Scrub Typhus

Scrub typhus is an acute, febrile, infectious illness that was first described in China in 313 AD. It is caused by Orientia (formerly Rickettsia) tsutsugamushi, an obligate intracellular gram-negative bacterium, which was first isolated in Japan in 1930. Although scrub typhus was originally recognized as one of the tropical rickettsial diseases, O tsutsugamushi differs from the rickettsiae with respect to cell-wall structure and genetic composition.

The term scrub typhus derives from the type of vegetation (ie, terrain between woods and clearings) that harbors the vector. However, this term is not entirely accurate, in that scrub typhus can also be prevalent in areas such as sandy beaches, mountain deserts, and equatorial rain forests.

US cases have been imported from regions of the “tsutsugamushi triangle,” which extends from northern Japan and eastern Russia in the north to northern Australia in the south and to Pakistan and Afghanistan in the west, where the disease is endemic. The range includes tropical and temperate regions, extending to altitudes greater than 3200 meters in the Himalayas. Scrub typhus is often acquired during occupational or agricultural exposures[2] because active rice fields are an important reservoir for transmission.[3]

Western medicine became especially interested in scrub typhus during military campaigns fought in East Asia. During World War II, 18,000 cases were observed in Allied troops stationed in rural or jungle areas of the Pacific theatre.[3] Scrub typhus was the second or third most common infection reported in US troops stationed in Vietnam[4] and still infects troops in the region.[5, 6] The US military continues to work on vector control, more accurate diagnostic tests, better vaccines, and improved surveillance methods.[7]

Currently, it is estimated that about 1 million cases of scrub typhus occur annually and that as many as 1 billion people living in endemic areas may have been infected by O tsutsugamushi at some time.[6] Because of reports of O tsutsugamushi strains with reduced susceptibility to antibiotics,[8] as well as reports of interesting interactions between this bacterium and HIV, a renewed interest in scrub typhus has emerged.[9, 10]

O tsutsugamushi, the pathogen that causes scrub typhus, is transmitted to humans through the bite of an infected chigger (see the image below), the larval stage of Leptotrombidium mites. These 6-legged, 0.2-mm larvae are not host specific and feed for 2-10 days on the skin fluids of the host. Wild rats serve as the natural reservoir for the chiggers (and represent a risk factor for human infection[2] ), but they are rarely infected with O tsutsugamushi.[3] When the chiggers feed on humans, infection occurs.

Chigger. Image taken from "Food and Environmental Hygiene Department" Web site and is reproduced under license from the Government of Hong Kong Special Administrative Region.

Orientia is also transmitted transovarially in mites and can unbalance the sex ratio of offspring in favor of females, further propagating infection.[3, 11] Chigger activity and subsequent human infection rates are determined by the particular Leptotrombidium species present (eg, akamushi, deliense, or pallidum), as well as by local conditions. Not surprisingly, positive correlations have been noted between chigger population abundance and human cases of scrub typhus.[12]

In tropical regions, scrub typhus may be acquired year round. In Japan, the chigger of Leptotrombidium akamushi is only active between July and September, when the temperature is above 25°C (77°F). In contrast, Leptotrombidium pallidum, which is found over a wide range, is active at temperatures of 18-20°C (64.4-68°F), from spring into early summer and autumn).[3, 13]

Humans acquire scrub typhus when an infected chigger bites them while feeding and inoculates O tsutsugamushi pathogens. The bacteria multiply at the inoculation site, and a papule forms that ulcerates and becomes necrotic, evolving into an eschar, with regional lymphadenopathy that may progress to generalized lymphadenopathy within a few days. In experimental infection, humans developed an acute febrile illness within 8-10 days of the chigger bite. Bacteremia was present 1-3 days before onset of fever.[14]

As in rickettsial diseases, perivasculitis of the small blood vessels occurs. The endothelium is involved; however, the basic histopathologic lesions suggest that macrophages might be more affected.[15]

O tsutsugamushi stimulates phagocytosis by the immune cells, and then escapes the phagosome. It replicates in the cytoplasm (see the image below) and then buds from the cell. The bacteria are able to harness the microtubule assembly inside the human cell for movement. Antibody-opsonized bacteria are still able to escape the phagosome but cannot effectively move on the microtubule; as a result, overall infectivity is decreased.[3]

Transmission electron micrograph depicts peritoneal mesothelial cell of mouse that had been experimentally infected intraperitoneally with Orientia tsutsugamushi. Several organisms are visible within mesothelial cell's cytoplasm.

