Tularemia

Geographic Distribution and Magnitude of Disease Burden

Tularemia, also known as rabbit fever or deer fly fever , is a zoonosis caused by a highly infectious, aerobic, gram-negative coccobacillus, F. tularensis . The natural reservoir for F. tularensis is small mammals such as rodents or rabbits. The bacterium is found throughout host animals in most of North America and Eurasia. In the United States, tularemia is most commonly caused by two subspecies of F. tularensis: F. tularensis subsp. tularensis (type A, which is subdivided into subtypes A1a, A1b, and A2), and F. tularensis subsp. holarctica (type B). In Europe and Eurasia, F. tularensis subsp. holarctica is the primary cause of tularemia. Human tularemia was first described in the United States in 1910 as “deer fly fever,” and the causative agent (at that time known as Bacterium tularense ) was identified after an outbreak of a plague-like illness of ground squirrels in Tulare County, California in 1911. In 1924, a United States Public Health Service physician, Edward Francis, identified B. tularense as the cause of human deer fly fever. To honor his contributions to the understanding of this organism, the bacterium was subsequently renamed F. tularensis .

In the United States, human tularemia is rare but has been documented in every state except Hawaii. Tularemia was much more common in the early part of the 20th century than it is now ( Fig. 91.1 ). Since 2000, most cases of tularemia have been reported from rural areas of the United States where infection of host animals is common (or enzootic), such as Arkansas, Kansas, Nebraska, and Missouri. In addition, many cases are reported from Martha’s Vineyard, Massachusetts, where hunting clubs imported infected rabbits from enzootic areas in the 1920s and 1930s ( Fig. 91.2 ). In 2018, the Centers for Disease Control and Prevention (CDC) received 229 reports of human tularemia, and from the years 2008 to 2018 there have been approximately 205 infections reported per year. Although the global incidence of tularemia has decreased markedly over the past 50 years, periodic outbreaks continue to occur, especially in Northern Europe and Eurasia. These outbreaks have been associated with drinking spring water, hunting, and other outdoor activities, and some have involved hundreds of cases of tularemia. Although rare in humans, tularemia occurs in a wide variety of animals and is maintained in an enzootic cycle with rodents and lagomorphs. Other animals, such as cats and nonhuman primates, may serve as incidental hosts. Outbreaks, or epizootics, of tularemia periodically occur in animal populations and may herald outbreaks of human disease.

Risk Factors

The animals most commonly associated with transmission of tularemia to humans in the United States include lagomorphs (rabbits and hares) and rodents (voles, squirrels, muskrats, and beavers). Although animals are the primary reservoir of F. tularensis , the infection can also be transmitted by insect bites (especially those of ticks or deer flies) or by contact with bacteria in the environment. Francisella tularemia tularensis is a hardy organism that can survive for extended periods in water, mud, and frozen animal carcasses. Tularemia has been reported after skin or mucous membrane contact with contaminated animals or their environment, ingestion of contaminated food or water, and inhalation of aerosolized bacteria ( Fig. 91.3 ). Activities associated with risk of tularemia include hunting, trapping, dressing, eating, or handling infected animals; activities that result in exposure to infected insects; farming or gardening with machinery that may aerosolize the carcasses of infected animals; and handling F. tularensis in a laboratory without appropriate personal protective equipment. Although inhalational tularemia does occur, the bacteria are not known to spread from person to person.

During and after World War II, several countries (including Japan, the former Soviet Union, and the United States) conducted research on the use of F. tularensis as a biologic weapon. More recently, most countries have suspended their biologic weapons research and destroyed their weapon stockpiles. However, as a highly infectious bacteria that can be easily mass-produced and aerosolized, with the potential to cause severe or fatal illness, F. tularensis continues to be designated a Category A Bioterrorism Agent by the CDC.

