Bull. Org. mond. Santd 11973, 49, 433-442 Bull. Wld Hlth Org. J

Rickettsiae and rickettsial

R. BREZINA,1 E. S. MURRAY,2 M. L. TARIZZO,3 & K. BOGEL 4

This paper summarizes present knowledge on rickettsiae and rickettsial diseases, and on their epidemiological characteristics, control, and public health significance. There are many natural foci of rickettsial diseases, from where the may spread to other areas in the world under changing socioeconomic conditions. Because of rapid long-distance travel, sporadic cases ofserious rickettsial diseases may today appearfarfrom endemic areas where the infection occurred. Even in endemic areas the disease may be misdiagnosed and deaths may occur as a result of inadequate treatment. Rapid treatment of rickettsial infections (preferably with ) is therefore most important. -borne , though no longer subject to the International Health Regulations, remains one ofthe diseases in the WHO epidemiological surveillance programme. This disease continues to be a major cause ofmorbidity and mortality in some parts ofAfrica and it is present also in parts ofthe Americas and ofAsia. remains a continuing and serious public health problem in areas ofSouth-East Asia and in the Western Pacific. The annual number ofreported cases of Rocky Mountain spotted in the USA showed an increase during the last two decades, which may be due to improved recognition as well as to increased outdoor activities and migration ofpeople from the city centres to the suburbs. Related forms of -borne typhus occur in South America, the Mediterranean region, Africa, South-East Asia, the Far East, and the Western Pacific. Increasing in number, though still sporadic, are reports of serious illness from chronic infection in many parts of the world.

After a rather long period of stagnation, rickettsial marily through their infected salivary glands directly diseases are now again the subject of interest and new into the bite. In lice and , rickettsiae do not approaches to their study are being developed, in infect the salivary glands but multiply in the cells of part because of the recognition of rickettsial disease the gut wall and are excreted in the faeces in large as a persisting and important cause of morbidity and amounts, contaminating the skin area around the mortality in certain countries. This paper is a synopsis bite. Rickettsiae may gain entry into the body of present knowledge on the epidemiological charac- through bites or other breaks in the skin, or dried teristics, control, and public health significance of aerial suspensions of them may be inhaled or may rickettsiae and rickettsial diseases. infect the conjunctival mucosa. Dried tissue fluids or the excreta of and may also be a source of HOST RANGE AND PATHOGENICITY infection. Once rickettsiae have penetrated the skin, they Rickettsiae are generally transmitted to man by multiply inside cells, reach the blood stream, and arthropod vectors, the only exception being Coxiella eventually become located in the endothelial cells of burneti, the agent of Q fever. small veins, arteries, and capillaries. These infected Infected ticks and mites transmit rickettsiae pri- endothelial cells enlarge, degenerate, and cause thrombus formation with partial or complete occlu- 1 Head, Department of Rickettsiae, Institute of Virology, sion of the vascular lumen. Mononuclear leucocytes Bratislava, Czechoslovakia (WHO Collaborating Centre for Rickettsial Reference and Research). and plasma cells infiltrate the adventitia. Focal ' Professor of Microbiology, Department of Micro- necrosis of the walls of small vessels leads to in- biology, Harvard School of Public Health, Boston, Mass., creased permeability, rupture, petechiae, and hae- USA. morrhages. The rupture of vessels and thrombosis ' Medical Officer, Diseases, WHO, Geneva, Switzer- land. interrupt the blood supply, causing macro- and ' Veterinary Public Health, WHO, Geneva, Switzerland. micro-infarcts and necrosis of the tissues.

3138 - 433 434 R. BREZINA ET AL.

