Francisella tularensis: Difference between revisions

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===Microbiology===
 
===Microbiology===
   
*A fastidious [[Stain::Gram-negative]] [[Cellular shape::coccobacillus]]
+
*A fastidious [[Stain::Gram-negative]] [[Shape::coccobacillus]]
 
**Very small on Gram stain, giving a "pink sand" appearance
 
**Very small on Gram stain, giving a "pink sand" appearance
 
**Do not stain well; fuchsine dye can help
 
**Do not stain well; fuchsine dye can help
 
**Needs cysteine to grow, so doesn't grow well on normal media
 
**Needs cysteine to grow, so doesn't grow well on normal media
  +
*Weakly catalase [[Oxidase::positive]], usually oxidase [[Oxidase::negative]], and urease [[Urease::negative]]
 
*Multiple subspecies, including ''tularensis'', ''holarctica'', ''novocida'', ''mediasiatica'', which are further subdivided into clades, and related species ''Francisella philomiragia'' and ''Francisella hispaniensis''
 
*Multiple subspecies, including ''tularensis'', ''holarctica'', ''novocida'', ''mediasiatica'', which are further subdivided into clades, and related species ''Francisella philomiragia'' and ''Francisella hispaniensis''
 
*Subspecies of importance to humans include:
 
*Subspecies of importance to humans include:
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*Zoonotic infection whose main animal reservoirs are rodents and rabbits
 
*Zoonotic infection whose main animal reservoirs are rodents and rabbits
**In North America, the most important reservoirs are [[Sylvilagus species]] (especially [[Sylvilagus nuttalii]], the cottontail rabbit) and [[Lepus species]] lagomorphs (rabbits), and a number of rodents including voles, squirrels, muskrats (especially in Canada), and beavers
+
**In North America, the most important reservoirs are [[Sylvilagus]] (especially [[Sylvilagus nuttalii]], the cottontail rabbit) and [[Lepus]] lagomorphs (rabbits), and a number of rodents including voles, squirrels, muskrats (especially in Canada), and beavers
 
**In Europe, the reservoirs include voles, hamsters, mice, and hares
 
**In Europe, the reservoirs include voles, hamsters, mice, and hares
 
*Essentially worldwide Northern Hemisphere distribution, especially in the US, Japan, Russia, and Scandinavian countries
 
*Essentially worldwide Northern Hemisphere distribution, especially in the US, Japan, Russia, and Scandinavian countries
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***In North America, by [[Vector::Amblyomma americanum]] ticks, [[Vector::Dermacentor variabilis]] ticks, [[Vector::Dermacentor andersoni]] ticks, [[Vector::Chrysops discalis]] deer flies
 
***In North America, by [[Vector::Amblyomma americanum]] ticks, [[Vector::Dermacentor variabilis]] ticks, [[Vector::Dermacentor andersoni]] ticks, [[Vector::Chrysops discalis]] deer flies
 
***In Europe, [[Vector::Aedes cinereus]] and [[Vector::Ochlerotatus exrucians]] mosquitoes are more important, as well as [[Vector::Chrysops relictus]] deer flies and [[Vector::Haematopota pluvialis]] horse flies
 
***In Europe, [[Vector::Aedes cinereus]] and [[Vector::Ochlerotatus exrucians]] mosquitoes are more important, as well as [[Vector::Chrysops relictus]] deer flies and [[Vector::Haematopota pluvialis]] horse flies
  +
***Requires a minimum of 24 hours of tick attachment to transmit to the host
 
**Direct contact with animal products, including skinning, dressing, and eating wild game
 
**Direct contact with animal products, including skinning, dressing, and eating wild game
 
***Viable in carcasses and dust for up to 136 days
 
***Viable in carcasses and dust for up to 136 days
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*Facultative intracellular growth
 
*Facultative intracellular growth
 
**Can infect and persist within erythrocytes, providing protection against [[aminoglycosides]]
 
**Can infect and persist within erythrocytes, providing protection against [[aminoglycosides]]
  +
  +
=== Virulence Factors ===
  +
  +
* Lipopolysaccharide is not well-recognized by TLR4
  +
* Capsule
  +
* Type IV pili binds to epithelial cells
  +
* Facultatively intracellular
   
