Zoonosis: Tularemia

In May 1981, a New Mexico man found his pet cat eating a dead rabbit. While removing the cat and rabbit from the house, the owner was bitten on the hand by his cat. Three days later, the cat became anorectic and listless. When examined the same day by a veterinarian, the cat had a rectal temperature of 40.6 C (105.1 F), but other abnormalities were not detected. No treatment was prescribed for the cat at this time.(1)

Four days later, the cat owner developed fever, chills, muscle aches, chest pain, and began coughing and vomiting. When examined by his physician 4 days later, he had a body temperature 39.4 C (102.9 F), and skin lesions resembling insect bites were noticed on several areas of his body. His total WBC count was normal with a left shift, and thoracic radiography revealed a left basilar infiltrate. Tularemia was suspected, and treatment with streptomycin was initiated. The cat's owner improved in 48 hours, and treatment was discontinued after 9 days.

The cat owner's antibody titer to Francisella tularensis increased from < 1:20 to greater than or equal to 1:640 in 2 weeks. When reexamined by the veterinarian one week after the initial examination, the cat appeared healthy, and a serum specimen obtained at that time had an F tularensis antibody titer of greater than or equal to 1:160.

When the cat's owner learned that he and his cat were infected with the same bacterium, he asked his veterinarian the following questions:

A: Francisella tularensis is a small, pleomorphic, heat-labile, gram-negative, rod-shaped bacterium. All isolates are antigenically similar, but they are differentiated epidemiologically and biochemically into type A and B strains. Type A organisms, in contrast to Type B organisms, are more virulent for rabbits and human beings, possess a citrulline ureidase system, and are able to use glycerol.(2,3)

Francisella tularensis may survive 3 to 4 months in mud, water, or decaying carcasses.(4) Heating cultures to 55 to 60 C for 10 minutes will kill the bacterium. Tricresol (1%), formalin (0.1%), and chlorine (1.0 ppm) will inactivate the bacterium.

A: Francisella tularensis has a worldwide distribution affecting more than 100 species of wild and domestic mammals, birds, fish, and reptiles. The type A strain, Francisella tularensis var tularensis, is found only in North America, is associated with tick-borne tularemia in rabbits, and produces classic disease in human beings. It is the most frequently isolated strain in the United States, accounting for approximately 70% of human cases, and it has a case fatality rate of 5 to 7%.(5) The type B strain, Francisella tularensis var palaearctica, is found throughout the world, except in Australia and Antarctica, and is associated with lower virulence for human beings, rabbits, and to a lesser extent guinea pigs and white mice, as measured by size of inoculum and survival time after infection.(2) The type B strain frequently is linked to waterborne disease of rodents.

A: Francisella tularensis may be transmitted by direct or indirect means, including numerous arthropod vectors, and may enter the host through several portals. Ticks are reported most frequently as the source of human infection in the United States, followed by rabbits.(6) Dogs and cats may be infected by tick or fly bites, ingestion of infected mammals, or possibly from contact with contaminated water. Infection in large domestic animals has been associated with tick exposure, but may occur by ingestion of food or water contaminated with the carcasses or excreta of infected animals.(7,8) An epizootic in Vermont muskrats was associated with waterborne transmission.(9)

Francisella tularensis may enter the host through cuts or abrasions in the skin, by penetration of the mucous membrane of the eye, respiratory tract, or oropharynx, or by percutaneous inoculation by arthropods.(10)

Tick species of importance in the transmission of F tularensis to human beings in the United States are Dermacentor variabilis, the "dog tick"; Dermacentor andersoni, the "wood tick"; and Amblyomma americanum, the "Lone Star tick."(11) These tick species feed on separate, and usually progressively larger, vertebrate hosts during the larval, nymphal, and adult stages of their life cycle. Francisella tularensis can be passed transstadially and transovanally in the tick, making it an effective vector as well as reservoir for infection.(5) The deerfly, Chrysops discalis, also is an important vector in North America.

