Chapter 26: Rickettsia and Related Genera

The human pathogens in the family Rickettsiaceae are small bacteria of the genera Rickettsia and Orientia. They are closely related to members of the family Anaplasmataceae that includes the genera Ehrlichia and Anaplasma. These organisms are obligate intracellular parasites that are transmitted to humans by arthropods. Many rickettsiae are transmitted transovarially in the arthropod, which serves as both vector and reservoir. Rickettsial infections, but not the ehrlichioses, typically are manifested by fever, rashes, and vasculitis. They are grouped on the basis of their clinical features, epidemiologic aspects, and immunologic characteristics (Table 26-1). Coxiella burnetii resides in the family Coxiellaceae and is more closely related to the genus Legionella; for convenience, it is discussed at the end of this chapter.

Properties of Rickettsiae

Rickettsiae are pleomorphic coccobacilli, appearing either as short rods (0.3 × 1–2 μm) or as cocci (0.3 μm in diameter). They do not stain well with Gram stain but are readily visible under the light microscope when stained with Giemsa stain, Gimenez stain, acridine orange, or other stains. However, immunohistochemical or immunofluorescence stains performed at a laboratory skilled in rickettsial diagnostics are the most useful methods for confirming a diagnosis of rickettsial infections.

Rickettsiae grow readily in yolk sacs of embryonated eggs. Pure preparations of rickettsiae for use in laboratory testing can be obtained by differential centrifugation of yolk sac suspensions. Many strains of rickettsiae also grow in cell culture, where the generation time is 8–10 hours at 34°C. Cell culture has replaced animal inoculation (except for Orientia species) and yolk sac cultivation for isolation of these organisms. For reasons of biosafety, isolation of rickettsiae should be done only in reference laboratories.

Rickettsiae have gram-negative cell wall structures that include peptidoglycan-containing muramic acid and diaminopimelic acid. The genus is divided into several groups. The typhus group, the spotted fever group, and the transitional group have species that are pathogenic to humans. Rickettsiae contain lipopolysaccharide and the cell wall proteins include the surface proteins OmpA and OmpB. These surface proteins are important in adherence to host cells and in the humoral immune response and also provide the basis for serotyping.

Rickettsiae grow in different parts of the cell. Those of the typhus group are usually found in the cytoplasm, and those of the spotted fever group are usually found in the nucleus. Rickettsial growth is enhanced in the presence of sulfonamides, and rickettsial diseases are made more severe by these drugs. Tetracyclines and chloramphenicol inhibit the growth of rickettsiae and can be therapeutically effective.

Most rickettsiae survive only for short times outside of the vector or host. Rickettsiae are quickly destroyed by heat, drying, and bactericidal chemicals. Dried feces of infected lice may contain infectious Rickettsia prowazekii for months at room temperature.

Rickettsial Antigens and Serology

The direct immunofluorescent antibody test can be used to detect rickettsiae in ticks and sections of tissues. The test has been most useful to detect Rickettsia rickettsii in skin biopsy specimens to aid in the diagnosis of Rocky Mountain spotted fever (RMSF); however, the test is performed in only a few reference laboratories.

Serologic evidence of infection occurs no earlier than the second week of illness for any of the rickettsial diseases. Thus, serologic tests are useful only to confirm the diagnosis, which is based on clinical findings (eg, fever, headache, rash) and epidemiologic information (eg, tick bite). Therapy for potentially severe diseases, such as RMSF and typhus, should be instituted before seroconversion occurs.

A variety of serologic tests have been used to diagnose rickettsial diseases. Most of these tests are performed only in reference laboratories. Antigens for the indirect immunofluorescence, latex agglutination, indirect immunoperoxidase tests, and enzyme immunoassay for RMSF are commercially available. Reagents for other tests are prepared only in public health or other reference laboratories. The indirect fluorescent antibody technique may be the most widely used method because of the availability of reagents and the ease with which it can be performed. The test is relatively sensitive, requires little antigen, and can be used to detect immunoglobulin M (IgM) and IgG. Rickettsiae partially purified from infected yolk sac material are tested with dilutions of a patient’s serum. Reactive antibody is detected with a fluorescein-labeled antihuman globulin. The results indicate the presence of partly species-specific antibodies, but cross-reactions are observed.