 
==Clinical Manifestations==
 
==Clinical Manifestations==
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**May have a [[Causes::relative bradycardia]] (more common in US than Europe)
 
**May have a [[Causes::relative bradycardia]] (more common in US than Europe)
 
*These symptoms may remit and relapse, presenting as a subacute [[Causes::relapsing fever]] over weeks, with associated weight loss, deconditioning, and lymphadenopathy
 
*These symptoms may remit and relapse, presenting as a subacute [[Causes::relapsing fever]] over weeks, with associated weight loss, deconditioning, and lymphadenopathy
*Bloodwork may show [[leukocytosis]] and elevated ESR, as well as occasional [[thrombocytopenia]], [[hyponatremia]], elevated liver enzymes, elevated CK, myoglobinuria, and steril pyuria
+
*Bloodwork may show [[leukocytosis]] and elevated ESR, as well as occasional [[thrombocytopenia]], [[hyponatremia]], elevated liver enzymes, elevated CK, myoglobinuria, and sterile pyuria
   
 
===Ulceroglandular Tularemia===
 
===Ulceroglandular Tularemia===
   
  +
*Most common
 
*Ulcer develops at site of inoculation with tender lymphadenopathy and systemic symptoms
 
*Ulcer develops at site of inoculation with tender lymphadenopathy and systemic symptoms
  +
*Ulcer can be red papule or vesicular (similar to HSV), then either heals or becomes necrotic
   
 
===Glandular Tularemia===
 
===Glandular Tularemia===
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*Acquired by direct inhalation, often from sheep shearing, landscaping, and microbiology laboratory work
 
*Acquired by direct inhalation, often from sheep shearing, landscaping, and microbiology laboratory work
  +
*Can also develop secondary to one of the other syndromes
  +
*Chest x-ray is non-specific
   
 
===Complications and Prognosis===
 
===Complications and Prognosis===
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*Without treatment, complications include meningitis, encephalitis, pericarditis, peritonitis, osteomyelitis, splenic rupture, and thrombophlebitis
 
*Without treatment, complications include meningitis, encephalitis, pericarditis, peritonitis, osteomyelitis, splenic rupture, and thrombophlebitis
 
*Rarely, [[Guillain-Barré syndrome]] following ulceroglandular tularemia
 
*Rarely, [[Guillain-Barré syndrome]] following ulceroglandular tularemia
  +
*Symptoms, especially neuropsychiatric symptoms, may persist for weeks after treatment
 
*Mortality is 60% without treatment, and decreases to 2 to 4% with antibiotics
 
*Mortality is 60% without treatment, and decreases to 2 to 4% with antibiotics
   
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*Diagnosis is primarily clinical, and treatment should be given while attempting to confirm with diagnostic testing
 
*Diagnosis is primarily clinical, and treatment should be given while attempting to confirm with diagnostic testing
  +
*Culture
+
=== Culture ===
**Notify lab that tularemia is suspected before sending samples
 
  +
**Gram stain is very rarely positive
 
 
*Notify lab that tularemia is suspected before sending samples
**May be isolated from blood, pleural fluid, lymph nodes, wounds, sputum, and gastric aspirates
 
 
*Gram stain is very rarely positive
**Grows slowly on standard culture media, needs cystine-rich media (e.g. chocolate agar, BHI, or cystine media)
 
 
*May be isolated from blood, pleural fluid, lymph nodes, wounds, sputum, and gastric aspirates
**Looks bacillary in logarithmic growth phase (small Gram-negative rod), slow-growing only on chocolate agar
 
 
*Grows slowly on standard culture media, needs cystine-rich media (e.g. chocolate agar, BHI, or cystine media)
*Serology is the most common test used to diagnose
 
 
*Looks bacillary in logarithmic growth phase (small Gram-negative rod), slow-growing only on chocolate agar
**Can use tube agglutination (used in Ontario and the US), microagglutination, hemagglutination, enzyme-linked immunosorbent assay (used in Europe), or immunochromatographic assay
 
