CHAPTER 83: RICKETTSIAL DISEASES

The rickettsiae are a heterogeneous group of small, obligately intracellular, gram-negative coccobacilli and short bacilli, most of which are transmitted by a tick, mite, flea, or louse vector. Except in the case of louse-borne typhus, humans are incidental hosts. Among rickettsiae, Coxiella burnetii, Rickettsia prowazekii, and R. typhi have the well-documented ability to survive for an extended period outside the reservoir or vector and to be extremely infectious: inhalation of a single Coxiella microorganism can cause pneumonia. High-level infectivity and severe illness after inhalation make R. prowazekii, R. rickettsii, R. typhi, R. conorii, and C. burnetii bioterrorism threats.

Clinical infections with rickettsiae can be classified according to (1) the taxonomy and diverse microbial characteristics of the agents, which belong to seven genera (Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia, Candidatus Neoehrlichia, and Coxiella); (2) epidemiology; or (3) clinical manifestations. The clinical manifestations of all the acute presentations are similar during the first 5 days: 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. Given the 15 etiologic agents with varied mechanisms of transmission, geographic distributions, and associated disease manifestations, the consideration of rickettsial diseases as a single entity poses complex challenges (Table 83-1).

Establishing the etiologic diagnosis of rickettsioses is very difficult during the acute stage of illness, and definitive diagnosis usually requires the examination of paired serum samples after convalescence. Heightened clinical suspicion is based on epidemiologic data, history of exposure to vectors or reservoir animals, travel to endemic locations, clinical manifestations (sometimes including rash or eschar), and characteristic laboratory findings (including thrombocytopenia, normal or low white blood cell [WBC] counts, elevated hepatic enzyme levels, and hyponatremia). Such suspicion should prompt empirical treatment. Doxycycline is the drug of choice for most of these infections. Only one agent, C. burnetii, has been documented to cause chronic illness. One other species, R. prowazekii, causes recrudescent illness (Brill-Zinsser disease) when latent infection is reactivated years after resolution of the acute illness.

Rickettsial infections dominated by fever may resolve without further clinical evolution. However, after nonspecific early manifestations, the illnesses can also evolve along one or more of several principal clinical lines: (1) development of a macular or maculopapular rash; (2) development of an eschar at the site of tick or mite feeding; (3) development of a vesicular rash (often in rickettsialpox and African tick-bite fever); (4) development of pneumonitis with chest radiographic opacities and/or rales (Q fever and severe cases of Rocky Mountain spotted fever [RMSF], Mediterranean spotted fever [MSF], louse-borne typhus, human monocytotropic ehrlichiosis [HME], human granulocytotropic anaplasmosis [HGA], scrub typhus, and murine typhus); (5) development of meningoencephalitis (louse-borne typhus and severe cases of RMSF, scrub typhus, HME, murine typhus, MSF, and [rarely] Q fever); and (6) progressive hypotension and multiorgan failure as seen with sepsis or toxic shock syndromes (RMSF, MSF, louse-borne typhus, murine typhus, scrub typhus, HME, HGA, and neoehrlichiosis).

Epidemiologic clues to the transmission of a particular pathogen include (1) environmental exposure to ticks, fleas, or mites during the season of activity of the vector species for the disease in the appropriate geographic region (spotted fever and typhus rickettsioses, scrub typhus, ehrlichioses, anaplasmosis); (2) travel to or residence in an endemic geographic region during the incubation period (Table 83-1); (3) exposure to parturient ruminants, cats, and dogs (Q fever); (4) exposure to flying squirrels (R. prowazekii infection); and (5) history of previous louse-borne typhus (recrudescent typhus).

Clinical laboratory findings, such as thrombocytopenia (particularly in spotted fever and typhus rickettsioses, ehrlichioses, anaplasmosis, and scrub typhus), normal or low WBC counts, mild to moderate serum elevations of hepatic aminotransferases, and hyponatremia, suggest some common pathophysiologic mechanisms.

Application of these clinical, epidemiologic, and laboratory principles requires consideration of a rickettsial diagnosis and knowledge of the individual diseases.

These diseases, caused by organisms of the genera Rickettsia and Orientia in the family Rickettsiaceae, result from endothelial cell infection and increased vascular permeability. Pathogenic rickettsial species are very closely related, have small genomes (as a result of reductive evolution, which eliminated many genes for biosynthesis of intracellularly available molecules), and are traditionally separated into typhus and spotted fever groups on the basis of lipopolysaccharide antigens. Some diseases and their agents (e.g., R. africae, R. parkeri, and R. sibirica) are too similar to require separate descriptions. Indeed, the similarities among MSF (R. conorii [all strains] and R. massiliae), North Asian tick typhus (R. sibirica), Japanese spotted fever (R. japonica), and Flinders Island spotted fever (R. honei) far outweigh the minor variations. The Rickettsiaceae that cause life-threatening infections are, in order of decreasing case-fatality rate, R. rickettsii (RMSF); R. prowazekii (louse-borne typhus); Orientia tsutsugamushi (scrub typhus); R. conorii (MSF); R. typhi (murine typhus); and, in rare cases, other spotted fever–group organisms. Some agents (e.g., R. parkeri, R. africae, R. akari, R. slovaca, R. honei, R. felis, R. massiliae, R. helvetica, R. heilongjiangensis, R. aeschlimannii, and R. monacensis) have never been documented to cause a fatal illness.

ROCKY MOUNTAIN SPOTTED FEVER

Epidemiology

RMSF occurs in 47 states (with the highest prevalence in the south-central and southeastern states) as well as in Canada, Mexico, and Central and South America. The infection is transmitted by Dermacentor variabilis, the American dog tick, in the eastern two-thirds of the United States and California; by D. andersoni, the Rocky Mountain wood tick, in the western United States; by Rhipicephalus sanguineus in Mexico, Arizona, and probably Brazil; and by Amblyomma cajennense and A. aureolatum in Central and/or South America. Maintained principally by transovarian transmission from one generation of ticks to the next, R. rickettsii can be acquired by uninfected ticks through the ingestion of a blood meal from rickettsemic small mammals.

