Tularemia and Q fever

TICK-BORNE DISEASES

0025–7125/02 $15.00
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TULAREMIA AND Q FEVER Elisa Choi, MD

Infections resulting from zoonoses are becoming increasingly recognized as an important epidemiologic problem. With the discovery of tick-borne organisms as the causative agents of several new emerging infections (i.e., Ehrlichia chaffeensis and Ehrlichia phagocytophilia for human monocytic ehrlichiosis and human granulocytic ehrlichiosis), there is an emphasis on early recognition of the clinical syndromes caused by these types of pathogens. Two relatively rarer syndromes, tularemia and Q fever, caused by Francisella tularensis and Coxiella burnetii, are reviewed here. These infections often present with nonspecific clinical findings, making diagnosis difficult without a high index of suspicion. Also, both organisms present challenges for definitive microbiologic identification, either because of the fastidious growth requirements of the organisms or because of the potential hazards of transmitting the infection to laboratory workers. Increased awareness of the clinical manifestations of infections caused by these two organisms would lead to more frequent recognition, which is the first step in improved management and treatment of these two human infections. TULAREMIA Synonyms for tularemia, the clinical syndrome caused by infection with the bacterial organism F. tularensis, such as deer-fly fever, rabbit fever, Francis’s disease, and Ohara’s disease, take their names either from historical background of the organism or from common sources of infection. Although tularemia is a relatively rare infection in the United

From the Beth Israel Deaconess Medical Center, Boston, Massachusetts

MEDICAL CLINICS OF NORTH AMERICA VOLUME 86 • NUMBER 2 • MARCH 2002

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States, with a stable incidence over several decades, increased recognition of its clinical manifestations, epidemiology, and pathogenesis may lead to more accurate diagnosis and more prompt initiation of appropriate treatment.

Historical Origins McCoy first discovered the causative agent of tularemia in 1911, in Tulare County, California.20 At the time, he was investigating possible outbreaks of bubonic plague after the 1906 San Francisco earthquake. The illness he was investigating, in ground squirrels, bore some resemblance to plague; however, the pathogen could not be recovered from the standard media. A year later, McCoy isolated the organism (on special coagulated egg medium) and originally named it Bacterium tularense, in reference to the site of its original discovery. Several years later, in 1921, Francis noted seven bacteriologically confirmed cases of infection with this newly discovered organism, and a year later, he noted six more additional cases of laboratory-acquired illness.20 Francis noted that McCoy’s original illness described in ground squirrels and another infection seen in Utah known as deer fly fever were caused by Bacterium tularense. Francis subsequently named this illness tularemia because this organism had been isolated from the blood of two patients, and evidence increasingly suggested that deer fly (acting as a vector) transmission of the organism required bacteremia. An illness known as Ohara’s disease, described in Japan in 1925 by Ohara, ultimately was confirmed to be the same disease as tularemia.20 Ohara noted that three Japanese patients had developed a febrile illness after having skinned, cooked, and eaten a hare. Ohara hypothesized that the patients had contracted their disease from contact with the hare, although at that time many of his contemporaries discounted his theory. Ultimately, Ohara was able to reproduce the disease by inoculation of the organism into his wife (a voluntary subject of his experiment), by rubbing the hearts and tissue fluid of autopsied dead hares onto her hand, and he subsequently recovered the organism from his wife’s lymph node, after she developed a febrile syndrome with lympadenopathy. Ohara was not able to find the organism consistently in lesions of the disease, however, and he was unable to isolate the pathogen in pure culture on artificial media. When Francis finally confirmed that the disease Ohara had described was the same entity as the tularemia that he had identified, Ohara’s findings were vindicated. Other significant discoveries that laid the foundation for current knowledge of this organism and of the clinical syndrome of tularemia included the discovery of the role of ticks in the transmission of the disease in 1924 by Parker and Spencer and later, in 1926, their description of transovarial transmission of the organism in ticks.20, 70 These findings helped establish the role of ticks as reservoirs of tularemia and provided

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further insight into the transmission and spread of this organism in human infection. In recognition of Francis’ numerous contributions to the study of tularemia, which he continued to investigate several more decades after his initial description of the clinical syndrome, he was nominated for a Nobel Prize by the American Medical Association. In 1959, he was honored for all his work in this field when the genus name of the organism was changed to Francisella. Epidemiology Human infection arises from several different routes of transmission, and tularemia can manifest as several different clinical syndromes. In humans, disease can arise through spread of infection from contact with vectors (including ticks, mosquitoes, biting flies, squirrel flies, biting gnats, and bedbugs), handling infected animals (rabbits, hares, rodents, voles, squirrels), ingestion of contaminated water or food, ingestion of inadequately cooked meat, scratches or bites from infected cats, inhalation of aerosols, or contact of mucosal surfaces (eyes, conjunctiva) by splashing of infected material or rubbing with contaminated fingers. Human-to-human transmission is not thought to be a clinically significant route of infection of tularemia.20, 70 F. tularensis is found worldwide. Human disease has been found in the United States, Mexico, and Canada. Although tularemia, which is a reportable illness, has been seen in all continental states in the United States (not Hawaii), it is seen predominantly in southern, southwestern, and midwestern states. It has been reported most commonly in Arkansas, Illinois, Missouri, Oklahoma, Tennessee, Texas, Utah, Virginia, and Wyoming, although there have been sporadic outbreaks in other states, including Massachusetts (where a tularemia outbreak was noted in Martha’s Vineyard) and Vermont. Since the 1950s, the reported incidence of tularemia has been declining steadily, with less than 300 cases per year (except 1983) reported since 1967.11, 15 A bimodal seasonal trend in peaks of transmission has been noted, with more frequent occurrence of disease seen in the spring and summer thought to be due predominantly to arthropod-borne transmission, and incidences of disease seen in fall and winter (more common hunting months) thought to be due to transmission of disease by mammalian vectors.11, 15, 20 Currently, most human disease in the United States appears in the spring and summer, likely reflecting the greater proportion of disease acquired through tick-borne transmission.15, 70 The ticks commonly known to transmit tularemia in the United States are Dermacentor andersoni, Dermacentor variabilis (the dog tick), and Amblyomma americanum (the Lone Star tick). Tularemia also is found in parts of Europe, the Middle East, and Asia.15 European countries known to have endemic tularemia include Sweden, Norway, and the former Soviet Union.77 In Asia, tularemia has

