on 22-Jul-2023 (Sat)

Transmission occurs primarily through inhalation of aerosols from contaminated soil or animal waste.

Because many human infections result in nonspecific or benign constitutional symptoms, establishing a diagnosis of Q fever often is challenging for clinicians

The causative organism, Coxiella burnetii, is an intracellular bacterium that tends to infect mononuclear phagocytes but can infect other cell types as well

Infection in humans usually occurs by inhalation of bacteria from air that is contaminated by excreta of infected animals. Other modes of transmission to humans, including tick bites, ingestion of unpasteurized milk or dairy products, and human-to-human transmission, are rare ( 1).

The national seroprevalence of Q fever is estimated to be 3.1% based on data from the National Health and Nutrition Examination Survey (2003–2004), and human infections have been reported from every state in the United States (5).

Q fever infections in humans and animals have been reported from every world region except Antarctica ( 6).

During an acute infection, an antibody response to C. burnetii phase II antigen is predominant and is higher than the response to the phase I antigen, whereas a chronic infection is associated with a rising phase I immunoglobulin G (IgG) titer

Although acute Q fever symptoms in humans vary, the condition typically is characterized by a nonspecific febrile illness, hepatitis, or pneumonia.

Asymptomatic infections followed by seroconversion have been reported in up to 60% of cases identified during outbreak investigations ( 6–8).

Onset of symptoms usually occurs within 2–3 weeks of exposure, and symptomatic patients might be ill for weeks or months if untreated.

Chronic Q fever can manifest within a few months or several years after acute infection and can follow symptomatic or asymptomatic infections. Chronic disease is rare (<5% of patients with acute infections) and typically is characterized by endocarditis in patients with preexisting risk factors such as valvular or vascular defects (9)

Unlike acute Q fever, which has a low mortality rate (<2%), chronic Q fever endocarditis is always fatal if untreated ( 10)

Diagnosis of chronic Q fever endocarditis can be extremely difficult because vegetative lesions are visualized by echocardiography in approximately 12% of patients ( 6).

Q fever is an occupational disease in persons whose work involves contact with animals, such as slaughterhouse workers, veterinarians, and farmers, although infection is not limited to these groups. Urban outbreaks and cases with no known exposure or close proximity to livestock have been reported, as have nonoccupational exposures such as through a hobby farm (a small farm that is not a primary source of income) (11).

Data collected from Q fever case report forms submitted to CDC during 2000–2010 indicate that 320 of 405 (79%) cases in patients who reported occupational status are recognized in patients who are not in previously defined high-risk occupations, and 243 of 405 (60%) cases are in patients who do not report livestock contact (CDC, unpublished data, 2010). These findings underscore the need for health-care professionals to consider Q fever in the differential diagnosis in patients with a compatible illness, even in the absence of occupational risk or history of direct contact with animal reservoirs.

Approximately 200 cases of acute Q fever were reported in U.S. military personnel who had been deployed to Iraq since 2003. Investigations of these cases linked illness to tick bites, sleeping in barns, and living near helicopter zones with environmental exposure resulting from helicopter-generated aerosols ( 12,13).

The largest known reported Q fever outbreak involved approximately 4,000 human cases and occurred during 2007–2010 in the Netherlands. This outbreak was linked to dairy goat farms near densely populated areas and presumably involved human exposure via a windborne route (14).

Prompt diagnosis and appropriate treatment shortens the illness and reduces the risk for severe complications (15,16)

Cattle, sheep, and goats are the primary reservoirs for C. burnetii. However, infection has been confirmed in multiple vertebrate species, including wildlife, marine mammals, domestic mammals, birds, and reptiles (17).

C. burnetii has been isolated from approximately 40 species of ticks, and possible tickborne transmission of C. burnetii to humans has been reported (18–20).

Human outbreaks and cases have been epidemiologically linked to exposure to multiple species including pigeons, dogs, and rabbits ( 21–23).

Human cases and outbreaks linked to exposure to infected parturient cats also have been reported ( 24–26).

The majority of animal infections are asymptomatic. Clinical illness in ruminants is primarily characterized by reproductive disorders such as abortion, stillbirth, endometritis, mastitis, and infertility (27)

The highest numbers of organisms are shed in birth products, although viable organisms also might be shed in the urine, milk, and feces of infected animals ( 28,29).

