84 Remak, Robert, 129 Saunders, H., 178 Reuter, Karl, 317 Sauvages, Franc¸ois Boissier de, 348, 353 Reverdin, Jacques-Louis and August, 148 Savitt, Todd L., 125–28, 306–9 Reynolds, Russell, 32 Sawin, Clark T., 146–49 Rhazes, 99, 213, 272, 301, 358 Schaudinn, Fritz, 317 Richards, Dickinson, 158 Scheele, Karl W., 153 Ricketts, Howard Taylor, 282, 284, 354 Schenck, B. R., 131 Ricord, Philippe, 152, 316 Schmorl, Georg, 281 Riggs, John, 246 Schneweiss, K. E., 162 Rixford, E., 130 Schoenlein, J. L., 129 Robbins, F. C., 259 Schultes, Johann, 289 Robin, Charles, 78 Schwartze, Hermann, 210–11 Robin, M., 127 Seguin,´ E., 143 Robinson, D., 321 Semmelweis, Philip Ignaz, 122, 266, 305 Robles, Rodolfo, 229 Semon, Felix, 148 Roca Lima, Henrique de, 354 Sennert, Daniel, 64, 187, 289 Rocha-Pima, H. da, 164 Sequin, E., 97 Rockefeller, John D., 168 Shakespeare, E., 352 Rogers, Leonard, 78 Sherman, M., 300 Rokitansky, Karl von, 80 Shrewsbury, J. F. D., 252–53 Rolleston, H., 177 ShunyuI,358¨ Rollo, John, 88 Sidenstricker, Virgil P., 24 Rontgen,¨ Wilhelm, 198 Silva, Piraja da, 291 Roos, E., 21 Silva Lima, J. da, 14 Rosenbach, D., 324 Simmons, James S., 88 Rosenstein, Nils von, 289, 361 Simoons, Frederick, 183 Rosen´ von Rosenstein, Nils, 145 Simpson, James, 112 Ross, J. R., 178 Sims, Marion, 328 Ross, Ronald, 10, 35 Slome, D., 321 Rosslin,¨ Eucharius, 112 Smith, C. E., 177 Roth, Martin, 17 Smith, Dale, 349–52 Rothberger, C. J., 104 Smith, Fred, 157 Rothenberg, Richard B., 150–53 Smith, Theobald, 35 Roussel, Theophile,´ 243 Snively, William, 220 Roux, Emile, 95 Snow, John, 77 Rowe, John, 219 Sommers, S. C., 178 Rubens, Peter Paul, 41 Soper, Fred, 37, 369 Rufus of Ephesus, 145, 358 Soper, George, 348 Rush, Benjamin, 87, 257 Soranus of Ephesus, 280 Russell, Richard, 224 Southey, R., 105 Rutty, John, 276 Speck, Reinhard S., 74–78 Ruysch, Frederik, 80 Spencer, Roscoe, 284 Spieghel, Adriaan van den (Spigelius), 348 S Spies, Tom, 244 Sabin, Albert, 87, 162, 259 Spriggs, E., 177 Sabouraud, Raymond, 129 Sprunt, Thomas, 175 Sachs, Bernard, 321 Starling, Ernest Henry, 104 Sadaqa ibn Ibrahim al-Sadhili, 232 Starr, Albert, 280 Saissy, Jean Antoine, 210 Steere, Allen, 203

378 Name Index

Steinbock, R. Ted, 134–36, 236–38, 280–82, 357–58 V Sternberg, George, 352 Valli, Eusebio, 273 Stewart, H. J., 105 Valsalva, Antonio, 210 Stiles, Charles, 167–68 Varandal, Jean, 71 Stirling, E. C., 364 Vaughan, Victor, 352 Stirling, J. L., 321 Veale, Henry, 287 Stockhausen, Samuel, 188 Vedder, Edward B., 48 Stokes, Adrian, 369 Velschius, G. H., 100 Stokes, William, 157, 350 Vergil, Polydore, 312 Stoll, Maxmilian, 289 Vesalius, Andreas, 80, 147 Strauss, Hermann, 177 Veuster, Damien de, 195 Strauss, Maurice, 312 Vianna, Gasper Oliveira de, 192 Strong, R., 164 Vieussens, Raymond, 103 Stubbs, Hugh, 253 Vieusseux, Gaspard, 215 Sutton, W. S., 143 Villemin, Jean-Antoine, 340 Suzuki, Masatsuga, 291 Vincent, H., 131 Svennerholm, L., 321 Virchow, Rudolph, 64, 132, 146, 199, 335, 340, Swieten, Gerard van, 297 354 Swift, Homer F., 278 Vitruvius, 186 Sydenham, Thomas, 23, 71, 74, 153, 177, 206, 213, Vivarelli, R., 25 278, 289, 305, 360–61 Vries, Hugo de, 140–41 Sylvius of Leyden, 69 Szent-Gyorgyi,¨ Albert, 298 W Walker, Ernest, 21 T Warren, A. C., 143 Takaki, K., 48 Warren, S., 178 Tanquerel des Planches, L., 187 Wassermann, August von, 317 Tasaka, S., 287 Watt, Robert, 361 Tay, Warren, 321 Weber, Klaus, 203 Taylor, David N., 345–49 Weichselbaum, Anton, 217, 257 Telian, Steven A., 208–11 Weil, A., 195–96 Terry, Robert, 17 Weir, R. F., 177 Theiler, Max, 369 Weiss, H., 330 Thierry de Hery,´ 315 Weller, T. H., 259 Thiery,` Franc¸ois, 243 Wells, Charles, 178 Thomas, Wolferstan, 13 Wells, William C., 145–46, 278 Thommasini, Giacomo, 257 West, J., 175 Thucydides, 251–54 Wharfton, Thomas, 147 Todd, E. W., 278 Wherry, W., 344 Tolhurst, Jean C., 132 Whistler, Daniel, 280 Tomlinson, Bernard, 17 White, Paul Dudley, 104 Torti, Francesco, 206 Whorton, James, 105–7 Toussaint, H., 31 Widal, Fernand, 347 Towne, Bradford, 320–23 Wilde, William, 210 Townsend, Charles, 68 Wilder, Russell M., 48 Tozzi, Luca, 103 Wilkinson, Lise, 29–31, 58–60 Troltsch, Anton von, 210 Wilks, Samuel, 178, 226–27 Trousseau, Armand, 32, 122, 241, 330 Willan, Robert, 162 Trowell, H. C., 24 Willebrand, E. A. von, 57 Tschermak, Erich von, 140–41 Williams, Robert R., 48 Williams, Watson, 254 U Willis, Thomas, 88, 103, 215, 226, 348, 361 Unger, L., 281 Wilson, Thomas W., 169–71 Unna, Paul, 162 Winterberg, H., 104 Urteaga-Ballon, Oscar, 67–69 Wiseman, Richard, 293–94

379 Name Index

Withering, William, 104–5 Y Wolbach, Burt, 284 Yersin, Alexandre, 61, 95 Wollaston, William H., 153 Young,William, 369 Wood, Corinne, 333 Woodward, Joseph, 349–50, 352 Z Wright, Almroth, 348 Zacharias, Pope, 171 Wright, James, 192 Zammit, Themistocles, 60 Wucherer, Otto, 127–28 Zenker, Friedrich, 336 Wullstein, H., 211 Zilva, S. S., 298 Wunderlich, Karl, 340 Zimmerman, L. E., 132 Wyatt, H. V., 258–61 Zinke, Georg Gottfried, 273 Wylie, John, 253, 312 Zinsser, Hans, 252, 312, 353, 355 Wyss, O., 360 Zollner,¨ F., 211

380 Subject Index

A Aedes albopictus, 35–36, 85–87, 369 a-a-a disease, 167 Aedes cinereus, 343 abattoir fever (Q fever), 190, 255, 267–70, 282 Aedes excrucians, 343 “abdominal apoplexy,” 32 Aedes simpsoni, 365 abdominal colic, 185 Aeromonas, 93 abnormal metabolism, 141 aflatoxin, 134 abortive polio, 258 Africa abruptio placentae, 111 African trypanosomiasis, 7–13 An Account of the Foxglove (Withering), 104–5 AIDS, 2–3, 5–6 acidosis, in milk sickness, 219 ainhum, 14 acquired immune deficiencysyndrome(AIDS), amebic dysentery, 20 1–7 anemia, 24–25 from blood transfusions, 54 anthrax, 30 characteristics, 1–3 arenaviruses, 38–39 histoplasmosis in, 165 ascariasis, 42 history, 3–5 bleeding disorders, 55–57 homosexualityand, 3–4 brucellosis, 59 origin of, 5–6 bubonic plague, 63 pneumonia in, 255 cancer, 65 strongyloidiasis and, 306 cholera, 77 toxoplasmosis in, 2, 330 cystic fibrosis, 84 transmission patterns, 1–2 cytomegalovirus infection, 85 tuberculosis and, 342 dengue, 86 acrodermatitis chronic atrophicans (ACA), 203 diabetes, 89–92 Actinomadura madurae, 131 Down syndrome, 98 actinomycetoma, 131 dracunculiasis, 98–100 active SCOM, 209 Ebola virus, 107–109 acute anterior poliomyelitis, 258. See also echinococcosis, 110 poliomyelitis emphysema, 113 acute coalescent mastoiditis, 209 encephalitis, 115 acute epiglottitis, 81–82 fascioliasis, 123 acute granulocytic leukemia, 197 favism, 124 acute laryngotracheitis, 82 filariasis, 125, 127 acute lymphatic leukemia, 197 fungal infections, 129, 131 acute lymphoblastic leukemia (ALL), 197 fungus poisoning, 134 acute lymphocytic leukemia, 197 gallstones, 135 acute myeloblastic leukemia, 197 gonorrhea, 151 acute myelocytic leukemia, 197 gout, 156 acute myelogenous leukemia, 197 heart-related diseases, 160 acute myeloid leukemia (AML), 197 herpes simplex, 161 acute nonlymphocytic leukemia (ANLL), 197 hookworm infection, 166–167 acute otitis media (AOM), 208–11 infectious hepatitis, 172 acute pulmonaryhistoplasmosis, 163 infectious mononucleosis, 174 adult T-cell leukemia, 197 influenza, 180 Aedes aegypti, 35, 36, 85–87, 365–66, 368–69 lactose intolerance, 183 Aedes africanus, 365 Lassa fever, 184–185

381 Subject Index

Africa (continued ) beriberi and, 46 leishmaniasis, 191–192 cirrhosis and, 79–81 leprosy, 192 diabetes and, 91 Lyme disease, 201 heart disease and, 160 malaria, 203, 204–206 lead poisoning from, 186–88 Marburg virus, 207–208 osteoporosis and, 237 meningitis, 215–217 tetanyand, 329 multiple sclerosis, 220 alcoholic fattyliver, 80–81 onchocerciasis, 228–230 “Aleppo boil,” 192 ophthalmia, 230, 234 alimentarytoxic aleukia, 133 osteoarthritis, 235–236 “alkali poisoning,” 218 osteoporosis, 238 alkalosis, 329 paragonimiasis, 240 alkaptonuria, 141 pellagra, 244 Allodermanyssus sanguineus, 285 pica, 247, 249–250 allopurinol, 154 pneumonia, 258 alpha-2-antiplasmin deficiency, 56 poliomyelitis, 260–261 Alzheimer’s disease, 14–19, 116 protein–energymalnutrition, 262, 264–265 Amanita caesarea, 133 Q fever, 269 Amanita muscaria, 133 rabies, 270–271, 274 Amanita pantherina, 133 relapsing fever, 275–277 Amanita phalloides, 133 rheumatic fever, 279 Amanita rubescens, 133 rickets, 282 Amanita verna, 133 schistosomiasis, 290–292 Amanita virosa, 133 sickle-cell anemia, 299–300 amaurotic familyidiocy,321 smallpox, 301, 303 Amblyomma americanum, 283 spotted fever, 285 Amblyomma cajennense, 283 strongyloidiasis, 306 amebiasis, from Carrion’s´ disease, 68 sudden unexplained death syndrome, 311 amebic dysentery, 19–21 syphilis, 313–314 amenorrhea, 27, 102, 120 syphilis, nonvenereal, 317, 319 American spotted fever (RockyMountain spotted tapeworm infection, 320 fever), 282–85 tetanus, neonatal, 326 American trypanosomiasis, 70–71 treponematoses, 332 Amerindians trichinosis, 334 diabetes, 90–92 tuberculosis, 337 gallstones, 134 typhoid fever, 346, 348 malaria, 206 typhus, epidemic, 354 osteoarthritis, 235–236 urolithiasis, 357 osteoporosis, 238 yaws, 362, 364 pellagra, 242 yellow fever, 36, 365–367, 369 pica, 249 “African lethargy,” 9 smallpox, 300–301 African trypanosomiasis, 7–13 typhus, epidemic, 353 characteristics, 7–9 aminopterin, 199 effects of colonialism on, 11–13 amnesia, 16 encephalitis lethargica and, 115 amphotericin B, 165 history, 9–13 amyloidosis, 145 treatment, 13 amyloid protein, 18–19 agnosia, in Alzheimer’s disease, 16 amylophagia, 247 AIDS. See acquired immune deficiency anaphylactic reaction, 96, 110 syndrome anasarca, 100 ainhum, 14 Ancylostoma duodenale, 165, 167 air-pollution disease, rickets as, 281 anemia, 21–26 albinism, 139, 141 in arthritis, 40 albuminuria, 145–46 from Carrion’s´ disease, 67–68 alcohol consumption fasciolopsiasis, 123

