|Classification and external resources|
Scrub typhus or Bush typhus is a form of typhus caused by the intracellular parasite Orientia tsutsugamushi, a Gram-negative α-proteobacterium of family Rickettsiaceae first isolated and identified in 1930 in Japan.
Although the disease is similar in presentation to other forms of typhus, its pathogen is not anymore included in genus Rickettsia with the typhus bacteria proper, but in Orientia. The disease is thus frequently classified separately from the other typhi.
Causes and geographical distribution
Scrub typhus is transmitted by some species of trombiculid mites ("chiggers", particularly Leptotrombidium deliense), which are found in areas of heavy scrub vegetation. The bite of this mite leaves a characteristic black eschar that is useful to the doctor for making the diagnosis.
Scrub typhus is endemic to a part of the world known as the tsutsugamushi triangle (after O. tsutsugamushi). This extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea into northern Australia in the south, and to Pakistan and Afghanistan in the west.
The precise incidence of the disease is unknown, as diagnostic facilities are not available in much of its large native range which spans vast regions of equatorial jungle to the sub-tropics. In rural Thailand and in Laos, murine and scrub typhus accounts for around a quarter of all adults presenting to hospital with fever and negative blood cultures  The incidence in Japan has fallen over the past few decades, probably due to land development driven decreasing exposure, and many prefectures report fewer than 50 cases per year.  It affects females more than males in Korea, but not in Japan, and this is conjectured to be because sex-differentiated cultural roles have women tending garden plots more often, thus being exposed to plant tissues inhabited by chiggers. The incidence is increasing day-by-day in southern part of Indian Peninsula.
Signs and symptoms
Symptoms include fever, headache, muscle pain, cough, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation. Morbilliform rash, eschar, splenomegaly and lymphadenopathies are typical signs. Leukopenia and abnormal liver function tests are commonly seen in the early phase of the illness. Pneumonitis, encephalitis, and myocarditis occur in the late phase of illness.
In endemic areas, diagnosis is generally made on clinical grounds alone. However, overshadowing of the diagnosis is quite often as the clinical symptoms overlap with other infectious diseases like Dengue Fever, Paratyphoid, and pyrexia of unknown origin (P.U.O). If the eschar can be identified it is quite diagnostic of Scrub typhus, but this is very unreliable in the native population whom have dark skin, and moreover, the site of eschar which is usually where the mite bites is often located in covered areas. Unless it is actively searched it is most likely that eschar would be missed. History of mite bite is often absent since the bite does not inflict pain and the mites are almost microscopic to be seen by a naked eye. Usually Scrub typhus is often labelled as P.U.O in remote endemic areas since blood culture is often negative, yet it can be treated effectively with chloramphenicol. Where there is doubt, the diagnosis may be confirmed by a laboratory test such as serology. Again, this is often unavailable in most endemic areas since the serological test involved is not included in the routine screening tests for P.U.O. especially in Burma or Myanmar. It may be a good idea to include Weil-Felix test in the screening serology protocol although its specificity is very poor.
The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test is the Weil-Felix test, but this is notoriously unreliable. The gold standard is indirect immunofluorescence, but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic. 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. Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests are severely limited by their cost. Serological methods are most reliable when a fourfold-rise in antibody titre is looked for. If the patient is from a non-endemic area, then diagnosis can be made from a single acute serum sample. In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals.
Other methods include culture and PCR, but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods have been summarised.
Without treatment, the disease is often fatal. Since the use of antibiotics, case fatalities have decreased from 4%–40% to less than 2%.
The drug most commonly used is doxycycline; but chloramphenicol is an alternative. Strains that are resistant to doxycycline and to chloramphenicol are common in northern Thailand. Rifampin and azithromycin are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline-resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage. Combination therapy with doxycycline and rifampicin is not recommended due to possible antagonism.
Other drugs that may be effective are clarithromycin, roxithromycin, and the fluoroquinolones, but there is no clinical evidence on which to recommend their use. Azithromycin or chloramphenicol is useful for infection in children or pregnant women.
There are currently no licensed vaccines available.
An early attempt to create a scrub typhus vaccine occurred in the United Kingdom in 1937 (with the Wellcome Foundation infecting around 300,000 cotton rats in a classified project called "Operation Tyburn"), but the vaccine was not used. The first known batch of scrub typhus vaccine actually used to inoculate human subjects was despatched to India for use by Allied Land Forces, South-East Asia Command (A.L.F.S.E.A.) in June 1945. By December 1945, 268,000 cc. had been despatched. The vaccine was produced at Wellcomes laboratory at Ely Grange, Frant, Sussex. An attempt to verify the efficacy of the vaccine by using a placebo group for comparison was vetoed by the military commanders, who objected to the experiment.