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been reported in Japan and China. In Japan, the disease also is known as Yato-byo, or wild rabbit disease.51 The Middle East has endemic tularemia in Turkey and Israel. In the United States, most human disease is acquired through tick-borne transmission because hunting and trapping of wild rabbits and other mammal reservoirs of F. tularensis is much less common than previously. In Europe and Japan, mosquito-borne disease and transmission from handling of infected animals seem to play a major role in the acquisition of human disease.51, 77 Natural infection by F. tularensis has been found in more than 100 vertebrates and invertebrates, most commonly in ticks, mosquitoes, fleas, and horse flies. Microbiology The classification of the different species within the genus of Francisella has been in transition. The most recently accepted nomenclature includes three different biovars of the species F. tularensis and a second species, Francisella philomiragia (previously known as Yersinia philomiragia). The three biovars of F. tularensis are F. tularensis biovar tularensis (also known as type A of Jellison or group A), F. tularensis biovar palaearctica (also known as type B of Jellison or group B; this biovar also has further subdivisions into F. tularensis biovar palaearctica mediasiatica, which is found in Central Asia, and F. tularensis biovar palaearctica japonica, which is found primarily in Japan), and F. tularensis biovar novicida.13 Two other phenotypically distinct variant strains have been isolated in humans, identified as Fx1 and Fx2.10 Clinically significant disease has been reported only rarely with F. tularensis biovar novicida and F. philomiragia. Most human disease is caused by the other two biovars of F. tularensis. F. tularensis biovar tularensis is a virulent form of the Francisella organism, found presumably only in North America, where it accounts for approximately 90% of cases of tularemia and where it is known to cause clinically severe disease with a mortality rate of 5%.15 Ticks and infected rabbits primarily transmit this subspecies in human infections. F. tularensis biovar palaearctica is known to cause disease in other parts of the world, where it causes a much less severe, milder, subclinical disease, with transmission of this subspecies occurring through rodents, aquatic animals, and water exposure.13 Francisella species are classified as facultative intracellular aerobic gram-negative coccobacilli that appear as small, nonmotile, pleomorphic, and pale-staining organisms on direct examination. It is a fastidious organism with relatively slow growth, and most strains require special nutritionally supplemented media for growth.13 Isolation of the organism from clinical specimens often is difficult, although attempts at culturing the organism on cysteine-rich media, chocolate agar, and Thayer-Martin agar may yield positive growth. Despite the difficulties in isolating the organism microbiologically, it remains viable in nature despite significant adverse conditions. The organism is able to persist in many different environments (water, soil,

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carcasses of animals) for several weeks. The organism can become aerosolized, and inhalation of these aerosolized organisms can lead to human infection. This particular route of infection creates significant hazards to laboratory personnel who may attempt to isolate the organism, and other means of isolation and diagnosis, such as biochemical testing and polymerase chain reaction, have been used instead. Pathogenesis Research, attempting to identify the potential virulence factors of Francisella species, has not yet identified conclusively the specific components of this organism that contribute to its infectivity. Some earlier investigations, which showed that a capsule-deficient mutant of F. tularensis live vaccine strain was killed rapidly by normal human serum, suggested that the organism’s bacterial capsule may play a protective role against the bactericidal effect of human serum.76 Another possible virulence mechanism is the organism’s ability to withstand the oxidants produced by the respiratory burst of polymorphonuclear leukocytes. Experiments have shown that the attenuated live vaccine strain is more susceptible to killing by various oxidants produced by the polymorphonuclear leukocytes.76 The exact virulence factor responsible for the wildtype bacteria’s resistance to these oxidizing products of polymorphonuclear leukocytes still remains to be determined. It is well known that F. tularensis is a highly virulent organism. Only 10 to 50 organisms (in some instances, ⬍10 organisms) are required to produce clinical disease in humans.13, 76 One study identified that an increase in a particular subset of T cells (V␥9 V␦2) could be shown in peripheral blood of individuals with tularemia, in contrast to individuals who were vaccinated with a live vaccine strain of the organism.52 Specific antigens of F. tularensis were able to stimulate release of tumor necrosis factor in vitro, and these same antigens seemed to be responsible for the proliferation of the T cells. Most investigations into the host defense response to F. tularensis have been able to determine the crucial role cell-mediated immunity plays in control and containment of infection with this organism.76 F. tularensis is similar to several other organisms, such as Chlamydia, Legionella, Listeria, Brucella, and Mycobacteria, in that it is an intracellular bacterium. The Francisella organism, in contrast to many extracellular bacteria, adapts to the intracellular environment of the macrophages and can be removed only after these phagocytes are activated by T lymphocytes. In distinction from extracellular bacteria, which require components of humoral immunity to be removed (e.g., polymorphonuclear leukocytes, complement, immunoglobulins), in Francisella (and other intracellular bacteria), humoral immunity does not seem to play a significant protective role.76 Despite the apparent lack of utility in host defense of humoral immunity, a strong antibody response is mounted on infection by the

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organism.76 This antibody response is fairly specific, although there is some notable cross-reactivity with Brucella, Proteus vulgaris Ox-19, and Yersinia. The agglutinating antibodies first start to appear at the end of the second week or during the third week of disease, and IgM antibodies do not appear earlier than IgG antibodies. Antibody titers reach their peak during the second month after disease onset or vaccination. Subsequently the antibody titers start to decline; demonstrable titers still can appear more than 10 years after disease, although the exact function of this persistent antibody response is not known.76 Opsonizing antibodies may be shown the third day of disease. These same opsonizing antibodies may help promote ingestion of the infecting organisms by activated mononuclear phagocytes. Previous experiments, involving passive transfer of immune serum to nonimmune animals and induction of serum antibodies through immunizations, failed to show a decrease in mortality in animals challenged by virulent strains of Francisella organisms, however. It has been concluded, based on these studies, that the humoral immune response, in the absence of cell-mediated immunity, is of little value in the host’s defense against F. tularensis, particularly virulent strains of this organism.76 Opsonizing antibodies, in particular, may play a role in the clearance of the bacteria from the bloodstream, however, by promoting uptake of the organism into peripheral organs such as the liver and by stimulating phagocytosis of the organism by activated macrophages.76 Studies in animal models using the live vaccine strain have led to the overall characterization of an early nonspecific immune response to the organism, which is followed by a subsequent immune response involving components of humoral immunity and cell-mediated immunity. The early response is composed largely of T lymphocytes.18, 76 Investigations have shown the production of cytokines, such as interleukin-12, tumor necrosis factor-␣, and interferon-␥, from skin samples in mice immunized with the live vaccine strain of the organism. Naive or control mice did not show similar production of these cytokines. The investigators in this study concluded that the production of such cytokines locally suggests a role for the skin as an essential barrier against infection with this organism.76 The cellular source of such cytokine production and how this component of the immune response fits in with the systemic host defense still remain to be elucidated. Clinical Presentation The clinical manifestations of tularemia are varied and diverse and can range from an asymptomatic illness to a full-blown toxemic presentation with septic shock and death. Classically, six distinct clinical syndromes have been described,20 but there is overlap of these categories of syndromes, and these syndromes are not mutually exclusive. The type of clinical syndrome often relates to the mode of transmission by which the infection was acquired and to the portal of entry of infection. The

