Orientia tsutsugamushi (Scrub Typhus)
Authors: Philippe Parola, M.D, Ph.D., Pr Philippe Brouqui, M.D, Ph.D., George Watt, M.D.
Microbiology
Orientia tsutsugamushi (formerly named Rickettsia tsutsugamushi) is the agent of scrub typhus. This bacteria had been classified for a long time in the order Rickettsiales as meeting the classic definition of rickettsiae: a short (0.5 X 1.2 to 3.0 microm) Gram-negative obligate intracellular bacteria retaining basic fuchsin when stained by the method of Gimenez (25). However, in the recent years the advent of molecular taxonomic methods in phylogenetic studies, particularly 16S rRNA sequence analysis, has enabled a reclassification of several bacterial species, including the rickettsiae. Then, the position of R. tsutsugamushi has been shown to be sufficiently distinct to justify the creation of a new genus, Orientia (32). O. tsutsugamushi presents a large number of serotypes. The major surface protein antigen is the 56-kDa protein including group-specific and strain-specific epitopes. However, several major serotypes (Karp, Kato, Gilliam, Kawasaki and Boryon) have been shown to present sufficient cross-reactivity with antigen from other strains to be used for the serological diagnostic.
Epidemiology
Scrub typhus (synonyms: chigger-borne rickettsiosis, tsutsugamushi disease, rural typhus) is an acute febrile rural zoonosis endemic in the Asia-Pacific region from Korea to Papua New Guinea and Queensland, Australia, and from Japan to India and Afghanistan. About 1 million cases have been estimated to occur each year and 1 billion people may be exposed (27). Endemic areas range from typical tropical secondary growth (scrub) vegetation to temperate zones and even the Himalayas. Although scrub typhus is essentially an occupational disease among rural residents engaged in agricultural or gathering activities, travelers or soldiers in the field may be infected when entering the biotope of the vectors (23, 39). The disease is transmitted by the bites of several species of larval-stage of trombiculid mites (commonly called "chiggers"), which are known as both reservoirs and vectors of the disease. They bite humans on any part of the body and feed for 2 to 10 days.
Clinical Manifestations
Symptoms occur usually 7-10 days after the chiggers’ bite. A papule at the bite site that later ulcerate forming a black crust or eschar is typically associated with fever, a drainage lymphadenopathy, a macular or maculopapular rash, headache and myalgia. However, eschar and rash may be absent or unnoticed. The severity of the disease varies from asymptomatic to fatal (up to 30%) with the susceptibility of the host and/or the virulence of the strain. Routine laboratory studies are of no diagnostic value, although leucopenia may occur.
Laboratory Diagnosis
The immunofluorescence and immunoperoxydase assays are known as the most reliable serologic tools, but dot blot immunoassay and ELISA tests have been developed and are commercially available (13, 14, 40). The Weil-Felix test using the cross reactivity of O. tsutsugamushi with Proteus OX-K is still used in endemic areas despite its poor sensitivity and specificity (13). The growth of O. tsutsugamushi in the laboratory requires living host cells (animal mouse models, embryonated eggs) or cell cultures. It can be seen in tissue by Giemsa or Gimenez staining. Also, PCR amplification and sequencing of the 56-kDa protein gene have been developed to detect and identify the bacteria in clinical samples or vectors (7, 8, 10).
Pathogenesis
Endothelial cells of most organs including skin, heart, lung, brain, kidney, pancreas, have been presented as the target cells of O. tsutsugamushi and the bacteria has also been located within cardiac muscle cells and in macrophages of liver and spleen (19). However, much of the basic biology and pathogenesis of O. tsutsugamushi is not known. Interestingly, most of the recent papers on scrub typhus concern the occurrence of scrub typhus in HIV1 infected patients and its consequences. Indeed, it has been shown that serum samples from scrub typhus infected patients and mice had an inhibitory effect on HIV1 in vitro and a decrease in HIV-1 copies number during acute scrub-typhus infection in some patients (35). Although preliminary and subject to controversies (1, 4), these data have led to the development of new research projects in HIV treatment (36).
