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Scrub typhus

Scrub typhus

Scrub typhus also known as tsutsugamushi disease or bush typhus, is a disease caused by a bacteria called Orientia tsutsugamushi 1. Scrub typhus is spread to people through bites of infected chiggers (Leptotrombidium larval mites). Approximately 5 to 14 days after being bitten by an infected Leptotrombidium larval mite, patients begin to exhibit manifestations of infection such as non-specific flu-like symptoms, fever, rash, eschar at the bite site, headache, myalgia, cough, generalized lymphadenopathy, nausea, vomiting, and abdominal pain 2. Fever and headache are the most common features among scrub typhus patients. Between 95% and 100% of confirmed cases were noted to have fever in several studies 3. The most common symptoms of scrub typhus include fever, headache, body aches, and sometimes rash. An eschar at the site of chigger feeding is a classic clinical feature of scrub typhus. It begins as a papule at the site of chigger feeding and then ulcerates and forms a black crust like a skin burn from a cigarette. When present, it occurs prior to the onset of fever and other symptoms 4. The presentation of eschar varies from 1%–97% of scrub typhus patients depending on the geographic areas and studies 5. It is more easily found on Caucasian and East Asian patients than on dark skinned South Asian patients 6. Most eschars develop on the front of the body (~80%). In male patients, eschars are primarily within 30 cm below the umbilicus. The other common locations are lower extremities and anterior chest. There is a different pattern in female patients, whose anterior chest, head and neck are the most prevalent areas 7. Eschars are also commonly present in the axillae of children in addition to the sites mentioned above 8.

Scrub typhus is a serious public health problem in the Asia-Pacific area including, but not limited to, Korea, Japan, China, Taiwan, India, Indonesia, Thailand, Sri Lanka, and the Philippines 9. Most cases of scrub typhus occur in rural areas of Southeast Asia, Indonesia, China, Japan, India, and northern Australia (see Figure 2 below). Anyone living in or traveling to areas where scrub typhus is found could get infected. It threatens one billion people globally, and causes illness in one million people each year 9. Scrub typhus can result in severe multiorgan failure with a case fatality rate up to 70% without appropriate treatment 9.

Scrub typhus should be treated with the antibiotic doxycycline. Doxycycline can be used in persons of any age. Antibiotics are most effective if given soon after symptoms begin. People who are treated early with doxycycline usually recover quickly.

Figure 1. Leptotrombidium mites (chiggers)

Leptotrombidium mites

Figure 2. Tsutsugamushi triangle (Scrub typhus area)

Tsutsugamushi triangle

Footnote: Worldwide map of countries with reported scrub typhus cases. The majority of scrub typhus cases occur in the “tsutsugamushi triangle” in the Asia-Pacific area. Countries with human cases are labeled with a star.

[Source 9 ]

Figure 3. Scrub typhus eschar

scrub typhus eschar

Footnote: Lower abdomen of a 33-year-old febrile man from a rural Taiwanese village showing an eschar, a necrotic lesion induced by a mite bite, measuring 15 mm.

[Source 10 ]

Figure 4. Scrub typhus rash

Scrub typhus rash
[Source 11 ]

Scrub typhus causes

Scrub typhus is caused by Orientia tsutsugamushi, an obligate intracellular gram-negative bacterium that lives primarily in Leptotrombidium akamushi (Brumpt) and Leptotrombidium deliense mites. Orientia tsutsugamushi organism is found throughout the mite’s body but is present in the greatest number in the salivary glands. When the mite feeds on rodents (e.g., rats, moles, and field mice, which are the secondary reservoirs) or humans, the parasites are transmitted to the host. Only larval Leptotrombidium mites (chiggers) transmit the disease. Chiggers usually feed on thin, tender or wrinkled skin. The feeding lasts 2 to 4 days 12. It has been shown that chiggers do not pierce the host skin but rather take advantage of hair follicles or pores 4. The saliva that the mites secrete can dissolve host tissue around the feeding site, and the mites ingest the liquefied tissue.