Scrub typhus may disseminate into multiple organs through endothelial cells and macrophages, resulting in the development of fatal complications.[16, 17] In 2009, an apparent association was reported apparent between high O tsutsugamushi blood polymerase chain reaction (PCR)-determined DNA loads and disease severity.[18]

Scrub typhus is caused by O tsutsugamushi, an obligate intracellular gram-negative bacterium that lives primarily in L akamushi and L deliense mites . This organism is found throughout the mite’s body but is present in the greatest number in the salivary glands. When the mite feeds on rodents (eg, rats, moles, and field mice, which are the secondary reservoirs) or humans, the parasites are transmitted to the host. Only larval Leptotrombidium mites (chiggers) transmit the disease.

O tsutsugamushi is very similar to the rickettsiae and indeed meets all of the classifications of the genus Rickettsia; this connection is demonstrated by the high degree of homology (90-99%) on 16S ribosomal sequencing. However, the cell walls are quite different, in that those of O tsutsugamushi lack peptidoglycan and lipopolysaccharide.[3] This pathogen does not have a vacuolar membrane; thus, it freely grows in the cytoplasm of infected cells.

There are numerous serotypes,[19] of which 5—Karp, Gilliam, Kawazaki, Boryon, and Kato—are helpful in serologic diagnosis. About half of isolates are seroreactive to Karp antisera, and approximately one-quarter of isolates are seroreactive to antisera against the prototype Gilliam strain.[20]

Risk factors

In 2009, behavioral factors were shown to be associated with scrub typhus during an autumn epidemic season in South Korea.[21] Taking a rest directly on the grass, working in short sleeves, working with bare hands, and squatting to defecate or urinate posed the highest risks. Wearing a long-sleeved shirt while working, keeping work clothes off the grass, and always using a mat to rest outdoors showed protective associations.

United States statistics

Scrub typhus has no significant presence in the United States itself. The only cases of scrub typhus reported in the United States derive from elsewhere—for example, US travelers who have recently been to one of the endemic areas, military personnel who have been stationed abroad, or persons who have emigrated from other countries.[13, 22]

International statistics

Scrub typhus is endemic in regions of eastern Asia and the southwestern Pacific (Korea to Australia) and from Japan to India and Pakistan.[2, 15, 23, 24, 25, 26]  Recently, there have been increased reports of infection in Northern India.[27]

It is generally a disease of rural villages and suburban areas and is normally not encountered in the cities.

Although most cases are undiagnosed, prospective studies in endemic areas reveal in incidence of 18-23%.[3, 28] Community surveys in Malaysia reported an incidence of 3.2-3.5% per month and a seroprevalence exceeding 80% in those older than 44 years.[29] Surveillance of military personal deployed in southeast Asia demonstrated seroconversion in 484 per 1000 population.[5]

The seasonal occurrence of scrub typhus varies with the climate in different countries because the mites are able to thrive as conditions change. The mites prefer the rainy season and certain areas (eg, forest clearings, riverbanks, and grassy regions). In the past few years, cases have been noted earlier in the season because of increased mite activity as the weather warms.[30] Areas in which mites thrive pose a greater risk to humans. The prevalence of scrub typhus in Japan has been rising, and much of the current research is based in Japan.

Age-, sex-, and race-related demographics

People of all ages are affected equally by scrub typhus. Men and women are affected with equal frequency. No race-related differences in incidence have been documented.

Prognosis varies and depends on the severity of illness, which relates to the different strains of O tsutsugamushi, as well as to host factors. Severe disease is uncommon with antimicrobial treatment. Prognostic indicators for severe disease have not been established.[31] Incomplete immunity and strain heterogeneity open the door to frequent reinfections. Immunity to the same strain is believed to last 3 years, whereas immunity to other strains may last as little as 1 month; however, repeat infections may be attenuated.[3]

In patients who are not treated, mortality ranges from 1% to 60%, depending on the patient’s age, the geographic area, and the particular strain responsible for the infection. In the preantibiotic era, mortality in Japan averaged 30%: 15% in patients aged 11-20 years, 20% in those aged 21-30 years, and 59% in those older than 60 years. In Taiwan, overall mortality was estimated at 11% but was only 5% in children and 45% in the elderly.