Humans become infected during tick season (in the Northern Hemisphere, from May to September), although some cases occur in winter. The mortality rate was 20–25% in the preantibiotic era and remains at ~3–5%, principally because of delayed diagnosis and treatment. The case-fatality ratio increases with each decade of life above age 20.

Pathogenesis

R. rickettsii organisms are inoculated into the dermis along with secretions of the tick’s salivary glands after ≥6 h of feeding. The rickettsiae spread lymphohematogenously throughout the body and infect numerous foci of contiguous endothelial cells. The dose-dependent incubation period is ~1 week (range, 2–14 days). Occlusive thrombosis and ischemic necrosis are not the fundamental pathologic bases for tissue and organ injury. Instead, increased vascular permeability, with resulting edema, hypovolemia, and ischemia, is responsible. Consumption of platelets results in thrombocytopenia in 32–52% of patients, but disseminated intravascular coagulation with hypofibrinogenemia is rare. Activation of platelets, generation of thrombin, and activation of the fibrinolytic system all appear to be homeostatic physiologic responses to endothelial injury.

Clinical manifestations

Early in the illness, when medical attention usually is first sought, RMSF is difficult to distinguish from many self-limiting viral illnesses. Fever, headache, malaise, myalgia, nausea, vomiting, and anorexia are the most common symptoms during the first 3 days. The patient becomes progressively more ill as vascular infection and injury advance. In one large series, only one-third of patients were diagnosed with presumptive RMSF early in the clinical course and treated appropriately as outpatients. In the tertiary-care setting, RMSF is all too often recognized only when late severe manifestations, developing at the end of the first week or during the second week of illness in patients without appropriate treatment, prompt return to a physician or hospital and admission to an intensive care unit.

The progressive nature of the infection is clearly manifested in the skin. Rash is evident in only 14% of patients on the first day of illness and in only 49% during the first 3 days. Macules (1–5 mm) appear first on the wrists and ankles and then on the remainder of the extremities and the trunk. Later, more severe vascular damage results in frank hemorrhage at the center of the maculopapule, producing a petechia that does not disappear upon compression (Fig. 83-1). This sequence of events is sometimes delayed or aborted by effective treatment. However, the rash is a variable manifestation, appearing on day 6 or later in 20% of cases and not appearing at all in 9–16% of cases. Petechiae occur in 41–59% of cases, appearing on or after day 6 in 74% of cases that manifest a rash. Involvement of the palms and soles, often considered diagnostically important, usually develops relatively late in the course (after day 5 in 43% of cases) and does not develop at all in 18–64% of cases.

Hypovolemia leads to prerenal azotemia and (in 17% of cases) hypotension. Infection of the pulmonary microcirculation leads to noncardiogenic pulmonary edema; 12% of patients have severe respiratory disease, and 8% require mechanical ventilation. Cardiac involvement manifests as dysrhythmia in 7–16% of cases.

Besides respiratory failure, central nervous system (CNS) involvement is the other important determinant of the outcome of RMSF. Encephalitis, presenting as confusion or lethargy, is apparent in 26–28% of cases. Progressively severe encephalitis manifests as stupor or delirium in 21–26% of cases, ataxia in 18%, coma in 10%, and seizures in 8%. Numerous focal neurologic deficits have been reported. Meningoencephalitis results in cerebrospinal fluid (CSF) pleocytosis in 34–38% of cases; usually there are 10–100 cells/μL and a mononuclear predominance, but occasionally there are >100 cells/μL and a polymorphonuclear predominance. The CSF protein concentration is increased in 30–35% of cases, but the CSF glucose concentration is usually normal.

Renal failure, often reversible with rehydration, is caused by acute tubular necrosis in severe cases with shock. Hepatic injury with increased serum aminotransferase concentrations (38% of cases) is due to focal death of individual hepatocytes without hepatic failure. Jaundice is recognized in 9% of cases and an elevated serum bilirubin concentration in 18–30%.

Life-threatening bleeding is rare. Anemia develops in 30% of cases and is severe enough to require transfusions in 11%. Blood is detected in the stool or vomitus of 10% of patients, and death has followed massive upper-gastrointestinal hemorrhage.

Other characteristic clinical laboratory findings include increased plasma levels of proteins of the acute-phase response (C-reactive protein, fibrinogen, ferritin, and others), hypoalbuminemia, and hyponatremia (in 56% of cases) due to the appropriate secretion of antidiuretic hormone in response to the hypovolemic state. Myositis occurs occasionally, with marked elevations in serum creatine kinase levels and multifocal rhabdomyonecrosis. Ocular involvement includes conjunctivitis in 30% of cases and retinal vein engorgement, flame hemorrhages, arterial occlusion, and papilledema with normal CSF pressure in some instances.

In untreated cases, the patient usually dies 8–15 days after onset. A rare presentation, fulminant RMSF, is fatal within 5 days after onset. This fulminant presentation is seen most often in male black patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and may be related to an undefined effect of hemolysis on the rickettsial infection. Although survivors of RMSF usually return to their previous state of health, permanent sequelae, including neurologic deficits and gangrene necessitating amputation of extremities, may follow severe illness.

Diagnosis

The diagnosis of RMSF during the acute stage is more difficult than is generally appreciated. The most important epidemiologic factor is a history of exposure to a potentially tick-infested environment within the 14 days preceding disease onset during a season of possible tick activity. However, only 60% of patients actually recall being bitten by a tick during the incubation period.