Localized cellular responses lead to the formation brain, suprarenal gland, or spleen of infected guinea- of nodules, commonly in the spleen, , kidneys, pigs. brain, heart, and skeletal muscles. Acute nonsup- Cotton rats and various species of African gerbils purative , both diffuse and local, is a are highly sensitive to R. prowazeki and are ideal for common occurrence. Apart from vascular damage isolation or research studies. caused by the organism or its toxin, other lesions are rare. Rickettsiaemia is present throughout most of Spottedfever group the acute febrile period. The overall pathological This group of rickettsiae, the agents of various features are similar in most rickettsial diseases; forms of infection in man, has been divided into however, the extent and degree of involvement vary 4 subgroups on the basis of antigenic characteris- and in general are indicated by the severity of the tics (8). Subgroup A consists of R. rickettsi and illness. R. siberica, the agents of Rocky Mountain spotted Fatalities occurring early in the acute phase of the fever (RMSF) and of north Asia tick typhus; sub- illness are generally due to vascular collapse; when group B is formed by R. conori, the agent of fievre they occur later, they are related to chronic vascular boutonneuse, and by R. parkeri, which causes infec- damage producing thrombosis and necrosis. tion in guinea-pigs but has not been identified as a The long survival of rickettsiae in various organs for man; subgroup C consists of R. akari and lymphatic tissues after infection of both man and and of R. australis, the agents of animals is a general characteristic in the pathogenesis (transmitted by mites, not by ticks) and of Queens- of rickettsial disease. land tick typhus; subgroup D includes only R. mon- tana, a new species isolated from Dermacentor ticks Classical typhus group in eastern Montana (USA) and not yet incriminated as a pathogen for man. All these rickettsiae multiply This group includes prowazeki and in the cytoplasm and in the nucleus of infected cells. R. mooseri (R. typhi), respectively the agents of Rickettsiae are transmitted transovarially by ticks, louse-borne (epidemic) typhus and of -borne or which therefore represent both the reservoir and the murine (endemic) typhus. R. canada, antigenically vector of the agent. The infection may be transmitted related to this group, has recently been incriminated to the vertebrate host by any of the larval stages and as a possible cause of infection in man (1). by the adult tick. Ticks remain infected for life, are Louse-borne typhus is essentially a human disease, not harmed by the rickettsiae, and pass them in their and flea-borne typhus is a disease ofrats occasionally faeces. Transmission to man, however, is believed to involving man. Domestic cats and the cat flea, occur primarily through the bite since rickettsiae also Ctenocephalides felis, have also been incriminated in invade the salivary glands of the ticks. All the the transmission of . rickettsiae of this group pass through natural cycles Contradictory evidence has been put forward by in wild or domestic animals. some authors with regard to the possible role of In man, RMSF may show very acute symptoms domestic animals in maintaining the chain of infec- with intense vascular lesions. In contrast with other tion with R. prowazeki. forms of tick typhus, rarely develop at the Several animal species have been shown to be site of the tick bite. The virulence of RMSF strains susceptible to infection with R. prowazeki and may vary considerably for man and for laboratory R. mooseri but only a few have practical use as animals. laboratory models. The chick embryo is by far the Rickettsialpox, the mildest of the rickettsial dis- most important of these and yolk sac cultures are eases of man, is caused by R. akari and transmitted routinely used for producing antigens and . by mites instead of ticks, and is mainly a disease of White mice are useful in testing for and in titrating . It is characterized in man by the presence of the toxin content of yolk sac preparations. vesicular lesions superimposed on the initial papules. Guinea-pigs are somewhat less sensitive and less predictable than chick embryos and mice. However, Scrub typhus they can be used for primary isolation. Intraperi- -borne scrub typhus, or tsutsugamushi, is toneal injection of infected human blood into guinea- caused by R. tsutsugamushi (R. orientalis), and is pigs leads to rickettsiaemia and a characteristic fever transmitted by a number of trombiculid mites that pattern. R. prowazeki can be isolated from the blood, act both as vector and as reservoir, thus playing a RICKETTSIAE AND RICKETTSIAL DISEASES 435 role similar to that of ticks in the transmission of the Man is the only known reservoir and the body etiological agent; transovarial transmission has also louse the only known natural vector. The faeces of been demonstrated. While the role of rodents and lice become infectious 5-10 days after an infectious other animals is yet to be clarified, the variation in meal; after that the lice remain infectious for life the virulence and antigenicity of strains is consider- although they are themselves unharmed. There is no able. transovarial passage of R. quintana in lice. The disease in man leads frequently to a chronic Q fever rickettsiaemia, R. quintana having been isolated from Q fever, caused by Coxiella burneti, is primarily a the blood of patients up to 2 years after an acute solidly established in domestic livestock the attack. True relapses have occurred as long as 20 world over; it is a widely disseminated chronic years after a primary attack. The chronic rickett- infection involving many organs of the infected siaemia and late relapses are obviously important hosts. Of primary importance to transmission is factors that help give rise to infection of the uterus and udder tissue in female over long periods of time. animals. The animal's