Polymerase chain reaction (PCR) testing of body fluids (e.g., feces, milk, and vaginal mucus) is a more reliable method to detect shedding, which might be intermittent.

The most common mode of transmission in humans is inhalation of infectious aerosols directly from birth fluids of infected animals or via inhalation of dust contaminated with dried birth fluids or excreta. C. burnetii is extremely resistant to physical stresses, including heat and desiccation and can survive in the environment for months to years. The bacteria can become airborne, traveling on wind currents for miles, resulting in outbreaks (35,36).

In one outbreak, Q fever cases were documented in persons who lived 10 miles from the farm that was the source of the outbreak. In a recent outbreak in the Netherlands, living within 2 km of an infected farm was a significant risk factor for infection ( 36–38). Less common routes of transmission include ingestion of raw milk and dairy products or contact with contaminated clothing (39,40).

The reported incidence and seroprevalence of acute Q fever is higher among persons aged ≥40 years than among younger persons, and disease severity increases with age (5,50). Persons aged 60–64 years have the highest age-related risk of Q fever in the United States (4).

In addition, males have a higher risk for symptomatic Q fever illness than females ( 6), which might be partly explained by sex-associated occupational exposures or the protective effects of 17β-estradiol in females, which has been validated in animal studies (51,52).

Although infections occur year round, acute Q fever cases in the United States peak in the spring. Seasonal incidence of acute Q fever likely correlates with livestock birthing times or farm management practices such as manure spreading (4,53,54).

When compiling a medical history, health-care providers should consider the following factors:

• occupations with increased contact with animals or animal products (particularly livestock), including veterinarians, butchers, slaughterhouse workers, farmers, and laboratory workers
• living in a rural area or living on or within 10 miles of a farm that houses livestock, particularly cattle, sheep, or goats
• recent travel to areas of higher risk for Q fever, such as rural, agricultural communities (domestic and international), areas with recent outbreaks such as the Netherlands, or regions such as the Middle East where the disease is highly endemic
• sexual contact with a person who has recently had Q fever or contact with contaminated clothing and linens leading to fomite transmission
• Q fever symptoms in a person who has a partner or family member who has received a diagnosis of Q fever
• chronic Q fever symptoms in anyone with a history of acute Q fever infection, particularly persons with valvular heart disease or a vascular graft or arterial aneurysm, immunosuppressed persons, and women who are pregnant

Although a detailed exposure history, including animal contact, might assist health-care providers in identifying potential Q fever in a patient, a lack of direct animal contact should not preclude a clinical suspicion of diagnosis because airborne transmission of C. burnetii can occur.

Person-to-person transmission of Q fever is possible but rarely reported

Adults

Symptomatic acute Q fever, which occurs in approximately half of infected persons, is characterized by a wide variety of clinical signs and symptoms. After an incubation period of 2–3 weeks, the most common clinical manifestation is a nonspecific febrile illness that might occur in conjunction with pneumonia or hepatitis (6). The most frequently reported symptoms include fever, fatigue, chills, and myalgia (Table 1).

Severe, debilitating headaches also are a frequent symptom, and lumbar punctures have been performed on patients for suspected meningitis who were later shown to have Q fever (J. Hartzell, MD, Walter Reed National Military Medical Center, 2012, personal communication). The headache might be retroorbital and associated with photophobia (6). In patients with acute Q fever illness, this has been misclassified as a new onset migraine headache or a potentially infected tooth because the headache pain radiates to the jaw (11).

Pneumonia is an important clinical manifestation of acute Q fever, and C. burnetii might be an underrecognized cause of community-acquired pneumonia. In North America in the 1980s, the prevalence of acute Q fever in 1,306 cases of community-acquired pneumonia in hospitalized patients was 30 cases (2.3%) (57).

Features of Q fever pneumonia are similar to other etiologies of community-acquired pneumonia and cannot be distinguished clinically, radiologically, or by any other routine laboratory evaluation.

Q fever pneumonia can range from mild to severe, and numerous patients have extrapulmonary manifestations (including severe headache, myalgia, and arthralgia). Cough is often present and is nonproductive in 50% of patients; upper respiratory signs are less likely to be reported in persons with Q fever pneumonia ( 58–62).

