Clinical Overview

Tularemia is a zoonosis caused by the Gram negative, facultative intracellular bacterium, nonmotile, obligately aerobic Francisella tularensis. In 1911, G. W. McCoy discovered the disease in Tulare County, California as a cause of a plague-like illness in ground squirrels. Edward Francis subsequently described transmission by deer flies via infected blood and coined the term tularemia in 1921. Tularemia occurs in North America, Europe, the Middle East, Russia and Japan. In the United States, the disease is most prevalent in Arkansas, Illinois, Missouri, Texas, Virginia and Tennessee, although cases have been reported from all states except Hawaii.

The principal reservoir of tularemia in North America is the tick and more than 10 species have been implicated. In North America, the rabbit is the most common vertebrate associated with transmission of tularemia.

The reported incidence in the United States since 1967 has been fewer than 200 cases per year.

F. tularensis is usually introduced into the host through breaks in the skin or through the mucous membranes of the eye, respiratory tract or gastrointestinal tract. Ten virulent organisms injected subcutaneously or 10 - 50 organisms given by aerosol can cause infection in humans.

F. tularensis has been considered an important biological warfare threat because of its very high infectivity after aerosolization.

Clinical Presentation

The disease is characterized by fever, localized skin or mucous membrane ulceration, regional lymphadenopathy and occasionally, pneumonia. Tularemia can be divided into the ulceroglandular (75 percent of patients) and the typhoidal (25 percent of patients) forms, based on the clinical signs. Patients with ulceroglandular tularemia have lesions on the skin or mucous membranes (including the conjunctiva), lymph nodes larger than 1 cm in diameter, or both. Patients with typhoidal tularemia, on the other hand, present with lymph nodes smaller than 1 cm in diameter and without skin or mucous membrane lesions. This simplified identification standard is suggested instead of the more complicated previous classification (i.e., ulceroglandular, glandular, oculoglandular, typhoidal), because it is more in keeping with the clinical, pathophysiological and prognostic aspects of the disease.

After an incubation period of 3 - 6 days, patients with the ulceroglandular form of the disease develop a constellation of symptoms consisting of fever, chills, headache, cough and myalgias. The fever is often accompanied by a pulse/temperature disassociation (i.e., the pulse increases less than 10 beats per min. per 1 degree F increase in temperature above normal). Patients may also complain of chest pain, vomiting, arthralgia, sore throat, abdominal pain, diarrhea, dysuria, back pain or stiff neck.

A cutaneous ulcer occurs in approximately 60 percent of patients and is the most common sign of tularemia. Ulcers are generally single lesions of 0.4 to 3.0 cm in diameter with heaped-up edges. Lesions associated with infection acquired from mammalian vectors are usually located on the upper extremities, whereas lesions associated with infection acquired from arthropod vectors are usually located on the lower extremities. Ulcerative lesions are almost always accompanied by regional lymphadenopathy.

Enlarged lymph nodes are seen in approximately 85 percent of patients, and may be the initial or the only sign of infection. Nodes are usually tender and 0.5 to 10 cm in diameter. Patients present with nonproductive or productive cough, and less commonly with pleuritic chest pain, shortness of breath or hemoptysis. Examination of the sputum is not helpful for making the diagnosis of tularemia pneumonia. Chest radiographs show that approximately 50 percent of patients have pneumonia, and 1 percent or fewer have hilar adenopathy without parenchymal involvement.

Approximately 30 percent of patients with ulceroglandular tularemia and 80 percent of patients with typhoidal tularemia have pneumonia. The higher incidence of pneumonia in patients with typhoidal tularemia probably accounts for the higher mortality associated with this form of the disease. Infrequent clinical syndromes associated with tularemia include pericarditis, enteritis, appendicitis, peritonitis, erythema nodosum and meningitis.

Patients usually do not have abnormalities in the hematocrit, hemoglobin or platelet levels. The peripheral white blood cell count may range between 5,000 and 22,000 cells per microliter, but it is usually only mildly elevated. Differential blood cell counts are usually normal, although patients may have a lymphocytosis late in the disease.

