TULAREMIA


SUMMARY


Signs and Symptoms: Ulceroglandular tularemia presents with a local ulcer and regional lymphadenopathy, fever, chills, headache and malaise. Typhoidal tularemia presents with fever, headache, malaise, substernal discomfort, prostration, weight loss and a non-productive cough.


Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. Chest x-ray may reveal a pneumonic process, mediastinal lymphadenopathy or pleural effusion. Routine culture is possible but difficult. The diagnosis can be established retrospectively by serology.


Treatment: Administration of antibiotics (streptomycin or gentamicin) with early treatment is very effective.


Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. It is administered once by scarification. A two week course of tetracycline is effective as prophylaxis when given after exposure.


Isolation and Decontamination: Standard Precautions for healthcare workers. Organisms are relatively easy to render harmless by mild heat (55 degrees Celsius for 10 minutes) and standard disinfectants.


OVERVIEW


Francisella tularensis, the causative agent of tularemia, is a small, aerobic non-motile, gram-negative cocco-bacillus. Tularemia (also known as rabbit fever and deer fly fever) is a zoonotic disease which humans typically acquire after contact of their skin or mucous membranes with tissues or body fluids of infected animals, or from bites of infected deerflies, mosquitoes, or ticks. Less commonly, inhalation of contaminated dusts or ingestion of contaminated foods or water may produce clinical disease. Respiratory exposure by aerosol would cause typhoidal or pneumonic tularemia. F. tularensis can remain viable for weeks in water, soil, carcasses, and hides, and for years in frozen rabbit meat. It is resistant for months to temperatures of freezing and below. It is rather easily killed by heat and disinfectants.


HISTORY AND SIGNIFICANCE


Tularemia was recognized in Japan in the early 1800’s and in Russia in 1926. In the early 1900’s, American workers investigating suspected plague epidemics in San Francisco isolated the organism and named it Bacterium tularense after Tulare County where the work was performed. Dr. Edward Francis, USPHS, established the cause of deer-fly fever as Bacterium tularense and subsequently devoted his life to researching the organism and disease, hence, the organism was later renamed Francisella tularensis


Francisella tularensis was weaponized by the United States in the 1950's and 1960's during the U.S. offensive biowarfare program, and other countries are suspected to have weaponized this agent. This organism could potentially be stabilized for weaponization by an adversary and theoretically produced in either a wet or dried form. It could then theoretically be delivered against U.S. forces in a similar fashion to the other bacteria discussed in this handbook.


CLINICAL FEATURES


After an incubation period varying from 1-21 days (average 3-5 days), presumably dependent upon the dose of organisms, onset is usually acute. Tularemia may appear in several forms in man depending upon the route of inoculation: ulceroglandular, glandular, typhoidal, oculoglandular, pharyngeal, and pneumonic tularemia. In humans, as few as 10 to 50 organisms will cause disease if inhaled or injected intradermally, whereas approximately 108 organisms are required with oral challenge.


Ulceroglandular tularemia (75-85 percent of cases) is most often acquired through inoculation of the skin or mucous membranes with blood or tissue fluids of infected animals. It is characterized by fever, chills, headache, and malaise, an ulcerated skin lesion and painful regional lymphadenopathy. The skin lesion is usually located on the fingers or hand.


Glandular tularemia (5-10 percent of cases) results in fever and tender lymphadenopathy but no skin ulcer.


Typhoidal tularemia accounts for 5-15 percent of naturally occurring cases and occurs mainly after inhalation of infectious aerosols, but can occur after intradermal or gastrointestinal challenge. It manifests as fever, prostration, and weight loss but without lymphadenopathy. Pneumonia may be associated with any form but is most common in typhoidal tularemia. Diagnosis of primary typhoidal tularemia is difficult, as signs and symptoms are non-specific and there frequently is no suggestive exposure history. Respiratory symptoms, substernal discomfort, and a non-productive cough may also be present. Radiologic evidence of pneumonia or mediastinal lymphadenopathy is most common with typhoidal disease but may or may not be present in all other forms of tularemia.


Oculoglandular tularemia (1-2 percent of cases) occurs after inoculation of the conjunctivae with infectious material. Patients have unilateral, painful, purulent conjunctivitis with preauricular or cervical lymphadenopathy. Chemosis, periorbital edema, and small nodular lesions or ulcerations of the palpebral conjunctiva are noted in some patients.


Oropharyngeal tularemia refers to primary ulceroglandular disease confined to the throat. It produces an acute exudative or membranous pharyngotonsillitis with cervical lymphadenopathy.


Pneumonic tularemia is an illness characterized primarily by pneumonia. Pneumonia is common in tularemia. It is seen in 30-80 percent of the typhoidal cases and in 10-15 percent of the ulceroglandular cases. The case fatality rate without treatment is approximately 5 percent for the ulceroglandular form and 35 percent for the typhoidal form. All ages are susceptible, and recovery is generally followed by permanent immunity.


DIAGNOSIS


Identification of organisms by staining ulcer fluids or sputum is generally not helpful. Routine culture is difficult, due to unusual growth requirements and/or overgrowth of commensal bacteria. Isolation represents a clear hazard to laboratory personnel and should only be attempted in BL-3 laboratory. The diagnosis can be established retrospectively serologically. A fourfold rise in the tularemia tube agglutination or microagglutination titer is diagnostic of infection. A single convalescent titer of 1:160 or greater is diagnostic of past or current infection. Titers are usually negative the first week of infection, positive the second week in 50-70 percent of cases and reach a maximum in 4-8 weeks.


MEDICAL MANAGEMENT


Standard Precautions are recommended for healthcare workers. Streptomycin (1 gm every 12 hours IM for 10-14 days) is the treatment of choice. Gentamicin 3-5 mg/kg/day divided TID parenterally for 10-14 days is also effective. Tetracycline and chloramphenicol treatment are effective as well, but are associated with significant relapse rates. Although laboratory related infections with this organism are very common, person-to-person spread is unusual and respiratory isolation is not required.


PROPHYLAXIS


Vaccine: A live, attenuated tularemia vaccine is available as an investigational new drug (IND). It is given by scarification. This vaccine has been administered to more than 5,000 persons without significant adverse reactions. This live vaccine strain (LVS) is of proven effectiveness in preventing laboratory acquired tularemia as well as in aerosol challenged human volunteers. LVS prevents typhoidal and ameliorates the ulceroglandular form of tularemia. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.


Antibiotics: Tetracycline 500 mg PO qid for two weeks is effective as prophylaxis when given after exposure.

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