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99 RICKETTSIAL INFECTIONS

99 RICKETTSIAL INFECTIONS
Harrison’s Manual of Medicine

99

RICKETTSIAL INFECTIONS

Tick- and Mite-borne Spotted Fevers

Rocky Mountain Spotted Fever (RMSF)

Mediterranean Spotted Fever (Boutonneuse Fever) and Other Spotted Fevers

Rickettsialpox
Flea- and Louse-borne Rickettsial Diseases

Endemic (Murine) Typhus (Flea-Borne)

Epidemic Typhus (Louse-Borne)
Chigger-Borne Scrub Typhus
Ehrlichiosis

Human Monocytotropic Ehrlichiosis

Human Granulocytotropic Ehrlichiosis
Q Fever
Bibliography

The rickettsiae are obligate intracellular bacterial parasites that appear as gram- negative coccobacilli and short bacilli. The majority of rickettsiae are maintained in nature by a cycle that involves an insect vector and an animal reservoir. Except for louse-borne typhus, humans are incidental hosts. Only Coxiella burnetii (the agent of Q fever) can survive for an extended period outside the mammalian reservoir or the insect vector.
TICK- AND MITE-BORNE SPOTTED FEVERS
Rocky Mountain Spotted Fever (RMSF)
EPIDEMIOLOGY   RMSF, so called because the first cases were described in the western U.S., has now been documented in 48 states and in Canada, Mexico, Costa Rica, Panama, Colombia, and Brazil. In the U.S., two types of ticks may transmit Rickettsia rickettsii to humans: the wood tick (Dermacentor andersoni) and the dog tick (D. variabilis). The likelihood that an individual tick carries R. rickettsii is small. From 1988 to 1997, the reported incidence of RMSF was 0.16–0.26 cases per 100,000 population in the U.S. The mortality rate (20–25% in the preantibiotic era) is now ~5% and is higher among males than females.
CLINICAL MANIFESTATIONS   Fever, headache, malaise, myalgia, nausea, vomiting, and anorexia are frequent but nonspecific manifestations during the first 3 d of clinical illness. Rash usually appears by the third day in half of cases, beginning as pink macules on the wrists and ankles. Lesions spread centripetally, convert to maculopapules that blanch on compression, and eventually become nonblanching and petechial. While diagnostically helpful when present, the rash does not appear until day 6 or later in 20% of cases; 10% of pts, including some with fatal cases, never develop a rash. Severe manifestations begin by the second week: widespread microvascular damage leads to increased vascular permeability, resulting in edema, hypovolemia, hypoalbuminemia, prerenal azotemia, and/or noncardiogenic pulmonary edema. Mechanical ventilation may be required—a poor prognostic sign. Encephalitis due to vascular injury is apparent in 26–28% of cases, often presenting as confusion and lethargy; stupor, delirium, ataxia, coma, and seizures are signs of more severe involvement. CSF pleocytosis, typically mononuclear, occurs in about one-third of cases. The CSF protein concentration may be elevated, but the CSF glucose level is usually normal. Nonspecific GI disturbances are common, as are mildly or moderately elevated serum aminotransferase concentrations (38%) and heme- positive vomitus or stools (10%); hepatic failure does not occur. In ultimately fatal untreated cases, the pt usually dies within 8–15 d after the onset of illness.
DIAGNOSIS   The diagnosis of RMSF during the acute stage is often difficult; early on, clinical and epidemiologic considerations (exposure within 12 d of onset to a potentially tick-infested environment during a season of possible tick activity) are more important than laboratory confirmation. During the acute phase, the only potentially diagnostic test is immunohistologic examination of a biopsy of involved skin. Serologic tests for RMSF are usually negative at presentation. Treatment should not be delayed while serologic results are pending. The most common confirmatory test is the indirect immunofluorescence assay, which is usually positive (titer, ³1:64) by day 7–10. Moreover, latex agglutination is usually positive (titer, ³1:128) at 1 week. Both tests are sensitive and highly specific. A solid-state enzyme immunoassay is also available. The Weil-Felix test is unreliable and should no longer be ordered.

TREATMENT
Therapy is most effective when given early. The treatment of choice for children and nonpregnant adults with RMSF is doxycycline (100 mg PO or IV q12h). The oral route should be used unless precluded by the pt’s condition. Tetracycline (25–50 mg/kg PO qd, divided q6h) is an equivalent alternative. For children with RMSF reinfection, up to 5 courses of doxycycline may be given without risk of dental staining. For pregnant women, chloramphenicol (50–75 mg/kg qd, divided q6h) can be used. ICU support may be necessary.

