Scrub Typhus

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Scrub Typhus Paul N. Newton, Nicholas P. J. Day

KEY FEATURES • Common, but under-recognized, cause of undifferentiated fever in Asia and Australia caused by Orientia tsutsugamushi, with some 1 billion people at risk. Recently locally acquired scrub typhus has been described in Chile in South America, and there is mounting evidence that Orientia is also present in Africa. • May also cause severe disease, such as meningoencephalitis, pneumonitis, jaundice, hypotensive shock, and death. • Transmitted by the bite of larval trombiculid mites (chiggers) in a wider diversity of habitats than “scrub” suggests. • Can be difficult to diagnose clinically; laboratory tests are inadequate. • There is some evidence that tetracycline- and chloramphenicol-resistant O. tsutsugamushi exist in northern Thailand. Elsewhere, tetracyclines, chloramphenicol, and rifampicin appear efficacious. • Synonyms: tsutsugamushi disease, chigger-borne rickettsiosis.

INTRODUCTION Scrub typhus was described in Japan in the 1800s and then in Malaysia in the 1920s, where it was distinguished from murine typhus. It was a major clinical problem in many Asian theaters of the Second World War and the Indochina Wars.1 Management was transformed by chloramphenicol and the tetracyclines. It remains a major, under-appreciated cause of undifferentiated fever in Asia. Diagnosis is greatly hampered by the lack of accurate and accessible laboratory diagnosis. Given the large populations of India and China, the numbers potentially exposed are enormous. With the growth of eco-tourism in Asia, more travelers are returning to non-endemic areas with this disease.

EPIDEMIOLOGY Scrub typhus occurs in the most populous rural areas of the world—across 13,000,000 km2 from the Pacific Rim, Southeast Asia, northern Australia, and northeast Asia across South and Central Asia as far west as Uzbekistan and including the Maldives (Fig. 68.1).1 This has been conventionally called the scrub typhus triangle, but it is more of a rhomboid than a triangle. There is increasing evidence that scrub typhus may be contracted outside this area, with autochthonous scrub typhus cases described in the Chiloé islands off the coast of Chile and serologic evidence that Orientia tsutsugamushi or a related species causes febrile illness in Kenyan children.2,3 Recent evidence suggests that the large epidemics of acute encephalitis attributed to the Japanese encephalitis virus in northern India may be caused, at least in part, by scrub typhus.4 There are no reliable estimates of community incidence and most are hospital derived, such as data showing that 3% of patients in Nepal and 15% of adult patients in Laos admitted with undifferentiated fever had scrub typhus.5,6 It predominantly afflicts

farmers, including their children, but may also affect urban populations through exposure in gardens or visits to the countryside. There are no known genetic predispositions. The name scrub typhus is misleading, as the disease can be contracted in many other habitats, including primary forest, beaches, gardens, and plantations. Indian patients with scrub typhus are more likely to have lived close to bushes and wood piles, to have worked on farms, to have seen rodents, and to have reared domestic animals, but are less likely to wash or change clothes after work. For Koreans, wearing a long-sleeved shirt while working, keeping work clothes off the grass, and always using a mat to rest on outdoors were protective.7 The most commonly reported serotypes are Karp, Kato, Gilliam, and Boryong, but the wide phenotypic and genotypic diversity of O. tsutsugamushi has major implications for the design of diagnostic tests and vaccines.1

