The typhus group

ELSEVIFR

The Typhus JOHN

D. BAXTER,

Epidemic

kmse-Borne)

Group MD

Typhus

Rickettsia prownzekii is the etiologic agent of epidemic typhus, which occurs in two clinical forms: the primary febrile illness and recrudescent infection (Brill-Zinsser disease). Epidemic typhus is transmitted by the body louse (Pediculus humanus corporis) and typically occurs during cold-weather months. Epidemic typhus is also known as louse-borne typhus, classic typhus, and sylvatic typhus.

EpidemiologJy The first epidemics that were attributed to epidemic typhus occurred in the late 15th century. In 1883, Dr. August Hirsch wrote: “The history of typhus is written in those dark pages of the world’s story which tell of the grievous visitations of mankind by war, famine, and misery of every kind.“’ Migration of populations, crowding, and cold weather result in proliferation of lice (Figure 11, which transmit R. prowazekii from person to person. It is estimated that 30 million casesoccurred in the Soviet Union and Eastern Europe between 1918 and 1922, with an estimated 3 million deaths.’ During World War II, epidemic typhus occurred in the concentration camps of Eastern Europe and in North Africa. Nowadays, most epidemic typhus cases have been reported from the rural highlands of Africa and Central and South America.’ The last outbreak of epidemic typhus in the United States occurred in 1922; until the 197Os,most cases of epidemic typhus in this country were due to BrillZinsser disease among survivors of concentration camps or immigrants from epidemic typhus zones of Eastern Europe.4 In 1975, Bozeman et al reported that R. prowazkii had been isolated from the southern flying squirrel (Glatmmys volans).5 The flying squirrel is distributed over the eastern United States, and transmission to humans is suspected to be by squirrel lice or fleas. Most casesof typhus reported from the southeastern United States have been associated with flying squirrel contact.“’ Human cases have been reported from North Carolina, Virginia, West Virginia, Georgia,

of Medicine, Cooper Hospital/University Medical of Medicine and Dentistry of Neul Jersey, Robert Wood /oIt~~so~~ Medical School at Camdell. Rddrrs ccwrspwzdence to Dr. Joh7 D. Baxter, Department of Medicine, Cooper Ho+ta//UMC, 407 Hmld~r~ Arwrue, Room 272, Camden, NJ 08103. t‘rom

Center.

tiw Drprtme~rt

lhrvrrsity

Tennessee, Massachusetts, and Pennsylvania. U.S. cases have typically occurred during the winter months in rural areas. Fifteen casesof sporadic epidemic typhus in the United States have been described in the literature, and an additional 13 cases were confirmed by the CDC.s In one report, all seven patients had direct or indirect contact with flying squirrels.’ Of the 28 known U.S. cases,22 occurred during November through February, and there has been a lack of evidence for personto-person transmission. These cases have generally been milder than classic epidemic typhus, but in a few instances, infection was life-threatening. The life cycle of epidemic typhus is believed to be initiated by a human case of primary epidemic typhus or by a case of recrudescent typhus, when the body louse feeds on an infected person. In the louse, the organism reproduces in the alimentary tract, yielding a large number of rickettsial organisms in its feces. The louse defecates while taking a blood meal, and the host then scratches the site, contaminating the bite wound with louse feces. Close personal or clothing contact is usually required to transmit lice from person to person. Infected lice usually die within 1 to 3 weeks from obstruction of the alimentary tract and do not transmit the organism to their offspring. Fleas or lice from flying squirrels nesting in the attics of houses during cold weather, or from direct contact with these infected rodents, are the likely vectors of infection in humans in the United States.