It is now known that there is enormous antigenic variation in Orientia tsutsugamushi strains, and immunity to one 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. A vaccine developed for one locality may not be protective in another locality, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine.
Severe epidemics of the disease occurred among troops in Burma and Ceylon during World War II (WWII). Several members of the U.S. Army's 5307th Composite Unit (Merrill's Marauders) died of the disease; and before 1944, there were no effective antibiotics or vaccines available.
World War II provides some indicators that the disease is endemic to undeveloped areas in all of Oceania in the Pacific Theater, although war records frequently lack assured diagnoses to desired by epidemiological statics—and many records of "high fever" evacuations were also likely to be other tropical illnesses. In the chapter entitled "The Green War", General MacArthur's biographer William Manchester identifies that the disease was one of a number debilitating afflictions affecting both sides on New Guinea in the running bloody Kokoda battles over unbelievably harsh terrains under incredible hardships— fought during a six month span all along the Kokoda Track in 1942-43, and mentions that to be hospital evacuated, Allied soldiers (who cycled forces) had to run a fever of 102°F—and that sickness casualties outnumbered weapons inflicted casualties 5:1. Similarly, the illness was a casualty producer in all the jungle fighting of the land battles of New Guinea campaign and Guadalcanal campaign. Where the allies had bases, they could remove and cut back vegetation or use DDT as a prophylaxis area barrier treatment, so tick induced sickness rates in forces off the front lines were diminished.
The disease was also a problem for US troops stationed in Japan after WWII, and was variously known as "Shichitō fever" (by troops stationed in the Izu Seven Islands) or "Hatsuka fever" (Chiba prefecture).
- Tseng BY, Yang HH, Liou JH, Chen LK, Hsu YH (February 2008). "Immunohistochemical study of scrub typhus: a report of two cases". Kaohsiung J. Med. Sci. 24 (2): 92–8. doi:10.1016/S1607-551X(08)70103-7. PMID 18281226.
- Pediatric Scrub Typhus, accessdate: 16 October 2011
- Pham XD, Otsuka Y, Suzuki H, Takaoka H (2001). "Detection of Orientia tsutsugamushi (Rickettsiales: Rickettsiaceae) in unengorged chiggers (Acari: Trombiculidae) from Oita Prefecture, Japan, by nested polymerase chain reaction". J Med Entomol 38 (2): 308–311. doi:10.1603/0022-2585-38.2.308. PMID 11296840.
- Seong S, Choi M & Kim I (2001). "Orientia tsutsugamushi infection: overview and immune responses". Microbes and Infection 3 (1): 11–21. doi:10.1016/S1286-4579(00)01352-6. PMID 11226850.
- Phongmany S, Rolain JM, Phetsouvanh R et al. (February 2006). "Rickettsial infections and fever, Vientiane, Laos". Emerging Infect. Dis. 12 (2): 256–62. doi:10.3201/eid1202.050900. PMC 3373100. PMID 16494751.
- Suttinont C, Losuwanaluk K, Niwatayakul K et al. (June 2006). "Causes of acute, undifferentiated, febrile illness in rural Thailand: results of a prospective observational study". Ann Trop Med Parasitol. 100 (4): 363–70. doi:10.1179/136485906X112158. PMID 16762116.
- Katayama T, Hara M, Furuya Y, Nikkawa T, Ogasawara H (June 2006). "Scrub typhus (tsutsugamushi disease) in Kanagawa Prefecture in 2001–2005". Jpn J Infect Dis. 59 (3): 207–8. PMID 16785710.
- Yamamoto S, Ganmyo H, Iwakiri A, Suzuki S (December 2006). "Annual incidence of tsutsugamushi disease in Miyazaki prefecture, Japan in 2001-2005". Jpn J Infect Dis. 59 (6): 404–5. PMID 17186964.
- Bang HA, Lee MJ, Lee WC (2008). "Comparative research on epidemiological aspects of tsutsugamushi disease (scrub typhus) between Korea and Japan". Jpn J Infect Dis 61 (2): 148–50. PMID 18362409.
- Watt G, Kantipong P, de Souza M et al. (2000). "HIV-1 suppression during acute scrub-typhus infection". Lancet 356 (9228): 475–479. doi:10.1016/S0140-6736(00)02557-5. PMID 10981892.
