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Rickettsial Infections


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Rickettsial Infections, Indian Pediatrics 2010

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Rickettsial Infections

  1. 1. REVIEW ARTICLERickettsial Infections: Indian PerspectiveNARENDRA RATHI AND AKANKSHA RATHICorrespondence to : Dr Narendra Rathi, Rathi Children’s Hospital and Maternity Home, Civil Lines, Akola 444 001, MS, India.drnbrathi@hotmail.comContext: Underdiagnosed and misdiagnosed rickettsial infections are important public health problems. They also leadto extensive investigations in children with fever of undetermined origin contributing to financial burden on families. Thepresent review addresses the epidemiology, clinical features, diagnosis and management issues of these infections,primarily for a practicing clinician.Evidence acquisition: We did a PubMed, Medline and Cochrane library search for literature available in last 40 years.Results : Rickettsial infections are re-emerging and are prevalent throughout the world. In India, they are reported fromMaharashtra, Tamil nadu, Karnataka, Kerala, Jammu and Kashmir, Uttaranchal, Himachal Pradesh, Rajasthan, Assamand West Bengal. In view of low index of suspicion, nonspecific signs and symptoms, and absence of widely availablesensitive and specific diagnosic test, these infections are notoriously difficult to diagnose. Failure of timely diagnosis leadsto significant morbidity and mortality. With timely diagnosis, treatment is easy, affordable and often successful withdramatic response to antimicrobials. As antimicrobials effective for rickettsial disease are usually not included in empiricaltherapy of nonspecific febrile illnesses, treatment of rickettsial disease is not provided unless they are suspected.Knowledge of geographical distribution, evidence of exposure to vector, clinical features like fever, rash, eschar, headacheand myalgia alongwith high index of suspicion are crucial factors for early diagnosis.Key words : Rickettsia, Spotted fever, Typhus fever, Vasculitis, Weil-Felix test.R ickettsial diseases are some of the most adults and children, despite availability of low cost, covert re-emerging infections of the effective antibiotic therapy. The greatest challenge to present times. They are generally clinician is the difficult diagnostic dilemma posed by incapacitating and notoriously difficult to these infections early in their clinical course whendiagnose; untreated cases can have fatality rates as antibiotic therapy is most effective(4).high as 30-35% but when diagnosed properly, they EPIDEMIOLOGYare often easily treated(1). Rickettsial infection hasbeen one of the great scourges of mankind, occuring Except Antartica, rickettsial infections are prevalentin devastating epidemics during times of war and throughout the world. For India, the reportedfamine. Napoleon’s retreat from Moscow was forced numbers are an underestimate due to lack ofby rickettsial disease breaking out among his troops. community based data and non-availability ofLenin is said to have remarked, in reference to confirmatory laboratory tests(5). Rickettsial diseaserickettsial disease rampant during Russian in India has been documented from Jammu andrevolution, that “either socialism will defeat the Kashmir, Himachal Pradesh, Uttaranchal, Rajasthan,louse or the louse will defeat the socialism”(2). Assam, West Bengal, Maharashtra, Kerala and TamilRickettsial infection in the past have taken more Nadu(1,6-8). Batra has reported a high magnitude oflives than all the wars combined together(3). scrub typhus, spotted fever and Indian tick typhusTickborne rickettsial diseases (TBRD) continue to caused by R. conorii(1). An extensive study oncause severe illness and death in otherwise healthy tickborne rickettsiosis in Pune district ofINDIAN PEDIATRICS 157 VOLUME 47__FEBRUARY 17, 2010