Orientia tsutsugamushi is very similar to the rickettsiae and meets all of the classifications of the genus Rickettsia; this connection is demonstrated by the high degree of homology (90-99%) on 16S ribosomal sequencing. However, the cell walls are quite different, in that those of Orientia tsutsugamushi lack peptidoglycan and lipopolysaccharide 13. This pathogen does not have a vacuolar membrane; thus, it freely grows in the cytoplasm of infected cells.

There are numerous serotypes 14, of which 5—Karp, Gilliam, Kawazaki, Boryon, and Kato—are helpful in serologic diagnosis. About half of isolates are seroreactive to Karp antisera, and approximately one-quarter of isolates are seroreactive to antisera against the prototype Gilliam strain 15.

US scrub typhus cases have been imported from regions of the “tsutsugamushi triangle,” which extends from northern Japan and eastern Russia in the north to northern Australia in the south and to Pakistan and Afghanistan in the west, where the disease is endemic (see Figure 2). The range includes tropical and temperate regions, extending to altitudes greater than 3200 meters in the Himalayas. Scrub typhus is often acquired during occupational or agricultural exposures 16 because active rice fields are an important reservoir for transmission 13.

Risk factors for scrub typhus

In 2009, behavioral factors were shown to be associated with scrub typhus during an autumn epidemic season in South Korea 17. Taking a rest directly on the grass, working in short sleeves, working with bare hands, and squatting to defecate or urinate posed the highest risks. Wearing a long-sleeved shirt while working, keeping work clothes off the grass, and always using a mat to rest outdoors showed protective associations.

Scrub typhus prevention

  • No vaccine is available to prevent scrub typhus.
  • Reduce your risk of getting scrub typhus by avoiding contact with infected chiggers.
  • When traveling to areas where scrub typhus is common, avoid areas with lots of vegetation and brush where chiggers may be found.

If you will be spending time outdoors:

  • Use Environmental Protection Agency (EPA)-registered insect repellents containing DEET or other active ingredients registered for use against chiggers, on exposed skin and clothing (https://www.epa.gov/insect-repellents/find-repellent-right-you).
    • Always follow product instructions.
    • Reapply insect repellent as directed.
    • Do not spray repellent on the skin under clothing.
  • If you are also using sunscreen, apply sunscreen before applying insect repellent.
  • If you have a baby or child:
    • Dress your child in clothing that covers arms and legs, or cover crib, stroller, and baby carrier with mosquito netting.
    • Do not apply insect repellent onto a child’s hands, eyes, or mouth or on cuts or irritated skin.
    • Adults: Spray insect repellent onto your hands and then apply to child’s face.
  • Treat clothing and gear with permethrin or purchase permethrin-treated items.
    • Permethrin kills chiggers and can be used to treat boots, clothing, and camping gear.
    • Treated clothing remains protective after multiple washings. See product information to learn how long the protection will last.
    • If treating items yourself, follow the product instructions carefully.
    • Do NOT use permethrin products directly on skin. They are intended to treat clothing.

Chemoprophylaxis regimens have included the following:

  • A single dose of doxycycline given weekly, started before exposure and continued for 6 weeks after exposure 18
  • A single oral dose of chloramphenicol or tetracycline given every 5 days for a total of 35 days, with 5-day nontreatment intervals

Reports of scrub typhus outbreaks in endemic areas and decreased effectiveness of antibiotic treatment suggest a continued need for a suitable vaccine 19.

Scrub typhus symptoms

Symptoms of scrub typhus usually begin within 10 days of being bitten. Signs and symptoms may include:

  • Fever and chills
  • Headache
  • Body aches and muscle pain
  • A dark, scab-like region at the site of the chigger bite (also known as eschar)
  • Mental changes, ranging from confusion to coma
  • Enlarged lymph nodes
  • Rash. About 25–50% of scrub typhus patients develop a rash. The rash is usually macular or maculopapular. Typically, it will begin on the abdomen of an infected individual and then spread to the extremities. Petechiae are uncommon.
  • The area around the bite may develop a necrotic skin lesion known as an eschar (see Figure 3). The eschar may appear before the individual begins to develop systemic symptoms. Common sites of an eschar are axilla, under the breast, and groin, and less often on the abdomen, back, and extremities. Multiple eschars have been reported.