Fever lasts a median of 10 days in untreated patients (range: 5–57 days); the majority of cases defervesce within 72 hours of doxycycline administration (63,64).

The duration of fever increases with age; one study demonstrated that 60% of patients aged >40 years had a fever duration of >14 days, compared with 29% of patients aged <40 years ( 64). In another study, 5%–21% of patients with acute Q fever had a maculopapular or purpuric rash (53)

Onset of symptoms can be gradual or abrupt, with variable severity.

Although mortality is <2% in patients with acute Q fever, in the Netherlands outbreak, which included approximately 4,000 reported cases, up to 50% of acute Q fever patients were hospitalized ( 6,38).

Less frequently described clinical symptoms include pericarditis, myocarditis, aseptic meningitis, encephalitis, and cholecystitis ( 53,65).

Children

Children with Q fever are less likely to have symptoms than adults and might have a milder illness. Acute Q fever in symptomatic children typically is characterized by a febrile illness, often accompanied by headache, weakness, cough, and other nonspecific systemic symptoms. Illness frequently is self-limited, although a relapsing febrile illness lasting for several months has been documented in some children (66). Gastrointestinal symptoms such as diarrhea, vomiting, abdominal pain, and anorexia are reported in 50%–80% of pediatric cases (66–68). Skin rash is more common in children than adults, with a prevalence as high as 50% among children with diagnosed cases (66–69). Q fever pneumonia is usually moderate with mild cough; respiratory distress and chest pain might occur.

Severe manifestations of acute disease are rare in children and include hepatitis, hemolytic uremic syndrome, myocarditis, pericarditis, encephalitis, meningitis, hemophagocytosis, lymphadenitis, acalculous cholecystitis, and rhabdomyolysis ( 70–74).

Adverse pregnancy outcomes are likely to be caused by vasculitis or vascular thrombosis resulting in placental insufficiency, although direct infection of the fetus has been documented (76). Of the reports that describe outcomes of infected pregnant women, none have documented an increased risk for congenital malformations because of infection (75,76).

The risk for adverse effects on the fetus and the risk that the mother will develop chronic Q fever are highest when an acute infection occurs during the first trimester (81,82)

Women infected with acute Q fever during pregnancy, including those who were asymptomatic or experienced no adverse pregnancy outcomes, might be at risk for recrudescent infection during subsequent pregnancies (83).

These women should be advised to avoid pregnancy for at least 1 month after diagnosis and treatment and should receive a pregnancy test to determine whether long-term antibiotic treatment is needed.

Pneumonia is one of the primary clinical manifestations of acute Q fever (6). Chest radiograph abnormalities are seen in the majority of patients with acute Q fever, although patients in the early stages of disease might have normal radiographic findings.

Radiographic evaluation of acute Q fever patients during the Netherlands outbreak showed infiltrates in >96% of patients ( 84). Radiographic patterns for acute Q fever pneumonia are nonspecific; the most common abnormalities are segmental or lobar consolidation, which might be unilateral or bilateral, involve upper or lower lobes, or feature multiple or single opacities. Patchy infiltrations are an uncommon feature of Q fever pneumonia (58,85,86).

Acute respiratory distress syndrome is a rare manifestation of Q fever but has occurred ( 87,88).

It is not possible to differentiate Q fever pneumonia from other causes of community-acquired pneumonia solely on the basis of radiographic findings.

Laboratory Findings

Although up to 25% of patients with acute Q fever have an increased leukocyte count, most patients have normal white blood cell counts. Mild thrombocytopenia in early illness, which occurs in approximately one third of patients, might be followed by subsequent thrombocytosis. Increased erythrocyte sedimentation rate, hyponatremia, hematuria, increased creatine kinase, and increased C-reactive protein levels have been reported.

The most common laboratory abnormalities are increased liver enzyme levels, which are observed in up to 85% of cases ( 89). Hyperbilirubinemia occurs in one in four patients (90–93). Hepatomegaly or splenomegaly (unrelated to thrombocytopenia) also might be present, although jaundice is rare (90).

