BLBK134-Schwartz March 17, 2009 21:4

Tropical Diseases in Travelers

EDITED BY Eli Schwartz md dtmh Chaim Tel Hashomer, and Sackler School of Medicine Tel Av iv, Israel

A John Wiley & Sons, Ltd., Publication

iii

BLBK134-Schwartz March 17, 2009 21:4

Tropical Diseases in Travelers

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Tropical Diseases in Travelers

EDITED BY Eli Schwartz md dtmh Chaim Sheba Medical Center Tel Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Av iv, Israel

A John Wiley & Sons, Ltd., Publication

iii BLBK134-Schwartz March 17, 2009 21:4

This edition first published 2009, C 2009 by Blackwell Publishing Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.w ile y.com/w ile y-blackwe ll The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Tropical diseases in travelers / edited by Eli Schwartz. p. ; cm. Includes index. ISBN 978-1-4051-8441-0 1. Tropical medicine. 2. Travel—Health aspects. I. Schwartz, Eli, Dr. [DNLM: 1. Tropical Medicine—methods. 2. Communicable Disease Control—methods. 3. Travel. WC 680 T8557 2009] RC961.T736 2009 616.9993—dc22 2008055877 A catalogue record for this book is available from the British Library.  Set in 9.25/11.5pt Minion by Aptara R Inc., New Delhi, India Printed and bound in Singapore 1 2009

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Dedicated with love to my wife Carmela and our children, Miriam, Aviad, and Naama

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Contents

List of Contributors, x Foreword, xii Acknowledgments, xiv

Part I Tropical Diseases in Travelers—General Aspects 1 Introduction, 3 Eli Schwartz 2 The Art of Travel Medicine a Century Ago, 5 Eli Schwartz 3 Epidemiology of Post-Travel Illnesses, 13 Pamela Rendi-Wagner and Eli Schwartz 4 Travelers as Sentinels for Disease Occurrence in Destination Countries, 27 David O. Freedman and Eli Schwartz 5 VFR (Visiting Friends and Relatives) Travelers, 35 Phyllis E. Kozarsky and Jay S. Keystone 6 Post-Tropical Screening, 45 Joanna S. Herman and Peter L. Chiodini

Part II Specific Infections 7 Dengue Fever, 53 Eli Schwartz 8 West Nile Fever, 65 Michal Chowers 9 Japanese Encephalitis in Travelers, 74 John Simon 10 Yellow Fever and Yellow Fever Vaccine-Associated Disease, 82 Elizabeth D. Barnett 11 Chikungunya: An Emerging Disease in Travelers, 92 Fabrice Simon, Elodie Vivier, and Philippe Parola 12 Ross River Virus, 101 Joseph Torresi 13 Viral Hemorrhagic Fevers, 107 Annelies Wilder-Smith

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viii Contents

14 Rabies and the Traveler, 119 Henry Wilde and Thiravat Hemachudha 15 Enterically Transmitted Hepatitis: Hepatitis A and E, 130 Nancy Piper Jenks and Eli Schwartz 16 Typhoid and Paratyphoid Fever, 144 Eli Schwartz 17 Bacterial Diarrhea, 154 Herbert L. DuPont 18 Rickettsial Diseases, 161 Mogens Jensenius and Philippe Parola 19 Relapsing Fever, 169 GilSidiandEliSchwartz 20 Leptospirosis, 175 Eyal Leshem and Eli Schwartz 21 Malaria in Travelers: Epidemiology, Clinical Aspects, and Treatment , 187 Eli Schwartz 22 Malaria Diagnosis in Travelers, 204 R. Scott Miller 23 Malaria—Prevention, 216 Eli Schwartz 24 Schistosomiasis, 229 Eli Schwartz 25 Filarial Infections, 243 Thomas B. Nutman 26 Human Trypanosomiasis: African and American Trypanosomiasis (Chagas Disease), 254 Johannes A. Blum 27 Cystic Echinococcosis, 264 Enrico Brunetti 28 Neurocysticercosis, 275 Eli Schwartz 29 Histoplasmosis and Other Endemic Fungal Infections, 282 Michael J. Segel and Eli Schwartz 30 Intestinal Protozoa: Giardia, Amebiasis, Cyclospora, Blastocystis hominis, Dientamoeba fragilis,andCryptosporidium parvum, 294 Karin Leder 31 Intestinal Helminths: Strongyloides stercoralis, Ascaris lumbricoides, Hookworm, Trichuris trichiuria, Enterobius vermicularis, Trichinella, Intestinal Tapeworms, and Liver Flukes, 303 Karin Leder 32 Leishmaniasis, 316 Eli Schwartz BLBK134-Schwartz March 17, 2009 21:4

Contents ix

33 Ectoparasites: Myiasis, Tungiasis, Scabies, 334 Eli Schwartz and Eric Caumes 34 Helminthic Skin Diseases in Travelers, 341 Eric Caumes 35 Delusional Parasitosis, 352 Eli Schwartz, Jay Keystone, and Henry Abramovitch

