Coxiella burnetii

Background

History

• Originally described in Australia in 1935 among workers at a meatworks
• Q fever, for query fever, because the doctor suspected a new infection

Microbiology

• Highly pleomorphic, intracellular, spore-forming, Gram-negative coccobacillus that causes Q fever
  • Enters cell passively
• Phase variation, with two phases that differ in their lipopolysaccharides and some other characteristics
  • Phase I: state in nature
• Related to rickettsiae

Epidemiology

• Zoonotic disease, most commonly of cattle, sheep, and goats
  • Also infected peripartum cats
  • Maintained in a transmission cycle with ticks or other arthropods
  • Ungulates often asymptomatic
  • Can be detected in air up to 2 weeks post-partum and in soil for 6 months
• Released by an infected animal during childbirth, though windborne spread can carry it at least 10 km
  • Placenta has an extremely high burden of bacteria
  • Can also be found in stool, urine, and milk
  • Unpasteurized milk
• Inhaled by humans with an incubation period of 20 days (1 to 39 days)
  • Dose-dependent incubation period
  • Chronic Q fever can be up to 6 months
• Worldwide distribution, except New Zealand
  • Hepatitis more in Europe, pneumonia more in US

Risk Factors

• Working with or near animals, especially peripartum
• Lab exposure
• Unpasteurized milk

Pathophysiology

• Bacteria enter lungs, where they proliferate in the macrophages and invade the bloodstream
  • Lives in the phagolysosome
  • Can cause graulomas
• Alternatively, can enter via tick bite or via ingestion
• Invasion of bloodstream causes systemic symptoms, with severity depending on the dose inhaled
• QPH1 is a more virulent strain

Clinical Manifestations

• Can present as asymptomatic, self-limited febrile illness lasting 2 to 14 days (most common), pneumonia, or hepatitis
  • Asymptomatic more common in pregnant women and children
• Infective endocarditis, osteomyelitis, CNS infection including aseptic meningitis
• Q fever in immunocompromised host, Q fever in infancy, Q fever in pregnancy
• Post-Q fever fatigue syndrome

Acute Q fever

• Fever is uniform finding in all syndromes
• Chills, headache (severe), fatigue, and myalgias that lasts 2-21 days (14)
• Can present with rash including urticaria
• Palpable purpura can be seen in chronic Q fever (that is, endocarditis)

Pneumonia

• Can present as an atypical pneumonia, a rapidly-progressing pneumonia, and an incidental pneumonia in a febrile patient (most common)
• A community-acquired pneumonia that doesn't respond to first-line antibiotics (like Legionella and pneumonic tularemia)
• Cough, though often not present, can be non-productive, productive, or bloody
• More common in Americas than Europe

Hepatitis

• Three forms:
  • An infectious hepatitis–like picture
  • Fever of unknown origin, with characteristic granulomas ("donut-like") on liver biopsy
  • An incidental finding in a patient with acute Q fever pneumonia
• More common in Europe and Americas

CNS infections

• Can cause Miller-Fischer variant of Guillain-Barré syndrome

Endocarditis

• Subacute or chronic febrile illess
• Clubbing and hepatosplenomegaly are common
• Higher titres are more convincing ≥1:6400

Diagnosis

• Not readily culturable (nor should you try), though you can see it with Giemsa stain
• PCR is possible though not common
• Causes a false-positive RF, APLA
• Main method of detection is serology

Serology

• Immunofluorescence assay is standard; no need for EIA
• Two phases of IgG antibodies (phase I and II)
  • Phase II corresponds more to acute
    • Positive if IgM >50 and IgG >200, or if there's a 4x rise in either titres
    • Detectable by 2 weeks, should be positive by 4
    • Peak at 2 months, then decrease except the IgG in cases of endocarditis
    • Also IgA, but not clinically relevant
  • Phase I corresponds more to chronic
    • Can test for IgG (useful) and IgA (useless) titres
    • IgG ≥ 800 consistent with chronic infection, and is one of the minor Duke criteria for endocarditis
    • IgG ≥ 6400 is suggestive of endovascular infection or endocarditis (major criteria),
• Two ways to diagnose acute infection
  • Retrospectively with a fourfold rise in both titres from acute to chronic stage, or
  • One-time phase II IgM >50 and IgG >2000
• Chronic infection is diagnosed clinically, with a phase I IgG titre greater than the phase II IgG titre, and both are at least IgG titre >1:1600
• IgM antibodies are usually undetectable by 4 months, though IgG may persist for more than a decade

Management

• Acute Q fever
  • Consider screening for bicuspid valve with TTE if high risk, or baseline TTE
  • Doxycycline 100mg po bid x 10-14 days
  • Second-line is fluoroquinolones or macrolides
  • Consider monitoring titres for some period afterwards
  • In patients with prosthetic heart valves, consider prolonged treatment as per chronic Q fever (like 1 year)
• Chronic Q fever
  • Definitely screen for endocarditis
  • Doxycycline + hydroxychloroquine 200mg/d continued until phase I IgG titres have decreased to ≤1:800
    • Hydroxychloroquine potentiates doxycycline in the phagolysosomes (makes the doxycycline bactericidal)
    • Monitor for ophthalmologic complications, and both have photosensitivity
    • Can adjust dose of hydroxychloroquine to target serum level 0.8 to 1.2 mcg/mL
  • Duration 1.5 years for native valve endocarditis, 2 years for prosthetic valve endocarditis
  • Measure titres every 3-6 months during treatment, then every 3 months for 2 years after completing treatment

Pregnancy

• Coxiella loves the placenta
• It can be a cause of flu-like illness in pregnant women with a potential exposure history
  • This can be associated with first-trimester pregnancy loss
• Doxycycline and fluoroquinolones are contraindicated
• TMP-SMX 1600/320 daily, make sure they're on folic acid supplementation
  • Continue it for the duration of pregnancy
  • Theoretic risk of hyperbilirubinemia in third trimester, so may consider holding it towards the end unless there's documented chronic infection
• High risk of developing chronic infection, so titres should be monitored for at least 2 years
  • If persistent IgG > 800, consider TEE

Prevention

• Vaccinate high-risk workers