chigger (Figure 1).7 The bite of the mite leaves a characteristic black eschar. The adult mites have a four-staged lifecycle: (1) egg, (2) larva, (3) nymph and (4) adult. The larva is the only stage (chigger) that can transmit the disease to humans and other vertebrates, since the other life stages (nymph and adult) do not feed on vertebrate animals. Both the nymph and the adult are free-living in the soil. Chigger mites act as the primary reservoirs for O. tsutsugamushi. Once they are infected in nature by feeding on the body fluid of small mammals, including the rodents, they maintain the infection throughout their life stages and as adults, pass the infection on to their eggs in a process called transovarial transmission. Similarly, the infection passes from the egg to the larva or adult in a process called transstadial transmission. In this way, chigger mite populations autonomously maintain their infectivity over long periods of time. Early workers thought that rodents were the natural reservoir of infection, but it is now believed that mites are both the vector and the reservoir.7 Clinical scrub typhus is not known to occur naturally in animals. This mite is fastidious in matters of temperature, humidity and food, and finds everything suitable in restricted areas. Scrub typhus is generally seen in people whose occupational or recreational activities bring them into contact with ecotypes favorable with vector chiggers.8

Scrub Typhus

V Ramasubramanian, P Senthur Nambi

Chapter 6

Figure 1: Chigger (larva of trombiculid mite)

INTRODUCTION AND HISTORYScrub typhus, caused by Orientia (formerly Rickettsia) tsutsugamushi, is an acute infectious disease of variable severity that is transmitted to humans by an arthropod vector of the Trombiculidae family. “Tsutsuga” means small and dangerous and “mushi” means insect or mite. It affects people of all ages including children. Humans are accidental hosts in this zoonotic disease. While scrub typhus is confined geographically to the Asia Pacific region, a billion people are at risk and nearly a million cases are reported every year.1

Scrub typhus was first described from Japan in 1899. It was a dreaded disease in pre-antibiotic era and a militarily important disease that affected thousands of soldiers in the far east during the second World War.2 The overall mortality varied from 7% to 9%, second only to malaria among infectious diseases. Furthermore, severe epidemics of the disease occurred among troops in Myanmar and Sri Lanka during the Second World War.3 In India, scrub typhus broke out in an epidemic form in Assam and West Bengal during the Second World War. Later, the presence of this disease was found throughout India in humans, trombiculid mites and rodents.4 It was the third most common infection reported in United States (US) troops stationed in Vietnam.5

The term “scrub” is used because of the type of vegetation (terrain between woods and clearings) that harbors the vector; however, the name is not entirely correct because certain endemic areas can also be sandy, semiarid and mountain deserts. The word “typhus” is derived from the Greek word “typhus”, which means “fever with stupor” or smoke.1

PATHOGENOrientia tsutsugamushi is an obligate intracellular Gram-negative bacterium that has a large number of serotypes. This pathogen does not have a vacuolar membrane and hence it grows freely in the cytoplasm of infected cells. Even though, it is recognized as one of the tropical rickettsioses diseases, it has a different cell wall structure and genetic composition than that of the rickettsiae. It includes heterogeneous strains classified in five major serotypes: (1) Boryon, (2) Gilliam, (3) Karp, (4) Kato and (5) Kawazaki.6 In each geographic area, there are several genetic variations and these differ from the genetic variants in other regions. Differentiation of serotypes is important for laboratory diagnosis.

EPIDEMIOLOGYScrub typhus is transmitted to humans and rodents by some species of trombiculid mites (“chiggers”, Leptotrombidium deliense and others). Humans acquire the disease from the bite of an infected

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Scrub typhus is endemic to a part of the world known as the “tsutsugamushi triangle”, which extends from northern Japan and far-eastern Russia in the north, to northern Australia in the south and to Pakistan in the west.9 Increase in the prevalence of scrub typhus has been reported from some Asian countries (Figure 2), which coincides with the widespread use of b-lactam antimicrobial drugs and urbanization in rural areas.10