NATURAL HISTORY, PATHOGENESIS, AND PATHOLOGY Scrub typhus is transmitted by chiggers—the third-stage larvae of Leptotrombidium mites (Fig. 68.2), which feed on the extracellular fluid of vertebrates such as rodents and humans. Mites are the main reservoir of O. tsutsugamushi, with the organisms maintained in the population by vertical transovarial transmission. Blood transfusion and needlestick injury have been recorded as transmitting scrub typhus. The genome of O. tsutsugamushi (≈2 million bp) is much larger than that of other members of Rickettsiaceae and is the most highly repeated bacterial genome sequenced.1 The median O. tsutsugamushi DNA load in blood is low (≈13 [0–310,253] copies/ mL); approximately half of patients have bacterial loads undetectable by current techniques.8 Post-mortem examination has demonstrated O. tsutsugamushi in endothelial cells of major organs. Significantly higher concentrations of gamma interferon and interleukin-10 occur during the acute than the convalescent phase. Comparison of patterns of endothelial and leukocyte activation in a range of “typhus-like” illnesses suggest mononuclear cell activation in scrub typhus. Evidence is accumulating that O. tsutsugamushi exhibits tropism for mononuclear cells rather than endothelial cells, at least in early infection.9 Intriguingly, evidence from Thailand suggests that HIV-1-suppressive factors are produced during some scrub typhus infections. There is increasing evidence that a second Orientia species, O. chuto, is a cause of human disease in the Middle East and possibly Africa.10

CLINICAL FEATURES The incubation period is approximately 6 to 14 days. Ten to fifty percent of patients may have an eschar—this variability probably reflects, at least in part, the extent to which patients are examined. Eschars, which are usually single and in secluded areas such as the axilla and groin, are painless, erythematous papules that develop a central black scab, resembling a cigarette burn (Fig. 68.3). They are not pathognomonic for scrub typhus, as similar lesions may be produced by spotted fever–group rickettsioses. Chiggers are minute and, unlike ticks, are not normally noticed. Patients may scratch off the characteristic black scab. Lymphadenopathy is more frequent than in sympatric murine typhus.5 Headache, myalgia, and dry cough frequently occur; a maculopapular erythematous

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? ?

?

O. chuto identified in a patient from Dubai There is serological evidence of Orientia infection in Kenyan children, and molecular evidence of Orientia chuto in chigger mites

O. tsutsugamushi recorded in southern Chile

Fig. 68.1  Map of the distribution of scrub typhus. Please note that this map disguises considerable heterogeneity between and within countries. A “?” represents an area where the presence of scrub typhus is suspected but not confirmed.

rash occurs in a minority of patients.1,5 Deafness, tinnitus, and conjunctival suffusion occur. Severe disease can manifest as pneumonitis, acute respiratory distress syndrome, jaundice with mildly raised transaminases, meningoencephalitis, coagulopathy, multi-organ failure, acute renal failure, acute transverse myelitis, myocarditis, and Guillain–Barré syndrome. Why some and not others develop severe disease is not understood. Mortality is positively correlated with blood bacterial load.8 O. tsutsugamushi DNA has been demonstrated in cerebrospinal fluid (CSF), with normal glucose, a mild increase in white cell density (ranging from 11%–88% lymphocytes) and raised protein.11 Scrub typhus appears to be less severe in children, but there have been no prospective comparisons between children and adults from the same population. Scrub typhus can cause serious adverse effects for mother and baby in pregnancy.12 Although homologous strain immunity persists for at least 1 to 3 years, immunity to heterologous Orientia strains is as short as 1 month. There are few data on the dynamics of IgM/IgG responses—the annual reversion of scrub typhus patients sera back to a titer of <1 : 50 was 61%.13

PATIENT EVALUATION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSIS The majority of scrub typhus patients are not diagnosed or treated. A patient with fever, headache, and myalgia with an eschar in an endemic area is likely to have scrub typhus. The differential diagnosis would include spotted fever–group rickettsiosis, which would also be expected to respond to tetracyclines. Scrub typhus eschars could be confused with the lesions of anthrax, tularemia, chancroid, lymphogranuloma venereum, and injury. In the absence of an eschar, few clinical features are helpful. Murine typhus, leptospirosis, Q fever, dengue, hemorrhagic fever with renal syndrome (HFRS), infectious mononucleosis, HIV seroconversion, septicemia (especially typhoid), and malaria are important differential diagnoses. In comparison with those with Q fever, Taiwanese patients with scrub typhus had a higher frequency of residence or travel in a mountainous region or offshore island and skin rash. In comparison to HFRS in China, eschar, regional lymphadenopathy, and maculopapular rash were more commonly found in patients with scrub typhus. In Laos, the presence of

