DISEASE

Francisella tularensis is a small pleomorphic, facultatively intracellular, Gram-negative coccobacillus, belonging to the class γ-Proteobacteria, order Thiotrichales, and family Francisellaceae. It is fastidious, usually requires cysteine for growth, and utilizes glucose as a carbon source, but is otherwise biochemically inert.

The organism is divided into four subspecies. Francisella tularensis ssp. tularensis (formerly Jellison type A) ferments glycerol, is highly virulent (particularly for laboratory rabbits), is found solely in North America, and is perhaps the most important in the context of disease. Francisella tularensis ssp. holarctica (formerly Jellison type B) is less virulent, but still an important cause of tularemia, and is found predominantly in Asia and Europe and only occasionally in North America. Francisella tularensis ssp. mediaasiatica has not been isolated from diseased humans and is found in Central Asia. Francisella tularensis ssp. novicida was previously F. novicida and is of low virulence for humans, with cases reported in the United States and Canada. Strains of F. tularensis ssp. tularensis cause the most severe disease in humans and rabbits, although all members of the species are highly mouse virulent. Francisella philomiragia is often found in water and causes disease only in the immunosuppressed.

Based on both 16S rDNA sequence comparisons and DNA–DNA hybridizations, F. tularensis has no close relatives, although the family Francisellaceae is relatively closely related to Piscirickettsia salmonis and ciliate and tick endosymbionts. The most closely related human pathogens (which are nonetheless distant) are Coxiella burnetii and Legionella spp., both of which have lifestyle similarities with F. tularensis.

Tularemia can take multiple clinical forms, depending on the portal of entry (Table 26-1). On the whole, it is plaguelike, and the infectious dose of highly virulent strains is astonishingly low, at only 10 to 50 colony-forming units. Most human cases result from arthropod bites (usually mosquitoes and ticks) previously fed on infected animals. If bacterial replication in skin at the point of entry causes formation of a distinct ulcer (Figure 26-1), the ensuing disease is called ulceroglandular tularemia. Organisms are transported from the ulcer to regional lymph nodes, where subsequent lesions resemble the buboes encountered in plague. Flulike signs appear after an incubation period of 3 to 5 days, with malaise, chills and fever, headache, sore throat, and myalgia; early misdiagnosis is common as a result of symptom nonspecificity. The organism may disseminate from the lymph node lesions to other sites throughout the body, including the lungs, in which case secondary pneumomic tularemia can result. Glandular tularemia is similar, but without an obvious route of entry. Glandular and ulceroglandular tularemia are the most common forms of the disease in humans. Hunters, trappers, and others in contact with infected animals or with arthropod vectors are the highest-risk groups, and infection is rarely fatal. Infection with low-virulence strains probably goes frequently undiagnosed.

TABLE 26-1 Clinical Syndromes Associated with Francisella tularensis Infection

FIGURE 26-1 Ulcer caused by Francisella tularensis on the hand.

(Courtesy Public Health Image Library, PHIL #2037, Centers for Disease Control and Prevention, Atlanta, 1963, P. Brachman.)

Primary pneumonic tularemia is rare, but is the most severe of all the forms of the disease. It follows inhalation of F. tularensis and is a much more serious form of the disease. The case fatality rate in untreated respiratory infection with F. tularensis ssp. tularensis is as high as 60%. Hilar lymph node enlargement, dry cough, pleural effusion, and retrosternal pain are common symptoms, although radiography may reveal interstitial infiltrates with minimal pulmonary symptoms.

Francisella tularensis infects more than 100 species of wild and domestic mammals, 25 species of birds, and even fish, amphibians, and reptiles. Lagomorphs and rodents are important reservoir hosts because they often develop fulminant disease when infected and are hosts for Ixodid ticks (genera Dermacentor, Ixodes, and Amblyomma), which are both reservoirs and vectors of disease. Francisella tularensis may be able to pass transovarially in ticks. Other biting or blood-sucking arthropods, including mosquitoes, may also be porters of infection. The role of arthropods in transmission of tularemia, and in particular the specific relationship between bacterium and arthropod, is poorly understood. Transmission of F. tularensis to predator species is simplified by the lethargy and sluggishness induced by the disease in its terminal phase.

Clinical disease in livestock is rare. Natural infection has occurred in captive nonhuman primates, including squirrel monkeys, black and red tamarins, talapoins, and a lowland gorilla, all with depression, anorexia, vomiting, diarrhea, lymphadenopathy, and petechial hemorrhage.

Dogs may be reservoirs for F. tularensis or maintenance hosts for tick vectors, but clinical illness is more common in cats. The infectious dose for cats is quite high in comparison with that for humans, but manifestations of tularemia in cats range from subclinical to mild lymphadenopathy with fever to fulminant, ultimately fatal disease. Signs can include anorexia, dehydration, listlessness, lingual or oral ulceration, lymphadenopathy, hepatomegaly, icterus, and pneumonia.

Gross lesions in cats include small multifocal necrotic foci throughout mandibular, cervical, mesenteric, and hilar lymph nodes, as well as liver, spleen, and lungs. Necrosis of cortical lymph node follicles and splenic white pulp is conspicuous. Submucosal lymphoid follicles in intestines are likewise affected, with ulceration of Peyer’s patches. Microscopic lesions manifest as focal or diffuse caseous necrosis surrounded by neutrophils, macrophages, and lymphocytes, in num bers varying with the stage of disease. Neither gross nor microscopic lesions are pathognomonic.

Natural infection in dogs is often associated with ingestion of wild rabbits, and is characterized by acute onset of anorexia, fever, lymphadenopathy, and necrotizing tonsillitis. Patients recover with supportive therapy. Experimental infections produce similar signs, and include fever, mucopurulent discharge from nose and eyes, and regional lymphadenopathy. Common seroconversion in dogs suggests that infection is equally common, and that illness is inapparent or mild.

Ovine tularemia can cause considerable morbidity and mortality, particularly in sheep in poor body condition, with poor nutritional status, and with heavy tick infestations. Affected sheep are pyrexic and anorexic, and have regional lymphadenopathy and diarrhea. Seroconversions suggest infection in cattle, but no definite clinical syndrome has been described. Infected mares and foals are febrile, dyspneic, depressed, tick infested, and lack coordination.