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six clinical syndromes are (1) ulceroglandular, (2) glandular, (3) typhoidal, (4) pneumonic, (5) oropharyngeal, and (6) oculoglandular. Initially, patients infected with Francisella species present with relatively abrupt onset of nonspecific symptoms, such as fevers, chills, malaise, and headache. The usual incubation period before onset of symptoms can range from 2 days to 2 weeks. Little information is known about the manifestations of tularemia in immunocompromised individuals, although there has been at least one case report of tularemic pneumonia (with findings of pulmonary granulomas) in a patient with chronic granulomatous disease39 and some anecdotal experience in a renal transplant patient with typical manifestations of ulceroglandular disease. Ulceroglandular disease accounts for most (80%) clinical illness resulting from Francisella infection.20 Most commonly, patients who develop this manifestation of tularemia have acquired the infection from animal bites, handling an infected animal, or tick exposures. Initially, these patients present with fever and a solitary ulcerative papular skin lesion. Ultimately, this lesion evolves, with the development of a blackened necrotic eschar at its center. This skin lesion may be accompanied by tender local regional lymphadenopathy and rarely with nodular lymphangitis. The location of the skin lesion is usually at the site of infection, where the exposure to the tick (or other arthropod vector), animal bite, or animal contact was on the skin. Glandular disease may occur in 15% of patients with tularemia. Patients with this form of Francisella infection present with single or multiple enlarged lymph nodes, in the absence of an identifiable cutaneous lesion. This category may represent a subcategory of the ulceroglandular disease, however, in that the patient may present with regional lymphadenopathy without a skin lesion simply because the individual may not have noticed the skin lesion initially, and it may have disappeared by the time the patient is evaluated medically. This type of presentation of tularemia may present a diagnostic challenge because the differential diagnosis of regional lymphadenopathy is broad and includes mycobacterial infection, cat-scratch disease (Bartonella infection), lymphogranuloma venereum, streptococcal or staphylococcal lymphadenitis, malignancy or lymphoma, fungal infection, and plague. In such cases, a precise epidemiologic and exposure history may be the only clue to the correct diagnosis. Oculoglandular tularemia is much rarer, occurring in approximately 1% of cases.15 This manifestation of tularemia usually arises in the setting of inoculation of the eye, either by contact with contaminated fingers or accidental squirting of blood from an engorged tick. Patients with this form of tularemia usually have conjunctivitis with associated preauricular lymph node enlargement. Significant periorbital edema and erythema may be present. Oropharyngeal disease also is relatively rare, accounting for less than 5% of cases of tularemia. The portal of entry in this form of the disease is the oropharynx because infection is thought to occur through

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ingestion of infected or undercooked animal meats, contaminated water, or other infected tissues or fluids. Patients present with fever and an exudative pharyngitis and occasionally with ulcerations of the oropharynx. This form of tularemia should be considered in patients who are being treated for more routine bacterial pharyngitis, who are not responding to apparently appropriate antibiotic coverage (usually penicillin or ampicillin). Similar to glandular tularemia, the differential diagnosis is broad, and the key to diagnosing tularemia accurately in this setting is eliciting a detailed exposure history. Typhoidal tularemia is an uncommon presentation of infection with Francisella.11, 20 Patients have symptoms of fevers, chills, and other minimal localizing symptoms. In more severe forms of typhoidal tularemia, the patient may seem to be in septic shock, with significant sequelae, such as disseminated intravascular coagulation. Despite the toxic presentation, blood cultures may be relatively low yield in isolating F. tularensis. This form of tularemia can occur with and without an accompanying pneumonia and should be part of the differential diagnosis for any patient who presents with a nonlocalizing systemic febrile illness. This type of tularemia, in particular, may be associated with other findings, such as mild-to-moderate transaminase elevations and rhabdomyolysis with secondary renal failure.20, 70 Tularemic pneumonia,28 or the pneumonic form of infection with Francisella tularensis, can arise from two different routes: inhalation or airborne exposure or hematogenous spread. Inhalation of the organism is seen most commonly in laboratory workers handling specimens in which F. tularensis is contained inadequately. It is seen much less commonly in community-acquired cases. Patients with pneumonic tularemia often present with the typhoidal form of the illness, in which case there is hematogenous spread of the organism to the lungs. The presence of pneumonia portends a significantly higher mortality from this infection, regardless of the route of transmission. There may be a greater likelihood of developing tularemic pneumonia in elderly patients.65 Although there have been classic descriptions of a triad of findings (ovoid opacities, pleural effusions, and hilar adenopathy) for tularemic pneumonia, these radiologic manifestations are neither sensitive nor specific enough to render them diagnostically useful. Radiographically, pneumonic tularemia can present in extremely varied ways,28 ranging from cavitary lesions (with occasionally a miliary pattern), patchy unilateral or bilateral infiltrates, lobar or segmental opacities, pleural effusions, hilar adenopathy, or nodular infiltrates. As with several of the other forms of tularemia, the accurate diagnosis is reached if an appropriate exposure history is elicited. Tularemic pneumonia should rise on the list of differential diagnoses in any patient who does not seem to respond adequately to ␤-lactam antibiotics (or other commonly used antibiotics to treat community-acquired pneumonia), which do not have activity against F. tularensis, especially if the individual is from an endemic area or if he or she has a suspicious exposure history. A history of vector exposure may be even less likely

