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 1800s and in Russia in
1926. In the early 1900s, 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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