Paschalis Vergidis
Matthew E. Falagas
DESCRIPTION 
Tularemia is a zoonotic infection caused by Francisella tularensis. The organism is responsible for a number of syndromes in humans that range from a plague-like ulceroglandular illness to pneumonia.
EPIDEMIOLOGY
Incidence
Tularemia is a rare disease, with fewer than 300 cases reported in the US annually.
Prevalence
- The disease occurs mainly in the Northern Hemisphere; it is not found in the UK. The disease has not been reported in Africa, South America, or Australia.
- Most cases in the US occur in the south central states Arkansas, Oklahoma, and Missouri.
- Tick-borne cases occur in the summer.
- Disease in the winter months is usually associated with skin contact with infectious organisms (hunting-associated cases).
- Infection is found to occur in over 100 species of small and large mammals, 25 species of birds, and 50 species of insects.
- Fish and amphibians may be infected.
- In the US, the rabbit is the most important reservoir of infection.
- Insects such as ticks, flies, and mosquitoes serve as vectors for disease in humans.
- Commonly found wood ticks, dog ticks, and lone star ticks are responsible for the majority of transmission in the US.
RISK FACTORS
High-risk professionals include hunters, farm workers, veterinarians, and laboratory workers.
GENERAL PREVENTION
- A live attenuated vaccine is available for people at high risk of infection. It does not provide complete protection but reduces the severity of disease.
- Protection from ticks is important.
- People who skin animals (hunters, trappers) should wear gloves.
PATHOPHYSIOLOGY
- Infection in humans can occur by one of the following routes:
- Bite from an arthropod vector (tick or mosquito).
- Skin contact with an infected carcass
- Inhalation of the organism, particularly by laboratory workers. (May be used as an agent of bioterrorism)
- Ingestion of meat contaminated with the bacterium
- Bite from an animal (including pets) that harbors the organism in the oropharynx
- The organism spreads from the site of entry to regional lymph nodes. Francisella replicates within host macrophages and disseminates via a lymphohematogenous route. Bacteremia is common in the early phase.
ETIOLOGY
- F. tularensis is an aerobic gram-negative rod.
- The organism is virulent, and small numbers of organisms on the skin can invade and lead to systemic illness.
- The organism
- Requires cysteine for growth
- Produces a
-lactamase - Is resistant to freezing and may persist for weeks in dead animals
- Is inactivated by heat
[Outline]
HISTORY
- The incubation period varies and averages 3–5 days.
- In most cases, cutaneous infection disseminates to regional lymph nodes prior to bacteremia.
- Bacteremia is associated with fever, chills, myalgias, headache, sore throat, and cough that continue for 1–4 days.
- Remission occurs for 1–3 days, followed by recurrent symptoms that can continue for several weeks.
PHYSICAL EXAM
- Fever may be associated with a pulse-temperature deficit.
- Some patients have a rash that begins as blotchy, macular, or maculopapular and progresses to pustular lesions.
- Ulceroglandular
- Accounts for 60–80% of cases.
- Ulcers appear at the skin site of inoculation and start as a red, painful papule, progressing to necrotic ulcers, which leave a scar.
- Regional lymph nodes become markedly enlarged and tender during this stage. They may stay enlarged for months.
- Half of patients with the ulceroglandular form have evidence of pneumonia, effusions, or hilar adenopathy on chest x-ray.
- Glandular
- There is no identifiable skin lesion
- Typhoidal
- Typhoidal disease is rare and may lead to fever of unknown origin.
- Presumably, the organism is ingested, but tick exposure may initiate the disease.
- Ulcers and lymphadenopathy are usually absent.
- Diarrhea is usually prominent.
- Most patients with the typhoidal form have abnormalities on chest x-ray and pneumonitis.
- Pneumonic
- Associated with inhalation of the organism or hematogenous spread.
- Patients present with a dry cough, pleuritic chest pain, fevers, and myalgias.
- Oculoglandular
- Inoculation in the eye may lead to an oculoglandular form of the illness.
- Painful conjunctivitis with yellow conjunctival ulcers and preauricular or cervical lymphadenopathy occurs.
- Oropharyngeal
- Ingestion of the bacteria may lead to this rare form of disease.
- The throat may contain a membrane that resembles diphtheria.
- Cervical lymphadenopathy is extensive.
ALERT
F. tularensis is an agent of bioterrorism. Notify public health authorities in cases with unusual epidemiologic history.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
- Modest elevation of the leukocyte count may occur
- Mild elevations of transaminases can be noted
- Sterile pyuria
- Rhabdomyolysis is a poor prognostic sign
- Diagnosis is often made serologically
- Tularemia tube agglutination testing is the most commonly used test.
- A single titer of 1:160 or higher is supportive of the diagnosis.
- A fourfold increase in convalescent serum is also supportive.
- Serologic tests may cross-react with Salmonella, Brucella, Yersinia, and Legionella species.
- Cultures require a media that contains cysteine
- Sputum gram stain usually does not demonstrate the organism
- Culture poses a risk for laboratory workers. Always notify laboratory personnel if tularemia is suspected so that they may take appropriate precautions
Imaging
- Chest x-rays often show patchy ill-defined infiltrates with pleural effusions.
- There is often associated hilar adenopathy.
- Nodular infiltrates 2–8 cm in size may be observed.
Diagnostic Procedures/Other
Lymph node biopsy is generally not required for diagnosis.
Pathological Findings
- Early tularemia: Areas of focal necrosis surrounded by neutrophils and macrophages.
- Late disease: Necrotic areas with caseating granulomata.
DIFFERENTIAL DIAGNOSIS
[Outline]
MEDICATION
First Line
- Drug of choice: Streptomycin 7.5–10.0 mg/kg every 12 h; intravenous or intramuscular delivery for 7–14 days (1)
- Gentamicin 3–5 mg/kg/d, divided every 8 h i.v. for 7–14 days
- Chloramphenicol plus streptomycin used with central nervous system involvement (CNS penetration of aminoglycosides is erratic)
Second Line
The following alternatives are to be used with caution:
- Tetracycline 1 g every day for 15 days has been associated with recurrences.
- Erythromycin is possibly effective, but resistance has been noted.
- Quinolones are possibly effective; however, clinical experience is lacking.
- Third-generation cephalosporins are not effective.
ADDITIONAL TREATMENT
Additional Therapies
Debridement of superinfected necrotic lesions or surgical drainage of lymph nodes.
IN PATIENT CONSIDERATIONS
Admission Criteria
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