milk is thus infected, but of major importance is the fact that at parturition the ANTIGENIC STRUCTURE infected products of conception contaminate the Classical typhus group environment and remain for months or years as a Three species belong to this group, R. prowazeki, source of infection for man, animals, and birds. R. mooseri, and R. canada. R. canada can be differen- Man contracts Q fever usually by inhaling infec- tiated from R. prowazeki and R. mooseri by the toxin tious dust generated from infected animals or their neutralization test- and by the complement fixation products. Clinically, Q fever in man is characterized test with mouse antiserum (9). The relationship by an interstitial regardless of the site of between R. canada and the group of entry of the infecting organism. C. burneti can spread rickettsiae, however, has not yet been clarified. through almost all the organs of the body forming The nature of the soluble antigen and the antigenic small lesions of varied character showing oedema, properties of various rickettsial fractions have been round cell infiltration, and patchy necrosis. Occa- reviewed (2). A thermolabile antigenic fraction capa- sionally the liver or heart may become intensely ble of inducing protection after a single vaccination involved leading to a frank hepatitis or a subacute of animals was recently obtained from the classical with vegetations. Although pathologic soluble antigen. Vaccination of human beings with lesions may be widespread both in man and animals, this antigen provoked no local or general reactions fatalities are rare. and was followed by the development of comple- Ticks are an important element in the maintenance ment-fixing, haemagglutinating, and toxin-neutraliz- of the Q fever reservoir in nature and transovarial ing antibodies (6). transmission of C. burneti has been demonstrated in The antigenic activities of intact R. prowazeki, and these arthropods. A wide variety of ticks have been of its cell wall, protoplasm, and soluble antigens in shown to be infected and in view of the extensive complement fixation (CF) and mouse protection tests host range of C. burneti many different host-vector differ in several points. The protoplasm antigens cycles probably occur. show the greatest specificity and heat lability in the Man to man transmission is rare. Recrudescence CF test. The cell wall and soluble antigens and intact of latent infections in man may occasionally occur rickettsiae contain more heat-stable CF antigens and and Q fever can remain latent in the tissues for tend to be more active than the protoplasm antigens 2-3 years. in the test. In Strains with mouse protection potency tests, of the Q fever agent different degrees the soluble antigens released by ether treatment are of virulence have been isolated. the most active. Trench fever Spottedfever group R. quintana, the agent of trench fever, has a very The division of this group into four subgroups has limited host range. Besides man and the louse, already been mentioned in the preceding section. several species of monkeys only have been shown to This differentiation was made on the basis of toxin- be infectable. The attempts to infect common labora- neutralization and complement fixation tests with tory animals have met with uniform failure. mouse species-specific sera. 436 R. BRESINA ET AL.

Scrub typhus group There are only a few data concerning the antigenic Except for the mouse cross-immunity tests, which differences among phase II strains. Antigenic differ- show a close relationship among the strains of this ences among phase I strains have not yet been group, other procedures, such as serum protection, observed. complement fixation, toxin neutralization, and vac- cination-challenge, reveal a considerable hetero- OTHER PROPERTIES OF RICKETTSIAE geneity within the species. The impossibility of de- tecting antibody induced by a variety of antigenically Morphology dissimilar strains of R. tsutsugamushi represents a Rickettsiae can usually be visualized with the serious difficulty in the serologic diagnosis of scrub ordinary light microscope. They tend to be some- typhus. Serotypes Gilliam, Kato, and Karp were what pleomorphic, varying in size and in shape from identified by complement fixation tests. The strains coccoidal, to bacillary, to filamentous, depending on of R. tsutsugamushi recovered from patients can be a the species and the conditions of growth. mixture of two or more antigenically distinctive Electron microscopy has greatly contributed to types. Moreover, among the strains of R. tsutsuga- knowledge of the structure of rickettsiae. Common mushi in Thailand, 5 distinctive antigenic types have to all studied so far are a trilamellar cell wall and a been recognized thus far: Gilliam, Karp, Kato, and trilamellar cytoplasmic membrane. Both these show 2 other types not previously described. the typical " unit membrane " structure of bacterial cells. Intracytoplasmic invaginations of the plasma Coxiella burneti membrane, DNA strands, ribosomes, electrolucent Coxiella burneti is the only rickettsia showing spheres, vacuoles, and membranous organelles have phase variation. This phenomenon is similar in many been observed. ways to the rough-smooth variation of Diplococcus pneumoniae. In nature, C. burneti has been found Chemical composition and metabolism only in phase I; in the laboratory, the adaptation to Comprehensive reviews of both the chemical com- growth in chick embryos produces phase II, which position and the metabolism of rickettsiae have been can be converted back to phase I by subsequent published by Paretski (15), Wisseman (18), and growth in laboratory animals. The essence of this Ormsbee (13). phenomenon lies in the alternation of two main anti- Rickettsiae possess complex cell walls, contain gens. The strains in phase I possess both antigens and both ribonucleic and deoxyribonucleic acids, syn- do not show positive results in a variety