Part III Syndromic Approach 36 Approach to Patients with Post-Travel Diarrhea, 361 Eli Schwartz and Bradley A. Connor 37 Approach to Patients with Fever, 370 Eli Schwartz 38 Approach to Returning Travelers with Skin Lesions, 379 Eric Caumes 39 Approach to Travel-Related Eosinophilia, 389 Eyal Meltzer and Eli Schwartz 40 Approach to Patients with Protracted Rheumatological Manifestations, 403 Eli Schwartz and Michael Ehrenfeld 41 Travel-Related Respiratory Infections, 413 Eyal Meltzer and Eli Schwartz 42 Neurological Signs and Symptoms in Travelers, 427 Einar P. Wilder-Smith and Annelies Wilder-Smith 43 Closing Remarks, 434 Eli Schwartz

Appendixes Appendix A: Drugs for Parasitic Infections, 436 Appendix B: Laboratory Tests for Tropical Diseases, 466

Index, 473 Color plate section follows page 274. BLBK134-Schwartz March 20, 2009 11:53

Contributors

Henry Abramovitch PhD Meir Medical Center, Mogens Jensenius MD Department of Medical Education, Kfar Saba, Israel Ulleval˚ University Hospital, Sackler School of Medicine, Oslo, Norway Tel Aviv University, Bradley A. Connor MD Tel Av iv, Israel Division of Gastroenterology and Jay S. Keystone MD Hepatology, Division of Infectious Disease, Weill Medical College of Cornell University, Elizabeth D. Barnett MD Toronto General Hospital, New York, USA Maxwell Finland Laboratory for Infectious University of Toronto, Diseases, Toronto, Ontario, Canada Boston Medical Center, Herbert L. DuPont MD Boston, Massachusetts, USA The University of Texas–Houston School of Public Health and Medical School, Phyllis E. Kozarsky MD Johannes A. Blum MD and Division of Infectious Diseases, Swiss Tropical Institute, Baylor College of Medicine Emory University School of Medicine, Basel, Switzerland and Atlanta, Georgia, USA St. Luke’s Episcopal Hospital, Houston, Texas, USA Enrico Brunetti MD Karin Leder MD University of Pavia Royal Melbourne Hospital, and Michael Ehrenfeld MD University of Melbourne IRCCS S. Matteo Hospital Foundation, Chaim Sheba Medical Center, and Pavia, Italy Tel-Hashomer Monash University, and Victoria, Australia Tel Aviv University Faculty of Medicine, Eric Caumes MD Tel Av iv, Israel ´ Departement des Maladies Infectieuses Eyal Leshem MD et Tropicales, Chaim Sheba Medical Center, Hopitalˆ Pitie-Salp´ etriˆ ere,` David O. Freedman MD Tel Hashomer, Israel University Pierre et Marie Curie, Division of Infectious Diseases, and Paris, France University of Alabama at Birmingham, Birmingham, Alabama, USA Sackler School of Medicine, Tel Aviv University, Peter L. Chiodini MD Tel Av iv, Israel Department of Parasitology, Thiravat Hemachudha MD Hospital for Tropical Diseases Faculty of Medicine, and Chulalongkorn University, Eyal Meltzer MD London School of Hygiene and Bangkok, Thailand Chaim Sheba Medical Center, Tropical Medicine, Tel Hashomer, Israel London, UK Joanna S. Herman MD and Department of Parasitology, Sackler School of Medicine, Hospital for Tropical Diseases, Tel Aviv University, Michal Chowers MD Tel Av iv, Israel Sakler School of Medicine, London, UK Tel Aviv University, Tel Av iv, Israel Nancy Piper Jenks CFNP R. Scott Miller and Hudson River Healthcare, Walter Reed Army Institute of Research, Infectious Disease Unit, Peekskill, New York, USA Silver Spring, Maryland, USA

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Contributors xi

Thomas B. Nutman MD Sackler School of Medicine, Joseph Torresi MD Laboratory of Parasitic Diseases, Tel Aviv University, Department of Infectious Diseases, National Institutes of Health, Tel Av iv, Israel Austin Hospital, Bethesda, Maryland, USA The University of Melbourne, Michael J. Segel MD Heidelberg, Victoria, Australia Philippe Parola MD Chaim Sheba Medical Center, Hopitalˆ d’Instruction des Armees,´ Laveran Tel Hashomer, Israel Elodie Vivier MD and Hopitalˆ d’Instruction des Armees´ Laveran, Institut de Medecine´ Tropicale de Service de Gil Sidi MD Marseille, France Sante des Armees,´ Le Pharo, Department of Infectious Diseases, Marseille, France Memorial Sloan Kettering Cancer Center, Henry Wilde MD New York, USA Faculty of Medicine, Pamela Rendi-Wagner MD Chulalongkorn University, Department of Epidemiology and Fabrice Simon MD Bangkok, Thailand Preventive Medicine, Hopitalˆ d’Instruction des Armees,´ Laveran Tel Aviv University, and Annelies Wilder-Smith MD Tel Av iv, Israel Institut de Medecine´ Tropicale du Service de Division of Infectious Diseases, and SantedesArm´ ees,´ Le Pharo, National University of Singapore Department of Specific Prophylaxis and Marseille, France and Tropical Medicine, Duke-NUS, Medical University Vienna, Singapore Vienna, Austria John Simon MD University of Hong Kong, Hong Kong, China Einar P. Wilder-Smith MD Eli Schwartz MD Division of Neurology, Chaim Sheba Medical Center, National University of Singapore Tel Hashomer, Israel Singapore and BLBK134-Schwartz March 17, 2009 21:4