382 Subject Index

glucose 6-phosphate dehydrogenase [G6PD] gallstones, 136 deficiency, 22, 23–24, 123–25 gangrene, 137 hemolytic, 23–24, 299 genetic disease, 139 from hookworm infection, 165–67 gonorrhea, 151–152 hypochromic, 73 leprosy, 194 iatrogenic, 22 measles, 213 in inflammatorybowel disease, 175–76 ophthalmia, 232 iron-deficiency, 21, 22–23, 26, 71–74, 248–49 periodontal disease, 246 in lead poisoning, 21, 185 pica, 248 in leishmaniasis, 192 plague of Athens, 251–254 in leukemia, 198 poliomyelitis, 260 malaria and, 22, 25–26 rabies, 272 in malnutrition, 263 rickets, 280 from parasites, 21 smallpox, 301 pernicious, 22 thalassemia, 26 and porotic hyperostosis, 26 tuberculosis, 338 from Q fever, 269 urolithiasis, 358 in scarlet fever, 289 antithrombin III deficiency, 57 sickle-cell, 22, 24–25, 125, 142, 256, 298–300 aortic insufficiency, 280 from strongyloidiasis, 306 aortic stenosis, 280 from tapeworm infection, 320 aphasia, 16 from trichuriasis, 336 aplastic crises, 299 aneurism, syphilis and, 314 apnea, 32, 308 “angel wings,” 166 apolipoprotein E (APOE4), 19 angina pectoris, 69, 155, 157. See also heart-related “apoplectic attack,” 31 diseases “apoplectic ictus,” 31 angiosclerosis. See hypertension apoplexy, 31–34. See also stroke angiotensin, 171 appendicitis, 176, 336 animal trponematosis, 314 apraxia, 16 ankylosing spondylitis, 41 Arachis hypogea, 133 ankylosis, 236 arboviruses, 34–38 The Annals of the Convent at Xanten (Mezeray),´ 121 characteristics, 34–35 Anopheles, 10, 204, 206–7 dengue, 35–36, 85–88, 366 Anopheles atroparvus, 206 encephalitides, 36–37 Anopheles labranchiae, 206 Japanese B encephalitis, 36, 38, 181–82, 366 Anopheles sacharovi, 206 treatment and control, 37–38 anorexia yellow fever, 35, 36, 282–83, 365–66 brucellosis and, 59 arenaviruses, 38–39, 107, 184–85 chlorosis and, 73 Argentine hemorrhagic fever (Junin), 38–39, 184 eclampsia and, 111 arrhythmias, in sudden infant death syndrome, malnutrition and, 262 308 nervosa, 26–29, 41, 73 arsenic, for leukemia, 198 in tremetol poisoning, 219 arteriosclerosis, 17, 136, 138, 155 in ulcerative colitis, 175 arthralgias, 163, 200, 202, 279, 287 anorexia nervosa, 26–29, 41, 73 arthritis, 39–42 anoxic convulsions, 360 in alkaptonuria, 141 anthrax, 29–31, 120, 348 in dracunculiasis, 99 antiquity gonococcal, 278 Alzheimer’s disease, 14 in gonorrhea, 150 anthrax, 30–31 in histoplasmosis, 163 arthritis, 41 in inflammatorybowel disease, 175–76 ascariasis, 42 in lupus erythematosus, 200 bacillarydysentery,44 in Lyme disease, 202 cancer, 63 in meningitis, 215 cirrhosis, 80 in mumps, 223 epilepsy, 118 osteoarthritis, 41, 133, 234–36, 239, 278

383 Subject Index arthritis, (continued ) ringworm, 130 in Paget’s disease of bone, 238 scarlet fever, 289 in rheumatic fever, 279 sudden infant death syndrome, 306 rheumatoid, 39–42, 53, 137, 201, 227 sudden unexplained death syndrome, 311 in rubella, 287 syphilis, 314 streptococcal infection and, 304 syphilis, nonvenereal, 319 ascariasis, 42, 255 tuberculosis, 337 Ascaris, 336 typhus, murine, 355 Ascaris lumbricoides, 42 typhus, scrub, 356 ascaris pneumonitis, 42 yaws, 364 ascites, 80, 100–3 autoimmune responses, 16, 22, 225–27. See also ascorbate, 26 acquired immune deficiencysyndrome; aseptic meningitis, 214 immune system dysfunction Asia. See East Asia; Middle and Near East; Russia; autoinfection, 306, 320 South Asia; Southeast Asia “autumnal fever,” 350 Asian SUDS, 309–11 autumnal hepatitis, 171. See also hepatitis aspergillosis, 128, 132 avian tuberculosis, 193 Aspergillus, 132 Ayurvedic medical text, 358 Aspergillus flavus, 134 azidothymidine (AZT), 6 Aspergillus fumigatus, 132 Aspergillus niger, 132 B aspiration pneumonia, 327 bacillarydysentery,21, 43–44 asthma, ascariasis and, 42 Bacillus anthracis, 29–30 asynapsis, 143 bacillus Calmette-Guerin´ (BCG), 338 Atharva Veda, 358 Bacillus lactimorbi, 218 “athlete’s foot,” 129 bacteremia, 347 atoxyl, 13 bacterial conjunctivitis, 231. See also conjunctivitis atrial fibrillation, 104 bacterial endocarditis, 304–5. See also endocarditis Australia and New Zealand bacterial pneumonia, 255. See also pneumonia AIDS, 1 Bacterium tularense, 344 beriberi, 46 Balantidium coli, 265 bubonic plague, 63 “Balkan influenza” (Q fever), 190, 255, 267–70, cirrhosis, 79 282 dengue, 86 Bancroftian filariasis, 125–28 echinococcosis, 110 Bangungut, 310 encephalitides, 36 “Bannwarth’s syndrome,” 203 filariasis, 127 “Barbados distemper,” 365 gout, 155–156 Bartonella bacilliformis, 67–68 heart-related diseases, 160 Bartonella verrugiformis, 67–68 hookworm infection, 167 bat rabies, 274 infectious hepatitis, 173 Bauerwetzel, 224 inflammatorybowel disease, 176 beef tapeworm, 319–20 influenza, 180 bejel, 317–18 lactose intolerance, 183 benign prostatic hypertrophy, 357 lead poisoning, 188 benign SCOM, 209 leprosy, 193 benign tertian malaria, 203 leptospirosis, 196 beriberi, 44–49, 101, 133, 298 Lyme disease, 201 “big-belly,” 290 measles, 213 bilharzia (schistosomiasis), 167, 290–92, 357 meningitis, 216 biliarycirrhosis, 79, 134 multiple sclerosis, 221–222 biliarystasis, 134 ophthalmia, 230 biliarytract disease, 106, 346 osteoporosis, 238 bipolar disease, leprosyas, 193 Paget’s disease of bone, 238 birth defects, 139–40 poliomyelitis, 260 Black Death, 49–52. See also bubonic plague Q fever, 267, 269–270 black lung, 52–54

384 Subject Index

“black measles” (RockyMountain spotted fever), history, 62–63 282–85 as Plague of Athens, 252, 253 bladder cancer, 65 Buerger’s diease, 137 bladder-stone disease, 357 bunions, 235 blains, 364 “butterfly” facial rash, 200 blastomycosis, 130–31 “button-scurvy,” 318 bleeding disorders, 54–57 byssinosis, 52–54 “bleeding fever,” 365 blennorrhagia, 316 C blindness, 300, 321 cachexia, 249, 335 blood cancer (leukemia), 66, 196–99, 254, cachexia Africana, 249 359 calcium deficiency, 329–30 “blue disease” (RockyMountain spotted fever), calculus, 245 282–85 Calomys, 39 bocio, 146 calorie deficiency, 262 Bolivian hemorrhagic fever, 38–39 “camp fever,” 352 bone loss. See osteoporosis Campylobacter, 43–44 Book of Medicine (Assyrian), 358 campylobacteriosis, 43–44, 93 “boomerang leg,” 364 Canada. See North America borborygmus, 183 cancer, 63–67 Bordetella parapertussis, 360 ancient occurrences, 63–64 Bordetella pertussis, 360 bladder, 65 Borrelia, 275 breast, 63–65 Borrelia burgdorferi, 201–3 causes, 64 Borrelia recurrentis, 275 cervix, 66–67, 161 botulism, 57–58, 115, 308 colorectal, 65–66 Bouchard’s nodes, 235 death rates, 160 boutonneuse fever, 285 gastric, 67 bovine rabies, 270 hepatitis B and, 172 bovine tuberculosis, 193, 337 kidney, 65 bradycardia, 27, 86, 196 leukemia, 66, 196–99 bradykinesia, 240–41 liver, 67, 81, 134, 172 brain damage, 185, 210, 264 lung, 65–66 brain tumors, epilepsyand, 117 lupus as, 199 “brandyliver,” 80 prostate, 65–66 “breakbone fever,” 87 scrotal, 64 breast cancer, 63–65 skin, 66, 281 Bright’s disease, 144–46 stomach, 65, 67 Brill’s disease, 353 strongyloidiasis and, 306 Brill-Zinsser disease, 353 thyroid, 66, 147 broad fish tapeworm, 320 uterine, 65 bronchiectasis, 360 Candida albicans, 2, 130 bronchitis, 113, 178, 276 candidiasis, 2, 130 bronchocele, 146 canine distemper, 212 bronchopneumonia, 70, 255, 327 canine rabies, 270–71, 275 brown lung, 52–54 Caplan’s syndrome, 53 Brucella, 351 Caraka Samhita, 41 Brucella abortus, 58–60 carate, 250–51 Brucella melitensis, 58–60 carbolic acid, 137 Brucella suis, 58–60 carcinoma, 63, 106, 175 brucellosis, 58–60, 108, 351 cardiac asthma, 101 Brugia malayi, 125 cardiac beriberi, 133 “bubas,” 364 cardiac disease. See heart disease bubonic plague cardiac insufficiency, 159 as Black Death, 49–52 cardiac murmurs, 158–59 characteristics, 60–62, 282–83 cardiogenic shock, 102

385 Subject Index cardiovascular disease, 264, 314. See also heart pinta, 250 disease; heart-related diseases poliomyelitis, 261 carditis, 279, 304–5 protein-energymalnutrition, 262 Caribbean RockyMountain spotted fever, 284 AIDS, 4 syphilis, 313 arenaviruses, 38 toxoplasmosis, 331 cancer, 65 yellow fever, 36, 366–369 Chagas’ disease, 70 cephalic tetanus, 324 cholera, 77 cephalopelvic disproportion, 264 cytomegalovirus infection, 85 Cercopithecus, 208 dengue, 86 cerebellar ataxia, 268 diabetes, 90 cerebral arteriosclerosis, 17 filariasis, 127 cerebral hemorrhage, 32, 111 glomerulonephritis, 145 cerebral infarction, 33 G6PD deficiency, 24 cerebral schistosomiasis, 291 hookworm infection, 166–168 cerebral toxoplasmosis, 330 lupus erythematosus, 201 “cerebrospinal fever,” 214 malaria, 204 cerebrospinal meningitis (CSM), 214–17 measles, 214 cerebrovascular attacks, 117 onchocerciasis, 228 cerebrovascular disease (CVD), 32–33, 117 ophthalmia, 234 cervical cancer, 66–67, 161 osteoarthritis, 235 cestode infection, 70. See also tapeworm infection pica, 249 Chagas’ disease, 70–71, 160 protein-energymalnutrition, 263 chancre, 162, 314, 316, 318 rabies, 274 chancroid, 316–17 schistosomiasis, 290 charbon malin, 29, 31. See also anthrax tetanus, neonatal, 326 Cheyne-Stokes respiration, 32 yaws, 362 chickenpox, 162, 285, 359–60 yellow fever, 36, 368–369 childbed fever, 265–67, 304 caries, bone, 294 China. See East Asia, China caries, dental, 245, 305 chincough, 360–62 carpal-tunnel syndrome, 40, 239 Chinese liver fluke, 81 carpopedal spasms, 329 chirimacha, 71 Carrion’s´ disease, 67–69 Chlamydia trachomatis, 230–31 cataracts, 287 chlorosis, 23, 71–74. See also iron deficiencyanemia catarrh, 69–70 cholangitis, 134 catherization, cardiac, 158 cholecystitis, 134 cellulitis, 121–22, 136, 266, 288, 304–5 cholelithiasis, 134–36 Central America cholera, 74–78, 93, 128, 180 AIDS, 2 cholera morbus, 74, 76 ainhum, 14 cholera nostras, 74 amebic dysentery, 20 cholesteatoma, 209 bacillarydysentery,43 cholesterol, 33, 134, 160 cholera, 77 chorea, 168–69, 304 dengue, 87 chorioretinitis, 84 filariasis, 125 Christianity gonorrhea, 151 Black Death and, 50–52 histoplasmosis, 163 epilepsyand, 119 hookworm infection, 166, 168 ergotism and, 120–21 influenza, 180–181 leprosyand, 194 leishmaniasis, 191 Saint Anthony’s fire and, 287–88 malaria, 204, 206 scrofula and, 293–94 mycoses, 130–131 sudden infant death syndrome and, 309 onchocerciasis, 228–229 Christmas disease, 54–55, 57 ophthalmia, 230 chromatolysis, 323 paragonimiasis, 240 chronic active hepatitis, 173. See also hepatitis

