Coxiella/Q Fever

Q fever is a bacterial zoonotic infection caused by Coxiella burnetii. Transmission occurs primarily through the inhalation of contaminated aerosols and exposure to infected animal products. The clinical presentation can vary and often result in mild disease with flu-like symptoms. Other manifestations include pneumonia, hepatitis, endocarditis, and aseptic meningitis. In a small percentage of patients, the disease can become chronic. A high degree of suspicion is required to make the diagnosis, which is aided using serology and PCR. Antibiotics are the mainstay of management.

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General Characteristics of Coxiella

General features of Coxiella

  • Gram-negative organisms
  • Pleomorphic rods
  • Strict intracellular 
  • Aerobic
  • Formerly designated as a Rickettsia
  • Classified as a Gammaproteobacteria

Clinically relevant species

Coxiella burnetii causes Q fever.

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Epidemiology and Pathogenesis

Epidemiology

  • Geographical distribution: 
    • Found worldwide, except in New Zealand
    • In the United States, the highest incidence is in the Midwest and California.
    • More common in rural areas
  • More common in men than women
  • More common in adults than children
  • Higher incidence in spring and summer

Reservoir

  • Ticks (main reservoir)
  • Mammals (including farm animals and pets)
  • Birds

Routes of transmission

  • Inhalation of aerosols
  • Consumption of contaminated milk
  • Intradermal inoculation

Host risk factors

  • Contact with farm animals:
    • Farmers
    • Slaughterhouse workers
    • Veterinary personnel
    • Shepherds
  • Individuals living near farms
  • Laboratory workers

Virulence factors

Antigenic phase variation:

  • Phase I:
    • Highly infectious
    • Contains smooth lipopolysaccharide (LPS)
    • Protects against host defense mechanisms
  • Phase II:
    • Noninfectious
    • Contains rough LPS (lacks terminal O antigen sugars)

Morphological variants:

  • Small-cell variant:
    • Spore-like appearance
    • Metabolically inactive
    • Resistant to environmental stress:
      • Heat
      • Desiccation
      • Chemicals
      • Pressure
  • Large-cell variant:
    • Metabolically active
    • Able to replicate in phagolysosomes

Escape from intracellular killing:

  • Inhibition of cathepsin fusion
  • Superoxide dismutase production

Pathophysiology

  • The organism is most commonly inhaled → phagocytosed by alveolar macrophages
  • Acidification in phagolysosome → transformation of C. burnetii into its metabolically active state (large-cell variant)
  • Replication → host cell rupture → organisms spread systemically, especially to the reticuloendothelial system (liver, spleen, and bone marrow)
  • Immune response results in non-necrotizing granulomas.
  • Autoantibody production can occur.

Clinical Presentation

Patients may present with a wide range of symptoms, and vary in severity from asymptomatic to severe disease.

Acute Q fever

The incubation period for acute infection is approximately 20 days. Patients may present with any of the following conditions:

  • Asymptomatic disease 
  • Flu-like illness (lasts 1–3 weeks):
    • Abrupt onset of high-grade fever
    • Fatigue
    • Headache with photophobia
    • Myalgias
    • Anorexia
  • Pneumonia (lasts 10–90 days):
    • Fever
    • Nonproductive cough
    • Acute respiratory distress
    • Pleuritic chest pain
  • Hepatitis (granulomatous):
    • Fever
    • Hepatomegaly
    • RUQ abdominal pain
    • Nausea and vomiting
    • Diarrhea
    • Transaminitis
  • Cardiac involvement:
    • Acute endocarditis (autoimmune)
    • Pericarditis
    • Myocarditis
  • Neurological involvement:
    • Aseptic meningitis
    • Encephalitis
    • Peripheral neuropathy

Chronic Q fever

Chronic infection may manifest months or years after an acute infection.