Q fever causes significant immune activation that might result in cross-reactivity with other laboratory tests for autoimmune or infectious processes or agents, including tests for antineutrophil cytoplasmic antibodies, human immunodeficiency virus (HIV), brucellosis, or rapid plasma reagin ( 94).

Prolonged fever (>10 days) with a normal leukocyte count, thrombocytopenia, and increased liver enzymes is suggestive of acute Q fever infection.

Adults

Chronic Q fever is rare, occurring in <5% of persons with acute infection, and might occur within a few months, years, or even decades after the initial acute infection (6). Chronic disease can occur after symptomatic or asymptomatic infections. Potential signs and symptoms include endocarditis, chronic hepatitis, chronic vascular infections, osteomyelitis, osteoarthritis, and chronic pulmonary infections (6). Although patients likely have lifelong immunity to reinfection, disease recrudescence might occur and has been well documented (95).

The patients at highest risk for chronic Q fever are those with valvular heart disease, a vascular graft, or an arterial aneurysm. Acute infection in immunosuppressed persons and pregnant women also has been linked to later development of chronic disease (6,96).

Endocarditis is the major form of chronic Q fever, comprising 60%–78% of all cases worldwide. Endocarditis is a severe condition that is invariably fatal due to heart failure if untreated and has a 10-year mortality rate of 19% in treated patients ( 97,98). The second most common form of chronic Q fever is infection of aneurysms or vascular prostheses, followed by chronic Q fever infections after pregnancy (98). However, during the Q fever outbreak in the Netherlands, vascular infections were the most common form of chronic disease reported (15).

A clinical assessment of patients with acute Q fever should be performed to determine whether they are at high risk for subsequent chronic infection. Approximately 40% of persons with a known valvulopathy with an acute Q fever diagnosis subsequently develop infective endocarditis (99). Patients with endocarditis are predominantly men aged >40 years (97).

Similar to other infective endocarditis etiologies, patients at highest risk for development of Q fever endocarditis after acute infection are those with a prosthetic valve, followed by patients with aortic bicuspid valves, mitral valve prolapse, and moderate mitral insufficiency ( 99,100).

Valvular vegetations usually are small and are detected by echocardiogram in approximately 12% of cases. Cardiologists evaluating the echocardiogram should be made aware of the suspected diagnosis of chronic Q fever because the lesions, which often are subtle, might be missed (97). A transesophageal echocardiogram (TEE) is more sensitive than a transthoracic echocardiogram (TTE) in detecting valvular defects; TEEs should be performed in patients with suspected endocarditis who have TTEs that are negative or not definitive (103). However, a negative echocardiogram, whether TTE or TEE, does not rule out a diagnosis of chronic Q fever endocarditis.

The initial clinical signs and symptoms in patients with chronic Q fever often are nonspecific and highly variable. Features might include fatigue, fever, abdominal or chest pain, weight loss, night sweats, or hepatosplenomegaly (101). Arterial embolism, pulmonary embolism, or deep venous thrombosis also might occur (97,102)

In a retrospective study of patients with Q fever endocarditis, the most common abnormality found by echocardiography in patients with chronic Q fever endocarditis was a newly discovered or worsening valvular insufficiency (97).

The mitral and aortic valves were most commonly affected. Patients often did not have a previous diagnosis of acute Q fever. The median onset time for endocarditis was 2.5 months (range: 1–66 months) after acute illness among those who received a diagnosis of acute Q fever ( 97).

Persons with arterial aneurysms or vascular grafts also are at risk for chronic Q fever, and C. burnetii vascular infection carries a high mortality rate even in treated patients (96,104). Treated patients have an estimated 3-year mortality rate of 25%, a rate much higher than patients with treated Q fever endocarditis, who have an estimated 3-year mortality rate of 7% (97,104).

The majority of C. burnetii vascular infections reported in the literature are aortic infections, which complicate an aortic aneurysm or previously placed endovascular prosthesis (104).

