eMedicine Specialties > Infectious Diseases > Bacterial Infections

Q Fever

Alexandre Lacasse, MD, MSc, Fellow in Infectious Diseases, University of Tennessee at Memphis
Kerry O Cleveland, MD, Associate Professor of Medicine, University of Tennessee College of Medicine; Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Methodist Healthcare of Memphis; Hari Polenakovik, MD, Consultant Physician in Infectious Diseases and General Medicine, Department of Medicine, Western Health, Australia; Annie Ruest, MD, FRCPC, Consultant Physician in Infectious Diseases and Medical Microbiology, Departments of Medicine and Medical Biology, Laval University, Quebec City, Canada; Christian P Sinave, MD, Associate Professor, Department of Medical Microbiology and Infectious Diseases, University of Sherbrooke, Canada

Updated: Nov 18, 2008

Introduction

Background

Q fever is a zoonosis caused by Coxiella burnetii, an obligate gram-negative intracellular bacterium. Most commonly reported in southern France and Australia, Q fever occurs worldwide (except in New Zealand). Edward Derrick first described the illness Q (for query) fever in 1937 during a cluster of acute febrile illness in abattoir workers in Queensland, Australia. The causative organism was later isolated from Derrick's patients by Burnet and Freeman. Simultaneously, Davis and Cox identified the same organism from ticks collected near Nine Mile Creek in Montana during an investigation of Rocky Mountain spotted fever. First named Rickettsia diaporica and Rickettsia burnetii, the current name of Coxiella burnetii was applied in 1948.

C burnetii infects various hosts, including humans, ruminants (cattle, sheep, goats), and pets. In rare cases, C burnetii infection in reptiles, birds, and ticks has been reported. C burnetii is excreted in urine, milk, feces, and birth products. These products, especially the latter, contain large numbers of bacteria that become aerosolized after drying. The bacterium is highly infectious, and only a few organisms can cause disease. Because of its sporelike life cycle, C burnetii can remain viable and virulent for months. Infection can be acquired via inhalation or skin contact, and direct exposure to a ruminant is not necessary for infection. Rare human-to-human transmissions involving exposure to the placenta of an infected woman and blood transfusions have been reported. Sexual transmission is also possible.

C burnetii infection in livestock often goes unnoticed. Acute C burnetii infection in humans is often asymptomatic or mistaken for an influenzalike illness or atypical pneumonia. In rare cases, C burnetii infection becomes chronic, with devastating results, especially in patients with pre-existing valvular heart disease. Because of its highly infectious nature, C burnetii is recognized as a potential agent of bioterrorism.

Pathophysiology

Initially classified as a species of the genus Rickettsia, C burnetii is now recognized as a bacterium within the gamma group of Proteobacteria. Genome and 16SrRNA sequencing have identified substantial homology with Legionella pneumophila, also a member of that taxonomic group. It is a pleomorphic gram-negative coccobacillus often acquired via inhalation of aerosols. Infection via ingestion of contaminated raw milk is possible but has not yet been confirmed.

C burnetii has two morphologic variants: the small-cell variant (SCV), which survives well in the environment because of its resistance to heat, pressure, and chemical agents; and the large-cell variant (LCV), which multiplies in the host monocyte and macrophage.¹ These variants are antigenically different.¹ The small-cell variant is a sporelike structure, enabling the organism to persist on fomites for more than a year. After passive entry into the host-cell phagosome, the organism delays the fusion of the phagosome with lysosomes, presumably using this delay to transform from the small-cell variant into the large-cell variant. Thereafter, the large-cell variant exploits and persists within the acidified phagolysosome of the monocytes and macrophages, using it as a nursery.² This process is thought to occur mainly in the lungs, the main port of entry of C burnetii.

Proliferation of organisms within the phagolysosome eventually ruptures the host cell. The infected pulmonary macrophages are also transported systemically, the reticuloendothelial system (liver, spleen, bone marrow) being the most heavily infected. Immune responses result in inflammation that manifests as formation of non-necrotizing granulomata, termed doughnut granulomata due to the characteristic appearance of a fibrin ring surrounding a fat vacuole. Although classically associated with acute Q fever, doughnut granulomata can develop in other conditions, such as visceral leishmaniasis, cytomegalovirus or Epstein-Barr infections, Hodgkin lymphoma, and allopurinol hypersensitivity reaction.

Like other gram-negative bacteria, C burnetii possesses a lipopolysaccharide as a virulence factor that is also responsible for an antigenic phase variation, an important property that was first utilized for serologic diagnosis by Bengtson in 1941.^1,2,3,4 Bacterial isolates from eukaryotic cell hosts are virulent and have a phase I (smooth) lipopolysaccharide that helps protect the microorganism from the host’s defense mechanisms. Isolates obtained after repeated passages through embryonated hens’ eggs are rendered avirulent by chromosomal deletions and have a phase II (rough) lipopolysaccharide. Antibodies against phase I and II antigens can be measured in sera of affected hosts. Phase II antibodies are positive in acute Q fever, whereas phase I antibodies remain elevated in chronic disease.

