INTRODUCTION — Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi). It is distributed throughout the Asia Pacific rim, being endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia, and northern portions of Australia. However, cases also occur in the United States, Canada, and Europe, being imported by tourists returning from endemic regions.
Scrub typhus is manifested clinically by high fever, intense generalized headache, diffuse myalgias, and, in many patients, rash and an eschar at the site of the chigger bite. The diagnosis is suggested by the clinical history (including visit to an endemic area) and physical findings and confirmed by serologic testing or biopsy of an eschar. (See "Scrub typhus: Clinical features and diagnosis".)
COURSE — Scrub typhus lasts for 14 to 21 days without treatment. Severe infections may be complicated by interstitial pneumonia, pulmonary edema, congestive heart failure, circulatory collapse, and a wide array of signs and symptoms of central nervous system dysfunction, including delirium, confusion, and seizures. Death may occur as a result of these complications, usually late in the second week of the illness.
By contrast, patients treated with appropriate antibiotics typically become afebrile within 48 hours of starting therapy [1]. This response to treatment may be useful diagnostically; failure of defervescence within 48 hours is often considered evidence that scrub typhus is not present, and that an alternate diagnosis such as malaria or dengue should be considered. However, in a 2004 report, 20 of 93 patients with serologically confirmed scrub typhus had a delay in defervescence to more than 48 hours, making the reliability of this long-standing clinical truism suspect [2]. The authors of another report retrospectively examined the clinical characteristics of 18 patients with Q fever (9), scrub typhus (7) or murine typhus (2) who failed to respond within 48 hours to treatment with doxycycline and compared their clinical features to 88 cases who responded promptly. Delayed defervescence was associated with jaundice and relative bradycardia [3].
TREATMENT
Choice of agent — Doxycycline (100 mg orally or intravenously twice daily) is the drug of choice for this illness. Azithromycin has been advocated as an alternative agent. (See 'Azithromycin' below.)
Chloramphenicol was the first drug shown to be effective in the treatment of scrub typhus, and is still commonly used in endemic regions. Doses of 250 to 500 mg orally or intravenously every six hours are effective.
An analysis of all treatment trials for scrub typhus published prior to 2000 concluded that only three trials comparing the efficacy of doxycycline and chloramphenicol were adequately designed to assess the two most relevant outcomes: time to resolution of fever and incidence of relapse. These three studies found no significant differences in outcomes in patients treated with doxycycline and those patients treated with chloramphenicol [4]. However, these studies were performed before the recognition that some strains of O. tsutsugamushi have reduced susceptibility to tetracyclines. Also, these studies did not examine the potentially important relationship between delays in treatment and outcome. In a retrospective review of 92 cases of severe rickettsial infection (that included 34 cases of proven scrub typhus), delayed administration of doxycycline was independently associated with the development of major organ dysfunction (OR 1.2; CI 1.0-1.5) and hospitalization >10 days (OR 1.4; CI 1.1-1.9) [5].
Duration — The optimal duration of therapy is uncertain. Although regimens as short as one day of doxycycline (400 mg given in two divided doses) have been advocated for the therapy of scrub typhus [6], it has been suggested that short courses of doxycycline or chloramphenicol are associated with an increased risk of relapse. In one study of three-day therapy, relapse occurred in three of seven patients treated with chloramphenicol and three of six treated with doxycycline; in comparison, no relapses were noted in 37 patients treated with either regimen for five days or longer [1].
However, subsequent larger trials have found short course therapy to be effective:
●In a multicenter trial, 116 patients with scrub typhus were randomized to receive seven days of tetracycline (500 mg four times daily) or three days of doxycycline (100 mg twice daily) [7]. The patients were followed for four weeks after completing therapy. The cure rate was 100 percent in the tetracycline group, and 94 percent in the doxycycline group. There were no relapses with either regimen.
●A randomized open-label treatment trial in South Korea (where strains of O. tsutsugamushi that have reduced susceptibility to tetracycline are thought to be uncommon) compared azithromycin with doxycycline for mild disease [2]. Ninety-three patients were assigned to receive a single dose of azithromycin (500 mg) or seven days of doxycycline (200 mg daily). Both antibiotics were clinically effective in reducing the number of days with fever, and at one-month follow-up, no relapses were observed in either group.
Pregnancy — Scrub typhus may cause spontaneous abortions or stillbirths in pregnant women [8-10]. As an example, a literature review that included information on 55 pregnant women with scrub typhus (including 3 who had both scrub typhus and malaria) found that 24 out of 55 patients (44 percent) had a poor neonatal outcome, defined as stillbirths, preterm birth, or low birth weight [9].