Foreword

It is with great pleasure that I write this preface to a new worms, leading to an immune-mediated acute syndrome and valuable book, Tropical Diseases in Travelers,edited (Katayama fever). In travelers, subsequent clinical disease by Professor Eli Schwartz. Professor Schwartz has assem- is often related to sporadic ectopic egg deposition that bled a diverse, international, and very talented team of leads to catastrophic neurologic involvement, dermato- contributors to address an important, yet underappreci- logic presentations, or other bizarre syndromes. Chronic ated, concept in tropical and travel medicine. The clinical schistosomiasis occurs after years of exposure, the pres- presentations of infectious disease may be different in ence of hundreds of adult worms, and the near continuous the non-immune, infrequently exposed traveler than the deposition of eggs into the portal circulation leading to immune and multiply exposed inhabitant in a tropical cirrhosis and portal hypertension. These are two very dif- environment. ferent diseases that occur in the local population or the The classic descriptions of the great tropical diseases returning traveler. began to appear in the 1800s as the Western powers be- This book also includes historically important diseases gan their imperial era in the Indian subcontinent, China, such as typhoid fever, which used to be more common Southeast Asia, and, finally, in Sub-Saharan Africa. Sud- in the developed world, and leptospirosis, which has a denly, soldiers, businessmen, missionaries, and settlers cosmopolitan distribution, but is more commonly en- needed to run the Western empires became casualties countered in the developing world. Providers of travel of infectious diseases of the tropics. Even in those early medicine may be the first to encounter these patients. days, clinicians recognized that clinical presentations in Information on how tropical diseases present in trav- otherwise healthy, non-immune, well-nourished adults elers has never before been captured in a single, easy- were different from those seen in the native populations. to-access publication. Professor Schwartz, as book editor The reasons for this difference included the size and fre- and co-author of numerous chapters, is eminently qual- quency of the infectious inoculum, the lack of any prior ified for this task. He has been an original thinker in immunity from past exposures or maternal immunity, travel medicine, always pushing the discipline to ques- and the fact that local populations often had a complex tion dogma and to consider new approaches. The other background of malnutrition, multiple co-infections, and contributors are also all experts in their field. far advanced diseases. Travel medicine is a relatively new discipline that has Symptoms in travelers are caused by far fewer organ- focused on the pre-travel aspect of traveler needs. This isms, leading to acute presentations with exuberant im- new book is the first to summarize the knowledge of mune reactions in the non-immune. Symptoms in local post-travel presentations in the otherwise non-immune populations may be manifest after years of multiple infec- and non-endemic population. With such focus, this book tions, with a large organism burden, organ system dam- will be useful to all practitioners, including primary care age from years of inflammation, and chronic disability. and infectious disease clinicians, who encounter the post- Finally, the genetic background of travelers is distinctly travel patient. . different than the local population that have co-evolved Tropical Diseases in Travelers is presented in four sec- with infections, such as malaria. tions. Following a useful general introduction is a de- Acute and chronic schistosomiasis are excellent exam- tailed discussion of multiple viral, bacterial, and parasitic ples. The acute syndrome can be seen following a single infections. The third clinically relevant section on the syn- exposure to fresh water and is caused by only a few adult dromic approach to patients will be useful in evaluating

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Foreword xiii

returning travelers with symptoms. The book concludes dramatically different diseases, depending on the back- with two helpful appendixes. ground immunity of the host, access to timely care, and In the globally connected world of the twenty-first cen- the pathogen load in the body. This book will help us all tury, the lines of travel and tropical medicine are blurred. to see the differences. Immigrants and refugees, displaced and discarded in their own world, may turn up at your first-world doorstep as Alan Magill MD, FACP, FIDSA tropical medicine patients, whereas soldiers and humani- Director, Division of Experimental Therapeutics, tarian workers may present with clinical presentations in Walter Reed Army Institute of Research the developing world, confusing those used to caring for President, International Society of Travel Medicine local populations. The same infectious agent can lead to (ISTM), 2009–2011 BLBK134-Schwartz March 17, 2009 21:4

Acknowledgments

I would like to begin by thanking the publisher, Blackwell- colleagues at the Center of Geographic Medicine and at the Wiley, for recognizing the value of a special volume on Department of Medicine C at Sheba Medical Center, Tel tropical diseases in travelers and for helping to bring this Hashomer, for engaging in constant dialogue with me over book to fruition. Special thanks go to Robin Bonner and the years concerning these topics and for their support Eleanor Umali of Aptara, for their dedication to the book’s during the writing of Tropical Diseases in Travelers. production and their commitment to meeting our target I end with our ancient verse: “Much have I learnt from date for publication. my masters, more from my colleagues, but the most from My gratitude goes to all of the contributors for their my own students” [Talmud of Babylon, Tractate Taanit, 6]. efforts and for sharing their experience and expertise to By the same token, I would like to thank all of my teach- produce such high-quality chapters. My special thanks to ers and colleagues, in Israel and abroad, from whom I have Nancy Piper-Jenks for her invaluable assistance during learned a great deal. However, a special thanks is dedicated the writing of this book. I would also like to thank my to my patients, from whom I have learned the most.