386 Subject Index chronic cavitaryhistoplasmosis, 163 in Marburg virus disease, 208 chronic dust-induced respiratorydisease, 52–54 in measles, 212 chronic granulocytic leukemia (CGL), 197 in rubella, 286 chronic kidneydisease, 145. See also simple acute, 231 glomerulonephritis in tularemia, 344 chronic lymphatic leukemia, 197 in varicella-zoster virus disease, 359 chronic lymphocytic leukemia (CLL), 197 viral, 231 chronic lymphogenous leukemia, 197 Conn’s syndrome, 170 chronic myelocytic leukemia, 197 consumption, 339. See also tuberculosis chronic myelogenous leukemia, 197 contagious abortion, 59 chronic myeloid leukemia (CML), 197 continued fever, 350 chronic schistosomiasis, 291 convulsions, 120, 185, 215, 329–30, 360 chronic suppurative otitis media (CSOM), 209 convulsive ergotism, 120 Chrysops discalis, 343–44 “coolie itch,” 165 chyluria, 125–27 corneal herpes, 161 cicatrizing trachoma, 231 coronaryarterydisease, 101, 157 cinchona, 206 coronarydisease, 159 cirrhosis, 79–81, 100, 173 coronaryheart disease, 157, 159–60 citreoviridin toxin, 133 cor pulmonale, 101 Claviceps purpurea, 120, 136 Corynebacterium diphtheria, 82–83, 94–95 clonorchiasis, 81 coryza, 82, 212, 251 Clonorchis sinensis, 81 cotton dust, 52–54 Clostridium botulinum, 57–58, 308 cowpox, 300, 303–4 Clostridium difficile, 93 Coxiella burnetii, 267–70 Clostridium perfringens, 93 coxsackievirus, 214 Clostridium tetani, 323, 326–27 “crab yaws,” 362 coal workers’ pneumoconiosis (CWP), 52–54 cranial nerve palsies, 202, 241 coccidioidomycosis, 130 craw-craw, 228 Cochin-China diarrhea, 306 creatine phosphokinase, 224 “cocktails,” antiviral, 6 cretinism (congenital hypothyroidism), 98, 147 colchicum, 154 Crohn’s disease, 106, 175–78 colds, 70, 82, 178 croup, 81–83. See also diphtheria cold sores, 161 cryptococcosis, 131–32 “colic,” 185 Cryptococcus, 214 “colica pictonum, 187 Cryptococcus farciminosus, 164 “colic of Poitou,” 187. See also lead poisoning Cryptococcus neoformans, 131–32 colon cancer, 65, 177 Culex tritaeniorhyncus, 181–82 color blindness, 140 Cushing’s syndrome, 170 colorectal cancer, 65–66, 177 cutaneous anesthesias, 39 congenital afibrinogenemia, 56 cutaneous anthrax, 29. See also anthrax congenital disorders, 140. See also genetic factors cutaneous degeneration, 40 congenital dysfibrinogenemia, 56 cutaneous diphtheria, 95 congenital heart disease, 97, 160, 261 cutaneous herpes, 161 congenital hypofibrinogenemia, 56 cutaneous hyperesthesia, 39 congenital hypothyroidism, 98, 147 cutaneous leishmaniasis, 191 congenital rubella syndrome (CRS), 286 cutaneous tuberculosis, 199 congenital syphilis, 85, 313, 333. See also syphilis cutaneous tularemia, 344 congestive heart failure, 100–1, 158, 166 cyanosis, 75, 86, 117, 256, 360 conjunctivitis, 231–34 Cyclops, 99 bacterial, 231 cynanche maligna, 289. See also diphtheria in Bolivian hemorrhagic fever, 39 cysticercosis, 320 in Ebola virus disease, 108 cystic fibrosis, 83–84, 261 in gonorrhea, 232 cystinuria, 141 granular, 230–31 cytogenetics, 143–44 from herpes simplex, 161 cytomegalic inclusion disease (CID), 84–85 history, 232–34 cytomegalovirus infection, 2, 84–85, 162, 255

387 Subject Index

D gout and, 154 DaCosta’s syndrome, 158–59 heart disease and, 160 dactylitis, 363 history, 88–89 DDT, 354 insulin-dependent (Type I), 88–89, 91 deafness, 223, 287 non-insulin-dependent (Type II), 88, 89–90, 91 “deer-flyfever,” 343–44 similarityto leprosy,194 deficiencydiseases. See also diet; malnutrition; thriftygene theoryand, 135 vitamins tropical, 88, 90–91 beriberi, 44–49 diarrhea. See also dysentery goiter, 146–49, 330 acute, 92–94 G6PD deficiency, 22, 23–24, 123–25, 205, 284 in amebic dysentery, 20 iron deficiencyanemia, 21, 22–23, 26, 71–74, anemia from, 23 248–49 in Argentine hemorrhagic fever, 39 pellagra, 242–44 ascariasis and, 42 rickets, 26, 280–82, 329–30 in bacillarydysentery,44 scurvy, 295–98 in cholera, 74–75 sudden infant death syndrome and, 308 in clonorchiasis, 81 tetany, 328–30 Cochin-China, 306 deforming arthrosis, 236 in colchicum, 154 degenerative joint disease. See osteoarthritis in cystic fibrosis, 83 dehydration, 263–64, 335 enteric, 340 Delaneyamendment of 1958, 66 in fasciolopsiasis, 123 “Delhi boil,” 192 in giardiasis, 93, 144 delirium, 215, 347 in inflammatorybowel disease, 175–76 delta agent, 174. See also hepatitis in lactose intolerance, 93, 183 dementia lead poisoning and, 185 in Alzheimer’s disease, 14–15, 17–19 in Legionnaires’ disease, 189 in cancer, 15 in leishmaniasis, 192 depression and, 15 in leukemia, 198 in Huntington’s disease, 168 malnutrition and, 93, 262 multi-infarct, 15 in Marburg virus disease, 208 in pellagra, 242 in measles, 212, 253 stroke and, 15 in pellagra, 242 in syphilis, 314 in pica, 249 demyelination, 221–22 in salmonellosis, 346 dengue, 35–36, 85–88, 366 salt depletion in, 170 dengue triad, 86 in tapeworm infection, 320 depression, 15, 178 tetanyand, 329 Dermacentor andersoni, 283, 343 in toxoplasmosis, 330 Dermacentor variabilis, 283 in trichinosis, 334 Dermacentroxenus rickettsi, 284. See also Rickettsia in trichuriasis, 336 rickettsii in tularemia, 344 dermatitis, 165, 242 in typhomalarial fever, 349 dermatophytosis, 128–30 diarrheal diseases, 92–94 dermatosis, 263 dichuchwa, 319 desert sores, 95 Dick test, 290 desquamation, 289 diet. See also deficiencydiseases; malnutrition; “devil’s fire,” 120 vitamins “dew poison,” 165 aflatoxins, 134 diabetes mellitus (DM), 88–92 beriberi and, 44–49 candida infection and, 132 cancer and, 66–67 characteristics, 91–92 diabetes mellitus and, 89–90 eclampsia and, 111 ergotism and, 120–21 gangrene in, 137 favism and, 123–25 gestational, 88, 91 fungus poisoning and, 132–34 glomerulopathies, 145 gallstones and, 134

388 Subject Index

goiter and, 148–49 dwarf tapeworm, 320 gout and, 154–56 dysentery, 105. See also diarrhea hookworm infection and, 166–67 amebic, 19–21 hypertension and, 169 bacillary, 21, 43–44 iron deficiencyanemia and, 21, 22–23, 26, 71–74 characteristics, 105 milk sickness and, 218 diarrheal diseases, 92–94 osteoporosis and, 237–38 enteric diarrhea and, 340 pellagra and, 242–44 dysmimia, 226 pica, 72, 188, 247–50 dyspepsia, 105–7, 166 protein-energymalnutrition, 261–65 dysphagia, 108, 226–27 rickets and, 280–82 dysphonia, 226 scurvyand, 295–98 dyspnea trichinosis and, 333–36 in brown lung, 53 typhoid fever and, 346 in croup, 82 urolithiasis and, 357 dropsyand, 101–2 in Victorian times, 72 in histoplasmosis, 163 Digitalis lanata, 105 in myasthenia gravis, 226 Digitalis purpurea, 105 in pneumonia, 256 diphtheria, 94–96 in varicella-zoster virus disease, 359 characteristics, 94–95 dysuria, 161, 291 croup and, 81–83 cutaneous, 95 E history, 95–96 ear infections scarlet fever and, 289, 305 acute otitis media, 208–11 tetanus and, 325 mastoiditis, 208–11, 304 Diphyllobothrium latum, 319–20 otitis media, 212, 289, 304, 360 diplopia, 226 otitis media with effusion, 209 Dipylidium canium, 319 East Asia discoid lupus erythematosus (DLE), 199–201 arenaviruses, 38–39 disseminated gonococcal infection (DGI), bubonic plague, 62, 63 150 cancer, 67 disseminated histoplasmosis, 163–64 cholera, 77 disseminated lupus erythematosus, 200 dengue, 86 distal radius fractures, 237 diabetes, 90 DNA. See genetic factors encephalitis, 115 dog tapeworm, 319 gonorrhea, 151 Down syndrome, 16, 19, 96–98, 143 herpes simplex, 161 DPT vaccine, 325–26 influenza, 180 dracunculiasis, 98–100 lactose intolerance, 183 Dracunculus medinensis, 98–99 leishmaniasis, 191 “drip,” 150 leptospirosis, 196 dropsy, 100–5 malaria, 204 in beriberi, 47 ophthalmia, 230 characteristics, 100–2 poliomyelitis, 261 history, 102–5 protein-energymalnutrition, 262 in hookworm infection, 166 rabies, 270 in hypertension, 170 sudden infant death syndrome, 306 in scarlet fever, 145–46, 289 tapeworm infection, 320 drug addiction, epilepsyand, 117 tetanus, neonatal, 326 drunken bread syndrome, 133 treponematoses, 332 “drybellyache,” 185, 187 typhus, scrub, 356 drygangrene, 136 yaws, 362 Dubin-Johnson syndrome, 56 China Duchenne muscular dystrophy (DMD), 224–25 amebic dysentery, 20 “Dumdum” fever (leishmaniasis), 191–92 anthrax, 30 duodenal ulcer, 107 ascariasis, 42

389 Subject Index

East Asia, China (continued ) inflammatorybowel disease, 176 beriberi, 45 Japanese B encephalitis, 181–182 Black Death, 49 lactose intolerance, 183 brucellosis, 59 leptospirosis, 195 bubonic plague, 63 leukemia, 198 cancer, 67 Lyme disease, 201 cholera, 76–77 ophthalmia, 230 clonorchiasis, 81 osteoporosis, 238 diabetes, 89, 91 paragonimiasis, 240 fasciolopsiasis, 123 schistosomiasis, 290–291 favism, 123 stroke, 33 filariasis, 125, 127–128 sudden infant death syndrome, 306 fungus poisoning, 133 sudden unexplained death syndrome, 309, gallstones, 134 311 goiter, 146 tuberculosis, 337, 339, 341 gout, 156 tularemia, 343–344 G6PD deficiency, 23 typhus, epidemic, 354 hookworm infection, 166 typhus, scrub, 356 inflammatorybowel disease, 176 urolithiasis, 357 Japanese B encephalitis, 182 Korea lead poisoning, 186, 188 beriberi, 45 leishmaniasis, 191 cholera, 77 leprosy, 195 diabetes, 89 leptospirosis, 196 fasciolopsiasis, 123 Lyme disease, 201 paragonimiasis, 240 malaria, 205 typhus, epidemic, 354 measles, 213 typhus, scrub, 356 meningitis, 215–216 eastern equine encephalitis (EEE), 35, 36, 38 ophthalmia, 230 East India Company, 296 paragonimiasis, 240 Ebers Papyrus, 99, 102, 162, 167, 232, 246 pica, 249 Ebola hemorrhagic fever (EHF), 109 rheumatic fever, 279 Ebola virus disease, 107–10, 208 schistosomiasis, 290–292 echinococcosis, 110 smallpox, 301–302 Echinococcus granulosis, 110, 319 tapeworm infection, 319 echovirus, 214 tuberculosis, 337–338 eclampsia, 110–12 typhomalarial fever, 349 eczema, 194, 251 typhus, scrub, 356 edema urolithiasis, 357–358 in beriberi, 47 Japan in eclampsia, 110 bacillarydysentery,43 in influenza, 181 beriberi, 45–48 in Japanese encephalitis, 182 bleeding disorders, 56–57 in kwashiorkor, 261, 263 botulism, 58 in pinta, 251 cancer, 65, 67 in trichinosis, 335 cholera, 77 effort syndrome, 159 cirrhosis, 79 “Egyptian chlorosis,” 166 clonorchiasis, 81 electrocardiogram, invention of, 157–58 diabetes, 89–91 elephantiasis, 125–28 Down syndrome, 98 embolic pneumonia, 255 encephalitis, 38 embolism, 137 filarisasis, 125 empeines, 250 fungus poisoning, 133 emphysema, 112–14, 163 gallstones, 134–135 empyema, 256 gout, 156 enanthem, 184, 208 hookworm infection, 166 encephalitides, 34, 36–37, 86

390 Subject Index encephalitis Ebola virus disease, 107–8 Japanese, 36, 38, 115, 181–82, 366 encephalitis lethargica, 114–16, 240–41 lethargica, 114–16, 179, 240–41 ET-NANBH, 174 Lyme disease and, 202 glomerulonephritis, 145 measles and, 212 gonorrhea, 151 meningitis and, 214 influenza, 179–81, 258 mumps and, 223 Japanese B encephalitis, 181 rabies and, 115 lead poisoning, 187 rubella and, 287 Legionnaire’s disease, 189–90 scrub typhus and, 356 measles, 213, 253 trichinosis and, 335 meningitis, 215–17 varicella-zoster virus disease and, 359 mumps, 224 encephalitis lethargica, 114–16, 179, 240–41 Plague of Athens, 251–54 encephalomyelitis, 196 pneumonia, 256 endemic bladder-stone disease, 357 polio, 258–61 endemic cretinism, 147–49 puerperal fever, 266 endemic goiter, 146–49 Q fever, 267, 269 endemic syphilis. See syphilis rabies, 274 endemic typhus, 355. See also typhus relapsing fever, 276–77 endemic yellow fever, 365. See also yellow fever rubella, 286 endocarditis scarlet fever, 288–89 anemia in, 72 smallpox, 301–2 Candida, 132 sporotrichosis, 131 drug abuse and, 159 sweating sickness, 276, 311–12 lupus and, 200 trachoma, 233–34 Q fever and, 267 trypanosomiasis, 10–13 streptococcal, 304–5 tuberculosis, 339–40, 342 endomyocardial fibrosis, 160 typhus, 275, 282–83, 353–55 energydeficiency,262 yellow fever, 365–69 enfermedad de Robles (onchocerciasis), 125, epidemic typhus, 275, 282–83, 353–55 228–30, 234 epidemic yellow fever, 365–69. See also yellow Entamoeba coli, 19 fever Entamoeba hartmanni, 19 Epidermophyton, 129 Entamoeba histolytica, 19–21, 105 Epidermophyton floccosum, 129 entericallytransmitted non-A, non-B hepatitis epilepsy, 31, 111, 116–19 (ET-NANBH), 171, 174 Epstein-Barr virus, 162, 174–75 enteric fever, 345. See also typhoid fever equine encephalitis, 115, 173 enteric infection, 93, 175 equine rabies, 270 enterobiasis, 116 ergot intoxication, 288 Enterobius vermicularis, 116 ergotism, 120–21 eosinophilia, in trichinosis, 335 characteristics, 120 epidemic parotitis, 222. See also mumps gangrene in, 136–37 epidemics history, 120–21 AIDS, 1–7 as Plague of Athens, 252–53 Alzheimer’s disease, 18 Saint Anthony’s fire in, 287–88 anthrax, 29–30 sweating sickness and, 312 bacillarydysentery,43 erosive arthritis, 42. See also arthritis beriberi, 46 erosive inflammatoryosteoarthritis, 235 Black Death, 49–52 erosive joint disease, 41 bubonic plague, 49–52, 60–63, 252–53, erysipelas, 121–22, 136, 257, 288, 304–5 282–83 erysipelas grave internum, 122 Carrion’s´ disease, 68–69 erythema, 208 cholera, 74–77 erythema chronicum migrans (ECM), 202–3 croup, 83 erythema marginatum, 277, 304 dengue, 86–87 erythema migrans, 203 diphtheria, 94 erythema nodosum, 163

