Scrub Typhus

Bush Fever
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Diagnosis and reasoning

Infectious disease specialists often have to deal with diseases from other countries - particularly the tropics; this young man is a good case in point. Returning from India after a military training course, he has presented with fever and a rash; this is a potential diagnostic dilemma encompassing a wide range of diagnoses: malaria, typhoid, typhus, leptospirosis, and arbovirus infections - particularly dengue fever. However, the examination finding of an ulcer in the groin with a central crust and erythematous halo provides a potent diagnostic clue, as it is highly suggestive of the pathognomonic eschar of scrub typhus. While the clinical and laboratory features of scrub typhus are notoriously non-specific, the reactive Indirect Fluorescence Antibody Test (IFA) combined with the supportive history and examination clinches the diagnosis. Note that symptomatic pleuropulmonary disease and pneumonitis are well documented in scrub typhus; the cough and infiltrates on chest X-ray are most likely due to this. While a blood culture is unnecessary for diagnostic purposes, this should be obtained anyway prior to commencement of antibiotic therapy. Thus, if the patient fails to achieve defervescence within 48 hours and a search for alternate possibilities has to be conducted, microbiological analysis will still be possible. Treatment with doxycycline has to be initiated without delay to abort progression of the disease. In-patient care is essential, as seemingly mild respiratory symptoms can presage the development of potentially fatal Acute Respiratory Distress Syndrome (ARDS). Isolation is not required, as the disease can only be transmitted to another human by the bite of an infected mite. The WHO recommends immediate case-based reporting of all suspected or confirmed cases in order to achieve a better understanding of the epidemiology of the disease and to aid the detection of outbreaks.


Discussion

Scrub typhus is an acute febrile illness endemic in many parts of Asia including India; it is caused by the obligate Gram negative bacterium Orientia tsutsugamushi. The disease is transmitted to humans by the bite of the larval stage of infected trombiculid mites; this typically occurs when individuals accidently encroach upon mite infested areas. The bacteria subsequently multiply at the inoculation site, and a papule forms that enlarges, ulcerates and undergoes central necrosis, evolving into an eschar with an erythematous halo. Note that this lesion is pathognomonic of the disease; it usually heralds the onset of symptoms. While the eschar is of critical diagnostic significance, it is often grossly undetected, as the lesions are usually painless and bereft of any itching sensation; thus a careful clinical examination is key towards their detection. Following the incubation period of 6 to 20 days, patients may experience generalized headache, lymphadenopathy, conjunctival injection, high fever, chills and rigors, anorexia, nausea, myalgia and apathy. The duration of scrub typhus is variable; it may last from 14 to 21 days without treatment. With progression of the disease, approximately 35% of patients develop a centrifugal maculopapular rash on the trunk. Additional symptoms include splenomegaly and a productive cough; in severe cases, delirium, pneumonitis, congestive heart failure, encephalitis and circulatory collapse may develop. Although the diagnosis of scrub typhus relies principally on clinical recognition aided by epidemiological considerations, confirmation of the diagnosis requires laboratory studies. The mainstay of laboratory diagnosis is serological tests. The Weil-Felix reaction is the most widely used, probably due to easy accessibility and simplicity to perform; however, a positive test only allows for a presumptive diagnosis, while a negative test does not necessarily exclude the disease. Currently, the most reliable diagnostic technique is the Indirect Fluorescence Antibody (IFA) Test. Other diagnostic tests include Rapid Immunochromatographic Tests for detection of IgM and IgG antibodies to certain specific antigens, Enzyme Linked Immunosorbent Assay(ELISA), Polymerase chain reaction (PCR) assays and the rapid diagnostic reagent for scrub typhus. Additional findings that may support the diagnosis include early lymphopenia with late lymphocytosis, thrombocytopenia, elevated transaminase levels and hypoalbuminemia. Histopathology may reveal perivasculitis of the small blood vessels; note that this is common to virtually any rickettsial infection. The treatment of scrub typhus primarily consists of antibiotic therapy and supportive care. Tetracycline derivatives (especially doxycycline) are the mainstay of treatment, while macrolides and fluoroquinolones can also be used. Patients with severe scrub typhus are at risk of progression into Disseminated Intravascular Coagulation (DIC); meticulous supportive care including complete bed rest, good nursing care, adequate diet, and proper attention to fluid and salt balance is important in avoiding this. Patients treated with appropriate antibiotics characteristically become afebrile within 48 hours of starting therapy. This response to treatment may be useful diagnostically; lack of defervescence within 48 hours is often considered to be evidence that scrub typhus is not present, and that an alternate diagnosis such as malaria or dengue should be considered instead. Scrub typhus is grossly undetected due to nonspecificity of clinical findings and limited availability of specific laboratory tests; as such the disease caused significant mortality in the pre antibiotic era. However, prompt diagnosis and treatment have brought down mortality dramatically in the recent past. Appropriate preventive measures should be take when visiting endemic areas; these include wearing protective clothing, and using insect repellents (diethyl toluamide, dibutyl phthalate, benzyl benzoate). Chemoprophylaxis with doxycycline is also recommended; chloramphenicol may instead be used. At the time of writing, there is no commercially available vaccine for scrub typhus.


Take home messages

  1. Scrub typhus is endemic in many parts of Asia including India; it is caused by a microbe transmitted to humans by the bite of an infected mite.
  2. The Eschar which occurs at the site of inoculation site is pathognomonic of the disease.
  3. The Weil-Felix reaction is neither sensitive nor specific for the disease; any results should be interpreted with caution.
  4. The Indirect Fluorescence Antibody (IFA) Test is the current gold standard for diagnosis.
  5. Doxycycline is the mainstay of antibiotic therapy.

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