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to be present, however, in patients with tularemic pneumonia than in other forms of the disease, possibly as a result of unwitting acquisition of the disease by inhalation of aerosolized organisms, which is recalled less readily than other routes of exposure (i.e., handling of animal carcasses, tick bites, animal bites, consuming contaminated food or water). A high index of suspicion, especially in this form of the disease, may enable the correct diagnosis and prompt initiation of adequate treatment. Diagnosis Many of the laboratory findings in tularemia are fairly nonspecific, and none are particularly diagnostic. Approximately 50% of patients may have abnormal liver function tests (primarily transaminases), and there may be evidence of creatinine kinase elevation as a result of rhabdomyolysis.20 The white blood cell count can range from 3000 to 15,000/␮L. The organism is difficult to isolate from cultures of blood, pleural fluid, sputum, or other specimens. F. tularensis requires cysteine for its growth, which is not present in most routine media used by microbiology laboratories. Also, if tularemia is suspected, laboratory personnel should be notified because the appropriate precautions to reduce transmission of infection need to be instituted, given the propensity for the organism to become aerosolized. Histopathologically, infection with F. tularensis produces granuloma formation, which can produce findings similar to those seen in tuberculosis (or other mycobacterial infection) or cat-scratch disease. The histopathologic findings vary, however, depending on the duration of the disease. Early on, during the first several days of infection, abscess formation with necrosis predominates histologically. Only after 2 to 3 weeks into the disease do granulomatous reactions start to appear. Because microbiologic data often are recovered unreliably, and histopathologic findings and clinical symptoms can be nonspecific, the diagnosis of tularemia usually is confirmed by serologic testing. Most experience has been with agglutination tests, with much of the published literature suggesting that a single titer of 1:160 or higher is supportive of the diagnosis of tularemia.20 Alternatively a fourfold or greater rise in titer between acute and convalescent serum specimens usually is confirmatory for the diagnosis.27 The detectable rise in agglutinating antibodies does not occur until at least 2 weeks after onset of disease (usually occurs within 2 to 4 weeks) so that serologic diagnosis is not possible in the early course of the illness. As noted previously, the antibody titer elevation may persist for many years, after infection and clinical disease. Also, there is some cross-reactivity in the serology for F. tularensis, most notably with Brucella species, Proteus Ox-19, or Yersinia species. Serologic testing should be performed in individuals with a reasonably high pretest probability or suspicion for clinical disease; it

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should not be used as a screening test for patients presenting with a nonspecific febrile illness. There have been several reports of successful isolation of F. tularensis by polymerase chain reaction (using the 16SrRNA gene and 17-kd lipoprotein gene of F. tularensis) in a variety of human specimens (ulcers, skin biopsy specimens, lymph node specimens, blood) in patients with the ulceroglandular form of tularemia.67 Further investigation is required, in particular, in patients with other forms of tularemia, to determine if polymerase chain reaction accurately and reliably enables a more rapid diagnosis, but preliminary reports seem promising. Currently, this diagnostic tool is being used only in research laboratories and is not available for general clinical use. Treatment The recommended treatment regimens for tularemia have been determined in the absence of any prospective controlled trials and are based largely on case reports and anecdotal experience, but despite this, there seems to be general agreement that the antibiotic of choice is streptomycin.19 Other generally accepted antibiotics for the treatment of tularemia include gentamicin, tetracycline (or doxycycline), and chloramphenicol. One overview of the different therapies in 199419 reported the best cure rate and fewest relapses with streptomycin and, in order of decreasing cure rates (and increasing relapse rates), gentamicin, tetracycline, and chloramphenicol. Part of the problem with tetracycline and chloramphenicol may be that these antibiotics are bacteriostatic (not bactericidal) against F. tularensis.19 Although streptomycin seems to be most optimal, however, based on comparison of cure rates and relapse rates, relative to some of the other antibiotic choices, the limiting factor for streptomycin is its availability; there often is a delay in obtaining this antibiotic promptly because of supply limitations. The overview of the various therapies19 concluded that gentamicin was an acceptable substitute for streptomycin, in terms of overall efficacy. There are some properties of aminoglycosides that may render them less effective in treating certain syndromes of tularemia.62 Aminoglycosides have poor activity in acidic, hypoxic environments, which may lead to relapse, especially in cases in which there are significant buboes, abscesses, or suppurative adenopathy involved. Also, F. tularensis is an intracellular pathogen, and aminoglycosides may access this organism relatively poorly because they tend not to penetrate intracellular compartments well. Although streptomycin continues to be the drug of choice for treating tularemia, more recent investigations have looked at other classes of antibiotics. Some of these antibiotics may have more optimal bioavailability and pharmacodynamics than aminoglycosides, such as the fluoroquinolones,38, 62, 64 and others have shown therapeutic success in limited

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investigations, such as erythromycin29 and imipenem-cilastatin. Rifampin and chloramphenicol also have activity against F. tularensis. There have been reports of successful outcomes treating tularemia with levofloxacin and ciprofloxacin.38 The fluoroquinolones, in particular, achieve therapeutic blood levels because of good oral absorption and obtain excellent intracellular penetration. Because they also are generally well tolerated, they seem to be a promising alternative to streptomycin or aminoglycoside therapy for tularemia, although further investigation is required before the quinolones can be regarded as a first-line alternative to streptomycin. One class of antibiotics that does not seem to be an alternative therapy for tularemia is the cephalosporins. Evidence has suggested therapeutic failures in several cases of tularemia with the use of ceftriaxone.12 Although the minimal inhibitory concentration of ceftazidime for F. tularensis is lower than that of ceftriaxone, given the lack of experience with ceftazidime and the negative outcomes of treating tularemia with ceftriaxone, the most prudent recommendation would be to avoid the use of cephalosporins in treating tularemia until further investigations are carried out. In certain settings of tularemia, streptomycin would not be the drug of choice. For tularemic meningitis (which is rare), streptomycin alone is a suboptimal choice because of its erratic concentrations in the cerebrospinal fluid.19 The recommended treatment regimen in this form of tularemia is chloramphenicol plus streptomycin. There is a scarcity of evidence in the setting of tularemia in pregnancy to guide therapy. Tetracycline and doxycycline should be avoided in pregnant women, in lactating women, and in children younger than 8 years old. Alternative options for therapy include erythromycin for mild disease and streptomycin or chloramphenicol for moderate-to-severe disease. Relapses can occur with any of the above-mentioned regimens, but they tend to be more common with the bacteriostatic agents of tetracycline and chloramphenicol. Repeat courses of antimicrobial therapy may be necessary, and aspiration and drainage of fluctuant lymph nodes may be required to alleviate symptoms. Tularemia has an overall mortality rate of 2% to 4%,20 and numerous complications can occur, including rhabdomyolysis with accompanying renal failure, acute respiratory distress syndrome, and meningitis. Although cases of pericarditis have been reported, infection with F. tularensis does not tend to cause endocarditis or myocarditis. Although there are ongoing experiments attempting to develop a tularemia vaccine, none currently is available in the United States. The best means of avoiding disease is through prevention of infection. Educating the public would increase the likelihood that tick exposures, contact with contaminated animal carcasses or with infected wildlife, and consumption of nonpotable water all would be kept to a minimum. Ultimately, this approach would have an impact on the incidence of human disease.