of serologic thesize their own structural and functional consti- reactions with sera containing only antibodies against tuents with their own enzymes, and generate high- the phase II antigen. The vaccines prepared from a energy phosphate bonds with energy derived from purified suspension of phase I, when tested in guinea- the oxidation of amino acids and carbohydrates. pigs, have 100-300 times the potency of those derived Rickettsial cell walls closely resemble the cell walls from phase Il, provided that the immunity is tested of Gram-negative bacteria in complexity of structure by the use of a strain in phase 1 (14). With trichloro- and in the presence of muramic and diaminopimelic acetic acid it is possible to extract from coxiellae in acid components. The purified cell walls of R. mooseri phase I an antigen that resembles serologically the and R. prowazeki contain protein, polysaccharide, corpuscular phase I antigen. and phosphorus in excess of that from nucleic acid This trichloroacetic acid extract of coxiellae can contamination. Further analyses show the presence be used as a vaccine producing both phase II and of 12-15 amino acids, including both lysine and the phase I antibodies and it often produces allergic skin distinctive diaminopimelic acid, and the presence of reactions. An antigenic component, with the serologic the amino sugars glucosamine and muramic acid. behaviour of phase I, can also be extracted with Teichoic acid has not been detected in R. mooseri. phenol from purified phase I suspensions. The DNA of C. burneti has been isolated and The presence of antigen I in C. burneti is related to characterized and found to be significantly different its basic properties. The shift from the naturally occur- from that of R. prowazeki. Several data suggest that ring phase I to egg-grown phase II is accompanied by the DNA of C. burneti possesses a double stranded changes in antigenic composition, immunogenicity, structure. density, autoagglutinability, staining properties, re- Energy production is apparently accomplished sistance to phagocytosis, and virulence. through the operation of part or all of the Krebs RICKETESIAE AND RICKETISIAL DISEASES 437 cycle. The principal energy-yielding substrate is glu- test with soluble or particulate antigens. Louse-borne tamate in the case of R. quintana, and pyruvate in and murine typhus can be differentiated by means of C. burneti. Oxidation is accompanied by phosphory- washed corpuscular suspensions of R. prowazeki and lation. The electron transport system appears to R. mooseri. R. canada, a new member of the typhus utilize phosphopyridine nucleotides and cyto- group (9), shares common antigens with R. prowa- chromes. zeki and especially with R. mooseri. However, this There is convincing evidence that rickettsiae pos- new agent has been shown to be different from both sess enzymatic mechanisms for the breakdown of R. prowazeki and R. mooseri when tested with carbohydrates, the formation of high-energy phos- antisera prepared in mice. The results of toxin phate bonds, and the synthesis of lipids and proteins. neutralization tests confirmed that this was a new The host cell contribution probably includes primary species of rickettsia. Several methods by means of substrates such as glutamate and pyruvate, factors CF and agglutination reactions allow the differentia- such asATP,NAD, and coenzymeA, and amino acids. tion of primary from secondary (Brill-Zinsser dis- ease) cases (10-12). Multiplication ofrickettsiae In the spotted fever group the soluble antigen of Rickettsiae, except R. quintana, are obligate intra- each strain is group-specific whereas washed antigens cellular parasites. It is generally accepted that rickett- allow for species differentiation. However, it was siae maintain their morphological integrity during shown that antisera from white mice infected with growth and multiplication. Binary fission is consid- various strains from the RMSF group contained ered to be the only mode of their multiplication; species-specific complement-fixing antibody that did Kordova and her associates (reviewed in (3)), how- not react with the soluble, cross-reacting CF group ever, found " filterable particles " in C. burneti and antigen ofheterologous rickettsiae ofthe same group. suggested some other form of replication. Koko- In the scrub typhus group there is a high degree of rin (7) studied various rickettsiae in tissue cultures antigenic heterogeneity among strains of R. tsutsuga- and suggested the existence of two developmental mushi. Purified or partly purified rickettsiae allow for stages: vegetative, dividing, and moving forms on the differentiating between the antigenically representa- one hand, and resting, immobile forms on the other. tive Gilliam, Karp, and Kato strains. Recently satis- Resting forms can persist in the cell for a very long factory antigens were prepared from infected tissue period of time, thus providing a possible explanation cultures. for latency in rickettsial infections. In Q fever, complement fixation is the test most frequently used for identifying Q fever antibodies although it is not the most sensitive method. Phase II DIAGNOSTIC PROCEDURES antibodies are of primary diagnostic value for the Laboratory methods for isolation of rickettsial strains detection of recent infection and phase II egg- The procedures for the isolation of rickettsiae are adapted strains must therefore be used for the well known. Guinea-pigs, mice, meriones, and cotton preparation of antigens. rats are the most useful animals for the isolation of Complement-fixing phase I antibodies are of little rickettsial strains from patients and animals, and importance for the diagnosis of Q fever in man as from ectoparasites with the exception of R. quintana. they can only indicate past or present persisting Tissue or cell cultures have been used for the infection. They are also found in cases of chronic propagation of various