Tularemia, aka ‘rabbit fever’: A rare disease and potential bioweapon
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Tularemia is a zoonotic disease caused by Francisella tularensis, an aerobic gram-negative coccobacillus. Francisella are slow growing, fastidious and difficult to cultivate.
Infection may occur from the bite of an infected tick or deer fly or other biting insect or from contact with an infected animal. Infection may also occur after swallowing or inhaling the bacteria or from exposure to laboratory accidents. In nature, infections occur most often in rabbits, hares and rodents, but many different mammals are susceptible to infection. It is a category A bioterrorism agent because of its pathogenicity and the ease with which it can be weaponized. It is dangerous to work with and must be handled very carefully in the laboratory using biosafety level 3 conditions. If used as a bioweapon, it would probably be by aerosolization.
Epidemiology
Tularemia is a rare disease in humans. From 2013 to 2018, about 200 cases of tularemia were reported each year in the United States. The highest incidence of cases per population has occurred in the Midwestern states of Arkansas, Oklahoma, Kansas and South Dakota. It tends to occur in warmer months. Tularemia is also a rare disease found in parts of the world other than the U.S.
Any hobby or occupation that involves increased exposure to insects and animals carries an increased risk for acquiring tularemia (eg, hunters, farmers, landscapers and veterinarians).
Tularemia is much more likely to occur in men than in women. This is probably because men are more often involved with hunting, farming and landscaping, making them more likely to be exposed to infected animals either directly or through biting insects. The very young and the middle aged are most often infected.
Pathogenesis
F. tularensis is a highly virulent microorganism. As few as 10 bacteria can cause severe infection.
Tularemia can be acquired in ways other than by direct exposure to an infected animal or from the bite of a tick or deer fly or other biting insect. The ticks that have been reported to transmit Francisella tularensis in the U.S. are Dermacentor variabilis, Dermacentor andersoni and Amblyomma americanum. Ingestion of water or food contaminated by infected animals can cause the disease. Contamination of the conjunctiva also can result in tularemia involving the eye. Inhalation of aerosolized bacteria may occur and produce infection. The aerosolization may be from a laboratory accident or from weaponized F. tularensis. In 2000, there was an interesting outbreak on Martha’s Vineyard, Massachusetts, which occurred from mowing grass where infected rabbits lived. This caused aerosolization of microorganisms, which, in turn, resulted in pneumonia.
After entry into the body, F. tularensis multiplies locally, causing tissue necrosis, then spreads to regional lymph nodes and then systemically via the bloodstream. Granulomas may form in areas of tissue infection and may caseate. The bacteria are not killed by polymorphonuclear leukocytes and are able to multiply in macrophages.
Symptoms
After an incubation period that usually lasts 3 to 6 days, there is acute onset of fever and generalized aches associated with one of the following syndromes depending mainly on the portal of entry of the infecting bacteria. When lymph nodes are clinically involved, the overlying skin may be erythematous, and the gland may suppurate. Tularemia may result in involvement of virtually any site (leading to meningitis, endocarditis, etc.) Secondary skin rashes are common in tularemia; papular and vesiculopapular rashes and erythema nodosum and erythema multiforme have been described.
Ulceroglandular tularemia
After the microorganisms enter the body from skin contact with an infected animal or an insect bite, an ulcer may appear at the point of entry with development of tender lymphadenopathy in the nodes draining that area. This is the most common form of tularemia, and it usually involves one of the extremities, most commonly with an ulcer on a hand and epitrochlear and axillary adenopathy if following contact with an infected animal, and an ulcer and adenopathy elsewhere on the body if following a tick bite. Lymph nodes may suppurate and drain. If left untreated, ulceroglandular disease has a mortality rate of 5% to 6%.
Glandular tularemia
This is essentially the same as ulceroglandular tularemia, but there is no formation of an ulcer, so the patient presents with regional adenopathy only.
Oculoglandular tularemia
Oculoglandular tularemia occurs when the microorganisms are introduced into the conjunctiva, usually by touch but occasionally by spray or splash. The clinical presentation includes conjunctival inflammation and preauricular tender adenopathy.
Oropharyngeal tularemia
This syndrome follows the ingestion of F. tularensis. The syndrome includes sore throat with mouth ulcers and tender cervical lymphadenopathy.
Pneumonic tularemia
Following inhalation of aerosolized F. tularensis, the patient develops pneumonia. Pneumonia also may result from hematogenous spread of the F. tularensis from other sites. Pleuritic chest pain is common.
Typhoidal tularemia
This is essentially sepsis or bacteremia without any localized symptoms.
Diagnosis
The diagnosis of tularemia is suggested by the presenting clinical syndrome (eg, an ulcer on an extremity with regional adenopathy and fever). A history of possible exposure, such as having skinned a rabbit, is also suggestive.
Testing for tularemia includes cultures of any involved site as well as blood using appropriate special culture media for F. tularensis. The organism is difficult to isolate because it is fastidious and slow growing. It does not grow well in liquid media. Blood cultures are often negative despite isolation from other sites.
The organism may be visualized microscopically by using direct fluorescent antibody techniques on specimens (swabs, scrapings or aspirations) from a site of infection. There are PCR tests available at some institutions. A rise in serum antibody titer is useful in diagnosing tularemia but only retrospectively.
Treatment
Aminoglycosides such as streptomycin and gentamicin are considered the drugs of choice for treatment of tularemia. Because of availability and familiarity and less ototoxicity, gentamicin is preferred, although streptomycin is the only aminoglycoside that is FDA approved for treatment of tularemia. Fluoroquinolones including ciprofloxacin and levofloxacin have been demonstrated to be effective, as have tetracyclines such as doxycycline. Of these drugs, only tetracyclines are approved by the FDA for the treatment of tularemia. Therapy is recommended for a duration of 10 to 21 days.
If fluctuance and suppuration occur in a lymph node, it should be drained by aspiration or incision and drainage.
With proper treatment, recovery is usually complete.
Prevention
Precautions against exposure to biting insects such as wearing long pants and sleeves and the use of insect repellents such as DEET and permethrin will help avoid tularemia. Use of gloves when handling rabbits and rodents in the wild also will help prevent tularemia.
Attenuated live F. tularensis vaccines have been used over many years, mainly in the former Soviet Union. In fact, in the 1940s and 1950s, as many as 60 million people were immunized in the Soviet Union. There is no FDA-approved vaccine for F. tularensis in the U.S.
- References:
- CDC. Tularemia. https://www.cdc.gov/tularemia/index.html. Accessed April 27, 2020.
- Ellis J, et al. Clin Microbiol Rev. 2002. doi:10.1128/CMR.15.4.631-646.2002.
- Jones CL, et al. Microbiol Mol Biol R. 2012;doi:10.1128/MMBR.05027-11.
- Kinkead L, Allen LAH. Immunol Rev. 2016;doi:10.1111/imr.12445.
- Rojas-Moreno C, et al. Open Forum Infect Dis. 2018;doi:10.1093/ofid/ofy176.
- Syrjälä H, et al. Acta Derm Venereol. 1984;64(6):513.
- Tikhenko NI, et al. Zh Mikrobiol Epidemiol Immunobiol. 2001;(6 Suppl):68-72.
- Weber IB, et al. Clin Infect Dis. 2012;doi:10.1093/cid/cis706.
- For more information:
- Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society of Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board Member.
Disclosure: Kaye reports no relevant financial disclosures.
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