391 Subject Index erythematous maculopapular rash, 184 histoplasmosis, 163 eschar, 285 hookworm infection, 166–167 Escherichia coli, 43, 93, 214 infectious hepatitis, 172 esophagitis, 106 inflammatorybowel disease, 176–177 espundia (leishmaniasis), 191–92 influenza, 179–180 essential fevers, 350 lactose intolerance, 183 essential hypertension, 169 lead poisoning, 185–188 estrogen, 134, 237 leprosy, 193–195 ET-NANBH, 171, 174. See also hepatitis leptospirosis, 195–196 eumycetoma, 131 Lyme disease, 201, 203 Eupatorium urtacaefolium, 218 malaria, 206–207 Europe Marburg virus, 207 AIDS, 1–2 meningitis, 215–216 amebic dysentery, 20 multiple sclerosis, 221 anemia, 25–26 mumps, 224 anthrax, 29–31 myasthenia gravis, 225 arenaviruses, 38 ophthalmia, 232–234 arthritis, 42 osteoarthritis, 235–236 ascariasis, 42 Paget’s disease of bone, 239–240 bacillarydysentery,44 Parkinson’s disease, 240 black and brown lung disease, 52–53 pellagra, 243–244 Black Death, 50–52 pica, 248–249 bleeding disorders, 55, 56 poliomyelitis, 259–261 botulism, 58 puerperal fever, 266–267 brucellosis, 58–59 Q fever, 267–270 bubonic plague, 60, 62–63 rabies, 272–274 cancer, 65 relapsing fever, 276–277 cholera, 74–75, 77 rheumatic fever, 279 cirrhosis, 79–80 rickets, 280–281 croup, 83 ringworm, 129 cystic fibrosis, 84 rubella, 286 cytomegalovirus infection, 85 Saint Anthony’s fire, 288 dengue, 86 scarlet fever, 288–290 diabetes, 90 scrofula, 293–294 diphtheria, 95 scurvy, 297–298 Down syndrome, 96 smallpox, 301–303 dropsy, 101–105 strokes, 32–33 Ebola virus, 109 sudden infant death syndrome, 306 echinococcosis, 110 sweating sickness, 311–312 emphysema, 113 syphilis, 314–316, 318 encephalitis lethargica, 115 tapeworm infection, 320 epilepsy, 119 Tay-Sachs disease, 322–323 ergotism, 120–121 tetanus, 325–326 fascioliasis, 123 tetanus, neonatal, 326 favism, 123–124 tetany, 330 fungal infections, 130–132 toxoplasmosis, 330 fungus poisoning, 133 trench fever, 331 gallstones, 135 treponematoses, 332 gangrene, 136, 138 trichinosis, 334–335 glomerulonephritis, 145 tuberculosis, 337, 339–341 goiter, 146–148 tularemia, 343, 345 gonorrhea, 151–152 typhoid fever, 348 gout, 154–155 typhomalarial fever, 350 G6PD deficiency, 23 typhus, epidemic, 353–354 heart-related diseases, 159–160 urolithiasis, 357–358 herpes simplex, 161 whooping cough, 361

392 Subject Index

yaws, 364 Fournier’s gangrene, 137 yellow fever, 36 fox rabies, 274–75 eustachian tube dysfunction, 209 framboesia, 362. See also yaws “evil fire,” 120 Francisella (Pasteurella) tularensis, 343–45 exanthema, 251, 289 Fraser, T. R., 22 exanthematous dermatoses, 359 “French disease,” 313. See also syphilis exercise, diabetes mellitus and, 90 “French pox,” 315. See also syphilis frostbite, 137, 194 F fulminating blood infection, 215 facio-scapulo-humeral dystrophy (FSHD), 225 functional asplenia, 256 factor VII deficiency, 56 functional dyspepsia, 105–6 “faeco-malarial fever,” 351 fungemia, 163 falciparum malaria, 300 fungus infections (mycoses), 128–32 false croup, 83 blastomycosis, 130–31 famine, pica and, 249 candidiasis, 2, 130 “famine fever,” 275, 352. See also relapsing fever coccidioidomycosis, 130 farcy, 164 cryptococcosis, 131–32 Fasciola hepatica, 123 histoplasmosis, 130, 163–65 fascioliasis, 123 opportunistic and iatrogenic, 131–32 fasciolopsiasis, 123 paracoccidioidomycosis, 130–31 Fasciolopsis buski, 123 rhinosporidiosis, 132 fat intake, 66, 90 ringworm, 129–30, 251 fattydegeneration, 94, 219 sporotrichosis, 131 fatty-liver disease (kwashiorkor), 261–63 fungus poisoning, 132–34 favism, 23–24, 123–25 furfuraceous idiocy, 143. See also Down syndrome Favus, 129 Fusarium, 133 febre maculosa brasiliera (RockyMountain spotted fever), 282–85 G febris miliaria rubra, 289 gallstones, 134–36 fersa, 213 gangosa, 362–64 fiber, diabetes and, 90 gangrene, 136–38 fibrin-stabilizing factor deficiency, 56 cancer and, 63 fibrosis, 80, 255 causes, 136–37 fiebre de Choix (RockyMountain spotted fever), characteristics, 136 282–85 in ergotism, 120 fiebre manchada (RockyMountain spotted fever), in erysipelas, 122 282–85 history, 137–38 “field fever,” 196 in Plague of Athens, 253 “fieryserpent,” 99 in Saint Anthony’s fire, 287 fievre boutonneuse, 285 “gaol fever,” 352 fi`evre jaune, 365 gas gangrene, 136 filarial worms, 125–28, 228–30 gastric cancer, 67 filariasis, 10, 125–28 gastric remittent fever, 351 fistulas, 176, 294 gastric tetany, 328 Fitzgerald trait, 55 gastritis, 106 “five-dayfever,” 331 gastroenteritis, 93–94, 327 Flaujeac trait, 55 gastrointestinal hemorrhage, 347 Flavivirus, 35, 36, 86, 181 gastrointestinal histoplasmosis, 164 Fleckfieber, 352 gastrointestinal tularemia, 344 Fletcher trait, 55 Gaucher’s disease, 320 flu. See influenza genetic disease, 138–44. See also genetic factors folic acid, 199 genetic drift, 322–23 follicular conjunctivitis, 232 genetic factors, 138–44 follicular hyperplasia, 174 in alkaptonuria, 141 “foot drop,” 185 in Alzheimer’s disease, 16 founder effect, 322 in anemia, 22, 26

393 Subject Index genetic factors, (continued ) G6PD deficiency. See glucose 6-phosphate in arthritis, 40, 141, 235 dehydrogenase deficiency birth defects, 139–40 grand mal seizures, 117–19 in bleeding disorders, 54–57 granular conjunctivitis, 230–31. See also in breast cancer, 65–66 conjunctivitis color blindness, 140 granulomas, 177 in cystic fibrosis, 83 grass tetany, 328 in diabetes mellitus, 89, 91 “Great Pestilence,” 49 in diphtheria, 94 “grip.” See influenza in Down syndrome, 96–98, 143 grosse vairolle, 315 in heart disease, 160 “ground itch” (hookworm infection), 165 in hemophilia, 140 “Guinea worm” (dracunculiasis), 98–100 history, 139–42 gumma, 314 in Huntington’s disease, 169 in hypertension, 169–71 H in inflammatorybowel disease, 175–77 Haemagogus, 36, 365 in lactose malabsorption, 183 Haemophilus influenzae type B, 81–82 molecular medicine and, 142–44 Hageman trait, 55 in multiple sclerosis, 222 hairballs, 247 in muscular dystrophies, 224–25 hairy-cell leukemia, 197 in Paget’s disease of bone, 239–40 hand-foot syndrome, 299 in polydactyly, 140 Hansen’s disease. See leprosy in sickle-cell anemia, 142, 298–300 Haplopappus heterophyllus, 218 in Tay-Sachs disease, 320–23 “hard measles,” 211–14 in trisomy, 96, 143 heart block, 202 genital herpes, 161–62. See also herpes viruses heartburn, 106 geophagy, 247–49 heart disease, 156–61. See also heart-related “German measles,” 285–87 diseases gestational diabetes, 88, 91 cardiac insufficiency, 159 giant-cell tumor of bone, 239 causes, 33, 160 giant intestinal fluke, 123 congenital, 97, 160, 261 Giardia lamblia, 93, 144 congestive heart failure, 100–1, 158, 166 giardiasis, 93, 144 coronary, 157, 159–60 gingivitis, 244–46 fattydegeneration, 94 “gin liver,” 80 genetic factors, 138 glandular fever (mononucleosis), 85, 174–75, heart-valve disorders, 267, 278 330 history, 156–61 glandular tularemia, 344 increase in, 159–60 glaucoma, 359 ischemic, 33, 159 glebfieber, 365 percussion technique, 156–57 glomerular disease, 101 rheumatic, 159, 277–80 glomerulonephritis (Bright’s disease), 144–46, heart murmurs, 47, 158–59 304–5 heart-related diseases. See also heart disease Glossina morsitans, 7 beriberi, 47, 101 Glossina palpalis, 7–8 cardiac asthma, 101 glucose 6-phosphate dehydrogenase [G6PD] cardiac beriberi, 133 deficiency, 22, 23–24, 123–25, 205, 284 Chagas’ disease, 70 glycosuria, 88 Down syndrome, 97 GM2(beta) gangliosidosis, 320–21 dropsyand, 100–1, 104 goiter, 146–49, 330 gout, 155 gonococcal conjunctivitis, 232 lupus, 200 gonococcal ophthalmia, 150 muscular dystrophy, 225 gonorrhea, 150–53, 214, 232, 316–17 myocarditis, 70, 268, 287, 304, 335 gout, 153–56, 185, 187, 234, 278. See also arthritis peripartum cardiac failure, 160 goutte asthenique primative, 40 strokes, 33 gozzo, 146 surgery, 280

394 Subject Index

typhoid fever, 347 hilar adenopathy, 163 Heberden’s nodes, 235–36 hip disease, 235. See also arthritis “Heine-Medin disease,” 258. See also poliomyelitis hip fracture, 237–38 helper T4 lymphocytes, 2 Histoplasma capsulatum, 130, 163–65 hematopoiesis, 84 histoplasmosis, 130, 163–65 hematuria, 291, 358 “His-Werner disease,” 331 hemiparesis, 202 HIV infection, 1–2, 5, 115. See also acquired hemiparkinsonism, 241 immune deficiencysyndrome hemiplegia, 237 Hmong people, 311 hemochromatosis, 79 Hodgkin’s disease, 254 hemoglobinura, 124 “holyfire,” 120 hemolysis, 23 honey, botulism from, 58 hemolytic anemia, 23–24, 299 hookworm infection, 165–68, 292 hemophilia, 54, 57, 140 horsepox, 304 Hemophilus influenzae, 214 hospital gangrene, 137–38 hemorrhagic conjunctivitis, 232 host-versus-graft reaction, 260 hemorrhagic dengue, 36, 85–87. See also dengue HSV-1 and 2 infections, 161–62 hemorrhagic mediastinitis, 30 human leukocyte antigens (HLA), 222, 226 hemorrhagic meningitis, 30 human lymphatic filariasis, 125 hemorrhagic pancreatitis, 310 Huntington’s disease (chorea), 168–69, hemorrhagic sepsis, 62 304 hemorrhoids, in dropsy, 102 hydatid cysts, 110 hemostasis, 54–57 hydatidosis, 110 hepatic ailments, 236, 264. See also liver hydrocele, 126 hepatitis, 171–74 hydrocephalus, 100 from blood transfusions, 54 hydronephrosis, 291 delta agent, 174 “hydrophobia” (rabies), 115, 270–75 entericallytransmitted non-A, non-B, 171, 174 hydrothorax, 100, 102–4 hepatitis A, 171–72 hydroureter, 291 hepatitis B, 67, 79–80, 101, 171–73 Hymenolepsis nana, 319–20 hepatitis C, 173 hypercholesterolemia, 101 Leptospira in, 195 hyperesthesia, 359 meningitis and, 214 hyperglycemia, 92 from mumps, 223 hyperkeratosis, 251 from prenatal rubella, 287 hyperlipidemia, 155 Q fever and, 267 hyperpiesis. See hypertension hepatitis A, 171–72 hyperplasia, 68, 182 hepatitis B, 67, 79–80, 101, 171–73 hypertension, 169–71 hepatitis C, 173 characteristics, 169–70 hepatocellular carcinoma, 79–80 dropsyand, 101 hepatosplenomegaly, 84, 269, 291 eclampsia and, 110–12 heredity, 138–44. See also genetic factors gangrene and, 138 herpes viruses gout and, 155 genital, 161–62 history, 170–71 herpes praeputialis, 162 primary vs. secondary, 169 herpes progenitalis, 162 salt-sensitive, 170 herpes simplex, 161–62 strokes and, 33 herpes zoster, 214, 359–60 WHO classification, 169 trigeminal nerve, 359 hyperthyroidism, 237 vulva, 162 hyperuricemia, 153–56 hex A deficiency, 321 hyperventilation tetany, 328 Hhamikah, 287 hypocalcemia, 328 hiatus hernia, 106 hypocalcemic convulsions, 329–30 “hidden fire,” 120 hypochromic anemia, 73 high blood pressure, 160, 169–71. See also hypoglycemia, 219, 263–64 hypertension hypomagnesemic convulsions, 329–30

