Scrub typhus is an acute zoonotic rickettsial disease caused by infection with the bacteria Orientia tsutsugamushi, which is transmitted to humans by the bite of larval trombiculid mites. Patients develop fever, a maculopapular rash, and lymphadenopathy.
Expanding the panel of antigens used for diagnosis and increasing sensitivity of serologic assays is necessary to identify new genotypes.
Signs & Symptoms
Scrub typhus is an acute zoonotic rickettsial disease caused by Orientia tsutsugamushi, an obligate intracellular Gram-negative bacteria. It is transmitted to humans by the bites of infected larval trombiculid mites, also known as chiggersFotnote 17 and occurs mostly in South and Southeast Asia and the Asia-Pacific region. However, scrub typhus has been reported in Chile and parts of AfricaFotnote 18.
Orientia tsutsugamushi invades human cells through the action of cell surface heparan sulfate proteoglycans that are found on the chigger larvae and host skin. Once internalized, it escapes from phagosomes and proliferates in the cytoplasm. It is spread to other eukaryotic cells by budding, similar to the way that enveloped viruses are spread.
Histologically, scrub typhus presents with focal and systemic vasculitis, primarily of small vessels. Vascular damage tends to be less severe than in Rocky Mountain spotted fever. Often, there is lymphohistiocytic perivascular infiltrates with vascular wall necrosis and thrombosis. Occasionally, glomerular vasculitis may be present.
The disease manifests with a high fever, headache, obtundation and dry cough. A maculopapular rash with an inoculation eschar at the site of the mite bite is found in about 50% of patients. Lymphadenopathy is common and splenomegaly can occur in 1/3 of cases. The prognosis is generally good but pneumonia, meningoencephalitis and multiorgan failure, especially when untreated, have been reported.
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The diagnosis of scrub typhus is made by clinical symptoms, patient history and laboratory tests, particularly increased transaminases, leukocytosis, and thrombocytopenia. A PCR test for O. tsutsugamushi can be performed on eschar and/or EDTA blood samples from the acute phase of the illness. Alternatively, Giemsa and Gimenez staining of the eschar and EDTA blood can be used to detect O. tsutsugamushi. Immunohistochemistry of the eschar can be useful for diagnosing the disease as well. Other useful diagnostic tests include ELISA and indirect immunofluorescence for antibodies to O. tsutsugamushi antigensFotnote 22. The bacterium is resistant to most antibiotics. Therefore, antibiotic treatment should be started only after confirmation of the infection. The duration of antibiotic therapy is usually 14 days. Relapses are rare after completing the course of antibiotics.
Diagnosis
Scrub typhus is an acute zoonotic rickettsial infection caused by Orientia tsutsugamushi, which is transmitted to humans through the bite of larval trombiculid mites (chiggers). It typically affects people living in tropical regions and has a high fatality rate in untreated cases. In endemic areas, it is an important cause of febrile illness. The disease is often underestimated by both health care professionals and the public. The incidence of tsutsugamushi disease is increasing in many endemic countries. This increase may be due to a combination of factors, including increased population growth, urbanization leading to changes in land use, diagnostic tests that allow more accurate case reporting and antimicrobial resistance.
The first clinical accounts of a fever associated with chiggers appear in an 1810 Chinese medical text called ‘Zhouhofang’ and in a 1917 report from Niigata prefecture in Japan. The term ‘Japanese river fever’ was later used in the literature to describe these mite-associated fevers. The causative organism was identified in 1930 and subsequently named Rickettsia orientalis. It is placed in a separate genus from other members of the family Rickettsia because it exhibits significant sequence divergence.
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Symptoms of scrub typhus are similar to other rickettsial infections and can include fever, headache, myalgia, obtundation and a dry cough. A pale maculopapular rash is also usually present, and an inoculation site eschar is observed in 50% to 90% of patients. Splenomegaly, a condition in which the lymph nodes become enlarged, is seen in 1/3 of cases. In severe cases, multiorgan failure, such as pneumonitis, meningoencephalitis and bleeding occurs.