Pathology

Rickettsiae multiply in endothelial cells of small blood vessels and produce vasculitis characterized by lymphocytes that surround the blood vessels. The cells become swollen and necrotic; there is thrombosis of the vessel, leading to rupture and necrosis. Vascular lesions are prominent in the skin, but vasculitis occurs in many organs and appears to be the basis of hemostatic disturbances. Disseminated intravascular coagulation and vascular occlusion may develop. In the brain, aggregations of lymphocytes, polymorphonuclear leukocytes, and macrophages are associated with the blood vessels of the gray matter; these are called “typhus nodules.” The heart shows similar lesions of the small blood vessels. Other organs may also be involved.

Immunity

In cell cultures of macrophages, rickettsiae are phagocytosed and replicate intracellularly even in the presence of antibody. The addition of lymphocytes from immune animals stops this multiplication in vitro. Infection in humans is followed by partial immunity to reinfection from external sources, but relapses occur (see the discussion of Brill-Zinsser disease).

Clinical Findings

Rickettsial infections are characterized by fever, headache, malaise, prostration, skin rash, and enlargement of the spleen and liver.

A. Typhus Group

1. Epidemic typhus (R prowazekii)—Disease is transmitted by the body louse in a human–louse cycle. In epidemic typhus, systemic infection and prostration are severe, and fever lasts for about 2 weeks. The disease is more severe and more often fatal in patients older than 40 years of age. During epidemics, the case fatality rate has been 6–30%.

2. Endemic typhus or murine typhus (Rickettsia typhi)—Infected flea feces rubbed into the bite wound is the method of transmission. The clinical picture of endemic typhus has many features in common with that of epidemic typhus, but the disease is milder and is rarely fatal except in elderly patients.

B. Spotted Fever Group

The spotted fever group resembles typhus clinically; however, unlike the rash in other rickettsial diseases, the rash of the spotted fever group usually appears after 3–5 days of illness, first on the extremities, then moves centripetally, and involves the palms and soles. Some, such as Brazilian spotted fever and RMSF, may produce severe infections possibly due to infection of endothelial cells that leads to vascular permeability and consequently complications such as pulmonary edema and hemorrhages; others, such as Mediterranean spotted fever, are mild. The case fatality rate varies greatly. RMSF is life-threatening for all age groups but mortality is usually much greater in elderly persons (up to 50%) than in young adults or children.

C. Transitional Group

Rickettsialpox (Rickettsia akari) is a mild disease with a vesicular rash resembling that of varicella. About 1 week before onset of fever, a firm red papule appears at the site of the mite bite and develops into a deep-seated vesicle that in turn forms a black eschar (see later discussion).

D. Scrub Typhus

Scrub typhus (Orientia tsutsugamushi)—This disease resembles epidemic typhus clinically. One feature is the eschar, the punched-out ulcer covered with a blackened scab that indicates the location of the mite bite. Generalized lymphadenopathy and lymphocytosis are common. Illness can be severe with associated cardiac and cerebral involvement leading to death in about 30% of patients.

Laboratory Findings

Isolation of rickettsiae is technically difficult and is of only limited usefulness in diagnosis. It is also hazardous and must be performed in a biosafety level 3 laboratory. Animal inoculation has been replaced by cell culture methods for cultivation of most of the rickettsiae. Appropriate specimens include heparinized plasma, buffy coat, and skin lesions. Organisms can be detected in cell cultures by molecular methods or by immunofluorescence staining.

In RMSF, some other rickettsial infections, and scrub typhus, skin biopsies taken from patients between the fourth and eighth days of illness may reveal rickettsiae by immunohistochemical stains that are available in a specialized laboratory at the Centers for Disease Control and Prevention.

The polymerase chain reaction (PCR) has been used to help diagnose RMSF, other diseases of the spotted fever group, murine typhus, and scrub typhus. Real-time PCR methods have enhanced sensitivity and allow for diagnosis before a serologic response. Appropriate specimens include tissues, plasma, peripheral blood, and buffy coat specimens. Molecular techniques have also been applied to detection of rickettsiae in the vectors as well. These assays are available on a limited basis primarily in reference laboratories.

Serology is the main method available to clinical laboratories for the diagnosis of rickettsial infections. The most widely used serologic tests are indirect immunofluorescence and enzyme immunoassays (see earlier discussion). Complement fixation is no longer used in most laboratories. An antibody rise should be demonstrated during the course of the illness. In RMSF, the antibody response may not occur until after the second week of illness.