Mediterranean Spotted Fever (Boutonneuse Fever) and Other Spotted Fevers
EPIDEMIOLOGY AND CLINICAL MANIFESTATIONS   A number of tick-borne rickettsial infections occur in the eastern hemisphere. Mediterranean spotted fever (boutonneuse fever), Kenya tick typhus, Indian tick typhus, Israeli spotted fever, and Astrakhan spotted fever are regional synonyms for the disease produced by Rickettsia conorii, which is prevalent in southern Europe, all of Africa, and southwestern and south-central Asia. High fever, rash, and—in most locales—an inoculation eschar at the site of the tick bite are characteristic. R. africae is prevalent in central, eastern, and southern Africa and causes African tick-bite fever, an illness milder than Mediterranean spotted fever. R. japonica causes Japanese (Oriental) spotted fever. R. australis causes Queensland tick typhus, an Australian illness characterized by maculopapular or vesicular rash and an inoculation eschar (a black necrotic area or crust with surrounding erythema).
DIAGNOSIS AND TREATMENT   Table 99-1 summarizes the laboratory diagnosis and treatment of the tick-borne spotted fevers and other rickettsial diseases. The spotted fevers are diagnosed presumptively on clinical and epidemiologic grounds, and the diagnosis is generally confirmed serologically. In an endemic area, pts presenting with fever, rash, and an inoculation eschar should be considered to have one of the rickettsial spotted fevers.

Table 99-1 Laboratory Diagnosis and Treatment of Selected Rickettsial Diseases

Rickettsialpox
EPIDEMIOLOGY   Rickettsia akari, the etiologic agent of rickettsialpox, infects mice and their mites and is transmitted to humans by mite bites. While formerly not uncommon in the northeastern U.S., the disease is now rarely diagnosed.
CLINICAL MANIFESTATIONS   The lesion at the site of the mite bite evolves from papular to vesicular and then to a painless black eschar with an erythematous halo. Regional lymphadenopathy is common. After a 10-d incubation period, malaise, chills, fever, headache, and myalgia begin. A macular rash begins 2–6 d later and evolves sequentially into papules, vesicles, and crusts that heal without scarring. Without treatment, the illness lasts for 6–10 d and is self-limited.
DIAGNOSIS AND TREATMENT See Table 99-1.
FLEA- AND LOUSE-BORNE RICKETTSIAL DISEASES
Endemic (Murine) Typhus (Flea-Borne)
EPIDEMIOLOGY   Murine typhus is a global disease caused by two rickettsial species, R. typhi and R. felis. R. typhi is classically maintained in rats and is transmitted to humans by the Oriental rat flea (Xenopsylla cheopis). R. felis has been characterized more recently and is maintained in a cycle involving opossums and cat fleas (Ctenocephalides felis). Fewer than 100 cases of endemic typhus are reported annually in the U.S. and occur year-round, mainly in warm areas.
CLINICAL MANIFESTATIONS   The incubation period is 8–16 d. Prodromal symptoms of headache, myalgia, arthralgia, nausea, and malaise may occur. The onset of acute illness is characterized by the abrupt onset of chills and fever; nausea and vomiting are nearly universal. Rash occurs in somewhat more than half of pts. It most often appears about the sixth day of the illness and, in contrast to the rash of RMSF, is mostly confined to the trunk, with sparse involvement of the extremities, palms, soles, and face. Early lesions are macular and are hidden in the axillae and inner surfaces of the arms; later, a more generalized, discrete maculopapular rash involves the upper part of the abdomen, shoulders, chest, arms, and thighs. A hacking, nonproductive cough is a frequent finding. CXRs are abnormal in ~25% of cases. Without treatment, the illness lasts an average of 12 d. Pts recover rapidly after defervescing; the case- fatality rate is 1%.
DIAGNOSIS AND TREATMENT See Table 99-1.
Epidemic Typhus (Louse-Borne)
EPIDEMIOLOGY   Epidemic typhus is caused by R. prowazekii and is transmitted to humans by the body louse (Pediculus humanus corporis), which lives on clothes and is associated with poor hygiene. Lice pass the infection from person to person. Epidemic typhus is associated with poverty, war, cold weather, and natural disasters. In the U.S., sporadic cases result from transmission by the fleas of flying squirrels. Brill-Zinsser disease is a recrudescent, mild form of epidemic typhus occurring years after the acute disease; R. prowazekii can remain dormant for years and reactivate if immunity wanes.
CLINICAL MANIFESTATIONS   Epidemic typhus resembles murine typhus but is more severe. The incubation period is ~7 d. Disease onset is abrupt, with prostration, severe headache, and rapidly mounting fever. Myalgias are usually severe. Rash appears by the fifth febrile day. It is initially macular and confined to the axillary folds but later involves the trunk and extremities and may become petechial and confluent. Photophobia, conjunctival injection, and ocular pain are frequent. In untreated cases, up to 40% of which are fatal, azotemia, multiorgan involvement, and digital gangrene may occur; 12% of such cases have prominent neurologic manifestations. Sporadic North American cases are much milder than epidemic cases. Brill-Zinsser disease resembles epidemic typhus. While it is not always mild, recovery is the rule.
DIAGNOSIS AND TREATMENT See Table 99-1.
CHIGGER-BORNE SCRUB TYPHUS
EPIDEMIOLOGY   Scrub typhus is caused by Orientia tsutsugamushi and is transmitted to humans by the bites of infected trombiculid mite larvae (genus Leptotrombidium). The disease occurs in areas of heavy scrub vegetation, typically during the wet season when mites lay their eggs. It is endemic in eastern and southern Asia, in northern Australia, and in islands of the western Pacific.
CLINICAL MANIFESTATIONS   Scrub typhus varies in severity from mild to fatal. After an incubation period of 6–21 d, the illness begins with fever, headache, myalgia, cough, and GI symptoms. Classic but infrequently observed signs include an inoculation eschar, regional lymphadenopathy, and a maculopapular rash. In severe cases, vascular injury may lead to encephalitis and interstitial pneumonia.
DIAGNOSIS AND TREATMENT See Table 99-1.
EHRLICHIOSIS
Ehrlichiae are small, gram-negative, obligately intracellular bacteria that grow as microcolonies in phagosomes. Visible vacuolar clusters of ehrlichiae within phagocytes are termed morulae. Two distinct Ehrlichia species cause human infections that can be severe and frequent. Their characteristics and treatment are listed in Table 99-2. Human monocytotropic ehrlichiosis (HME) is caused by E. chaffeensis, which infects predominantly mononuclear cells in blood and tissues. Human granulocytotropic ehrlichiosis (HGE) is caused by a member of the E. phagocytophila group, which infects cells of myeloid lineage.