peripheral lymphadenopathy, chest signs, and eschars are clinically useful signs that suggest scrub, rather than murine, typhus.5 Laboratory diagnosis of scrub typhus is difficult. Culture (requiring BSL3 facilities) is 100% specific but has low sensitivity. Immunofluorescence (IFA) and immunoperoxidase IgM and IgG antibody tests have been commonly used, but these are expensive, are rarely accessible, and are bedeviled by subjectivity of interpretation and uncertainty as to the most appropriate cut-off titers in different communities.14 Ideally, they should be interpreted by comparing titers between paired acute and convalescent samples. Karp, Gilliam, and Kato prototypic antigens are usually used in IFAs and therefore may not detect antibodies to other strains. The Weil–Felix (WF) OXK test is still commonly used in Asia but has low sensitivity. Recently developed enzyme-linked immunosorbent assays (ELISAs) and serologically based rapid diagnostic tests have good sensitivity and specificity and, when available, are replacing both the IFA and WF tests. Conventional and quantitative real-time polymerase chain reaction (PCR) assays for the detection of O. tsutsugamushi in blood, eschar tissue, and CSF have been developed.15,16 However, there remain great difficulties in diagnosing scrub typhus in rural endemic areas. Mixed infections may occur with, for example, leptospirosis, but given the persistence of antibodies, distinguishing these from serial infections without culture or PCR techniques is difficult.

TREATMENT Given the difficulties of making a timely laboratory diagnosis and the significant minority who develop severe disease, empirical treatment should be considered for all patients with scrub typhus in the differential diagnosis. The diversity of O. tsutsugamushi suggests it is unlikely that one treatment regimen will be appropriate across the wide distribution of this organism. Chloramphenicol- and doxycycline-resistant scrub typhus have been described in northern Thailand,17 but there are no subsequent published data on this clinical problem. Interpretation of data informing treatment decisions is difficult, as studies are few, often of small sample size, and “relapses” were usually not proven to be relapses of scrub typhus rather than another cause of fever (Table 68.1). Current data suggest that

CHAPTER 68  Scrub Typhus



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Maintaining hosts

Incidental hosts

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?

Larvae Established colony (mite island)

Dispersal: may form new mite islands

Eggs Larvae

Adult Nymph

Nonparasitic postlarval stages in soil Fig. 68.2  The life cycle of O. tsutsugamushi. (Adapted with permission from Audy JR. Red mites and typhus. London: The Athlone Press, University of London; 1968.)

Fig. 68.3  An eschar on a Lao patient with scrub typhus. (Taken by Dr Rattanaphone Phetsouvanh.)

fluoroquinolones are inferior to doxycycline as therapy for scrub typhus. For uncomplicated disease, the data available do not allow generalizable conclusions of the duration of doxycycline therapy or whether a loading dose is required. In Laos and Thailand, a 7-day treatment course of 2 mg/kg twice daily after a loading dose of 4 mg/kg is administered. There is evidence from Malaysia that shorter courses may be efficacious.18 Upper gastrointestinal side effects are common; patients should be counseled to take

doxycycline with plenty of fluid, during meals, and while sitting or standing. Chloramphenicol, telithromycin, rifampicin, and azithromycin are potential alternatives.19–24 There are few data to guide the antibiotic treatment of severe disease—parenteral or nasogastric doxycycline, azithromycin, and chloramphenicol are potential options. Appropriate supportive care is essential. The treatment of scrub typhus in pregnancy is problematic—chloramphenicol (although contraindicated in the last trimester), azithromycin, and rifampicin have been used. In children, the risks of short-course doxycycline are almost certainly exceeded by the benefit of effective cure. In a retrospective analysis of children with scrub typhus, no significant differences in fever clearance times were found between doxycycline, chloramphenicol, and roxithromycin therapy.25 Mortality is very variable, ranging from 0% to 70% in untreated patients (median 6%), for reasons that are unclear.26 Delayed administration of doxycycline has been associated with major organ dysfunction and prolonged hospitalization, emphasizing the importance of early empirical doxycycline therapy. Relapse was described during volunteer experiments in Malaysia, but whether this is an important phenomenon in clinical practice is uncertain. Insecticides have been used to control chiggers, both in high-risk habitats and on blankets and clothes, but neither is currently practical in rural Asia for farmers (who are at most risk of scrub typhus). For short-term adult visitors, weekly 200 mg doxycycline

