Chapter 291. Tularemia

Tularemia is a highly infectious zoonotic disease caused by several subspecies of the gram- negative bacterium Francisella tularensis (eTable 291.1).

Francisella tularensis is a small, aerobic, nonmotile gram-negative bacterium first identified in 1911 by Dr. Edward Francis, after an outbreak of plaguelike disease in rodents in Tulare County, California. Infection has been reported in humans since 1914.2

In the United States, nearly all human cases of tularemia are caused by F tularensis subspecies tularensis (Type A, 66%) or F tularensis subspecies holarctica (Type B, 34%).3

Epidemiology and Pathophysiology

Mammals provide the primary reservoir for F tularensis, including ground squirrels, rabbits, hares, voles, muskrats, water rats, and other rodents.2 Human infection typically occurs after handling infected animals or after a bite from an arthropod vector.4 In the United States, biting flies and ticks are the primary arthropod vectors. In Europe and the former Soviet Union, ticks and mosquitoes have been reported to transmit infection.2 Infection can also occur after ingestion of contaminated food or water or after inhalation of the organism from decaying animal carcasses, contaminated straw, or other sources.4 There have been several large waterborne outbreaks of tularemia in Europe and the former Soviet Union.1 The largest airborne outbreak of tularemia was reported among farmers in Sweden in the 1960s, attributed to the aerosolization of organisms from rodent-infested hay.1 There has been no documented person-to-person transmission of tularemia.4

Infections with F tularensis are found only in the northern hemisphere. In the United States cases are reported from the eastern seaboard, Arkansas, Missouri, Oklahoma, and the central mountain regions. Other endemic areas include Eurasia, particularly the former Soviet Union, Japan, and the Scandinavian countries. Tularemia is not a World Health Organization (WHO) reportable disease. The incidence of disease is believed to have decreased significantly around the world in the past 50 years, largely attributed to the decrease in wild rabbits sold in markets and the introduction of clean water supplies.2

In the United States, 1939 marked the peak incidence of tularemia, with 2300 cases reported that year.4 In contrast, 142 cases were reported in the United States in 2000.4 Cases have been reported in all states except Hawaii, with over 50% of all cases are reported in Arkansas, Missouri, and Oklahoma.1,3

There have been two reported outbreaks of pneumonic tularemia in the United States, both occurring in Martha’s Vineyard (1978, 2000). The first outbreak was attributed to dogs, shaking and aerosolizing F tularensis after rolling in infected animal carcasses. The second was likely caused by brush cutting over infected animal carcasses, effectively aerosolizing the bacteria.7

The groups at highest risk include those who live in rural areas, farmers, hunters, forestry workers ,and laboratory workers.1 Over 70% of those infected are male, reflecting their greater participation in these higher risk activities.3 Human outbreaks tend to parallel outbreaks among wildlife reservoirs or surges in the wildlife populations.2 Most infections occur between May and September, corresponding to times of higher tick and other arthropod vector activity.3 Cases reported in the winter months usually occur in hunters and trappers who handle infected carcasses.

Clinical Manifestations

The clinical syndromes associated with F tularensis infection vary according to the site of entry. The incubation period, from exposure to initial disease manifestations, is typically 3 to 6 days but can range from 1 to 14 days depending on the size of the inoculum.1 Most patients report a prodromal period with the sudden onset of chills, fever (38–40°C), headache, and generalized aches.3 During this phase, bacteria are disseminated from the site of entry via the lymphatic system to regional lymph nodes and the bloodstream. During this brief bacteremic period, infection can spread to the spleen, liver, lungs, kidneys, skeletal system, or central nervous system.3

Ulceroglandular and glandular tularemia represent 65% of reported cases of tularemia, occurring more commonly in younger patients (median age 37 years and 11 years respectively).3 The patient with ulceroglandular tularemia typically has an ulcer at the site of bacterial entry and regional lymphadenopathy. Usually, patients are infected via the bite of an arthropod vector or cuts or abrasions on their hands when directly handling infected animal carcasses. A papule develops at the site of bacterial entry that becomes pustular and eventually ulcerates.3 These ulcers are tender and can persist for months without proper treatment. Regional lymph nodes begin to enlarge within several days after the ulcer develops (Fig. 291-1). Glandular tularemia occurs via the same disease process as ulceroglandular tularemia, but there is no ulcer noted.3 Glandular tularemia is reported more commonly in children, who often present with tender lymphadenopathy and no history of ulceration or other skin lesion. In some cases, the ulcer is not recognized before it heals spontaneously and patients present with lymphadenopathy alone.5 The regional lymphadenopathy in both ulceroglandular and glandular tularemia is very tender, with erythema of the overlying skin and eventual suppuration in some cases (see Fig. 291-2).5,6

