Tularemia


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 agglutinateF. tularensis appear within 1 week of infection, but are most pronounced at 2 weeks.

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 daysor 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 orCiprofloxacin, 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 orCiprofloxacin, 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.


Patient Handouts

What is tularemia? 
Tularemia is a disease caused by the bacterium Francisella tularensis that infects both animals and people. Although infection occurs among many wild and domestic animals, the rabbit is most often involved in disease outbreaks. Tularemia is extremely rare in Anne Arundel County.

How does a person become infected with Tularemia? 
Hunters, hikers, or other people who spend a great deal of time outdoors and who may come in contact with wild animals and their carcasses or who may be bitten by infected ticks are at greater risk for exposure to this organism. Tularemia has been weaponized in state-sponsored bioweapons programs and could, theoretically, be released as a bioterrorism agent.

Can tularemia be spread person to person? How is tularemia spread? 
The common sources of exposure include inoculation of the skin or mucous membranes with blood or tissue while handling infected animals or meat from infected animals; being bitten by infected ticks or biting flies; and handling or eating insufficiently cooked rabbit meat. Less common means of spread include drinking contaminated water, inhaling dust from contaminated soil, or handling contaminated pelts or paws of animals. Human-to-human transmission has not been documented.

What are the symptoms of tularemia?
The symptoms of tularemia depend on whether the bacteria enter through the skin, gastrointestinal tract, lungs or eyes. Tularemia most often is recognized by the presence of a skin ulcer at the location where the bacteria entered the skin and by swollen glands. Ingestion of the organism may produce a throat infection, abdominal pain, diarrhea and vomiting. Inhalation of the organism may produce a pneumonia-like illness. If the organism infects the eyes, it can cause painful swelling of the lids, red eyes and visual pain.

How soon after infection do symptoms appear?
Symptoms can appear within 1 to 14 days, with most occurring within 3 to 5 days.

How is tularemia diagnosed?
Tularemia can be diagnosed by culturing the bacteria from blood, sputum or wounds; however, it can be difficult to grow. It also can be diagnosed with antibody testing.

What is the treatment for tularemia?
Certain antibiotics, such as streptomycin or gentamicin, are effective in treating tularemia.

Does past infection with tularemia make a person immune? 
Most persons who have been infected with this organism will become immune to re-infection; however, re-infection has been occasionally reported in laboratory workers.

How can tularemia be prevented? 
Rubber gloves, masks, and eye protection should be used when skinning or handling animal carcasses (especially rabbits). Wild rabbit and rodent meat should be cooked thoroughly before eating. Wells and other waters contaminated with dead animal carcasses should not be used. Insect repellants and long clothing should be used when walking through areas known to contain F. tularenis-infected deer flies and ticks.

Could tularemia be used for bioterrorism?
Yes. Tularemia is one of the agents that could be used for bioterrorism because it is highly infectious, would be easy to distribute, and would cause many people to become seriously ill or die. Release of tularemia as a bioterrorism agent would probably be in the form of an aerosol.

Additional information may be obtained from the Centers for Disease Control and Prevention at www.cdc.gov


Trainings/Powerpoint Presentations

The Bioterrorist Agents: Tularemia Presentation (2003) can be viewed as a PowerPoint or as a PDF

The BW Agents: Tularemia Presentation (2003) can be viewed as a PowerPoint or as a PDF


Additional Resources

Essential Reading

Dennis DT, Henderson DA, Inglesby TV, et al. Tularemia as a Biological Weapon: Medical and Public Health Management. JAMA 2001;285:2763-73.

Additional Readings

Centers for Disease Control and Prevention. Tularemia – United States, 1990-2000. Morbidity and Mortality Weekly Report. 2002;51(09);182-4.

Cross JT, Enderlin G, Jacobs RF, Morales L. Streptomycin and alternative agents for the treatment of tularemia: review of literature. Clin Infect Dis 1994;19(1):42-47. (Abstract available Pub Med)

Internet Resources

Centers for Disease Control and Prevention

Center for Infectious Disease Research and Policy of University of Minnesota

Tularemia Fact Sheet, MDH