  +
**IgM and IgG appear together, usually after 2 weeks and peak at 4 to 5 weeks
 
  +
=== Serology ===
**Can persist for at least 10 years
 
  +
**Presumptive positive with a single titre ≥1:160 (tube agglutination) or ≥1:128 (microagglutination), but this can also be compatible with remote infection
 
 
*The most common test used to diagnose
**Definitive diagnosis is made with a four-fold rise in acute and convalescent serology collected 2 to 3 weeks apart, with at least one test being above the threshold for presumptive positive
 
 
*Can use tube agglutination (used in Ontario and the US), microagglutination, hemagglutination, enzyme-linked immunosorbent assay (used in Europe), or immunochromatographic assay
**May cross-react with [[Brucella]], [[Proteus]] OX19, [[Legionella]], and [[Yersinia]]
 
 
*IgM and IgG appear together, usually after 2 weeks and peak at 4 to 5 weeks
 
*Can persist for at least 10 years
 
*Presumptive positive with a single titre ≥1:160 (tube agglutination) or ≥1:128 (microagglutination), but this can also be compatible with remote infection
 
*Definitive diagnosis is made with a four-fold rise in acute and convalescent serology collected 2 to 3 weeks apart, with at least one test being above the threshold for presumptive positive
 
*May cross-react with [[Brucella]], [[Proteus]] OX19, [[Legionella]], and [[Yersinia]], but titres normally aren't particularly high, as well as with environmental, non-pathogenic [[Francisella]]
  +
  +
=== Other ===
  +
 
*DFA and PCR are available at reference labs
 
*DFA and PCR are available at reference labs
  +
*Slide agglutination of a colony as a rapid test to identify
 
*Automated methods should not be used, due to the risk of aerosolization, and may also misindentify as [[Haemophilus]] or [[Aggregatibacter]] species
 
*Automated methods should not be used, due to the risk of aerosolization, and may also misindentify as [[Haemophilus]] or [[Aggregatibacter]] species
   
 
==Management==
 
==Management==
   
  +
*Due to the presence of a β-lactamase and the fact that it's facultatively intracellular, it is not treated with any β-lactam antibiotics
 
*For severe disease, [[Is treated by::streptomycin]] 10 mg/kg (max 1 g) IM q12h for 7 to 10 days
 
*For severe disease, [[Is treated by::streptomycin]] 10 mg/kg (max 1 g) IM q12h for 7 to 10 days
**Alternatives include [[Is treated by::gentamicin]] or [[Is treated by::amikacin]]
+
**Alternatives include [[Is treated by::gentamicin]] 2.5 mg/kg IM/IV q8h or [[Is treated by::amikacin]]
 
*For mild to moderate disease, alternatives include:
 
*For mild to moderate disease, alternatives include:
 
**[[Is treated by::Doxycycline]] 100 mg po bid for 14 to 21 days
 
**[[Is treated by::Doxycycline]] 100 mg po bid for 14 to 21 days
 
**[[Is treated by::Ciprofloxacin]] 500 mg po bid for 10 to 14 days
 
**[[Is treated by::Ciprofloxacin]] 500 mg po bid for 10 to 14 days
*For meningitis, use an aminoglycoside (as above) plus either IV ciprofloxacin, doxycycline, or chloramphenicol for 14 to 21 days
+
*For meningitis, use an [[Aminoglycosides|aminoglycoside]] (as above) plus either IV [[ciprofloxacin]], [[doxycycline]], or [[chloramphenicol]] for 14 to 21 days
**Aminoglycosides have poor CNS penetration
+
**[[Aminoglycosides]] have poor CNS penetration
  +
*Pregnant women or children are usually treated with [[ciprofloxacin]]
   
 
==Prevention==
 
==Prevention==
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*Live attenuated vaccine derived from ''holarctica''
 
*Live attenuated vaccine derived from ''holarctica''
  +
  +
=== Post-Exposure Prophylaxis ===
  +
  +
* Only given after aerosolized exposure
  +
* [[Doxycycline]] or [[ciprofloxacin]] for 14 days
   
 
===Lab Safety===
 
===Lab Safety===
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*Should be suspected with any slowly-growing, small, and poorly-staining Gram-negative coccobacillus is isolated on chocolate agar but not blood agar
 