There are 2 seasonal peaks in reported human cases.(6) The first peak is in the summer and coincides with peak activity of the tick vector in a geographic region. A second, usually smaller, peak is in the winter (November, December) during the hunting season, as a result of contact with infected rabbits.

Human studies have determined that as few as 10 bacilli can induce infection when inhaled or injected intradermally, whereas 10(8) organisms are required with oral challenge.(12) Although F tularensis has been isolated from the nasopharynx of experimentally infected dogs, transmission from infected to uninfected dogs in the same pen did not occur.(13) Person to person spread has not been documented, and tularemia is thought to be transmitted rarely by the bite or scratch of an infected animal.

A: Yes. After an incubation period of 3 to 5 days (range, 1 to 14 days), fever, chills, malaise, and fatigue develop in almost all patients; however, 5 distinct clinical forms of disease have been recognized in human beings.(12) The variety of clinical forms frequently relate to the route of transmission and virulence of the infecting strain of organism.

The ulceroglandular form is characterized by an ulcerated skin lesion and lymphadenopathy. This form represents 75 to 85% of reported cases. Fever and lymphadenopathy without ulceration characterize the glandular form, which accounts for 5 to 10% of cases. The typhoidal form (5 to 15% of cases) is associated with fever, prostration, and weight loss, without lymphadenopathy. Signs of the oculoglandular form (1 to 2% of cases) include unilateral conjunctivitis and preauricular or cervical lymphadenopathy. Pharyngotonsillitis with cervical lymphadenopathy is characteristic of the oropharyngeal form of disease.

Pleuropulmonary complications develop in 30 to 80% of typhoidal cases and in 10 to 15% of ulceroglandular cases. The death rate is highest among patients with the typhoidal form of disease or those with pleuropulmonary complications.(12)

A: There are few reports citing the clinical characteristics of tularemia in domestic and wild animals. Fever, anorexia, and listlessness are associated with clinical disease in cats.(1) In 1944, Johnson(13) experimentally infected 7 dogs with F tularensis. These dogs developed rectal temperatures of 39.4 to 40.6 C (103 to 105 F), ocular and nasal discharge, abscessation at the injection sites, and a vesiculopapular rash in the axillary and inguinal regions. All of the dogs recovered without treatment. Reference was made to the similar clinical appearance to dogs with canine distemper.

In 1959, Claus et al(7) reported on a mare and 5 foals with tularemia. All had signs of depression, were incoordinated, had a fever, and were heavily infested with ticks. In addition, the mare had signs of stiffness and limb edema. Ovine tularemia has been associated with fever, signs of depression, labored breathing, diarrhea, lagging behind the band, and heavy tick infestation.(8) In the adult pig, disease remains latent, but young pigs develop fever, dyspnea, and signs of depression.(14) Cattle appear to be resistant.(15)

A: There is considerable variation in gross and histopathologic changes between species. The most typical gross lesion is found on the surfaces of the spleen, liver, and lymph nodes, and consists of white-gray foci of necrosis that often are slightly raised, varying in size from pin-point to a few millimeters in diameter (Fig 1).(16)

Figure 1—Abdominal viscera from a rabbit with tularemia. Notice multiple discrete pale foci of necrosis throughout the liver (1) and spleen (2). (Photograph courtesy of Colorado Division of Wildlife.)

In addition, slight to extensive pneumonia has been reported in dogs.(13)

Microscopically, the lesions have a central area of caseous necrosis surrounded by a zone of lymphocytes with a few neutrophils and macrophages.(16) Thrombosis of small blood vessels frequently is observed.

A: The index of suspicion should be increased in areas where tularemia is known to develop in human beings or animals. In such areas, tularemia should be included in the differential diagnoses when a dog or cat develops a febrile illness, has a history of ingesting wild rodents or lagomorphs, and/or has heavy tick infestation. Tularemia should be suspected in domestic farm animals from endemic areas with compatible clinical illness, and tick infestation and/or evidence of contamination of food or water by rodents.

