Harrisons Manual of Medicine, 18th Ed.

CHAPTER 105. Rickettsial Diseases

Microbiology

Rickettsiae are obligate intracellular gram-negative coccobacilli and short bacilli usually transmitted by tick, mite, flea, or louse vectors. Except in the case of louse-borne typhus, humans are incidental hosts.

Clinical Manifestations

The clinical manifestations of all the acute rickettsial presentations are similar during the first 5 days and consist of nonspecific symptoms: fever, headache, and myalgias with or without nausea, vomiting, and cough. As the course progresses, clinical manifestations—including occurrence of a macular, maculopapular, or vesicular rash; eschar; pneumonitis; and meningoencephalitis—vary from one disease to another. (See Table 105-1 and details below.)

TABLE 105-1 FEATURES OF SELECTED RICKETTSIAL INFECTIONS

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TICK- AND MITE-BORNE SPOTTED FEVERS

ROCKY MOUNTAIN SPOTTED FEVER (RMSF)

Epidemiology

Caused by R. rickettsii, RMSF has the highest case-fatality rate of all rickettsial diseases.

• In the United States, the prevalence is highest in the south-central and southeastern states. Most cases occur between May and September.

• A rare presentation of fulminant RMSF is seen most often in male black pts with G6PD deficiency.

• RMSF is transmitted by different ticks in different geographic areas—e.g., the American dog tick (Dermacentor variabilis) transmits RMSF in the eastern two-thirds of the United States and in California, and the Rocky Mountain wood tick (D. andersoni) transmits RMSF in the western U.S.

Pathogenesis

Rickettsiae are inoculated by the tick after ≥6 h of feeding, spread lymphohematogenously, and infect numerous foci of contiguous endothelial cells. Increased vascular permeability, with edema, hypovolemia, and ischemia, causes tissue and organ injury.

Clinical Manifestations

The incubation period is ~1 week (range, 2–14 days). After 3 days of nonspecific symptoms, half of pts have a rash characterized by macules appearing on the wrists and ankles and subsequently spreading to the rest of the extremities and the trunk.

• Lesions ultimately become petechial in 41–59% of pts, appearing on or after day 6 of illness in ~74% of all cases that include a rash. The palms and soles become involved after day 5 in 43% of pts but do not become involved at all in 18–64%.

• Pts may develop hypovolemia, prerenal azotemia, hypotension, noncardiogenic pulmonary edema, renal failure, hepatic injury, and cardiac involvement with dysrhythmias. Bleeding is a rare but potentially life-threatening consequence of severe vascular damage.

• CNS involvement—manifesting as encephalitis, focal neurologic deficits, or meningoencephalitis—is an important determinant of outcome. In meningoencephalitis, CSF is notable for pleocytosis with a mononuclear cell or neutrophil predominance, increased protein levels, and normal glucose levels.

• Laboratory findings may include increased plasma levels of acute-phase reactants such as C-reactive protein, hypoalbuminemia, hyponatremia, and elevated levels of creatine kinase.

Prognosis

Without treatment, the pt usually dies in 8–15 days; fulminant RMSF can result in death within 5 days. The mortality rate is 3–5% despite the availability of effective antibiotics, mostly because of delayed diagnosis. Survivors of RMSF usually return to their previous state of health.

Diagnosis

Within the first 3 days, diagnosis is difficult, since only 3% of pts have the classic triad of fever, rash, and known history of tick exposure. When the rash appears, the diagnosis should be considered.

• Immunohistologic examination of a cutaneous biopsy sample from a rash lesion is the only useful diagnostic test during acute illness, with a sensitivity of 70% and a specificity of 100%.

• Serology, most commonly the indirect immunofluorescence assay (IFA), is usually positive 7–10 days after disease onset, and a diagnostic titer of ≥1:64 is usually documented.

TREATMENT Rocky Mountain Spotted Fever

• Doxycycline (100 mg bid PO or IV) is the treatment of choice for both children and adults but not for pregnant women and pts allergic to this drug, who should receive chloramphenicol.

• Treatment is given until the pt is afebrile and has been improving for 2 or 3 days.

OTHER TICK-BORNE SPOTTED FEVERS

• R. conorii causes disease in southern Europe, Africa, and Asia. The name for R. conorii infection varies by region (e.g., Mediterranean spotted fever, Kenya tick typhus).

– Disease is characterized by high fever, rash, and—in most locales—an inoculation eschar (tâche noire) at the site of the tick bite.

– A severe form of disease with a mortality rate of ~50% occurs in pts with diabetes, alcoholism, or heart failure.