rickettsiae, but their value in Q fever endocarditis. primary isolation has not been confirmed. The CF test for trench fever provides a rapid R. quintana can be propagated from the blood of diagnostic procedure, which can be used in conjunc- patients directly on blood agar. Erythrocytes (hemin) tion with isolation of R. quintana from the patient's are essential components of media; in a liquid blood. Both particulate and soluble antigens can be medium, fetal calf serum satisfied the requirement of prepared from whole R. quintana propagated on R. quintana for a red blood cell lysate. blood agar. Agglutination reaction. The microagglutination test Serologic methods for the study and diagnosis of for typhus antibodies described by Fiset et al. (5) is a rickettsial infections very reliable method for detecting typhus antibodies. Complement fixation test. The most frequently The test appears to have the same limits of resolution used serologic method is the complement fixation as the standard tube agglutination tests and is more 438 R. BREZINA ET AL. sensitive than the CF test in distinguishing between tions. It fails in approximately 75 % of sporadic or murine and louse-borne typhus infections. recrudescent cases of typhus. In scrub typhus it may Infections of the spotted fever group can be be positive in no more than 50 % of cases. detected by Giroud's slide microagglutination test 5. The haemolymph (haemocyte) test. with semipurified suspensions of R. conori. This is an economical, rapid, and simple test for In Q fever, highly purified haematoxylin-stained detecting rickettsiae in nature and in laboratory antigens are used in the method described by Fiset experiments (4, 16). The presence of rickettsiae in et al. (5). These are phase I antigens converted to ticks can be detected by examining the haemolymph phase II by treatment with trichloroacetic acid. The obtained by amputating the distal portion of one or method has been further improved by Schramek more legs. The smears are fixed by heat; stained by et al. (17) producing phase II antigens by oxidizing the Gimenez method, and examined microscopically the phase I antigens with periodate. Natural phase If for the presence of rickettsiae or rickettsia-like orga- strains cannot be used for this agglutination test as nisms. If positive, additional smears from the same they tend to agglutinate spontaneously and are ticks are examined by the direct or indirect fluores- strongly agglutinated by normal serum. cent antibody method with sera or immunoglobulins Microagglutination on plastic plates with stained against the various rickettsial groups or against antigens is more sensitive than CF with phase II rickettsiae known or assumed to occur in the area. antigens. It is also suitable for demonstrating the Adult ticks, both engorged and unengorged, may be phase I antibody with phase I antigen. During the used for the haemocyte test. past two decades several agglutination methods have All tick-borne rickettsiae can be identified by the been elaborated for detecting Q fever antibodies: the haemocyte test. In scrub typhus the indirect fluores- capillary agglutination test (CAT), the agglutination- cent antibody method has been reported to be group- resuspension test, and the radioisotope precipitation specific, allowing the use of any strain for the test (RIPT). diagnosis. Other tests. These are useful in particular instances Some other tests may be used for special purposes and include the following. such as cross-immunity tests (with live or killed 1. The passive haemagglutination test (PHT). rickettsiae for immunization), and the serum-protec- This test, which requires sheep or human group 0 tion test. erythrocytes sensitized with ESS (erythrocyte sensi- The formation of plaques by rickettsiae in some tizing substance), is sensitive, group specific, and types of tissue cultures may lead to the elaboration of appears to be particularly useful in detecting recent more precise methods for the titration of rickettsiae infections in both typhus and RMSF group rickett- and their differentiation. sioses. In Q fever the passive haemagglutination test can PUBLIC HEALTH SIGNIFICANCE be used for detecting phase I antibodies. The erythro- cyte sensitizing factor consists of a phenol extract of Louse-borne typhus the phase I antigen. Epidemic louse-borne typhus, historically one of the 2. The toxin major epidemic diseases, typically spreads during neutralization test. times of wars and civil disturbances. Since the agent A test of this type is used in cases of rickettsiae of is the transmitted by body lice, the disease is still present typhus and RMSF group. It is valuable for where socioeconomic standards are low and where evaluating vaccine potency in the typhus group; in lice are abundant. the spotted fever group this test is useful for studying In the present century, the main foci of the disease antigenic structure. have been in the highlands of northern and eastern 3. The intradermal sensitivity test. Africa and in . The disease is also This involves a skin reaction of the delayed type. A present in the mountainous regions of Central positive skin test against C. burneti is considered to America, north-western South America, southern be a contraindication for vaccination against Q fever. Asia, and of southern Africa. 