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
• Patients may have lifelong immunity following infection

Acute Q Fever

• Fever is uniform finding in all syndromes
• Chills, headache (often severe, may be retroorbital), 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)
• Bloodwork shows normal white count (occasionally leukocytosis), mild thrombocytopenia (in early disease, can be followed by later thrombocytosis), liver enzyme rises (quite common), hyperbilirubinemia
• Can have hepatomegaly or splenomegaly

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

Chronic Q Fever

• May occur months, years, or decades after initial infection
• Can include endocarditis, chronic hepatitis, chronic endovascular infections, osteomyelitis, arthritis, and chronic lung infections

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 illness
• New or worsening valve dysfunction is the most common finding on echo, followed by vegetations, valvular thickening, calcifications, cardiac abscesses, stenosis, prosthetic valve dysfunction, and pericardial effusion
  • More commonly affects the mitral and aortic valves
• Clubbing and hepatosplenomegaly are common
• Higher titres are more convincing ≥1:6400

Post-Q Fever Fatigue Syndrome

• Occurs in about 20% of patients following acute Q fever
• Characterized by debilitating fatigue, with or without nausea, headaches, night sweats, myalgias, muscle fasciculations, lymphadenopathy, arthralgias, irritability and depression, poor concentration, and poor short-term memory
• Diagnosed when the symptoms last for more than a year

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 titre
    • Detectable by 2 weeks, should be positive by 4 weeks
    • Peaks at 2 months, then decreases (except the IgG in cases of endocarditis)
    • Can plateau at 1:1024 or above and persist for months to years after treatment
    • Can also measure IgA, but not clinically relevant
  • Phase I corresponds more to chronic infections
    • Can test for IgG (useful) and IgA (useless) titres
    • Typically increases more slowly over time in chronic infections
    • Typically plateaus below 1:1024 after treatment for acute infection, though occasionally some can peak above that before declining
      • Persistence above 1:1024 can suggest chronic infection
    • 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
• 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

Phase II IgG	Phase I IgG	Interpretation
≤ 1:128	< 1:16	No serologic evidence of infection; if possibly within the first 2 weeks of illness, consider repeating in 3 to 6 weeks
≥ 1:256	< 1:16	Possible recent infection; if acute infection suspected, repeat in 3 to 6 weeks to assess for 4-fold increase in phase II titres
≥ phase I titre	≥ 1:16	Possible recent or remote infection; if acute infection suspected, repeat in 3 to 6 weeks to assess for 4-fold increase in phase II titres
< phase I titre	≥ 1:16 and ≤ 1:512	Possible remote infection; if chronic infection is suspected, repeat in 3 to 6 weeks to assess for increase in phase I titres
< phase I titre	≥ 1:1024	Possible chronic infection, correlate clinically

Antibody	Symptom Onset
	<7 days	2-3 weeks	3 months	6 months	1 year
Phase II IgM	10-80	320	640	160	64
Phase II IgG	<10	320	640	1280	640
Phase I IgM	<10	80	320	160	<10
Phase I IgG	<10	<10	320	160	160

Management

Acute Q Fever

• Consider screening for bicuspid valve with TTE if high risk, or baseline TTE
• Doxycycline 100 mg 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)
• Monitor post-treatment serology regularly for several years to ensure it does not progress to chronic Q fever

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
• In acute Q fever, start TMP-SMX DS 1 tablet (800 mg/160 mg) p.o. twice daily, and 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

Chronic Q Fever

• Definitely screen for endocarditis
• By clinical scenario
  • Endocarditis or vascular infection: doxycycline 100 mg p.o. q12h and hydroxychloroquine 200 mg p.o. q8h, for at least 18 months
  • Non-cardiac organ disease: doxycycline 100 mg p.o. q12h and hydroxychloroquine 200 mg p.o. q8h
  • Postpartum with elevated titers >12 months after delivery: doxycycline 100 mg p.o. q12h and hydroxychloroquine 200 mg p.o. q8h for 12 months
• Some recommend continuing 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

Post-Q Fever Fatigue Syndrome

• The Qure study demonstrated that cognitive behavioural therapy (CBT) leads to improved fatigue severity, while doxycycline made no difference compared to placebo1

Prevention

• Vaccinate high-risk workers