  • Endocarditis (culture negative):
    • Low-grade fever
    • Night sweats
    • Fatigue
    • Dyspnea
    • Septic thromboembolism
    • Heart failure
  • Pericardial effusion
  • Chronic hepatitis
  • Osteomyelitis
  • Septic arthritis
  • Mononeuritis
  • Interstitial fibrosis
  • Pseudotumors
  • Glomerulonephritis

Complications

Q fever in pregnancy is associated with:

  • Spontaneous abortion
  • Intrauterine fetal growth restriction
  • Premature delivery

Diagnosis

Q fever lacks a distinct clinical presentation; therefore, the diagnosis relies on a high index of suspicion based on the patient’s risk factors.

Laboratory evaluation

Diagnostic testing:

  • Indirect immunofluorescence for IgG and IgM (high sensitivity and specificity)
  • PCR to detect C. burnetii DNA
  • Cultures:
    • Does not grow in routine cultures
    • Requires special biosafety containment due to its infectivity

Supporting evaluation:

  • Normal WBC count (90% of cases)
  • Thrombocytopenia
  • ↑ ALT and AST → hepatitis
  • Associated autoantibodies:
    • Antiphospholipid antibodies
    • Lupus anticoagulant
  • Liver biopsy → granulomatous changes

Imaging

  • Chest X-ray: consolidation, pleural effusion → pneumonia
  • Echocardiography: vegetation on a heart valve → endocarditis
  • Ultrasound: hepatomegaly → granulomatous hepatitis

Management and Prevention

Management

Antibiotic therapy includes:

  • Doxycycline (preferred)
  • Trimethoprim-sulfamethoxazole
  • Clarithromycin
  • Fluoroquinolones
  • Hydroxychloroquine may be added to doxycycline in patients with:
    • Cardiovascular involvement
    • Chronic Q fever

Prevention

  • Human vaccines:
    • Recommended for individuals with occupational risk
    • Contraindicated in previously exposed individuals
  • Animal vaccines to reduce bacterial shedding
  • Proper disposal of placenta and birth products
  • Avoid unpasteurized milk products
  • Routine testing of animals
  • Quarantine imported animals

Comparison with Similar Gammaproteobacteria

Table: Comparison of similar bacterial species and diseases
OrganismCoxiella burnetiiLegionella pneumophilaFrancisella tularensis
Characteristics
  • Gram negative
  • Pleomorphic
  • Aerobic
  • Spore-like formation
  • Gram negative
  • Pleomorphic
  • Aerobic
  • Non-spore-forming organisms
  • Flagellated
  • Gram negative
  • Pleomorphic
  • Aerobic
  • Non-spore-forming organisms
Reservoir
  • Ticks
  • Mammals
  • Birds
Aquatic
  • Ticks
  • Mammals
  • Birds
Transmission
  • Inhalation of aerosols
  • Contact with contaminated animal products
  • Inhalation of aerosols
  • Aspiration
  • Via ticks
  • Contact with contaminated animal products
  • Inhalation of aerosols
Clinical presentationQ fever
  • Legionnaires disease
  • Pontiac fever
Tularemia
Diagnosis
  • Serology
  • PCR
  • Urinary antigen
  • PCR
  • Culture
  • Culture
  • Serology
  • PCR
ManagementDoxycycline
  • Fluoroquinolones
  • Macrolides
Streptomycin