Scrub typhus is prevalent in many parts of India but specific data are not available. It is a re-emerging infectious disease in India.11 There have been outbreaks in areas located in the sub-Himalayan belt, from Jammu to Nagaland. There were reports of scrub typhus outbreaks in Himachal Pradesh, Pondicherry, Tamil Nadu, Sikkim and Darjeeling.12-14 The seasonal occurrence of scrub typhus varies with the climate in different countries. The period of epidemic is influenced by the activities of the infected mite. It occurs more frequently during the rainy season. However, outbreaks have been reported during the cooler season in southern India.15 Certain areas such as forest clearings, riverbanks and grassy regions provide optimal conditions for the infected mites to thrive. Scrub typhus is difficult to recognize because the symptoms and signs are often nonspecific. The nonspecific presentation and lack of the characteristic eschar in 40–60% of patients lead to misdiagnosis and under-reporting. On the other hand, diagnostic facilities are not

available in all places. Therefore, the precise incidence of the disease is unknown. Mortality rates in untreated patients range from 0–30%.

CLINICAL FEATURESThe clinical spectrum of scrub typhus is broad, with most infections being of mild-to-moderate severity. After an incubation period of 7–21 days (mean, 10–12 days), the first sign of disease in patients is a vesicular lesion at the site of mite feeding, which later on becomes an eschar or an ulcer with regional lymphadenopathy. An eschar is seen at the site of the chigger bite and are often found in the groin, axilla, genitalia and neck (Figures 3A to C).7 It forms in one-half of the primary infections, whereas in secondary infections it occurs only in a minority of the cases.16 It is the single most important clue for diagnosis and is pathognomonic when seen by an experienced physician. Rarely multiple eschars may be found, for example, under a trouser belt. Fever commences a few days later accompanied by headache, myalgia and cough. It is the most common complaint starting abruptly, and has the usual typhus accompaniments of suffused conjunctiva, severe headache, drowsiness, apathy, pain in the shins and other muscles, and more characteristically lymphadenopathy and hepatosplenomegaly.17 Severe headache occurs almost invariably and is a key criterion for identifying suspected cases. A spotted rash on the trunk may appear. The disease may get complicated by interstitial pneumonitis, adult respiratory distress syndrome (ARDS) (Figure 4), acute hepatic failure, acute renal failure, disseminated intravascular coagulation (DIC), meningitis and myocarditis.18 The chances of developing ARDS is more in patients of scrub typhus who have higher white blood cell (WBC) counts, lower hematocrit, higher bilirubin levels and delayed treatment with antibiotics.19 Abdominopelvic lymph nodes may be enlarged especially in the para-aortic, portahepatic and in the splenic hilum. It may involve other abdominopelvic organs including the gastrointestinal (GI) tract and kidneys. There may be bleeding in case of GI tract involvement.

DIAGNOSIS• Blood counts: Normal WBC or leukocytosis may be seen.

Thrombocytopenia may occur. • Liver function tests: Elevated transaminases may be seen in 75–

95% of patients. Hypoalbuminemia occurs in about half the cases while hyperbilirubinemia is not uncommon.

• Renal function tests: Creatinine may be elevated in severe cases.• Chest X-ray: It may reveal pneumonitis, pleural effusion or

bilateral infiltrates.• Ultrasound abdomen: It may reveal liver or spleen enlargement.

Figure 2: Endemic areas of scrub typhus in AsiaSource: World Health Organization

Figures 3A to C: Eschar in (A) shoulder, (B) scrotum and (C) neck

A B C

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Chapter 6 Scrub TyphusSection 1

• The recommended treatment duration is 7–14 days. Treatmentfor less than a week is initially curative but may be followed by relapse.

• Doxycyclineisthedrugofchoice.• In caseof small childrenandpregnantwomen, azithromycin is

the drug of choice. It has been shown to have comparable efficacy when compared to doxycycline in a small trial.23

• Rifampicinhasalsobeenusedasanalternativedrug.Importantly,it should not be used alone because of the risk of resistance. It has been used in combination with azithromycin. A combination therapy with doxycycline and rifampicin should be used in areas where there is poor response to doxycycline alone.24

• Antibiotic therapy brings about prompt disappearance of thefever and dramatic clinical improvement. Rapid defervescence after antibiotic treatment is so characteristic that it is used as a diagnostic test for O. tsutsugamushi infection.25

• Meticulous supportive management is necessary to abortprogression to DIC and septic shock. Further studies are needed to improve antibiotic treatment of severe and resistant scrub typhus as well as to improve treatment in children and pregnant women.