Diagnosis

Tularemia can be diagnosed by recovery of F. tularensis in culture or from serologic evidence of infection in a patient with a compatible clinical syndrome. Although the organism is difficult to culture, it can be recovered from blood, ulcers, conjunctival exudates, sputum, gastric washings and pharyngeal exudates. Recovery may be possible even after the institution of appropriate antibiotic therapy.

Most diagnoses of tularemia are made serologically using enzyme-linked immunosorbent assay (ELISA). Measurable levels of antibodies that agglutinate F. tularensis appear within 1 week of infection, but are most pronounced at 2weeks.

Treatment

Patients with tularemia who do not receive appropriate antibiotic treatment may have a prolonged illness characterized by malaise, weakness, weight loss and other symptoms that last for months. Before the availability of effective antibiotics, ulceroglandular and typhoidal tularemia had mortalities of approximately 4 percent and 35 percent respectively. With appropriate treatment, tularemia has an overall mortality of approximately 1 percent to 2.5 percent.

Streptomycin is the drug of choice for the treatment of tularemia. The drug is bactericidal and patients treated with streptomycin usually respond within 48 hours of its administration. Relapses are uncommon and resistance has not been reported. Bacteriostatic drugs such as chloramphenicol and tetracycline are often efficacious, but relapses occur if the drug is given too early in the course of the disease or if is not continued long enough. To date, there is only limited clinical experience with erythromycin and the fluoroquinolones.

Current treatment recommendations are as follows:

Adults: preferred choices are Streptomycin, 1 gm IM twice daily for 10 days or Gentamicin, 5 mg/km IM or IV once daily for 10 days.

Adults: alternative choices are Doxycycline, 100 mg IV twice daily for 14-21 days or Chloramphenicol, 15 mg/kg IV 4 times daily for 14-21 days or Ciprofloxacin, 400 mg IV twice daily for 10 days.

Children: preferred choices are Streptomycin, 15 mg/kg IM twice daily (maximum daily dose, 2 gm) for 10 days or Gentamicin, 2.5 mg/kg IM or IV 3 times daily for 10 days.

Children: alternative choices are Doxycycline, >45 kg, give adult dosage for 14-21 days <45 kg, give 2.2 mg/kg IV twice daily for 14 - 21 days or Ciprofloxacin, 15 mg/kg IV twice daily for 10 days (maximum daily dose, 1 gm) or Chloramphenicol, 15 mg/kg IV 4 times daily for 14 - 21 days (maximum daily dose, 4 gm).

Recommendations for Mass postexposure prophylaxis are as follows:

Adults (including pregnant women): Doxycycline, 100 mg PO twice daily for 14 days or Ciprofloxacin, 500 mg PO twice daily for 14 days.

Children: Doxycycline >45 kg: adult dosage <45 kg: 2.2 mg/kg PO twice daily for 14 days or Ciprofloxacin, 15 mg/kg PO twice daily for 14 days (maximum daily dose, 1 gm).

Transmissibility and Infection Control

A live attenuated vaccine was used in the United States until recently to protect laboratory workers at high risk for F. tularensis exposure. The vaccine currently is not available and is under review by the US Food and Drug Administration. Because the incubation period for tularemia is usually 3 - 5 days and immunity following vaccination takes about 2 weeks to develop, postexposure vaccination is not considered a viable public health strategy to prevent disease in the event of a mass exposure.

Person-to-person transmission of tularemia has not been documented; therefore, standard precautions are considered adequate for patients with tularemia. Standard precautions include the following practices related to direct patient care: hand washing, gloves, masks, eye protection, face shields and gowns. Commercially available bleach or a 1:10 dilution of household bleach and water is considered adequate for cleaning contaminated surfaces.

The risk of environmental contamination following an intentional release of F. tularensis is expected to be minimal and no special environmental decontamination procedures are recommended.

As with any bioterrorism agent, a case or suspected case of plague in someone living or working in the County should be immediately reported by phone to the Anne Arundel County Department of Health at 410-222-7256. To report communicable diseases, click here for instructions.