Treatment

Tetracyclines, preferably doxycycline, are effective, provided treatment is started early. Doxycycline is given daily orally and continued for 3–4 days after defervescence. In severely ill patients, the initial doses can be given intravenously. Chloramphenicol also can be effective.

Sulfonamides enhance the disease and are contraindicated. There is limited clinical experience with the fluoroquinolones, although they have been shown to have in vitro activity.

Epidemiology

A variety of arthropods, especially ticks and mites, harbor rickettsia-like organisms in the cells that line the alimentary tract. Many such organisms are not evidently pathogenic for humans.

The life cycles of different rickettsiae vary. R prowazekii has a life cycle in humans and the human louse (Pediculus humanus corporis and Pediculus humanus capitis). The louse obtains the organism by biting infected human beings and transmits the agent by fecal excretion on the surface of the skin of another person. Whenever a louse bites, it defecates at the same time. Scratching the area of the bite allows the rickettsiae excreted in the feces to penetrate the skin. As a result of the infection, the louse dies, but the organisms remain viable for some time in its dried feces. Rickettsiae are not transmitted from one generation of lice to another. Delousing large proportions of the population with insecticides has controlled typhus epidemics.

Brill-Zinsser disease is a recrudescence of an old typhus infection. The rickettsiae can persist for many years in the lymph nodes of an individual without any symptoms being manifest. The rickettsiae isolated from such cases behave like classic R prowazekii; this suggests that humans themselves are the reservoir of the rickettsiae of epidemic typhus. Typhus epidemics have been associated with war and the lowering of standards of personal hygiene, which in turn have increased the opportunities for human lice to flourish. If this occurs at the time of recrudescence of an old typhus infection, an epidemic may be set off. Brill-Zinsser disease occurs in local populations of typhus areas as well as in persons who migrate from such areas to places where the disease does not exist. Serologic characteristics readily distinguish Brill disease from primary epidemic typhus. Antibodies arise earlier and are IgG rather than the IgM detected after primary infection. They reach a maximum by the 10th day of disease. This early IgG antibody response and the mild course of the disease suggest that partial immunity is still present from the primary infection.

In the United States, R prowazekii has an extrahuman reservoir in the southern flying squirrel, Glaucomys volans. In areas where southern flying squirrels are indigenous (southern Maine to Florida to the center of the United States), human infections have occurred after bites by ectoparasites of this rodent. Infection between humans occurs by the human body louse Pediculus humanus corporis. Recent reports indicate that epidemic typhus may be increasing in some areas; R prowazekii is considered a biothreat agent.

R typhi has its reservoir in the rat, in which the infection is inapparent and long lasting. Rat fleas carry the rickettsiae from rat to rat and sometimes from rats to humans, who develop endemic typhus. Cat fleas can serve as vectors. In endemic typhus, the flea cannot transmit the rickettsiae transovarially.

O tsutsugamushi has its true reservoir in the mites that infest rodents. Rickettsiae can persist in rats for more than 1 year after infection. Mites transmit the infection transovarially. Occasionally, infected mites or rat fleas bite humans, and scrub typhus results. The rickettsiae persist in the mite–rat–mite cycle in the scrub or secondary jungle vegetation that has replaced virgin jungle in areas of partial cultivation. Such areas may become infested with rats and trombiculid mites.

R rickettsii may be found in healthy wood ticks (Dermacentor andersoni) and is passed transovarially. Infected ticks in the western United States occasionally bite vertebrates such as rodents, deer, and humans. To be infectious, the tick carrying the rickettsiae must be engorged with blood because this increases the number of rickettsiae in the tick. Thus, there is a delay of 45–90 minutes between the time of the attachment of the tick and its becoming infective. In the eastern United States, the dog tick Dermacentor variabilis and Rhipicephalus sanguineus ticks transmit RMSF. Dogs are hosts to these ticks and may serve as a reservoir for tick infection. Small rodents are another reservoir. Most cases of RMSF in the United States now occur in the eastern and southeastern regions.

R akari has its vector in bloodsucking mites of the species Liponyssoides sanguineus. These mites may be found on the mice (Mus musculus) trapped in apartment houses in the United States where rickettsialpox has occurred. Transovarial transmission of the rickettsiae occurs in the mite. Thus, the mite may act as a true reservoir as well as a vector. R akari has also been isolated in eastern Europe, South Africa, and Korea.