  2. 2. RATHI AND RATHI RICKETTSIAL INFECTIONSMaharashtra revealed that Indian tick typhus exists (passage of the organism from infected arthropods toas zoonosis(9). their progeny seen in spotted fever group and scrub typhus) wherein arthropods act as vector as well asMICROBIOLOGICAL ASPECTS reservoir; or without transovarial transmission seen in typhus fever group, wherein arthropods act only asFamily Rickettsiaceae comprise a group of microor- vector. Man is an accidental host except for louseganisms that phylogenetically occupy a position be- borne epidemic typhus caused by Rickettsiatween bacteria and viruses. Rickettsiae are small, prowazekii. Transmission to humans occurs bynonflagellate, gram negative pleomorphic cocco-ba- infected arthropod vector or exposure to infectedcilli adapted to obligate intracellular parasitism and animal reservoir host. Vector to human transmissiontransmitted by arthropod vectors. They are primary occur as vector defaecate while feeding (flea feedingparasites of arthropods like lice, fleas, ticks and mites, reflex) so that faces contaminate pruritic bite woundsin which they are found in the alimentary canal. In (seen with typhus fever group) or primarily by bite,vertebrates, including humans, they infect vascular where regurgitation of infected saliva occurs duringendothelium and reticulo-endothelial cells. Family feeding (seen with spotted fever group and scrubRickettsiaceae comprises three genera namely Rick- typhus).They are not transmissible directly fromettsia, Orientia and Ehrlichia. Former members of person to person except by blood transfusion orthis family, Coxiella burnetii which causes Q fever organ transplantation(10).and Rochalimaea quintana causing trench fever havebeen excluded because the former is not primarily PATHOLOGYarthropod-borne and the latter not an obligate intrac- These organisms after entering human body, multiplyellular parasite(2). Being obligate intracellular para- locally and enter the bloodstream. Then they invadesites, these organisms donot grow on cell free media their target cells, which are vascular endothelium,and need tissue cultures and laboratory animals for reticuloendothelial cells and in case of Ehrlichiosistheir isolation. Various members of this family can be and Anaplasmosis, blood cells. Once inside hostgrouped into four biogroups based on the li- cells, organisms multiply and accumulate in largepopolysaccharide group antigen, as shown in Table I. numbers before lysing the cell (in case of typhusPATHOGENESIS group) or they escape from cell, damaging its membrane and causing influx of water (in case ofThese organisms grow in alimentary canal of spotted fever group). Unlike rickettsiae in the spottedarthropods. Arthropods maintain the infection fever group, which can survive and replicate fornaturally by either transovarial transmission several days after the death of their host cells, TABLE I BIOGROUPS OF RICKETTSIACEAE(12)Biogroup Disease Vector Host OrganismSpotted fever Rocky Mountain spotted fever (RMSF) tick dogs, rodents Rickettsia rickettsii Rickettsialpox mite mice Rickettsia akari Indian tick typhus / Boutonneuse fever/ tick dogs, rodents Rickettsia conorii Mediterranean spotted fever (MSF)Typhus Epidemic louse borne typhus louse human Rickettsia prowazekii Brill-Zinsser disease (recrudescent typhus) louse human Rickettsia prowazekii Endemic/Murine flea borne typhus flea rats Rickettsia typhiScrub typhus Scrub typhus chigger rodents Orientia tsutsugamushiMiscellaneous Ehrlichioses and Anaplasmosis tick deer,dogs,rodents Ehrlichia , Anaplasma TIBOLA (tick borne lymphadenopathy) tick wild boar Rickettsia slovaca DEBONEL tick wild boar Rickettsia slovacaDEBONEL: Dermacentor borne necrosis-eschar-lymphadenopathy.INDIAN PEDIATRICS 158 VOLUME 47__FEBRUARY 17, 2010
  3. 3. RATHI AND RATHI RICKETTSIAL INFECTIONSrickettsiae of the typhus group die rapidly after killing lumber region, thigh and calf is seen in variabletheir host cells(11). proportion of cases. Headache is noted less frequently in young children than in adults, but when Vasculitis is the basic pathogenetic mechanism. it occurs, it is often intractable to therapy(16).Vasculitis is responsible for skin rash, microvascularleakage, edema, tissue hypoperfusion and end-organ Rash: Though rash is considered as hallmark ofischemic injury. Formation of thrombi can lead to rickettsial disease, it is neither seen at presentationtissue infarction and hemorrhagic necrosis. nor in all the patients(17,18). Thus it should beInflammation and vascular leakage leads to remembered that spotted fevers could be spotless too!interstitial pneumonitis, noncardiogenic pulmonary Rash usually becomes apparent after 3-5 days ofedema, cerebral edema and meningoencephalitis. onset of symptoms. Initially rash is in the form ofInfection of endothelial