• R. africae causes African tick-bite fever, which occurs in sub-Saharan Africa and the Caribbean and is the rickettsiosis most frequently imported into Europe and North America.

• Tick-borne spotted fever is diagnosed on the basis of clinical and epidemiologic findings; the diagnosis is confirmed by serology or detection of rickettsiae.

• Doxycycline (100 mg PO bid for 1–5 days), ciprofloxacin (750 mg bid PO for 5 days), or chloramphenicol (500 mg qid PO for 7–10 days) is effective for treatment.

RICKETTSIALPOX

Epidemiology

Rickettsialpox is caused by R. akari and is maintained by mice and their mites. Recognized principally in New York City, rickettsialpox has been reported in other urban and rural locations in the United States as well as in Ukraine, Croatia, Mexico, and Turkey.

Clinical Manifestations

A papule forms at the site of the mite bite and develops a central vesicle that becomes a painless black-crusted eschar surrounded by an erythematous halo. Lymph nodes draining the region of the eschar enlarge.

• After an incubation period of 10–17 days, malaise, chills, fever, headache, and myalgia mark disease onset.

• A macular rash appears on day 2–6 of illness and evolves sequentially into papules, vesicles, and crusts that heal without scarring.

• If untreated, fever lasts 6–10 days.

TREATMENT Rickettsialpox

Doxycycline is the drug of choice for treatment.

FLEA- AND LOUSE-BORNE TYPHUS GROUP RICKETTSIOSES

ENDEMIC MURINE TYPHUS (FLEA-BORNE)

Etiology and Epidemiology

Caused by R. typhi, endemic murine typhus has a rat reservoir and is transmitted by fleas.

• Humans become infected when Rickettsia-laden flea feces are scratched into pruritic bite lesions; less often, the flea bite itself transmits the organisms or aerosolized rickettsiae from flea feces are inhaled.

• In the United States, endemic typhus occurs mainly in southern Texas and southern California; globally, it occurs in warm (often coastal) areas throughout the tropics and subtropics.

• Flea bites often are not recalled by pts, but exposure to animals such as cats, opossums, raccoons, skunks, and rats is reported by ~40%.

• Risk factors for severe disease include older age, underlying disease, and treatment with a sulfonamide drug.

Clinical Manifestations

Prodromal symptoms 1–3 days before the abrupt onset of chills and fever include headache, myalgia, arthralgia, nausea, and malaise; nausea and vomiting are nearly universal early in illness.

• Rash is apparent at presentation (usually ~4 days after symptom onset) in 13% of pts; 2 days later, half of the remaining pts develop a maculopapular rash that involves the trunk more than the extremities, is seldom petechial, and rarely involves the face, palms, or soles.

• Pulmonary disease is common, causing a hacking, nonproductive cough in 35% of pts. Almost one-fourth of pts who undergo CXR have pulmonary densities due to interstitial pneumonia, pulmonary edema, and pleural effusions.

• Laboratory abnormalities include anemia, leukopenia early in the course, leukocytosis late in the course, thrombocytopenia, hyponatremia, hypoalbuminemia, mildly increased hepatic aminotransferase levels, and prerenal azotemia.

• Complications may include respiratory failure, hematemesis, cerebral hemorrhage, and hemolysis.

• The duration of untreated disease averages 12 days (range, 9–18 days).

Diagnosis

The diagnosis can be based on culture, PCR, cross-adsorption serologic studies of acute- and convalescent-phase sera, or immunohistology, but most pts are treated empirically.

TREATMENT Endemic Murine Typhus (Flea-Borne)

Doxycycline (100 mg bid for 7–15 days) is effective. Ciprofloxacin provides an alternative if doxycycline is contraindicated.

EPIDEMIC TYPHUS (LOUSE-BORNE)

Etiology and Epidemiology

Epidemic typhus is caused by R. prowazekii and is transmitted by the human body louse. Eastern flying squirrels and their lice and fleas maintain R. prowazekii in a zoonotic cycle.

• The louse lives in clothing under poor hygienic conditions, particularly in colder climates and classically at times of war or natural disaster.

• Lice feed on pts with epidemic typhus and then defecate the organism into the bite at their next meal. The pt autoinoculates the organism while scratching.

• Brill-Zinsser disease is a recrudescent and mild form of epidemic typhus whose occurrence years after acute illness suggests that R. prowazekii remains dormant in the host, with reactivation when immunity wanes.

Clinical Manifestations

Epidemic typhus presents abruptly with the onset of high fevers, prostration, severe headache, cough, and severe myalgias. Photophobia with conjunctival injection and eye pain is also common.