Geographic Occurrence

A. Epidemic Typhus

This potentially worldwide infection has disappeared from the United States, Britain, and Scandinavia. It is still present in the Balkans, Asia, Africa, Mexico, and the Andes mountains of South America. In view of its long duration in humans as a latent infection (Brill-Zinsser disease), it can emerge and flourish quickly under proper environmental conditions, as it did in Europe during World War II because of the deterioration of community hygiene.

B. Endemic Murine Typhus

Disease exists worldwide, especially in areas of high rat infestation. It may exist in the same areas as—and may be confused with—epidemic typhus or scrub typhus.

C. Scrub Typhus

Infection is seen in the Far East, especially Myanmar (Burma), India, Sri Lanka, New Guinea, Japan, western Australia, eastern Russia, China, and Taiwan. The larval stage (chigger) of various trombiculid mites serves both as a reservoir, through transovarian transmission, and as a vector for infecting humans and rodents.

D. Spotted Fever Group

These infections occur around the globe, exhibiting as a rule some epidemiologic and immunologic differences in different areas. Transmission by a tick of the Ixodidae family is common to the group. The diseases that are grouped together include RMSF and Colombian, Brazilian, and Mexican spotted fevers; Mediterranean (boutonneuse), South African tick, and Kenya fevers; North Queensland tick typhus; and North Asian tickborne rickettsioses.

E. Rickettsialpox

The human disease has been found among inhabitants of apartment houses in the northern United States. However, the infection also occurs in Russia, Africa, and Korea.

Seasonal Occurrence

Epidemic typhus is more common in cool climates, reaching its peak in winter and waning in the spring. This is probably a reflection of crowding, lack of fuel, and low standards of personal hygiene, which favor louse infestation.

Rickettsial infections that must be transmitted to the human host by vector reach their peak incidence at the time the vector is most prevalent—the summer and fall months.

Control

Control must rely on breaking the infection chain, treating patients with antibiotics, and immunizing when possible. Patients with rickettsial disease who are free from ectoparasites are not contagious and do not transmit the infection.

A. Prevention of Transmission by Breaking the Chain of Infection

1. Epidemic typhus—Delousing with insecticide

2. Murine typhus—Rat proofing buildings and using rat poisons

3. Scrub typhus—Clearing from campsites the secondary jungle vegetation in which rats and mites live

4. Spotted fever—Similar measures for the spotted fevers may be used, including clearing of infested land, personal prophylaxis in the form of protective clothing such as high boots and socks worn over trousers, tick repellents, and frequent removal of attached ticks.

5. Rickettsialpox—Elimination of rodents and their parasites from human domiciles

Concept Checks

• Rickettsia are pleomorphic coccobacilli that are obligate intracellular pathogens similar to gram-negative bacteria but they do not stain with Gram stain.

• Rickettsia can be cultivated in cell culture lines and yolk sacs, but immunohistochemical or immunofluorescent stains, serology, or molecular methods are usually used for their detection in clinical material.

• The hallmark of infection with Rickettsia is vasculitis.

• Rickettsia can be divided into the typhus, spotted fever, and transitional groups; O tsutsugamushi causes scrub typhus. Vectors, clinical manifestations, and geographic distributions vary by group.

• Disease may be mild as in the case of Rickettsialpox or severe as in RMSF.

• Doxycycline is the drug of choice.

The ehrlichiae that cause disease in humans have been classified in a limited number of species based in large part on sequence analysis of rRNA genes. The pathogens are as follows: Ehrlichia chaffeensis, which causes human monocyte ehrlichiosis (HME); Ehrlichia ewingii, which causes E ewingii ehrlichiosis; and Anaplasma phagocytophilum, which causes human granulocyte anaplasmosis (HGE). The same genera contain additional species that infect animals but apparently not humans. The human pathogens in the group have animal reservoirs and can cause disease in animals as well.

The Ehrlichia group organisms are obligate intracellular bacteria that are taxonomically grouped with the rickettsiae. They have tick vectors (see Table 26-1).

Properties of Ehrlichiae

Ehrlichiae and Anaplasma are small (0.5 μm), obligate intracellular, gram-negative bacteria. They infect circulating leukocytes, erythrocytes, and platelets, where they multiply within phagocytic vacuoles, forming clusters with inclusion-like appearance. These clusters of ehrlichiae are called morulae, which is derived from the Latin word for mulberry. The ehrlichiae and chlamydiae (see Chapter 27) resemble each other in that both are found in intracellular vacuoles. The ehrlichiae, however, are similar to the rickettsiae in that they are able to synthesize adenosine triphosphate (ATP); the chlamydiae are not able to synthesize ATP.