Some authorities advocate use of azithromycin in pregnant women for its safety profile and in vitro efficacy. In addition, a case series reported the outcomes of eight pregnant women infected with O. tsutsugamushi who were treated with a single 500 mg dose of azithromycin, and all recovered fully and delivered healthy infants [8]. However, there was no difference in outcome in pregnant women treated with or without azithromycin in the cohort described above [9].
Strains with reduced susceptibility to tetracycline — Some strains of O. tsutsugamushi are resistant or unresponsive to therapy with tetracyclines (including doxycycline). Some experts have proposed the use of alternative drugs, such as azithromycin or combination therapy including a rifamycin.
Azithromycin — Azithromycin may be a suitable alternative treatment for patients with refractory disease who are from locations where doxycycline-resistant strains of O. tsutsugamushi have been found [11]. Several studies have evaluated the use of azithromycin for the treatment of scrub typhus [2,12-14]. As examples:
●In an open-label study that compared a seven-day course of doxycycline with a three-day course of azithromycin in 57 Thai patients with proven scrub typhus, treatment failure occurred in one patient receiving azithromycin and in none of the patients receiving doxycycline [12].
●In a retrospective case control study involving 146 Korean patients with complicated scrub typhus matched by propensity score at the time doxycycline or azithromycin was initiated, there was no difference in outcome between the two groups in terms of time to defervescence or length of hospital stay [13].
Combination therapy — A second randomized trial performed in an area of northern Thailand (where strains of O. tsutsugamushi with reduced susceptibility to tetracycline are prevalent), compared the efficacy of doxycycline alone to the combination of doxycycline and rifampin in 86 patients with mild scrub typhus infection. The median duration of fever was significantly shorter in the 24 patients treated with daily doses of 900 and 600 mg of rifampin (mean fever clearance times 22.5 and 27.5 hours, respectively) than in 52 patients treated with doxycycline therapy alone (mean fever clearance time 52 hours) [15].
PREVENTION — No vaccine is available to prevent the transmission of scrub typhus. Furthermore, the antigenic heterogeneity of O. tsutsugamushi suggests that the prospect of future vaccine development will be a difficult undertaking [16]. Thus, current attempts at prevention consist of chemoprophylaxis and mite control.
Chemoprophylaxis — Several studies have demonstrated that chemoprophylaxis with a long-acting tetracycline is highly effective when used by non-immune individuals living or working in areas in which scrub typhus is endemic. In one report, for example, clinical disease occurred in only 1 of 10 individuals treated with a weekly 200 mg dose of doxycycline, despite exposure to an environment in which chiggers infected with O. tsutsugamushi were prevalent [17]. All of the patients developed antibodies to scrub typhus. In contrast, clinical disease occurred in 9 of 10 control subjects who were simultaneously exposed to the same environment, but did not take chemoprophylaxis.
Mite control — The use of insect repellants and miticides such as N,N-diethyl-3-methylbenzamide (DEET) are highly effective when applied to both clothing and skin. Permethrin and benzyl benzoate are also useful agents when applied to clothing and bedding. Focal areas such as military camps or specialized work areas can be treated with chlorinated hydrocarbons such as lindane, dieldrin, or chlordane. These chemicals are highly effective against trombiculid mites, although they may cause secondary environmental problems.
Intensive efforts at rodent control may paradoxically increase the risk of human disease. In this setting, chiggers lose their preferred and normal hosts, thereby becoming more likely to bite humans.
SUMMARY AND RECOMMENDATIONS
●Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi, which is distributed throughout Asia and northern portions of Australia. (See 'Introduction' above.)
●Doxycycline and chloramphenicol are comparable in shortening clinical illness and the incidence of relapse of infection. However, chloramphenicol is associated with significant drug toxicity, such as bone marrow suppression. We suggest doxycycline for treatment of scrub typhus. (See 'Treatment' above.)
●Scrub typhus may cause spontaneous abortions in pregnant women. Azithromycin is an alternative drug to treat scrub typhus, which has an acceptable safety profile in pregnant women. (See 'Pregnancy' above.)
●Several studies have demonstrated that chemoprophylaxis with a long-acting tetracycline is highly effective when used by nonimmune individuals living or working in areas in which scrub typhus is endemic. The use of insect repellants and miticides are highly effective when applied to both clothing and skin. Permethrin and benzyl benzoate are also useful agents when applied to clothing and bedding. (See 'Prevention' above.)