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Tropical Diseases in I Travelers—General Aspects

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1 Introduction Eli Schwartz Chaim Sheba Medical Center, Tel Hashomer, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

The explosion of global travel during recent decades has descriptions of these diseases in indigenous populations, been well documented, and it has become common to not in travelers. see travelers from the developed world venturing to more The significant distinctions between travelers to devel- and more remote corners of our planet. Exotic travel ex- oping countries and local residents are apparent through poses people to exotic diseases, which they subsequently differencesinthetypesofinfectionscommonlyseenin take with them to other places. The SARS (severe acute the two populations, as well as in the clinical presentations respiratory syndrome) epidemic illustrates how one per- and management of these diseases. son, who journeyed from an endemic area of China to Epidemiologically, these distinctions reflect differences Hong Kong, was able to infect several people at a hotel, in the likelihood of exposure to the infections, as well as who themselves became infected transporters of SARS, intensity of exposure, which is typically higher among in- allowing its worldwide spread. A more recent example is digenous populations. For example, melioidosis (caused the Chikungunia outbreak that began in the regions of by the gram-negative soil- and water-associated bac- the Indian Ocean and spread to Africa and India. Travel- terium Burkholderia pseudomallei) is a common cause of ers then carried the disease into Europe, thus causing its community-acquired sepsis in northern Thailand, yet the documented autochthonous outbreak in Italy. Therefore, disease is rarely seen in travelers. The same is true for try- tropical diseases are no longer confined to the tropics. panosomiasis (sleeping sickness), filarial infections, and The term tropical diseases is not limited to ailments ac- cholera, which are rarely seen in travelers. quired from a particular tropical geographic area of the Outbreaks of yellow fever are commonly reported world. Indeed, tropical diseases such as yellow fever and among local residents in endemic regions, but are virtually malaria were once a very important cause of morbidity never seen in travelers—in this case, most likely because and mortality in regions as far north as Boston, USA. of their high uptake of the efficacious yellow fever vaccine. Instead, we are referring to diseases acquired in the devel- Disparate background immunity also affects the way in oping world, where public health standards are lower and which some diseases manifest. For example, malaria in hygiene and sanitation are not customary. For this reason, adult populations in endemic countries may not cause we are encountering numerous infectious diseases that life-threatening disease, whereas in traveler populations, were at one point endemic worldwide and had been con- even low-grade parasitemia may cause a severe and life- trolled or eradicated in industrialized countries during threatening condition. the twentieth century. In many developing countries, hepatitis A is not viewed As physicians who encounter returning travelers with as an important problem because most children are in- various tropical diseases, we see a clear picture of these fected at a young age, when infection is mild and of- so-called “exotic diseases” presenting in a unique fash- ten unrecognized. Older children and adults are therefore ion in travelers. In fact, these diseases tend to manifest immune to the disease. However, the virus regularly con- very differently in nonimmune travelers than in indige- taminates food and water and poses a significant threat to nous populations of the tropics. Textbooks focusing on nonimmune travelers who enter the area. tropical diseases understandably limit their descriptions Clinical manifestations are also often different. These to the classical presentation of such tropical diseases, with manifestations may be based on previous immunity and/or other not-yet-defined immunological causes. Ex- Tropical Diseases in Travelers, 1st edition. Edited by E. Schwartz. cellent examples are the manifestations of infection with c 2009 by Blackwell Publishing, ISBN: 978-1-4051-8441-0. the various species of schistosome worms. This disease,

