View source for Francisella tularensis

*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 [[Stain::Gram-negative]] [[Shape::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 [[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''
*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
**Vector-borne
***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
***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
***Viable in carcasses and dust for up to 136 days
**Inhalation of aerosolized vectors (e.g. lawn-mowing), contact with contaminated water or mud, and animal bites of animals that have killed infected reservoir hosts (e.g. cats killing rodents)
**Potential for [[Bioterrorism agents|bioterrorism]], especially with waterborne or aerosol transmission

===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)
*[[Toll-like receptors|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 [[Usual incubation period::3 to 5 days]] (range [[Incubation period 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 [[Causes::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 [[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
*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==

*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
**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:
**[[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
*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
*Pregnant women or children are usually treated with [[ciprofloxacin]]

==Prevention==

===Vaccination===

*Live attenuated vaccine derived from ''holarctica''

=== Post-Exposure Prophylaxis ===

* Only given after aerosolized exposure
* [[Doxycycline]] or [[ciprofloxacin]] for 14 days

===Lab Safety===

*This is a [[Biosafety risk groups|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
{{DISPLAYTITLE:''Francisella tularensis''}}
[[Category:Gram-negative bacilli]]
[[Category:Animal exposures]]