Patients might have culture-negative aortitis ( 105). Spondylodiscitis and vertebral involvement might occur and should prompt testing for Q fever in patients with aortic defects (104)

Pregnant Women

Women infected with Q fever during pregnancy are at high risk for developing chronic Q fever, possibly because of a failure to mount an appropriate immune response to acute infection or the ability of C. burnetii to use placental trophoblasts as a replicative niche (106,107). The earlier during pregnancy a woman is infected, the greater her risk for development of chronic disease (75)

Children

Chronic Q fever is rarely reported in children. Pediatric chronic Q fever manifests most frequently as chronic relapsing or multifocal osteomyelitis, blood-culture–negative endocarditis, or chronic hepatitis (108). Children with Q fever osteomyelitis often experience a prolonged course with recurrent episodes affecting multiple bones before diagnosis (71,109). Like adults, children who are immunocompromised or have underlying heart valve disease might be at higher risk for chronic Q fever.

Although a laboratory diagnosis of acute Q fever can be made on the basis of serologic results, the requirement of a fourfold rise in phase II IgG antibody titer between acute and convalescent samples for definitive diagnosis makes this primarily a retrospective diagnosis (Table 3). For a definitive diagnosis in the early stages of acute Q fever illness, serologic testing in combination with PCR is recommended. PCR of whole blood or serum can be positive very early after symptom onset but becomes negative as the antibody titer increases and after administration of antibiotics (Table 4).

Treatment should never be withheld pending receipt of diagnostic test results or discontinued because of a negative acute serologic or PCR result. Conversely, because antibodies might remain detectable for months to years after infection, treatment should not be provided based solely on elevated titers (such as those detected through routine screening or baseline occupational assessments) without clinical manifestation of acute illness (e.g., fever, pneumonia, hepatitis, or other acute symptoms)

C. burnetii exists in two antigenic phases, phase I and phase II. Phase I is the virulent, highly infectious form that undergoes a transition to phase II, the avirulent form, during serial laboratory passages in embryonated eggs or cell cultures. In acute infection, the phase II antibody response to C. burnetii appears first and is higher than the phase I antibody response (6).

For serologic testing, the indirect immunofluorescence assay (IFA) is commercially available and is the most commonly used method for serologic diagnosis of Q fever in the United States.

The most commonly used means of confirming the diagnosis of acute Q fever is demonstration of a fourfold rise in phase II IgG by IFA between serum samples from the acute and convalescent phases taken 3–6 weeks apart. Ideally, the first serum specimen should be taken during the first week of illness.

Because results from different laboratories can differ significantly, using the same laboratory service whenever possible can provide the most accurate results (126).

Seroconversion typically occurs 7–15 days after symptoms appear, and 90% of patients seroconvert by the third week of illness. Immunoglobulin M (IgM) antibodies to phase II antigen develop in the second week of acute illness, with an increase in phase II IgG occurring almost simultaneously. In successfully treated or spontaneously resolving disease, IgG and IgM titers to phase I antigen might continue to increase in later specimens but typically do not exceed phase II titers.

Regardless of whether the infection is symptomatic or asymptomatic, after the infection, antibodies might remain detectable for many months, for years, or for life (127).

In the absence of positive PCR results and the ability to obtain an acute serum sample, a single positive convalescent serum sample (IgG phase II ≥1:128) in a patient who has been ill >1 week indicates a probable acute infection

IgM results provide ancillary information to the IgG titers; however, because of persistence (>1 year in some cases), the IgM test provides limited diagnostic value as a standalone test. IgM antibodies have a much lower specificity than IgG and might have a higher cross-reactivity. Cross-reactions between Coxiella, Legionella, and Bartonella species have been reported (128,129).

Because early doxycycline treatment (within the first 3 days of symptoms) is most effective, treatment of a patient suspected of having Q fever should be based on clinical findings and should not be delayed while awaiting laboratory confirmation (16). No evidence indicates that early administration of doxycycline blunts the antibody response or prevents seroconversion (130,131).

For PCR results to be useful, the clinical sample must be obtained in the acute phase of infection (optimally during the first 2 weeks of symptom onset) and either before or shortly after (within 24–48 hours) antibiotic administration.

When appropriate samples are drawn (i.e., during the acute phase and before or shortly after antibiotic administration), PCR results are positive in almost all patients with early acute Q fever before the antibody response develops ( 133).

Serologic Testing

Chronic Q fever is diagnosed primarily by serologic testing. Establishing an identifiable nidus of chronic infection (e.g., endocarditis, vascular infection, or osteomyelitis) is required, as is laboratory confirmation.

