INTRODUCTION — Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi). This disease was first described by the Chinese in the third century, but the first description of its classic features did not appear in the western literature until the end of the nineteenth century. Knowledge about scrub typhus increased dramatically during World War II due to its common occurrence in soldiers fighting on both sides in the Pacific theater.
The epidemiology, clinical features, and diagnosis of scrub typhus will be reviewed here. Treatment of this disorder is discussed separately. (See "Scrub typhus: Treatment and prevention".)
MICROBIOLOGY — O. tsutsugamushi is a gram-negative coccobacillus that is antigenically distinct from the typhus group rickettsiae. This organism has features that are common to and distinct from other rickettsiae.
●Like all rickettsiae, it cannot be propagated in cell-free media. (See "Biology of Rickettsia rickettsii infection".)
●Unlike other rickettsiae, the trilaminar outer membrane of O. tsutsugamushi is unique in its morphology.
●O. tsutsugamushi is unique in that it is released from infected cells by budding from the plasma membrane of host cells. It may then be phagocytosed by adjacent cells while still coated with its original host cell membranes. Rickettsial phospholipase A2 appears to be involved as a mediator of entry into host cells with subsequent release from phagosomes and injury to the host cell [1].
●Organisms disseminate widely after initial inoculation into the skin. One study showed that O. tsutsugamushi could be detected by staining mononuclear cells in the peripheral blood of three of seven patients studied with acute scrub typhus [2].
There are three variants or strains of O. tsutsugamushi (Karp, Gilliam, and Kato). Infection with one strain does not preclude reinfection with a different strain.
EPIDEMIOLOGY — O. tsutsugamushi is primarily distributed throughout the Asia Pacific rim. Scrub typhus is endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia, and in the tropical (northern) regions of Australia [3,4]. Scrub typhus has also been reported in Chile [5,6]; three cases were identified between 2015 and 2016 [6]. Other reports include a case of scrub typhus in a patient who may have been infected with O. tsutsugamushi while in West Africa [7], and a patient from Dubai who developed infection with a new species of Orientia (O. chuto), which had a similar nucleotide sequence to that of O. tsutsugamushi [8].
Accurate surveillance data on the incidence of scrub typhus are not available because a diagnosis is often unconfirmed, overlooked, or confused with other endemic febrile illnesses. However, some experts have estimated that up to 1 million cases occur annually in southeastern Asia [9]. A report summarizing the epidemiological aspects of 27,391 confirmed cases of scrub typhus diagnosed in China from 2006 to 2012 illustrates a number of important epidemiological aspects of scrub typhus in endemic areas [10]:
●Farmers accounted for approximately two-thirds of all reported cases
●Incidence rates were highest in people aged 40 to 60 years of age, but young children had higher rates of infection than young adults
●Approximately 80 percent of cases occurred during summer and autumn (July to November)
●Geographic clustering of cases was observed, with a few southeastern Chinese provinces, accounting for a large proportion of all reported cases
Although most cases of scrub typhus occur in rural areas, a number of cases have been acquired in settings such as suburban Bangkok, where the seroprevalence exceeds 20 percent [11], as well as urban areas, such as Beijing and Seoul [10,12].
Vectors — The reservoir and vector of scrub typhus are larval trombiculid mites of the genus Leptotrombidium. These larval mites (also known as chiggers) maintain the infection in successive generations via transovarial transmission. At least 8 of the known 60 species of trombiculid mites are capable of transmitting scrub typhus. The disease typically occurs 7 to 10 days after the bite of an infected chigger (range 6 to 19 days).
Ecology — Scrub typhus is characteristically a geographically focal disease. Transmission of O. tsutsugamushi may occur in sharply delineated "mite islands" that consist of focal locations of scrub vegetation as small as a few square meters. Mites live on the vegetation, and moisture and temperature conditions are ideal for propagation of chiggers and their small rodent hosts. The risk of disease transmission from chigger bites may be extremely high when humans enter these mite islands. As an example, a classic study performed over 50 years ago found that nearly all Australian soldiers on training exercises in Queensland who camped in a small geographic area developed scrub typhus. In contrast, no soldiers who camped in nearby areas developed the disease [13].