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4 Chapter 1

which is one of the most common infections in the trop- present in nonimmune travelers, resulting in a more ac- ics, is a leading cause of morbidity due to late and chronic curatepictureoftheirnaturalhistory.Inaddition,there stages of infection (i.e., hematuria, urinary retention, in are generally fewer confounders or additional infections Schistosoma hematobium infection, and portal hyperten- (e.g., malnutrition, HIV, or other tropical disease infec- sion with S. mansoni). These manifestations, however, are tions) that might impact the natural history of the disease. rarely seen in travelers. They most commonly present with The fact that there is usually more thorough patient acute schistosomiasis, which occurs several weeks after ex- follow-up in industrialized countries offers an opportu- posure and leads to Katayama syndrome, a hypersensitiv- nity for further assessment of the outcomes of infectious ity reaction to the helminth antigen. Katayama syndrome diseases over the long term. For example, assessing the is in fact the principal presentation of schistosomiasis in efficacy of malaria prophylaxis for Plasmodium vivax in- travelers, causing significant morbidity, whereas among fection can hardly be done in an endemic area because local residents, it is virtually nonexistent, and therefore late infection cannot be differentiated from re-infection. barely discussed in tropical disease textbooks. However, there are opportunities for long-term follow-up Malaria is another example, in that it always presents in travelers who return to nonendemic countries. Indeed, as a significant febrile disease among nonimmune travel- observing returning travelers from vivax endemic areas ers and yet it can often occur without fever among local has allowed us to conclude that current malaria prophy- populations. laxis is actually inadequate for vivax prevention. Methods of diagnosis may differ. For example, in en- The study of infectious diseases in travelers may also demic countries, diagnosing helminth infections among elucidate the natural history of many cosmopolitan dis- the indigenous population is done by finding ova in the eases, such as leptospirosis, that are seen less frequently stool. Serology is usually inadequate because it cannot dif- these days in industrialized countries. Sporadic cases and ferentiate between current and past infection and, there- outbreaks do occur in industrialized countries, although fore, will almost always be positive. they tend to be missed by clinicians. The understanding In the case of travelers, however, the situation is the of diseases in travelers can contribute to the clinician’s contrary; due to low worm burden, ova are infrequently knowledge and awareness of disease when it occurs at found in stool. Moreover, because travelers can present home. with illness during the helminthic migration phase, de- Practicing travel medicine may also help in managing tection of ova in stool is biologically unlikely. Therefore, patients who have not traveled, such as those with diar- the most important diagnostic tools in travelers are sero- rheal diseases. The evaluation of patients with diarrheal logical methods. diseases in the travel clinic is a large part of everyday There are also variations in treatment.Therearecom- practice and can teach non-travel-medicine practitioners mon misconceptions that the best available treatments about differential diagnosis and methods of detection and and most knowledgeable approaches to the treatment management, so that lengthy and expensive evaluations of tropical diseases are found in endemic countries. In may not be necessary. tropical countries, the most accessible drugs are low-cost Travel medicine is a relatively new discipline and is a medicine, rather than the best available. Thus, malaria subspecialty that has continued to evolve over recent years. may still be treated in local populations with older drugs A number of textbooks that focus on pretravel health to which resistance has developed; however, for the non- issues and the prevention of illness in travelers are now immune traveler, this treatment may be fatal. available. As another example, we have shown that the most effec- This book is a first attempt at drawing together knowl- tive (albeit expensive) treatment of Leishmania braziliensis edge accumulated in recent years in the area of “post- is liposomal amphotericin B; yet, antimonial drugs, which travel”—those issues concerning the manifestation of are older and more toxic drugs, are used in endemic coun- tropical diseases and their diagnosis and treatment in tries because of their lower costs. Thus, choosing the cor- travelers. The traveler, as a sentinel, has given us the op- rect drug and dosage should be tailored to nonimmune portunity to observe these diseases from another perspec- travelers. tive. This knowledge can help us to understand better the The study of tropical diseases in travelers offers the morbidity and mortality of these diseases and, more im- advantage of exploring the natural history of these dis- portant, to appropriately evaluate and treat the traveler eases in a clearer light. First of all, these tropical diseases whomaybeilluponreturninghome. BLBK134-Schwartz March 13, 2009 20:20

The Art of Travel Medicine 2 a Century Ago Eli Schwartz Chaim Sheba Medical Center, Tel Hashomer, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

In a lecture given about one hundred years ago, Sir Patrick changes that have occurred both in the tropics and in Manson addressed an issue that remains highly relevant industrialized countries since then (Table 2.1). today. The title of his lecture was “Diagnosis of Fever in The major points that I would like to highlight include Patients from the Tropics.” the following. As a reminder, Dr. Patrick Manson (1844–1922) was a British parasitologist (born in Scotland) and founder of the field of tropical medicine. He was the first to The common mistakes among clinicians discover (1877–1879) that filariasis (Filaria bancrofti)is who see the returned traveler from a mosquito-borne disease; transmission of a disease by the tropics an insect was a revolutionary idea at the time. He hy- pothesized that malaria could also be transmitted by mosquitoes, which was subsequently proven to be cor- The most important mistake, according to Manson, was rect through the research of Sir Ronald Ross in India. the overdiagnosis of “tropical disease” among those who In 1890, Dr. Manson settled in London, where he orga- returned to the UK. He called on the diagnostician to nized the London School of Tropical Medicine (1899). He “disabuse his mind” of thinking that any fever occurring was knighted in 1903 and continued to practice medicine in a patient from the tropics must be a tropical fever. He until his death. His fieldwork in several tropical regions of was concerned that cosmopolitan diseases, which were the world led him to his pioneer observations on tropical the common diseases of his time, would be ignored by diseases, which were then also used to treat colonists and physicians. The significant mundane diseases of his time soldiers who encountered infectious diseases unknown in were tuberculosis, syphilis, typhoid, sepsis, and malignant the temperate European climate. His book Tropical Dis- diseases. eases (1898) became the classic textbook on this subject. In our era, there are two major changes. First and fore- The British Empire at this time ruled over a vast and ex- most is that the ordinary infectious diseases that Manson pansive domain, encompassing about a quarter of Earth’s mentioned no longer occur routinely in industrialized total land area; as was often said, “The sun never sets on countries, which corresponds to the changes in epidemi- the British Empire.” From a medical point of view, this ology of diseases throughout the twentieth century. Al- meant that repatriating soldiers or other British officials though, at the beginning of the twentieth century, infec- back to the UK took several weeks, which is a long period tious diseases continued to be the leading cause of mor- of time, exceeding the incubation time of many diseases. bidity and mortality, with improved hygienic conditions, Dr. Manson’s lecture (Appendix, this chapter), which followed by the introduction of vaccines and antibiotics, was published in the British Medical Journal in 1909 [1], there was a progressive decline of infectious diseases [2]. may shed some light on the common diseases among The current situation is that cardiovascular and malignant travelers of that time, as well as highlight some of the diseases are the major causes of mortality, whereas infec- tious diseases account for only about 5% of mortality, in contrast to the current situation in developing countries, Tropical Diseases in Travelers, 1st edition. Edited by E. Schwartz. where infectious diseases are still the major cause of death c 2009 by Blackwell Publishing, ISBN: 978-1-4051-8441-0. (Figures 2.1a and 2.1b) [3].