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PART 3  Bacterial Infections

TABLE 68.1  Summary of Clinical Trial and Clinical Case Series Evidence for Antibiotic Therapy for Scrub Typhus20 Location and Sample Size

Outcome

Chloramphenicol 3 g every 24 h for 3 days vs. tetracycline 2 g every 24 h for 3 days

Vietnam (60)

Similar fever clearance times

3

[22]

Doxycycline 200 mg stat vs. tetracycline 500 mg every 6 h for 7 days

Malaysia (55)

Similar fever clearance times

3

[18]

Doxycycline 100 mg every 12 h for 3 days vs. tetracycline 500 mg every 6 h for 7 days

South Korea (116)

Similar fever clearance times

3

[23]

Doxycycline 200 mg followed by 100 mg every 12 h for 7 days vs. rifampicin 300 mg every 12 h for 7 days vs. rifampicin and doxycycline combined in doses as noted earlier

Northern Thailand (126)

Rifampicin and doxycycline combined inferior to the other two single-agent groups. Fewer patients febrile at 48 h in the rifampicin group compared with the doxycycline group (RR 0.41, 95% CI, 0.22–0.77)

3

[24]

Doxycycline 2.5 mg/kg every 12 h, chloramphenicol 50 mg/kg/d in 3–4 doses, or roxithromycin 5 mg/kg every 12 h

South Korea (39 children)

Fever clearance times not significantly different

4

[25]

Azithromycin single 500 mg dose vs. 200 mg doxycycline every 24 h for 7 days

South Korea (93)

Fever clearance and cure rates not significantly different

3

[19]

Telithromycin 800 mg every 24 h for 5 days vs. doxycycline 100 mg every 12 h for 5 days

South Korea (92)

Fever clearance and cure rates not significantly different

3

[20]

Azithromycin single 1000 mg dose followed by 500 mg every 24 h for 2 days vs. 200 mg doxycycline followed by 100 mg every 12 h for 7 days

Thailand (57)

At 48 h after initiation of treatment, a significantly higher proportion of the doxycycline-treated group were afebrile than with azithromycin-treated group (P = 0.03)

3

[6]

Therapies

Category

Ref.

Category 1, double blind study; 2, clinical trial <20 subjects; 3, clinical trial >20 subjects; 4, series; 5, anecdotal case reports. CI, Confidence interval; RR, relative risk. All clinical trials involved random allocation of treatment.

reduces the risk of contracting scrub typhus. There is currently no safe and effective vaccine available. REFERENCES