Clinical Findings

The incubation periods after a tick bite for both HME and HGE can range from 5 to 21 days. The clinical manifestations of ehrlichiosis in humans are nonspecific and include fever, chills, headache, myalgia, nausea or vomiting, anorexia, and weight loss. These manifestations are very similar to those of RMSF without the rash. E chaffeensis frequently and A phagocytophilum less often cause severe or fatal illness. Complications with HME include meningoencephalitis; renal failure; myocarditis; and respiratory failure, among other life-threatening syndromes, including shock. Seroprevalence studies suggest that subclinical ehrlichiosis occurs frequently.

Laboratory Findings

Laboratory abnormalities with HME and HGE include leukopenia, lymphopenia, thrombocytopenia, and elevated hepatic enzymes. The diagnosis is confirmed by observing typical morulae in white blood cells (granulocytes in HGA or E ewingii and mononuclear cells in the case of HME). The sensitivity of microscopic examination for morulae is greatest during the first week of infection and ranges from 25% to 75%.

The indirect fluorescent antibody test can also be used to confirm the diagnosis. Antibodies are measured against E chaffeensis and A phagocytophilum. E chaffeensis is also used as the substrate for E ewingii because the two species share antigens. Seroconversion from less than 1:64–1:128 or greater or a fourfold or greater rise in titer makes a confirmed serologic diagnosis of HME in a patient with a clinically compatible illness.

Multiple methods have been described for PCR detection of ehrlichiae in EDTA (ethylenediaminetetraacetic acid)-anticoagulated blood. Culture using a variety of tissue culture cell lines also can be used. PCR and culture are performed in experienced reference laboratories and in a small number of commercial laboratories.

Treatment

Tetracycline, commonly in the form of doxycycline, is cidal for ehrlichiae and is the treatment of choice. Therapy is administered for 5–14 days. Rifamycins also are ehrlichiacidal. Limited data suggest that fluoroquinolones and chloramphenicol are not useful.

Epidemiology and Prevention

The incidence of human ehrlichioses is not well defined. E chaffeensis has been found in ticks in at least 14 states in the southeastern, south central, and mid-Atlantic regions of the United States, but cases of HME have been reported in more than 30 states. This area corresponds to the area of distribution of the Lone Star tick, Amblyomma americanum. Cases of human monocytotropic ehrlichiosis in the western United States and in Europe and Africa suggest other tick vectors such as D variabilis. In Oklahoma, which has the highest incidence of RMSF, human monocytotropic ehrlichiosis is at least as common. More than 90% of cases occur between mid April and October, and more than 80% of cases are in men. Most patients give histories of tick exposure in the month before onset of illness.

Cases of human granulocytotropic ehrlichiosis occur in the upper Midwest and East Coast states and in West Coast states. These areas correspond to the distribution of the tick vectors Ixodes scapularis and Ixodes pacificus, respectively.

Concept Checks

• The pathogens that cause the human ehrlichioses include E chaffeensis, the cause of HME; E ewingii, the cause of Ewingii ehrlichiosis; and Anaplasma phagocytophilum, the cause of HGE.

• The Ehrlichia group consists of obligate intracellular bacteria transmitted by tick vectors.

• Ehrlichia and Anaplasma species infect circulating leukocytes in which they multiply within phagocytic vacuoles and form morulae.

• The clinical manifestations of ehrlichiosis in humans are nonspecific and include fever, chills, headache, myalgias, nausea or vomiting, anorexia, and weight loss.

• Diagnosis is made by demonstration of morula within the respective leukocytes (relatively insensitive) and by serology or PCR.

• Doxycycline is the drug of choice for treatment.

Properties

C burnetii is a small obligate organism that has a membrane similar to gram-negative bacteria. However, it does not stain with the Gram stain but does stain with Gimenez. C burnetii, which causes Q fever, is resistant to drying. This organism may survive pasteurization at 60°C for 30 minutes and can survive for months in dried feces or milk. This may be because of the formation of endospore-like structures by C burnetii. Coxiellae grow only in cytoplasmic vacuoles.