cells also induces pink, blanching, discrete macules whichprocoagulant activity that promotes coagulation subsequently becomes maculopapular, petechial orfactor consumption, platelet adhesion and leucocyte hemorrhagic (Fig.1). Sometimes palpable purpuraemigration and may result in clinical syndrome (typical of vasculitis) is seen. Occasionally petechiaesimilar to disseminated intravascular enlarge to ecchymosis and gangrenous patches maycoagulation(12). develop. Rarely gangrene of digits, earlobes, scrotum, nose or limbs may occur secondary toCLINICAL FEATURES vasculitis and thrombosis. Distribution of rash isEarly signs and symptoms of these infections are initially near ankles, lower legs and wrists. Thereafternonspecific and mimic benign viral illnesses, making rash spreads centripetally to involve whole body.diagnosis more difficult(13). Symptomato-logy may Presence of rash on palms and soles, considered sovary from mild to severe. Unless there is a high index typical of rickettsial disease, can be seen in otherof suspicion, it is likely to be missed as the clinical diseases like infective endocarditis, syphilis,presentation may mimic other common infections in meningococcemia, enteroviral diseases and adversethe tropics(14). Incubation period of various drug reactions. The rash of typhus group rickettsiosesrickettsial infections varies between 2-21 days. is quite atypical, initially appearing on trunk,Clinical manifestations of rickettsial infections are spreading centrifugally and usually sparing palmsdetailed herein. and soles.Fever: Fever of undetermined origin is the most Eschar: A necrotic eschar at the inoculating site isfrequent presentation of rickettsial disease. Fever is seen in variable proportion of Indian tick tuphus,usually abrupt onset, high grade, sometimes with scrub typhus and rickettsialpox cases. The site ofchills, occasionally with morning remissions and initial tick bite is inapparent in other rickettsialassociated with headache and myalgia. Diagnosis of infections. Eschar, a black necrotic area, resemblesrickettsial disease should always be considered in the skin burn of cigarette butt (Fig.2). A necroticpatients with acute febrile illness accompanied with eschar usually has an erythematous rim and isheadache and myalgia, particularly in endemic areas associated with regional lymphadenopathy.with history of tick exposure or contact with dogs. Inone study, 24% among 180 children (less than 14 Generalised lymphadenopathy and hepato-years age) admitted with acute febrile illness in whom splenomegaly are seen in majority of scrub typhusother common causes for fever were excluded, were patients(19).clinically and serologically confirmed to have scrubtyphus or other rickettsial infections. Scrub typhus Systemic features: Clinical features referable toformed the largest group (62.8%) followed by spotted various systems are sometimes seen in rickettsialfever (32.6%) and endemic typhus fever (4.7%)(15). infections. Gastrointestinal symptoms including nausea, vomiting, abdominal pain and diarrhea areHeadache and Myalgia: Severe frontal headache and seen with varying frequency. Constipation is seengeneralised myalgia specially in muscles of the particularly in epidemic typhus. RespiratoryINDIAN PEDIATRICS 159 VOLUME 47__FEBRUARY 17, 2010
  4. 4. RATHI AND RATHI RICKETTSIAL INFECTIONS FIG. 1 Hemorrhagic rash of rickettsial infection. FIG. 2 Eschar in left inguinal region.symptoms include cough and distress are sometimes 2. Neurological: Meningoencephalitic syndrome isseen. Neurological manifestations like dizziness, known to occur with rickettsial infections. In fact,drowsiness, disorientation, tinnitus, photophobia, rickettsial infections should be included indelirium, meningismus, and visual disturbances; are differential diagnosis of aseptic meningitis andseen more commonly with typhus group encephalitis in patients exposed to endemic areasrickettsioses. The word ‘typhus’ refers to cloudy state specially when accompanied by renal insufficiencyof consciousness (‘typhos’: cloud or smoke). and/or jaundice(20, 21).Miscellaneous: Periorbital edema, conjunctival 3. Renal: Acute renal failure is associated with badhyperemia, epistaxis, acute reversible hearing loss prognosis and can be a presenting feature ofand arthralgia are sometimes reported. rickettsial disease. The possibility of scrub typhusSEVERE