During the Second World War, scrub typhus had a profound effect on military personnel in a number of endemic areas. The highest mortality rate was among United States troops along the Pacific coast of Japan between 1 November 1943 and 1 September 1944, with a total of 1098 scrub typhus cases and 8.9% death rates reported [84]. In contrast, a lower death rate was seen in British Army soldiers during the same period. A possible explanation for this difference is the variation in serotypes of O tsutsugamushi between different endemic areas, which may influence the severity of symptoms and the course of the disease.
Treatment
The bacterial agent that causes scrub typhus, Orientia tsutsugamushi, is an obligate intracellular Gram-negative rod bacteria. The organism is transmitted to humans by the bites of larval trombiculid mites (chiggers).
After a silent incubation period of 10 days or more, the disease begins with acute fever and a headache followed by obtundation, fatigue, myalgia, vomiting, a pale macular rash and an inoculation eschar at the site of the chigger bite. Lymphadenopathy is common, including painful satellite lymph nodes. In severe cases, multiple organ failure and death may occur.
Symptoms and signs of scrub typhus are similar to those of many other zoonotic tick-borne diseases, so accurate diagnosis is challenging. A patient’s history of travel to endemic areas, a characteristic rash, a positive hemagglutination assayFootnote 43 and indirect immunofluorescence testingFootnote 44 with antibody directed against O. tsutsugamushi may all be useful in making the diagnosis.
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A PCR assayFootnote 45 can confirm O. tsutsugamushi antigens in a patient’s blood or eschar sample, but this test is not widely available. Indirect immunoperoxidase and ELISA-based testsFootnote 36 are rapid methods with high specificity for O. tsutsugamushi antibodies.
Treatment of scrub typhus is usually successful, but in some patients the bacterium becomes resistant to antibioticsFootnote 46. Antibiotic resistance is a serious problem that requires increased awareness by medical professionals and the public.
Scrub typhus is an important cause of febrile illness in people who live and work in rural, tropical environments. It is also an important cause of disease and disability in the military, as well as among travelers to endemic areas. Infection is particularly dangerous for infants, older adults and immunocompromised individuals. Although scrub typhus is often misdiagnosed, it is a treatable and preventable disease. The development of an effective vaccine is a major goal. In the meantime, diligent insect repellent use and careful patient education are important for prevention of chigger bites. Also, patients with high risk factors should have an annual screening for chiggers. If a patient develops a rash after a recent chigger bite, immediate diagnosis and treatment with an appropriate antibiotic is recommended.
Prevention
Known as scrub typhus or mite-borne typhus, tsutsugamushi disease is a febrile illness caused by the bacteria Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi). Like other diseases in the order of rickettsial diseases, tsutsugamushi is transmitted by the bite of trombiculid mites, namely chiggers or Leptotrombidium scutellare and L. pallidum. In humans, the bacteria are transmitted through a primary lesion called a macular rash and lymphadenopathy. Scrub typhus is endemic to an area of the Asia-Pacific that extends from northern Japan and Korea to India and Australia. During World War II and the Korean and Vietnam conflicts, it was one of the most common causes of acute febrile illness among military personnel stationed in endemic areas.
Although the name scrub typhus derives from the shrub vegetation in which it has historically occurred, the disease is not limited to such environments and can be found in sandy beaches, mountain deserts, and equatorial rain forests as well. It is also endemic to a broad region referred to as the Tsutsugamushi Triangle, an area that includes Northern Japan, Korea, Southeast Asia, and the Southwest Pacific from Thailand in the west to Pakistan in the east.
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While in its natural host, Orientia tsutsugamushi can be maintained by vertical transmission from infected larvae to earlier instars (protonymph and deutonymph) or horizontal transmission via the chiggers themselves. Humans can be infected with O tsutsugamushi by consuming contaminated food or water, and they may be infected through accidental or purposeful contact with chiggers that are themselves feeding on a human host.
Because the tsutsugamushi bacterium is resistant to many commonly used antibiotics, tsutsugamushi infection is becoming a significant problem worldwide. The spread of this infection is likely related to increasing travel and tourism, increased population growth in endemic regions, urbanization that alters land use, and the availability of specific diagnostic tests and changes in antimicrobial prescribing practices. Additionally, the discovery of new Orientia species that cause scrub typhus and other rickettsial diseases has led to concerns about global distribution of these pathogens and the need for improved epidemiologic surveillance. Despite these challenges, researchers continue to advance in vaccine and diagnostic research for tsutsugamushi and other rickettsial diseases.
