Tularemia (Francisella tularensis)

Etiology

Francisella tularensis is a small, nonmotile, pleomorphic, catalase-positive gram-negative coccobacillus. It can be classified into 4 main subspecies: Francisella tularensis subsp. tularensis (type A), F. tularensis subsp. holarctica (type B), F. tularensis subsp. mediasiatica , and F. tularensis subsp. novicida . Type A can be further subdivided into 4 distinct genotypes designated A1a, A1b, A2a, and A2b, with A1b appearing to produce more serious disease in humans. Although all subspecies of F. tularensis can cause human infections, types A and B are most common and type A is the most virulent. F. tularensis is an intracellular organism than can infect a number of host cell types, including macrophages, hepatocytes, and epithelial cells. It is one of the most virulent bacterial pathogens known, with as few as 10 microorganisms causing infections in humans and animals.

Epidemiology

Tularemia is primarily found in the Northern hemisphere. Type A is found predominantly in North America, whereas type B is found throughout the Northern hemisphere, including North America, Europe, and Asia. Human infections with type B are usually milder and have lower mortality rates compared to infections with type A. F. tularensis subsp. mediasiatica appears to be restricted to central Asia, whereas F. tularensis subsp. novicida has been isolated in North America, Australia, and Southeast Asia.

According to the Centers for Disease Control and Prevention (CDC), the number of annual reported cases of tularemia in the United States from 2005 to 2015 ranged from 93 to 315 per year. In 2015 the number of cases reported in the United States was the highest it had been over the past 50 years. Tularemia occurs all over the Unites States, with the majority of cases reported from central states ( Fig. 233.1 ). The overall U.S. incidence of tularemia in 2015 was 0.10 per 100,000 residents; Wyoming (3.58/100,000), South Dakota (2.91/100,000), Nebraska (1.32/100,000), Kansas (1.17/100,000), and Colorado (0.95/100,000) were states with the highest incidence.

Although cases of tularemia occur all year, most cases and outbreaks occur in warm, summer months (May-August). Tularemia is more common in males, and there is a bimodal distribution based on age, with peaks in childhood (5-9 yr) and later adulthood (65-69 yr), potentially because of greater opportunities for environmental and animal exposures at these ages. Fig. 233.2 shows the distribution of tularemia by age and gender from 2001 to 2010 in the United States.

Pathogenesis

Of all the zoonotic diseases, tularemia is unusual because of the different modes of transmission of disease. A large number of animals serve as a reservoir for this organism. In the United States, rabbits and ticks are the principal reservoirs. Dogs may be an intermediate vector. In the United States, Amblyomma americanum (lone star tick), Dermacentor variabilis (dog tick), and Dermacentor andersoni (wood tick) are the most common tick vectors. These ticks usually feed on infected small rodents and later feed on humans. Deer flies ( Chrysops spp.) can also transmit tularemia and are present in the western United States. F. tularensis subsp. tularensis is carried by rabbits, ticks, and tabanid flies (e.g., deer flies), whereas subsp. holarctica is associated with aquatic habitats and transmitted primarily by mosquitoes, but also aquatic rodents (beavers, muskrats), hares, voles, ticks, tabanid flies, and ingestion of contaminated water (e.g., ponds, rivers).

The organism can penetrate both intact skin and mucous membranes (eyes, mouth, gastrointestinal [GI] tract, or lungs). Transmission can occur through the bite of infected ticks or other biting insects, by contact with infected animals or their carcasses, by consumption of contaminated foods or water, or through inhalation, as might occur in a laboratory setting or if a machine (e.g., lawn mower) runs over infected animal carcasses. However, this organism is not transmitted from person to person. The most common portal of entry for human infection is through the skin or mucous membrane. Hunting or skinning infected wild rodents, such as rabbits or prairie dogs, has been the source of infection in numerous reports. Domesticated animals such as cats and hamsters can also transmit tularemia.

Usually >10 ⁸ organisms are required to produce infection if F. tularensis bacteria are ingested, but as few as 10 organisms may cause disease if they are inhaled or injected into the skin (i.e., insect bite). Infection with F. tularensis stimulates the host to produce antibodies, which have only recently been recognized as important in the immune response to this organism. The F. tularensis envelope is largely responsible for virulence and plays major roles in the ability of the organism to evade the immune system, attach to and invade cells, and cause severe disease. The body is most dependent on cell-mediated immunity to contain and eradicate F. tularensis . Tularemia is usually followed by specific protection; thus chronic infection or reinfection is unlikely.