*Should be suspected with any slowly-growing, small, and poorly-staining Gram-negative coccobacillus is isolated on chocolate agar but not blood agar
 
*Automated laboratory identification systems should ''not'' be used, because the risk of aerosol generation
 
*Automated laboratory identification systems should ''not'' be used, because the risk of aerosol generation
*Commonly misidentified by automated methods as [[Haemophilus species|Haemophilus]] or [[Aggregatibacter]] species
 
 
{{DISPLAYTITLE:''Francisella tularensis''}}
 
{{DISPLAYTITLE:''Francisella tularensis''}}
 
[[Category:Gram-negative bacilli]]
 
[[Category:Gram-negative bacilli]]

Latest revision as of 12:25, 8 July 2023

  • Zoonontic infection carried on rodents and rabbits and transmitted by biting insects
  • Presentation depends on route of entry: (ulcero)glandular, oculoglandular, pharyngeal, typhoidal, or pneumonic
  • Treatment is streptomycin

Background

Microbiology

  • A fastidious Gram-negative coccobacillus
    • Very small on Gram stain, giving a "pink sand" appearance
    • Do not stain well; fuchsine dye can help
    • Needs cysteine to grow, so doesn't grow well on normal media
  • Weakly catalase positive, usually oxidase negative, and urease negative
  • Multiple subspecies, including tularensis, holarctica, novocida, mediasiatica, which are further subdivided into clades, and related species Francisella philomiragia and Francisella hispaniensis
  • Subspecies of importance to humans include:
    • Subspecies tularensis (type A strains)
      • Found in North America and rarely Europe
      • Two major clades (AI and AII) and four subclades (AIa, AIb, AIIa, and AIIb)
      • Overall the subspecies is the most virulent subspecies, and specifically the AIb subclade is the most virulent strain
    • Subspecies holarctica (type B strains)
      • Found in the entire northern hemisphere as well as Australia
      • Four major clades (B4 in North America, B6 in Western Europe, B12 in Eastern Europe and Central Asia, and B16 in Japan and other areas in Eastern Asia) and a number of subclades
    • Subspecies novicida
      • Rare cause of disease in humans, usually in immunocompromised hosts, and presents with bacteremia rather than tularemia
    • Subspecies mediasiatica does not cause disease in humans

History

  • Discovered in 1911 in Tulare county, California
  • Many names: deer fly fever, rabbit fever, water rat trappers disease, etc...

Epidemiology

  • Zoonotic infection whose main animal reservoirs are rodents and rabbits
    • In North America, the most important reservoirs are Sylvilagus (especially Sylvilagus nuttalii, the cottontail rabbit) and Lepus lagomorphs (rabbits), and a number of rodents including voles, squirrels, muskrats (especially in Canada), and beavers
    • In Europe, the reservoirs include voles, hamsters, mice, and hares
  • Essentially worldwide Northern Hemisphere distribution, especially in the US, Japan, Russia, and Scandinavian countries
    • In Canada, occurs mostly in the Prairies
  • Transmission through a number of mechanisms

Pathophysiology

  • Infectious dose depends on route, but is as low as 10 to 50 organisms when injected intradermally or inhaled (or several orders of magnitude higher if ingested)
  • TLR4 has less affinity for its LPS compared to other bacteria
  • Capsule inhibits IgM and complement C3
    • Capsule-deficient strains are both less immunogenic and less virulent
  • Facultative intracellular growth
    • Can infect and persist within erythrocytes, providing protection against aminoglycosides

Virulence Factors

  • Lipopolysaccharide is not well-recognized by TLR4
  • Capsule
  • Type IV pili binds to epithelial cells
  • Facultatively intracellular

