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
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, 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)
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
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
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