Frequency

United States

Q fever became a reportable disease in 1999. Prior to then, the annual incidence rate was 21 cases. From 2000 to 2004, the mean annual incidence of Q fever rose to 51 cases. The incidence was highest in the Midwest states, whereas the largest total number of cases was reported in California. Indeed, Q fever was reported to be endemic to California during the 1950s.⁵ More recently, Q fever has been reported in US military personnel deployed in Iraq and in Afghanistan, including some patients who were infected without known animal exposure.³

International

First described in Australia in 1937, multiple reports of Q fever clusters have been described over the years. In southern France and Spain, Q fever is highly prevalent, being the second most common cause of community-acquired pneumonia and causing 5-8% of endocarditis cases. More recently, a few clusters of Q fever were reported in the province of Nova Scotia, Canada, and were related to exposure to parturient cats.

Moreover, acute disease seems to have regional variations. An influenzalike illness is the most common presentation of Q fever in Australia. Hepatitis has been reported in France, southern Spain and Ontario, Canada. Pneumonia is more common in Crete; Switzerland; Nova Scotia, Canada; and the Basque region of Spain. The reason for these variations is unknown, but animal studies suggest important strain differences could be a factor.

Mortality/Morbidity

Acute Q fever is usually self-limited. Chronic Q fever, with its most common cause, endocarditis, carries mortality rates that can exceed 60%.

Race

Q fever has no reported racial predilection.

Sex

Symptomatic Q fever is more common in males.³ In Australia and France, males are 5-fold and 2.5-fold more likely than females to develop disease, respectively. Moreover, men accounted for 77% of Q fever cases reported in the United States. Occupational exposure could represent a selection bias. Infection during pregnancy can lead to premature birth, low birth weight, and spontaneous abortion. Chronic Q fever has also been associated with recurrent miscarriages.

Age

Where cattle are the reservoir, the disease is most prevalent in active men aged 25-40 years. Patients older than 15 years are more likely to present with clinical symptoms. Symptomatic Q fever is rare in children but, if present, manifests as in adults, whether acute or chronic.³

Clinical

History

• Acute Q fever
  • Sixty percent of patients with Q fever are asymptomatic. The incubation period varies from 2-6 weeks.
  • Acute Q fever has 3 main clinical presentations, as follows:^6,5,4
    • It may manifest as a self-limited influenzalike febrile illness of abrupt onset, which is often accompanied by headache, myalgia, and chills. The temperature returns to normal within 5-14 days.
    • Pneumonia, usually mild in nature or as an incidental radiographic finding, is rarely fulminant but occasionally progresses to acute respiratory distress syndrome.
    • Hepatitis, usually with mild elevation of transaminases (2-3 times the reference range), may be associated with antismooth muscle, antiphospholipid, or antinuclear antibodies. Jaundice and acute gastrointestinal symptoms are rare. Manifestations resolve within 2-3 weeks.
  • Cardiovascular and neurologic manifestations develop in approximately 1% of patients and include pericarditis, myocarditis, and meningoencephalitis.
  • Dermatologic manifestations in the form of erythema nodosum or other nonspecific exanthemas may also be associated with acute disease. Rash is not a typical feature of Q fever, but skin manifestations were reported in up to 20% of French patients.⁶
  • Obstetric manifestations include spontaneous abortion.
  • Other rare presentations have included thyroiditis, mediastinal lymphadenopathy, pancreatitis, mesenteric panniculitis, epididymitis, orchitis, priapism, inappropriate secretion of antidiuretic hormone, optic neuritis, Guillain-Barré syndrome, and extrapyramidal neurologic disease.
  • Most common symptoms include fever (88-100%), fatigue (97-100%), myalgia (47-69%), chills (68-88%), sweats (31-98%), headache (68-98%), dry cough (24-90%),
  • Less common symptoms include confusion, pleuritic chest pain, dyspnea, nausea, vomiting, and diarrhea.
• Chronic Q fever
  • Among patients with acute infection, 0.2%-1.4% may develop chronic infection, but few data are available regarding this. Chronic infection may not manifest until months or even years after acute infection.^6,5,4
  • Endocarditis is the main clinical presentation of chronic Q fever, usually occurring in patients with pre-existing cardiac disease including valve defects, rheumatic heart disease, and prosthetic valves. Patients in immunocompromised states (eg, due to AIDS, renal failure, hematologic cancer [including lymphoma], and long-term corticosteroid use) are also susceptible. Patients may present with heart failure or nonspecific symptoms, including low-grade fever, fatigue, chills, arthralgia, and night sweats.
  • Other systemic manifestations include the following:
    • Vascular (infections of aneurysms or grafts)
    • Osteoarticular (osteomyelitis, coxitis, spondylodiskitis, arthritis)
    • Obstetric (spontaneous abortion, premature labor [likely due to placentitis])
    • Hepatic (chronic hepatitis)
    • Pulmonary (interstitial fibrosis, pseudotumor)
    • Renal (glomerulonephritis)
  • Chronic fatigue syndrome has also been described in approximately 10% of patients, more than 6 months following acute Q fever.
  • Q fever could be added to the organisms involved in TORCH syndrome (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex).