Confirmation of the diagnosis can be made by isolating the bacterium in culture, identifying the bacterium in tissue, or by serologic testing. Materials suitable for bacteriologic culturing include blood, exudate, or biopsy material from a local lesion or lymph node. Francisella tularensis cannot be cultured on routine laboratory media, but several commercial preparations are available, including glucose cysteine agar with thiamine, or cystine heart agar.(17) On cystine-glucose-blood agar, smooth gray colonies surrounded by a green discoloration of the medium reach maximum size of 1 to 4 mm in 3 to 5 days.(18) Automated equipment used to culture bacteria from the blood of septicemic patients also will support growth of the bacterium. Except in laboratories with adequate facilities for biocontainment, culturing of F tularensis is discouraged because of the risk of laboratory-acquired infection.(19)

A single titer of greater than or equal to 1:80 is presumptive evidence of tularemia in animals, but detection of a four-fold rise in antibody titer by tube agglutination test between acute and convalescent serum specimens is confirmatory for a serologic diagnosis.(20) Direct and indirect immunofluorescent techniques are available to detect the presence of F tularensis in clinical specimens.

A: Tularemia has been reported in all of the United States except Hawaii. The states of Arkansas, Missouri, and Oklahoma reported 94/170 (55%) of human cases for 1986 (Fig 2).

Figure 2—Reported human cases of tularemia by county, United States, 1986. (Reprinted with permission from Centers for Disease Control. Summary of notifiable diseases, United States 1986. MMWR 1987: 35.

There are several possible sources of information on the prevalence of tularemia in a given state. The state health department can provide information on the number of human cases and county of origin in the state. A university diagnostic laboratory or the state wildlife agency also may provide information regarding species and geographic origin of animal isolates, or the results of serologic surveys.

A: In most states where tularemia is endemic, the state health department will process specimens and/or conduct serologic testing for the diagnosis of tularemia. University diagnostic laboratories and commercial and reference laboratories also may provide diagnostic services. Most laboratories prefer serologic testing to avoid the risk of laboratory-acquired infection.

A: Streptomycin (15 to 20 mg/kg of body weight/day) remains the drug of choice for human patients in whom the diagnosis of tularemia is confirmed.(21) However, gentamicin (5 mg/kg/day) has been recommended as an acceptable alternative because of favorable results in human patients and because of the advantage of broad-spectrum coverage before establishing a diagnosis. In 1980, Mason et al(21) determined that gentamicin would completely inhibit growth of F tularensis in broth at 2 µg/ml, and that it was bactericidal at a concentration of 5 µg/ml. The dosages of streptomycin required to achieve the same effects were 10 µg and 20 µg, respectively. The smaller difference between inhibitory and bactericidal concentrations for gentamicin is further support for its use in the treatment of tularemia.

Results of in vivo studies involving mice and monkeys have not indicated the same advantage for gentamicin as was found in the in vitro experiments. Instead, much higher doses than those recommended for human beings are necessary to protect these species.(21,22)

Tetracycline and chloramphenicol, both of which are bacteriostatic for F tularensis, may be useful, but because organisms persist in tissues of hosts treated with these agents until destroyed by host defense mechanisms, relapses often develop after cessation of treatment.(23)

Critical studies of treatment in domestic animals have not been reported. Perusal of the veterinary literature indicates that streptomycin and tetracyclines are effective in animals; however, prolonged treatment may be necessary.(8,24)

A: Control of ectoparasites and confinement to reduce the likelihood of ingestion of infected mammals will reduce the risk of disease in domestic pets living in endemic areas. Avoidance of tick-infested pastures, spraying with insecticides during the months when tick populations are greatest, and taking precautions to minimize the contamination of food and water with carcasses or excreta of infected rodents will reduce disease in domestic livestock.