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6 Chapter 2

(a) (b) 15.9 6 18.7

7.9 32.3 21.6 9.5 0.7

5.6

24.2 9.8 47.9

Deaths from infectious & parasitic diseases (%) Deaths from infectious & parasitic diseases (%) Deaths from cancer (%) Deaths from cancer (%) Deaths from circulatory diseases (%) Deaths from circulatory diseases (%) Perinatal death (%) Perinatal death (%) Deaths from injury (%) Deaths from injury (%) Deaths from other causes (%) Deaths from other causes (%) Figure 2.1 Causes of mortality. (a) Developed world. (b) Developing world.

The second development, which followed the first, is era and in almost all case series of febrile ill returned that the principal question of differential diagnosis in re- travelers, malaria is the leading cause (see Chapter 3). turning travelers today is not between tropical infectious However, he stated that “there is no disease so easily and diseases and ordinary infectious diseases but rather be- so surely recognized as malaria.” He made this statement tween tropical infectious diseases and chronic, often in- in spite of the fact that a laboratory diagnosis of malaria curable Western diseases. Our role in dealing with the was not easily made as compared to this day and age. A health of returning travelers therefore is to re-emphasize malaria diagnosis one hundred years ago was based on one to physicians who practice medicine in the industrialized of three options, in the following order of importance: world that infectious diseases still exist in the world. Trav- One was the periodiccharacteroffever,demonstrating elers returning from endemic areas may carry with them a rise in fever every 2–3 days. an infectious disease that could be either life-threatening, The second option was the result of a therapeutic trial or associated with intolerable symptoms, and which, in of quinine, a successful trial showing a response within either case, may have the potential of a simple and rapid 48–72 hours. cure. An example of the latter is a returned traveler with Last, diagnosis was made with the use of a microscope. a few weeks of diarrhea. A Western physician may tend To have a reliable microscopic test, the patient could not to think about chronic conditions such as inflammatory be under quinine treatment, but just as important, the bowel disease or malignancy and may fail to consider the microscopist “should know his business.” According to possibility of parasitic infections such as giardiasis that Manson, extensive training was needed to make an accu- can be cured within a few days of treatment. rate diagnosis and to avoid “comic” mistakes. Currently, in travelers with malaria who present usu- ally within a few days after the onset of their fever, the synchronous pattern of the fever with a periodicity of 2–3 The importance of malaria days (tertian malaria) is rarely seen (see Chapter 21). Thus, diagnosis must be based on the malaria smear. The lack of One of the issues that appears to be constant through- experience of microscopists continues to be an important out this period of a century is the importance of malaria. issue, particularly because most laboratory technicians Malaria was the commonest of all tropical febrile infec- have not seen many cases of malaria. Therefore, there are tions in Manson’s time. This remains unchanged in our ongoing attempts to find easier, friendlier methods for BLBK134-Schwartz March 13, 2009 20:20

The Art of Travel Medicine a Century Ago 7

Table 2.1 Comparison of the status of diseases during Manson period and our time.

Travel-related diseases in the 1900s Status of diseases in 1900s Status of the diseases in the 2000s

Malaria—leading cause Common Malaria—leading cause Hepatitis Hepatitis is almost never seen in travelers owing to vaccine Hepatitis E—on the rise Liver abscess Liver abscess—occasionally seen Brucellosis Brucellosis—hardly seen Visceral leishmaniasis (Kala-Azar) Less common Seen as co-infection in HIV patients Trypanosoma Rarely seen Filaria Rarely seen Relapsing fever Rarely seen, and mainly from recreational activities in developed countries Dengue fever Not seen Very common Yellowfever Veryrareowingtovaccineeffect Typhoid, tuberculosis, syphilis Cosmopolitan Now mostly tropical diseases Endocarditis, sepsis Cosmopolitan diseases, but rarely seen Malignancy Not a common cause for fever

malaria diagnosis. In recent years the antigen-detection other illnesses. This is not the case today with returning rapid test has become a helpful tool, although it cannot travelers, but this situation reminds us of scenarios in en- replace malaria smears (see Chapter 22). Further develop- demic countries (mainly in Sub-Saharan Africa), where ment of the polymerase chain reaction (PCR) method for many illnesses are attributed to malaria without a thor- commercial use may significantly improve our ability to ough examination and definitive diagnosis, thus missing diagnose malaria and more accurately identify the malaria many other treatable diseases [5]. species. However, the most common and the most important problem we encounter these days in malaria diagnosis in The incubation time industrialized countries is the lack of physician awareness of the risk of malaria exposure in returning travelers and Although Dr. Manson did not mention the term “incuba- their failure to consider malaria as a potential cause of tion period” directly, he clearly mentioned several diseases fever. The mortality rate from malaria in Western coun- that were not relevant to the practitioner seeing the re- tries is high, reaching about 2–3% of all falciparum cases, turning patient. The two major examples he gave were and about 10–15% among patients with severe malaria. dengue fever and yellow fever; these diseases “need not to An important factor in this poor outcome is the delay of be considered.” These diseases belong to the flaviviruses diagnosis by physicians [4]. and were well known at that time. Yellow fever was a major Malaria was a common disease in Dr. Manson’s time, killer during the period (e.g., it was one of the major foes but it seemed to be, as it currently is in the hyperendemic during the Panama Canal construction). However, these countries, a “background” disease. Therefore, another im- viral infections have short incubation periods of about 1 portant message he wanted to convey was not to miss other week. Transportation during that era was mainly by sea, diagnoses due to a self-proclaimed malaria diagnosis. As which meant that the travel time from most areas in the he described at that time, when the patient came in and British empire back to London was lengthy, eliminating told the doctor that he had malaria, the reason for his diseases with short incubation times. (Around the world visit was principally to get treatment for his own diagno- even in 80 days was an illusion, as illustrated by the clas- sis. Under the name of “malaria fever,” the patient might sic science fiction novel written by Jules Verne, who lived in fact have tuberculosis, endocarditis, a liver abscess, or during the same period.) BLBK134-Schwartz March 13, 2009 20:20