- Moriuchi M, Tamura A, Moriuchi H. (2003). "In vitro reactivation of human immunodeficiency virus-1 upon stimulation with scrub typhus rickettsial infection". Am J Trop Med Hyg 68 (5): 557–561. PMID 12812345.
- Koh GCKW, Maude RJ, Paris DH, Newton PN, & Blacksell SD (2010). "Diagnosis of Scrub Typhus". Am J Trop Med Hyg 82 (3): 368–370. doi:10.4269/ajtmh.2010.09-0233. PMC 2829893. PMID 20207857.
- Pradutkanchana J, Silpapojakul K, Paxton H et al. (1997). "Comparative evaluation of four serodiagnostic tests for scrub typhus in Thailand". Trans R Soc Trop Med Hyg 91 (4): 425–8. doi:10.1016/S0035-9203(97)90266-2. PMID 9373640.
- Bozeman FM & Elisberg BL (1963). "Serological diagnosis of scrub typhus by indirect immunofluorescence". Proc Soc Exp Biol Med 112: 568–73. doi:10.3181/00379727-112-28107. PMID 14014756.
- Yamamoto S & Minamishima Y (1982). "Serodiagnosis of tsutsugamushi fever (scrub typhus) by the indirect immunoperoxidase technique". J Clin Microbiol 15 (6): 1128–l. PMC 272264. PMID 6809786.
- Kelly DJ, Wong PW, Gan E, Lewis GE Jr (1988). "Comparative evaluation of the indirect immunoperoxidase test for the serodiagnosis of rickettsial disease". Am J Trop Med Hyg 38 (2): 400–6. PMID 3128129.
- Blacksell SD, Bryant NJ, Paris, DH et al. (2007). "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 44 (3): 391–401. doi:10.1086/510585. PMID 17205447.
- Eamsila C, Singsawat P, Duangvaraporn A et al. (1996). "Antibodies to Orientia tsutsugamushi in Thai soldiers". Am J Trop Med Hyg 55 (5): 556–9. PMID 8940989.
- Watt G, Parola P (2003). "Scrub typhus and tropical rickettsioses". Curr Opin Infect Dis 16 (5): 429–436. doi:10.1097/00001432-200310000-00009. PMID 14501995.
- Tay ST, Nazma S, Rohani MY (1996). "Diagnosis of scrub typhus in Malaysian aborigines using nested polymerase chain reaction". Southeast Asian J Trop Med Public Health 27 (3): 580–3. PMID 9185274.
- Kim, DM; Yun, NR; Yang, TY; Lee, JH; Yang, JT; Shim, SK; Choi, EN; Park, MY; Lee, SH (2006). "Usefulness of nested PCR for the diagnosis of scrub typhus in clinical practice: A prospective study". Am J Trop Med Hyg 75 (3): 542–545. PMID 16968938.
- Sonthayanon P, Chierakul W, Wuthiekanun V et al. (December 2006). "Rapid diagnosis of scrub typhus in rural Thailand using polymerase chain reaction". Am. J. Trop. Med. Hyg. 75 (6): 1099–102. PMID 17172374.
- Kim DM, Byun JN (2008). "Effects of Antibiotic Treatment on the Results of Nested PCRs for Scrub Typhus". J Clin Microbiol 46 (10): 3465–. doi:10.1128/JCM.00634-08. PMC 2566087. PMID 18716229.
- Watt G, Chouriyagune C, Ruangweerayud R et al. (1996). "Scrub typhus infections poorly responsive to antibiotics in northern Thailand". Lancet 348 (9020): 86–89. doi:10.1016/S0140-6736(96)02501-9. PMID 8676722.
- Kollars TM, Bodhidatta D, Phulsuksombati D et al. (2003). "Short report: variation in the 56-kD type-specific antigen gene of Orientia tsutsugamushi isolated from patients in Thailand". Am J Trop Med Hyg 68 (3): 299–300. PMID 12685633.
- Phimda K, Hoontrakul S, Suttinont C et al. (2007). "Doxycycline versus Azithromycin for Treatment of Leptospirosis and Scrub Typhus". Antimicrob Agents Chemother 51 (9): 3259–63. doi:10.1128/AAC.00508-07. PMC 2043199. PMID 17638700.
- Panpanich R, Garner P (2009). "Antibiotics for treating scrub typhus". In Panpanich, Ratana. Cochrane Database Syst Rev (1): CD002150. doi:10.1002/14651858.CD002150. PMID 10796680.
