Unresolved problems related to scrub typhus: a seriously neglected life-threatening disease.

Ecology and epidemiology. Scrub typhus is a life-threatening infectious disease that presents as an acute undifferentiated febrile illness. Its agent,Orientia tsutsugamushi, is an obligately intracytosolic bacterium that is transmitted by feeding larval trombiculid mites, which are the reservoir of the agent and the only life stage that feeds on a vertebrate host. Nymphal and adult trombiculid mites live in the soil and feed on the eggs of insects. Mites maintain the organisms by transovarian transmission as well as transtadial transmission through the mite’s lifecycle. Although mites transmit O. tsutsugamushi to vertebrate hosts such as rodents, only a small proportion of uninfected mites acquire Orientia during feeding on infected animals, and the ingested Orientia do not establish disseminated infection in the mites and are not transmitted transovarially to the next generation. It seems that chigger cofeeding on rodents is more relevant for effective mouseto-mite transmission of Orientia than feeding on rickettsemic hosts. Thus, the true role of rodents as reservoirs requires additional investigation, because there may be marked genetic variability in chiggers with respect to the ability to acquire rickettsiae by feeding. Also, rodents may be better considered as dead-end hosts just as humans are rather than a reservoir. However, the evolutionary selection of tremendous antigenic diversity of the immunodominant major 56 kDa surface protein presents an enigma if immune variation plays no role in survival of O. tsutsugamushi. The potential immunomodulatory effects of the saliva of larval mites on the pathogenesis of and immunity to infection with O. tsutsugamushi remain undetermined. One million cases of scrub typhus occur each year with an estimated 10% case fatality rate unless treated appropriately, very likely resulting in more deaths than dengue. Currently, scrub typhus has predominantly been reported from an area extending from the Russian Far East and Korea in the north to northern Australia in the south and Afghanistan in the west, and it includes islands of the western Pacific and Indian Oceans, including Japan, Taiwan, Philippines, Papua New Guinea, Indonesia, and Sri Lanka. This geographical range may be an underrepresentation, because case reports have been published from Africa and South America. The recent isolation of a novel species O. chuto acquired by a patient in Dubai, the detection of another divergentOrientia transmitted to a patient in Chile, and serologic diagnoses of scrub typhus acquired in Africa indicate that a wider geographic distribution and genetic diversity of the genus should be investigated. The burden of disease in rural areas of Asia is large, with studies showing scrub typhus causing up to 20% of febrile hospital admissions, an incidence of infections of greater than 3% of the population monthly, seroprevalence over 50% of the population, despite a significant annual rate of reversion to seronegativity of 50% of cases, and a seroconversion rate of 484 per 1,000 person-years. In 1999, the World Health Organization (WHO) stated, “Scrub typhus is probably one of the most underdiagnosed and underreported febrile illnesses requiring hospitalization in the region. ” This opinion remains valid today and could justifiably be adjusted to scrub typhus is probably the single most prevalent, under-recognized, neglected, and severe but easily treatable disease in the world. This ancient disease is currently undergoing increased awareness both because of re-emergence and rising incidence in previously unrecognized areas and improved diagnostic testing. It is apparent that scrub typhus has been recognized to occur frequently now in places where the illness was nearly forgotten, including India, Sri Lanka, the Maldives, and Micronesia. However, scrub typhus has also emerged in regions north of the Yangtse River in China, where it was not known previously. The emergence of scrub typhus should also take into consideration the expansion of farmlands that have generated ideal habitats for trombiculid mites. The potential relationship with global climate change is unclear. Greater recognition in some countries, such as Thailand, Laos, Taiwan, and Japan, may reflect increased medical investigations and application of new diagnostic methods. The critical unresolved issues regarding epidemiology emphasize the need to determine the reasons for emergence and re-emergence and the true incidence of this neglected disease, for which calculated days of disability-adjusted years of life lost (DALYs) have not been determined and to which appropriate attention has not been paid (Table 1). Clinical manifestations. Scrub typhus ranges from a mild to a fatal illness. The early clinical manifestations are an eschar, representing localized cutaneous necrosis at the site of mite feeding (which is not always present), and regional lymphadenopathy followed subsequently by fever, headache, myalgia, generalized lymphadenopathy, cough, gastrointestinal symptoms, transient hearing loss, and rash. Progression of severe scrub typhus may manifest as acute respiratory distress, meningoencephalitis, gastrointestinal bleeding, acute renal failure, hypotensive shock, and coagulopathy. Unresolved clinical issues include the reason for the wide range of occurrence of eschars (7–97%), the reason for rash and severity of illness, and the need for characterization and determination of the mechanisms of the coagulopathy, hemorrhages, interstitial pneumonia, and meningoencephalitis. There is currently no unified approach to assess and stratify *Address correspondence to David H. Walker, Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609. E-mail: dwalker@utmb.edu