395 Subject Index hyponatremia, 263 pneumonia in, 255–56 hypotension, 27, 39, 86 similarityto leukemia, 198 hypothermia, 27, 263–64, 308 sweating sickness and, 312 hypothyroidism, 47, 72, 148, 226 Ingrassia, Giovanni, 289 hypotonia, 196, 321 insulin, 89 hypovolemic shock, 39 insulin-dependent diabetes, 88–89, 91. See also hypoxia, 82, 308, 324 diabetes mellitus hysteria, anorexia nervosa as, 28 intermittent fevers, 204. See also malaria interstitial pneumonia, 85 I intracranial hemorrhage (ICH), 33 iatrogenic anemia, 22 intravascular coagulation, 111 IBD (inflammatorybowel disease), 175–78 intruded yaws, 364 ichthiosismus, 58 involutional osteoporosis, 237 icterus, 196 iodine deficiency, 148–49 “ictus,” 31 irkintia, 319 idiopathic adenitis, 175 iron deficiencyanemia, 21, 22–23, 26, 71–74, idiopathic calcium-stone disease, 357 248–49 ileal ulceration, 177. See also Crohn’s disease ischemia, 33 Ilheus virus, 36 ischemic heart disease, 159 immune system dysfunction. See also acquired “Italian eruptive fever,” 285 immune deficiencysyndrome Ixodes dammini, 201, 203 Alzheimer’s disease, 16 Ixodes holocyclus, 285 myasthenia gravis, 225–27 pernicious anemia, 22 J pneumocystis pneumonia, 254–55 Jacksonian seizures, 118 pneumonia, 255–56 “jail distemper,” 352 immunosuppressive drugs, 200 Japan. See East Asia, Japan impetigo, 304 Japanese encephalitis, 36, 38, 115, 181–82, 366 “incipient stroke,” 33 “Japanese flood fever,” 356 India. See South Asia jaundice “Indian tick-typhus,” 285 in Carrion’s´ disease, 68 indigestion (dyspepsia), 105–7, 166 in clonorchiasis, 81 indomethacin, 154 in cytomegalovirus infection, 84 “industrial anthrax,” 29 in Ebola virus disease, 108 infant botulism, 57–58 in fascioliasis, 123 infantile beriberi, 45, 48 in favism, 124 infantile edema (kwashiorkor), 261–63 in hepatitis, 171 infantile gastroenteritis, 94 in leptospirosis, 195–96 infantile paralysis, 258. See also poliomyelitis in mononucleosis, 175 infantile pellagra (kwashiorkor), 261–63 in Q fever, 268 infantile scurvy, 295, 297 in relapsing fever, 275, 276 infantile tetany, 329 in yellow fever, 365 infectious hepatitis, 171–74 jejunitis, 178 infectious mononucleosis, 85, 174–75, 330 Jews, diseases and infectious parotitis, 222. See also mumps Black Death, 51 infectious pneumonia, 255. See also pneumonia bleeding disorders, 56 infertility. See sterility Crohn’s disease, 176 inflammatorybowel disease (IBD), 175–78 diabetes, 91 influenza, 178–81 favism, 123 catarrh in, 70 leprosyand, 194 characteristics, 178–79 Tay-Sachs disease, 321–23 croup and, 81 Judah, Rabbi, 54 encephalitis lethargica and, 114–15 jungle yellow fever, 365, 369 history, 114–15, 179–81 Junin virus (Argentine hemorrhagic fever), 38–39, influenza A, 179 184 as Plague of Athens, 253 juvenile Paget’s disease, 239

396 Subject Index

K lead intoxication, 186 kala-azar, 191–92 lead poisoning, 185–88 Kaposi’s sarcoma, 1 anemia from, 21 Kaschin-Beck disease, 133 characteristics, 185 “Katayama disease,” 290 epilepsyand, 117 keratitis, 226 history, 185–88 keratoconjunctivitis, 359 pica and, 247, 249–50 Kerner’s disease, 58 left ventricular hypertrophy, 104 ketoacidosis, 219 Legionella, 189 ketoconazole, 165 Legionella pneumophila, 190 ki denga pepo, 86 Legionnaires’ disease, 189–91, 255 kidneycancer, 65 Leishmania braziliensis, 191–92 kidneys Leishmania donovani, 191 dropsyand, 101, 104 leishmaniasis, 191–92 glomerulonephritis, 144–46 “lemming fever,” 343 gout and, 153–56 Leototrombidium deliensis, 356 kidneycancer, 65 lepromatous leprosy, 194 nephritis, 72, 106, 195, 223, 289, 335 leprosy(Hansen’s disease), 192–95 nephrotic syndrome, 101 characteristics, 192–94 renal arterystenosis, 170 ergotism and, 120 renal failure, 111, 154, 185 eye diseases in, 234 renal-stone disease, 357 history, 194–95 schistosomiasis, 291 similarityto elephantiasis, 126 secondaryhypertensionand, 169 similarityto measles, 213 sickle-cell anemia and, 299 similarityto pinta, 251 kidneystones, 153, 175 similarityto syphilis,332 “King’s Evil,” 293–94 Leptospira, 195–96 “kissing disease” (mononucleosis), 85, 174–75, 330 Leptospira biflexa, 196 Klebsiella pneumoniae, 257 Leptospira interrogans, 196 Klebs-Loffler¨ bacillus, 94. See also Corynebacterium leptospirosis, 108, 195–96 diphtheria leucocythemia, 199. See also leukemia Kleinfelter’s syndrome, 143 leukemia, 66, 196–99, 254, 359 knee disease, 235. See also arthritis leukoma, 232 knokkel-koorts, 87. See also dengue leukopenia, 200 “Koch’s lymph,” 341 levodopa, 241 koilonychia, 22 lipitudo, 294 Koplik’s spots, 212 Listeria, 214 Korea. See East Asia, Korea “Listerism,” 138 Korsakoff’s psychosis, 47 lithophagia, 247. See also pica Kropf, 146 liver kwashiorkor, 261–263 arthritis and, 236 kyphoscoliosis, 225 cancer, 67 childhood malnutrition and, 264 L cirrhosis and, 79–81, 100–1 labial herpes, 161–62 fascioliasis and, 123 La Crosse virus, 37 hepatitis, 171–74 lactose intolerance/malabsorption, 93, 182–83 hepatocellular carcinoma, 79–80 lacunar infarction, 33 hepatosplenomegaly, 84, 269, 291 laryngitis, 81 inflammatorybowel disease and, 175 laryngotracheitis, 81 leptospirosis and, 196 laryngotracheobronchiopneumonitis, 82 Q fever and, 269 laryngotracheobronchitis, 82 liver cancer, 67, 81, 134, 172 Lassa fever, 38, 107, 184–85 liver flukes, 67, 123 late effects of polio (LEP), 260 “liver rot,” 123 latent syphilis, 313. See also syphilis Loa loa, 125 lead encephalopathy, 188 lobar pneumonia, 255–57, 276. See also pneumonia

397 Subject Index

“lockjaw,” 324, 326–27. See also tetanus endemic, 205 locomotor ataxia, 314 hepatitis from, 171 louse-borne relapsing fever, 275–77 history, 205–7 Ludwig’s angina, 82–83 “malarial fevers,” 350–52 lues hispanica, 315 malnutrition and, 262 lues venerea, 315–16 pernicious, 350 lumbago, 236. See also osteoarthritis relapsing fever and, 275 lung cancer, 65–66 sickle-cell trait and, 205, 300 lung flukes, 240 similarityto African trypanosomiasis,9 lungs similarityto Ebola virus disease, 107–8 lung cancer, 65–66 similarityto Lassa fever, 184 in paragonimiasis, 240 stable vs. unstable, 205 pulmonaryanthrax, 29–30 thalassemia, 22, 26 pulmonarydisease, 83 typhomalarial fever, 71 pulmonaryedema, 100, 103 mal de la rosa (pellagra), 194, 242–44 pulmonaryfibrosis, 40 mal de pinto, 250–51 pulmonaryheart disease, 101 mal des ardents, 288 pulmonarytuberculosis, 337–38, 340 mal de Siam, 365 lupus erythematosus (LE), 137, 194, 199–201 mal d’estomac, 249 lupus vulgaris, 199, 339 malignant pustule (anthrax), 29–31 Lutzomyia, 191 malignant tertian malaria, 203 Lyme borreliosis, 201–3 malnutrition, 261–65 lymphadenitis, 30, 344 diarrhea and, 93 lymphadenopathy, 2, 85, 253, 286 dropsyand, 100–1 lymphangitis, 126 fungal infections and, 132 lymphedema, 126 history, 264–65 lymphocytic choriomeningitis (LCM), 38–39, 184 in inflammatorybowel disease, 175 lymphocytic meningoradiculitis, 203 kwashiorkor, 261–63 lymphocytosis, 85, 268 measles and, 213 lymphogranuloma venereum, 316 protein-energy, 261–65 lymphoid aggregates, 177 tetanyand, 329 lymphoma, 147 typhomalarial fever and, 349 lymphoproliferative disorders, 197 malnutrition diabetes, 91. See also diabetes mellitus lymph scrotum, 126–27. See also filariasis Malta fever, 58–60, 192, 351–52 marasmic kwashiorkor, 261–62 M marasmus, 261–64 maal, 213 Marburg virus, 107–8, 207–8 Macaca cynomolgus, 108 marrow failure, 268 Machupo virus (Bolivian hemorrhagic fever), “Marseilles exanthematic fever,” 285 38–39, 184 masern, 213 macronodular cirrhosis, 79 mastitis, 265 maculopapular rash, 85, 174, 208 mastoiditis, 208–11, 304 Madura foot, 131 Mastomys natalensis, 108, 184 “madura mycosis,” 131 masura, 213 Madurella grisea, 131 maternal tetany, 328 Madurella mycetomatis, 131 maturity-onset diabetes of youth, 88. See also magnesium deficiency, 328–29, 357 diabetes mellitus magnesium tetany, 328 measles, 211–14 maize, pellagra and, 242–44 characteristics, 212 malacia, 247 diarrhea in, 93 maladie v´en´erienne, 315 encephalitis lethargica and, 115 malaria, 203–7 eye diseases in, 234 anemia and, 22, 25–26, 123–24 history, 212–14 from Carrion’s´ disease, 68 introduction to North America, 206 characteristics, 203–5 malnutrition and, 262 discoveryof cause, 10, 35 meningitis and, 214

398 Subject Index

Paget’s disease and, 239 meningoencephalitis, 268 as Plague of Athens, 252–53 mental retardation smallpox and, 212, 301 Down syndrome and, 96–98 vaccination, 212, 214 goiter and, 147 meconium ileus, 83 muscular dystrophy and, 225 Mediterranean area prenatal rubella and, 287 Black Death, 49 “Meuse fever,” 331 bleeding disorders, 55 Mexican typhus, 284 brucellosis, 58–60 microcephaly, 84 bubonic plague, 62 Micrococcus melitensis, 351 echinococcosis, 110 micronodular cirrhosis, 79 favism, 123–124 microsporosis, 129 filariasis, 126 Microsporum, 129 G6PD deficiency, 23–24 Microsporum audouinii, 129 ophthalmia, 230 Microsporum canis, 129 poliomyelitis, 258 Microsporum gypseum, 130 protein–energymalnutrition, 265 Middle and Near East ringworm, 129 AIDS, 2 sickle-cell anemia, 26, 300 anemia, 25–26 syphilis, 314 anthrax, 30 syphilis, nonvenereal, 317 ascariasis, 42 tapeworm infection, 319 Black Death, 49–51 typhomalarial fever, 349 bleeding disorders, 56–57 Mediterranean fever, 59–60 bubonic plague, 62 “Mediterranean spotted fever,” 285 cholera, 74, 76–77 Mediterranean type of G6PD deficiency, 23, 124 diabetes, 89, 91 megacephaly, 321 dracunculiasis, 98, 100 megacolon, 70–71 echinococcosis, 110 megaesophagus, 70–71 encephalitides, 36 mehlnahrschaden,¨ 264 favism, 123–124 melanoma, 66 filariasis, 126 melarsoprol, 13 gout, 156 meningeal histoplasmosis, 164 G6PD deficiency, 23 meningism, 182, 196 hookworm infection, 167–168 meningitic tularemia, 344 inflammatorybowel disease, 176 meningitis, 214–17 lead poisoning, 185–186 anthrax and, 30 leishmaniasis, 191–192 characteristics, 214–15 leprosy, 194 diabetes mellitus and, 89 malaria, 204 epilepsyand, 116 measles, 213 history, 215–17 onchocerciasis, 228–229 Leptospira in, 195 ophthalmia, 230, 232–233 lymphocytic choriomeningitis, 38–39, 184 pellagra, 243–244 mastoiditis and, 210 poliomyelitis, 261 mumps and, 223 protein–energymalnutrition, 265 poliomyelitis and, 214, 258 relapsing fever, 277 rubella and, 214 rickets, 282 scarlet fever and, 289 rubella, 287 similarityto Lymedisease, 202 Saint Anthony’s fire, 287 streptococcal organisms and, 304 schistosomiasis, 291–292 treatment, 217 smallpox, 301–302 trichinosis and, 335 sudden infant death syndrome, 306 tubercular, 214, 338 syphilis, nonvenereal, 317–319 types, 214 trench fever, 331 meningitis epidemica, 214 trichinosis, 334 meningococcal meningitis, 214 tuberculosis, 339