8 Chapter 2

Days Milllions be alert to the possibility of multiple infections. The “zoo 400 900 phenomenon,”which refers to a patient’s acquiring several 350 800 pathogens, is not uncommon, especially in dealing with

300 700 intestinal infections. Additionally, febrile infections can 600 be caused by simultaneous infections (see Chapter 37). 250 500 Manson urges his audience not to fall into the trap 200 400 of limiting findings to one diagnosis, and if there is just 150 one diagnosis, to be sure that it fully explains the case. 300 During this time, he stated, “In tropical disease, malaria 100 200 is apt to complicate everything, so that multiple infection 50 100 is rather the rule rather than the exception.” In our time, 0 0 that might be the rule in the malaria-endemic countries, 1850 1900 1950 2000 but it is not the rule among travelers. However, vigilance Days to circle the globe International arrivals is needed, and whenever the course of the disease does not correspond with the specific diagnosis, a search for Figure 2.2 Around the world in 80 days? another pathogen should be made. The shrinking world, a process that has progressed rapidly since the time of Manson, has led to the bor- One of the major changes that began during the second der crossing of many diseases. Thus, physicians now must part of the twentieth century was the public aviation ser- be familiar with many diseases, irrespective of their geo- vice, which today enables us to circumnavigate the globe graphic locations and incubation time. In addition, there within 36 hours (Figure 2.2). The idea corresponding to is a substantial increase in the number of travelers, who this change, that “the world has become a global village,” are mostly short-term travelers, not the long-term expa- assumes medical significance in that the incubation time triates as seen by Manson, and therefore not immune to is no longer a barrier in transmitting disease from one side diseases from outside of their own environment. These of the globe to the other. Add to this the fact that traveling conditions of the twenty-first century have shed new light outside country borders is no longer confined to a select on and revealed new aspects of the old tropical diseases. group of people but instead has become a popular trend Physicians in the West are thus further challenged to un- (approximately 900 million travelers annually), and the derstand and manage this vast array of travel and tropical public health significance is obvious. diseases. In relation to the diseases mentioned above, dengue is widespread worldwide and has become the most prevalent arbovirus. For travelers, it is a major threat and is seen very often. According to the GeoSentinel data, dengue is now References the second most common disease in returning travelers and is the first cause of fever outside Sub-Saharan Africa 1 Manson P. An address on the diagnosis of fever in patients (see Chapter 7). from the tropics: delivered at a meeting of the Westmin- Yellow fever is rarely seen in travelers, but this is a ster Division of the Metropolitan Counties Branch. Br Med J result of another change that has occurred since Dr. Man- 1909;1:704–6. son’s time—the development of a highly effective vaccine, 2 Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. which has dramatically changed the morbidity map of the JAMA 1999;281:61–6. disease. 3 WHO (2002) 2nd ed. National Cancer Control Programme, Policies and Managerial Guidelines. World Health Organiza- The vigilance needed for the clinician tion, Geneva. who sees these patients 4 Kain KC, Harrington MA, Tennyson S, Keystone JS. Imported malaria: prospective analysis of problems in diagnosis and management. Clin Infect Dis 1998;27:142–9. In Western medicine, we are taught that we should try 5 Amexo M, Tolhurst R, Barnish G, Bates I. Malaria misdi- to find one disease that will explain or encompass all of agnosis: effects on the poor and vulnerable. Lancet 2004; the patient’s symptoms. In tropical medicine, we should 364:1896–8. BLBK134-Schwartz March 13, 2009 20:20

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Appendix: “Diagnosis of Fever in Patients from the Tropics,” by Sir Patrick Manson (1909) [1] BLBK134-Schwartz March 13, 2009 20:20

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12 Chapter 2 BLBK134-Schwartz March 17, 2009 13:15

