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Tularemia Fact Sheet

Tularemia in Humans at CECDP

Synopsis of Tularemia
Tularemia, also known as deerfly fever or rabbit fever, is an infectious zoonotic disease caused by the bacterium Francisella tularensis. F. tularensis was originally isolated in 1911 by McCoy and Chapin, from ground squirrels with a plague-like illness in California. Natural hosts for tularemia includes the following: lagomorphs (rabbits, cottontails, and hares), rodents (voles, squirrels, muskrats, beaver, and lemmings), and prairie dogs. The insects that feed on these animals serve as primary vectors for transmission of the disease to other animals and humans. Humans function as the terminal hosts since they do not transmit the disease to other humans or other animals. Tularemia is found throughout North America, Eastern Europe, and Asia. There are two subspecies of the bacteria, Type A, which is common in North America and is highly virulent, and Type B, which is common in Europe and Asia and is milder form. In the U.S., there are approximately 200 reported cases each year with a fatality rate of less than two percent. Most cases occur in rural areas of the south-central and Midwestern states during the summer and winter months. Between 1990 and 2000, half of all reported tularemia cases in the U.S. occurred in Missouri, Oklahoma, Kansas, and Arkansas.
  • Primary vectors:
    • Ticks (Amblyomma americanum, Dermacentor andersoni, Dermacentor variabilis, Ixodes scapularis, Ixodes pacificus, and Ixodes dentatus)
    • Mosquitoes (Aedes cinereus and Aedes excrucians)
    • Biting flies (Chrysops discalis [deerfly], Chrysops aestuans, Chrysops relictus, and Chrysozona pluvialis)
  • Transmission in humans occur by one of the following:
    • Tick, deerfly, or other biting insects
    • Handling infected animal tissue or fluids
    • Eating or drinking food or water contaminated by the bacteria
    • Inhalation of infectious aerosols (dust from contaminated hay, aerosols generated by lawn mowing and brush cutting)
    • Exposure in the laboratory setting (inhalation of infectious aerosols, handling cultures or other infectious materials, accidental percutaneous exposure)
  • Hunters, trappers, meat processors, cooks, sheep herders and shearers, muskrat farmers, and laboratory personnel are at greatest risk for acquiring tularemia
  • More detailed information on Tularemia published by the Clinical Microbiology Reviews.11
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Clinical Signs and Symptoms
Animals
  • Incubation period: 1 to 10 days
  • Tularemia has been reported in sheep, dogs, cats, pigs, and horses; cattle appear to be resistant.
  • Lagomorphs (rabbits, hares, etc) and rodents
    • Signs of disease are not usually seen, instead animals are found dead or dying
    • Signs that may be seen
      • Weakness
      • Fever
      • Anorexia
      • Diarrhea
      • Dyspnea
      • Ulcers
      • Abscesses
      • Lymphadenopathy
      • Strange behavior
        • Easily captured because they run slowly
        • Rub their noses and feet on the ground
        • Muscle twitches
  • Sheep
    • Seen following severe winters and/or heavy tick infestations
    • Signs and symptoms
      • Fever
      • Weight loss
      • Lymphadenopathy
      • Dyspnea
      • Diarrhea
    • Strange behaviors
      • Isolate from the rest of the flock
      • Rigid gait
      • High mortality rate in the young
      • Pregnant ewes may abort
  • Equine
    • Fever
    • Depression
    • Dyspnea
    • Ataxia
    • Stiffness
    • Limb edema
  • Swine
    • Adults - latent
    • Young
      • Fever
      • Dyspnea
      • Depression
  • Companion animals
    • Cats
      • Fever
      • Depression
      • Anorexia
      • Listlessness
      • Apathy
      • Ulcerated tongue and palate
    • Dogs
      • Fever
      • Anorexia
      • Myalgia
      • Ocular and nasal discharge
      • Abscess at site of infection
  • Post-mortem lesions
    • Lesions consistent with septicemia
      • Caseous necrosis of lymph nodes
      • Multiple grayish-white foci of necrosis in the spleen, liver, bone marrow, and lungs
      • Hypertrophied spleen
      • Congested and edematous lungs
Humans
  • Incubation: 3 to 15 days
  • Clinical description (illness is characterized by several distinct forms):
    • Ulceroglandular (cutaneous ulcer with regional lymphadenopathy) - 45% to 85% of naturally occurring cases:
      • Route of infection: skin or mucous membranes
      • Fever
      • Chills
      • Headache
      • Malaise
      • Painful lymph nodes (may suppurate and drain profusely)
      • Inflamed papule that quickly turns into a pustule which ulcerates
      • Single ulcers on extremities with thin, colorless, scanty exudates
    • Glandular (regional lymphadenopathy with no ulcer) - 10% to 25% of naturally occurring cases
      • Route of infection: skin or mucous membranes
      • Fever
      • Tender lymphadenopathy without skin ulcers
    • Oculoglandular (conjunctivitis with preauricular lymphadenopathy) - less than 5% of naturally occurring cases
      • Route of infection: conjunctiva
      • Painful, unilateral, purulent conjunctivitis with preauricular or cervical lymphadenopathy
      • Chemosis (possible)
      • Periorbital edema
      • Multiple small nodules or ulcerations on conjunctiva