399 Subject Index

Middle and Near East (continued ) myocardial infarction, 157 tularemia, 343 myocardial insufficiency, 101 typhoid fever, 346, 348 myocarditis urolithiasis, 357–358 in Chagas’ disease, 70 miliarytuberculosis, 337–38 in prenatal rubella, 287 militaryophthalmia, 234 in Q fever, 268 milk sickness, 218–20 streptococcal infection and, 304 Milzbrand, 29 in trichinosis, 335 mitral stenosis, 72, 279 myxedema, 148–49 Mobala virus, 39 moist gangrene, 136 N molecular medicine, 142–43 Nanukayami fever, 196 mongolism (Down syndrome), 16, 19, 96–98, 143 National Institute on Aging, 18 monkeypox, 300 Necator americanus, 165, 167 monocytic leukemia, 197 necrosis, 136, 182. See also gangrene mononucleosis, 85, 174–75, 330 necrotizing fasciitis, 137 Mopeia virus, 39 Negri bodies, 271, 274 morbilli, 211–14 Neill-Mooser phenomenon, 355 Morbillivirus, 212, 239 Neisseria gonorrhoeae, 150 De Morbis Veneris (Astruc), 316 Neisseria meningitidis, 214, 217 morbus carcerum, 352 nematode infection, 227–28 morbus gallicus, 311, 315–16. See also syphilis ascariasis, 42, 255 morbus hungaricus, 353 dracunculiasis, 98–100 morbus venereus, 315–16 enterobiasis, 116 morbus virgineus, 71 filariasis, 10, 125–28 mosaic Down syndrome, 96 onchocerciasis, 125, 228–30, 234 mucocutaneous leishmaniasis, 191 pinta, 250–51, 317–18, 333, 362 mucormycosis, 132 strongyloidiasis, 306 mucoviscidosis, 83–84 trichinosis, 239, 333–36 “mud fever,” 196 trichuriasis, 336 multi-infarct dementia, 15 neonatal tetanus, 324, 326–28 multiple sclerosis (MS), 201, 220–22 neonatal tetany, 329 mumps, 222–24 nephritis. See also kidneys characteristics, 222–23 anemia in, 72 diabetes mellitus and, 89 dyspepsia in, 106 encephalitis lethargica and, 115 Leptospira in, 195 history, 223–24 in mumps, 223 meningitis and, 214 in scarlet fever, 289 Paget’s disease and, 239 in trichinosis, 335 murine typhus, 282, 352, 355 nephrolithiasis, 153, 175 MurrayValleyencephalitis, 36 nephrotic syndrome, 101 muscular atrophies, 224 neurasthenia, 28, 106 muscular dystrophy, 224–25 neuritis, 196, 221, 223, 242 mushroom poisoning, 132–34 neurofibrillarydegeneration, 16 Muslims, 50–51, 282 neurosis, 241 Mus musculus, 38 neurosyphilis, 314 myalgia, 39, 208 niacin deficiency, 242–44 myasthenia gravis, 225–27 Niemann-Pick disease, 320 mycardial failure, 104 “nine-dayillness,” 329 mycetism, 132–33 “nine-daymeasles,” 211–14 mycetoma, 128, 131 njovera, 319 Mycobacterium leprae, 192–95 Nocardia, 131 Mycobacterium tuberculosis, 193, 336–37, 342 nondisjunction, 96, 143 Mycoplasma pneumoniae, 81 non-insulin-dependent diabetes, 88, 89–90, 91. mycoses, 128–32. See also fungus infections See also diabetes mellitus mycotoxicosis, 132, 133–34 nonvenereal syphilis, 317–19, 332

400 Subject Index

North America. See also United States nutrition. See deficiencydiseases; diet; malnutrition AIDS, 1–2 nutritional edema (kwashiorkor), 261–63 amebic dysentery, 20 nutrition-infection interactions, 262 anemia, 24, 26 nutrition-infection stress, 263 anorexia nervosa, 29 anthrax, 30 arenaviruses, 38 O arthritis, 41 obesity, 33, 90, 134–35, 155 ascariasis, 42 obstructive airways disease, 52 black and brown lung, 52 Oceania. See Australia and New Zealand; Pacific bubonic plague, 63 Islands cancer, 65 oculogyric crisis, 114, 241 Chagas’ disease, 70 Ohara’s disease, 343, 345 cholera, 75–77 oligoarticular arthritis, 202 cirrhosis, 79 oliguria, 102, 111 diabetes, 92 Onchocerca volvulus, 125, 228–30 Down syndrome, 96 onchocerciasis, 125, 228–30, 234 emphysema, 113 ophthalmia, 230–34, 294. See also conjunctivitis encephalitides, 37 ophthalmia neonatorum, 231 filariasis, 125 ophthalmic tularemia, 344 gallstones, 135 ophthalmoplegia, 226 gout, 155 opisthotonos, 324 heart-related diseases, 160 oral candidiasis, 128, 130 herpes simplex, 161 oral contraceptives, 33 histoplasmosis, 163 orchitis, 223, 268 hypertension, 171 oreillons, 224 infectious hepatitis, 172 “Oriental sore,” 192 influenza, 180 Ornithodoros, 275 malaria, 204, 206 Oroyo fever, 67–69 meningitis, 216 orthopnea, 101 multiple sclerosis, 220–221 osteitis, 363 myasthenia gravis, 225 osteitis deformans (Paget’s disease of bone), 238–40 mycoses, 130–131 osteoarthritis (OA), 234–36 ophthalmia, 230, 234 characteristics, 235–36 pinta, 250–251 in fungus poisoning, 133 poliomyelitis, 261 heart valves and, 278 rabies, 271, 274 history, 41, 236 rheumatic fever, 279 Paget’s disease and, 239 ringworm, 129 osteomalacia, 236–37, 280–82 RockyMountain spotted fever, 284–285 osteomalacic tetany, 328 schistosomiasis, 291 osteomyelitis, 304 scurvy, 297 osteoporosis, 236–38 sudden infant death syndrome, 306 in anorexia nervosa, 27 tapeworm infection, 320 characteristics, 237–38 tetanus, 325 history, 238 tetanus, neonatal, 326 osteomalacia and, 236–37, 282 treponematoses, 332 post-menopausal, 237 trichinosis, 334 otitis media tuberculosis, 337 acute, 208–11 tularemia, 343 in measles, 212 typhus, epidemic, 353 in scarlet fever, 289 urolithiasis, 357 streptococcal infection, 304 “North Asia tick-typhus,” 285 in whooping cough, 360 Norwalk virus, 93 otitis media with effusion (OME), 209 Nova poenitentialis Quadragesima... (Bethencourt), otorrhea, 210 316 ovarian dropsy, 100

401 Subject Index

P Chinese liver fluke, 81 Pacific Islands dracunculiasis, 98–100 AIDS, 2, 5 echinococcosis, 110 bacillarydysentery,43 enterobiasis, 116 clonorchiasis, 81 fascioliasis, 123 diabetes, 90–91 fasciolopsiasis, 123 encephalitides, 36 filariasis, 125–28 encephalitis lethargica, 115 giardiasis, 93, 144 filariasis, 125–127 hookworm infection, 165–68, 292 gout, 156 iron deficiencyanemia and, 21, 23 hookworm infection, 166 leishmaniasis, 191–92 lactose intolerance, 183 malaria, 203–7 leprosy, 193 nematode infection, 227–28 lupus erythematosus, 201 onchocerciasis, 125, 228–30, 234 measles, 213 paragonimiasis, 240 ophthalmia, 230 pinta, 250–51, 317–18, 333, 362 pica, 250 pneumocystis pneumonia, 254–55 plague of Athens, 253 relapsing fever, 275–77 ringworm, 129 rickettsial diseases, 282–83, 352–55 syphilis, 314 schistosomiasis, 167, 290–92, 357 typhus, scrub, 356 strongyloidiasis, 306 yaws, 362 tapeworm infection, 70, 110, 319–20 padaavalmika, 131 toxoplasmosis, 330–31 Paget’s disease of bone, 238–40 trichinosis, 333–36 Paget’s disease of the breast, rectum, and skin, trichuriasis, 336 239 yaws, 313–14, 317–18, 332–33, 362–65 “Pahvant Valleyplague,” 343 parathyroid hormone, 237 pain crisis, in sickle-cell anemia, 299 parathyroid tetany, 328 palpebral edema, 174 paratyphoid fever, 345 pamaquine, 23 paresis, 258, 314 pancreas, childhood malnutrition and, 264 parkinsonian crises, 241 pancreatitis, 108, 134, 310 Parkinson’s disease, 114–15, 240–41 papophagia, 247 parotitis, 222–24 Paracoccidioides brasiliensis, 130 paroxysmal nocturnal dyspnea, 101, 103 paracoccidioidomycosis, 130–31 Pasteurella, 345 paragonimiasis, 240 “patriotic fever,” 366 Paragonimus westermani, 240 “peapickers’ disease,” 196 parahemophilia, 56 peau d’orange, 121 parainfluenza virus types 1 and 2, 82, 239 pedal edema, 102 paralysis Pediculus humanus capitis, 352 in beriberi, 47 Pediculus humanus corporis, 352 in diphtheria, 94 pellagra, 194, 242–44 in Japanese B encephalitis, 182 pelvic inflammatorydisease (PID), 150 in lead poisoning, 185 penicillin, 258 in myasthenia gravis, 226 Penicillium citreoviride, 133 in poliomyelitis, 258 pentosuria, 141 paralysis agitans, 241. See also Parkinson’s disease peptic ulcer dyspepsia, 105, 107 paralytic polio, 258. See also poliomyelitis pericarditis, 223, 268, 304 Paramyxovirus, 222 periodic fever, 349–50 parangi, 365 “periodic typhoid,” 352 parasitic diseases. See also malaria; nematode periodontal disease (pyorrhea), 244–47 infection periodontitis, 244 African trypanosomiasis, 7–13 periorbital edema, 174–75 amebic dysentery, 19–21 periostitis, 363 ascariasis, 42, 255 peripartum cardiac failure, 160 Chagas’ disease, 70–71 peripleumonin, 257

402 Subject Index peritonitis in histoplasmosis, 164 in amebic dysentery, 20 history, 256–58 in gonorrhea, 150 in influenza, 178 in inflammatorybowel disease, 175 interstitial, 85 in puerperal fever, 266 in Legionnaires’ disease, 189–91 in trichinosis, 335 in lupus erythematosus, 200 pernicious anemia, 22 malnutrition and, 262 pernicious malaria, 350 in measles, 212, 253 pertussis, 325, 360–62 moist vs. dry, 257 el peste, 365 pneumocystic, 1–2, 254–55 petechial rash, 84 in Q fever, 267–68 pharyngitis, 85, 288, 304 in relapsing fever, 276 pheochromocytoma, 170 in scrub typhus, 356 Phlebotomus, 181, 192 streptococcal, 304 Phlebotomus verrucarum, 68 in tetanus, 324 phlegmon, 122 in trichinosis, 335 phlyctenular conjunctivitis, 232 in tularemia, 344 phthisis, 72, 339–40. See also tuberculosis in whooping cough, 360 pica, 72, 188, 247–50 pneumonic plague, 49, 61 Pichinde virus, 38 pneumonitis, 255, 287. See also pneumonia pinta, 250–51, 317–18, 333, 362 Pneumovirus, 239 pinworms, 116 pokkuri, 311 placentitis, 268 poliomyelitis, 258–61 plague. See also bubonic plague AIDS and vaccinations for, 6 cause of, 345 characteristics, 258–60 decline in leprosyand, 195 hepatitis A virus and, 172 ergotism and, 120 history, 260–61 pneumonia in, 255 late effects of polio, 260 sweating sickness and, 311 meningitis and, 214, 258 Plague of Athens, 251–54 vaccines, 6, 259–61 plaque, dental, 245 “Polish fever,” 331 plaque of demyelination, 221–22 polyarthritis, 40–41, 278. See also arthritis Plasmodium, 203–4, 265 polyarticular gout, 41 Plasmodium falciparum, 25, 108, 203–6, polydactyly, 140 300 polygraph, invention of, 157 Plasmodium malariae, 203–4 polymyositis, 226 Plasmodium ovale, 203–4 Pontiac fever, 188–90, 255 Plasmodium vivax, 203–4 pork tapeworm, 320 pleurisy, 257, 335 porotic hyperostosis, 26 pleuropneumonia, 200 post-menopausal osteoporosis, 237–38 pleuropulmonarytularemia, 344 postoperative synergistic gangrene, 137 plumbism. See lead poisoning Pott’s disease, 137 pneumococcal infection, 256 Powassan virus encephalitis, 37 pneumocystic pneumonia, 1, 2, 254–55 Praomys jacksoni, 39 Pneumocystis carinii, 254 Praomys natalensis, 39, 184 pneumonia, 255–58 prednisone, 200 in African trypanosomiasis, 9 preeclampsia, 111 antisera, 258 pregnancy, diseases during in ascariasis, 42 candida infection, 132 aspiration, 327 conjunctivitis, 231 bronchopneumonia, 70, 255, 327 cytomegalovirus, 84–85 characteristics, 255–56 Ebola, 108 cold temperatures and, 256 ergotism, 120 in cytomegalovirus infection, 85 erysipelas, 122 dropsyand, 103 gestational diabetes, 88, 91 in encephalitis lethargica, 115 gonorrhea, 150