Imported disease — The ease of air travel and relatively long incubation period of scrub typhus (up to two weeks) allow the disease to occur in tourists returning to regions where it is not endemic, and where clinicians are not familiar with its clinical and epidemiologic features. Cases of scrub typhus have been described in tourists returning to the United States, Canada, and Europe from endemic regions [14-17].
INCUBATION PERIOD — Infection commonly presents as an acute febrile illness 7 to 10 days after the bite of an infected larval trombiculid mite (chigger) [18].
CLINICAL MANIFESTATIONS
Overview — Scrub typhus may begin insidiously with headache, anorexia, and malaise, or start abruptly with chills and fever. As the illness evolves, most patients develop the following symptoms:
●Fever, which typically lasts for long periods in untreated patients (median 14.4 days; range 9-19) [9]
●Intense generalized headache
●Diffuse myalgias
Rash, eschar, and other signs and symptoms may also be present. (See 'Rash' below and 'Eschar' below and 'Other signs and symptoms' below.)
The severity of infection can range from mild signs and symptoms to multiorgan failure and death [9,19,20]. A systematic review, which included a total of 19,644 patients with untreated scrub typhus, reported a median mortality rate of 6 percent (range: 0-70 percent) [9]. Mortality rates varied widely by location and were increased in older patients. In addition, the presence of myocarditis, delirium, and pneumonitis were associated with a fatal outcome, but gender and the presence of eschar were not. There may also be a relationship between the level of rickettsial DNA in blood samples at the time of admission and the risk of mortality [18].
Elderly patients are more likely to have severe illness and complications compared with younger patients. As an example, a retrospective study from a single medical center evaluated 615 Korean patients >16 years of age with scrub typhus [21]. Forty-six percent of patients >65 years developed one or more complication compared with 23 percent of younger patients. Acute kidney injury, mental confusion and dyspnea were more common in older patients, whereas the frequency of fever, rash, and eschars were similar in both groups. Delays in therapy were also associated with a higher risk of complications. The average time from onset of illness to effective therapy was modestly greater in patients with complications compared with those without complications (approximately 7 versus 6 days).
Rash — Approximately one-half of all patients develop a characteristically nonpruritic, macular or maculopapular rash. The rash typically begins on the abdomen and spreads to the extremities. The face is also often involved. Rarely, petechiae may develop.
Eschar — A painless papule often appears at the site of the infecting chigger bite. Subsequent central necrosis then occurs, which in turn leads to the formation of a characteristic eschar with a black crust (picture 1). One or multiple eschars may develop before the onset of systemic symptoms. Occasionally, eschars can be atypical and lack a typical black crust [22].
The frequency of eschars in patients with scrub typhus is highly variable. As an example, in one report, eschars developed in 36 of 74 (46 percent) American servicemen in South Vietnam [23]; however, another study found an incidence of 60 to 88 percent [24]. Eschars may be overlooked if a careful clinical exam (including inspection of the genitalia and skin folds under the breast) is not performed.
Other signs and symptoms — Other signs and symptoms may also be seen in scrub typhus:
●Localized, and subsequent generalized lymphadenopathy, occurs in the majority of patients, and may be accompanied by inflammation of the lymphatic sinuses, splenomegaly, and portal triaditis.
●Acute kidney injury [21].
●Nausea, vomiting, and/or diarrhea are prominent findings in approximately one-fourth of patients. Endoscopy was performed in 58 patients with scrub typhus and prominent gastrointestinal symptoms selected from 256 patients with scrub typhus seen at a single Korean center over a five-year period. All patients had one or more endoscopic abnormalities, and 33 of 56 patients had changes consisting of superficial ulcers, erosions, or actively bleeding ulcers. Moreover, the presence of endoscopic lesions in the upper gastrointestinal tract was correlated with the occurrence of cutaneous lesions and severity of illness [25].