Physical

• Acute Q fever⁴
  • Signs of pneumonia include high-grade fever and nonspecific crackles, rhonchi or wheezing; less frequently, patients present with signs of consolidation or pleural effusion.
  • Hepatitis manifests as hepatomegaly or, in rare cases, jaundice.
  • Meningeal signs, pericardial rub, and signs of heart failure may be present.
  • Up to 20% of patients with acute Q fever present with associated nonspecific exanthemas, most commonly a maculopapular rash on the trunk. Erythema nodosum has also been described.
• Chronic Q fever⁴
  • Endocarditis manifests as low-grade fever (or no fever), augmentation of a known heart murmur, signs of heart failure, hepatosplenomegaly, clubbing, arterial emboli, and purpuric rash.
  • Aortic and mitral valves are more often involved.

Causes

Q fever is most often related to animal exposure. However, because of the persistence of Coxiella organisms in nature as a sporelike structure, C burnetii can infect people with no known contact with animals. For example, an outbreak of Q fever was reported in people living along a road on which farm vehicles contaminated with straw and manure traveled.

Differential Diagnoses

Other Problems to Be Considered

Placentitis
Vascular graft infections
Osteomyelitis

Workup

Laboratory Studies

Nonspecific studies

• Acute Q fever
  • CBC count usually shows a normal WBC count, mild thrombocytopenia, and, in rare cases, hemolytic anemia.
  • Liver function tests usually show mild elevation of transaminases and alkaline phosphatase without hyperbilirubinemia.
  • Several positive autoimmune antibodies, including antismooth muscle and antiphospholipid, may be seen.
  • Cerebrospinal fluid examination may show a mononuclear pleocytosis with mildly increased protein concentration and normal glucose levels.
  • C burnetii can be seen on smears or frozen tissue prepared with a routine Giemsa stain.
  • Histopathologic changes consistent with doughnut granulomata are not specific for C burnetii.
• Chronic Q fever
  • Elevated sedimentation rate
  • Elevated gamma globulins (polyclonal)
  • Rheumatoid factor
  • Anemia of chronic disease
  • Increased creatinine levels

Cultures

Q fever can be definitively diagnosed via culture isolation of C burnetii. This is technically difficult and can be performed in only laboratories equipped with biosafety level 3 containment.

Serology

Most cases of Q fever are diagnosed based on detection of phase I and II antibodies. The 3 serological techniques used for diagnosis include indirect immunofluorescence, complement fixation, and enzyme-linked immunosorbent assay (ELISA). Significant titers may take 2-4 weeks to appear. Laboratory values vary considerably, so clinicians must interpret results according to their local standards.

• Indirect immunofluorescence is currently the preferred method.
  • Acute Q fever
    • Phase II IgM of 1:50 or more; usually undetectable after 4 months but can last 12 months or more
    • Phase II IgG of 1:200 or more
    • Phase II titers of 1:100 or less make the diagnosis of acute Q fever unlikely.
    • In a reference French laboratory, these values showed 100% specificity.
  • Chronic Q fever
    • Phase I IgG of 1:800 more is considered diagnostic of endocarditis (one of major modified Duke criteria).
    • Phase II IgM titers are lower or absent.
    • Phase II IgG titers are usually greater than 1:1600. They can last up to 12 years after an outbreak.
    • The main predictive criterion of clinical cure is detection of phase I IgG titer of less than 1:200.
• Complement fixation is less sensitive and specific than indirect immunofluorescence. The time to positivity may take longer than IF. Different cutoff values are also used. IgG levels usually fall within 3 years.
• ELISA is comparable to indirect immunofluorescence.
• A 4-fold increase between acute and convalescent paired sera yields the highest specificity.
• False-positive results may occur in legionellosis and leptospirosis.
• Serologic follow-up to detect a rise in phase I IgG titers of 1:800 or more can be performed twice every 3 months. If detected, transesophageal echocardiography and serum real-time polymerase chain reaction (PCR) techniques can be performed in an attempt to diagnose endocarditis.^3,7 Sensitivities may be as low as 18% in early disease.