SUSCEPTIBILITY IN VITRO AND IN VIVO
Since O. tsutsugamushi is a strictly intracellular bacteria, in vitro susceptibility testing cannot be done by traditional culture methods. Thus experimental systems for in vitro testing include the murine animal model, embryonated eggs and cell culture methods (i.e., mouse fibroblast cells L929) in specialized laboratories. Cells are incubated with various concentrations of antibiotics and harvested for evaluation of rickettsial growth using direct microscopic counts of stained cells, flow cytometry, the plaque reduction assay or the microplaque colorimetric assay (11, 24, 26, 31).
In late 1940’s, in vitro and in vivo studies on scrub typhus antibiotics susceptibility showed that chloramphenicol was an effective treatment of the disease (29). In 1951, quantitative assays performed on eggs or cell culture showed that both bacteriostatic antibiotics chloramphenicol and the tetracyclines were the most effective drugs, whereas beta-lactams and aminoglycosides are not effective (9). To date, chloramphenicol is still commonly used in many endemic areas and the tetracyclines, mainly doxycycline remains the reference drugs. Until recently, relevant antibiotics resistance to these drugs had not been reported. However, scrub typhus responding poorly to conventional doxycycline and/or chloramphenicol treatment was reported in northern Thailand in 1996. This report was supported by both in vivo and in vitro tests (33). Moreover, both chloramphenicol and doxycycline have restricted use and are contraindicated in pregnant women and also in young children for doxycycline. Thus, the need to test the efficiency of alternative antibiotics was required.
Rifampin had been previously shown to be effective in vitro (18). Further, when tested by in vitro cell culture system, azithromycin was shown to be effective against doxycycline-resistant strains of O. tsutsugamushi (31). In 1999, two pregnant women from northern Thailand were successfully treated by azithromycin (37). The efficiency of azithromycin in pregnant women had previously been reported (3). However, further testing with mice animal models showed that azithromycin resistant strains are not uncommon in northern Thailand (G. Watt, personal data). The correlation between animal models, cell culture and clinical report is not always consistent. For example, ciprofloxacin was shown to be effective in preventing death in a mouse animal model (15). Furthermore, one case of scrub typhus in Nepal was successfully treated by ciprofloxacin in 1989 (5). However, the available cell culture systems studies showed that ciprofloxacin is not effective against O. tsutsugamushi (17, 24).
ANTIMICROBIAL THERAPY
Drug of Choice
The tetracyclines and chloramphenicol remain the standard reference treatment for scrub typhus (Table 1). Unless contraindicated, doxycycline is the preferred treatment and the usual adult oral dose is 100 mg twice daily for 7 days. Tetracycline taken at 500 mg every 6h for 7 days may be also used. Few studies have shown that shorter courses of doxycycline treatment (single dose, or 3-day regimen) were comparable to the standard duration; however, rigorous studies of shorter duration of therapy are indicated. The use of doxycycline is limited by its contraindication in pregnant women and young children or its side effects including photosensitivity and gastrointestinal symptoms.
Chloramphenicol is the most common alternative to the tetracyclines. The usual adult dosage is 500 mg every 6 hours for 7 days or 50-75/mg/kg/day in children. Its use is limited by contraindication in pregnant women and the risk of induced aplasia.
Both tetracyclines and chloramphenicol may be used intravenously in case of vomiting or severe disease. However, chloramphenicol is usually the drug of choice in severe cases in many endemic areas because intravenous doxycycline is not available there.
Alternative Therapy
Based on the preliminary published in vitro data and clinical studies, rifampin (one-week 600-900 mg/day oral treatment) (38) and azithromycin (500 mg on the first day followed by 250 mg daily for 2 to 4 more days) (3, 37) are alternatives to doxycycline and chloramphenicol (Table 1 and Table 2). Both azithromycin and rifampin are also options in pregnant women (Table 2). On the other hand, the use of clarithromycin (400 mg/day for 12 to 19 days) (16) or ciprofloxacin (500mg twice a day) in the treatment of scrub typhus requires confirmation (5).