●Respiratory complaints are often present; cough occurred in 45 percent of patients in one study [23]. Rarely, acute respiratory distress syndrome may occur. In one case series, pulmonary complaints were present in 62 percent of 130 Thai patients with scrub typhus. Sixty-five percent of these 130 patients had radiographic abnormalities at presentation. The most common abnormalities were bilateral reticular opacities (49 percent), cardiomegaly (29 percent), and congestive heart failure (19 percent) [26].
●Relative bradycardia occurs commonly in patients with scrub typhus [27-29]. Relative bradycardia has been defined as a median increase in heart rate <10 beats/min per 1ºC increase in temperature [27].
●Involvement of blood vessels in the central nervous system may produce meningitis, with a predominant mononuclear cell response. Meningitis and encephalitis syndromes occurred in 9 of 72 patients in a report from Thailand [30]. Acute hearing loss or tinnitus occurred in six patients who presented with scrub typhus after being ill for more than one week [31]. Only two of these six patients had concurrent symptoms of encephalitis.
●While pericardial effusion has been reported in autopsy series, clinical pericarditis is not common. However, a clinical case has been published from Korea of pericarditis in which the organism was demonstrated by indirect immunofluorescence of pericardial fluid [32]. Myocarditis may also occur in some patients.
DIAGNOSIS — As with all rickettsial diseases, no laboratory test is diagnostically reliable in the early phases of scrub typhus. The disease is usually recognized when clinicians correlate the presence of compatible clinical signs, symptoms, and laboratory features, with epidemiologic clues (eg, recent exposure to environments in which chiggers are known or suspected to be present).
Patients with scrub typhus may develop the following laboratory abnormalities:
●Most patients with severe illness develop thrombocytopenia.
●Elevations in hepatic enzymes, bilirubin, and creatinine.
●Leukopenia or leukocytosis can occur, but most have a normal white blood cell count.
While these laboratory findings are relatively nonspecific, four methods can be used to more definitively confirm the presence of O. tsutsugamushi infection: serology, biopsy, culture, and polymerase chain reaction.
Serology — The indirect fluorescent antibody (IFA) test remains the mainstay of serologic diagnosis. This test is available in most state health laboratories, which send the specimens to the Centers for Disease Control in Atlanta, GA. A battery of antigens from common strains of O. tsutsugamushi should be used to detect convalescent antibodies because of the organism's antigenic heterogeneity.
Among patients living in endemic areas, the serologic diagnosis of acute infection must be differentiated from background immunity against scrub typhus. A 2007 review made the following recommendations for diagnosis using the IFA assay [33]:
●A conclusive diagnosis of acute scrub typhus infection using the IFA assay should be based upon at least a fourfold increase in titer in paired samples drawn at least 14 days apart.
●A single measurement may be informative when there are locally validated criteria for a positive test. When a single measurement is performed, the most common cutoff titer is 1:50 (range 1:10 to 1:400).
A single measurement may also be used to make a preliminary diagnosis in travelers who live in areas in which scrub typhus is not endemic and who have recently returned from an endemic area [33]. However, only paired titers can make a definitive diagnosis [33,34].
An enzyme-linked immunosorbent assay and a passive hemagglutination assay have also been developed for the diagnosis of scrub typhus [35,36], and a dot blot immunoassay dipstick, which is undergoing clinical evaluation, may permit rapid diagnosis of scrub typhus [37]. The Weil Felix test, based upon a fortuitously discovered cross reaction between anti-rickettsial antibodies and Proteus antigens (OX2 and OX19), is neither specific nor sensitive. Thus, its use is no longer advised.
Biopsy of an eschar or generalized rash — The pathological hallmark of scrub typhus is a lymphohistiocytic vasculitis. Damage to endothelial cells occurs early in infection, leading to widespread vascular dysfunction. This endothelial injury causes a loss of vascular integrity, egress of plasma and plasma proteins, and microscopic and macroscopic hemorrhages. Thus, the histologic changes in biopsies of eschars include focal areas of cutaneous necrosis surrounded by a zone of intense vasculitis, with perivascular collections of lymphocytes and macrophages. Thrombosis of small blood vessels can also occur. Demonstration of these typical vasculitic changes can be diagnostic, even when rickettsiae are not demonstrable by fluorescent antibody conjugates.