Etiology

and Pa thogenesis

R. proeaazekii is a coccobacillary obligate intracellular organism that reproduces by binary fission and is closely related antigenically to R. typhl (the agent of murine typhus). After local infection at the site of the louse bite, the organism infects the endothelial cells of capillaries and small blood vessels, producing a vasculitis. Platelet and fibrin deposition results in occlusion of vessels. Tissue biopsy reveals perivascular infiltration with lymphocytes, plasma cells, polymorphonuclear leukocytes, and histiocytes, with or without necrosis of the vessel. Giemsa or Gimenez staining is useful for identifying the organism in the cytoplasm of cells.’ The vasculitis is most prominent in the skin, heart, central nervous system, skeletal muscle, and kidneys. Gangrene of the skin can occur if local thrombosis is severe.

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Table 2. The Tvphus Group Disease Epidemic Murine Scrub

typhus typhus

typhus

Clinical

Pathogen

Vector

Geographic Distribution

louse

Africa, Central & South America, Eastern U.S. Worldwide costal areas, Texas, California Asia, Australia

R. prowazekii

Body

R. typhi and ELB agent

Rat and cat flea

R. tsutsugamushi

Larval

mite

Manifestations

Patients with epidemic typhus typically have 1 to 3 days of malaise before abrupt onset of severe headache, fevers, chills, and myalgia.’ In a review of 60 patients with epidemic typhus in Ethiopia, all patients were reported to have complained of severe headache and fever.’ A petechial rash was described in 33% of patients, and 5% had a macular erythematous rash; however, the authors noted that rash was difficult to detect in these dark-skinned patients. The rash was most evident on the trunk but could also be seen on the extremities. In a

Figure 1. Human body louse. Typical size is 2-4 mm. (Courtesy of Catherine Looby, M.D., Cooper Hospital/UMC, Jersey.)

Camden, New

Typical Rash Maculopapular and petechial (trunk to extremities) Macular and maculopapular Macular and maculopapular (trunk to extremities) with eschar

few patients, petechiae were also found on the conjunctival and soft palate. Typically, the rash of epidemic typhus begins in the axillary folds and upper trunk on about the fifth day of illness and spreads to the extremities. The rash initially appears as nonconfluent erythematous macules that blanch on pressure. After several days the rash becomes maculopapular and petechial, affecting the trunk and extremities and sparing the face, palms, and soles. Of the 28 known cases in the United States, 15 have been described in detail. Of these 15 reported cases, eight had rash that was described as maculopapular or petechial. The rash was typical in distribution, but was fleeting in a few patients. All patients had fever, but headache was absent in five of them. Six patients had neurologic symptoms other than headache, ranging from meningismus to coma. In uncomplicated epidemic typhus, fever usually resolves after 2 weeks of illness if untreated, but recovery of strength usually takes 2 to 3 months. Mortality is quite variable, with the highest rates among those over 60 years of age. With the use of appropriate antibiotics, fever resolves within 72 hours of the initiation of therapy. Headache usually resolves after 7 days of treatment. The more serious complications of typhus include gangrene and cerebral thrombosis secondary to vasculitis. When it occurs, gangrene is usually symmetric, affecting the distal fingers and toes. Treatment is usually nonsurgical in these cases; however, extensive gangrene of an extremity may require surgical amputation. Neurologic deficits due to cerebral thrombosis usually take 2 to 4 weeks to resolve, and residual deficits are uncommon. Cases of indigenous epidemic typhus acquired in the United States responded quickly to appropriate antibiotic therapy, with recovery occurring in most patients after 48 hours. Four of the patients did not receive specific therapy for epidemic typhus. Three of these patients recovered in 14 days, and the fourth patient developed renal failure requiring dialysis but eventually recovered over a period of months. Laboratory abnormalities in patients with epidemic typhus include mild thrombocytopenia (in approximately 40% of patients). Elevations of aspartate aminotransferase and lactate dehydrogenase occur in most patients. These laboratory abnormalities usually resolve

within 14 days of the initiation of therapy. The white blood cell count is usually normal, but it may be elevated in a minority of patients.’ Diagnosis