The differential diagnosis for early clinical manifestations of RMSF (fever, headache, and myalgia without a rash) includes influenza, enteroviral infection, infectious mononucleosis, viral hepatitis, leptospirosis, typhoid fever, gram-negative or gram-positive bacterial sepsis, HME, HGA, murine typhus, sylvatic flying-squirrel typhus, and rickettsialpox. Enterocolitis may be suggested by nausea, vomiting, and abdominal pain; prominence of abdominal tenderness has resulted in exploratory laparotomy. CNS involvement can masquerade as bacterial or viral meningoencephalitis. Cough, pulmonary signs, and chest radiographic opacities can lead to a diagnostic consideration of bronchitis or pneumonia.

At presentation during the first 3 days of illness, only 3% of patients exhibit the classic triad of fever, rash, and history of tick exposure. When a rash appears, a diagnosis of RMSF should be considered. However, many illnesses considered in the differential diagnosis also can be associated with a rash, including rubeola, rubella, meningococcemia, disseminated gonococcal infection, secondary syphilis, toxic shock syndrome, drug hypersensitivity, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, Kawasaki syndrome, and immune complex vasculitis. Conversely, any person in an endemic area with a provisional diagnosis of one of the above illnesses could have RMSF. Thus, if a viral infection is suspected during RMSF season in an endemic area, it should always be kept in mind that RMSF can mimic viral infection early in the course; if the illness worsens over the next couple of days after initial presentation, the patient should return for reevaluation.

The most common serologic test for confirmation of the diagnosis is the indirect immunofluorescence assay. Not until 7–10 days after onset is a diagnostic titer of ≥64 usually detectable. The sensitivity and specificity of the indirect immunofluorescence IgG assay are 89–100% and 99–100%, respectively. It is important to understand that serologic tests for RMSF are usually negative at the time of presentation for medical care and that treatment should not be delayed while a positive serologic result is awaited.

The only diagnostic test that has proven useful during the acute illness is immunohistologic examination of a cutaneous biopsy sample from a rash lesion for R. rickettsii. Examination of a 3-mm punch biopsy from such a lesion is 70% sensitive and 100% specific. The sensitivity of polymerase chain reaction (PCR) amplification and detection of R. rickettsii DNA in peripheral blood is improving. However, although rickettsiae are present in large quantities in heavily infected foci of endothelial cells, there are relatively low quantities in the circulation. Cultivation of rickettsiae in cell culture is feasible but is seldom undertaken because of biohazard concerns. The recent dramatic increase in the reported incidence of RMSF correlates with the use of single-titer spotted fever–group cross-reactive enzyme immunoassay serology. Few cases are specifically determined to be caused by R. rickettsii. Currently, many febrile persons who do not have RMSF present with cross-reactive antibodies, possibly because of previous exposure to the highly prevalent spotted fever–group rickettsia R. amblyommii.

TREATMENT

Prevention

Avoidance of tick bites is the only available preventive approach. Use of protective clothing and tick repellents, inspection of the body once or twice a day, and removal of ticks before they inoculate rickettsiae reduce the risk of infection. Prophylactic doxycycline treatment of tick bites has no proven role in preventing RMSF.

MEDITERRANEAN SPOTTED FEVER (BOUTONNEUSE FEVER), AFRICAN TICK-BITE FEVER, AND OTHER TICK-BORNE SPOTTED FEVERS

Epidemiology and clinical manifestations

R. conorii is prevalent in southern Europe, Africa, and southwestern and south-central Asia. Regional names for the disease caused by this organism include Mediterranean spotted fever, Kenya tick typhus, Indian tick typhus, Israeli spotted fever, and Astrakhan spotted fever. The disease is characterized by high fever, rash, and—in most geographic locales—an inoculation eschar (tâche noire) at the site of the tick bite. A severe form of the disease (mortality rate, 50%) occurs in patients with diabetes, alcoholism, or heart failure.

African tick-bite fever, caused by R. africae, occurs in rural areas of sub-Saharan Africa and in the Caribbean islands and is transmitted by Amblyomma hebraeum and A. variegatum ticks. The average incubation period is 4–10 days. The mild illness consists of headache, fever, eschar, and regional lymphadenopathy. Amblyomma ticks often feed in groups, with the consequent development of multiple eschars. Rash may be vesicular, sparse, or absent altogether. Because of tourism in sub-Saharan Africa, African tick-bite fever is the rickettsiosis most frequently imported into Europe and North America. A similar disease caused by the closely related species R. parkeri is transmitted by A. maculatum in the United States and by A. triste in South America.

R. japonica causes Japanese spotted fever, which also occurs in Korea. Similar diseases in northern Asia are caused by R. sibirica and R. heilongjiangensis. Queensland tick typhus due to R. australis is transmitted by Ixodes holocyclus ticks. Flinders Island spotted fever, found on the island for which it is named as well as in Tasmania, mainland Australia, and Asia, is caused by R. honei. In Europe, patients infected with R. slovaca after a wintertime Dermacentor tick bite manifest an afebrile illness with an eschar (usually on the scalp) and painful regional lymphadenopathy.

Diagnosis

Diagnosis of these tick-borne spotted fevers is based on clinical and epidemiologic findings and is confirmed by serology, immunohistochemical demonstration of rickettsiae in skin biopsy specimens, cell-culture isolation of rickettsiae, or PCR of skin biopsy, eschar, or blood samples. Serologic diagnosis detects antibodies to antigens shared among spotted fever–group rickettsiae, hindering identification of the etiologic species. In an endemic area, a possible diagnosis of rickettsial spotted fevers should be considered when patients present with fever, rash, and/or a skin lesion consisting of a black necrotic area or a crust surrounded by erythema.

TREATMENT

RICKETTSIALPOX

R. akari infects mice and their mites (Liponyssoides sanguineus), which maintain the organisms by transovarial transmission.

Epidemiology

Rickettsialpox is recognized principally in New York City, but cases have also been reported in other urban and rural locations in the United States and in Ukraine, Croatia, Mexico, and Turkey. Investigation of eschars suspected of representing bioterrorism-associated cutaneous anthrax revealed that rickettsialpox occurs more frequently than previously realized.