Culture — Culture of this organism is available in only a few centers. Specialized laboratory facilities with rigorous quality control and laboratory safety measures are required.
Polymerase chain reaction — Polymerase chain reaction (PCR) technology applied to the blood of patients with scrub typhus can definitively establish the diagnosis, even in the minority of patients who lack IgM antibodies early in the course of infection [38-40]. The sensitivity of a nested PCR assay using buffy coat preparations was 82 percent and the specificity was 100 percent in a study of 135 Korean patients with possible scrub typhus [40]. Similar findings were found in a cohort of Chinese patients using conventional PCR targeting the 16S rRNA gene [41]. In addition to serum PCR, eschar PCR also appears to be a sensitive and specific assay for scrub typhus despite prior antibiotic treatment [42]. However, these tests are only available in specialized centers that have access to the required primers and laboratory facilities.
DIFFERENTIAL DIAGNOSIS — Scrub typhus may be confused with a number of different infectious illnesses.
●Malaria and dengue share some common clinical features and similar endemic patterns with scrub typhus. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Dengue virus infection: Clinical manifestations and diagnosis".)
●Leptospirosis is a common disease in some tropical regions where scrub typhus also occurs. Rarely, coinfection with scrub typhus and leptospirosis may occur. In one study of 296 febrile Thai patients, 69 patients (23 percent) had leptospirosis; 57 patients (19 percent) had scrub typhus and 11 patients (4 percent) had evidence of coinfection with leptospira and O. tsutsugamushi [43]. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
●Other rickettsial diseases, such as infections with the spotted fever group of rickettsiae (eg, Rickettsia australis, Rickettsia japonica, and Rickettsia sibirica), may mimic scrub typhus. Infection with R. australis and R. sibirica may even be associated with a localized eschar at the site of the infecting tick bite. These diseases can be almost identical, particularly when there is no history of tick bite. Fortunately the treatment for these other rickettsial diseases is identical to that for scrub typhus. (See "Other spotted fever group rickettsial infections".)
●Scrub typhus may mimic infection with Salmonella typhi in areas of the tropics where typhoid fever is common. This confusion is particularly true in patients who lack a rash or localized eschar, and in whom gastrointestinal symptoms are prominent. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
●The eschar in patients with scrub typhus can also be confused with the skin lesions seen in patients with anthrax and with a spider bite. (See "Clinical manifestations and diagnosis of anthrax" and "Diagnostic approach to the patient with a suspected spider bite: An overview", section on 'Management overview'.)
SUMMARY AND RECOMMENDATIONS
●Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi). (See 'Introduction' above.)
●O. tsutsugamushi is a gram-negative coccobacillus that is antigenically distinct from the typhus group rickettsiae. (See 'Microbiology' above.)
●Scrub typhus is endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia, and Australia. The reservoir and vector of scrub typhus are larval trombiculid mites of the genus Leptotrombidium. Imported disease has been described in tourists returning from endemic areas. (See 'Epidemiology' above.)
●Scrub typhus may begin insidiously with headache, anorexia, and malaise, or start abruptly with chills and fever. As the illness evolves, most patients develop high fever, worsening of headache severity, and myalgias. An eschar or rash may develop in a subset of patients. (See 'Clinical manifestations' above.)
●The severity of infection can range from mild symptoms and signs to multiorgan failure. Elderly patients and those with delays in therapy are more likely to develop complications. (See 'Overview' above.)
●Diagnostic methods for confirmation of O. tsutsugamushi infection include serology, biopsy, culture, and polymerase chain reaction. The indirect fluorescent antibody (IFA) test remains the mainstay of serologic diagnosis; a four-fold rise in titers over a 14-day period is conclusive. Culture and polymerase chain reaction (PCR) testing is only available in specialized research facilities. The pathological hallmark of scrub typhus on skin biopsy is a lymphohistiocytic vasculitis. (See 'Diagnosis' above.)
●The differential diagnosis of scrub typhus includes malaria, dengue, leptospirosis, and other rickettsial diseases. (See 'Differential diagnosis' above.)