1. Kelly DJ, Fuerst PA, Ching WM, Richards AL. Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. Clin Infect Dis 2009;48(Suppl. 3):S203–30. 2. Weitzel T, Dittrich S, López J, et al. Endemic scrub typhus in South America. N Engl J Med 2016;375(10):954–61. 3. Maina AN, Farris CM, Odhiambo A, et al. Q fever, scrub typhus, and rickettsial diseases in children, Kenya, 2011-2012. Emerg Infect Dis 2016;22(5):883–6. 4. Murhekar MV. Acute encephalitis syndrome and scrub typhus in India. Emerg Infect Dis 2017;23(8):1434. 5. Phongmany S, Rolain JM, Phetsouvanh R, et al. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis 2006;12:256–62. 6. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus. Antimicrob Agents Chemother 2007;51:3259–63. 7. Kweon SS, Choi JS, Lim HS, et al. A community-based case-control study of behavioral factors associated with scrub typhus during the autumn epidemic season in South Korea. Am J Trop Med Hyg 2009;80:442–6. 8. Sonthayanon P, Chierakul W, Wuthiekanun V, et al. Association of high Orientia tsutsugamushi DNA loads with disease of greater severity in adults with scrub typhus. J Clin Microbiol 2009;47:430–4. 9. Paris DH, Jenjaroen K, Blacksell SD, et al. Differential patterns of endothelial and leucocyte activation in ‘typhus-like’ illnesses in Laos and Thailand. Clin Exp Immunol 2008;153:63–7. 10. Masakhwe C, Linsuwanon P, Kimita G, et al. Identification and characterization of Orientia chuto in trombiculid chigger mites collected from wild rodents in Kenya. J Clin Microbiol 2018;56(12):pii: e01124-18. 11. Dittrich S, Rattanavong S, Lee SJ, et al. Rickettsia and leptospira as neglected but treatable causes of central nervous system infection. Lancet Glob Health 2015;3:e104–11. 12. Mathai E, Rolain JM, Verghese L, et al. Case reports: scrub typhus during pregnancy in India. Trans R Soc Trop Med Hyg 2003;97:570–2. 13. Saunders JP, Brown GW, Shirai A, Huxsoll DL. The longevity of antibody to Rickettsia tsutsugamushi in patients with confirmed scrub typhus. Trans R Soc Trop Med Hyg 1980;74:253–7.

14. Blacksell SD, Bryant NJ, Paris DH, et al. Scrub typhus serologic testing with the indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to a lot of confusion. Clin Infect Dis 2007;44:391–401. 15. Paris DH, Aukkanit N, Jenjaroen K, et al. A highly sensitive quantitative real-time PCR assay based on the groEL gene of contemporary Thai strains of Orientia tsutsugamushi. Clin Microbiol Infect 2009;15:488–95. 16. Paris DH, Blacksell SD, Newton PN, Day NP. Simple, rapid and sensitive detection of Orientia tsutsugamushi by loop-isothermal DNA amplification. Trans R Soc Trop Med Hyg 2008;102:1239–46. 17. Watt G, Chouriyagune C, Ruangweerayud R, et al. Scrub typhus infections poorly responsive to antibiotics in northern Thailand. Lancet 1996;348:86–9. 18. Brown GW, Saunders JP, Singh SL, et al. Single dose doxycycline therapy for scrub typhus. Trans R Soc Trop Med Hyg 1978;72:413–16. 19. Kim YS, Yun HJ, Shim SK, et al. A comparative trial of a single dose of azithromycin versus doxycycline for the treatment of mild scrub typhus. Clin Infect Dis 2004;39:1329–35. 20. Kim DM, Yu KD, Lee JH, et al. Controlled trial of a 5-day course of telithromycin versus doxycycline for treatment of mild to moderate scrub typhus. Antimicrob Agents Chemother 2007;51:2011–15. 21. Wee I, Lo A, Rodrigo C. Drug treatment of scrub typhus: a systematic review and meta-analysis of controlled clinical trials. Trans R Soc Trop Med Hyg 2017;111(8):336–44. 22. Sheehy TW, Hazlett AD, Turk RE. Scrub typhus: a comparison of chloramphenical and tetracycline in its treatment. Arch Intern Med 1973;132:77–80. 23. Song JH, Lee C, Chang LW, et al. Short course doxycycline treatment versus conventional tetracycline therapy for scrub typhus: a multiple randomized trial. Clin Infect Dis 1995;21:506–10. 24. Watt G, Kantipong P, Jongsakul K, et al. Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. Lancet 2000;356:1057–61. 25. Lee KY, Lee HS, Hong JH, et al. Roxithromycin treatment of scrub typhus (tsutsugamushi disease) in children. Pediatr Infect Dis J 2003;22:130–3. 26. Taylor AJ, Paris DH, Newton PN. A systematic review of mortality from untreated scrub typhus (Orientia tsutsugamushi). PLoS Negl Trop Dis 2015;9(8):e0003971.