MANIFESTATIONS AND COMPLICATIONS should be borne in mind whenever a patient of fever present with varying degree of renal insufficiencyRickettsial infections sometimes produce severe life particularly if eschar exists alongwith history ofthreatening manifestations and takes a fulminant environmental exposure(22,23).course. Fulminant course of rickettsial infections,particularly spotted fever group is known to occur in 4. Disseminated intravascular coagulation likepatients with glucose-6-phosphate dehydrogenase syndrome, hepatic failure, gangrene and myocarditis(G6PD) deficiency. Following are the life are sometimes seen in rickettsioses.threatening manifestations of rickettsial infections. LABORATORY FINDINGS1. Respiratory: Interstitial pneumonitis andnoncardiogenic pulmonary edema secondary to No single laboratory finding is specific for earlypulmonary microvascular leakage are occasionally diagnosis. Various laboratory abnormalities found inobserved. rickettsial diseases are described below.INDIAN PEDIATRICS 160 VOLUME 47__FEBRUARY 17, 2010
  5. 5. RATHI AND RATHI RICKETTSIAL INFECTIONSHematology: Total leucocyte count, during early conditions where definitive investigations are notcourse of the disease, is normal to low normal with available(26,27). Isaac, et al.(28) havemarked shift to left. Later in the course of the disease, demonstrated that the sensitivity of Weil-Felixit shows leucocytosis in 30% of cases(24). Low was 30% at a breakpoint titre of 1:80, but theplatelet counts are present in about 60% cases(16). specificity and positive predictive value wereErythrocyte sedimentation rate is usually high. 100%. Hence Weil-Felix test is still not entirely obsolete but has to be interpreted in the correctBiochemistry: Hyponatremia and hypoalbumi- clinical context(6).nemia, reflecting increased vascular permiability, aresometimes helpful in differentiating rickettsial (b) IFA: This is a reference serological method forinfections from other acute infections. Thrombo- diagnosis of rickettsial diseases and is consideredcytopenia, hyponatremia and normal to low leuco- ‘gold standard’. It is not available in India. Ascyte count are certain clues to early diagnosis. with all other serological methods, it usuallyHepatic transaminase values are frequently elevated. provides retrospective diagnosis and sensitivityBlood urea is elevated due to prerenal mechanisms. is enhanced by testing paired sera (acute and convalescent).Serology: Microimmunoflorescence, immuno-peroxidase assay, latex agglutination, indirect Polymerase chain reaction assay: It can be used tohemagglutination, enzyme-linked immunosorbent detect rickettsial DNA in whole blood, buffy coatassay, dot blot immunoassay (including dipstick test) fraction or tissue specimen. It is the most rapid assayand Weil-Felix test are the various serological for the diagnosis. It has certain disadvantages likemethods available for diagnosis of rickettsial varying levels of sensitivity, high cost anddiseases. Of these, only Weil-Felix test is easily nonavailability.available in India. As all these tests detect antibodies,they would be able to make diagnosis only after 5-7 Immunohistochemistry and isolation ofdays of onset of disease and hence play no role for organism: in cell culture or laboratory animals areinitiation of therapy in a suspected case. other methods restricted to research laboratories.(a) Weil-Felix test: The sharing of antigens between DIAGNOSIS rickettsia and proteus is the basis of this No rapid laboratory tests are available to diagnose heterophile antibody test. It demonstrates rickettsial infection early in the course of disease. It agglutinins to Proteus vulgaris strain OX 19, OX is emphasized again that the only crucial factor for 2 and OX K. Most of the Western literature has early diagnosis is high index of suspicion. Following advised against performing this test for diagnosis five factors taken together should help in diagnosis, of rickettsial infections(12). The poor sensitivity which can then be confirmed with serology. of the WF test is now well demonstrated but a good correlation between the results of the WF 1. Compatible clinical presentations: Various test and detection of IgM antibodies by an clinical situations where a diagnosis of rickettsial indirect immunofluorescence assay (IFA) is often disease should be considered are fever