Clinical Manifestations

  • Incubation period of 3 to 5 days (range 1 to 21 days)
  • The first symptom is usually a papule at the site of inoculation that develops into an ulcer over 1 to 2 days, but this may go unnoticed
  • This is followed by fever which likely corresponds to initial lymphohematogenous dissemination
    • Other common symptoms include chills, headache, malaise, anorexia, and fatigue
    • May also have cough, myalgias, chest discomfort, vomiting, sore throat, abdominal pain, and diarrhea
    • May have a relative bradycardia (more common in US than Europe)
  • These symptoms may remit and relapse, presenting as a subacute relapsing fever over weeks, with associated weight loss, deconditioning, and lymphadenopathy
  • Bloodwork may show leukocytosis and elevated ESR, as well as occasional thrombocytopenia, hyponatremia, elevated liver enzymes, elevated CK, myoglobinuria, and sterile pyuria

Ulceroglandular Tularemia

  • Most common
  • Ulcer develops at site of inoculation with tender lymphadenopathy and systemic symptoms
  • Ulcer can be red papule or vesicular (similar to HSV), then either heals or becomes necrotic

Glandular Tularemia

  • Ulcer is undetectable or healed, only lymphadenopathy and systemic illness remains

Oculoglandular Tularemia

  • Entry through the conjuctiva
  • Rare

Pharyngeal Tularemia

  • Entry through the oropharynx, with exudative pharyngitis/tonsillitis
  • May be difficult to distinguish from other forms of tularemia that also may have sore throat

Typhoidal Tularemia

  • Febrile illness without lymphadenopathy or ulcer, sometimes with diarrhea
  • May involve endocarditis
  • Patient often has an underlying chronic disease
  • Often rapidly-progressive and fatal

Pneumonic Tularemia

  • Acquired by direct inhalation, often from sheep shearing, landscaping, and microbiology laboratory work
  • Can also develop secondary to one of the other syndromes
  • Chest x-ray is non-specific

Complications and Prognosis

  • Suppurative lymphadenopathy is the most common complication despite antibiotics, and may require drainage
  • Severe disease may cause DIC, renal failure, rhabdomyolysis, jaundice, and hepatitis
  • Without treatment, complications include meningitis, encephalitis, pericarditis, peritonitis, osteomyelitis, splenic rupture, and thrombophlebitis
  • Rarely, Guillain-Barré syndrome following ulceroglandular tularemia
  • Symptoms, especially neuropsychiatric symptoms, may persist for weeks after treatment
  • Mortality is 60% without treatment, and decreases to 2 to 4% with antibiotics

Diagnosis

  • Diagnosis is primarily clinical, and treatment should be given while attempting to confirm with diagnostic testing

Culture

  • Notify lab that tularemia is suspected before sending samples
  • Gram stain is very rarely positive
  • May be isolated from blood, pleural fluid, lymph nodes, wounds, sputum, and gastric aspirates
  • Grows slowly on standard culture media, needs cystine-rich media (e.g. chocolate agar, BHI, or cystine media)
  • Looks bacillary in logarithmic growth phase (small Gram-negative rod), slow-growing only on chocolate agar

Serology

  • The most common test used to diagnose
  • Can use tube agglutination (used in Ontario and the US), microagglutination, hemagglutination, enzyme-linked immunosorbent assay (used in Europe), or immunochromatographic assay
  • IgM and IgG appear together, usually after 2 weeks and peak at 4 to 5 weeks
  • Can persist for at least 10 years
  • Presumptive positive with a single titre ≥1:160 (tube agglutination) or ≥1:128 (microagglutination), but this can also be compatible with remote infection
  • Definitive diagnosis is made with a four-fold rise in acute and convalescent serology collected 2 to 3 weeks apart, with at least one test being above the threshold for presumptive positive
  • May cross-react with Brucella, Proteus OX19, Legionella, and Yersinia, but titres normally aren't particularly high, as well as with environmental, non-pathogenic Francisella

Other

  • DFA and PCR are available at reference labs
  • Slide agglutination of a colony as a rapid test to identify
  • Automated methods should not be used, due to the risk of aerosolization, and may also misindentify as Haemophilus or Aggregatibacter species

Management

Prevention

Vaccination

  • Live attenuated vaccine derived from holarctica

Post-Exposure Prophylaxis

Lab Safety

  • This is a biosafety risk group 3 organism
  • Should be suspected with any slowly-growing, small, and poorly-staining Gram-negative coccobacillus is isolated on chocolate agar but not blood agar
  • Automated laboratory identification systems should not be used, because the risk of aerosol generation