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Q FEVER Q fever is a zoonotic infection that can manifest as acute and chronic disease and is relatively rare in the United States. Similar to tularemia, it is becoming increasingly recognized as a significant worldwide public health problem. Although the causative agent of Q fever, C. burnetii, is found among many different wildlife, humans are the only hosts that are known to develop disease from infection with this organism.50 The true prevalence of Q fever may be underestimated because of underrecognition, especially because this disease can be asymptomatic in infected individuals.26 As health care providers become more aware of this disease, however, more prompt diagnosis will lead to earlier appropriate treatments, which will minimize the frequency of sequelae from the chronic form of this infection. Historical Perspectives The name Q fever (for query fever) initially was coined in 1937 by Derrick to describe outbreaks of a febrile illness seen in abattoir workers in Queensland, Australia. In 1935, Derrick had started investigating these outbreaks, but he was unsuccessful in isolating the causative agent of this disease, despite attempts at inducing febrile illnesses in guinea pigs, and he hypothesized that the organism causing this disease may be a virus.44 Burnet and Freeman later elucidated the rickettsial nature of the causative agent of Q fever, after performing further experiments in guinea pigs. They had received some of the original infectious material that Derrick had isolated, and they reproduced the febrile illness in guinea pigs, mice, and monkeys. Burnet and Freeman saw small rods on Giemsa-stained sections of spleen from the infected experimental animals, which possessed rickettsial characteristics. Based on Burnet and Freeman’s findings, Derrick and colleagues investigated epidemiologic aspects of this disease further and attempted to identify a possible arthropod vector. As a result of their investigations, they concluded that ticks or other arthropods may transmit Q fever and that wild animals were the natural reservoirs for the causative organism of this disease, with domestic animals possibly serving as secondary reservoirs. Concurrently but independently, in the United States, Davis and Cox were gathering information on Rocky Mountain spotted fever. Previous experiments on guinea pigs, in which a febrile illness was induced in these animals by tick exposure, led to a disease that had features atypical for Rocky Mountain spotted fever. At this time, Burnet and Freeman and Cox and Davis had been able to show that the suspected causative agent of this Q fever disease possessed rickettsial properties. In 1938, Cox was able to grow the organism in embryonated eggs. The link between the discoveries of these two independent groups

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arose in 1938. Dyer (of the National Institutes of Health) traveled to Hamilton, Montana, where Cox and Davis were based, to obtain further information about this rickettsial organism. Dyer became infected with this organism, and guinea pigs that were inoculated with Dyer’s blood developed a febrile illness. Rickettsiae were seen in spleen samples from these ill animals. Dyer then established the connection between the organism identified by Cox and Davis with the organism isolated by Burnet and Freeman when he inoculated guinea pigs with samples of the Q fever agent that Burnet had sent to him, which were obtained from spleen samples removed from infected animals. After inoculation, Dyer showed that these animals were protected from a subsequent challenge with the organism isolated from his own blood. This demonstration of cross-immunity seemed to prove that the organism discovered by Burnet and Freeman and the infectious agent found by Cox and Davis (which was the same organism with which Dyer became infected) were the same. Although this rickettsia originally was further named Rickettsia burnetii in 1938, it was later named C. burnetii, after the new genus Coxiella had been created. This new name honored Burnet and Cox for their contributions to the discovery of this organism. Epidemiology Q fever is found worldwide, and this zoonotic infection has many different reservoirs, including arthropods (mainly ticks),57 birds, and mammals. The source of human infection usually is cattle, sheep, goats, and farm animals. There have been reports of transmission of disease through contact with other animals, such as dogs, cats, rabbits, pigeons,73 and rats. C. burnetii can be found in the urine, feces, and milk of infected mammals. Infection can reactivate during pregnancy, and Q fever can cause abortions in sheep, goats, and cattle. In humans, disease can result from inhalation of contaminated aerosol, from contact with body fluids of infected livestock, or from exposure to skins or placenta of infected animals. Most commonly, occupational exposure leads to infection and disease, although there have been reports of transmission of C. burnetii through the consumption of raw milk. Congenital infection can occur through transplacental transmission, and blood transfusions and intradermal inoculations also have been reported as sources of infection. Because of the increased risk of occupational exposure leading to infection with C. burnetii, individuals with the greatest likelihood of acquiring Q fever include those who have frequent contact with farm animals; those who have exposure to manure, straw, or dust from farms; and those who work in microbiology laboratories. Other risks that have been identified, particularly from a large epidemiologic survey from France,78 include living in a rural area, contact with pregnant or newborn farm animals, and consumption of raw milk. Pregnant women can develop fevers, premature labor, or spontaneous abortion from Q fever.58