Elements brought out in the history may include the following:

  • Travel to an area where scrub typhus is endemic
  • Chigger bite (often painless and unnoticed)
  • Incubation period of 6-20 days (average, 10 days)
  • Headaches, shaking chills, lymphadenopathy, conjunctival injection, fever, anorexia, and general apathy
  • Rash; a small, painless, gradually enlarging papule, which leads to an area of central necrosis and is followed by eschar formation

People with severe illness may develop organ failure and bleeding, which can be fatal if left untreated.

The symptoms of scrub typhus are similar to symptoms of many other diseases. See your health care provider if you develop the symptoms listed above after spending time in areas where scrub typhus is found.

Physical findings may include the following 20:

  • Site of infection marked by a chigger bite
  • Eschar at the inoculation site (in about 50% of patients with primary infection and 30% of those with recurrent infection)
  • High fever (104-105°F [40-40.5°C]), occurring more than 98% of the time
  • Tender regional or generalized lymphadenopathy, occurring in 40-97% of cases
  • Less frequently, ocular pain, wet cough, malaise, and injected conjunctiva
  • Centrifugal macular rash on the trunk
  • Enlargement of the spleen, cough, and delirium
  • Pneumonitis or encephalitis
  • Central nervous system (CNS), pulmonary, or cardiac involvement
  • Rarely, acute renal failure, shock, and disseminated intravascular coagulation (DIC)

Most patients have thrombocytopenia and may also show elevated levels of liver enzymes, bilirubin, or creatinine. Enlargement of the spleen and liver may be observed. Severe manifestations usually develop after the first week of untreated illness and may include multiple organ dysfunction syndrome with hemorrhaging, acute respiratory distress syndrome, encephalitis, pneumonia, renal or liver failure, and even death. During pregnancy, scrub typhus frequently leads to spontaneous abortion. Relapses may occur following apparent recovery in cases where inadequate treatment has occurred. Relapse is usually less severe than the initial presentation.

Scrub typhus complications

Severe complications such as multiorgan failure occur in some cases. The severe multiorgan manifestations include jaundice, acute renal failure, pneumonitis, acute respiratory distress syndrome (ARDS), myocarditis, septic shock, meningoencephalitis, pericarditis, and disseminated intravascular coagulation (DIC) 21. The lung is one of the main target organs for Orientia, leading to pulmonary complications of variable severity. Interstitial pneumonia may occur in severe cases 2. Meningitis and/or encephalitis can develop in severe illness, causing patients to become agitated, delirious or even have seizures. Focal neurological signs are rare but have been known to occur. Laboratory tests may demonstrate changes in cerebrospinal fluid similar to those found in viral or tuberculous meningitis 22. Patients may also develop the complications of hearing loss or hearing impairment during scrub typhus infection 23. The case fatality rate of scrub typhus varies among different countries, regions, and areas as well as different studies 24. The case fatality can be up to 30–70% if no appropriate treatment is received while the median case fatality rate for untreated patients is 6% and for treated patient is 1.4% 25. Therefore, development of effective measures to treat, control and prevent the disease is a critical public health issue.

Scrub typhus diagnosis

Diagnosing scrub typhus early in its course can be difficult because many conditions can present with a high fever; however, the presentation of the rash, a history of exposure to endemic areas, and the presentation of the sore caused by the bite can be diagnostic. If you have recently traveled, tell your health care provider where and when you traveled.

A reliable diagnostic laboratory test in the early phase of scrub typhus illness is not currently available; therefore, scrub typhus diagnosis is based on clinical findings and epidemiologic setting. Treatment should never be withheld pending diagnostic tests.

Your health care provider may order blood tests to look for scrub typhus or other diseases. Laboratory testing and reporting of results can take several weeks, so your health care provider may start treatment before results are available.