Differential Diagnosis

  • Lyme disease: an infection caused by Borrelia burgdorferi, which is transmitted by the Ixodes tick. Presentation depends on the stage of the disease and may include a characteristic erythema migrans rash. A rash is generally not seen in Q fever. Neurological, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis relies on clinical findings and tick exposure, and is supported by serological testing. Antibiotics, including doxycycline and ceftriaxone, are used for treatment. 
  • Rocky Mountain spotted fever: a tick-borne disease caused by Rickettsia rickettsii. Patients present with a classic triad of fever, headache, and rash. A rash is generally not present in Q fever. Other symptoms include malaise, GI distress, and neurological symptoms of confusion, lethargy, and stupor. Diagnosis is made based on clinical features, biopsy of the skin rash, and serological testing. Management involves antibiotics, usually doxycycline.
  • Ehrlichiosis and anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms include fever, headache, and malaise. A rash is uncommon, but petechial or maculopapular rashes can occur. The diagnosis is made using PCR, which differentiates these diseases from Q fever. Management of both diseases is with doxycycline.
  • Babesiosis: a tick-borne infection caused by Babesia. Patients can be asymptomatic or develop fever, fatigue, malaise, and arthralgias. Asplenic, immunocompromised, and elderly patients are at risk for severe disease, causing hemolytic anemia, thrombocytopenia, hepatosplenomegaly, renal failure, and death. Diagnosis is confirmed with a peripheral blood smear, serological testing, and PCR. Management includes antibiotics, such as atovaquone plus azithromycin.
  • Brucellosis: a zoonotic infection caused by several species of Brucella that spreads predominantly through ingestion or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. The history, presentation, serology, and culture data are used in the diagnosis. Brucellosis can be differentiated from Q fever based on serology. Management involves a combination of antibiotics, including doxycycline, rifampin, and aminoglycosides. 
  • Infectious mononucleosis: a disease caused by the Epstein-Barr virus, which is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. Diagnosis is based on clinical features and testing, which includes a heterophile antibody test or serology. Clinical presentation and serology help differentiate mononucleosis from Q fever. Management is supportive. 
  • Viral hepatitis: liver inflammation caused by the hepatitis virus. Patients may present with a viral prodrome of fever, anorexia, and nausea. Right upper quadrant abdominal pain, jaundice, and transaminitis may also occur. The diagnosis is made based on viral serological testing, which helps differentiate viral hepatitis from Q fever. Management of acute hepatitis is supportive.

References

  1. Marrie, T.J. (2010). Q fever pneumonia. Infect Dis Clin North Am. https://reference.medscape.com/medline/abstract/20171543
  2. Marrie, T.J., Raoult, D. (2005). Coxiella burnetii (Q fever). Mandell GL, Bennett JE, Dolin R, Eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Churchill Livingstone.
  3. Marrie, T.J., Stein, A., Janigan, D., Raoult, D. (1996). Route of infection determines the clinical manifestations of acute Q fever. J Infect Dis. https://reference.medscape.com/medline/abstract/8568318
  4. Hartzell, J.D., Wood-Morris, R.N., Martinez, L.J., Trotta, R.F. (2008). Q fever: Epidemiology, diagnosis, and treatment. Mayo Clin Proc. https://reference.medscape.com/medline/abstract/18452690
  5. Terheggen, U., Leggat, P.A. (2007). Clinical manifestations of Q fever in adults and children. Travel Med Infect Dis. https://reference.medscape.com/medline/abstract/17448942
  6. Cleveland, K.O. (2019). Q fever. In Brusch, J.L. (Ed.), Medscape. Retrieved April 9, 2021, from https://emedicine.medscape.com/article/227156-overview
  7. Neupane, K., Kaswan, D. (2020). Coxiella burnetii. [online] StatPearls. Retrieved April 9, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK557893/
  8. Petri, Jr., W.A. (2020). Q fever. [online] MSD Manual Professional Version. Retrieved April 9, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/rickettsiae-and-related-organisms/q-fever
  9. Raoult, D. (2019). Microbiology and epidemiology of Q fever. In Mitty, J. (Ed.), UpToDate. Retrieved April 9, 2021, from https://www.uptodate.com/contents/microbiology-and-epidemiology-of-q-fever
  10. Raoult, D. (2020). Clinical manifestations and diagnosis of Q fever. In Mitty, J. (Ed.), UpToDate. Retrieved April 9, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-q-fever
  11. Raould, D. (2020). Treatment and prevention of Q fever. In Mitty, J. (Ed.), UpToDate. Retrieved April 9, 2021, from https://www.uptodate.com/contents/treatment-and-prevention-of-q-fever

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