Pneumonic tularemia is caused by the inhalation of as few as 10 F tularensis organisms. Tularemia is highly pathogenic when inhaled, requiring as few as 10 organisms to cause clinical disease. Patients most commonly present with a dry or slightly productive cough, retrosternal chest pain, and constitutional symptoms consistent with the tularemia prodrome described above,4,5 Patients may also have purulent sputum, hemoptysis, dyspnea, tachypnea, or pleuritic chest pain.5 but may also present with purulent sputum, hemoptysis, dyspnea, tachypnea, or pleuritic chest pain.5 Most commonly, there will be ill-defined infiltrates on chest radiographs, although hilar adenopathy and pleural effusions have also been reported.4 The difference in virulence between type A tularemia and type B is most pronounced in pneumonic tularemia. Type A infection leads to fulminant disease, whereas type B is much milder and frequently presents with only hilar adenopathy.7

The other clinical syndromes seen after tularemia infection are relatively rare. Typhoidal tularemia is tularemia sepsis without any localizing symptoms (most likely acquired through inhalation). It is most likely acquired through inhalation. Patients present with a flulike prodrome, progressing to mental status changes and shock.3 They may have prominent gastrointestinal symptoms (abdominal pain, diarrhea) or pulse-temperature dissociation.6 If untreated, typhoidal tularemia is fatal in 30% to 60% of cases.

Oculoglandular tularemia occurs when the conjunctiva are the initial site of infection, usually following the transfer of bacteria on a patient’s fingertips from infected tissue to the eye. Patients present with ulcers and nodules on the conjunctiva, with associated photophobia, chemosis, and vasculitis.3 Without treatment, infection spreads to the preauricular lymph nodes. Oropharyngeal tularemia occurs following ingestion of infected food or water and is also very rare. Patients present with a sore throat, tonsillar enlargement, and a yellow white pseudomembrane on physical examination.3 They may also have associated lymphadenopathy, which is typically unilateral. After ingestion of infected food or water, patients may also present with stomatitis alone, although this is very rare.1

Pneumonic disease is the most likely manifestation expected if tularemia were utilized as a biologic weapon and should be suspected in any outbreak of rapidly progressive respiratory disease that fails to respond to traditional therapy.1

Diagnosis

Routine laboratory evaluations are of limited usefulness in the diagnosis of tularemia. A complete blood count can be completely normal, or may have a slightly increased white blood cell count with increased mononuclear cells.6 Liver function tests and inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein are only slightly elevated.6

Definitive diagnosis of tularemia is complicated by its poor growth with routine laboratory culture and the exposure risk it presents to microbiology staff. The organism can be cultured from lymph node tissues, sputum samples, blood samples, pharyngeal washings, and fasting gastric aspirates (if inhalational), but the laboratory should be notified that tularemia is suspected so that workers may optimize recovery of this technically difficult organism and protect themselves from accidental inhalation. Cultures should be held for a minimum of 10 days to allow adequate time for colonies to appear on routine microbiology agars. Several specific assays, including pulse field gel electrophoresis for differentiating strains, polymerase-chain-reaction-based assays, immunohistochemical staining, and direct fluorescent antibody staining, are available only in select reference and research laboratories and are not routinely utilized.1

Diagnosis is usually made by documenting an antibody response to tularemia infection, which appears 10 to14 days after the onset of symptoms.2 The most commonly employed agglutination tests will detect combined immunoglobulin M and immunoglobulin G.6 Tube agglutination testing for tularemia is considered positive with a single titer greater than 1:160 or with a 4-fold increase in titers over the course of the illness. Microagglutination can also be used and is considered positive with a single titer greater than 1:128.6 Antibody titers can remain elevated for years following infection, although the degree of protection from reinfection this provides is unclear. It is important to note that antibody-based testing would not be useful during an outbreak of tularemia, given the delay in antibody production after onset of disease.