MORTALITY IN SCRUB TYPHUSMortality rates in untreated patients range from 0% to 30% and tend to vary with patients age and region of infection. In the pre-antibiotic era, mortality rates in Japan averaged 30%. In Taiwan, the overall mortality was estimated at 11%, but only 5% in children and as high as 45% in the elderly. With appropriate treatment, mortality is quite rare. However, mortality is still approximately 15% in many areas due to missed or delayed diagnosis.16 Mortality is higher if severe complications like ARDS develop.

PREVENTION

Avoidance of Mite—Human Contact• Avoidmiteinfestedareas• Wearprotectiveclothing• Personal prophylaxis against the mite vector by impre-gnating

clothes with miticidal chemicals (permethrin and benzyl benzoate) and the application of mite repellants (diethyl toluamide) to exposed skin surfaces

• Eliminatemites fromsitesbyapplicationof chlorinatedhydro-carbons (lindane, dieldrin and chlordane) to the ground and vegetation in camps and other populated zones in endemic areas.

ChemoprophylaxisWeekly once dose of 200 mg doxycycline is effective. It should be considered for nonimmune people sent to work in endemic areas and in high-risk travelers.

VaccineThere are no effective vaccines for scrub typhus. There is enormous antigenic variation in O. tsutsugamushi strains and immunity to one

Figure 4: Adult respiratory distress syndrome (ARDS) in a patient with scrub typhus

SPECIFIC TESTS

Serology• ThecheapestandmosteasilyavailableserologicaltestistheWeil-

Felix test. It is easy to perform and results are available overnight. Fifty percent of patients have a positive test result during the second week. However, this test lacks specificity and sensitivity.20

• The gold standard is indirect immunofluorescence antibody(IFA). Indirect immunoperoxidase (IIP) is a modification of the standard IFA method that can be used with a light microscope, and the results of these tests are comparable to those from IFA.20 Serological methods are most reliable when a fourfold rise in antibody titer is looked for.

• Qualitative enzyme-linked immunosorbent assay (ELISA)for detection of immunoglobulin M (IgM) antibodies to O. tsutsugamushi in serum is now commercially available. This makes use of an O. tsutsugamushi derived recombinant antigen mixture. This test aids in the diagnosis of human exposure to O. tsutsugamushi species.

CultureThe organism can be grown in tissue culture or mice from the blood of patients with scrub typhus. Isolation of O. tsutsugamushi requires biosafety level-3 facilities and the median time to positivity is 27 days.

Polymerase Chain ReactionPolymerase chain reaction (PCR) is possible from skin rash biopsies, lymph node biopsies or ethylenediaminetetraacetic acid (EDTA) blood. O. tsutsugamushi can be demonstrated by standard and by nested PCR.21 Real-time PCR assays are as sensitive as standard PCR but are more rapid and can give quantitative results.22

TREATMENT• Treatmentofscrubtyphusmustbeinitiatedearly inthecourse

of the disease, based on a presumptive diagnosis, to reduce mortality and morbidity (Table 1).

TABLE 1 │ Scrub typhus—treatment options

Drug of choice Doxycycline 100 mg BDAlternatives Azithromycin 500 mg OD

Chloramphenicol 500 mg QIDChildren and pregnant women Azithromycin 500 mg ODDrug-resistant serotypes Azithromycin + rifampicin

Doxycycline + rifampicin

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strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, in order to give an acceptable level of protection. This complexity continues to hamper efforts to produce a viable vaccine.

POINTS TO REMEMBER• Scrubtyphusisare-emergingdiseaseinIndia.• Itisanimportantcauseofcommunityacquiredundifferentiated

febrile illness in India. • Ithastobeconsideredinthedifferentialdiagnosisofsepsisand

multiorgan dysfunction syndrome. • Searchforanescharinhiddenareasofbody• Doxycyclineisthedrugofchoice.• DiagnosisisdonebyIgMscrubtyphusELISA.

REFERENCES 1. Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin

Infect Dis. 2003;16(5):429-36. 2. Groves MG, Harrington KS. Scrub typhus. In: Beran GW (Ed). Handbook

of Zoonoses, 2nd edition. Florida: CRC Press; 1994. pp. 663-8. 3. McCallum JE. Military Medicine: From Ancient Times to the 21st

Century, Illustrated edition. California: ABC-CLIO, Inc.; 2008. p. 383. 4. Park K. Epidemiology of Communicable Diseases. In: Park K (Ed).

