June 27, 2003
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Tularemia (also known as rabbit fever) is caused by the bacterium Francisella tularensis.
Tularemia most often affects lagomorphs (rabbits and hares) and rodents; however, it has been reported as affecting more than 100 species of wild and domestic mammals. In North America, infections are most common in snowshoe hares, black-tailed jackrabbits, and eastern and desert cottontails. Infections in birds, fish, amphibians, and reptiles are relatively rare. Carnivores are susceptible, but require high doses of the bacterium to become infected and rarely exhibit obvious signs of disease.
Domestic animals and humans are usually considered accidental hosts; however, outbreaks occurring in sheep in Canada, the United States, and Russia have resulted in high mortality. Outbreaks have also been identified in commercially bred mink, beaver, and fox. Although not common, disease has been identified in domestic cats. Dogs appear to be resistant to infection, but may serve as reservoirs for the bacterium or maintenance hosts for the tick vector. The global incidence of tularemia in humans is not well documented, but the number of reported cases has declined in recent years.
Geographically, tularemia has been reported in Canada, Mexico, and the United States (all states except Hawaii). With the exception of the Iberian Peninsula, tularemia is distributed throughout Europe and Mediterranean Africa, and has been identified in China, Iran, Israel, Japan, Korea, Russia, and Turkey.
Ticks are the most important vectors of F. tularensis, transferring the bacterium between rabbits, hares, and rodents and serving as an interepizootic reservoir. Horseflies, mosquitoes, sucking lice, and biting flies may also serve as vectors. In endemic areas, transmission to humans and other domestic vertebrates usually occurs via bites from infected arthropods, or the bacterium may enter scratches or knife cuts exposed to infected animal tissues. Tularemia may also be transmitted by ingestion of infected tissues or contaminated water, and by inhalation of aerosolized particles. Sheep and domestic cats can be a source of infection for man. Human-to-human transmission is considered to be rare.
Clinical signs of tularemia in animals and humans
Rabbits, hares, and rodents—Clinical signs in rabbits, hares, and rodents have not been well described, because affected animals have most often been found dead. Experimentally infected animals exhibit weakness, fever, ulcers, regional lymphadenopathy, and abscesses. Death usually ensues in 8 to 14 days.
Sheep—Tularemia in sheep is typically a seasonal disease, coinciding with tick infestations. Clinical signs include fever, rigid gait, diarrhea, frequent urination, weight loss, and difficulty breathing. Affected sheep may isolate themselves from the remainder of the flock. Death is most common in young animals, and pregnant ewes may abort.
Cattle—Natural infection is evident from reports of seroconversion; however a clear clinical picture has not emerged.
Horses—Reports of clinical disease in horses are limited; however, fever, dyspnea, incoordination, and depression have been described. Affected horses have had extensive tick infestation.
Domestic cats—Cats infected with F. tularensis experience disease ranging from nonclinical infection to sepsis and death. Clinical signs may include fever, depression, lymphadenopathy, abscesses, oral or lingual ulceration, gastroenteritis, hepatomegaly, splenomegaly, icterus, anorexia, weight loss, pneumonia, and sepsis.
Dogs—Reports describing clinical signs of tularemia in dogs are limited, although there is ample evidence of seroconversion. Natural infection apparently occurs with some regularity, but clinical illness is inapparent or mild. Clinical signs observed are related to mode of transmission and include fever, mucopurulent oculonasal discharge, pustules at inoculation sites, lymphadenopathy, and anorexia. In most cases, disease has been self-limiting with supportive treatment.
Humans—The incubation period is typically 3 to 5 days, but may range from 1 to 14 days. Fever, chills, malaise, cephalagia, myalgia, and vomiting are followed by more specific signs of disease that depend on route of entry: ulceroglandular, glandular, typhoidal, oropharyngeal, oculoglandular, or pulmonary. All forms of tularemia can progress to pleuropneumonia, meningitis, sepsis, shock, and death.
Ulceroglandular tularemia is the most common form (75 to 85% of reported cases). An ulcer is evident at the site of entry, usually the fingers or hands in cases associated with exposure to rabbits, hares, or rodents. Ulceration progresses to necrosis and lymphadenopathy; lymph nodes may suppurate, ulcerate, and become sclerotic. Signs of glandular tularemia are similar, but no skin ulcer is evident.
Pulmonary tularemia represents about 30% of contracted infections and is caused by inhalation of aerosolized bacteria. Pneumonia in one or both lungs is the typical clinical sign.
Typhoidal tularemia results from ingestion of contaminated food or water, and is uncommon. Clinical signs include fever, prostration, weight loss, gastroenteritis, and sepsis. Mortality rates can range from 40 to 60% if prompt treatment is not sought. Oropharyngeal tularemia is also contracted through ingestion of F. tularensis and results in acute pharyngeotonsillitis, which may be exudative or membranous, with cervical lymphadenopathy.
Oculoglandular tularemia results from contamination of the conjunctiva. Ulcerated papules, which are usually located on the lower eyelid, are accompanied by lymphadenopathy.
ELISA, hemagglutination, microagglutination, and tube agglutination are used to identify agglutinating antibodies in serum. Definitive diagnosis is through isolation of F. tularensis from clinical specimens (e.g., blood, exudates, biopsy samples); however, many laboratories are reluctant to attempt this because of associated risks with infecting laboratory personnel. Results of routine laboratory tests (e.g., complete blood counts and serum biochemical analyses) are usually nonspecific.
Tularemia is generally a postmortem diagnosis in wild animals. For sheep, clinical confirmation is through serology or isolation of the etiologic agent. For humans, a presumptive diagnosis is based on clinical signs and a history of exposure. In nonendemic areas, a single convalescent titer of 1:160 or greater is considered diagnostic. In endemic areas, acute and convalescent titers are required and a 4-fold change of titer between samples obtained 2 to 4 weeks apart is considered to be diagnostic.
For humans and other animals, tick control is an important part of prevention. Contact with untreated water should be avoided when contamination with F. tularensis is suspected, and wild game should be thoroughly cooked before consumption. In endemic areas, handling of dead and moribund animals should be avoided. Gloves should be worn when handling wild game, their skins, and carcasses. Equipment used in the diagnosis, care, or collection of animals suspected or known to be infected should be properly disposed of (contaminated medical waste) or disinfected.
The attenuated live vaccine that was available for laboratory workers and others at risk of exposure under an Investigational New Drug protocol is no longer available.
Streptomycin and tetracycline are the antibiotics of choice for treating wild and domestic animals. For humans, streptomycin has been preferred, with tetracyclines (especially doxycycline), gentamicin, and chloramphenicol as alternatives. Fluoroquinolones have also shown promise in the treatment of tularemia. Chloramphenicol has been used to treat associated meningitis.
Healthcare professionals assisting animal and human patients should wear personal protective clothing (e.g., gowns, gloves, and face masks). Because F. tularensis is a highly infectious organization, diagnostic laboratories should be notified that tularemia is on the list of differential diagnoses when specimens are submitted. Biosafety at level 2 is recommended for diagnostic work on suspect material; biosafety at level 3 is required for culture. Tularemia is a reportable disease in the United States. Internationally, tularemia is not a notifiable disease.
Use of tularemia as a biological weapon
F. tularensis is classified as a Category A agent of bioterrorism because of its high infectivity, ease of dissemination, and its potential to cause severe disease. Anticipated mechanisms for dissemination include contamination of food or water and aerosolization.
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