Scrub Typhus (Orientia tsutsugamushi)

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Chapter 221 Scrub Typhus (Orientia tsutsugamushi)

Megan E. Reller, J. Stephen Dumler

Scrub typhus is an important cause of acute febrile illness in South and East Asia and the Pacific. Recent reports suggest the emergence of doxycycline-resistant strains. Concurrent scrub typhus can inhibit the replication of HIV virus.

Etiology

The causative agent of scrub typhus, or tsutsugamushi fever, is Orientia tsutsugamushi, which is distinct from other spotted fever and typhus group rickettsiae (see Table 220-1). O. tsutsugamushi lacks both lipopolysaccharide and peptidoglycan in its cell wall. Like other vasculotropic rickettsiae, O. tsutsugamushi infects endothelial cells and causes vasculitis, the predominant clinicopathologic feature of the disease. However, the organism also infects cardiac myocytes and macrophages.

Epidemiology

Approximately 1 million infections occur each year, and it is estimated that more than 1 billion people are at risk. Scrub typhus occurs mostly in Asia, including areas delimited by Korea, Pakistan, and northern Australia. Outside these tropical and subtropical regions, the disease occurs in Japan, the Primorye of far eastern Russia, Tajikistan, Nepal, and nontropical China, including Tibet. Cases imported to the USA and other parts of the world are reported. Most infections in children are acquired in rural areas. In Thailand, scrub typhus is the cause of 1-8% of acute fevers of unknown origin. Infections are most common during rainy months, usually June through November. Reported cases in boys are higher than in girls.

Transmission

O. tsutsugamushi is transmitted via the bite of the larval stage (chigger) of a trombiculid mite (Leptotrombidium), which serves as both vector and reservoir. Transovarial transmission (passage of the organism from infected ticks to their progeny) and transmission of the organism from infected animals to mites both occur. Because only the larval stage takes blood meals, a role for horizontal transmission from infected rodent hosts to uninfected mites has not been proved. Multiple serotypes of O. tsutsugamushi are recognized, and some share antigenic cross reactivity; however, they do not stimulate protective cross immunity.

Pathology and Pathogenesis

The pathogenesis of scrub typhus is uncertain. Recent studies suggest that the process is stimulated by widespread infection of vascular endothelial cells, which corresponds to the distribution of disseminated vasculitic and perivascular inflammatory lesions observed in histopathologic examinations. In autopsy series, the major result of the vascular injury appears to be hemorrhage. However, it is very likely that the vascular injury initiated by the infection is sustained by immune-mediated inflammation that together cause significant vascular leakage. The net result is significant vascular compromise and ensuing end-organ injury, most often manifested in the brain and lungs, as with other vasculotropic rickettsioses.

Clinical Manifestations and Laboratory Findings

Scrub typhus can be mild or severe in children. Most patients present with fever for 9-11 days (range, 1-30 days) before seeking medical care. Regional or generalized lymphadenopathy is reported in 23-93% of patients, hepatomegaly in about two thirds, and splenomegaly in about one third of children with scrub typhus. Gastrointestinal symptoms, including abdominal pain, vomiting, and diarrhea, occur in up to 40% of children at presentation. A single painless eschar with an erythematous rim at the site of the chigger bite is seen in 7-68% of cases, and a maculopapular rash is present in <30%. Leukocyte and platelet counts are most commonly within normal ranges, although thrombocytopenia occurs in one quarter to one third of children, and leukocytosis is observed in about 40%.

Diagnosis and Differential Diagnosis

Owing to the potential for severe complications, diagnosis and decision to initiate treatment should be based on clinical suspicion and confirmed by O. tsutsugamushi serologic tests such as indirect fluorescent antibody (IFA) or immunoperoxidase assays. The IFA assay is 92% sensitive with ≥11 days of fever. Although the rickettsiae can be cultivated using tissue culture methods, and polymerase chain reaction tests appear highly sensitive, these diagnostic methods are not widely available. The differential diagnosis includes fever of unknown origin, enteric fever, typhoid fever, dengue hemorrhagic fever, other rickettsioses, tularemia, anthrax, dengue, leptospirosis, malaria, and infectious mononucleosis.

Treatment and Supportive Care

The recommended treatment regimen for scrub typhus is doxycycline (4 mg/kg/day PO or IV divided every 12 hr, maximum 200 mg/day). Alternative regimens include tetracycline (25-50 mg/kg/day PO divided every 6 hr, maximum 2 g/day) or chloramphenicol (50-100 mg/kg/day divided every 6 hr IV, maximum 4 g/24 hr). If used, chloramphenicol should be monitored to maintain serum concentrations of 10-30 µg/mL. Therapy should be continued for a minimum of 5 days and until the patient has been afebrile for ≥3 days to avoid relapse. However, a single dose of oral doxycycline was reported effective for all 38 children treated with this regimen in a large series of children with scrub typhus from Thailand. Most children respond rapidly to doxycycline or chloramphenicol within 1-2 days (range, 1-5 days). Highly virulent or potentially doxycycline-resistant O. tsutsugamushi strains have emerged in some regions of Thailand. Clinical trials showed that azithromycin may be as effective and that rifampicin is superior to doxycycline in such cases. Likewise, a retrospective analysis in Korean children with scrub typhus showed that roxithromycin was as effective as either doxycycline or chloramphenicol, suggesting a role as an alternative therapy for children or pregnant women. The use of ciprofloxacin in pregnant women resulted in an adverse outcome in 5 of 5 pregnancies among Indian women. Intensive care may be required for hemodynamic management of severely affected patients.

Complications

Serious complications include pneumonitis in 20-35% and meningoencephalitis in approximately 10% of children. Acute renal failure, myocarditis, and a septic shock–like syndrome occur much less often. Cerebrospinal fluid examination shows a mild mononuclear pleocytosis with normal glucose levels. Chest x-rays reveal transient perihilar or peribronchial interstitial infiltrates in most children who are examined. The case fatality rate in untreated patients may be as high as 30% if left untreated, although deaths in children are uncommon.

Prevention

Prevention is based on avoidance of the chiggers that transmit O. tsutsugamushi. Protective clothing is the next most useful mode of prevention. Infection provides immunity to reinfection by homologous but not heterologous strains; however, because natural strains are highly heterogeneous, infection does not always provide complete protection against reinfection.

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