In contrast to acute Q fever infection, chronic infection is associated with continued increasing phase I IgG titers (typically ≥1:1024) that might be higher than phase II IgG. However, there are reports of chronic Q fever patients who retain extremely high phase II IgG antibody titers that equal or exceed their phase I IgG titers ( 135,136)

It is possible for a patient with previously diagnosed acute Q fever who no longer has clinical symptoms to have increased phase I IgG titers for several months that subsequently decrease or stabilize without ever progressing to chronic disease ( 135,137).

Reported rates of PCR positivity in blood or serum of patients with Q fever endocarditis have ranged from 33% to 64% (97,135,136).

PCR can be performed on cerebrospinal fluid, pleural fluid, bone marrow, bone biopsies, liver biopsies, milk, placenta, and fetal tissue.

Cultivation of C. burnetii is not recommended for routine diagnosis because the process is difficult, time consuming, and dangerous; culture requires a biosafety level 3 (BSL-3) laboratory because bacteria are highly infective and can be hazardous for laboratory workers.

The majority of acute Q fever cases resolve spontaneously within 2–3 weeks, even without treatment.

Treatment is most effective if given within the first 3 days of symptoms, shortens the illness, and reduces the risk for severe complications (15,16).

Other antibiotic regimens that can be used if doxycycline is contraindicated because of allergies include moxifloxacin, clarithromycin, trimethoprim/sulfamethoxazole, and rifampin ( 75,140,141).

Treatment for acute Q fever is not routinely recommended for asymptomatic persons or for those whose symptoms have resolved, although it might be considered in those at high risk for developing chronic Q fever. In one study of acute Q fever patients who were monitored over time for progression to chronic disease, those who eventually had chronic Q fever were more likely to have not received appropriate doxycycline treatment during their acute illness because their symptoms were mild or they were asymptomatic ( 15).

Patients with acute Q fever should undergo a careful clinical assessment to determine whether they might be at risk for progression to chronic Q fever because patients at high risk require closer observation during the convalescent period. A thorough clinical assessment should include review of possible immunosuppressive conditions, pregnancy testing when appropriate, and assessment for vascular and heart valve defects because certain valvular lesions might not be detectable by auscultation (142).

A medical history and clinical examination alone might not be sufficient to identify patients with existing heart valve defects ( 143,144); health-care providers should use their clinical judgment to determine the most appropriate tools for assessment of risk (Figure).

Patients who are healthy and have no identified risk factor for chronic illness should receive a clinical and serologic evaluation approximately 6 months after diagnosis of acute infection to identify potential progression to chronic disease.

Phase I and phase II IgG and IgM antibodies should be measured to endpoint by IFA and compared with previous titers. Patients with a phase I IgG antibody titer ≥1:1024 should be carefully assessed for clinical evidence of progression to chronic Q fever infection.

If a patient has no serologic or clinical evidence of progression to chronic infection, serologic monitoring can either be discontinued or continued less frequently if deemed appropriate by the health-care provider. However, patients should be advised to seek medical care immediately should symptoms of chronic Q fever occur at any time throughout their lives.

Patients with cardiovascular risk factors for chronic disease (e.g., heart valve defect, vascular graft, or aneurysm) at the time of acute infection should be serologically monitored and receive a physical examination at intervals of 3, 6, 12, 18, and 24 months (Figure). Women infected during pregnancy should be serologically and clinically monitored at the same intervals (3, 6, 12, 18, and 24 months) after delivery.

If there is no evidence of an increase in phase I IgG titers ≥1:1024 after 2 years and no evidence of clinical progression to chronic infection, serologic monitoring may be discontinued or continued less frequently if deemed appropriate by the health-care provider.

In all monitored patients, diagnosis of chronic Q fever is based on a rising or elevated phase I IgG titer (typically ≥1:1024) and an identifiable nidus of infection (e.g., endocarditis, vascular infection, and osteomyelitis)

Adults who receive a diagnosis of chronic Q fever should receive a treatment regimen of doxycycline and hydroxychloroquine (100 mg of doxycycline twice daily with 200 mg of hydroxychloroquine three times daily); duration of treatment might vary by the site of infection (Table 2) (6).