With appropriate antibiotic treatment, mortality from scrub typhus is quite rare, and the recovery period is short and usually without complications.[3, 30] However, mortality is still approximately 15% in some areas as a consequence of missed or delayed diagnosis.[32] If severe complications such as acute respiratory distress syndrome (ARDS) arise, mortality may still be high.[33]

Patients with scrub typhus may present early or later in the course of their disease. In the United States, a history of travel to the endemic area must be sought, specifically probing for exposures in rural areas and contact with vegetation or the ground.[3, 6, 13]

Inoculation through the chigger bite is often painless and unnoticed. The incubation period lasts 6-20 days (average, 10 days). After incubation, persons may experience headaches, shaking chills, lymphadenopathy, conjunctival infection, fever, anorexia, and general apathy. The fever usually reaches 40-40.5°C (104-105°F).

A small painless papule initially appears at the site of infection and enlarges gradually. An area of central necrosis develops and is followed by eschar formation. The eschar (if present) is well developed at the initiation of the fevers, which may drive the patient to seek medical attention.[3, 4, 11, 34, 35]

Diagnosing scrub typhus early in its course can be difficult because many conditions can present with a high fever; however, the presentation of the rash, a history of exposure to endemic areas, and the presentation of the sore caused by the bite can be diagnostic.

The site of infection is marked by a chigger bite. Approximately 50% of patients with primary infection and 30% of patients with recurrent infection develop an eschar at the inoculation site (see the images below). Given the appropriate history, the eschar is often pathognomonic, but it may be missed by an inexperienced observer.

Typical eschar.

Eschar on neck.

Eschar on scrotum.

In prospective studies, trained investigators were able to locate an eschar on 68-87% of patients.[8, 34] In adults, the eschar is often truncal, whereas children may have lesions in the perineum.[36] The incidence of an eschar on head, face or neck is estimated to be approximately 5%.[37] Multiple eschars may be present.[4] The eschar may also abrade, leaving an ulcer reminiscent of primary syphilis.

The presence or absence of eschar was thoroughly examined in a study of 176 Korean patients with scrub typhus confirmed by immunofluorescent assay.[36] In this study, 162 (92%) cases had eschar, with 128 (79.5%) on the front of the body. In men, eschars were detected within 30 cm below the umbilicus (19 patients; 35.8%), on the lower extremities (12 patients; 22.6%) and on the chest above the umbilicus (11 patients; 20.8%). In women, the most prevalent area was the chest above the umbilicus (44 patients; 40.7%).

Patients experience abrupt onset of high fever (40-40.5°C [104-105°F]), headache, malaise, and myalgia approximately 10 days after infection. At that time, the eschar (if present) is well formed. Fever is the most commonly reported complaint, occurring more than 98% of the time.[3, 11] Tender regional or generalized lymphadenopathy may provide a clue to diagnosis and is reported in 40-97% of cases. Less frequently, ocular pain, wet cough, malaise, and injected conjunctiva are present.[4, 8, 34, 11, 38]

Toward the end of the first week, approximately 35% (reported range, 15-93%) of patients develop a centrifugal macular rash on the trunk. The rash may progress to become papular (see the image below).[4, 11, 35] It may be transient and easily missed.[3] Additional symptoms at this time may include enlargement of the spleen, cough, and delirium. Pneumonitis or encephalitis may develop during the second week.

Maculopapular rash.

Some patients may have central nervous system (CNS) involvement with tremors, nervousness, slurred speech, nuchal rigidity, or deafness during the second week of the disease. However, results from cerebrospinal fluid (CSF) analysis are either normal or indicate a low number of monocytes. Severe CNS involvement (eg, seizure or coma) is rare. If acute hearing loss is present (as may be the case in as many as one third of patients, according to some reports), it strongly points toward scrub typhus.[3, 6]

Some evidence of pulmonary involvement (eg, cough, tachypnea, or pulmonary infiltrates) is often present.[34] Respiratory compromise may progress to acute respiratory distress syndrome (ARDS), especially in the elderly.[33]

Cardiac involvement is often minor and rare; however, cases of fatal myocarditis have been reported.[39] Infection with O tsutsugamushi may cause a relative bradycardia,[40] which, when combined with rash, may raise concern for typhoid fever.[8]

Scrub typhus may rarely cause acute renal failure, shock, and disseminated intravascular coagulation (DIC).[3]

If the patient does not receive treatment, symptoms may last for more than 2 weeks; with treatment, the patient recovers within 36 hours.