The possibility of epidemic typhus should be entertained in the presence of acute febrile illness, headache, and rash during cold-weather months, especially under conditions favoring human infestation with body lice, such as crowding and poor hygiene. Because the disease is uncommon in the United States and presenting symptoms can be variable, the diagnosis of epidemic typhus should be considered if a patient has symptoms consistent with Rocky Mountain spotted fever during November through February. Unlike Rocky Mountain spotted fever, which begins in the extremities and progressescentripetally, the rash of epidemic typhus starts in the axillary folds and upper trunk and spreads centrifugally, sparing the palms and soles. Although there are characteristic pathologic findings with rickettsial infection, there are no reports of diagnosis by skin biopsy.” For many years, the We&Felix agglutination reaction was the standard for serologic diagnosis; however, there is considerable crossreactivity between rickettsial speciesand a lack of specificity with this test. More sensitive methods have been developed in recent years, including the microimmunofluorescent and plate microagglutination tests.’ Acute and convalescent serum should be obtained for detection of fourfold rise in specific antibody titers. Polymerase chain reaction has also been applied to detection of R. prowazekii and may prove useful in the future for rapid diagnosis of this infection.” The differential diagnosis for epidemic typhus includes Rocky Mountain spotted fever, murine typhus, meningococcemia, measles, typhoid fever, bacterial meningitis, secondary syphilis, leptospirosis, relapsing fever, infectious mononucleosis, and rubella?

Treatment

and Prevention

Tetracyclines and chloramphenicol are highly effective in the treatment of epidemic typhus. Because of a long half-life, doxycycline has been shown to be effective against epidemic typhus when administered as a single oral dose; however, the standard recommended treatment is doxycycline 200 mg per day for 5 days.“,” If the patient is too ill to take drugs orally, tetracycline, doxycycline, or chloramphenicol can be administered intravenously. Because antibiotic therapy does not eradicate rickettsia in lice-infested patients, delousing is essential in the management of a typhus outbreak. If appropriate treatment is begun promptly, complications, including mortality, can be avoided in most cases. Prevention efforts are aimed at reducing conditions associated with proliferation of the human body louse. These measures include regular bathing and washing of

clothes and the use of long-acting insecticides. The synthetic pyrethroid permethrin is effective and longlasting when applied as a dust or spray to clothing and bedding. Fabric treated with permethrin retains toxicity to body lice even after numerous washings. Doxycycline prophylaxis may provide protection if taken in typhus-endemic areas and may also be effective in interrupting a typhus outbreak.’ A typhus vaccine is available and provides some level of protection, but it is indicated only for persons at high risk of acquiring R. prowazekii.‘”

Brill-Zinsser

Disease

Brill-Zinsser disease occurs as recrudescence of previous infection with R. prowazekii. In the United States, it occurs primarily in immigrants from Eastern Europe who acquired epidemic typhus during World War II. It is believed that stress or a waning immune system may reactivate earlier infection2 The clinical symptoms are usually milder than primary epidemic typhus and more closely resemble those of murine typhus. Patients with Brill-Zinsser disease lack specific IgM antibody and have elevated IgG antibody to R. pmumekii. Treatment is identical to that of primary epidemic typhus.

Murine

Typhus

Murine typhus, also known as endemic typhus, is caused by Rickettsia typhi and a newly recognized rickettsia, the ELB agent. Transmission of R. fyphi to humans occurs from the rat flea (Xenopsylla cheopis) and the rat louse (Polyplax spinulosa), while the ELB agent is associated with cat fleas (Ctenocephalidesfelis).9~L4J1” Murine typhus typically occurs in temperate and subtropical seaboard regions during warm-weather months.