A combination regimen is necessary to eradicate the organism because hydroxychloroquine raises the pH in the acidified phagosomal compartment and, in combination with doxycycline, has been shown to have in vitro bactericidal activity against C. burnetii.

Because of potential retinal toxicity from long-term use of hydroxychloroquine, a baseline ophthalmic examination should be performed before treatment and every 6 months thereafter. Both doxycycline and hydroxychloroquine can cause photohypersensitivity, and hypersensitivity to sunlight is a potential complication with acute and chronic treatment regimens. Hydroxychloroquine is contraindicated in persons with glucose-6-phosphate dehydrogenase deficiency and persons with retinal or visual field deficits.

During treatment for chronic Q fever, patients should receive monthly serologic testing for C. burnetii phase I and II IgG and IgM antibodies and monthly clinical evaluations. If an appropriate treatment response is not achieved, monthly monitoring for hydroxychloroquine plasma levels (which should be maintained at 0.8–1.2 µg/mL) and doxycycline plasma levels (which should be maintained at ≥5 µg/mL) should also be performed during the treatment (145,146).

Treatment should continue for at least 18 months for native valve infections and at least 24 months for prosthetic valve infections ( 97).

Although treatment of vascular infections, such as infected aneurysms or grafts, is less clearly defined because of the smaller patient group, duration of antibiotic therapy reported in recovered patients is similar (18–24 months) (104). Early surgical intervention improves patient survival and might be necessary to remove an infected graft if the patient does not respond to antibiotic therapy (104,105).

Treatment and management of rarer manifestations of chronic disease (e.g., osteoarticular infections) depends on clinical and serologic response, and consultation with an infectious disease physician is recommended.

The definition of a cured case of chronic fever on the basis of serologic testing previously was defined as phase I IgG ≤1:200, although other researchers have recommended a phase I IgG cutoff of <1:800 to determine treatment duration (145,147). Because these specific titer dilutions are not available from commercial laboratories in the United States, they are more difficult to interpret in the United States.

Rather than rely on indiscriminate application of predetermined cutoff titers, health-care providers should use serologic testing as a tool to ensure that the phase I IgG is decreasing during treatment in conjunction with recovery from clinical symptoms. A patient who has been treated appropriately for ≥18 months and has recovered from clinical symptoms but whose phase I IgG remains ≥1:1024 might not benefit from continued treatment.

One study found that a favorable prognostic indicator for treated endocarditis patients who had no progression of clinical disease yet who were not considered cured on the basis of serologic testing was a fourfold decrease in phase I IgG and IgA and the complete disappearance of phase II IgM ( 97).

Twice yearly serologic monitoring of treated patients should continue for a minimum of 5 years after treatment, and lifelong serologic monitoring might be warranted in patients with severe valvular defects ( 97).

Treatment of pregnant women who received an acute Q fever diagnosis during pregnancy with trimethoprim/sulfamethoxazole throughout pregnancy has been shown to significantly decrease the risk for adverse consequences for the fetus (75)

Doxycycline is classified as a category D drug because of demonstrated concerns about the effects of tetracyclines on the bone structure and dentitia of the developing fetus (see drug categories for pregnancy at http://chemm.nlm.nih.gov/pregnancycategories.htm ). An effective alternative, trimethoprim/sulfamethoxazole, has been used as a treatment in pregnant women who received an acute Q fever diagnosis, although the drug is classified as a category C drug.

The use of trimethoprim/sulfamethoxazole during pregnancy might increase the risk for congenital abnormalities (primarily including urinary tract and cardiovascular abnormalities) because of antifolate effects ( 148), and concomitant use of folic acid is recommended. Research to assess the potential fetal risk from trimethoprim/sulfamethoxazole during pregnancy has been inconclusive (149).

Acute and Chronic Q Fever in Children

Doxycycline is the drug of choice for treatment of acute Q fever in children and is recommended for patients aged ≥8 years and for severe infections in children of any age.

The pediatric doxycycline dose for treatment of acute Q fever is 2.2 mg/kg twice per day for 2 weeks (maximum 100 mg per dose).

Children aged <8 years who are considered high risk and should therefore receive the full 2-week treatment with doxycycline include children who are hospitalized or have severe illness, children with preexisting heart valvulopathy, children who are immunocompromised, or children with delayed Q fever diagnosis who have experienced illness for >2 weeks without resolution of symptoms.