Clinical manifestations

A papule forms at the site of the mite’s feeding, develops a central vesicle, and becomes a 1- to 2.5-cm painless black crusted eschar surrounded by an erythematous halo (Fig. 83-2). Enlargement of the regional lymph nodes draining the eschar suggests initial lymphogenous spread. After an incubation period of 10–17 days, during which the eschar and regional lymphadenopathy frequently go unnoticed, disease onset is marked by malaise, chills, fever, headache, and myalgia. A macular rash appears 2–6 days after onset and usually evolves sequentially into papules, vesicles, and crusts that heal without scarring (Fig. 83-3); in some cases, the rash remains macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain, cough, conjunctivitis, or photophobia. Without treatment, fever lasts 6–10 days.

Diagnosis and treatment

Clinical, epidemiologic, and convalescent serologic data establish the diagnosis of a spotted fever–group rickettsiosis that is seldom pursued further. Doxycycline is the drug of choice for treatment.

FLEA-BORNE SPOTTED FEVER

An emerging rickettsiosis caused by R. felis occurs worldwide. Maintained transovarially in the geographically widespread cat flea Ctenocephalides felis, the infection has been described as moderately severe, with fever, rash, and headache as well as CNS, gastrointestinal, and pulmonary symptoms.

EPIDEMIC (LOUSE-BORNE) TYPHUS

Epidemiology

The human body louse (Pediculus humanus corporis) lives in clothing under poor hygienic conditions and usually in impoverished cold areas. Lice acquire R. prowazekii when they ingest blood from a rickettsemic patient. The rickettsiae multiply in the louse’s midgut epithelial cells and are shed in its feces. The infected louse leaves a febrile person and deposits infected feces on its subsequent host during its blood meal; the patient autoinoculates the organisms by scratching. The louse is killed by the rickettsiae and does not pass R. prowazekii to its offspring.

Epidemic typhus haunts regions afflicted by wars and disasters. An outbreak involved 100,000 people in refugee camps in Burundi in 1997. A small focus was documented in Russia in 1998; sporadic cases were reported from Algeria, and frequent outbreaks occurred in Peru. Eastern flying squirrels (Glaucomys volans) and their lice and fleas maintain R. prowazekii in a zoonotic cycle.

Brill-Zinsser disease is a recrudescent illness occurring years after acute epidemic typhus, probably as a result of waning immunity. R. prowazekii remains latent for years; its reactivation results in sporadic cases of disease in louse-free populations or in epidemics in louse-infested populations.

Rickettsiae are potential agents of bioterrorism (Chap. 10). Infections with R. prowazekii and R. rickettsii have high case–fatality ratios. These organisms cause difficult-to-diagnose diseases and are highly infectious when inhaled as aerosols. Organisms resistant to tetracycline or chloramphenicol have been developed in the laboratory.

Clinical manifestations

After an incubation period of ~1–2 weeks, the onset of illness is abrupt, with prostration, severe headache, and fever rising rapidly to 38.8°–40.0°C (102°–104°F). Cough is prominent, developing in 70% of patients. Myalgias are usually severe. A rash begins on the upper trunk, usually on the fifth day, and then becomes generalized, involving the entire body except the face, palms, and soles. Initially, this rash is macular; without treatment, it becomes maculopapular, petechial, and confluent. The rash often goes undetected in black skin; 60% of African patients have spotless epidemic typhus. Photophobia, with considerable conjunctival injection and eye pain, is common. The tongue may be dry, brown, and furred. Confusion and coma are common. Skin necrosis and gangrene of the digits as well as interstitial pneumonia may occur in severe cases. Untreated disease is fatal in 7–40% of cases, with outcome depending primarily on the condition of the host. Patients with untreated infections develop renal insufficiency and multiorgan involvement in which neurologic manifestations are frequently prominent. Overall, 12% of patients with epidemic typhus have neurologic involvement. Infection associated with North American flying squirrels is a milder illness; whether this milder disease is due to host factors (e.g., better health status) or attenuated virulence is unknown.

Diagnosis and treatment

Epidemic typhus is sometimes misdiagnosed as typhoid fever in tropical countries (Chap. 62). The means even for serologic studies are often unavailable in settings of louse-borne typhus. Epidemics can be recognized by the serologic or immunohistochemical diagnosis of a single case or by detection of R. prowazekii in a louse found on a patient. Doxycycline (200 mg/d, given in two divided doses) is administered orally or—if the patient is comatose or vomiting—intravenously. Although under epidemic conditions a single 200-mg oral dose is effective, treatment is generally continued until 2–3 days after defervescence. Pregnant patients should be evaluated individually and treated with chloramphenicol early in pregnancy or, if necessary, with doxycycline late in pregnancy.

Prevention

Prevention of epidemic typhus involves control of body lice. Clothes should be changed regularly, and insecticides should be used every 6 weeks to control the louse population.

ENDEMIC MURINE TYPHUS

Epidemiology

R. typhi is maintained in mammalian host/flea cycles, with rats (Rattus rattus and R. norvegicus) and the Oriental rat flea (Xenopsylla cheopis) as the classic zoonotic niche. Fleas acquire R. typhi from rickettsemic rats and carry the organism throughout their life span. Nonimmune rats and humans are infected when rickettsia-laden flea feces contaminate pruritic bite lesions; less frequently, the flea bite transmits the organisms. Transmission can also occur via inhalation of aerosolized rickettsiae from flea feces. Infected rats appear healthy, although they are rickettsemic for ~2 weeks.

Murine typhus occurs mainly in Texas and southern California, where the classic rat/flea cycle is absent and an opossum/cat flea (C. felis) cycle is prominent. Globally, endemic typhus occurs mainly in warm (often coastal) areas throughout the tropics and subtropics, where it is highly prevalent though often unrecognized. The incidence peaks from April through June in southern Texas and during the warm months of summer and early fall in other geographic locations. Patients seldom recall exposure to fleas, although exposure to animals such as cats, opossums, and rats is reported in nearly 40% of cases.