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Some reports suggest that patients with human immunodeficiency virus (HIV) infection may have a greater seroprevalence of symptomatic Q fever, especially in comparison with random blood donors; HIV-positive patients had almost three times higher prevalence of disease, which seemed suggestive of blood-borne transmission of C. burnetii.56 Older individuals and immunocompromised patients are at greater risk for acquiring the chronic form of Q fever.59 Endocarditis is the most common manifestation of chronic Q fever, and patients with pre-existing valvular heart disease are at greatest risk for this complication of chronic Q fever.59 There also have been reports of acquisition of C. burnetii infection in patients with vascular graft and prostheses. Q fever has a worldwide geographic distribution, although the incidence of disease varies widely among different regions of the world. In North America, a significant number of cases of Q fever have been reported in Nova Scotia. In Israel and southern France, the incidence of acute Q fever is 50 cases per 100,000 individuals per year, with the incidence of Q fever endocarditis much rarer, at 1 case per 1 million individuals per year. Seasonal variation in the incidence of disease in Europe occurs, with most acute Q fever cases occurring in the spring and summer.78 Other parts of Europe where outbreaks have been reported include northern Spain, Switzerland, Great Britain, and Germany (Berlin). Microbiology and Pathogenesis Although C. burnetii historically had been classified as a rickettsial organism, its taxonomy has been revised. It no longer is classified as a Rickettsia; instead, it has been placed in the ␥ subdivision of the proteobacteria category, based on molecular sequencing of the 16S rRNA encoding gene.74 C. burnetii seems more closely related to Francisella and Legionella species than to Rickettsia.74 The organism appears as a small pleomorphic rod, with a membrane that bears some similarity to those of gram-negative bacteria.41 C. burnetii is a strict intracellular bacterium, and it has some distinctive characteristics, which contribute to its pathogenicity. The organism undergoes a sporulation-like process, and this results in the organism becoming protected from the external environment, where it can survive for extended periods.41 C. burnetii also can survive within phagolysosomes,41 at the acidic pH of 4.5, and under these conditions (which would be detrimental for many organisms), Coxiella species are able to replicate and undergo metabolism. In addition, the organism enters the host cells through passive entry by phagocytosis.41 In the mammalian host, C. burnetii infects the macrophage and takes up residence there as its host cell. The organism multiplies in the large vacuole (phagolysosome), which results from the fusion of multiple cell lysosomes,43 and the macrophage is unable to kill the organism. C. burnetii also undergoes a type of antigenic variation, called phase varia-

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tion,41 in which there is variable presentation of lipopolysaccharide. Phase I antigens are expressed by the organism, when it is isolated from humans or animals, and in this form, the organism is infectious (one bacterium may be enough to cause human infection). After the organism is subcultured in cells or in embryonated eggs, there is an antigenic shift to phase II antigens, through modification of the lipopolysaccharide, and in this form, the organism is not infectious. This antigenic shift can be detected, and the distinction between phase I and phase II antigens can determine whether the form of clinical disease is acute or chronic Q fever.57 There have been at least 20 different genotypes of C. burnetii identified,54 and variability in the composition of the lipopolysaccharide can be detected among different strains. Despite this, there is not that much genetic heterogeneity between the different strains of C. burnetii.74 The genome of the organism variably may contain an integrated plasmid sequence; four different plasmid types have been described. The hypothesis that there may be some correlation between the clinical manifestations of acute or chronic Q fever based on the antigenic variation (phase I or phase II) or plasmid type54 is unproven and largely thought to be unlikely at this time.

Clinical Presentation Some of the difficulty in diagnosing Q fever accurately may be due to the frequent manifestation of this disease as a mild or asymptomatic clinical illness. Various epidemiologic surveys have reported the prevalence of asymptomatic disease to be 50% of documented cases. When Q fever presents symptomatically, however, it can be divided broadly into acute and chronic forms, with duration of infection as a commonly designated temporal distinction between the two forms. Infection lasting more than 6 months is considered chronic Q fever57; conversely, infection of less than 6 months’ duration is considered acute Q fever. Acute infection typically manifests as a self-limited febrile or flulike illness, pneumonia, or hepatitis.57 The incubation period from time of infection to onset of clinical disease is estimated at 2 to 5 weeks, with an average incubation time of 20 days. Despite the typical presentations described, the clinical manifestations nevertheless can be extremely varied and can lead to atypical presentations. One large case series, evaluating 1383 patients with Q fever from France who were identified based on positive serum serologies over a 14-year period (1985–1998), noted that 77% of the cases identified were acute Q fever. Of patients with acute disease, hepatitis, pneumonia with hepatitis, pneumonia alone, and fever were the most common presentations, in descending order of frequency.59 The investigators also found age and host factor predisposition associated with the types of clinical manifestations, with younger patients tending to present with

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hepatitis and older immunocompromised patients more commonly presenting with pneumonia. A flulike illness is overall the most common manifestation of acute Q fever, with a typically abrupt onset of high-grade fevers of 104F (40C), with myalgias, headache, and fatigue as frequently associated symptoms. The nonspecific nature of this type of presentation makes it much less likely that individuals who present in this manner will be diagnosed accurately with acute Q fever, unless there is a high index of suspicion or the health care provider can elicit an epidemiologic or exposure history that is strongly suggestive of infection with C. burnetii. The diagnosis frequently may be missed in this type of presentation, especially because this form of acute Q fever is self-limited and may resolve without further interventions or treatments. When pneumonia is the presenting syndrome, there may be a greater likelihood of accurate disease recognition. The prevalence of acute Q fever pneumonia is approximately 6% to 7% in several parts of the world, in particular, Israel and Nova Scotia, where acute infection with C. burnetii can be a significant cause of community-acquired pneumonia.57 In other regions of the world, such as Switzerland and northern Spain, pneumonia is the most common presenting syndrome of acute Q fever. Patients with C. burnetii pneumonia usually present with mild disease, with nonproductive cough, fever, and a paucity of findings on physical examination of the lungs. Radiographic findings also are nonspecific, with chest radiographic appearances often resembling that of viral pneumonias. Pleural effusions occasionally can occur, although presentation with acute respiratory distress syndrome is much rarer. Clinical disease can last 10 days to 3 months, with a significant mortality rate of greater than 1%.57 Hepatitis can be another manifestation of acute Q fever, and it can be varied in presentation. Patients can present with a clinically asymptomatic hepatitis with transaminase elevations and fever, or they can have prominent hepatomegaly and abdominal discomfort, although usually without significant jaundice. A third variation of the hepatitis presentation can be a prolonged fever without any other localizing signs, which ultimately shows characteristic granulomas on liver biopsy examination. A classic description of the granulomatous pathology seen in the liver in Q fever hepatitis is as a doughnut-like granuloma because of the presence of a lipid-like vacuole that is surrounded by a fibrinoid ring.26 Other varied presentations of acute Q fever include pericarditis or myocarditis (rare, approximately in 1% of cases), severe headache with aseptic meningitis with or without encephalitis (also rare, in approximately 1% of cases), and maculopapular or purpuric rashes (approximately 10% of cases).78 As previously mentioned, there are many other manifestations of acute Q fever, which often present challenges for the clinician in diagnosing this disease accurately. Other clinical presentations include seizures, polyradiculoneuritis, optic neuritis, gastroenteritis, pancreatitis, erythema nodosum, lymphadenopathy, hemolytic ane-