Molecular techniques

In certain reference laboratories, PCR techniques can be used on resected cardiac valves with greater sensitivity than serum assays. C burnetii organisms can persist in tissues even after prolonged antimicrobial treatment.⁵ Although still controversial, serum PCR may be used to diagnose acute Q fever in the first 2 weeks of the disease. It should also be reserved for seronegative patients in the subsequent 2 weeks and not used later than 4 weeks following onset.⁷

Imaging Studies

• Acute Q fever
  • Chest radiography frequently shows nonspecific segmental or lobar abnormalities. Multiple round opacities and pleural effusions may also be visible.
  • Echocardiography may show pericardial effusion with pericarditis.
• Chronic Q fever
  • Chest radiography may reveal signs of interstitial fibrosis and pseudotumor.
  • Echocardiography may show vegetations, although less frequently than observed with other organisms. Rates as low as 12% have been reported. These vegetations tend to be smaller and located beneath endothelial surfaces.⁵

Other Tests

Acute Q fever: ECG may show T-wave abnormalities if myocarditis and pericarditis are present.

Histologic Findings

Classic doughnut granulomata may be observed in the liver and bone marrow. They consist of a fibrin ring surrounding an empty fat vacuole. These granulomata, although frequently associated with Q fever, are not specific. They can also occur in Hodgkin lymphoma, typhoid fever, cytomegalovirus infection, infectious mononucleosis, and allopurinol hypersensitivity.

Treatment

Medical Care

• Acute Q fever
  • Symptoms of acute Q fever usually resolve spontaneously within 2 weeks, but antibiotic treatment has been shown to reduce the duration of disease, especially if initiated within 3 days of illness onset. The optimal duration of treatment has not been adequately studied. Antibiotics are given for 14-21 days, usually in an outpatient setting.
  • Doxycycline has been the agent most frequently investigated.⁸ It is currently the treatment of choice.
  • Fluoroquinolones can be used as alternatives. Ofloxacin and pefloxacin have been used with success in patients. Ciprofloxacin demonstrated higher MIC values than other fluoroquinolones and doxycycline. Levofloxacin showed bacteriostatic activity in vitro.⁸
  • Fluoroquinolones may offer a theoretical advantage in meningoencephalitis since they possess better cerebrospinal fluid penetration. A more recent literature review demonstrated that the choice of antimicrobial therapy (doxycycline vs fluoroquinolones) did not affect resolution of acute disease or severity of neurologic sequelae.³
  • Macrolides, especially azithromycin and clarithromycin, can be used as alternatives, but some strains of C burnetii show resistance.³
  • Trimethoprim-sulfamethoxazole (TMP-SMX) has also been used.^3,4
  • No reliable regimen is available for children (<8 y) or pregnant women. Macrolides or TMP-SMX may be options in these populations.^6,3
  • Adjuvant corticosteroid treatment has been used in antimicrobial-nonresponsive hepatitis.
• Chronic Q fever
  • Chronic C burnetii infections are very difficult to treat. A prolonged combined antimicrobial regimen is recommended. Hospitalization may be warranted for intractable heart failure.
  • No drug used alone has been shown to be bactericidal against C burnetii. Therefore, prolonged combination therapy is recommended because of the high rate of relapse with treatment of shorter duration. No consensus on the ideal duration of therapy has been reached, but serial measurement of antibody titers should likely be used as a guide to duration of therapy.
  • The most current recommendation for endocarditis is combination treatment with doxycycline and hydroxychloroquine for at least 18 months. An alternative option is combination of doxycycline and a fluoroquinolone for at least 3-4 years. Other proposed alternatives include doxycycline or fluoroquinolones with rifampin therapy, although significant drug interactions could limit these regimens.³
  • The use of hydroxychloroquine is based on the assumption that it will elevate the pH within the phagolysosome vacuole of the monocyte, where C burnetii resides. This might affect the metabolism of the organism, rendering it more susceptible to the effects of doxycycline.
  • Endovascular complications should also be treated with doxycycline and hydroxychloroquine in combination, although the optimal regimen is not well defined.³
  • Osteoarticular infections should also be treated with prolonged antimicrobial combination therapy, along with surgical debridement. A regimen of doxycycline and hydroxychloroquine, with or without rifampin, has been suggested.³

Surgical Care

• Valvular replacement is indicated for intractable heart failure. C burnetii can persist on endocardial tissue even after valve replacement; therefore, antibiotics should be continued following surgery.
• Surgical treatment can affect survival in endovascular complications such as mycotic aneurysm or vascular graft infections.³
• Surgical debridement is also recommended for osteoarticular infections.³

Consultations

• Infectious disease specialist
• Cardiothoracic, vascular, and orthopedic surgeons in selected cases

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antibiotics

Drugs are used that provide in vivo or in vitro activity in C burnetii infections .