Epidemiology of Post-Travel 3 Illnesses Pamela Rendi-Wagner1 and Eli Schwartz2 1Tel Aviv University, Tel Aviv, Israel and Medical University Vienna, Vienna, Austria 2Chaim Sheba Medical Center, Tel Hashomer, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Introduction itinerary, duration, and purpose of travel [3, 4]. However, the majority of health problems reported by travelers are Disease surveillance is a prerequisite for the assessment of mild conditions, such as diarrhea, respiratory infections, health risks and the evaluation of established preventive and skin disorders [5]. measures. It enables us to identify changing epidemio- Traveling to endemic countries has become increasingly logical patterns and groups of high-risk travelers possibly popular for all age groups. In recent years, the numbers requiring modifications and optimal targeting of exist- of senior, pregnant, and pediatric travelers have steadily ing intervention concepts or the introduction of novel increased. In a population that visited a travel clinic prior strategies. Moreover, information on the epidemiology of to travel, 14% were above 55 years of age [6]. According specific infections also provides guidance for differential to an airport survey, 30% of US travelers were 50 years diagnoses in ill returned travelers, facilitating the assess- of age or older. Elderly people represent a growing group ment and quantification of disease risks. of travelers with a considerable rate of comorbidity [7]. International travel is becoming increasingly popular. Also, Stauffer et al. estimated that 4% of overseas travel- The current estimate of 846 million international arrivals ers are infants and children [8]. This is confirmed by an represents an average growth of 4.2% between 1995 and Israeli study reporting a proportion of more than 5% for 2006, with Sub-Saharan Africa being one of the major the age group below 18 years of age [9]. This varying de- contributors to this rise. The leading travel destination is mography of travelers increasingly needs to be taken into Europe, with more than 460 million travelers, followed by consideration in dealing with post-travel illness. Asia, the Americas, the Middle East, and Africa. With re- This lack of surveillance data for imported cases of gard to long-term prospects, the number of international infectious diseases prompted the establishment of various travelers is expected to reach nearly 1.6 billion by the year travel-related surveillance systems. 2020 (Figure 3.1) [1]. The GeoSentinel Surveillance Network started in 1995 Undoubtedly, travel is related to enhanced health risks, through a collaborative agreement between the Interna- most notably when travelers visit areas where the com- tional Society of Travel Medicine (ISTM) and the Centers municable disease burden is high, sanitation is poor, and for Disease Control and Prevention (CDC) and consists the quality of medical care is limited. Each year, about of specialized travel/tropical medicine clinics on six con- 50 million people travel from industrialized to develop- tinents recording information on ill travelers [10]. The ing countries [2]. About 20–70% of international travelers main aims of the GeoSentinel Surveillance Network are report travel-related illnesses, usually dependent on des- to monitor global trends in disease occurrence among tination and other travel conditions, including season, travelers and to ascertain risk factors and morbidity in groups of travelers categorized by travel purpose and type of traveler. A few years later, in 1999, the European Network on Im- ported Infectious Disease Surveillance (TropNetEurop) Tropical Diseases in Travelers, 1st edition. Edited by E. Schwartz. was founded, serving as a European electronic network c 2009 by Blackwell Publishing, ISBN: 978-1-4051-8441-0.

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14 Chapter 3

1,600 Actual Forecast 1,400 1.6 bn South Africa 1,200 Middle East 1.0 bn 1,000 Africa East Asia/Pacific 846 mn 800 Americas 600 Europe 400

200

0 1950 1960 1970 1980 1990 2000 2010 2020 Figure 3.1 Trend of international tourist arrivals, 1950–2020. (From the World Tourism Organization, http://www.unwto.org/pub/rights.htm.)

of 37 clinical sites related to importation of the major ofallpeoplewhotraveledtothesamedestinationduring tropical diseases. the same observation period (denominator). Data of this For the first time, these novel sentinel surveillance sys- kind,however,arerare. tems allow the identification of temporal and geographic trends in infectious disease occurrence in traveling pop- ulations worldwide. Through the global surveillance of Population-based risk infectious diseases in travelers, refugees, and immigrants, Only a few studies have supplied such specific population- valuable persuasive science-based information about im- based risk figures, which provide a useful pretravel tool portant aspects of post-travel morbidity is generated to for travelers for assessment and rating of disease-specific guide post-travel diagnosis, develop adequate pretravel geographic risks. The data are limited to selected traveling prevention strategies, and hopefully lead to travelers’ im- population groups and/or geographic areas, such as Israeli proved health. travelers in Bolivia contracting cutaneous leishmaniasis This chapter summarizes results of available systematic (attack rate, 1 in 300 travelers) [11] or sufferers from studies investigating the epidemiology of post-travel ill- myiasis in the Amazon basin (attack rate 1 in 190 travelers) nesses, including data on the above-mentioned large-scale [12]. surveillance systems. In-depth epidemiology of specific In a recent survey, the rabies exposure risk among long- diseases, however, is covered in the specific chapters. term travelers was estimated to be 2.66 per 1000 travelers per month [13].

Methods of investigations for post-travel Serosurveys morbidity Serosurveys performed pre- and post-travel may likewise provide estimates of disease attack rates. This approach Generally, two different categories of post-travel disease has been used, for instance, to evaluate the incidence epidemiology data exist. of dengue fever in populations traveling to selected ge- ographic regions. Dutch travelers to Asia (with a median stay of 1 month) had a seroconversion rate of 2.9% [14]. Disease attack rate An Israeli survey performed among travelers who had Attack rates of specific diseases is calculated by dividing spent at least 3 months in a tropical area observed a se- thenumberofilltravelers(numerator)bythenumber roconversion rate of 6.7% [15]. A survey of tuberculin