without observed(25). This can be used as a screening source, pyrexia of unknown origin (PUO), fever with test, which detects more cases than misdiagnosed rash (rash which is petechial, involving palms and ones and when positive, is reasonably specific. In soles, having centripetal spread), fever with eschar, spite of all its drawbacks, Weil-Felix test still meningoencephalitis or aseptic meningitis, acute serves as a useful and cheap diagnostic tool for renal insufficiency with eschar, and infective laboratory diagnosis of rickettsial disease(1). vasculitidis. Either four fold rise in agglutinin titre in paired sera or single titre of more than 1:320 is 2. Tick bite or tick exposure: Tick bite is painless and considered diagnostic for infection with these histoty of tick bite is present in less than 50% of febrile agents. The use of this test is accepted in cases. Hence absence of tick bite should not dissuadeINDIAN PEDIATRICS 161 VOLUME 47__FEBRUARY 17, 2010
  6. 6. RATHI AND RATHI RICKETTSIAL INFECTIONS KEY MESSAGES • Rickettsial infections are prevalent in various parts of India. • These are one of the most difficult infections to diagnose in their early course and high index of suspicion is the key to early diagnosis. • Fever, rash, headache, myalgia, lymphadenopathy and eschar are various clinical features of these infections. • Epidemiological features and history of exposure to vector are crucial for diagnosis. • Failure of early diagnosis is associated with significant mortality and morbidity and also leads to expensive PUO workup. • Therapy is easy and affodable with dramatic results and needs to be started on clinical suspicion, as there is no specific test for early diagnosis. • Doxycycline is the drug of choice and it can be used safely even in chldren below 8 years of age.a pediatrician from considering the diagnosis of Thus, rickettsial infection should be suspected inrickettsial disease. Patient should be completely presence of above clinical features in a patient withexposed to look for ticks on body and clothing. likelihood of tick exposure. They should undergoOutdoor actvities in areas with high uncut grass, relevant hematological and biochemical testing andweeds, low bushes or animal sheds where ticks are those with high probability of rickettsial infectionoften seen is a definite risk factor. Contact with should be treated with appropriate dog in whom history of tick attachment or tick Failure of defervescence within 48 hours should leadremoval is forthcoming can be useful. to search for alternative diagnosis.3. Epidemiological data: Diagnosis should be DIFFERENTIAL DIAGNOSISconsidered in areas known for rickettsial disease. Rickettsial diseases can be easily confused with aBut in absence of multicentric studies, one would not variety of viral (measles, enteroviral exanthems,know prevalence in particular area. Occurrence of dengue, infectious mononucleosis), protozoalsimilar illness (like index case) simultaneously or (malaria), bacterial (meningococcemia, typhoid,sequentially in family members or family pets can be leptospirosis, toxic shock syndrome, scarlet fever)a useful link as small ‘islands’ of infected ticks may and collagen vascular (Kawasaki disease, otheroccur in discrete geographic units such as vasculitis) diseases, and adverse drug reactions.neighborhood or parks(16). Invasive meningococcal disease may not be reliably distiguished from rickettsial disease clinically, hence4. Suggestive laboratory features: Normal to low one may need to treat for both conditions, afterleucocyte count with marked left shift, sending cerebrospinal fluid and blood forthrombocytopenia, hyponatremia and mildly appropriate studies(4). The possibility of rickettsialelevated hepatic transaminases are compatible with disease should be considered in those leptospirosisdiagnosis of rickettsial disease, although absence of patients who present with atypical features orthese does not rule it out. respond poorly to therapy(29).5. Rapid defervescence with appropriate antibiotics: TREATMENTIt is so characteristic that it can be used as adiagnostic test for rickettsial disease. In fact if fever Definitive treatment should be instituted on the basisfails to respond in 48 hours, one should review the of clinical and epidemiological clues as early asdiagnosis. Severely ill patients with multiple organ possible to avoid severe disease and fataldysfunction may take longer period of time to outcome(30,31). Various antibiotics useful forrespond. treating rickettsial diseases are tetracyclines,INDIAN PEDIATRICS 162 VOLUME 47__FEBRUARY 17, 2010