Laboratory studies in patients with scrub typhus may reveal the following:

  • Early lymphopenia with late lymphocytosis
  • Decreased CD4:CD8 lymphocyte ratio
  • Thrombocytopenia
  • Hematologic manifestations may be confused with dengue infection
  • Elevated transaminase levels (75-95% of patients)
  • Hypoalbuminemia (50% of cases)

Laboratory studies of choice are serologic tests for antibodies, including the following:

  • Indirect immunoperoxidase test (IIP)
  • Indirect fluorescent antibody test (IFA)
  • Dot immunoassay
  • Rapid immunochromatographic tests for detection of IgM and IgG
  • Polymerase chain reaction (PCR) assay
  • Rapid diagnostic reagent for scrub typhus
  • Weil-Felix OX-K strain agglutination reaction

Chest radiography may reveal pneumonitis, especially in the lower lung fields.

Serologic assays are the most frequently used methods for confirming cases of scrub typhus. The indirect immunofluorescence assay (IFA) is generally considered the reference standard, but is usually not available in developing countries where this disease is endemic. Other serological tests include ELISA and indirect immunuoperoxidase (IIP) assays. Weil-Felix OX-K agglutination assays may be used in some international settings but lack sensitivity and specificity and are not generally used in the United States. These assays can detect either IgG or IgM antibodies. Diagnosis is typically confirmed by documenting a four-fold rise in antibody titer between acute and convalescent samples. Acute specimens are taken during the first week of illness and convalescent samples are taken 2–4 weeks later. IgG antibodies are considered more accurate than IgM, but detectable levels of IgG antibody generally do not appear until 7–10 days after the onset of illness.

Because antibody titers may persist in some individuals for years after the original exposure, only demonstration of recent changes in titers between paired specimens can be considered reliable confirmation of an acute scrub typhus infection. The most rapid and specific diagnostic assays for scrub typhus rely on molecular methods like polymerase chain reaction (PCR), which can detect DNA in a whole blood, eschar swab or tissue sample. Immunostaining procedures can also be performed on formalin-fixed tissue samples. Since scrub typhus is not common in the United States, confirmatory tests are not typically available at state and local health departments; nonetheless, indirect immunofluorescence assay (IFA), culture, and PCR (polymerase chain reaction) assays can all be performed at the Centers for Disease Control and Prevention (CDC) through submission from state health departments.

Scrub typhus treatment

Doxycycline is the treatment of choice for suspected scrub typhus in persons of all ages. Recommended dosages of doxycycline 26:

  • Adults: 100 mg twice per day
  • Children under 45 kg (100 lbs): 2.2 mg/kg body weight twice per day

Treatment alternatives primarily for patients with severe doxycycline allergy or women who are pregnant include azithromycin, chloramphenicol, or rifampin. Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Single-dose or short courses of doxycycline may lead to a relapse in illness.

Scrub typhus prognosis

Scrub typhus prognosis varies and depends on the severity of illness, which relates to the different strains of Orientia tsutsugamushi, as well as to host factors. Severe disease is uncommon with antimicrobial treatment. Prognostic indicators for severe disease have not been established 27. Incomplete immunity and strain heterogeneity open the door to frequent reinfections. Immunity to the same strain is believed to last 3 years, whereas immunity to other strains may last as little as 1 month; however, repeat infections may be attenuated 13.

In patients who are not treated, mortality ranges from 1% to 60%, depending on the patient’s age, the geographic area, and the particular strain responsible for the infection. In the preantibiotic era, mortality in Japan averaged 30%: 15% in patients aged 11-20 years, 20% in those aged 21-30 years, and 59% in those older than 60 years. In Taiwan, overall mortality was estimated at 11% but was only 5% in children and 45% in the elderly.

With appropriate antibiotic treatment, mortality from scrub typhus is quite rare, and the recovery period is short and usually without complications 28. However, mortality is still approximately 15% in some areas as a consequence of missed or delayed diagnosis 29. If severe complications such as acute respiratory distress syndrome (ARDS) arise, mortality may still be high 30.

References
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