Clinical manifestations

The incubation period of experimental murine typhus averages 11 days (range, 8–16 days). Headache, myalgia, arthralgia, nausea, and malaise develop 1–3 days before onset of chills and fever. Nearly all patients experience nausea and vomiting early in the illness.

The duration of untreated illness averages 12 days (range, 9–18 days). Rash is present in only 13% of patients at presentation for medical care (usually ~4 days after onset of fever), appearing an average of 2 days later in half of the remaining patients and never appearing in the others. The initial macular rash is often detected by careful inspection of the axilla or the inner surface of the arm. Subsequently, the rash becomes maculopapular, involving the trunk more often than the extremities; it is seldom petechial and rarely involves the face, palms, or soles. A rash is detected in only 20% of patients with darkly pigmented skin.

Pulmonary involvement is frequently prominent; 35% of patients have a hacking, nonproductive cough, and 23% of patients who undergo chest radiography have pulmonary densities due to interstitial pneumonia, pulmonary edema, and pleural effusions. Bibasilar rales are the most common pulmonary sign. Less common clinical manifestations include abdominal pain, confusion, stupor, seizures, ataxia, coma, and jaundice. Clinical laboratory studies frequently reveal anemia and leukopenia early in the course, leukocytosis late in the course, thrombocytopenia, hyponatremia, hypoalbuminemia, mildly increased serum hepatic aminotransferases, and prerenal azotemia. Complications can include respiratory failure, hematemesis, cerebral hemorrhage, and hemolysis. Severe illness necessitates the admission of 10% of hospitalized patients to an intensive care unit. Greater severity is generally associated with old age, underlying disease, and treatment with a sulfonamide; the case-fatality rate is 1%. In a study of children with murine typhus, 50% suffered only nocturnal fevers, feeling well enough for active daytime play.

Diagnosis and treatment

Serologic studies of acute- and convalescent-phase sera can provide a diagnosis, and an immunohistochemical method for identification of typhus group-specific antigens in biopsy samples has been developed. Cultivation and PCR are used only infrequently and are not widely available. Nevertheless, most patients are treated empirically with doxycycline (100 mg bid orally for 7–15 days) on the basis of clinical suspicion. Ciprofloxacin provides an alternative if doxycycline is contraindicated.

SCRUB TYPHUS

Epidemiology

O. tsutsugamushi differs substantially from Rickettsia species both genetically and in cell wall composition (i.e., it lacks lipopolysaccharide). O. tsutsugamushi is maintained by transovarial transmission in trombiculid mites. After hatching, infected larval mites (chiggers, the only stage that feeds on a host) inoculate organisms into the skin. Infected chiggers are particularly likely to be found in areas of heavy scrub vegetation during the wet season, when mites lay eggs.

Scrub typhus is endemic and reemerging in eastern and southern Asia, northern Australia, and islands of the western Pacific and Indian Oceans. Infections are prevalent in these regions; in some areas, >3% of the population is infected or reinfected each month. Immunity wanes over 1–3 years, and the organism exhibits remarkable antigenic diversity.

Clinical manifestations

Illness varies from mild and self-limiting to fatal. After an incubation period of 6–21 days, onset is characterized by fever, headache, myalgia, cough, and gastrointestinal symptoms. Some patients recover spontaneously after a few days. The classic case description includes an eschar where the chigger has fed, regional lymphadenopathy, and a maculopapular rash—signs that are seldom seen in indigenous patients. Fewer than 50% of Westerners develop an eschar, and fewer than 40% develop a rash (on day 4–6 of illness). Severe cases typically manifest with encephalitis and interstitial pneumonia due to vascular injury. The case-fatality rate for untreated classic cases is 7% but would probably be lower if all mild cases were diagnosed.

Diagnosis and treatment

Serologic assays (indirect fluorescent antibody, indirect immunoperoxidase, and enzyme immunoassays) are the mainstays of laboratory diagnosis. PCR amplification of Orientia genes from eschars and blood also is effective. Patients are treated with doxycycline (100 mg bid orally for 7–15 days), azithromycin (500 mg orally for 3 days), or chloramphenicol (500 mg qid orally for 7–15 days). Some cases of scrub typhus in Thailand are caused by strains that have high doxycycline or chloramphenicol minimal inhibitory concentrations (MICs) but that are susceptible to azithromycin and rifampin.

Ehrlichioses are acute febrile infections caused by members of the family Anaplasmataceae, which is made up of obligately intracellular organisms of five genera: Ehrlichia, Anaplasma, Wolbachia, Candidatus Neoehrlichia, and Neorickettsia. The bacteria reside in vertebrate reservoirs and target vacuoles of hematopoietic cells (Fig. 83-4). Three Ehrlichia species and one Anaplasma species are transmitted by ticks to humans and cause infection that can be severe and prevalent. E. chaffeensis, the agent of HME, and an E. muris–like agent (EMLA) infect predominantly mononuclear phagocytes; E. ewingii and A. phagocytophilum infect neutrophils. Infection with Candidatus Neoehrlichia mikurensis is less well characterized, but the agent has been identified in human blood neutrophils.

Ehrlichia, Candidatus Neoehrlichia, and Anaplasma are maintained by horizontal tick-mammal-tick transmission, and humans are only inadvertently infected. Wolbachiae are associated with human filariasis, since they are important for filarial viability and pathogenicity; antibiotic treatment targeting wolbachiae is a strategy for filariasis control. Neorickettsiae parasitize flukes (trematodes) that in turn parasitize aquatic snails, fish, and insects. Only a single human neo-rickettsiosis has been described: sennetsu fever, an infectious mononucleosis–like illness that was first identified in 1953 and is associated with the ingestion of raw fish containing N. sennetsu–infected flukes.