Epidernioiogy Murine typhus is transmitted when an infected flea defecates while feeding on a human host, and irritation from the bite causes the host to scratch and inoculate rickettsiae into the bite wound. Transmission of infection occurs from infected flea to mammalian host to uninfected fleas. Infection of the midgut epithelial cells in the flea persists for the duration of its life. Most reported human cases of murine typhus have occurred in areas with large rat populations.” Human infection is usually due to the presence of rats and their infected fleas in indoor environments. Murine typhus is one of the most prevalent rickettsial infections throughout the world. The widespread distribution of murine typhus in many coastal areas is attributed to the introduction of infected rats and their fleas from ships.” Outbreaks have been reported in Australia, China, Kuwait, and Thailand.“’ In the United States, 20,000 to 50,000 casesof murine typhus were reported annually in the ear1.y 194Os,most

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BAXTER

in the southeastern and Gulf Coast states. The incidence of murine typhus in the United States declined rapidly when rat control programs were instituted after World War II.i7 Currently, murine typhus persists at a low level in the United States, with most cases reported from the Rio Grande Valley of southern Texas and southern California.‘“,‘9 Seasonal incidence of human infection appears to be correlated with the presence of vector fleas in the environment; most casesoccur from April through August in southern Texas.‘s Cases reported from southern Texas have been more frequently associated with exposure to the cat flea (which inhabits cats, opossums, raccoons, and skunks) than with that to the rat flea.

Etiology

and Pathogenesis

R. typhi is an obligate intracellular bacterium that infects endothelial cells in mammalian hosts. ELB (tentatively named for the California laboratory where it was first identified in cat fleas) is a newly described rickettsial agent of murine typhus that is indistinguishable from R. typhi with currently available serologic reagents; however, genetic analysis has shown unique DNA sequences for both R. typhi and ELB. The first observation of a human infection by the ELB agent was reported from Texas in 1994, and PCR was needed to discriminate it from the closely related R. typhus.” Widespread endothelial infection results in a systemic vasculitis that may affect any organ.” In fatal cases, organ damage secondary to vasculitis has been described in the lungs, kidneys, myocardium, brain, and liver parenchyma. Interstitial myocarditis is believed to be a major risk factor for death in these patients.21 Obliterative thrombovasculitis and perivascular nodules of the skin at autopsy resemble lesions of epidemic typhus2i In tissue, immunofluorescent R. typhi can be demonstrated in many organs and are especially numerous in foci of vasculitis.20 Widespread infection of the hepatic sinusoidal lining cells and the endothelium of vessels in portal regions results in injury to adjacent hepatocytes and may cause localized symptoms or liver function abnormalities.18

Clinical

Manifestations

After an incubation period of 6 to 14 days, the illness usually presents with an abrupt onset of symptoms.‘* The most common presenting symptom is fever (in 96% of cases),followed by headache (45%), chills (44%), and nausea (33%).18 At presentation, rash is present in only 18% of patients, but over the course of illness, 54 to 63% develop rash.‘s,22Rash appears at various intervals after the onset of fever, with a median onset at 6 days and a range of up to 18 days.” In one study, rash developed an average of 2 days after initial physician contact.18 The classic triad of fever, headache, and rash has limited

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usefulness for an immediate or early diagnosis. Therefore, the absence of rash or lack of petechiae should not dissuade the clinician from a diagnosis of murine typhus. In a study of 80 patients with murine typhus, the appearance of rash was described as macular (in 49%), maculopapular (29%70), papular (14%), petechial (6%), and morbilliform (3%)? The rash most frequently affects the trunk (72 to 88%), but it is also found on the extremities (38 to 55%).‘8,2’ Involvement of the palms has been noted in rare cases. Spread of rash from the trunk to extremities and from the extremities to the trunk appears to be equally frequent.‘s Laboratory abnormalities include mild leukopenia and thrombocytopenia, in a minority of patients, The most frequent laboratory abnormalities in patients with murine typhus are mildly elevated serum aspartate aminotransferase levels (90%), elevated alanine aminotransferase levels (73%), elevated lactate dehydrogenase levels (87%), mild hyponatremia (60%), and hypocalcemia (79%). Mild renal insufficiency occurs in a minority of patients (22%). Central nervous system abnormalities other than headache are unusual, and cerebra1 spinal fluid is usually normal.” The clinical course of murine typhus is usually uncomplicated, and fatalities are uncommon (<5%).18 When complications occur, the most frequent include neuropsychiatric abnormalities, seizures, renal insufficiency, respiratory failure, and jaundice. With initiation of appropriate antibiotic therapy, most patients have resolution of fever within 3 days. Increased severity of infection has been associated with older age, delayed diagnosis, and sulfa-containing antibiotics.