Doxycycline (Vibramycin)

First-line agent for both acute and chronic diseases. Bacteriostatic drug that interferes with bacterial protein synthesis by binding to 30S ribosome.

Dosing

Adult

Acute Q fever: 100 mg PO bid for 14 d
Chronic Q fever: 100 mg PO bid for at least 3 y when combined with ofloxacin (or pefloxacin); 100 mg PO bid for at least 18 mo when combined with hydroxychloroquine

Pediatric

<8 years: Contraindicated
>8 years: 2-4 mg/kg/d PO divided q 12 h

Interactions

Antacids, milk, iron- or zinc-containing medications, didanosine, and sucralfate minimally diminish absorption; Tegretol and chronic ethanol ingestion decrease effects; reduces action of oral contraceptives; may potentiate effect of anticoagulants; BUN augmentation reported when used with diuretics

Contraindications

Documented hypersensitivity; pregnant women

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Adverse effects include photosensitivity (rare) and permanent tooth discoloration in children due to enamel hypoplasia

Ofloxacin (Floxin)

An alternative to doxycycline in acute Q fever. A derivative of pyridine carboxylic acid with broad-spectrum bactericidal effect.

Dosing

Adult

Acute Q fever: 200 mg PO q8h for 14-21 d
Chronic Q fever: 200 mg PO tid with doxycycline for at least 3 y

Pediatric

Not established

Interactions

Antacids, sucralfate, and iron- or zinc-containing medications diminish absorption; increases risk of seizures when used with AINS drugs

Contraindications

Documented hypersensitivity; pregnant women

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Dosage adjustment is required in renal failure; adverse effects include nausea, vomiting, abdominal discomfort and diarrhea, mild headache and dizziness, allergic rash, and photosensitivity; avoid in nursing mother (excreted in breast milk)

Rifampin (Rifadin, Rifadin IV, Rimactane)

Used to treat all forms of tuberculosis in combination with at least one other antituberculous drug. Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription. Cross-resistance has only been shown with other rifamycins; combination therapy with doxycycline should be continued for chronic Q fever for at least 18 mo.

Dosing

Adult

600 mg PO/IV qd

Pediatric

10-20 mg/kg PO/IV; not to exceed 600 mg/d

Interactions

Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid or pyrazinamide may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Obtain CBCs and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Sulfamethoxazole and Trimethoprim (Bactrim, Bactrim DS, Septra, Septra DS)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Dosing

Adult

160 mg TMP-800 mg SMX PO q12h (1 double strength tab q12h)

Pediatric

<2 months: Do not administer
>2 months: 10-12 mg/kg/d, based on TMP, PO divided bid (50-60 mg/kg/d, based on SMX, divided bid)

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use during last trimester of pregnancy due to potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus)
Dosage adjustments (adult adjustments)
CrCl (mL/min) 80-50: Recommended IV dose q18h
CrCl 50-10: Recommended IV dose q24h
CrCl <10: Not recommended
HD: 4-5 mg/kg after HD
During peritoneal dialysis: 0.16-0.8 g q48h
Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholics, elderly, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in G-6-PD deficient individuals; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.
Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Treats mild-to-moderate microbial infections.
Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Has a long tissue half-life.

Dosing

Adult

Day 1: 500 mg PO
Days 2-5: 250 mg PO qd; may need to repeat if symptoms do not resolve

Pediatric

<6 months: Not established
>6 months:
Day 1: 10 mg/kg PO once; not to exceed 500 mg/d
Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d

Interactions

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine

Contraindications

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function or prolonged QT intervals

Antimalarial drugs

These agents are used for their alkalinizing action within the phagolysosomal compartment of monocyte, where C burnetii resides.

Hydroxychloroquine (Plaquenil)

Used in chronic Q fever, with doxycycline, which is more effective. Fewer relapses than with doxycycline and ofloxacin. Treatment duration can be shortened.

Dosing

Adult

200 mg PO tid with doxycycline for at least 18 mo; dosage reduction to 200 mg PO bid or qd if gastrointestinal intolerance develops

Pediatric

Not established

Interactions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity to drug or 4-aminoquinoline compounds; preexisting retinopathy

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in hepatic or renal disease; adverse effects include retinopathy, corneal opacities, rash, pigmentation changes, alopecia, photosensitivity, nausea, diarrhea, abdominal pain; should be avoided in porphyria or psoriasis

Follow-up

Further Outpatient Care

• Acute Q fever
  • Baseline transthoracic echocardiography should be performed to assess for vegetations.³
  • Follow-up serology should be performed at least twice over 6 months. If phase I IgG antibodies are found in titers of 1:800 or more, transesophageal echocardiography should be performed along with serum PCR measurements, when possible.³
• Chronic Q fever
  • Monthly follow-up serology and clinical assessment are recommended during antimicrobial therapy and for the first 6 months following withdrawal, then every 6 months for 2 years, and possibly yearly thereafter.
  • Phase I IgG titers of 1:200 or less are the best predictor of cure.
  • Perform echocardiography every 3 months during antimicrobial therapy and every 6 months for the first 2 years following drug withdrawal.
  • High-risk populations should be screened for glucose-6-phosphate dehydrogenase deficiency before receiving hydroxychloroquine.
  • If hydroxychloroquine is used, a yearly ophthalmologic evaluation is required to rule out retinal toxicity.
  • Patients should be reminded of photosensitivity risk while on doxycycline therapy.