Although short courses (≤5 days) of doxycycline for the treatment of rickettsial infections such as Rocky Mountain spotted fever have not resulted in significant dental staining in children, the possible long-term dental effects of 2 weeks of doxycycline in children aged <8 years have not been well studied (150).

Because acute Q fever is frequently a mild or self-limiting illness with a low risk for death or a poor prognosis, health-care providers should use their clinical judgment to determine whether a 2-week course of doxycycline treatment should be used to treat Q fever infections in children aged <8 years who have a mild or uncomplicated illness. For these patients, health-care providers might consider a 5-day course of doxycycline, which does not cause dental staining. Children with continued mild symptoms after a short course of doxycycline can be treated with 14 days of trimethoprim/sulfamethoxazole.

Alternative long-term treatments that might be considered in children with chronic Q fever include use of a fluoroquinolone (e.g., moxifloxacin or levofloxacin) with rifampin or trimethoprim/sulfamethoxazole with doxycycline.

Summary of Q Fever Treatment and Management

• Because of the delay in seroconversion often necessary to confirm diagnosis, antibiotic treatment should never be withheld pending laboratory tests or discontinued on the basis of a negative acute specimen. In contrast, treatment of chronic Q fever should be initiated only after diagnostic confirmation.
• Treatment for acute or chronic Q fever should only be provided for patients with clinically compatible cases and not based on elevated serologic titers alone (see Pregnancy section for exception).
• Doxycycline is the drug of choice, and 2 weeks of treatment is recommended for adults, children aged ≥8 years, and for severe infections in patients of any age.
• Children aged <8 years with uncomplicated illness may be treated with trimethoprim/sulfamethoxazole or a shorter duration (5 days) of doxycycline.
• Women who are pregnant when acute Q fever is diagnosed should be treated with trimethoprim/sulfamethoxazole throughout the duration of pregnancy.
• Serologic monitoring is recommended after an acute Q fever infection to assess possible progression to chronic infection. The recommended schedule for monitoring is based on the patient's risk for chronic infection.

TABLE 2. Recommended antibiotics and dosages* for treatment of acute and chronic Q fever
Indication	Adults	Children ¶	Pregnant women
Acute Q fever †	Doxycycline § 100 mg twice a day for 14 days	≥8 years: Doxycycline: 2.2 mg/kg per dose twice a day for 14 days (maximum 100 mg per dose)	Trimethoprim/sulfamethoxazole: 160 mg/800 mg twice a day throughout pregnancy ††
<8 years with high risk criteria**: Doxycycline: 2.2 mg/kg per dose twice a day for 14 days (maximum: 100 mg per dose)
<8 years with mild or uncomplicated illness: Doxycycline 2.2 mg/kg per dose twice a day for 5 days (maximum 100 mg per dose). If patient remains febrile past 5 days of treatment: trimethoprim/sulfamethoxazole 4–20 mg/kg twice a day for 14 days (maximum: 800 mg per dose)
Chronic Q fever
Endocarditis or vascular infection	Doxycycline §§ 100 mg twice a day and hydroxychloroquine ¶¶ 200 mg three times a day ≥18 months	Recommend consultation***	Recommend consultation †††
Noncardiac organ disease §§§	Doxycycline 100 mg twice a day and hydroxychloroquine 200 mg three times a day	Recommend consultation***	Recommend consultation †††
Postpartum ¶¶¶ with serologic profile for chronic Q fever	Doxycycline 100 mg twice a day and hydroxychloroquine 200 mg three times a day for 12 months	—	—
Post-Q fever fatigue syndrome****	No current recommendations	No current recommendations	No current recommendations
* All drug dosages are oral regimens. † Prophylactic treatment after a potential Q fever exposure is not recommended; treatment is not recommended for asymptomatic infections or after symptoms have resolved, although it might be considered in persons at high risk for development of chronic Q fever. § Patients may take doxycycline with food to avoid stomach upset but should have no dairy products within 2 hours (before or after) of taking medication. Doxycycline should not be taken with antacids or bismuth-containing products, and patients should avoid taking it immediately before going to bed or ly

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FIGURE. Q fever management algorithm*