Recent CDC analyses of laboratory-documented human tularemia reported in the United States from 1964 through 2004 found that infections tend to be acquired during the warmer months (72% occurred from May through September) and are geographically diverse (type A1 infections cluster toward the eastern United States, type A2 infections occur toward the west, and type B is primarily clustered through the southern and central western areas of the country). Men constitute the majority of infections (74%), and younger age appears to be a risk for infections with type A, compared with type B (median age 38 vs. 50 years) ( Fig. 91.4 ). Overall, 6% of infections occurred among persons with an immunocompromising condition (e.g., malignancy, organ transplant, or human immunodeficiency virus [HIV] infection). A source of infection was reported for 42% of the cases, and in this subgroup, direct animal contact accounted for about half of all infections (47% of type A and 53% of type B). Among persons with infection associated with animal contact, 53% of type A infections were attributed to lagomorphs and 30% to cats. No persons with type B infection reported lagomorph contact; those infections were linked to either rodents (33%) or cats (22%). Tularemia attributed to insects accounted for 44% of type A infections and 29% of type B infections; among infections resulting from insect bites, tick exposure (87%) was reported more commonly than contact with deer flies. A small proportion of types A (8%) and B (18%) infections were associated with multiple exposures or landscaping activities.

Clinical Features

The clinical presentation and severity of tularemia vary according to the anatomical portal of entry, the virulence of the F. tularensis strain involved, and the size of the bacterial inoculum; as few as 10 bacteria can cause human disease. The incubation period for tularemia is typically 3 to 5 days (range, 1 to 14 days). The clinical spectrum of tularemia is quite variable, ranging from localized infection to life-threatening systemic illness; forms include ulceroglandular, glandular, pneumonic, typhoidal, oculoglandular, pharyngeal, and septic syndromes ( Fig. 91.5 ). After entry of F. tularensis via skin or mucous membranes, the bacteria disseminate to local lymph nodes and subsequently spread via the bloodstream to additional lymph nodes and organs, primarily the spleen, liver, kidney, lungs, and pleura. Regardless of the form of infection, untreated tularemia may become chronic, with fever, malaise, weight loss, and adenopathy lasting months.

Tularemia most commonly manifests as ulceroglandular or glandular disease (about 60% to 80% of infections) that follows entry of the bacteria into disrupted skin from contact with an infected animal or via the bite of an infected insect. A papule appears at the site of inoculation and, similar to other presentations of tularemia, the skin lesion is usually accompanied by the abrupt onset of symptoms of a systemic disease: chills, fever, headache, malaise, and myalgias. The skin lesion becomes pustular and tender with local lymphadenopathy, then ulcerates and may develop an eschar; the involved lymph nodes may become fluctuant and suppurate. In glandular tularemia, a less common form, a skin or mucosal lesion is not apparent.

About 15% of naturally infected persons have pneumonic tularemia, which may result from inhalation of bacteria or by hematogenous spread from another site. The occurrence of atypical infections, either in terms of clinical presentation or geographic location, and temporal clusters of pneumonic tularemia might indicate an act of deliberate infections. Typical signs and symptoms are similar to those of community-acquired pneumonia including fever, cough, and dyspnea. In early pneumonic tularemia, chest radiographic imaging may show nonspecific changes consistent with pneumonia such as diffuse peribronchial infiltrates that progress to patchy or lobar involvement with pleural effusions and perihilar lymphadenopathy. However, many patients demonstrate systemic findings alone and lack significant pulmonary involvement. In one study in which volunteers were intentionally exposed to aerosolized tularemia, up to 75% had no pulmonary signs or symptoms at the onset of illness. However, more serious complications can occur following pneumonic tularemia such as septic shock, acute respiratory distress syndrome, respiratory failure, and death. Less common presentations of tularemia include typhoidal (a systemic illness that does not involve specific organs or lymph nodes and lacks an obvious site of inoculation), oculoglandular (inoculation of the conjunctiva with mucosal ulceration and local lymphadenopathy), and oropharyngeal (ingestion of bacteria followed by oropharyngeal mucosal ulceration and local lymphadenopathy). Although rare, sepsis is the most serious form of tularemia, a systemic illness that may rapidly progress to shock, multisystem organ failure, and death.

Laboratory findings in tularemia are nonspecific and may include mild leukocytosis with normal differential hemoglobin and platelet counts are typically normal, the nonspecific markers of inflammation erythrocyte sedimentation rate and C-reactive protein are elevated, as well as abnormalities associated with multiorgan dysfunction, including elevated serum aminotransferases and creatine kinase.