Table 99-2 Comparison of Two Human Ehrlichioses: Human Monocytotropic Ehrlichiosis (HME) and Human Granulocytotropic Ehrlichiosis (HGE)

Human Monocytotropic Ehrlichiosis
EPIDEMIOLOGY   The major vector for E. chaffeensis infection is the Lone Star tick (Amblyomma americanum); the white-tailed deer is an important reservoir host. Most U.S. cases have occurred in the south-central, southeastern, and mid-Atlantic regions. Cases have also been documented in Africa and Europe. Disease acquisition in the U.S. is most common in May–July and in rural areas. The median age of HME pts is 44 years, and 75% are male.
CLINICAL MANIFESTATIONS   Clinical illness occurs in about one- third of persons who seroconvert. The median incubation period is 8 d, and the median duration of clinical illness is 23 d. Manifestations are nonspecific and include (in order of decreasing frequency) fever, headache, myalgia, malaise, GI involvement (nausea, vomiting, diarrhea), rash, cough, and confusion. Severe cases can include respiratory insufficiency, neurologic involvement, GI bleeding, and/or opportunistic viral or fungal infection. The mortality rate is 2–3%. Laboratory findings suggestive of the diagnosis include thrombocytopenia, leukopenia, and elevated serum levels of aminotransferases. Ehrlichial morular inclusions are seldom seen in peripheral blood. Bone marrow is hypercellular and may have noncaseating granulomas.
DIAGNOSIS   Clinical suspicion of HME should be triggered by fever in the setting of tick exposure in an endemic area within the previous 3 weeks, leukopenia and/or thrombocytopenia, and increased aminotransferase concentrations in serum. PCR of peripheral blood may be positive for E. chaffeensis DNA during acute illness. Antibodies to the organism may be detected by indirect immunofluorescence during convalescence. A titer of ³1:64 is considered positive.

TREATMENT
Once HME has been presumptively identified, treatment should be initiated promptly. Tetracyclines (e.g., doxycycline, 100 mg q12h) shorten the course of illness and should be continued for 3–5 d after defervescence. Use of chloramphenicol is controversial.