- Mahajan SK, Rolain J-M, Sankhyan N, Kaushal RK, Raoult D (2008). "Pediatric scrub typhus in Indian Himalayas". Indian Journal of Pediatrics 75 (9): 947–9. doi:10.1007/s12098-008-0186-3. PMID 18810342.
- Watt, G; Kantipong, P; Jongsakul, K; Watcharapichat, P; Phulsuksombati, D (1999). "Azithromycin Activities against Orientia tsutsugamushi Strains Isolated in Cases of Scrub Typhus in Northern Thailand". Antimicrob Agents Chemother 43 (11): 2817–2818. PMC 89570. PMID 10543774.
- Choi EK, Pai H (1998). "Azithromycin therapy for scrub typhus during pregnancy". Clin Infect Dis 27 (6): 1538–9. doi:10.1086/517742. PMID 9868680.
- Kim YS, Lee HJ, Chang M, Son SK, Rhee YE, Shim SK (2006). "Scrub typhus during pregnancy and its treatment: a case series and review of the literature". Am J Trop Med Hyg 75 (5): 955–9. PMID 17123995.
- <Please add first missing authors to populate metadata.> (2003). "Efficacy of azithromycin for treatment of mild scrub-typhus infections in South Korea". Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother 43: abstract no. L–182.
- Mathai E, Rolain JM, Verghese L, Mathai M, Jasper P, Verghese G, Raoult D (2003). "Case reports: scrub typhus during pregnancy in India". Trans R Soc Trop Med Hyg 97 (5): 570–2. doi:10.1016/S0035-9203(03)80032-9. PMID 15307429.
- Watt G, Kantipong P, Jongsakul K et al. (2000). "Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial". Lancet 356 (9235): 1057–1061. doi:10.1016/S0140-6736(00)02728-8. PMID 11009140.
- Arguin PM, Kozarsky PE, Reed C (eds.) (2008). [Chapter 4: Rickettsial Infections Chapter 4: Rickettsial Infections]
|chapter-url=missing title (help). CDC Health Information for International Travel, 2008. Mosby. ISBN 0-323-04885-4.
- "AWIC Newsletter: The Cotton Rat In Biomedical Research".
- <Please add first missing authors to populate metadata.> (2 April 1946). "Far East Report". Hansard.
- Thomson Walker W (1947). "Scrub Typhus Vaccine". Br Med J 1 (4501): 484–7. doi:10.1136/bmj.1.4501.484. PMC 2053023. PMID 20248030.
- Shirai A, Tanskul PL, Andre, RG et al. (1981). "Rickettsia tsutsugamushi strains found in chiggers collected in Thailand". Southeast Asian J Trop Med Public Health 12 (1): 1–6. PMID 6789455.
- Kang JS, Chang WH (1999). "Antigenic relationship among the eight prototype and new serotype strains of Orientia tsutsugamushi revealed by monoclonal antibodies". Microbiol Immunol 43 (3): 229–34. doi:10.1111/j.1348-0421.1999.tb02397.x. PMID 10338191.
- Kelly DJ, Fuerst PA, Ching W-M, Richards AL (2009). "Scrub typhus: The geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi". Clinical Infectious Diseases 48 (s3): S203–30. doi:10.1086/596576. PMID 19220144.
- Audy JR (1968). Red mites and typhus. London: University of London, Athlone Press. ISBN 0-485-26318-1.
- Kearny CH (1997). Jungle Snafus...And Remedies. Cave Junction, Oregon: Oregon Institute of Science & Medicine. p. 309. ISBN 1-884067-10-7.
- Smallman-Raynor M, Cliff AD (2004). War epidemics: an historical geography of infectious diseases in military conflict and civil strife, 1850–2000. Oxford: Oxford University Press. pp. 489–91. ISBN 0-19-823364-7.
- William Manchester (1978). "The Green War". American Caesar. Little Brown Company. pp. 297–298. ISBN 0-316-54498-1.
- Manchester, p. Six months to recapture Buna and Gona from July 21–22, 1942
- Ogawa M, Hagiwara T, Kishimoto T et al. (1 August 2002). "Scrub typhus in Japan: Epidemiology and clinical features of cases reported in 1998". Am J Trop Med Hyg. 67 (2): 162–5. PMID 12389941.
- A film clip of the 1945 United States training film "Tsutsugamushi Prevention" is available for free download at the Internet Archive [more]