ENDPOINTS FOR MONITORING THERAPY
Scrub typhus responds promptly to effective treatment, with patients becoming afebrile within 24 to 48 hours. This was previously considered as an aid for the diagnosis as most therapies in the field are empiric; and failure of a rapid clinical response often suggests another diagnosis or presence of antibiotic resistance. Early administration of treatment shortens the disease course, reduces mortality and accelerates convalescence, although early studies suggested that initiation of tetracycline therapy before day 5 of illness are associated with relapses 5 to 10 days after therapy (28). To date, none of the laboratory tests for the diagnosis have been shown to be useful for monitoring the follow-up, including serology or molecular methods. Reinfection with O. tsutsugamushi is frequent in endemic areas but acquired immunity is incomplete. Immunity with homologous strains may last for up to several years, but immunity to heterologous strains decreases after several weeks even if the disease is usually milder (41).
The mortality of scrub typhus remains high (15% in northern Thailand) because of multiple factors, including late presentation, delayed diagnosis or misdiagnosis, inappropriate presumptive treatment with beta-lactams and lower level of drug susceptibility (6, 41).
VACCINES
There are no vaccines available for Orientia tsutsugamushi.
PREVENTION
Chemoprophylaxis: There is no vaccine currently available against scrub typhus. Thus prevention is based on avoiding the bites of chiggers. Currently, the best method to avoid arthropod bites comprises two components: a topical DEET (N,N-Diethyl-m-toluamide) repellent applied to exposed skin and treatment of clothing with permethrin. A weekly dose of 200 mg doxycycline is also effective in the prevention of scrub typhus (20, 21). To date, it is not know if the 100mg daily doxycycline regimen recommended for chemoprophylaxis against malaria is efficient to prevent scrub typhus. Although weekly chloramphenicol is also effective, concerns of bone marrow aplasia have limited its use as prophylaxis.
CAVEATS AND COMMENTS
Clinical Diagnosis
Scrub typhus may be difficult to diagnose as the typical clinical signs (eschar, rash) may lack or because the clinical presentation may be similar to other bacterial or viral diseases occurring in the same endemic areas. Reference diagnostic tests are usually not available in the field and response to therapy is often used as a diagnostic aid. The emergence of drug resistance which has been reported in northern Thailand suggests that clinical response to therapy may now be unreliable. New drugs including rifampin and azithromycin may be an alternative.
Clinical Trials and Quality of Evidence
Chloramphenicol is still commonly used in many endemic areas and the tetracyclines, mainly doxycycline remains the reference drugs. However, only few clinical trials are available. In order to provide clinical practice guidelines based on high quality of evidence in trials (12), randomized and pseudorandomized clinical studies available until 1997 and comparing any antibiotic regimens with no antibiotics or alternative treatment were recently reviewed by Panpanich and Garner (22). Time to fever resolution and incidence of relapse were analyzed for the different regimens. Only three studies were considered evaluable. One small study conducted in Vietnam showed no statistical difference between chloramphenicol and tetracycline, but patients had been enrolled on mostly clinical features and were treated for at least 3 days although the total length of treatment was decided by clinicians and not reported (28). In the second study, no statistical difference was found between a single dose of 200 mg of doxycycline (n=31) and 7-day tetracycline (n=24) regimen. However, the relatively insensitive Weil-Felix test was used for the diagnosis and clinicians could alter treatment after 48 hours. Furthermore, the number of subject included in these studies and the statistical methods did not support the conclusion of equivalent efficiency (2). Finally, Song compared a 3-day course regimen of doxycycline (n=66) with the standard 7-day tetracycline regimen (n=50) among 116 patients with immunofluorescence documented scrub typhus in Korea. The two groups did not differ regarding the cure rate (100% vs. 93.9% for tetracycline and doxycycline, respectively), time for defervescence and relapse (no relapse reported in either study over the 4 week follow-up) (30). However, the method used did not support the conclusion that both regimens were equivalent. No intention-to-treat analyses were available for these trials.