• A rash appears on the upper trunk around the fifth day of illness and spreads to involve all body-surface areas except the face, palms, and soles.

• Confusion and coma, skin necrosis, and gangrene of the digits are noted in severe cases.

• Untreated, the disease is fatal in 7–40% of cases. Pts develop renal failure, multiorgan involvement, and prominent neurologic manifestations.

Diagnosis

Epidemic typhus is sometimes misdiagnosed as typhoid fever. The diagnosis can be based on serology, immunohistochemistry, or detection of the organism in a louse found on a pt. Cross-adsorption IFA can distinguish R. prowazekii from R. typhi.

TREATMENT Epidemic Typhus (Louse-Borne)

Doxycycline (100 mg bid) is given until 2 or 3 days after the pt has defer-vesced, although a one-time dose of 200 mg has proved effective under epidemic conditions.

SCRUB TYPHUS

• Orientia tsutsugamushi, the agent of scrub typhus, is transmitted by larval mites or chiggers in environments with heavy scrub vegetation.

• Disease occurs during the wet season. It is endemic in eastern and southern Asia, northern Australia, and the Pacific islands.

• The classic case description includes an eschar at the site of chigger feeding, regional lymphadenopathy, and maculopapular rash—signs rarely seen in indigenous pts; Westerners commonly do not present with all three findings. Severe cases include encephalitis and interstitial pneumonia.

• Scrub typhus can be diagnosed by serologic assays (IFA, indirect immunoperoxidase, and enzyme immunoassays); PCR analysis of eschars and blood is also effective.

• A 7- to 15-day course of doxycycline (100 mg bid) or chloramphenicol (500 mg qid) or a 3-day course of azithromycin (500 mg qd) is effective.

EHRLICHIOSES AND ANAPLASMOSIS

Two distinct Ehrlichia species and one Anaplasma species—all obligately intracellular organisms—are transmitted by ticks to humans and cause infections that can be severe and prevalent.

HUMAN MONOCYTOTROPIC EHRLICHIOSIS (HME)

Etiology and Epidemiology

HME is caused by Ehrlichia chaffeensis and, in the United States, generally occurs in southeastern, south-central, and mid-Atlantic states. The incidence can be as high as 414 cases per 100,000 population.

• E. chaffeensis is transmitted by the Lone Star tick (A. americanum), and white-tailed deer are the major reservoir.

• Most pts are male; the median age of pts is 53 years.

• E. ewingii causes an illness similar to, but less severe than, that due to E. chaffeensis.

Clinical Manifestations

Clinical findings are nonspecific and include fever (96%), headache (72%), myalgia (68%), and malaise (77%). Nausea, vomiting, diarrhea, cough, rash, and confusion may be noted.

• The median incubation period is 8 days.

• Disease can be severe: up to 62% of pts are hospitalized and ~3% die. Complications include a toxic shock–like syndrome, respiratory distress, meningoencephalitis, fulminant infection, and hemorrhage.

• Leukopenia (61%), thrombocytopenia (73%), and elevated serum aminotransferase levels (84%) are common.

Diagnosis

Because HME can be fatal, empirical antibiotic therapy based on clinical diagnosis is required. PCR testing before initiation of antibiotic therapy or retrospective serodiagnosis to detect increased antibody titers can be performed. Morulae are seen in <10% of peripheral-blood smears.

Treatment

Treatment with doxycycline (100 mg PO/IV bid) or tetracycline (250–500 mg PO q6h) is effective and should be continued for 3–5 days after defervescence.

HUMAN GRANULOCYTOTROPIC ANAPLASMOSIS (HGA)

Etiology and Epidemiology

HGA is caused by Anaplasma phagocytophilum and, in the U.S., occurs mainly in northeastern and upper midwestern states.

• The geographic distribution is similar to that of Lyme disease and Babesia microti infection, given the shared I. scapularis tick vector.

• HGA incidence peaks in May through July, but the disease can occur year-round.

Clinical Manifestations

Given high seroprevalence rates in endemic areas, it appears that most people develop subclinical infections.

• After an incubation period of 4–8 days, pts develop fever (91%), myalgia (77%), headache (77%), and malaise (94%).

• Severe complications—respiratory insufficiency, a toxic shock–like syndrome, and opportunistic infections—occur most often in elderly pts.

• On laboratory examination, pts are found to have leukopenia, thrombocytopenia, and elevated serum aminotransferase levels.

Diagnosis

HGA should be considered in pts with influenza-like illness during May through December and in pts with atypical severe presentations of Lyme disease.