403 Subject Index pregnancy, diseases during (continued ) Pseudomonas, 214 herpes simplex Psilocybe, 133 HIV-2 infection, 161 psoriasis, 194, 251 hookworm infection, 166 ptosis, 226–27 infectious hepatitis, 174 pudendagra, 315 Japanese B encephalitis, 182 puerperal erysipelas, 122 Lyme disease, 202 puerperal fever, 265–67, 304–5 malaria, 205 puerperal sepsis, 122, 265–66, 304 mumps, 223 “puking disease,” 218 pica, 247–50 Pulex irritans, 61 polio, 259–60 pulmonaryanthrax, 29–30. See also anthrax preeclampsia and eclampsia, 111–12 “pulmonaryapoplexy,”32 puerperal fever, 265–67 pulmonarydisease, 83 rubella, 286–87 pulmonaryedema, 100, 103 streptococcal infections, 305 pulmonaryfibrosis, 40 syphilis, 313 pulmonaryheart disease, 101 tetanus, 324 pulmonarytuberculosis, 337–38, 340. See also toxoplasmosis, 330–31 tuberculosis presclerosis. See hypertension punctuate rash, 289 primaquine sensitivity, 24 purpurea epidemica maligna, 289 primaryacquired cholesteatoma, 209 pustule maligne, 29 primaryhypertensivecardiovascular disease. “putrid malignant fever,” 348 See hypertension pyelonephritis, 170 primarypulmonaryhistoplasmosis, 163 pyorrhea, 244–47 progressive massive fibrosis, 52 pyorrhea alveolaris, 246 prostate cancer, 65–66 pyrexia, 312 prostate hypertrophy, 357 protease inhibitors, 6 Q protein C deficiency, 57 Q fever, 190, 255, 267–70, 282 protein-energymalnutrition (PEM), 261–65, 329 quadriplegia, 321 protein malnutrition quartan malaria, 204 ascariasis and, 42 Queensland tick-typhus, 285 diabetes and, 90 quinacrine, 200 history, 264–65 “quintan fever,” 331 kwashiorkor, 261–63 porotic hyperostosis in, 26 R protein C, 57 “rabbit fever,” 343 protein-energymalnutrition, 261–65, 329 rabies, 115, 270–75 protein S, 57 raccoon rabies, 275 urolithiasis, 357–58 rachitis, 281. See also rickets protein S deficiency, 57 radesyge, 318 proteinuria, 111–12, 184 radon gas, 66 Proteus, 214 la rage (rabies), 270–75 protozoan infection, 265 Rainbow family, 43 African trypanosomiasis, 7–13 RamseyHunt’s syndrome,359 amebic dysentery, 19–21 “raspberrytongue,” 289 Chagas’ disease, 70–71, 160 Rats, Lice, and History (Zinsser), 252 classification, 265 Rattus rattus, 61 giardiasis, 93, 144 Raynaud’s syndrome, 136–37 leishmaniasis, 191–92 recombinant DNA techniques, 142–43 in malaria, 203–7 recurrent herpes, 161 pneumocystic pneumonia, 1, 2, 254–55 red-cell aplasia, 299 toxoplasmosis, 330–31 “red measles,” 211–14 pruritis, 228 “red-water fever,” 290 Pseudallescheria boydii, 131 “regional gastritis,” 178 pseudohypertrophy, 225 relapsing fever, 275–77

404 Subject Index

“renal apoplexy,” 32 Rift Valleyfever, 38 renal arterystenosis, 170 Riggs’ disease, 246 renal failure, 111, 154, 185 right heart failure, 79 renal-stone disease, 357 “right-sided colitis,” 178 respiratoryfailure, 225 right ventricular failure, 101 respiratory syncytial virus (RSV), 239 Rig Veda, 358 restriction fragment length polymorphisms (RFLPs), rinderpest, 212 142 ringworm, 128–30, 251 reticulocytosis, 68 risus sardonicus, 324, 327 retroviruses, 3. See also acquired immune “river blindness” (onchocerciasis), 228–30 deficiencysyndrome Rochalima quintana, 331 reverse transcriptase (RT), 6 Rocio virus, 36 Reye’s syndrome, 115 Rockefeller Foundation, 168, 292, 369 rheumatic diseases (lupus), 199–201 RockyMountain spotted fever, 282–85 rheumatic fever, 277–80 rossalia, 213, 289 characteristics, 277, 279–80 rotavirus, 93 dropsyand, 101 Rotheln, 287 history, 278–79, 305 roundworms, 227–28. See also nematode infection rheumatic heart disease in, 159, 277–80 rubella, 89, 214, 285–87 scarlet fever and, 288–89 rubeola, 211–14. See also measles streptococcal infection and, 304–5 Rubivirus, 286 “rheumatic gout,” 40 Russia rheumatism, 39–42, 155. See also osteoarthritis; botulism, 58 rheumatic fever; rheumatoid arthritis cholera, 75–76 rheumatismus nodosus, 40 diabetes, 90 rheumatoid arthritis, 39–42, 53, 137, 201, 227 dracunculiasis, 100 “rheumatoid osteoarthritis,” 40 echinococcosis, 110 rhinitis, 286 ergotism, 120–121 rhinopharyngitis mutilans (gangosa), 362–63 fungus poisoning, 133 rhinosporidiosis, 132 giardiasis, 144 Rhinosporidium seeberi, 132 influenza, 180 Rhipicephalus sanguineus, 283, 285 leptospirosis, 196 riboflavin deficiency, 45 Lyme disease, 201 rickets, 26, 280–82, 329–30 meningitis, 216 Rickettsia, 282 mumps, 224 Rickettsia akari, 285 ophthalmia, 230, 234 Rickettsia australis, 285 Paget’s disease of bone, 240 Rickettsia burnetii, 269 poliomyelitis, 260 Rickettsia conorii, 285 rabies, 273 Rickettsia diaporica, 269 relapsing fever, 277 rickettsiae, 190 rickets, 281 rickettsial diseases, 282–83 ringworm, 129 epidemic typhus, 352–55 smallpox, 301 murine typhus, 282, 352, 355 tapeworm infection, 320 pneumonia in, 255 tuberculosis, 342 Q fever, 190, 255, 267–70, 282 tularemia, 343–345 RockyMountain spotted fever, 282–85 typhus, epidemic, 354 scrub typhus, 282–83, 355–56 urolithiasis, 357–358 trench fever, 282, 331 “Russian flu,” 180. See also influenza rickettsialpox, 285 “Russian intermittent fever,” 331 Rickettsia mooseri, 355 Russian spring-summer encephalitis (RSSE), 37–38 Rickettsia prowazekii, 352–54, 355 Rickettsia rickettsii, 283–84 S Rickettsia siberica, 285 “sacred disease,” 118–19 Rickettsia tsutsugamushi, 356 “sacred fire,” 122, 288 Rickettsia typhi, 355 safura, 249

405 Subject Index

St. Louis encephalitis, 36 serosal meningitis, 196 Saint Anthony’s fire, 120–21, 122, 136, 287–88 serotonin, 242 “saint’s fire,” 120 “serous apoplexy,” 31 Saint Vitus’ dance (Sydenham’s chorea), 168, 277, sexuallytransmitted diseases. See also acquired 278 immune deficiencysyndrome Salmonella, 43, 93, 345 cervix cancer as, 67 Salmonella typhi, 345–47, 349, 351 gonorrhea, 150–53, 232 salmonellosis, 68, 345–46 hepatitis B, 172 salt intake, 67, 169–70 herpes genitalis, 161–62 salt-sensitive hypertension, 170 syphilis, 312–17 sampling error, 322 venereal warts, 316 sang de rate, 29 “shaking palsy” (Parkinson’s disease), 114–15, “sanguinous apoplexy,” 31 240–41 “Sao˜ Paulo typhus” (Rocky Mountain spotted fever), “shank fever,” 331 282–85 Shigella, 43–44, 105 sarcoma, 63 Shigella boydii, 43 sarcomatous degeneration, 239 Shigella dysenteriae, 43–44 saturnine gout, 185 Shigella flexneri, 43 scabies, 263 Shigella sonnei, 43–44 scarlet fever, 288–90 shigellosis, 43, 93 characteristics, 288–89 “shin fever,” 331 chickenpox and, 359 shingles, 359 diphtheria and, 289, 305 ship beriberi, 298 erysipelas and, 121 “ship fever,” 352 glomerulonephritis in, 144–46 shock, 215, 256, 312, 347 history, 289–90 Shosin beriberi, 45 streptococcus infection, 304–5 “sibbens,” 318, 364 Schick test, 96 Siberian tick-typhus, 285 Schistosoma, 290 “Siberian ulcer,” 345 Schistosoma haematobium, 290–92 sickle-cell anemia, 298–300 Schistosoma japonicum, 290–91 characteristics, 299 Schistosoma mansoni, 160, 290–92 discoveryof, 142 schistosome dermatitis, 291 functional asplenia in, 256 schistosomiasis, 167, 290–92, 357 gallstones in, 134 schverbaujck, 295 history, 24–25, 299–300 scleroderma, 137 malaria and, 125, 205, 300 sclerosis, 246 red blood cell metabolism, 22 scopolamine, 241 sickle-cell trait and, 142 scorbuck, 295 sickle-cell trait, 24–25, 142, 298–300 scrofula, 147, 193, 292–94, 339 “sick stomach,” 218 scrotal cancer, 64 silver nitrate, 232 scrub typhus, 282–83, 355–56 simian immunodeficiencyvirus (SIV), 5 scurvy, 120, 295–98, 349 simian T lymphotropic virus (STLV)-III, 3 secondaryacquired cholesteatoma, 209 Simulium, 228–30 secondarygout, 153 Simulium damnosum, 229 secondarysyphilis,313 “sinking typhus,” 215 seizures, 116–19, 324. See also epilepsy sinusitis, 178 senile dementia of the Alzheimer type (SDAT), sitomania, 27 17–18 skerljevo, 319 senile gangrene, 137 skin cancer, 66, 281 senile osteoporosis, 237 skunk rabies, 275 sepsis, 304, 326 sleeping sickness, 7–13 septic angina, 133 “sleepydistemper,” 9 septicemia, 30, 59, 120, 132 sliding hiatus hernia, 106 septicemic plague, 49, 62 “slows/sloes,” 218–19 sequestration crisis, 299 smallpox, 300–4

406 Subject Index

AIDS and vaccines for, 6 leprosy, 193 characteristics, 300–1 leptospirosis, 196 chickenpox and, 359 malaria, 204, 206–207 eradication, 303–4 mycoses, 130–132 ergotism and, 120 onchocerciasis, 228 eye diseases in, 234 ophthalmia, 230 hepatitis and vaccines for, 171 Paget’s disease of bone, 238 history, 301–4 paragonimiasis, 240 introduction to North America, 206 pica, 249 measles and, 212, 301 pinta, 250–251 as Plague of Athens, 252, 253 poliomyelitis, 261 vaccine, 302–4 rabies, 274 variolation, 302–4 ringworm, 129 Smallpox Eradication Programme, 303 RockyMountain spotted fever, 284–285 smoking scarlet fever, 289 arteriosclerosis and, 137 schistosomiasis, 290–291 cancer and, 65–66 syphilis, 313 Crohn’s disease and, 176 tapeworm infection, 320 emphysema and, 113 trichinosis, 334 heart disease and, 160 tuberculosis, 338 osteoporosis and, 237 tularemia, 343 “snail fever,” 290 yaws, 362, 364 snakeroot poison, 218–20 yellow fever, 36, 366–369 sofersa, 213 South Asia soldier’s heart, 158–59 AIDS, 5 “South African tick-bite fever,” 285 ainhum, 14 South America amebic dysentery, 20 ainhum, 14 anemia, 25–26 anemia, 26 arthritis, 41 anthrax, 30 ascariasis, 42 arenaviruses, 38 beriberi, 46 ascariasis, 42 Black Death, 49 beriberi, 46–47 brucellosis, 59 bleeding disorders, 56 bubonic plague, 63 Bolivian hemorrhagic fever, 39 cholera, 74–77 brucellosis, 59 diabetes, 89, 92 bubonic plague, 63 dracunculiasis, 98–100 Carrion’s´ disease, 68 encephalitides, 36 Chagas’ disease, 70–7 fasciolopsiasis, 123 cholera, 77 favism, 124 dengue, 86 filariasis, 125–127 diabetes, 92 fungus infections, 131–132 encephalitides, 37–38 G6PD deficiency, 23 fascioliasis, 123 histoplasmosis, 163 filariasis, 127 hookworm infection, 165–167 fungus poisoning, 133–134 infectious hepatitis, 172 gallstones, 135 lead poisoning, 186 glomerulonephritis, 145 leishmaniasis, 191–192 goiter, 148 leprosy, 192–193, 195 heart-related diseases, 160 malaria, 204 herpes simplex, 161 ophthalmia, 230 histoplasmosis, 163 osteoporosis, 238 hookworm infection, 166–167 paragonimiasis, 240 hypertension, 170–171 pellagra, 244 influenza, 180 pica, 249 leishmaniasis, 191–192 poliomyelitis, 261

407 Subject Index

South Asia (continued ) spinal hyperostosis, 41 rabies, 271 spinal tuberculosis, 338 relapsing fever, 275–276 Spirometra, 319 smallpox, 303 spleen, in sickle-cell anemia, 299 tapeworm infection, 319 splenic apoplexy(anthrax), 29–31 trichinosis, 334 splenic fever (anthrax), 29–31 tuberculosis, 339 splenic infarction, 299 typhomalarial fever, 349 splenomegaly, 268, 276, 349 typhus, scrub, 356 sporadic goiter, 147 urolithiasis, 357–358 Sporothrix schenckii, 131 whooping cough, 361 sporotrichosis, 131 yaws, 362, 365 “spotted fever,” 214–15, 283–85, 352 Southeast Asia “spotted typhus” (Rocky Mountain spotted fever), AIDS, 5 282–85 ainhum, 14 staphylococcal infection, 253 amebic dysentery, 20 Staphylococcus aureus, 81–82, 93, 137 ascariasis, 42 starchydystrophy(kwashiorkor), 261–64 beriberi, 45–46, 48–49 status thymico-lymphaticus, 309 bubonic plague, 61 Stegomyia fasciata, 365 cholera, 75–77 stenosis, 126 clonorchiasis, 81 sterility, 150, 223, 300 dengue, 35–36, 87–88 stethoscope, invention of, 157 diabetes, 90 “stiff joints,” 218 fasciolopsiasis, 123 Stokes-Adams disease, 157 filariasis, 125, 127 stomach cancer, 65, 67 G6PD deficiency, 23 Stomoxys calcitrans, 343 histoplasmosis, 163 “strangers’ fever,” 366 hookworm infection, 166 streptococcal diseases, 304–5 influenza, 180 diphtheria, 94–96 Japanese B encephalitis, 181 dropsyand, 101 lead poisoning, 186 erysipelas, 121–22 leishmaniasis, 191 gangrene, 136–38, 137 leprosy, 193 history, 305 malaria, 205 as Plague of Athens, 252 ophthalmia, 230 poststreptococcal glomerulonephritis, 145–46 paragonimiasis, 240 puerperal fever, 265–67, 304–5 pica, 250 rheumatic fever, 159, 277–80 protein–energymalnutrition, 264–265 scarlet fever, 288–90 relapsing fever, 275 Streptococci classification, 304–5 schistosomiasis, 290, 292 streptococcal endocarditis, 304–5 smallpox, 301 streptococcal pharyngitis, 277 sudden unexplained death syndrome, 309–311 streptococcal tonsillitis, 83, 94, 288–89 syphilis, 313–314 Streptococcus (Diplococcus) pneumoniae, 81–82, 214, typhoid fever, 346 255–57 typhus, murine, 355 Streptococcus pyogenes, 82, 121–22, 137 typhus, scrub, 356 Streptococcus viridans, 305 urolithiasis, 357 Streptothrix madurae, 131 yaws, 362 stress, 106–7, 170, 263 “southern typhoid fever,” 351 stroke, 17, 31–34, 202 sowda (onchocerciasis), 228–30 Strongyloides fulleborni, ¨ 206 “Spanish flu,” 180–81. See also influenza Strongyloides stercoralis, 206 sparaganosis, 319 strongyloidiasis, 306 spasmodic croup, 81–83 strumae, 147, 293–94 sphingolipidoses, 320 subarachnoid hemorrhage, 276 sphygmomanometer invention, 170 subluxation, 236 “spinal apoplexy,” 32 sudden infant death syndrome (SIDS), 58, 306–9