Scrub typhus patients who are not treated may develop serious complications and may even die. Mortality ranges from 1% to 60%, depending on the geographic area and the pathogenic strain. Death can occur either from the primary infection or from secondary complications (eg, pneumonitis, encephalitis, or circulatory failure). Most fatalities occur by the end of the second week of infection.

Scrub typhus has an increased potential for complications when patients are older than 60 years, present without eschar, or have white blood cell (WBC) counts higher than 10,000/μL.[41] This condition represents an important cause of fever associated with poor pregnancy outcomes in refugee camps on the Thai-Burmese border.[42]  Another study reported that more than a third of pregnant women with murine typhus or scrub typhus infection have poor neonatal outcomes.[43, 44]

Routine laboratory studies in patients with scrub typhus reveal early lymphopenia with late lymphocytosis. A decrease in the CD4:CD8 lymphocyte ratio may also be noted. Thrombocytopenia is also seen.[34, 6] The hematologic manifestations may raise the suspicion of dengue infection.[32, 3]

Elevated transaminase levels may be present in 75-95% of patients. Hypoalbuminemia occurs in about 50% of cases, whereas hyperbilirubinemia is rare. These findings may be especially prevalent in children.[34, 47] In adults, elevated transaminase levels relate to severity of disease.[11, 6] Transaminitis combined with other symptoms and exposure history may suggest possible leptospirosis. Coinfection with leptospirosis has been reported.[3, 48]

Laboratory studies of choice are serologic tests for antibodies. The main confirmatory tests are the indirect immunoperoxidase test and the immunofluorescent assay.[49] An infection is confirmed by a 4-fold increase in antibody titers between acute and convalescent serum specimens. A single high titer with classic clinical features is considered a probable case. Serology for all suspected subtypes should be requested.[6]

The indirect fluorescent antibody test is sensitive and provides results in a couple of hours.[50] It uses fluorescent antihuman antibody to detect specific antibody from patient serum bound to a smear of scrub-typhus antigen. A dot immunoassay has also been used in the serodiagnosis of scrub typhus.

A study of 2 rapid immunochromatographic tests for detection of IgM and IgG against O tsutsugamushi determined that both assays were more sensitive and specific than the standard immune immunofluorescence assay for the early diagnosis of scrub typhus.[51]

A study by Varghese et al that included 203 patients previously confirmed to have scrub typhus reported that IgM levels gradually declined but remained elevated above the diagnostic cutoff up to 12 months post-infection.[52]

O tsutsugamushi has been identified by means of the polymerase chain reaction (PCR) technique in clinical specimens.[53, 6, 54] Performing nested PCR on the eschar might be a rapid diagnostic test for scrub typhus in the early, acute stage.[55]

In 2007, Cao et al reported on the development of a rapid diagnostic reagent for scrub typhus.[56]

The Weil-Felix OX-K strain agglutination reaction can be used to aid in diagnosis of scrub typhus. It may be the only serologic test available in less developed countries; unfortunately, it is not a very sensitive assay.[3]

Chest radiography may reveal pneumonitis,[28, 33] especially in the lower lung fields.[57]

Histologically, the basic pathologic change is focal or disseminated vasculitis caused by the destruction of endothelial cells and the perivascular infiltration of leukocytes.[58]

The current treatment for scrub typhus is administration of a tetracycline (most commonly doxycycline).[59] Chloramphenicol is also effective, and macrolides have been used as well. Relapses may occur if the antibiotics are not taken for a long enough period. Intravenous (IV) antibiotics may be administered to patients who are seriously ill and unable to swallow pills.

When patients who are HIV-positive become infected with certain strains of scrub typhus, their viral load can dramatically decrease. This is an important area of research. A proposed hypothesis is that patients infected with HIV who acquire scrub typhus have a powerful immune response raised to the scrub typhus and that is being turned against the HIV.[60]

Diet and activity are as tolerated. Inpatient care may be necessary for patients with severe scrub typhus. In such cases, meticulous supportive management is necessary to abort progression to disseminated intravascular coagulation (DIC) or circulatory collapse.