• Peripheral-blood films may reveal morulae in neutrophils in 20–75% of infections.

• PCR testing before antibiotic therapy or retrospective serologic testing demonstrating a ≥4-fold rise in antibody titer can confirm the diagnosis.

Treatment

Doxycycline (100 mg PO bid) is effective, and most pts defervesce within 24–48 h. Pregnant women and children <8 years old may be treated with rifampin.

PREVENTION

HME and HGA are prevented by avoidance of ticks in endemic areas, use of protective clothing and tick repellents, careful tick searches after exposures, and prompt removal of attached ticks.

Q FEVER

Microbiology

Coxiella burnetii—the etiologic agent of Q fever—is a small, pleomorphic coccobacillus with a gram-negative cell wall that exists intracellularly.

Epidemiology and Pathogenesis

A worldwide disease, Q fever is a zoonosis. Cattle, sheep, and goats are responsible for most cases of human infection; many other animals can serve as vectors of transmission or as reservoirs of disease.

• C. burnetii localizes to the uterus and mammary glands of infected female mammals. It is reactivated in pregnancy and is found at high concentrations in the placenta. At parturition, the organism is dispersed as an aerosol, and infection usually follows inhalation.

• Abattoir workers, veterinarians, farmers, and other persons who have contact with infected animals, and particularly with newborn animals or infected products of conception, are at risk.

• In the U.S., there are 28–54 cases per year; in Australia, there are 30 cases per 1 million population per year.

Clinical Manifestations

The specific presentation of acute Q fever differs geographically (e.g., pneumonia in Nova Scotia and granulomatous hepatitis in Marseille); chronic Q fever almost always implies endocarditis.

• Acute Q fever: After an incubation period of 3–30 days, pts may present with flulike syndromes, prolonged fever, pneumonia, hepatitis, pericarditis, myocarditis, meningoencephalitis, and infection during pregnancy.

– Symptoms are often nonspecific (e.g., fever, fatigue, headache, chills, sweats, nausea, vomiting, diarrhea, cough, and occasionally rash).

– Multiple rounded opacities on CXR in pts in endemic areas are highly suggestive of Q fever pneumonia.

– The WBC count is usually normal, but thrombocytopenia occurs. During recovery, reactive thrombocytosis can develop.

– Prolonged fatigue, along with a constellation of nonspecific symptoms (e.g., headaches, myalgias, arthralgias), can follow Q fever (post–Q fever fatigue syndrome).

• Chronic Q fever: Pts with C. burnetii endocarditis typically have prior valvular heart disease, immunosuppression, or chronic renal failure.

– Fever is absent or low grade; pts may be ill for >1 year before diagnosis.

– Valvular vegetations are best seen with transesophageal echocardiography rather than transthoracic echocardiography, which identifies vegetations in only 12% of cases. The vegetations differ from those in bacterial endocarditis of other etiologies and manifest as endothelium-covered nodules on the valve.

– The disease should be suspected in all pts with culture-negative endocarditis.

– Although C. burnetii can be isolated by a shell-vial technique, most laboratories are not permitted to attempt isolation because of the organism’s highly contagious nature. PCR testing of tissue or biopsy specimens can be used, but serology is the most common diagnostic tool; IFA is the method of choice.

TREATMENT Q Fever

• Acute Q fever is treated with doxycycline (100 mg bid for 14 days).

– Quinolones are also efficacious.

– If Q fever is diagnosed during pregnancy, trimethoprimsulfamethoxazole should be administered up to term.

• The currently recommended treatment for chronic Q fever is doxycycline (100 mg bid) and hydroxychloroquine (200 mg tid; plasma concentrations maintained at 0.8–1.2 μg/mL) for 18 months.

– In vitro, hydroxychloroquine renders doxycycline bactericidal against C. burnetii.

– The minimal inhibitory concentration (MIC) of doxycycline for the pt’s isolate should be determined and serum levels monitored, with a goal of a serum level–to–doxycycline MIC ratio of ≥1.

– Pts should be advised about photosensitivity and retinal toxicity risks with treatment.

– Pts who cannot receive doxycycline-hydroxychloroquine should be treated with at least two agents active against C. burnetii. The combination of rifampin (300 mg once daily) plus doxycycline (100 mg bid) or ciprofloxacin (750 mg bid) has been used with success.

– Treatment should be given for at least 3 years and discontinued only if phase I IgA and IgG antibody titers are ≤1:50 and ≤1:200, respectively.

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For a more detailed discussion, see Walker DH, Dumler JS, Marrie T: Rickettsial Diseases, Chap. 174, p. 1407, in HPIM-18.