4. Weil-Felix reaction. During and immediately after the Second World The Weil-Felix reaction is still a useful test in all War the disease spread again from its endemic foci in rickettsioses except for Q fever, trench fever, and North Africa and eastern Europe through most of rickettsialpox. However, it has several serious limita- Europe causing very severe epidemics among pris- RICKETTSIAE AND RICKE1TSIAL DISEASES 439 oners of war and in concentration camps in Europe it is still present, it remains one of the most impor- and in Asia. tant causes of illness in some parts of Africa and a Despite the existence of conditions favouring the problem in parts of the Americas and of Asia. The spread of the disease, the development of persistent development of tourism, rapid communications, and insecticides and their massive application to the international travel in general make it possible for control of the vectors made it eventually possible to cases to occur far from endemic foci; if not recog- limit somewhat the extent of epidemics. The develop- nized in time, it may present a considerable risk to ment of specific vaccines prepared from rickettsiae the individual, if not to the community. Also, it must grown in the yolk sac of embryonate eggs or in the be emphasized that the very reasons allowing for the lungs of laboratory animals significantly contributed presence and dissemination of the infection and of to the effective control of the disease; this was further the disease make it difficult to apply preventive and facilitated by the improvement in living conditions control measures. that occurred after the end of the Second World Patients with Brill-Zinsser disease are a potential War. source of infection in other countries, but spread of Since then the number of countries from which the disease still requires that the patient be also cases are reported has considerably diminished. The infested with lice at the time of his relapse. great majority of the cases now reported are from the highlands of central and eastern Africa, namely from Other rickettsial infections , Rwanda, and . A large number of cases of Brill-Zinsser disease (late relapses or recru- Murine typhus causes practically no public con- descent louse-borne typhus) are reported from some cern. It is in fact one of the relatively mild rickettsial eastern European countries. diseases and its cycle in nature is relatively easy to In Burundi, epidemic waves occurred in 1933-34, interrupt, Xenopsylla cheopis, the normal vector of in 1939, and in 1945-46. During the latter period, R. mooseri, being easy to control. 3 752 cases and 429 deaths were recorded; in the The number of reported cases of Rocky Mountain endemic area the average number of lice on each spotted fever in the USA, which slowly decreased person was approximately 40. A new epidemic started from 1951 to 1960, has since risen from approxima- in Burundi in 1967, with a peak of 17 200 cases tely 200 to 305 in 1967, 298 in 1968, 498 in 1969, 380 reported in 1970. The number of cases since then has in 1970, 432 in 1971, and 528 in 1972. The majority decreased, but there were still 2 817 cases in 1973. of the cases are now reported from states east of the Although the reported number of deaths caused by Mississippi river. This rise in reported cases may well typhus ranged between approximately 1 % and 3 % of be due to better recognition. However, mass migra- the number of cases, the mortality rate in 1971 from tions from the city centres to the suburbs have typhus was estimated by physicians practising in the brought people into closer contact with the tick country at 5-20 %. Cases of louse-borne typhus reservoir of the disease and this is believed by many started to be reported from neighbouring Rwanda in to be responsible for the recent increases in the 1971 with a peak of 5 509 cases and 78 deaths number of cases. Where the disease is relatively reported for 1973. In Ethiopia 2 000-3 000 cases are frequent, as for instance in Maryland, Virginia, and usually notified every year from all provinces, but North and South Carolina, early recognition and only a few deaths are reported. Most of the cases treatment are the rule. Elsewhere in North America reported from other countries are from mountainous the disease is so infrequent that it is often misdiag- regions, where the climatic and socioeconomic fac- nosed and a number of deaths occur each year tors facilitate a close association between the human because of inadequate treatment. Sporadic cases of population and the louse vector. the same type of disease, caused by the same agent Resistance of the louse vector to the commonly (R. rickettsi), are also reported from South America. used insecticides (DDT, gamma-HCH, and in a few Other forms of tick-borne typhus are of recognized cases organophosphorus compounds) has occurred minor public health significance in localized geo- in some areas as a consequence of their use for vector graphic areas: in the Mediterra- control or for agricultural purposes. nean region, African and Indian tick typhus, Queens- Although louse-borne typhus cannot be consid- land tick typhus in Australia, and Siberian tick ered as a major risk from the point of view of its typhus in North-Eastern Asia. The incidence of the spreading to other countries from the regions where disease is generally low and the clinical features so 440 R. BREZINA ET AL. mild that there is very little public interest in control character of the human illness when it does occur measures. accounts for the absence of any public health interest Rickettsialpox is the mildest of all the rickettsial in this disease. diseases. In the USA at the time when the disease was first discovered in the mid-1940s, over 160 cases CONTROL MEASURES were reported from New York. For several years thereafter about 180 cases were reported annually Treatment ofhuman rickettsioses from alone, but more recently only The broad-spectrum , namely the tetra- occasional sporadic cases have been reported from cyclines and , are the drugs of choice North America. Reports of the rickettsialpox orga- for the specific treatment of all rickettsial diseases. nism occurring in Korea and as well as in the Tetracyclines are preferred to chloramphenicol be- USA indicate that it may have a worldwide distribu- cause of the higher risk of untoward reactions with tion. Rickettsialpox poses a minor public health the latter. The treatment should be prolonged to problem only because it could appear in an epidemic. avoid the occurrence of relapses upon withdrawal of form if there should