Deterrence/Prevention

• Vaccine prophylaxis^9,1,5
  • Vaccine is primarily used in at-risk people, such as veterinarians, abattoir workers, farmers, or others in occupations that require close contact with animals.
  • A whole-cell killed vaccine (Q-Vax) has been licensed in Australia since 1989. Prevaccination screening is essential and includes history, skin testing, and serology, usually by indirect immunofluorescence. All 3 components must be negative before vaccine administration. Occasionally, large local reactions are reported.
  • Acellular vaccines include a trichloroacetic extracted vaccine (Chemovaccine) from the former Czechoslovakia and a chloroform-methanol residue vaccine (CMR) from the United States. They have been promoted to be as effective as Q-Vax, but with fewer side effects. Phase I human trials using CMR proved that vaccination was safe. Although its efficacy has been demonstrated in rodents, sheep, and nonhuman primates, human data are lacking.
  • No vaccine is available for children.
• Avoid ingestion of raw milk and exposure to animal birth products (eg, placenta), especially in the setting of immunosuppression, pregnancy, or known valvular heart disease.
• C burnetii must be cultured in biosafety level 3 laboratories.

Complications

• Chronic fatigue syndrome has been reported as a complication of acute Q fever.
• Chronic Q fever endocarditis can lead to severe heart failure.
• Reactivation of Q fever has been reported during pregnancy.

Prognosis

• Acute Q fever is a self-limited disease.
• Chronic Q fever carries mortality rates that can exceed 60%. Frequent relapses (50%) are observed despite adequate therapy.

Miscellaneous

Medicolegal Pitfalls

• Failure to obtain a specific serology in patients presenting with culture-negative endocarditis
• Failure to recognize specific host risk factors in patients with classic Q fever clinical presentations

References

1. Waag DM. Coxiella burnetii: host and bacterial responses to infection. Vaccine. Oct 16 2007;25(42):7288-95. [Medline].

2. Cutler SJ, Bouzid M, Cutler RR. Q fever. J Infect. Apr 2007;54(4):313-8. [Medline].

3. Hartzell JD, Wood-Morris RN, Martinez LJ, et al. Q fever: epidemiology, diagnosis, and treatment. Mayo Clin Proc. May 2008;83(5):574-9. [Medline].

4. Marrie TJ, Raoult D. Coxiella burnetii (Q fever). In: Mandell: Principles and Practice of Infectious Diseases. 6^th ed. Philadelphia, Pa: Churchill Livingstone; 2005:2296-303.

5. Karakousis PC, Trucksis M, Dumler JS. Chronic Q fever in the United States. J Clin Microbiol. Jun 2006;44(6):2283-7. [Medline].

6. Terheggen U, Leggat PA. Clinical manifestations of Q fever in adults and children. Travel Med Infect Dis. May 2007;5(3):159-64. [Medline].

7. Fenollar F, Raoult D. Molecular diagnosis of bloodstream infections caused by non-cultivable bacteria. Int J Antimicrob Agents. Nov 2007;30 Suppl 1:S7-15. [Medline].

8. Brouillard JE, Terriff CM, Tofan A, et al. Antibiotic selection and resistance issues with fluoroquinolones and doxycycline against bioterrorism agents. Pharmacotherapy. Jan 2006;26(1):3-14. [Medline].

9. Parker NR, Barralet JH, Bell AM. Q fever. Lancet. Feb 25 2006;367(9511):679-88. [Medline].

10. Boschini A, Di Perri G, Legnani D, et al. Consecutive epidemics of Q fever in a residential facility for drug abusers: impact on persons with human immunodeficiency virus infection. Clin Infect Dis. Apr 1999;28(4):866-72. [Medline].

11. Carrascosa M, Pascual F, Borobio MV, et al. Rhabdomyolysis associated with acute Q fever. Clin Infect Dis. Nov 1997;25(5):1243-4. [Medline].

12. Dupont HT, Thirion X, Raoult D. Q fever serology: cutoff determination for microimmunofluorescence. Clin Diagn Lab Immunol. Mar 1994;1(2):189-96. [Medline].