HUMAN MONOCYTOTROPIC EHRLICHIOSIS

Epidemiology

More than 8404 cases of E. chaffeensis infection had been reported to the Centers for Disease Control and Prevention (CDC) as of April 2013. However, active prospective surveillance has documented an incidence as high as 414 cases per 100,000 population in some U.S. regions. Most E. chaffeensis infections are identified in the south-central, southeastern, and mid-Atlantic states, but cases have also been recognized in California and New York. All stages of the Lone Star tick (A. americanum) feed on white-tailed deer—a major reservoir. Dogs and coyotes also serve as reservoirs and often lack clinical signs. Tick bites and exposures are frequently reported by patients in rural areas, especially in May through July. The median age of HME patients is 52 years; however, severe and fatal infections in children also are well recognized. Of patients with HME, 60% are male.

E. chaffeensis has been detected in South America, Africa, and Asia.

Clinical manifestations

E. chaffeensis disseminates hematogenously from the dermal blood pool created by the feeding tick. After a median incubation period of 8 days, illness develops. Clinical manifestations are undifferentiated and include fever (96% of cases), headache (72%), myalgia (68%), and malaise (77%). Less frequently observed are nausea, vomiting, and diarrhea (25–57%); cough (28%); rash (26% overall, 6% at presentation); and confusion (20%). HME can be severe: 49% of patients with documented cases are hospitalized, and ~2% die. Severe manifestations include a toxic shock–like or septic shock–like syndrome, adult respiratory distress syndrome, cardiac failure, hepatitis, meningoencephalitis, hemorrhage, and—in immunocompromised patients—overwhelming ehrlichial infection. Laboratory findings are valuable in the differential diagnosis of HME; 61% of patients have leukopenia (initially lymphopenia, later neutropenia), 73% have thrombocytopenia, and 84% have elevated serum levels of hepatic aminotransferases. Despite low blood cell counts, the bone marrow is hypercellular, and noncaseating granulomas can be present. Vasculitis is not a component of HME.

Diagnosis

HME can be fatal. Early empirical antibiotic therapy based on clinical diagnosis diminishes adverse outcomes. This diagnosis is suggested by fever with a known tick exposure during the preceding 3 weeks, thrombocytopenia and/or leukopenia, and increased serum aminotransferase levels. Morulae are demonstrated in <10% of peripheral-blood smears. HME can be confirmed during active infection by PCR amplification of E. chaffeensis nucleic acids in blood obtained before the start of doxycycline therapy. Retrospective sero-diagnosis requires a consistent clinical picture and a fourfold increase in E. chaffeensis antibody titer to ≥64 in paired sera obtained ~3 weeks apart. Separate specific diagnostic tests are necessary for HME and HGA.

EWINGII EHRLICHIOSIS AND EHRLICHIA MURIS–LIKE INFECTIONS

Ehrlichia ewingii, originally a neutrophil pathogen causing fever and lameness in dogs, resembles E. chaffeensis in its tick vector (A. americanum) and vertebrate reservoirs (white-tailed deer and dogs). An E. muris–like agent (EMLA) has been discovered and identified as the cause of human infections in Wisconsin and Minnesota. E. ewingii and EMLA illnesses are similar to but less severe than HME. Many cases occur in immunocompromised patients. No specific serologic diagnostic tests for ewingii or EMLA ehrlichiosis are readily available.

CANDIDATUS NEOEHRLICHIA MIKURENSIS INFECTION

Candidatus Neoehrlichia mikurensis, a bacterium in a phylogenetic clade between Ehrlichia and Anaplasma, was originally identified in Ixodes ricinus ticks from the Netherlands and in mice and Ixodes ovatus ticks from Japan. By means of broad-range 16S rRNA gene amplification and sequence analysis, this organism was identified as the cause of severe and sometimes prolonged febrile illnesses in European immunocompromised patients with tick bites or exposures and in Chinese patients with a mild febrile illness after being bitten by Ixodes persulcatus and Haemaphysalis concinna ticks. The clinical presentation is similar to those of HME and HGA. Specific diagnostic methods have been developed but are not widely available.

TREATMENT

PREVENTION

HME, ewingii ehrlichiosis, EMLA infection, and Candidatus N. mikurensis infection can be prevented by the avoidance of ticks in endemic areas. The use of protective clothing and tick repellents, careful postexposure tick searches, and prompt removal of attached ticks probably diminish infection risk.

HUMAN GRANULOCYTOTROPIC ANAPLASMOSIS

Epidemiology

As of April 2013, 10,181 cases of HGA had been reported to the CDC, most in the upper midwestern and northeastern United States; the geographic distribution is similar to that for Lyme disease because of the shared I. scapularis tick vector. White-footed mice, squirrels, and white-tailed deer in the United States and red deer in Europe are natural reservoirs for A. phagocytophilum. HGA incidence peaks in May through July, but the disease can occur throughout the year with exposure to Ixodes ticks. HGA often affects males (59%) and older persons (median age, 51 years).

Clinical manifestations

Seroprevalence rates are high in endemic regions; thus it seems likely that most individuals develop subclinical infections. The incubation period for HGA is 4–8 days, after which the disease manifests as fever (75–100% of cases), myalgia (77%), headache (82%), and malaise (97%). A minority of patients develop nausea, vomiting, or diarrhea (22–39%); cough (27%); or confusion (17%). Rash (6%) is almost invariably concurrent erythema migrans attributable to Lyme disease. Most patients develop thrombocytopenia (75%) and/or leukopenia (55%) with increased serum hepatic aminotransferase levels (83%).

Severe complications occur most often in the elderly and include adult respiratory distress syndrome, a toxic shock–like syndrome, and life-threatening opportunistic infections. Meningoencephalitis is rarely documented with HGA, but brachial plexopathy, cranial nerve involvement, and demyelinating polyneuropathy are reported. For HGA, 7% of patients require intensive care, and the case-fatality rate is 0.6%. Neither vasculitis nor granulomas are components of HGA. While co-infections with Borrelia burgdorferi and Babesia microti (transmitted by the same tick vector[s]) occur, there is little evidence of comorbidity or persistence. HGA is rarely acquired via transfusion.