Human Granulocytotropic Ehrlichiosis
EPIDEMIOLOGY   Most U.S. cases of HGE occur in the upper Midwest and in the Northeast, in May–July, and in a distribution similar to that of Lyme disease. Ixodes ticks—particularly I. scapularis (dammini) but also I. pacificus and I. ricinus—are probable vectors. Mammalian reservoir hosts are incompletely defined. HGE predominantly affects males and older persons.
CLINICAL MANIFESTATIONS   The incubation period is 4–8 d. HGE presents as a flulike illness, with fever, malaise, and headache. GI symptoms (nausea, vomiting, and diarrhea), cough, and confusion are less frequent. Rash is rare. Thrombocytopenia, leukopenia, anemia, and elevated serum aminotransferase levels are common. Morulae are commonly found in PMNs in the peripheral blood. The mortality rate is <1%, but nearly 7% of pts require management in the ICU. As in HME, opportunistic infections and respiratory insufficiency may occur. The possibility of coinfection with Borrelia burgdorferi (Lyme disease) or Babesia microti (babesiosis) should be entertained in all HGE cases, since the I. scapularis (dammini) vector is shared by all three agents.
DIAGNOSIS   HGE should be suspected in a pt with fever and flulike symptoms who has been exposed to an environment infested with the appropriate ticks, especially if thrombocytopenia is detected. PCR may be useful acutely. Serodiagnosis by indirect immunofluorescence assay may provide retrospective confirmation, with a convalescent E. phagocytophila group antibody titer of ³1:80.

TREATMENT
Doxycycline (100 mg PO bid) is therapeutically effective. Rifampin has been associated with clinical improvement in pregnant pts with HGE. Most treated pts defervesce within 24–48 h.

Q FEVER
EPIDEMIOLOGY   Q fever is a zoonosis caused by C. burnetii, an organism with a global distribution. The primary sources of human infection are infected cattle, sheep, and goats. In the infected female mammal, C. burnetii localizes to the uterus and mammary glands, reaches high concentrations in the placenta, and is dispersed as an aerosol at parturition. Infection follows inhalation of aerosolized organisms, ingestion of infected milk, or transfusion of infected blood. Abattoir workers and veterinarians are at particular risk. Rare cases of person-to-person transmission have followed delivery of an infant to an infected woman or autopsy of an infected cadaver.
CLINICAL MANIFESTATIONS   Acute Q Fever   With an incubation period of 3–30 d, Q fever may present in a variety of ways. Recognized syndromes include a flulike illness, prolonged fever, pneumonia, hepatitis, pericarditis, myocarditis, meningoencephalitis, and infection during pregnancy. Symptoms are nonspecific; fever, extreme fatigue, and severe headache are common. Chills, sweats, nausea, vomiting, diarrhea, cough, and nonspecific rash may also occur. Neurologic manifestations are infrequent. Thrombocytopenia is noted in ~25% of cases during the acute phase. Multiple rounded opacities on CXR are common and are highly suggestive of Q fever pneumonia in the appropriate epidemiologic setting.
Chronic Q Fever   Chronic Q fever almost always implies endocarditis. This infection occurs in pts with previous valvular heart disease, immunosuppression, or chronic renal insufficiency. Nonspecific symptoms may exist for up to 1 year before diagnosis. Fever is absent or low-grade. Hepatomegaly and/ or splenomegaly is usually detectable. The diagnosis should be considered in all pts with valvular heart disease, unexplained purpura, renal insufficiency, stroke, and/or progressive heart failure. A positive rheumatoid factor titer, an elevated ESR or C-reactive protein level, and/or an elevated gamma globulin concentration also suggests this diagnosis.
DIAGNOSIS   Serology (CF, ELISA, or indirect immunofluorescence) is the diagnostic tool of choice. Indirect immunofluorescence is sensitive and specific and can be used to diagnose both acute and chronic Q fever. PCR can be used to amplify C. burnetii DNA from tissue specimens. Culture of the organism is possible but potentially dangerous.

TREATMENT
Acute Q fever is treated with doxycycline (100 mg q12h for 14 d) or a quinolone. Chronic Q fever is treated with at least two active agents—e.g., doxycycline (100 mg q12h) plus rifampin (300 mg/d). A minimum treatment duration of 3 years is recommended. An alternative 18-month regimen— doxycycline plus hydroxychloroquine (600 mg/d)—is under investigation.

Bibliography

For a more detailed discussion, see Walker D, Raoult D, Dumler JS, Marrie T: Rickettsial Diseases, Chap. 177, p. 1065, in HPIM-15.

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