Diagnosis The early diagnosis of murine typhus is based on clinical suspicion. In the appropriate clinical setting, particularly in endemic areas, therapy should be initiated while laboratory confirmation is awaited. Because specific antibodies are frequently absent during the acute illness, serologic diagnosis can be made by obtaining acute and convalescent serum for specific rickettsial antibodies. The indirect fluorescent antibody, latex agglutination, and solid phase immunoassay tests are sensitive serologic assays that use specific R. typhi antigens. Fourfold titer increases or a single convalescent titer of 2128 is considered diagnostic of murine typhus. Half of patients can be diagnosed serologically after 1 week of illness and virtually all patients after 15 days of symptoms.” Newer but less tested means for diagnosing murine typhus include immunofluorescent staining of R. typhi in tissue and polymerase chain reaction.19,20 The differential diagnosis of murine typhus, which is similar to that of epidemic typhus, includes Rocky Mountain spotted fever, ehrlichiosis, meningococcemia, measles, typhoid fever, bacterial and viral meningitis,

secondary syphilis, drome, and Kawasaki

Treatment

leptospirosis, disease.23

toxic

shock

syn-

and Prevention

voir of the organism ovarial transmission

Etiology

because of the high rates of transof the organism to their offspring.

and Pathogenesis

Tetracyclines and chloramphenicol are effective in treating R. typhi infection. For adults, the recommended dosage of doxycycline is 200 mg per day and of chloramphenicol, 2 gm per day. l2 Treatment should be continued for 7 to 15 days or until 2 to 3 days after defervescence. In severely ill patients, intravenous tetracycline, doxycycline, or chloramphenicol may be used. Single-dose therapy is not recommended because relapse may occur. Limited evidence suggests that quinalones may be effective alternatives in treating rickettsial diseases.” Ciprofloxacin was reported to be effective in one case of murine typhus in Europe.24 Prevention of murine typhus is directed primarily at control of the flea vector and mammalian reservoirs of infection. Control of rat populations and insecticide dusting campaigns have brought epidemics of murine typhus under control. All suspected cases of murine typhus should be reported to local health authorities because of the potential for epidemic spread. No effective vaccine is available for murine typhus. Recovery from natural infection confers long-lasting immunity to reinfection.”

R. tsutsugamushi is an obligate intracellular bacterium that is unique among rickettsia species because of the presence of several antigenic variants and a lack of peptidoglycan and lipopolysaccharide.2” Despite the large number of serotypes (including Karp, Gilliam, Kato, Kawasaki, and Kuroki), there is sufficient crossreactivity with antigens from major serotypes with other strains to permit serologic diagnosis with the indirect fluorescent antibody test.2”‘2x The infected chigger inoculates R. tsutsugamushi while feeding on the human host. The organism multiplies at the bite wound site, producing a painless small papule. The lesion enlarges, undergoes central necrosis, and forms a black crust, which is the eschar.“” Tender regional lymphadenopathy occurs in association with the eschar, which is followed by generalized lymphadenopathy. Rickettsemia results in disseminated vasculitis and perivasculitis of the small blood vessels. Multipleorgan impairment is common; in particular, CNS manifestations with meningitis, encephalitis, and deafness may occur. 25,29Less commonly affected organs include the kidneys, liver, and lungs.