Diagnosis

HGA should be included in the differential diagnosis of influenza-like illnesses during seasons with Ixodes tick activity (May through December), especially with known tick bite or exposure. Concurrent thrombocytopenia, leukopenia, or elevated serum levels of alanine or aspartate aminotransferase further increase the likelihood of HGA. Many HGA patients develop Lyme disease antibodies in the absence of clinical findings consistent with that diagnosis. Thus, HGA should be considered in the differential diagnosis of atypical severe Lyme disease presentations. Peripheral-blood film examination for neutrophil morulae can yield a diagnosis in 20–75% of infections. PCR testing of blood from patients with active disease before doxycycline therapy is sensitive and specific. Serodiagnosis is retrospective, requiring a four-fold increase in A. phagocytophilum antibody titer (to ≥160) in paired serum samples obtained 1 month apart. Since seroprevalence is high in some regions, a single acute-phase titer should not be used for diagnosis.

TREATMENT

Prevention

HGA prevention requires tick avoidance. Transmission can be documented as few as 4 h after a tick bite.

The agent of Q fever is Coxiella burnetii, a small intracellular prokaryote that only recently was grown in cell-free medium. C. burnetii, a pleomorphic coccobacillus with a gram-negative cell wall, survives in harsh environments; it escapes intracellular killing in macrophages by inhibiting the final step in phagosome maturation (cathepsin fusion) and has adapted to the acidic phagolysosome by producing superoxide dismutase. Infection with C. burnetii induces a range of immunomodulatory responses, from immunosuppression in chronic Q fever to the production of autoantibodies, particularly those to smooth muscle and cardiac muscle.

Q fever encompasses two broad clinical syndromes: acute and chronic infection. The host’s immune response (rather than the particular strain) most likely determines whether chronic Q fever develops. C. burnetii survives in monocytes from patients with chronic Q fever, but not in monocytes from patients with acute Q fever or from uninfected subjects. Impairment of the bactericidal activity of the C. burnetii–infected monocyte is associated with overproduction of interleukin 10. The CD4+/CD8+ ratio is decreased in Q fever endocarditis. Very few organisms and a strong cellular response are observed in patients with acute Q fever, while many organisms and a moderate cellular response occur in chronic Q fever. Immune control of C. burnetii is T cell–dependent, but 80–90% of bone marrow aspirates obtained years after recovery from Q fever contain C. burnetii DNA. C. burnetii’s ready multiplication within trophoblasts accounts for the high concentrations it can reach in the placenta.

Epidemiology

Q fever is a zoonosis. The primary sources of human infection are infected cattle, sheep, and goats. However, cats, rabbits, pigeons, and dogs also serve as sources for transmission of C. burnetii to humans. The wildlife reservoir is extensive and includes ticks, coyotes, gray foxes, skunks, raccoons, rabbits, deer, mice, bears, birds, and opossums. In female animals C. burnetii localizes to the uterus and mammary glands. Infection is reactivated during pregnancy and after radiotherapy in mouse models. High concentrations of C. burnetii are found in the placenta. At the time of parturition, the bacteria are released into the air, and infection follows inhalation of aerosolized organisms by a susceptible host. Windstorms can generate C. burnetii aerosols months after soil contamination during parturition. Individuals up to 18 km from the source have been infected. Because it is easily dispersed as an aerosol, C. burnetii is a potential agent of bioterrorism (Chap. 10), with a high infectivity rate and pneumonia as the major manifestation.

Determining the source of an outbreak of Q fever can be challenging. An outbreak of Q fever at a horse-boarding ranch in Colorado in 2005 was due to spread of infection from two herds of goats that had been acquired by the owners. PCR testing confirmed the presence of C. burnetii in the soil and among the goats. Of 138 persons who lived within 1 mile of the ranch and who were also tested, 11 (8%) had evidence of C. burnetii infection, and 8 of these 11 individuals had no direct contact with the ranch.

Persons at risk for Q fever include abattoir workers, veterinarians, farmers, and other individuals who have contact with infected animals (particularly newborn animals) or products of conception. The organism is shed in milk for weeks to months after parturition. The ingestion of contaminated milk in some geographic areas probably represents a major route of transmission to humans. A recent outbreak of Q fever associated with ingestion of raw milk confirms the oral route of transmission. In rare instances, person-to-person transmission follows labor and childbirth in an infected woman, autopsy of an infected individual, or blood transfusion. Some evidence suggests that C. burnetii can be sexually transmitted among humans. Crushing an infected tick between the fingers has resulted in Q fever; the implication is that percutaneous transmission can occur.

Infections due to C. burnetii occur in most geographic locations except New Zealand and Antarctica. Thus Q fever can be associated with travel. The number of reported cases of Q fever in the United States ranges from 28 to 54 per year. More than 70% of these cases occur in males, and April, May, and June are the most common months for acquisition. Q fever continues to be common in Australia, with 30 cases per 1 million population per year. Cases among abattoir workers in Australia declined dramatically as a result of a vaccination program. An outbreak of Q fever began in the Netherlands in 2007, and by 2010 more than 4000 cases had been reported. Pneumonia was a common manifestation in this outbreak. The outbreak was due to a combination of high-density goat farming in areas abutting large urban populations and environmental factors. Farms where spread did not occur had high vegetation densities and lower groundwater concentrations.

The primary manifestations of acute Q fever differ geographically (e.g., pneumonia in Nova Scotia and granulomatous hepatitis in Marseille). These differences could reflect the route of infection (i.e., ingestion of contaminated milk for hepatitis and inhalation of contaminated aerosols for pneumonia) or strain differences. In the Netherlands outbreak, sequelae of infection in pregnant women were rare; this was not the case among pregnant women elsewhere.

Young age seems to be protective against disease caused by C. burnetii. In a large outbreak in Switzerland, symptomatic infection occurred five times more often among persons >15 years of age than among younger individuals. In many outbreaks, men are affected more commonly than women; the proposed explanation is that female hormones are partially protective.