be a large buildup of infected the . vectors and their hosts in close association with man. A new , , better absorbed Scrub typhus poses a continuing serious and im- and more slowly excreted than other compounds of portant public health problem. While the disease this group, has recently been used successfully for the may be mild, the severe clinical form is common, treatment of louse-borne typhus in endemic areas. with a 20-60 % mortality if not treated in time. Since The development of resistance to antibiotics com- the ubiquitous mite serves as both vector and reser- monly used in the treatment of rickettsial diseases voir and has numerous small animal hosts, R. tsutsu- has been induced under laboratory conditions, but as gamushi appears to be not eradicable at least with the far as is known it has not been observed in the field. mite control measures now available. In the scrub Chemoprophylaxis requires even more special typhus endemic area of South-East Asia and the attention than chemotherapy with regard to the Pacific Islands there is always the possibility of dosage and the duration of treatment in order to sporadic cases or localized outbreaks, and no vaccine obtain suppression of overt symptoms and the devel- is available to help in control. As a result of travel, opment of active protection. A combination of sporadic cases of the disease may appear in any part chemoprophylaxis and vaccination with killed vac- of the world. cine has been successfully used against scrub typhus. Q fever is a continuing and significant public health problem. While there are not many human Vector control cases reported in the literature, pilot serologic sur- Since all rickettsial diseases (Q fever excepted) are veys in certain high-risk groups and in animals transmitted to man through the bite or excreta of indicate that many undiagnosed cases occur. There is infected arthropods, the obvious control measure widespread seeding of domestic livestock throughout would be the elimination of the vectors. Although the world with C. burneti and in many areas the theoretically the control of lice and fleas is relatively incidence of infection in animals is rising. The disease easy because of their close association with man and in man occurs in livestock handlers and processors of his immediate environment, it is much more difficult animal products, especially in abattoirs and textile to control transmission by ticks and mites. These plants. The milk of infected animals contains C. bur- arthropods in natural environments have life cycles neti, but there is conflicting evidence as to how much associated with a multitude of wild animals that are infection as well as how much overt disease is themselves difficult to eliminate or to control. transmitted through milk. Rickettsialpox is the only mite-borne rickettsial There are an increasing number of reports, al- disease that appears to be controllable by attacking though still sporadic, of serious illnesses such as its vector, Allodermanyssus sanguineus, or its host, endocarditis, pericarditis, and hepatitis resulting from the , or both. chronic Q fever infection. Resistance to pesticides may present a severe The only known epidemics of trench fever oc- problem. The resistance to chlorinated hydrocarbons curred during the First and Second World Wars. is stable and so high that it excludes its routine use in The virtual disappearance of the disease from public many areas. Resistance to is not a stable notice for nearly 50 years combined with the mild characteristic and depends on continual exposure. RICKETTSIAE AND RICKE1TSIAL DISEASES 441

Some new organophosphorus compounds and other Other methods rapidly degradable pesticides are therefore being sought. In general, the only practical measure against tick- and mite-borne typhus is personal protection against Vaccination the arthropod vector with repellents or by means of Dead and live vaccines have been prepared against adequate clothing to prevent the attachment of the louse-borne typhus. A single dose of the dead vaccine vectors. (Cox type) may prepare for a booster effect at any time within 15 years. However, there are significant Health regulations problems in the methods of assay for standardizing this vaccine. Soluble antigen vaccines may offer some Louse-borne typhus was one of the six quaran- advantages as the antibody response appears earlier. tinable diseases subject to the International Sanitary With the live vaccine (strain E) there is the problem Regulations. These have been replaced as of 1 Janu- of late reactions (more properly termed mild disease) ary 1971 by the new International Health Regula- that occurred in 0-14% of the vaccinees in different tions to which only , , yellow fever, and studies. A reversion to virulence after passage in smallpox will henceforth be subject. laboratory animals has been reported from one Louse-borne typhus, however, remains one of the laboratory, but was not fully confirmed by two diseases in the WHO epidemiological surveillance others. programme, together with , influenza, A killed vaccine against Rocky Mountain spotted paralytic poliomyelitis, and malaria. Under this pro- fever is available and is indicated for persons at high gramme, Member States are requested to inform the risk (such as laboratory workers). Organization of the occurrence of any outbreak of Killed crude C. burneti vaccines are available but the disease, providing pertinent details, and the severe and persistent local reactions have contraindi- Organization is responsible for the dissemination to cated their use. Purified phase I and live vaccines are Member States of such information received. In under experimental study. A trichloroacetic-acid order to facilitate the implementation of this pro- extract from the phase I purified suspension promises gramme a technical guide for typhus surveillance has to be very effective in preventing human disease. been prepared by WHO (19).