Scrub Typhus

Clinical

Scrub typhus is a febrile illness, endemic in Southeast Asia, that is caused by Rickettsia tsutsugamushi. Transmission to humans occurs from larval mites, known as chiggers. Cases imported into the United States have been reported; they may occur more frequently as Southeast Asia becomes an increasingly popular tourist destination.‘s

Epidemiology The area in which scrub typhus occurs naturally forms a triangle bounded by northern Japan and southeastern Siberia to the north; Queensland, Australia, to the south; and Pakistan to the west.25 R. tsutsugumushi infection is associated with rural habitats that harbor the larval mite vector. Mites and chiggers stay within several meters of where they hatch, inhabiting circumscribed areas within scrub forests, tall grass, or plantations. Exposure occurs when people camp, raft, or walk into these so-called mite islands of infection. During World War II, there were 18,000 cases of scrub typhus in Allied soldiers; during the Vietnam war, there was a ratio of one scrub typhus case to every 50 to 100 cases of malaria.““,” R. tsutsugumushi infection is transmitted to humans through the bite of the larval stage of the thrombiculid mite (chigger). These mites represent the major reser-

Manifestations

The skin papule appears within 2 days after the chigger feeds and progresses to an eschar during the h- to 18day incubation period. The onset of symptoms is usually abrupt, with unremitting fever, chills, and headache. In a review of 87 American soldiers who were infected with scrub typhus in South Vietnam, all were reported to have fever, headache, and anorexia.‘7 Other symptoms were chills (80%), cough (45%), myalgia (32%), and nausea (28%). The most common physical finding was generalized lymphadenopathy (85%). An eschar was found in 46% of these soldiers, most commonly in the calf area around boot tops (Figure 2) but also in the groin, axilla, and inguinal area. The ulcerative lesion was usually covered with an eschar, surrounded by a raised erythematous circle 1 to 2 cm in diameter; however, in moist skinfolds, the eschar was often absent. Forty-three percent of these soldiers had splenomegaly, and only 34% had a maculopapular eruption, which appeared from the third to eighth day of fever and persisted for an average of 4.2 days. When present, the rash typically occurs on the trunk and spreads to the extremities. It usually begins as a macular eruption and then may become papular (Figure 3). The adenopathy of scrub typhus is easily palpable, with nodes ranging in size from small kernals to large spongy glands, but usually only those that drain the eschar are tender or suppurative. Other clues to the

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tions, as recently seen in a traveler returning from Thailand who developed adult respiratory distress syndrome, renal failure, coma, and hyperbilirubinemia and survived with residual blindness, nerve deafness, a cognitive defect, and gait ataxia.25 This patient had traveled in northern Thailand, which has a 15% case fatality rate with scrub typhus and frequent multiple-organ involvement. The severity of symptoms with scrub typhus varies widely partly because of the virulence of the infecting strain of R. tsutsugumushi.26

Diagnosis

Figure 2.

Eschar o# scrub typhus. (Reprinted with permission,

from Bermanet al.’ ) presence of scrub typhus are deafness and tinnitus, as well as conjunctival suffusion.25 Other symptoms that may occur, particularly in untreated patients, are neuropsychiatric abnormalities such as confusion, delirium, slurred speech, and nuchal rigidity. In one report, 9 of 72 patients with scrub typhus presented with meningitis or encephalitis.29 CSF profiles were similar to those of viral and tuberculous meningitis.29 Deafness and tinnitus may occur in up to one-third of scrub typhus patients. Laboratory findings typically include a normal white blood cell count, with a lymphocytosis in most patients. The lymphocytes often have an atypical appearance. About half of the patients have elevations in aspartate aminotransferase levels; 20% of patients have proteinuria.27 With appropriate therapy, fever usually resolves within 48 hours. In untreated patients, fever usually last an average of 14 days. In the preantibiotic era, death rates of up to 50% were reported from Japan.25Administration of appropriate antibiotic therapy shortens the duration of illness and greatly reduces the risk of death.‘6 Untreated patients may suffer many complica-