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mia, hypoplastic anemia, thyroiditis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), glomerulonephritis resulting from antiphospholipid antibodies, and splenic rupture. Chronic Q fever, defined as infection lasting for greater than 6 months, seems to affect approximately 5% of patients infected with C. burnetii. In this form of the disease, the organism multiplies in the host cell (macrophage) and produces a significant bacteremia that leads to large amounts of antibodies and immune complexes that are produced against the infecting organism. This host immune defense against C. burnetii is largely responsible for the inflammation that ultimately leads to the manifestations of chronic Q fever infection. The most frequently affected organs are the heart, arteries, bones, and liver. The most common infectious syndrome resulting from this form of Q fever is endocarditis (most typically in patients who are immunocompromised or who have pre-existing valvular heart disease), with an estimated prevalence of 77% in patients with chronic Q fever, based on the results of the previously mentioned 14-year epidemiologic survey of Q fever cases in France.59 The same study noted that 23% of patients with documented Q fever suffered from the chronic form of the disease. Endocarditis seems to represent a particularly severe and fatal form of chronic Q fever infection; the mortality from Q fever endocarditis was 24% in at least one case series of Q fever cases.5 Compounding the diagnostic difficulties in Q fever endocarditis, in particular, are the lack of any typical presentations in this form of chronic Q fever and the nonspecific nature of the clinical symptoms with which patients present. Constitutional symptoms (e.g., fever, generalized weakness, malaise, fatigue, weight loss, chills, night sweats, anorexia), congestive heart failure (presenting as dyspnea, angina, palpitations), and valvular dysfunction may be some of the initial presenting symptoms.71 Conventional blood cultures usually are not able to detect growth of the causative organism, and vegetations are seen infrequently on echocardiography. All these factors lead to a long interval from onset of disease to diagnosis, reported to be 12 to 24 months.71 Most patients (90%) with Q fever endocarditis have pre-existing valvular abnormalities, and many of these patients develop symptoms of congestive heart failure.71 A significant proportion of cases of C. burnetii involve prosthetic valve endocarditis,5 and left-sided valves are involved more commonly. In contrast to endocarditis caused by other agents, however, in C. burnetii endocarditis, peripheral manifestations frequently are found, including splenomegaly, hepatomegaly, purpuric rash (on the extremities or mucosal surfaces), embolic manifestations, immune complex glomerulonephritis (causing hematuria), and digital clubbing. Most laboratory findings in Q fever endocarditis are relatively nonspecific and include anemia, thrombocytopenia, elevated erythrocyte sedimentation rate, transaminase elevations, and elevations in creatinine kinase or lactate dehydrogenase.5, 71 Other positive laboratory findings include positive rheumatoid factor, low titer positive anti–smooth muscle antibodies,

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antiphospholipid antibodies, antimitochondrial antibodies, and positive Coombs’s test. Cryoglobulins also may be present and are thought to play a role in the pathogenesis of Q fever endocarditis. Other less common manifestations of chronic Q fever infection include infection of aneurysms or vascular grafts,25 hepatic fibrosis or cirrhosis (complicating hepatitis), and osteomyelitis or osteoarthritis, with rare reports of pericardial effusions, pulmonary interstitial fibrosis, amyloidosis, mixed cryoglobulinemia, or malignancy-like presentations (pseudotumor of the lung, mimicking lymphoma).57 These presentations of chronic Q fever infection more likely occur months or years after the acute disease and represent long-term sequelae of untreated (and possibly undiagnosed) acute Q fever infection. The acute and chronic forms of disease have been described in pregnancy, although only scattered case reports in the literature represent acquisition of clinically significant illness during human pregnancies. In animals, C. burnetii reactivates during pregnancy and may lead to spontaneous abortion, premature delivery, or low fetal birth weight. Most cases of Q fever infection in pregnant women represent asymptomatic infection in the mother, although complications of infection with C. burnetii during pregnancy may lead to fetal death in utero, placental inflammation, and hematologic complications. The significance and incidence of congenital Q fever infection is unknown, although intrauterine transmission of C. burnetii has been reported.72 Diagnosis Because the organism is relatively difficult to culture and isolate microbiologically, diagnosis often rests on serologic confirmation of infection with C. burnetii. Laboratory findings are nonspecific, but leukocytosis (or more commonly normal white blood cell count), elevated erythrocyte sedimentation rate, elevated creatinine kinase, and thrombocytopenia all may be present.26 Moderate hepatic transaminase elevations are seen frequently, approximately 2 to 10 times normal values. Autoantibodies, such as antiphospholipid antibodies, anti–smooth muscle antibodies, and antimitochondrial antibodies, frequently are present in Q fever.26 The significance of these autoantibodies and the role they may play, if any, in pathogenesis of this infection still are not elucidated fully, however. Because of the difficulties in isolating the organism, and because of the relatively high mortality rate associated with sequelae of some forms of chronic infection (as in endocarditis), Q fever should be considered as a diagnostic possibility in all suspected cases of culturenegative endocarditis, especially in cases in which there is a provocative exposure history. Several different techniques have been employed for serologic testing for Q fever, with microimmunofluorescence the most commonly used method currently. IgG, IgM, and IgA antibody titers can be distinguished by this technique, and antibodies to phase I and phase II