UMIt RICKETITSIES ET RICKETTSIOSES

Dans la presente etude sont resumees les connaissances fait intervenir comme reservoirs des animaux domestiques actuelles concernant les rickettsies et les rickettsioses, et ou sauvages. La transmission transovarienne chez les notamment leurs caracteristiques epid6miologiques, leur arthropodes, demontree pour les rickettsies du groupe de importance en sante publique et les moyens de lutte a leur la fievre pourpree (chez des tiques) et du typhus de brousse opposer. (chez des acariens) joue un r6le important dans la I1 existe de nombreux foyers naturels de rickettsioses, A persistance des infections dans les foyers naturels. Pour la partir desquels elles peuvent se propager dans d'autres fievre des tranchees, l'homme est le seul reservoir connu; regions du monde A la faveur de changements des des infections persistantes chez l'homme et chez le pou conditions soicio-6conomiques. La rapidite des voyages A assurent le maintien du cycle malgr6 l'absence de transmis- longue distance fait que l'on assiste aujourd'hui A l'appari- sion transovarienne de Rickettsia quintana chez le pou. tion de cas sporadiques, parfois graves, dans des endroits Le typhus epidemique A poux, bien que raye de la liste tres 6loignes des zones d'endemicite. Meme dans ces des maladies soumises au Reglement sanitaire internatio- dernieres, il arrive que ces affections ne soient pas nal, reste l'une des maladies figurant au programme de diagnostiquees et des deces peuvent survenir si un traite- surveillance 6pidemiologique de l'OMS; cette affection est ment correct, de preference par les tetracyclines, n'est pas responsable d'une morbidite et d'une mortalite impor- appliqu6 rapidement. tantes dans certaines parties de l'Afrique, et des cas sont Les rickettsies sont g6neralement transmises A l'homme signales localement dans les Ameriques et en Asie. Le par des arthropodes (poux, puces, tiques et acariens); seule typhus de brousse pose toujours un serieux probleme de Coxiella burneti, agent dela fievre Q, fait exception. Pour sante publique en certains endroits de l'Asie du Sud-Est et certaines especes de rickettsies, le cycle naturel d'infection du Pacifique Occidental. Aux Etats-Unis d'Amerique, le 442 R. BRESINA ET AL.

nombre annuel de cas signales de fievre pourpr&e des Am6rique du Sud, dans la region mediterraneenne, en montagnes Rocheuses a augment6 pendant les deux Afrique, en Asie du Sud-Est, en Extreme-Orient et dans le dernieres decennies; les raisons possibles en sont de Pacifique Occidental. Bien que sporadiques, les cas d'affec- meilleurs diagnostics et une migration accrue de popula- tions graves dues a une infection chronique par la fievre Q tions du centre des villes vers les faubourgs. Des affections sont en augmentation dans beaucoup de regions du apparentees, transmises par des tiques, sont observees en globe.

REFERENCES

1. BOZEMAN, M. F. J. inf. Dis., 121: 367 (1970). 10. MURRAY, E. S. ET AL. Proc. Soc. exp. Biol. Med., 2. BREZINA, R. Zbl. Bakt., I Abt. Orig., 206: 313 (1968). 119: 291 (1965). 3. BREZINA, R. Curr. top. Microbiol. Immunol., 47: 20 11. MURRAY, E. S. ET AL. J. Immunol., 94: 723 (1965). (1969). 12. MURRAY, E. S. ET AL. J. Immunol., 94: 734 (1965). 4. BURGDORFER, W. Am. J. trop. Med., 19: 1010 (1970). 13. ORMSBEE, R. A. Ann. Rev. Microbiol., 23: 275 (1969). 5. FISET, P. ET AL. Acta Virol., 13: 60 (1969). 14. ORMSBEE, R. A. ET AL. J. Immunol., 92: 404 (1964). 6. GOLINEVICH, E. M. ET AL. Vestn. Akad. med. Nauk, 15. PARETSKI, D. Zbl. Bakt., I Abt. Orig., 206: 283 (1968). 10: 77 (1969). 16. AEHACEK, J. ET AL. Acta Virol., 15: 237 (1971). 7. KOKORIN, J. N. Acta virol., 12: 31 (1968). 17. SCHRAMEK, S. ET AL. Acta Virol., 16: 487 (1970). 8. LACKMAN, D. B. ET AL. Hlth Lab. Sci., 2: 135 (1965). 18. WISSEMAN, Ch. L. Jr. Zbl. Bakt., I Abt. Orig., 206; 9. MCKIEL, J. A. ET AL. Canad. J. Microbiol., 13: 503 299 (1968). (1967). 19. Wkly epidem. Rec., No. 28: 273-275 (1971).