  7. 7. RATHI AND RATHI RICKETTSIAL INFECTIONSpreferably doxycycline, chloramphenicol, macro- intellectual content, will act as guarantor. AR: review oflides(32,33) specially, azithromycin, clarithromycin, literature, drafting and microbiological aspects. Finalroxythromycin, and fluroquinolones, specially manuscript was approved by both authors.ciprofloxacin, ofloxacin, pefloxacin, levofloxa- Funding : None.cin(12). Doxycycline is the drug of choice. Oral Competing interest : None stated.treatment is used unless patient is vomiting orobtunded. Dose is 5 mg/kg/day in two divided doses REFERENCESfor children below 45 kg and 200 mg/day in two 1. Batra HV. Spotted fevers and typhus fever in Tamildivided doses for children above 45 kg. Duration of Nadu – commentary. Indian J Med Res 2007; 126:therapy should be at least 3 days after defervescence 101-103.or minimum 5-7 days. 2. Jayaram Paniker CK. Ananthanarayan and Paniker’s Textbook of Microbiology. 7th ed. Use of tetracycline to treat children below 8 years University Press Pvt Ltd; 2008; no longer a subject of controversy (34-36). It hasbeen observed that cosmetically perceptible staining 3. Kelly DJ, Richards A, Temenak J, Strickman D,of teeth require six or more multiple day courses of Dasch GA. The past and present threat of rickettsialtherapy. Because TBRD can be life threatening and disease to military medicine and international public health. Clin Infect Dis 2002; 34 (suppl 4): Slimited courses with tetracycline class antibiotics 145-169.donot pose a substantial risk for tooth staining, theAmerican Academy of Pediatrics committee on 4. Chapman AS, Bakken JS, Folk SM, Paddock CD,infectious diseases revised it’s recommendations in Bloch KC, Krusell A, et al. Diagnosis and management of tickborne rickettsial diseases.1997 and has identified doxycycline as the drug of MMWR Recomm Rep 2006; 55: 1-27.choice for treating presumed or confirmed RMSF inchildren of any age(37). 5. Chugh TD. Emerging and reemerging bacterial diseases in India. J Biosci 2008; 33: 549-555. Chloramphenicol has more side effects and needs 6. Mahajan SK, Kashyap R, Kanga A, Sharma V,hematological monitoring. On many occasions, Prasher BS, Pal LS. Relevance of Weil-Felix test influroquinolones are associated with clinical failures diagnosis of scrub typhus in India. J Assoc Physdespite good in vitro activity. Clarithromycin can be India 2006; 54: 619-621.considered a valid alternative to tetracycline and 7. Mathai E, Lloyd G, Cherian T, Abraham OC,chloramphenicol, especially for children less than 8 Cherian AM. Serological evidence of continuedyears of age(32,33). Occasional cases with presence of human rickettsiosis in southern India.resistance to doxycycline are treated with macrolides Ann Trop Med Parasitol 2001; 95: 395-398.or rifampin. Sulfonamides are contraindicated in 8. Sundhindra BK, Vijaykumar S, Kutti AK.rickettsial diseases as they increase morbidity and Rickettsial spotted fevers in Kerala. Natl Med Jmortality either by delaying institution of India 2004; 17: 51-52.appropriate antibiotics or directly stimulating thegrowth of organisms. 9. Padbidri VS, Rodrigues JJ, Shetty PS. Tick-borne rickettsiosis in Pune district, Maharashtra, India. Int Good supportive therapy is needed in critically ill J Zoonoses 1984; 11: 45-52.patients as iatrogenic cerebral and pulmonary edema 10. Centre of Disease Control and Prevention (CDC).is easily precipitated due to preexsisting micro- Rickettsial Diseases. Available at http://vascular leakage. Judicious use of corticosteroids is by some in meningoencephalitis(12). sub_rickettsial.htm. Accessed 30 May, 2009.Supportive care is also needed for hypovolemia, 11. Gregory AD, Jennifer HM. Other rickettsia species.coagulopathy, seizures and intercurrent infections. In: Sarah SL, Larry KP, Charles GP, editors. Principles and Practice of Pediatric InfectiousContributors: NR: concept, design, analysis and Diseases. 2nd ed. Philadelphia: Churchillacquisition of data, revised manuscript for important Livingstone; 2003. p. 945-951.INDIAN PEDIATRICS 163 VOLUME 47__FEBRUARY 17, 2010
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