To reduce morbidity and mortality, treatment of scrub typhus must be initiated early in the course of the disease, on the basis of a presumptive diagnosis. Patients respond more promptly than in rickettsial infections, with resolution of fever expected within 24-36 hours.

The treatment of choice is tetracycline or doxycycline.[61] (O tsutsugamushi strains with reduced susceptibility to doxycycline have been identified, especially in northern Thailand.[8, 5, 62] ) A 7-day antibiotic regimen is usually effective.[4] Relapse may occur and necessitate administration of additional courses of antibiotics.[38]

Newer macrolides may be appropriate for children and pregnant women.[8, 38] In a small trial, azithromycin was shown to have efficacy comparable to that of doxycycline.[48] Rifampin and azithromycin have been used successfully in areas where scrub typhus is resistant to conventional therapy.[5, 8, 63]

In another small trial, roxithromycin was as effective as doxycycline and chloramphenicol for the treatment of scrub typhus[64] ; however, a subsequent study found it to be ineffective.[34] In a prospective, open-label, randomized trial of Korean patients with mild-to-moderate scrub typhus, the efficacy and safety of a 5-day telithromycin regimen compared favorably with those of a 5-day doxycycline regimen.[65]

Studies of fluoroquinolones have yielded mixed results, and their use cannot be advocated at this time.[61, 66, 67]

Consultation with an infectious diseases specialist should be considered if the patient does not improve on antibiotics or has atypical symptoms. The persistence of viable O tsutsugamushi was evaluated in patients who had recovered from scrub typhus.[68] O tsutsugamushi may cause a chronic latent symptomatic infection in spite of what is now considered adequate antibiotic therapy.

Further studies are needed to improve antibiotic treatment of severe and resistant scrub typhus, as well as to improve treatment in children and pregnant women.

Preventive measures in endemic areas include the use of protective clothing and insect repellents (potentially including plant essential oils[69] ). Short-term vector reduction using environmental insecticides and vegetation control can be instituted.

Chemoprophylaxis regimens have included the following:

• A single dose of doxycycline given weekly, started before exposure and continued for 6 weeks after exposure[1]

• A single oral dose of chloramphenicol or tetracycline given every 5 days for a total of 35 days, with 5-day nontreatment intervals

Reports of scrub typhus outbreaks in endemic areas and decreased effectiveness of antibiotic treatment suggest a continued need for a suitable vaccine.[70] At present, no such vaccine is available.[71]

Antibiotics are necessary to eradicate Orientia tsutsugamushi infection. Doxycycline is of proven efficacy, though resistance has been documented in parts of northern Thailand. Macrolides are equally efficacious. Azithromycin is desirable for pregnant women and for children. Rifampin is often used where doxycycline resistance is present.[72] Telithromycin is a promising new antibacterial agent for patients with scrub typhus.

Class Summary

Tetracycline derivatives (eg, doxycycline) are the mainstays of scrub typhus treatment. Chloramphenicol is also used. Rifampin and azithromycin have been used successfully in areas where scrub typhus is resistant to conventional therapy. The efficacy and safety of a 5-day telithromycin regimen has compared favorably with those of a 5-day doxycycline regimen.

Tetracycline

Tetracycline inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits.

Doxycycline (Doxy 100, Doryx, Vibramycin, Adoxa, Oraxyl)

Doxycycline is a synthetic antibiotic derived from tetracycline. It inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It is effective against a large number of pathogens.

Chloramphenicol

Chloramphenicol binds to 50S ribosomal subunits of bacteria and inhibits bacterial growth by inhibiting protein synthesis. Oral chloramphenicol is no longer available in the United States. Serum levels must be closely monitored and the dosage appropriately adjusted to achieve therapeutic concentrations (peak, 10-20 µg/mL; trough, 5-10 µg/mL).

Azithromycin (Zithromax, Zmax)

Azithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Rifampin (Rifadin)

Rifampin inhibits DNA-dependent bacterial (but not mammalian) RNA polymerase activity in susceptible cells. No known cross-resistance of microbes occurs, except when other rifamycins are involved. Rifampin is readily absorbed after oral dosing. Renal and hepatobiliary routes of elimination are active.

Telithromycin (Ketek)

Telithromycin inhibits bacterial protein synthesis by binding the 50S ribosomal subunit at 2 sites.