Only one report of a properly randomized controlled trial was conducted among 126 recruited patients with mild typhus in northern Thailand (38), where doxycycline and chloramphenicol resistance had been previously reported (33). The median duration of fever was significantly shorter in patients treated by 900 mg of rifampin (n= 24) and in those treated with 600 mg of rifampin (n= 26) than in patients receiving doxycycline (n= 28). Defervescence at 48h was also resolved in higher proportion of patients in the rifampin groups. All drugs were taken for 7 days. Analysis was per protocol and no intention to treat analysis was performed because patients withdrawn from study were not monitored. Although the study demonstrated that rifampin was more effective than doxycycline in mild scrub typhus, it must be pointed out that doxycycline resistance occurs in northern Thailand, although it has not been reported elsewhere. The efficacy of rifampin in severe cases has not yet been evaluated. Moreover, some points have to be clarified. During the first year of this study, one arm included the combination of doxycycline plus rifampin, but this combination therapy was withdrawn because of lack of efficacy. The reason for the failure is unclear. Currently, rifampin should be considered only as an alternative treatment, especially in northern Thailand.
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Tables
Table 1. Antibiotic Treatment for Scrub Typhus (except pregnant women), strength of recommendation and quality of evidence
| Regimen | Grade * | Adults | Children > 8 year-old | Children < 8 year-old |
|---|---|---|---|---|
| Standard | A II | Doxycycline: 100 mg every 12 h for 7 days a, b Or Tetracycline: 500 mg every 6h for 7 days | Doxycycline for 7 days: . 5 mg/ kg /day up to 100 lb . adult dosage if more than 100 lb | Chloramphenicol a for 7 days: 50 mg/kg/day divided dose every 6 h |
| Alternative 1 | A II | Chloramphenicol b 500 mg every 6 h for 7 days | ||
| Alternative 2 | A I | Rifampin c, e: 900 mg (or 15mg/kg) for 7 days | ||
| Alternative 3 | B III | Azithromycin d, e: 500 day 1 and 250 mg daily for 2-4 more days | ||
a Short-term regimen (100 mg every 12 h for 3 days or 200 mg single dose) have been reported to be effective in mild cases but more studies are required
b Intravenous drug may be used in case of vomiting or severe disease. However, chloramphenicol is usually the drug of choice in severe cases as intravenous doxycycline is not available in many endemic areas.
c Supported by in vitro data and one study in the treatment of mild cases in northern Thailand. See comments in the text.
d Supported by in vitro data and few reports in the treatment of pregnant women.
e Not approved by FDA for this indication
* Strength of recommendation and quality of evidence as reported in reference 12.
· A : Good evidence to support a recommendation for use
· B : Moderate evidence to support a recommendation for use
· I : Evidence from >= 1 properly randomized controlled trial
· II : Evidence from >= 1 well designed clinical trial without randomization from cohort or case-controlled analytic studies
· III : Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or report of expert committees
Table 2. Antibiotic Treatment for Scrub Typhus in Pregnant Women.
| Regimen | Grade * | Pregnant women |
|---|---|---|
| Standard | Both doxycycline and chloramphenicol are contraindicated. No standard treatment. | |
| Options 1 | B III | Azithromycin a, b: 500 day 1 and 250 mg daily for 2-4 more days |
| Options 2 | B III | Rifampin c, b 900 mg (or 15mg/kg) for 7 days |
a Supported by in vitro data and few case reports.
b Not approved by FDA for this indication
c Although it has not been clinically tested in pregnant women, its use can be supported by in vitro data, one study
in the treatment of mild cases in northern Thailand and regarding the poor therapeutic options in pregnant women.
* Strength of recommendation and quality of evidence as reported in reference 12. See Table 1.
What's New
Tsai CC, Lay CJ, et al. Levofloxacin versus tetracycline antibiotics for the treatment of scrub typhus. Int J Infect Dis. 2009 Jun 3.
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Reviews
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History
Kelly, D et al. Scrub Typhus: The Geographic Distribution of Phenotypic and Genotypic Variants of Orientia tsutsugamushi. Clinical Infectious Diseases 2009;48:i–i. DOI: 10.1086/596577.