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TULAREMIA

Agent: As a naturally occurring plague-like disease ("rabbit fever") of temperate areas of North America and Eurasia, tularemia is a bacterial zoonosis (disease transmitted from animals to humans) caused by the Gram-negative coccobacillus, Francisella tularensis. F. tularensis is highly infectious, requiring an inoculum of 10 or fewer organisms; and remains viable in the environment for weeks in cool weather (Cieslak & Eitzen, 2000; Johns Hopkins University, 2000). There are two strains of F. tularensis, with type A being the most virulent and likely to be weaponized. It is probable that the Soviet Union produced strains that are resistant to antibiotics and vaccines and there is no reason to think that these remain only in Russian laboratories (Dennis, Inglesby, Henderson, Bartlett, Ascher, Eitzen, Fine, Friedlander, Hauer, Layton, Lillibridge, McDade, Osterhoim, O'Toole, Parker, Pen, Russell, & Tonat, 2001). The release of 50 kilograms of F. tularensis as an aerosol under ideal conditions over a city of five million people would result in an estimated 250,000 incapacitating casualties, including 19,000 deaths (World Health Organization [WHO], 1970).

Routes of Infection: Weaponized tularemia can be delivered by aerosol and infection may be through inhalation of the aerosol or exposure (skin, mucous membranes, respiratory tract, or gastrointestinal tract) to contaminated soil, water, food, or animals. Laboratory personnel are at risk if handling dishes or containers with specimens of F tularensis. Transmission from person to person is not known to occur.

Incubation: The usual incubation period is 3-5 days with a range of 1-14 days depending on virulence of the infecting strain, size of inoculum, and site of inoculum (Chin, 2000; Dennis et al, 2001).

CLINICAL FINDINGS & TREATMENT

Signs & Symptoms: Presentation of tularemia is related to the route of introduction and the virulence of the agent. Inhalation is the most likely initial route in BW, but with a major epidemic, other routes would emerge over time. Initial presentation with inhalation is usually the abrupt onset of an acute febrile illness progressing most significantly to pneumonia; but also to pharyngitis, bronchiolitis, pneumonitis, pleural effusion, and hilar lymphadenopathy (all discussed in greater detail immediately below). Inhalation also commonly produces a primary septicemic syndrome without significant respiratory signs or symptoms and with a high case fatality rate (Chin, 2000; Dennis et al, 2001, Dennis, 2000).

Constitutional symptoms of tularemia include abrupt onset of fever, headache, chills, rigors, rhinitis, sore throat, generalized body aches, and low back pain. A dry cough, substernal pain, and chest tightness are common. There may or may not be common signs of pneumonia such as purulent sputum, hemoptysis, dyspnea, pleuritic, pain, or tachypnea. Gastrointestinal disturbances such as nausea, vomiting, and/or diarrhea may occur. If untreated, constitutional symptoms progress and include malaise, anorexia, weight loss, and debility. (Dennis et al, 2001). The most likely clinical presentations of BW tularemia are summarized below (1-3), followed by presentation of naturally occurring tularemia:

  1. Typhoidal tularemia is a systemic illness without signs of inoculation or organ localization; and presenting with fever, nausea, vomiting, abdominal pain, and diarrhea.
  2. Septic tularemia is a systemic illness initially presenting similarly to typhoidal, and characterized by fever and a systemic inflammatory response, which may include disseminated intravascular coagulation with bleeding, acute respiratory distress syndrome, multi-organ failure, confusion, coma, and shock.
  3. Pneumonic tularemia may occur from inhalation or hematogenous spread from a primary site. Manifestations include pharyngitis, bronchiolitis, pneumonitis, pleural effusion, hilar lymphadenopathy, and systemic illness. As previously noted, inhalation also commonly causes systemic illness without signs of respiratory illness. Radiographic evidence may be absent in the early stages of pneumonic constitutional illness; and some patients will have minimal or no evidence at any stage. Positive findings include peribronchial infiltrates, bronchopneumonia, pleural effusion, and hilar lymphadenopathy. Pneumonia may become severe leading to respiratory failure and death.
  4. Oropharyngeal tularemia results from ingesting contaminated food or water and is characterized by exudative pharyngitis, tonsillitis, and sometimes ulceration of the oropharynx and cervical or retro-pharyngeal lymphadenopathy.
  5. Ulceroglandular tularemia results from direct inoculation (e.g., vector bite or handling infected material) and is characterized by constitutional symptoms followed by a papule at the inoculation site. The papule becomes pustular and ulcerates and is associated with regional lymphadenitis. Oculoglandular tularemia occurs when the eye is contaminated.
  6. Glandular tularemia usually is a result of an infected insect bite and is similar to ulceroglandular except there is not a skin ulcer.

Diagnosis: Suspicion of attack with tularemia should be aroused by an outbreak of clustered acute undifferentiated febrile illness with atypical pneumonia, pleuritis, and hilar lymphadenopathy. The development of similar illness among laboratory personnel should arouse strong suspicion. Definitive diagnosis is confounded by a lack of widely available means of rapid testing. F tularensis grows slowly (e.g., 14 days) in the laboratory where clinical diagnosis is confirmed by culture. Rapid diagnostic procedures are available through the National Public Health Laboratory Network. Some research or reference laboratories are able to perform antigen detection assays, polymerase chain reaction, immunoblotting, and other specialized techniques (Chin, 2000; Dennis et al, 2001).

Differential Diagnosis: The primary differentials in an outbreak are plague, anthrax, legionellosis, Q fever, typhoid, and brucellosis. Numerous differentials exist for individual cases (Dennis, 2000).

Treatment: Duration of treatment varies as shown below.

Mass casualties or post-exposure (All regimens are for 14 days):
Adults: Doxycycline 100 mg po every 12 hours OR ciprofloxacin 500 mg po every 12 hours (the latter is not USDA approved).
Children: If 45 kg or larger, give doxycycline 100 mg po every 12 hours and if <45 kg, give doxycycline 2.2 mg/kg po every 12 hours OR ciprofloxacin 15 mg/kg po every 12 hours (no more than one gm/24 hours). Human-to-human transmission is unknown, hence exposure to an infected person does not warrant treatment.

Contained casualties:
Adults: Streptomycin one g IM every 12 hours for 10 days. Gentamicin is an alternative, and is given 5 mg/kg/24 hours IM or IV once daily for 10 days.
Children: Streptomycin 15 mg/kg IM every 12 hours (up to 2 g/24 hours) or gentamicin 2.5 mg/kg IM or IV every 8 hours (not USDA approved) for 10 days. Other choices are IV doxycycline, IV chloramphenicol, or IV ciprofloxacin for 14-21 days (Dennis et al, 2001).
In an outbreak, antimicrobial susceptibility should begin immediately in a biological safety level (BSL) 3 laboratory (state health department) to determine if drug-resistant strains of tularemia are being used.

Protection: Isolation of persons with tularemia is not necessary. Standard precautions should be used by hospital and other personnel in contact with patients. Laboratory procedures should be conducted in BSL 2 conditions. Bodies should be handled using standard precautions. Contaminated clothing or linens should be disinfected using standard procedures (Dennis et al, 2001).

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