13. Fenollar F, Fournier PE, Carrieri MP, et al. Risks factors and prevention of Q fever endocarditis. Clin Infect Dis. Aug 1 2001;33(3):312-6. [Medline].

14. Fenollar F, Thuny F, Xeridat B, et al. Endocarditis after acute Q fever in patients with previously undiagnosed valvulopathies. Clin Infect Dis. Mar 15 2006;42(6):818-21. [Medline].

15. Field PR, Mitchell JL, Santiago A, et al. Comparison of a commercial enzyme-linked immunosorbent assay with immunofluorescence and complement fixation tests for detection of Coxiella burnetii (Q fever) immunoglobulin M. J Clin Microbiol. Apr 2000;38(4):1645-7. [Medline].

16. Foucault C, Lepidi H, Poujet-Abadie JF, et al. Q fever and lymphadenopathy: report of four new cases and review. Eur J Clin Microbiol Infect Dis. Oct 2004;23(10):759-64. [Medline].

17. Fournier PE, Casalta JP, Piquet P, et al. Coxiella burnetii infection of aneurysms or vascular grafts: report of seven cases and review. Clin Infect Dis. Jan 1998;26(1):116-21. [Medline].

18. Fournier PE, Etienne J, Harle JR, et al. Myocarditis, a rare but severe manifestation of Q fever: report of 8 cases and review of the literature. Clin Infect Dis. May 15 2001;32(10):1440-7. [Medline].

19. Fournier PE, Marrie TJ, Raoult D. Diagnosis of Q fever. J Clin Microbiol. Jul 1998;36(7):1823-34. [Medline].

20. Graham JV, Baden L, Tsiodras S, et al. Q fever endocarditis associated with extensive serological cross-reactivity. Clin Infect Dis. Mar 2000;30(3):609-10. [Medline].

21. Kazar J. Coxiella burnetii infection. Ann N Y Acad Sci. Dec 2005;1063:105-14. [Medline].

22. Korman TM, Spelman DW, Perry GJ, et al. Acute glomerulonephritis associated with acute Q fever: case report and review of the renal complications of Coxiella burnetii infection. Clin Infect Dis. Feb 1998;26(2):359-64. [Medline].

23. Krol V, Kogan V, Cunha BA. Q fever bioprosthetic aortic valve endocarditis (PVE) successfully treated with doxycycline monotherapy. Heart Lung. Mar-Apr 2008;37(2):157-60. [Medline].

24. Kruszewska D, Lembowicz K, Tylewska-Wierzbanowska S. Possible sexual transmission of Q fever among humans. Clin Infect Dis. Jun 1996;22(6):1087-8. [Medline].

25. Lepidi H, Houpikian P, Liang Z, et al. Cardiac valves in patients with Q fever endocarditis: microbiological, molecular, and histologic studies. J Infect Dis. Apr 1 2003;187(7):1097-106. [Medline].

26. Levy PY, Carrieri P, Raoult D. Coxiella burnetii pericarditis: report of 15 cases and review. Clin Infect Dis. Aug 1999;29(2):393-7. [Medline].

27. Lovey PY, Morabia A, Bleed D, et al. Long term vascular complications of Coxiella burnetii infection in Switzerland: cohort study. BMJ. Jul 31 1999;319(7205):284-6. [Medline].

28. Marmion BP, Ormsbee RA, Kyrkou M, et al. Vaccine prophylaxis of abattoir-associated Q fever: eight years' experience in Australian abattoirs. Epidemiol Infect. Apr 1990;104(2):275-87. [Medline].

29. Marrie TJ, Raoult D. Q fever-a review and issues for the next century. Int J Antimicrob Agents. 1997;8(3):145-61. [Medline].

30. Maurin M, Raoult D. Bacteriostatic and bactericidal activity of levofloxacin against Rickettsia rickettsii, Rickettsia conorii, 'Israeli spotted fever group rickettsia' and Coxiella burnetii. J Antimicrob Chemother. Jun 1997;39(6):725-30. [Medline].

31. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. Oct 1999;12(4):518-53. [Medline].

32. Milazzo A, Featherstone KB, Hall RG. Q fever vaccine uptake in South Australian meat processors prior to the introduction of the National Q Fever Management Program. Commun Dis Intell. 2005;29(4):400-6. [Medline].

33. Milazzo A, Hall R, Storm PA, et al. Sexually transmitted Q fever. Clin Infect Dis. Aug 1 2001;33(3):399-402. [Medline].

34. Musso D, Raoult D. Coxiella burnetii blood cultures from acute and chronic Q-fever patients. J Clin Microbiol. Dec 1995;33(12):3129-32. [Medline].

35. Nausheen S, Cunha BA. Q fever community-acquired pneumonia in a patient with Crohn's disease on immunosuppressive therapy. Heart Lung. Jul-Aug 2007;36(4):300-3. [Medline].