Q: What measures do you recommend to "high-risk" clients to reduce their exposure to F tularensis?

A: Avoiding contact with arthropod vectors and known source animals is the basis of prevention of tularemia. Clients who handle sick animals should take precautions by using rubber gloves and a face mask. When entering tick-infested areas, the use of tick repellent and protective (one-piece) clothing combined with frequent body searches and prompt removal of ticks can reduce the risk of human transmission.

Hunters, trappers, and those who prepare and eat wild game should use rubber gloves when skinning, dressing, or preparing game, should disinfect equipment after use, and should cook meat thoroughly.

A modified live vaccine is available from USAMRIID, Fort Detrick, Md, on an Investigational New Drug basis. Use of this vaccine has reduced the incidence of the typhoid form and the severity of ulceroglandular tularemia, and is recommended for use in laboratory personnel working with the organism.(19)

Tularemia exists in endemic areas where the causative organism circulates between arthropod vectors and a variety of mammals, birds, reptiles, and fish.(25) Human beings and domestic animals are at risk when they come into contact with reservoirs or vectors that are part of this natural cycle. Veterinarians should be aware of the presence of tularemia in their practice area, and should consider this disease in the differential diagnoses of febrile illness in any species when there is tick infestation and/or a history of ingestion of rodents or lagomorphs.

Tularemia in human beings, as well as in domestic and wild animals, may go unrecognized because the clinical signs usually are nonspecific and patients frequently recover with or without appropriate treatment.(25) Local die-off of rabbit or rodent populations rarely are recognized or investigated. During the 10-year period (1977-1986), an average of 225 cases of tularemia in human beings have been reported each year in the United States.(26) Reported cases are believed to represent only a fraction of the cases. A few serologic surveys have indicated the prevalence of infection in domestic animal species,(15,20,27-30) but there is little information on which to estimate the prevalence of clinical disease. McKeever et al(20) found that 2/32 (6.2%) feral cats from endemic areas in Georgia and Florida had antibody titers greater than or equal to 1:80, indicating F tularensis infection. Two serosurveys of dogs conducted in association with epidemic of disease in human beings, have shown 29/60 (48%) and 56/90 (62%) had antibody titers of greater than or equal to 1:40 to F tularensis.(27,28)

1. Packer RM, Harrison LR, Matthews CF, et al. Tularemia associated with domestic cats--Georgia, New Mexico. MMWR 1982; 31:39-41.

2. Olsufien NG, Emelyanova OS, Dunayeva TN. Comparative study of strains of B tularense in the old and new world and their taxonomy. J Hyg Epidemiol Microbiol Immunol 1959; 3:138-149.

3. Marchette NJ, Nicholes PS. Virulence and citrulline ureidase activity of Pasteurella tularensis. J Bacteriol 1961; 82:26-32.

4. Meyer KF. Tularemia. In: Dubos RJ, Hirsch JG, eds. Bacterial and mycotic infections of man. 4th ed. Philadelphia: JB Lippincott Co, 1965; 681-697.

5. Jellison WL. Tularemia in North America 1930-1974. Missoula, Mont: University of Montana Foundation, 1974; 20-21.

6. Boyce JM. Recent trends in the epidemiology of tularemia in the United States. J Infect Dis 1975; 131:197-199.

7. Claus KD, Newhall JH, Mee D. Isolation of Pasteurella tularensis from foals. J Bacteriol 1959; 78:294-295.

8. Frank FW, Meinershagen WA. Tularemia epizootic in sheep. Vet Med 1961; 56:374-378.

9. Young LJ, Bicknell DS, Archer BG, et al. Tularemia epidemic: Vermont, 1968. N Engl J Med 1969; 280:1253-1260.

10. Benenson AS, ed. Control of communicable diseases in man. 14th ed. Washington, DC: American Public Health Association, 1985; 417-420.