Park’s Textbook of Preventive and Social Medicine, 20th edition. Jabalpur: Banarsidas Bhanot; 2009. p. 262.

5. Berman SJ, Kundin WD. Scrub typhus in South Vietnam: A study of 87 cases. Ann Intern Med. 1973;79(1):26-30.

6. Tamura A, Ohashi N, Urakami H, et al. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. nov., as Orientia tsutsugamushi comb. nov. Int J Syst Evol Microbiol. 1995;45(3):589-91.

7. Lerdthusnee K, Khuntirat B, Leepitakrat W, et al. Scrub typhus: vector competence of Leptotrombidium chiangraiensis chiggers and transmission efficacy and isolation of Orientia tsutsugamushi. Ann N Y Acad Sci. 2003;990:25-35.

8. Walker JS, Chan CT, Manikumaran C, et al. Attempts to infect and demonstrate transovarial transmission of R. tsutsugamushi in three species of Leptotrombidium mites. Ann N Y Acad Sci. 1975;266:80-90.

9. McCrumb FR, Stockard JL, Robinson CR, et al. Leptospirosis in Malaya. I. Sporadic cases among military and civilian personnel. Am J Trop Med Hyg. 1957;6(2):238-56.

10. Seong SY, Choi MS, Kim IS. Orientia tsutsugamushi infection: overview and immune responses. Microbes Infect. 2001;3(1): 11-21.

11. Padbidri VS, Gupta NP. Rickettsiosis in India: a review. J Indian Med Assoc. 1978;71(4):104-7.

12. Kamarasu K, Malathi M, Rajagopal V, et al. Serological evidence for wide distribution of spotted fevers & typhus fever in Tamil Nadu. Indian J Med Res. 2007;126(2):128-30.

13. Sharma A, Mahajan S, Gupta ML, et al. Investigation of an outbreak of scrub typhus in the Himalayan region of India. Jpn J Infect Dis. 2005;58(4):208-10.

14. Vivekanandan M, Mani A, Priya YS, et al. Outbreak of scrub typhus in Pondicherry. J Assoc Physicians India. 2010;58:24-8.

15. Mathai E, Rolain JM, Verghese GM, et al. Outbreak of scrub typhus in southern India during the cooler months. Ann N Y Acad Sci. 2003;990:359-64.

16. Watt G. Scrub typhus. In: Warrell DA, Cox TM, Firth JD (Eds). Oxford Textbook of Medicine, 5th edition. USA: Oxford University Press; 2010. pp. 919-24.

17. Cowan GO, Friman G, Günther G. Rickettsial infections. In: Gordon CC, Zumla A (Eds). Manson’s Tropical Diseases, 22nd edition. London: Saunders Ltd.; 2008. pp. 885-902.

18. Pang KR, Wu JJ, Huang DB, et al. Rickettsial infections. In: Tyring SK, Lupi O, Hengge UR (Eds). Tropical Dermatology, 1st edition. London: Churchill Livingstone; 2006. pp. 290-2.

19. Wang CC, Liu SF, Liu JW, et al. Acute respiratory distress syndrome in scrub typhus. Am J Trop Med Hyg. 2007;76(6): 1148-52.

20. Kelly DJ, Wong PW, Gan E, et al. Comparative evaluation of indirect immunoperoxidase test for the serodiagnosis of rickettsial disease. Am J Trop Med Hyg. 1988;38(2):400-6.

21. Manosroi J, Chutipongvivate S, Auwanit W, et al. Early diagnosis of scrub typhus in Thailand from clinical specimens by nested polymerase chain reaction. Southeast Asian J Trop Med Public Health. 2003;34(4):831-8.

22. Singhsilarak T, Leowattana W, Looareesuwan S, et al. Short report: detection of Orientia tsutsugamushi in clinical samples by quantitative real-time polymerase chain reaction. Am J Trop Med Hyg. 2005;72(5):640-1.

23. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus. Antimicrob Agents Chemother. 2007;51(9):3259-63.

24. Watt G, Chouriyagune C, Ruangweerayud R, et al. Scrub typhus infections poorly responsive to antibiotics in northern Thailand. Lancet. 1996;348(9020):86-9.

25. Panpanich R, Garner P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev. 2000;(2):CD002150.