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antigens are detected. Seroconversion usually is detected within 1 to 2 weeks after onset of clinical disease, and approximately 90% of patients with C. burnetii infection have detectable antibodies by the third week after onset of symptoms.26 Antibody titers of greater than 1:200 for anti–phase II IgG and greater than 1:50 for anti–phase II IgM are indicative of acute infection.26 A single anti–phase I IgG antibody titer of greater than 1:800 and IgA titer of greater than 1:100 indicate evidence of chronic infection with C. burnetii. IgM titers can be variable and may not be as helpful diagnostically. In chronic Q fever endocarditis, there is a high titer antibody response to phase I and phase II antigens of the organism. The antibody titers assayed by microimmunofluorescence reach their highest levels approximately 4 to 8 weeks after the onset of acute Q fever, with gradually decreasing levels over the subsequent 12 months. If high levels of anti–phase I antibodies persist despite therapy or if antibodies reappear in high titer, after previously being undetectable or present only in low titers, this may herald the development of chronic Q fever infection. The antibody titers may be used to monitor the response to therapy, especially in Q fever endocarditis. In individuals who are at particularly high risk for the development of chronic infection with C. burnetii (patients with valvular heart disease, immunodeficiencies, or vascular abnormalities), repeated serologic testing should be undertaken, especially in the setting of previously documented or diagnosed acute Q fever infection or unexplained recurrent febrile episodes. If acute Q fever has been diagnosed, repeat serologic testing monthly for at least 6 months is recommended. In addition to the challenges of microbiologic isolation of C. burnetii in culture, there are hazards to attempted diagnosis by these means. The organism is highly infective, and particularly because human infection can occur through inhalation of aerosolized organisms, to attempt to culture C. burnetii, special biosafety containment procedures and protocols must be in place. Investigations into the use of polymerase chain reaction technology to diagnose Q fever have produced some promising results, with successful detection of the organism in cell cultures and clinical isolates.26 Several laboratories, particularly in Europe, use polymerase chain reaction technology (with primers that yield sensitive, specific, and reliable results) to aid in diagnosing this disease. Polymerase chain reaction–based diagnostic approaches still have not become widely or conveniently available in many parts of the world, however, and serology currently remains the most widely used diagnostic method. Treatment The acute form of Q fever infection is a self-limited illness that resolves after several weeks. This situation has made large-scale studies to investigate the efficacy of various antibiotic regimens problematic. Most literature that has examined antibiotic therapies for Q fever are largely case based and anecdotal, and comparative studies evaluating

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different therapeutic regimens are lacking. At least one randomized study investigated the efficacy of tetracycline versus placebo in treatment of Q fever and found evidence of therapeutic benefit with treatment.53 Currently, recommendations for first-line therapy for Q fever (in adults) support the use of doxycycline because of its improved pharmacokinetic and adverse effects profile. Other clinical trials have investigated the utility of fluoroquinolones as an alternative treatment for Q fever, and these studies have reported success with these agents (ofloxacin, perfloxacin). Although erythromycin has been used successfully as therapy for Q fever pneumonia, there have been reports of treatment failures, even with high-dose parenteral therapy. The role of erythromycin in treatment of Q fever infection is more controversial, and although other macrolides ultimately may prove to be useful alternative therapies for this disease, further studies likely will need to be undertaken before more conclusive recommendations can be made. Several anecdotal reports have advocated the efficacy of other antibiotics, particularly in the treatment of Q fever pneumonia, such as cotrimoxazole, chloramphenicol, and lincomycin. The self-limited nature of acute Q fever infection makes it difficult, however, to assess accurately the clinical benefits of these (and other) antibiotic regimens. Some in vitro experiments suggest that co-trimoxazole may be an alternative to tetracyclines and fluoroquinolones, particularly in situations in which the latter two classes of antibiotics may be contraindicated (in pediatric or pregnant patients), although further clinical studies need to be performed to validate the preliminary in vitro findings. Consensus opinion regarding the treatment of Q fever endocarditis is hampered by a relative lack of conclusive evidence; however, clinical experience with combination therapy with hydroxychloroquine and doxycycline has led to successful outcomes. In one study that compared several dozen patients with Q fever endocarditis treated with either hydroxychloroquine and doxycycline or a fluoroquinolone and doxycycline, investigators found that patients treated with the first regimen had no observed relapses when treated for longer than 18 months and a greater cure rate compared with the patients treated with the second regimen.55 In vitro evidence suggests a possible mechanism for the therapeutic success of the hydroxychloroquine and doxycycline regimen because a 1 g/mL amount of chloroquine seemed to make doxycycline bactericidal against intracellular organisms. The tetracyclines as a class usually are bacteriostatic, particularly against intracellular organisms, such as C. burnetii. In general, combination therapy has been proposed as the most optimal means of attempting medical cure for Q fever endocarditis. Other combination regimens that can be used include doxycycline plus rifampin (may have some difficulties in rifampin’s interactions with anticoagulants) and ciprofloxacin or ofloxacin plus doxycycline.57 The optimal duration of therapy for Q fever endocarditis is debated, but long-term therapy seems to be the rule. The doxycycline and hydroxy-

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chloroquine treatment regimen is recommended for at least 18 months,55 and other regimens may need to be continued for variable durations, from 3 years to lifetime therapy. After initiation of effective antimicrobial therapy, the patient usually becomes afebrile within 1 week, and over the course of the subsequent 2 weeks to 3 months, the patient has resolution of most of the other associated symptoms of Q fever endocarditis, including hematologic abnormalities, organomegaly, and hepatic transaminase elevations. Serologic testing is recommended during therapy for Q fever endocarditis, with repeat testing on a monthly basis for 1 year of therapy and decreased interval testing (every 3 months for several more years, then decreasing to every 6 months indefinitely) thereafter to ensure adequate success of therapy and to survey for possible relapse. In patients with Q fever hepatitis, there are some anecdotal reports of successful therapy with a combination of prednisone and an antibiotic. Adjunctive prednisone therapy may be considered in individuals with Q fever hepatitis, who have persistent fevers, persistent high elevations of erythrocyte sedimentation rate, or high titers of autoantibodies, especially when these occur despite antibiotic therapy. A short, tapering, 1week course of prednisone therapy may be indicated if patients with Q fever hepatitis have not started to defervesce after several days of antibiotic therapy. For acute Q fever infection, in general, a 2-week course of doxycycline currently is the recommended first-line therapy. Fluoroquinolones may be an alternative regimen, particularly in the case of more unusual manifestations of acute Q fever infection, such as meningitis or encephalitis, because of the unreliable penetration of the tetracyclines into the cerebrospinal fluid. Recommendations for pediatric or pregnant patients are problematic because there are insufficient clinical data to recommend conclusively alternative agents, such as macrolides or co-trimoxazole.55

SUMMARY The zoonotic infections caused by Francisella tularensis and Coxiella burnetii, tularemia and Q fever, respectively, are two less commonly encountered clinical illnesses that are becoming increasingly recognized as epidemiologically important human diseases. The prevalence of tularemia and Q fever can be positively impacted by increased awareness of the clinical entities that arise from infection by these arthropod-borne organisms. Improved recognition of these clinical syndromes will lead to greater diagnostic accuracy in recognizing these diseases in patients. Ultimately, more stringent measures to prevent infection may be required, through raising public awareness, since current therapeutic regimens for these two diseases are limited, and knowledge of the pathogenesis of these two organisms are still in developing stages.

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