Francisella tularensis (Tularemia)

Description of Pathogen and Epidemiology

Francisella tularensis, the etiologic agent of tularemia, is a small, fastidious, non−spore-forming, strictly aerobic gram-negative coccobacillus, which is nonmotile and nonpiliated and has a thin capsule composed mostly of lipid. Tularemia is a zoonotic disease; in addition to humans, who are accidental hosts, >100 animal species are affected, particularly ground squirrels, rabbits, hares, voles, prairie dogs, and muskrats. ^, The bacteria is most frequently transmitted by ticks and biting flies, but infections can be transmitted by direct contact with rabbits or other infected animals or their aerosols, especially related to skinning, dressing, or mowing over infected animals. Domestic animals, especially cats but also dogs, sheep, and hamsters, occasionally have been implicated. ^{, ,} Infections also can be transmitted through contaminated food or water (possibly facilitated by the organism’s survival within amoebas) and by mosquitoes in certain regions of Europe. ^{, ,} Person-to-person transmission of F. tularensis has occurred through transplant of infected organs ; person-to-person spread through contact with infected ulcers was reported rarely in the early 20th century but is not an important mode of transmission. There is potential for the use of F. tularensis as a biologic weapon by the intentional release of organisms, and F. tularensis is classified as a Tier 1 select biologic threat agent by the Centers for Disease Control and Prevention (CDC). ^,

Human disease is due primarily to two subspecies: F. tularensis subsp. tularensis (type A) and F. tularensis subsp. holarctica (type B), both found primarily in the Northern Hemisphere. ^{, ,} Type A strains are more virulent than type B strains and are found almost exclusively in North America, with subclades A1a and A1b predominating in the eastern half of the US, California, and Oregon, and subclade A2 in the western US. Type B strains are found throughout the northern hemisphere but including in Europe and Asia. Cottontail rabbits, three species of ticks— Amblyomma americanum (lone star tick), Dermacentor andersoni (wood tick), and Dermacentor variabilis (dog tick)—and biting flies are the main source of the type A subspecies. In the US, most cases occur from May through September, correlating with increased tick activity and outdoor exposures. Approximately 100–200 cases of tularemia are reported annually. From 2001 to 2010, 1208 cases of tularemia were reported to the CDC from 47 states; the highest numbers of cases were in the contiguous states of Missouri, Arkansas, and Oklahoma. Children aged 5–9 years and men aged >55 years had the highest annual incidence.

Subspecies B is less virulent and can result in self-limited or subclinical infection; however, it has caused severe illness and even death. Subspecies B undergoes a waterborne cycle predominantly, with aquatic rodents such as muskrats, beavers, and ground voles as reservoirs. Transmission occurs through these rodents and, in Europe, mosquitoes. Subspecies B has a worldwide distribution in the northern hemisphere between latitudes 30°N and 71°N, which includes the continents of Europe, Asia, and North America.

Pathogenesis and Immunity

The portal of entry is most commonly the skin through a wound or from the bite of a tick or fly, but entry also can occur through the conjunctivae, respiratory tract through aerosols, or oropharynx. ^, F. tularensis is highly transmissible; an inoculum size as small as 10 organisms through the skin is sufficient to induce tularemia in experimental infection of humans. Regardless of the route of inoculation, bacteria usually invade regional lymph nodes and are disseminated to other organs through bacteremia.

F. tularensis is a facultative intracellular pathogen that survives and multiplies within macrophages. Infection generally results in humoral and cellular immune responses and protection against reinfection. Protection chiefly is mediated by a cellular immune process in which bacteria are killed by macrophages activated by specifically committed T lymphocytes, but humoral immunity also has been demonstrated to contribute to immunity. Protective immunity develops approximately 2 weeks after infection and is long lasting.

Clinical Manifestations

Important clues to the diagnosis of tularemia are a history of a tick or fly bite, exposure to live or dead rabbits or squirrels (or other wild or domestic animals, including other rodents), mowing or landscaping activities, or consumption of poorly cooked game meat. Clinical manifestations appear after an incubation period of 2–10 days (ranging up to 21 days). The most common clinical syndromes include lymphadenopathy and are termed ulceroglandular and glandular tularemia, which account for 80% of reported cases. Other clinical syndromes include oropharyngeal, oculoglandular, typhoidal, and pneumonic ( Table 171.1 ). Regional lymphadenopathy, fever, and malaise are the most commonly reported symptoms in children with tularemia. ^,

Glandular and Ulceroglandular

Ulceroglandular disease manifests as swollen, tender lymph nodes in the inguinal, cervical, or axillary regions, usually from the bite of a bloodsucking arthropod. Lymphadenopathy in the inguinal region develops more frequently in patients with tick-associated infection than in those with rabbit-associated infection. Multiple enlarged lymph nodes can occasionally be observed. Lymphadenopathy can be accompanied by systemic symptoms and typically is preceded by a swollen papule or, at times, a vesicle distal to the involved lymph nodes that can evolve into an ulcer with raised edges. In young children, the disease more commonly manifests as lymphadenopathy without an ulcer. Ulcers on the upper extremities usually result from exposure to infected mammals and occur in hunters and ranchers. Ulcerated lesions can persist for weeks if untreated.

Approximately half of children with tularemia present with glandular or ulceroglandular disease. ^, Children are less likely to present with ulceroglandular disease than adults; however, this may be due to the increased likelihood of children receiving a tick bite in the head, neck, and inguinal regions where an ulceration may be overlooked ( Fig. 171.1 ) .

Oculoglandular

Oculoglandular disease results from conjunctival infection, usually acquired from contaminated fingers. A review of tularemia patients in Missouri from 2000 to 2007 found that younger patients more commonly presented with oculoglandular tularemia than older patients. Multiple, small, well-demarcated nodules can be seen on the conjunctiva in association with inflammation and edema. Pain is a major symptom, causing the patient to seek medical care early in the course of the infection and sometimes before the development of preauricular lymphadenopathy. The associated enlarged preauricular lymph node is painful, a feature unique to oculoglandular infection due to F. tularensis and coccidioides, which distinguishes it from the oculoglandular syndrome of cat-scratch disease, sporotrichosis, tuberculosis, and syphilis.

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