11. Harwood RF, James MT. Entomology in human and animal health. 7th ed. New York: Macmillan Publishing Co, Inc,1979; 403-404.

12. Boyce JM. Francisella tularensis (tularemia). In: Mandell GL, Douglass RG, Bennett JE, eds. Principles and practice of infectious disease. 2nd ed. New York: John Wiley & Sons, 1979; 1290-1294.

13. Johnson HN. Natural occurrence of tularemia in dogs used as a source of canine distemper virus. J Lab Clin Med 1944; 29:906-915.

14. Blood DC, Henderson JA. Veterinary medicine. 6th ed. London: Bailliere Tindall, 1974; 603-604.

15. McChesney TC, Narain J. A five-year evaluation of tularemia in Arkansas. J Arkansas Med Soc 1983; 80:257-262.

16. Jones TC, Hunt RD. Veterinary pathology. 5th ed. Philadelphia: Lea & Febiger, 1983; 616-618.

17. Eigelsbach HT, McGann VG. The genus Francisella. In: Starr MP, Stolp H, Truper HG, et al, eds. The prokaryocytes. New York: Springer-Verlag, 1981; 1086-1090.

18. Owen CR, Buker EO, Jellison WL, et al. Comparative studies of Francisella tularensis and Francisella novicida. J Bacteriol 1964; 87:676-683.

19. Burke DS. Immunization against tularemia: analysis of the effectiveness of live Francisella tularensis vaccine in prevention of laboratory-acquired tularemia. J Infect Dis 1977; 135:55-60.

20. McKeever S, Schubert JH, Moody MD, et al. Natural occurrence of tularemia in marsupials, carnivores, lagomorphs, and large rodents in southwestern Georgia and northwestern Florida. J Infect Dis 1958; 103:120-126.

21. Mason WL, Eigelsbach HT, Little SF, et al. Treatment of tularemia, including pulmonary tularemia, with gentamicin. Am Rev Respir Dis 1980; 121:39-45.

22. Sawyer WD, Dangerfield HG, Hogge AL, et al. Antibiotic prophylaxis and therapy of airborne tularemia. Bacteriol Rev 1966; 30:542-548.

23. Corwin WC, Stubbs SP Further studies on tularemia in the Ozarks: review of forty-four cases during a three-year period. JAMA 1952; 149:343-345.

24. Anonymous. Tularemia. In: Fraser CM, ed. Merck veterinary manual. 6th ed. Rahway, NJ: Merck and Co, Inc, 1986; 406-407.

25. Olsen PF. Tularemia. In: Hubbert WT, McCulloch WF, Schnurrenberger PR, eds. Diseases transmitted from animals to man. Springfield, Ill: Charles C Thomas, Publisher, 1975; 191-223.

26. Summary of notifiable diseases, United States, 1986. Centers for Disease Control, 1987; 35:51.

27. Schmid GP, Kornblatt AN, Connors CA, et al. Clinically mild tularemia associated with tick-borne Francisella tularensis. J Infect Dis 1983; 148:63-67.

28. Markowitz LE, Hynes NA, de la Cruz P, et al. Tick-borne tularemia: an outbreak of lymphadenopathy in children. JAMA 1985; 254:2922-2925.

29. Thorpe BD, Sidwell DE, Johnson KL, et al. Tularemia in the wildlife and livestock of the Great Salt Lake Region, 1951 through 1964. Am J Trop Med 1965; 14:622-637.

30. Calhoun EL, Mohr CO, Alford HI. Dogs and other mammals as hosts of tularemia and of vector ticks in Arkansas. Am J Hyg 1956; 63:127-135.

A recent report suggests that tularemia should be considered in cats with a history of ingestion of wild prey and that manifest signs of malaise, lymphadenopathy, and oral ulcers.(1)

1. Baldwin CJ, Panciera RJ, Morton RJ, et al. Acute tularemia in three domestic cats. J Am Vet Med Assoc 1991;199:1602-1605.

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