Clinicians must have a high index of suspicion for scrub typhus in febrile patients who return from endemic areas. Patients may lack the classic eschar and rash associated with scrub typhus. In the absence of rash and eschar, the presence of lymphadenopathy and lymphocytosis often leads to a mistaken diagnosis of infectious mononucleosis. 27 In the approp riate setting, empiric therapy should be initiated while serologic confirmation is awaited. A variety of serologic assays have been used in the diagnosis of scrub typhus. The Weil-Felix slid agglutination test lacks sensitivity but is easy to perform in less developed areas of the world. The indirect fluorescent antibody test is more sensitive and specific than the Weil-Felix test3’ Acute and convalescent titers reveal a peak in antibody titer after the second week of illness. A more recently developed assay, the immunoperoxidase test, has been reported to be easier to perform than the fluorescent assay and is equivalent in terms of sensitivity and specificity. 30,31A fourfold rise in convalescent titers is considered diagnostic. Treatment within the first few days of symptoms may blunt the antibody response. Maximum titers of patients treated after 7 days of symptoms averaged between 1:640 and 1:1,280, as compared to patients treated promptly, who had maximum antibody titers between 1:40 and 1:160.27 Polymerase chain reaction has been used to detect R. tsutstcgumushiDNA from peripheral blood and skin biopsy specimens in patients with acute scrub typhus.32 The differential diagnosis of scrub typhus includes other rickettsial diseases,typhoid fever, brucellosis, leptospirosis, infectious mononucleosis, toxoplasmosis, and dengue fever.26

Treatment

and Prevention

Tetracyclines and chloramphenicol are both effective in treating scrub typhus. A comparative study of tetracycline and chloramphenicol for the treatment of scrub typhus revealed that tetracycline eliminated fever and other symptoms of disease more rapidly.33 The recommended dose of doxycycline is 200 mg per day and of tetracycline, 2 gm per day for adults.i* Clinical relapses are relatively common in patients given a short course of therapy, especially when treatment is begun before

References 1. Perine PL, Chandler BP,Krause DK, et nl. A clinicoepide-

miological study of epidemic typhus in Africa. Clin Infect Dis 1992;14:1149-58. 2. Saah AJ. Rickettsia prowazekii. In: Mandeli GL, Bennett

JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Churchill L.ivingstone, 1995:1735-7. 3. World Health Organization. Louse-borne typhus, 19831984.Weekly Epidemiol Ret 1984;57:45--b. 4. McDade JE, Shepard CC, Redus MA, CCal. Evidence of Rickettsiu prowmekii infection in the United States.Am J Trop Med Hyg 1980;29:277-84. 5. Bozeman FM, Masiello SA, Williams My-;, et al. Epidemic typhus rickettsiae isolated from flving squirrels. Nature 1975;255:545-7. 6. Duma RJ, SonenshineDE, Bozeman FM. et al. Epidemic typhus in the United States associatedwith flying squir-

rels. JAMA 1981;245:2318-23. 7. SonenshineDE, Bozeman FM, Williams MS, et al. Epizootiology of epidemic typhus (RickeftG ~nmomrkii) in flying squirrels. Am J Trop Med Hyg 1978:27:339--49. 8. Kaplan JE, McDade JE, Newhouse VF. “suspectedRocky

Mountain spotted fever in the winter-t>pidemic typhus? (letter). N Engl J Med 1981;305:1648. 9. Myers SA, Sexton DJ. Dermatologic manifestations of arthropod-borne diseases. infect Dis Clin %rth Am 1994;8:

Figure 3. pcmissim,

Maculopnyrhr

from Rrrmai~

rash of scrub typhus. (Reprinted, with

et nl.")

the fourth or fifth day of illness.3” Treatment for 2 weeks reduces the likelihood of relapse. In an animal model, ciprofloxacin appears to be as effective as chloramphenicol;‘” it has been used successfully to treat one patient with scrub typhus.” After injection with R. tsutsqmushi, long-lasting immunity to homologous strains is achieved, but immunity is only temporary for heterologous strains. In endemic areas, repeated episodes of scrub typhus may occur because of the many different serotypes of R. fsufsugnmushi.‘h

An effective vaccine for prevention of scrub typhus has not been developed, owing to the antigenic diversity of the various serotypes. Chemoprophylaxis with weekly doses of 200 mg of doxycycline can prevent scrub typhus infection.“‘,” Chemoprophylaxis should be considered for travelers at high risk for disease, such as those who are hiking or camping in endemic areas.25 Contact with chiggers can be reduced by not sitting or lying directly on the ground in endemic areas and by applying repellent to the tops of boots and socks and to the hem of trousers.