Other disorders that are included in the differential diagnosis of ulceroglandular tularemia include Staphylococcal or streptococcal skin infection, cutaneous anthrax, pasteurellosis, sporotrichosis and blastomycosis. Glandular disease must be differentiated from viral infections (CMV, HIV, EBV), atypical mycobacteria and lymphoma. Disorders including inhalational plague, anthrax, mycoplasma, C trachomatis, C Psittaci, Legionellosis, Q fever, hantavirus, brucellosis, toxoplasmosis, leptospirosis and SARS may present similarly to pulmonary tularemia. Typhoidal tularemia is similar to typhoid fever caused by salmonella (eTable 291.2).

Treatment

Gentamicin or streptomycin remain the drugs of choice for tularemia treatment.3 Both are bactericidal against F tularensis and have been used successfully for decades. Gentamicin is currently more widely available in the United States and is the most commonly used therapy for tularemia. Patients are most often treated with IV/IM gentamicin for 7 to 10 days with a relatively low rate of relapse if treatment is initiated in the first week of symptoms.3 There are studies underway to evaluate once-daily gentamicin regimens for tularemia, but there are currently no dosing guidelines for once-daily treatment. Gentamicin is also safe to use during pregnancy for the treatment of tularemia.

Tetracyclines and chloramphenicol are bacteristatic against F tularensis and have been used in the past for treatment, given the ease of oral dosing. These drugs have been associated with a high rate of treatment failure and relapse and are not recommended as first-line therapy for tularemia.3 Tetracyclines are sometimes used to complete therapy, after a short course of gentamicin, but are rarely used alone. If used, tetracyclines should be given for at least 10 to 14 days, as the relapse rate may be lower with prolonged treatment.3

Fluoroquinolones have been shown to have good in vitro activity against F tularensis¸ but their effectiveness against type A tularemia, which is seen more commonly in the United States, is unclear.4 Although they are not considered first-line therapy, they could be considered for patients who cannot tolerate gentamicin or tetracyclines. Most published studies report the successful use of ciprofloxacin in animal models and outbreak settings, with very little data available on the other fluoroquinolones.2,8 In an outbreak in Spain (type B), ciprofloxacin had a lower failure rate and fewer side effects than oral doxycycline.2 There have also been small reports published in the United States describing the successful use of oral ciprofloxacin in children.9F tularensis is resistant to β-lactam antibiotics, as well as most macrolides.2

Postexposure antibiotics are recommended for high-risk laboratory exposures or biologic attacks, but are not recommended for contacts of those infected with tularemia or those with lower risk exposures (tick bites, animal exposure, etc).6 For laboratory exposures or in a mass casualty situation, the current prophylactic and treatment regimen recommended by the Centers for Disease Control and Prevention (CDC) is oral doxycycline or ciprofloxacin.1

Ulceroglandular and glandular tularemia are rarely fatal, even without treatment. Early treatment (within 7 days of onset) is associated with a lower risk of complications and faster healing. If symptoms have been present for greater than 2 weeks before treatment is initiated, the risk of lymph node suppuration is much greater (30–40%).1 With delayed or no treatment, healing of the ulcer can be prolonged. Pneumonic tularemia has a mortality rate of 30% to 60% if untreated.6

Prevention

Patients hospitalized with tularemia require no isolation beyond standard precautions as person-to-person transmission has not been reported with tularemia. Laboratory personnel should be notified before any potential tularemia specimen is submitted for processing.6

There are currently no widely available vaccines against tularemia in the United States. In the United States, a live vaccine strain (LVS) vaccine has been successfully used in high risk laboratory workers since the 1960s, with a marked decreased in the incidence of typhoidal disease in this high-risk group but it is under review by the Food and Drug Administration (FDA) for general use as its efficacy and virulence potential have yet to be fully characterized.3

Water chlorination has virtually eliminated waterborne epidemics of tularemia in the United States.3 In endemic areas, the CDC recommends that people wear gloves or other protective equipment when handling dead animals and that insect bites be minimized. Landscapers and other such workers should also check the area thoroughly for any animal carcasses, as brush cutting can aerosolize the organism from decaying animal tissue.3 Tularemia has been studied for use as a biologic or bioterrorist weapon, so in an outbreak of pulmonary tularemia appropriate agencies should be notified.9