Antigens and Antigenic Variation

When grown in cell culture, C burnetii exhibits various phases. These phases are associated with differences in virulence. Phase I is the virulent form that is found in humans with Q fever and in infected vertebrate animals. It is the infectious form of the organism and the lipopolysaccharide expressed during this phase appears to be a key virulence factor. Phase II forms are not infectious and occur only by serial passage in cell cultures. Patients with clinical illness mount antibodies to both phase I and phase II antigens.

Epidemiology

C burnetii is found in ticks, which transmit the agent to sheep, goats, and cattle, but transmission by ticks to humans is uncommon. Workers in slaughterhouses and in plants that process wool and cattle hides have contracted the disease as a result of handling infected animal tissues. C burnetii is transmitted by the respiratory pathway rather than through the skin. There may be a chronic infection of the udder of the cow or goat. In such cases, the rickettsiae are excreted in the milk and rarely may be transmitted to humans by ingestion of unpasteurized milk.

Infected sheep may excrete C burnetii in the feces and urine and heavily contaminate their skin and woolen coat. The placentas of infected cows, sheep, goats, and cats contain the organism, and parturition creates infectious aerosols. The soil may be heavily contaminated from one of the above sources, and the inhalation of infected dust leads to infection of humans and livestock. It has been proposed that endospores formed by C burnetii contribute to its persistence and dissemination. Coxiella infection is now widespread among sheep and cattle in the United States. Coxiella can cause endocarditis (with a rise in the titer of antibodies to C burnetii, phase I) in addition to pneumonitis and hepatitis.

Clinical Findings

A. Q Fever

This disease is recognized around the world and occurs mainly in persons associated with goats, sheep, dairy cattle, or parturient cats. It has attracted attention because of outbreaks in veterinary and medical centers where large numbers of people were exposed to animals shedding Coxiella species.

Infections may be acute or chronic. Acute disease resembles influenza, nonbacterial (atypical) pneumonia, and hepatitis. There is a rise in the titer of specific antibodies to C burnetii, phase II. Transmission results from inhalation of dust contaminated with the organism from placenta, dried feces, urine, or milk or from aerosols in slaughterhouses.

Chronic Q fever is infection that lasts more than 6 months. Infective endocarditis is the most common form of disease in this phase. Blood cultures for bacteria are negative, and there is a high titer of antibodies to C burnetii, phase I. Virtually all patients have preexisting valve abnormalities or have some form of immune compromise.

Laboratory Findings

C burnetii can be cultivated in cell cultures, but this should only be done in experienced biosafety level 3 laboratories. Serology is the diagnostic method of choice, and indirect immunofluorescence is considered the best method. PCR has been useful in diagnosing culture-negative endocarditis caused by C burnetii.

Treatment

Doxycycline is the drug of choice for the treatment of acute Q fever. The newer macrolides have also been shown to be effective in the treatment of acute pneumonia. Chronic Q fever requires prolonged treatment for 18 months or longer with a combination of doxycycline and hydroxychloroquine. Duration of treatment is long as mentioned earlier and should be determined by decrease in phase I antibody titers. In endocarditis, combination therapy is necessary to prevent relapse; occasionally, valve replacement is required and can prolong survival.

Prevention

The presently recommended conditions of “high-temperature, short-time” pasteurization at 71.5°C for 15 seconds are adequate to destroy viable Coxiella species.

For C burnetii, an investigational vaccine made from infected egg yolk sacs is available. This vaccine has been used for laboratory workers who handle live C burnetii but currently is only commercially available in Australia.

Concept Checks

• C burnetii is a small obligate organism that has a membrane similar to gram-negative bacteria, does not stain with Gram stain, multiplies within vacuoles, and causes the disease Q fever.

• C burnetii exists in two antigenic forms called phase I and phase II. Phase I is the virulent form that is found in humans with Q fever and infected vertebrate animals, and it is the infectious form. Phase II is the avirulent form.

• C burnetii is found in sheep, goats, cattle, and a variety of other animals, which are usually asymptomatic. Transmission to humans is by inhalation of contaminated dirt from animal feces, products of conception, or dust from animal products such as contaminated hides.

• Q fever is characterized by acute and chronic infections. Acute pneumonia and hepatitis are associated with antibodies to phase II antigens; endocarditis is the most common form of chronic infection and is associated with antibodies to phase I antigens.

• Diagnosis is clinically suspected and confirmed largely by serology or PCR performed in reference laboratories that have developed and verified their own assays.

• Doxycycline in the drug of choice in both acute and chronic infections. In chronic infections, it is combined with hydroxychloroquine.