Clinical manifestations

Acute q fever

The symptoms of acute Q fever are nonspecific; common among them are fever, extreme fatigue, photophobia, and severe headache that is frequently retro-orbital. Other symptoms include chills, sweats, nausea, vomiting, and diarrhea, each occurring in 5–20% of cases. Cough develops in about half of patients with Q fever pneumonia. Neurologic manifestations of acute Q fever are uncommon; however, in one outbreak in the United Kingdom, 23% of 102 patients had neurologic signs and symptoms as the major manifestation. A nonspecific rash may be evident in 4–18% of patients. The WBC count is usually normal. Thrombocytopenia occurs in ~25% of patients, and reactive thrombocytosis (with platelet counts exceeding 10⁶/μL) frequently develops during recovery. Chest radiography can show opacities similar to those seen in pneumonia caused by other pathogens, but multiple rounded opacities in patients in endemic areas suggest a diagnosis of Q fever pneumonia.

Acute Q fever occasionally complicates pregnancy. In one series, it resulted in premature birth in 35% of cases and in abortion or neonatal death in 43%. Neonatal death (previous or current) and lower infant birth weight are three times more likely among women seropositive for C. burnetii.

After the usual incubation period of 3–30 days, 1070 patients with acute Q fever in southern France presented with hepatitis (40%), both pneumonia and hepatitis (20%), pneumonia (17%), isolated fever (14%), CNS involvement (2%), and pericarditis or myocarditis (1%). Acalculous cholecystitis, pancreatitis, lymphadenopathy, spontaneous rupture of the spleen, transient hypoplastic anemia, bone marrow necrosis, hemolytic anemia, histiocytic hemophagocytosis, optic neuritis, and erythema nodosum were less common manifestations.

Post–q fever fatigue syndrome

Prolonged fatigue can follow Q fever and can be accompanied by a constellation of symptoms including headaches, sweats, arthralgia, myalgias, blurred vision, muscle fasciculations, and enlarged and painful lymph nodes. Long-term persistence of a noninfective, nonbiodegraded complex of Coxiella cell components, with its antigens and specific lipopolysaccharide, has been detected in the affected persons. Patients who develop this syndrome have a higher frequency of carriage of HLA-DRB1*11 and of the 2/2 genotype of the interferon γ intron 1 microsatellite.

Chronic q fever

Chronic Q fever almost always implies endocarditis and usually occurs in patients with previous valvular heart disease, immunosuppression, or chronic renal insufficiency. Fever is usually absent or low grade. Valvular vegetations are detected in only 12% of patients by transthoracic echocardiography, but the rate of detection is higher (21–50%) with transesophageal echocardiography. The vegetations in chronic Q fever endocarditis differ from those in bacterial endocarditis, manifesting as endothelium-covered nodules on the valves. A high index of suspicion is necessary for timely diagnosis. Patients with chronic Q fever are often ill for >1 year before the diagnosis is made. The disease should be suspected in all patients with culture-negative endocarditis. In addition, all patients with valvular heart disease and an unexplained purpuric eruption, renal insufficiency, stroke, and/or progressive heart failure should be tested for C. burnetii infection. Patients with chronic Q fever have hepatomegaly and/or splenomegaly, which—in combination with rheumatoid factor, elevated erythrocyte sedimentation rate, high C-reactive protein level, and/or increased γ-globulin concentrations (up to 60–70 g/L)—suggests this diagnosis. Other manifestations of chronic Q fever include infection of vascular prostheses, aneurysms, and bone as well as chronic sternal wound infection. Unusual manifestations include chronic thrombocytopenia, mixed cryoglobulinemia, and livedo reticularis.

Diagnosis

Isolation of C. burnetii from buffy-coat blood samples or tissue specimens by a shell-vial technique is easy but requires a biosafety level 3 laboratory. PCR detects C. burnetii DNA in tissue specimens, including paraffin-embedded samples. Serology is the most commonly used diagnostic tool. Indirect immunofluorescence is sensitive and specific and is the method of choice. Rheumatoid factor should be adsorbed from the specimen before testing. With chronic infection, the titer to phase I antigen is usually much higher than that to phase II antigen (i.e., C. burnetii that has truncated lipopolysaccharide associated with gene deletions during laboratory passages), and the diagnosis should not be based on serology alone. Rather, the entire clinical setting must be taken into consideration. An anti–phase I IgG titer of ≥6400 would be considered a major criterion for the diagnosis of chronic Q fever, while a titer of ≥800 but ≤6400 would be a minor criterion. In acute Q fever, a fourfold rise in titer can be demonstrated between acute- and convalescent-phase serum samples.

Fluorodeoxyglucose positron emission tomography combined with CT (FDG-PET/CT) can be useful because it can detect not only valvular infection but also intravascular infection elsewhere as well as osteomyelitis.

TREATMENT

Prevention

A whole-cell vaccine (Q-Vax) licensed in Australia effectively prevents Q fever in abattoir workers. Before administration of the vaccine, skin testing with intradermal diluted C. burnetii vaccine is performed, serologic testing is undertaken, and a history of possible Q fever is sought. Vaccine is given only to patients with no history of Q fever and negative results in serologic and skin testing.

Good animal-husbandry practices are important in preventing widespread contamination of the environment by C. burnetii. These practices include isolating aborting animals for up to 14 days, raising feed bunks to prevent contamination of feed by excreta, destroying aborted materials (by burning and burying fetal membranes and stillborn animals), and wearing masks and gloves when handling aborted materials. Vaccination of sheep and goats and a culling program were effective in the Netherlands outbreak. Only seronegative pregnant animals should be used in research settings, and only seronegative animals should be permitted in petting zoos.

During an outbreak of Q fever and for 4 weeks after it ceases, blood donations should not be accepted from individuals who live in the affected area.

Acknowledgment

The contributions of Didier Raoult, MD, to this chapter in previous editions are gratefully acknowledged.