689-712. 10. Carl M, Tibbs CW, Dobson ME, et al. Diagnosis of acute typhus infection using the polymerase r.hain reaction. J Infect Dis 1990;161:791-3. 11. Perine PL, Krause DW, Awoke A, et al. Single-dosedoxycycline treatment of louse-borne relapsing fever and epidemic typhus. Lancet 1974;2:742-4. 12. Raoult D, Drancourt M. Antimicrobial therapy of rickettsial diseases. Antimicrob Agents Chrmother 1991;35: 2457-62. 13. Centers for Disease Control and I’rCvent:on ‘Typhus vaccine. MMWR 1978;27:189. 14. Azad AF, Traub R. Transmission oi mur!ne typhus rickettsiae by Xe~opsylla clzeopis, with notes GVIexperimental infection and effects of temperature. Am I Trap Med Hyg 1985;34:555-63. ET, Azad AF. Infection of colo15. Adam JR, Schmidtmann nized cat fleas, Ctrnocephalides f~li:: (Bou
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Rickettsia typhi in fatal murine typhus. Am J Clin Path01 1989;91:720-4. Binford CH, Ecker HD. Endemic (murine) typhus. Report of autopsy findings in three cases. Am J Clin Path01 1947; 17:797-806. Betz TG, Rawlings JA, Taylor JP, et al. Endemic typhus in Texas. Tex Med 1983;79:48-53. Dumler JS, Walker DH. Murine typhus. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995:1737-9. Strand 0, Stromberg A. Case report: Ciprofloxacin treatment of murine typhus. Stand J Infect Dis 1990;22:503-4. Watt G, Strickman D. Life-threatening scrub typhus in a traveler returning from Thailand. Clin Infect Dis 1994;18: 624-6. Saah AJ. Rickettsia tsutsugamushi. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Church Livingstone, 1995:1740-l. Berman SJ, Kundin WD. Scrub typhus in South Vietnam, a study of 87 cases. Ann Intern Med 1973;79:2630. Ohashi N, Tamura A, Sakurai H, et al. Characterization of a new antigenic type, Kuroki, of Rickettsia tsutsugamuski isolated from a patient in Japan. J Clin Microbial 1990;28: 2111-3.

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K, Ukkachoke C, Krisanapan S, et al. Rick29. Silpapojakul ettsial meningitis and encephalitis. Arch Intern Med 1991; 151:1753-7. 30. Kelly DL, Wong PW, Can E, et al. Comparative evaluation of the serodiagnosis of rickettsial disease. Am J Trop Med Hyg 1988;38:400-6. 31. Kelly DL, Wong PW, Gan E, et al. Multi-laboratory evaluation of a scrub typhus diagnostic kit. Am J Trop Med Hyg 1990;43:301-7. 32. Sugita Y, Nagatani T, Okuda K, et al. Diagnosis of typhus infection with Rickettsia tsutsugamuski by polymerase chain reaction. J Med Microbial 1992;37:357-60. 33. Sheehy TW, Hazlett D, Turk RE. Scrub typhus, a comparison of chloramphenicol and tetracycline in its treatment. Arch Intern Med 1973;132:77-80. 34. McClain JB, Joshi B, Rice R. Chloramphenicol, gentamicin, and ciprofloxacin against murine scrub typhus. Antimicrab Agents Chemother 1988;32:285-6. 35. Twartz JC, Shirai A, Selvaraju G, et al. Doxycycline prophylaxis for human scrub typhus. J Infect Dis 1982;146: 811-8. 36. Olson JG, Bourgeois AL, Fang RCY, et al. Prevention of scrub typhus: Prophylactic administration of doxycycline in a randomized double blind trial. Am J Trop Med Hyg 1980;29:989-97.