408 Subject Index sudden unexplained death syndrome (SUDS), Texas cattle fever, 312 309–11 Texas redwater fever, 35 sudor anglicus, 311–12 thalassemia, 22, 26, 125 suffocative angina, 83. See also diphtheria thalassemia minor, 22 sulfa drugs, 217 thiamine deficiency(beriberi), 44–49 sunlight, rickets and, 281–82 “three-daymeasles,” 285–87 surgical erysipelas, 122 thriftygene theory,135 “swamp fever,” 196 throat distemper epidemic, 94 “swamp sickness,” 218 thromboangiitis obliterans, 137 sweating sickness, 276, 311–12 thrombophlebitis, 266 “swimmer’s itch,” 291 thrombosis, 54, 56–57, 137 “swineherd’s disease,” 196 thrush, 128, 130 Sydenham’s chorea, 168, 277, 278 thryoid, enlarged, 146. See also goiter sylvan yellow fever, 365 thymic enlargement, 309 symmetrical erosive polyarthritis, 41 thymoma, 226 symptomatic fevers, 350 thyroid cancer, 66, 147 syncope, 102, 157 thyroid conditions, 47, 72, 98, 147–48, 226–27, synovitis, 236 237 syphilis, 312–19 thyroiditis, 147, 227 characteristics, 313–14 tick-borne relapsing fever, 275–77 encephalitis lethargica and, 115 tick-borne typhus (Rocky Mountain spotted fever), eye diseases in, 234 282–85 history, 315–17 tick spotted typhus (Rocky Mountain spotted nonvenereal, 317–19, 332 fever), 282–85 similarityto gonorrhea, 152 tina, 250 similarityto herpes simplex, 162 tinea, 128–30 similarityto leprosy,194 tinea canis, 129 similarityto Lymedisease, 201 tinea capitis, 129, 132 similarityto pinta, 250 tinea corporis, 129 stages, 313 tinea cruris, 129 unitarian vs. nonunitarian theory, 313–14, 318, tinea imbricata, 129 332–33 tinea pedis, 129 yaws and, 313–14, 317–18, 362–64 tinnitus, 210 syphilitic chancre, 162, 314 “tires,” 218 systemic lupus erythematosus (SLE), 199–201, “Tobia petechia fever” (RockyMountain spotted 226 fever), 282–85 tonic rigidity, 310 T tonic seizures, 324 tabardillo, 284, 352 tonsillitis, 288 tabes dorsalis, 314 Torula histolytica, 132 Tacaribe virus, 38, 184 toxemia, 110, 300, 335 tachycardia, 102, 166, 277 toxicosis, pica and, 248 tachypnea, 101 toxic-shock syndrome, 253 Taenia saginata, 319–20 Toxoplasma gondii, 2, 330 Taenia solium, 319–20 toxoplasmosis, 330–31 Talmud, 358 trachoma, 230–33 tapeworm infection, 110, 319–20 “trail typhus” (Rocky Mountain spotted fever), tartar, dental, 245 282–85 tartar emetic, 257 transcient ischemic attacks (TIAs), 32 tau protein, 18–19 translocation Down syndrome, 96 Tay-Sachs disease (TSD), 320–23 transovarial transmission (TOT), 37 Tenebrio, 320 traumatic erysipelas, 122 tenesmus, 44, 92 travelers’ diarrhea, 92, 144 tertiaryyaws,364 trematodes, 290, 331 tetanus, 99, 323–26 trembles, 218–19 tetany, 328–30 tremetol poisoning, 218–20

409 Subject Index tremor, 240–41 eye diseases in, 234 trench fever, 282, 331 history, 159, 338–42 Treponema carateum, 250–51, 313, 331 intestinal, 178 Treponema pallidum, 202, 250–51, 312–14, 317–18, leprosyand, 193 331, 363 lupus and, 200 Treponema pertenue, 217, 251, 331, 362–63 malnutrition and, 262 treponematoses, 331–33 meningitis and, 214, 338 nonvenereal syphilis, 317–19 miliary, 337–38 pinta, 250–51, 317–18, 333, 362 pneumonia in, 255 syphilis, 312–19 pulmonary, 337–38, 340 taxonomy, 250, 363–64 scrofula and, 292–94 unitarian vs. nonunitarian theory, 313–14, 318, similarityto histoplasmosis, 163–65 332–33 spinal, 338 yaws, 313–14, 317–18, 332–33, 362–65 Tay-Sachs disease and, 322 Triatoma, 71 treatment, 337, 341–42 trichiasis, 231, 233 types, 337 Trichinella spiralis, 333–34 vaccine, 338 trichinosis, 239, 333–36 in Western Europe, 159 trichophagia, 247 tularemia, 252, 255, 342–45 Trichophyton, 129 Turner’s syndrome, 143 Trichophyton concentricum, 129 typhoidal tularemia, 344 Trichophyton ferrugineum, 129 typhoid fever, 345–49 Trichophyton mentagrophytes, 129 characteristics, 345–47 Trichophyton rubrum, 129 Ebola virus misdiagnosis as, 107 Trichophyton schoenleinii, 129 history, 347–49, 350 Trichophyton verrucosum, 130 paratyphoid fever, 345 Trichophyton violaceum, 129 similarityto pneumonia, 256 trichophytosis, 129 similarityto relapsing fever, 276 trichuriasis, 336 similarityto trichinosis, 336 Trichuris trichiura, 335, 336 similarityto tularemia, 343 trismus, 324, 327 “southern,” 351 trismus nascentium, 326 “Typhoid Mary,” 348–49 trisomy, 96, 143 as typhus-like fevers, 350–52, 354 tropical chlorosis, 166. See also hookworm typhomalarial fever, 71, 349–52 infection typhus, 352–55 tropical diabetes, 88, 90–91. See also diabetes Brill’s disease and, 353 mellitus characteristics, 352–53 “tropical dysentery,” 21 continued fevers as, 350 Trypanosoma brucei gambiense, 7–9 Cox vaccine, 354 Trypanosoma brucei rhodesiense, 7–9 epidemic, 352–55 trypanosomes, 7–8, 70–71 ergotism and, 120 trypanosomiasis, 7–13, 192. See also African murine, 282, 352, 355 trypanosomiasis as Plague of Athens, 252 Trypanosomiasis cruzi, 70–71 relapsing fever and, 275 tsara’ath, 194. See also leprosy scrub, 282–83, 355–56 tsetse flies, 7–8, 11–12. See also African similarityto relapsing fever, 276 trypanosomiasis similarityto trench fever, 331 tsutsugamushi, 282–83, 355–56 sweating sickness and, 311 tubercular meningitis, 338 typhoid fever and, 348–52, 354 tuberculoid leprosy, 193–94 typhus exanthematicus, 352 tuberculosis, 336–42 typhus historique, 352 avian and bovine, 193, 337 typus cerebralis, 214 Carrion’s´ disease and, 68 characteristics, 336–38 U chlorosis and, 72 ulcerative colitis, 175–78 current situation, 342 ulcerative conjunctivitis, 344

410 Subject Index ulcerative plantar papules, 362 milk sickness, 218–220 ulceroglandular infection, 343–44 multiple sclerosis, 220–222 umbilical hernia, 327 mumps, 223–224 undulant fever, 58–60 myasthenia gravis, 225 United States. See also North America mycoses, 130–131 AIDS, 1–5 ophthalmia, 234 Alzheimer’s disease, 14, 18 osteoarthritis, 235 amebic dysentery, 20 osteoporosis, 237–238 anemia, 26 Paget’s disease of bone, 238–240 bacillarydysentery,43, 44 pellagra, 242, 244 beriberi, 46 pica, 247, 249–250 black and brown lung disease, 53 pneumonia, 258 bleeding disorders, 55–57 poliomyelitis, 259–261 botulism, 58 puerperal fever, 267 bubonic plague, 61 Q fever, 268–270 cancer, 65–66 rabies, 271, 274–275 Chagas’ disease, 70 relapsing fever, 276–277 cholera, 75–77 rheumatic fever, 279–280 cirrhosis, 79 rickets, 282 croup, 83 RockyMountain spotted fever, 283–285 cystic fibrosis, 84 rubella, 286 cytomegalovirus infection, 85 scarlet fever, 288–289 dengue, 35–36, 86 schistosomiasis, 291 diabetes, 89–91 scurvy, 296–297 diphtheria, 94 sickle-cell anemia, 299 Down syndrome, 98 strokes, 32–33 dropsy, 101 strongyloidiasis, 306 Ebola virus, 108–109 sudden infant death syndrome, 306 eclampsia, 111 sudden unexplained death syndrome, encephalitis lethargica, 115 309–310 epilepsy, 116 syphilis, 313, 315 ergotism, 120–121 tapeworm infection, 320 favism, 124 Tay-Sachs disease, 323 filariasis, 127 tetanus, 325 giardiasis, 144 tetanus, neonatal, 326 glomerulonephritis, 145 toxoplasmosis, 331 goiter, 148 trichinosis, 334–336 gonorrhea, 151–152 trichuriasis, 336 G6PD deficiency, 23 tuberculosis, 339–342 heart-related diseases, 159–160 tularemia, 343–345 histoplasmosis, 163–164 typhoid fever, 346–349 hookworm infection, 165–168 typhomalarial fever, 349–352 Huntington’s disease, 169 typhus, epidemic, 354 hypertension, 170 typhus, murine, 355 infectious hepatitis, 173 typhus, scrub, 356 infectious mononucleosis, 174 yellow fever, 36, 367–369 inflammatorybowel disease, 176 “Universal Plague,” 49 influenza, 180 urban yellow fever, 365. See also yellow fever La Crosse virus, 37 uric acid, gout and, 153–56 lead poisoning, 187–188 urolithiasis, 357–58 Legionnaires’ disease, 189–190 uterine cancer, 65 lupus erythematosus, 201 uterine hemorrhage, 102 Lyme disease, 201, 203 malaria, 204, 206–207 V measles, 214 valleyfever, 130 meningitis, 215–216 valvular damage, 159

411 Subject Index valvular disease, 101, 278–79 Willimas trait, 55 varicella, 85, 255 Wilson’s disease, 80 varicella-zoster virus disease, 162, 359–60 “Wolhynian fever,” 331 Variola major, 300 woolsorters’ disease (anthrax), 29–31 Variola minor, 300, 303 World Health Organization (WHO) variolation, 302–4 on African sleeping sickness, 10–11 vascular spasms, 137 cancer classification, 64 vasculitis, 137 Global Program on AIDS, 4 vasoconstriction, 324 gradations of goiter, 147 venereal diseases. See sexuallytransmitted on horizontal health services, 10 diseases hypertension classification, 169 venereal syphilis. See syphilis influenza identification, 181 venereal warts, 316 malaria eradication campaigns, 207 Venezuelan equine encephalitis, 36, 38 measles vaccinations, 212, 214 venom, gangrene from, 137 neonatal tetanus program, 326, 328 verruga peruana, 67–69 Onchocerciasis Control Programme, 230 vertebral fractures, 237 smallpox eradication, 303 vesicular rickettsiosis, 285 on tuberculosis, 342 Vibrio cholerae, 73, 74, 78 on yaws, 362 Victorian times, 72, 106 wound botulism, 57–58. See also botulism viral conjunctivitis, 231 “wrist drop,” 185 viremia, 184, 259, 365 Wuchereria bancrofti, 125–28 “virgin’s disease,” 23 virgin-soil epidemic, 252–54 X virus amaril, 365 Xenopsylla cheopis, 61, 355 virus croup, 83 X-rayphotographs, 341 visceral leishmaniasis, 191 vitamins. See also deficiencydiseases; diet Y B vitamins, 22, 242, 357 yatobyo, 343 vitamin A, 121, 263, 357 yaws, 313–14, 317–18, 332–33, 362–65 vitamin B6,357 yellow fever, 365–69 vitamin B12,22 characteristics, 282–83, 365–66 vitamin C, 295–98 encephalitis lethargica and, 115 vitamin D, 237, 280–82, 329–30 eradication efforts, 369 vitiligo, 250 hepatitis from, 171 vomito negro, 365 similarityto Ebola virus disease, 108 von Willebrand’s disease, 55, 57 similarityto Marburg virus disease, 207 similarityto relapsing fever, 276 W transmission, 35, 36 “water fever,” 196 vaccine, 36, 38, 173, 369 water itch (hookworm infection), 165 vector control, 37 weakness, in myasthenia gravis, 226–27 Yellow Fever Commission, 369 weaning, timing of, 262–63 “yellow jack,” 365 “Weil’s disease,” 195–96 Yersinia, 43, 93 Wernicke’s encephalopathy, 46 Yersinia pestis, 49, 60–62 western equine encephalitis, 36 West Nile virus, 36 Z Whipple, George H., 22 zara’ath, 194. See also leprosy whooping cough, 360–62 Ziegenpeter, 224

412