36. Ordi-Ros J, Selva-O'Callaghan A, Monegal-Ferran F, et al. Prevalence, significance, and specificity of antibodies to phospholipids in Q fever. Clin Infect Dis. Feb 1994;18(2):213-8. [Medline].

37. Raoult D. Treatment of Q fever. Antimicrob Agents Chemother. Sep 1993;37(9):1733-6. [Medline].

38. Raoult D, Houpikian P, Tissot Dupont H, et al. Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med. Jan 25 1999;159(2):167-73. [Medline].

39. Raoult D, Marrie T. Q fever. Clin Infect Dis. Mar 1995;20(3):489-95; quiz 496. [Medline].

40. Raoult D, Marrie T, Mege J. Natural history and pathophysiology of Q fever. Lancet Infect Dis. Apr 2005;5(4):219-26. [Medline].

41. Raoult D, Tissot-Dupont H, Foucault C, et al. Q fever 1985-1998. Clinical and epidemiologic features of 1,383 infections. Medicine (Baltimore). Mar 2000;79(2):109-23. [Medline].

42. Rolain JM, Boulos A, Mallet MN, et al. Correlation between ratio of serum doxycycline concentration to MIC and rapid decline of antibody levels during treatment of Q fever endocarditis. Antimicrob Agents Chemother. Jul 2005;49(7):2673-6. [Medline].

43. Rolain JM, Lambert F, Raoult D. Activity of telithromycin against thirteen new isolates of C. burnetii including three resistant to doxycycline. Ann N Y Acad Sci. Dec 2005;1063:252-6. [Medline].

44. Sawaishi Y, Takahashi I, Hirayama Y, et al. Acute cerebellitis caused by Coxiella burnetii. Ann Neurol. Jan 1999;45(1):124-7. [Medline].

45. Senn L, Franciolli M, Raoult D, et al. Coxiella burnetii vascular graft infection. BMC Infect Dis. Dec 7 2005;5:109. [Medline].

46. Spelman DW. Q fever: a study of 111 consecutive cases. Med J Aust. Jun 26 1982;1(13):547-8, 551, 553. [Medline].

47. Stein A, Raoult D. Q fever during pregnancy: a public health problem in southern France. Clin Infect Dis. Sep 1998;27(3):592-6. [Medline].

48. Tissot Dupont H, Raoult D, Brouqui P, et al. Epidemiologic features and clinical presentation of acute Q fever in hospitalized patients: 323 French cases. Am J Med. Oct 1992;93(4):427-34. [Medline].

49. Zhang G, Samuel JE. Vaccines against Coxiella infection. Expert Rev Vaccines. Oct 2004;3(5):577-84. [Medline].

Keywords

Q fever, query fever, Coxiella burnetii, C burnetii, Rickettsia burnetii, R burnetii, Rickettsia diaporica, R diaporica, zoonosis, zoonotic transmission, farm animals, livestock, bacterial infection, farm infection, chronic Q fever, chronic fatigue syndrome

Contributor Information and Disclosures

Author

Alexandre Lacasse, MD, MSc, Fellow in Infectious Diseases, University of Tennessee at Memphis
Alexandre Lacasse, MD, MSc is a member of the following medical societies: American College of Physicians, American Medical Association, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Kerry O Cleveland, MD, Associate Professor of Medicine, University of Tennessee College of Medicine; Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Methodist Healthcare of Memphis
Kerry O Cleveland, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, and Society for Healthcare Epidemiology of America
Disclosure: Nothing to disclose.

Hari Polenakovik, MD, Consultant Physician in Infectious Diseases and General Medicine, Department of Medicine, Western Health, Australia
Hari Polenakovik, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Annie Ruest, MD, FRCPC, Consultant Physician in Infectious Diseases and Medical Microbiology, Departments of Medicine and Medical Biology, Laval University, Quebec City, Canada
Annie Ruest, MD, FRCPC is a member of the following medical societies: Canadian Infectious Disease Society and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Christian P Sinave, MD, Associate Professor, Department of Medical Microbiology and Infectious Diseases, University of Sherbrooke, Canada
Christian P Sinave, MD is a member of the following medical societies: American Society for Microbiology and Canadian Infectious Disease Society
Disclosure: Nothing to disclose.

Medical Editor

John M Leedom, MD, Professor of Medicine, Keck School of Medicine, University of Southern California; Chief, Division of Infectious Diseases, Department of Internal Medicine, Los Angeles County, University of Southern California Medical Center
John M Leedom, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Joseph F John Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: BioMerieux Honoraria Review panel membership; Cubist Honoraria Review panel membership; Pfizer Honoraria Speaking and teaching; Merck Stock dividends stock holdings

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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