    • Oropharyngeal (stomatitis or pharyngitis or tonsillitis and cervical lymphadenopathy) - less than 5% of naturally occurring cases
      • Route of infection: inhalation, skin inoculation, ingestion
      • Acute exudates or membranous pharyngotonsillitis with cervical lymphadenopathy
    • Pneumonic (primary pleuropulmonary disease) - less than 5% of naturally occurring cases
      • Route of infection: inhalation or secondary hematogenous
      • Severe, sometimes fulminant, atypical pneumonia
      • Lung consolidation (possible)
      • Delirium (possible)
      • Dry, unproductive cough with decreased breath sounds
      • Substernal discomfort
    • Typhoidal (febrile illness without localizing signs and symptoms) - less than 5% of naturally occurring cases
      • Route of infection: inhalation, skin inoculation, or ingestion
      • Fever
      • Prostration
      • Headache
      • Nausea
      • Weight loss
      • Weakness
      • Chills and drenching sweats
  • Case-fatality rate - approximately 2%
  • Click here for more human-related information on tularemia posted on the UAB Website for Bioterrorism and Emerging Infectious Education.7
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Diagnosis and Treatment
Diagnostic Samples
  • Since tularemia is highly infectious to humans, samples should be collected and handled with all appropriate precautions (i.e., gloves, masks, and eye shields)
  • In animals
    • Aspirates from enlarged lymph nodes
    • Infected tissue samples
    • serum
  • In humans
    • Blood
    • Sputum
    • Ulcer biopsy
Differential Diagnosis
  • In animals, the differential diagnoses include plague, staphylococcal and streptococcal infections, cat scratch fever, sporotrichosis, and tick paralysis.
  • In humans, the differential diagnoses include influenza, anthrax, plague, acute pneumonia, and Q fever.
Clinical Diagnosis
  • Clinical diagnosis is supported by evidence or history of a tick or deerfly bite, exposure to tissues of a mammalian host of F. tularensis, or exposure to potentially contaminated water.
Laboratory Tests
  • Probable case - a clinically compatible case with laboratory results indicative of presumptive infection versus confirmed case - a clinically compatible case with confirmatory laboratory results
  • Presumptive diagnosis is based on the following (can be done in a few hours)
    • Elevated serum antibody titer(s) to F. tularensis antigen (without documented fourfold or greater change) in a patient with no history of tularemia vaccination or
    • Detection of F. tularensis in a clinical specimen by fluorescent assay
  • Confirmatory diagnosis is based on the following (takes 24 to 24 hours)
    • Isolation of F. tularensis in a clinical specimen or
    • Fourfold or greater change in serum antibody titer to F. tularensis antigen
  • Standard tests
    • LRN-approved Gram stain - tiny, faintly staining, pleomorphic gram-negative rods
    • Bacteriologic culture
    • Biochemical screening:
      • Oxidase-negative
      • Weakly catalase-positive
      • Urea-negative
      • Nitrate-negative
      • Nonmotile
      • Beta-lactamase-positive
    • Other tests:
      • Direct fluorescent antibody (DFA) stain
      • Slide agglutination
      • Antimicrobial susceptibility testing
      • Serology (antibody detection)
      • Polymerase chain reaction (PCR)
      • Mouse inoculation
      • Cellular fatty acid analysis
      • Immunohistochemistry
  • Click here for more information on basic protocols for level A laboratories published by the CDC.9
Treatment
  • In animals
    • Remove ticks as soon as possible
    • Antibiotics
      • Streptomycin
    • Vaccines
      • Not marketed specifically for animals
  • In humans
    • Supportive care
    • Antibiotics
      • Doxycycline
      • Ciprofloxaicin
      • Streptomycin
      • Gentamicin
    • Vaccine
      • FDA is currently reviewing a vaccine; however, its future availability is uncertain due to the length of time it takes for the vaccine to work (~ 2 weeks)
      • US Department of Defense also has developed an experimental vaccine; however, health officials have limited the use of this vaccine to laboratory and other high-risk workers.
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Economic Consequences and Disease Eradication
Economic Consequences
  • Costs associated with eradication efforts and treatment.
  • Increased costs passed on to consumers
  • Medical costs associated with treatment
Disease Eradication
  • Tularemia was removed from the list of nationally notifiable diseases in 1994. However, due to growing concern for its use as a biological weapon, tularemia has been reinstated as a notifiable disease as of 2000.
  • Prevention
    • Vector avoidance or protection
      • Ticks, flies, mosquitoes, other biting insects
      • Rodents
    • Use insect repellent containing the ingredient DEET on skin
    • Treat clothing with insect repellant containing permethrin
    • Inspect entire body (head to toe) for ticks after being outdoors
    • Personal protection (gloves, masks, goggles, etc.)
      • When handling carcasses of dead animals
      • Potential aerosolization in endemic areas
    • Wash hands often with soap and warm water, especially when handling animal carcasses
    • Cook food thoroughly
    • Drink water from safe sources only
  • Viability
    • The bacteria can survive for weeks at low temperatures in water, moist soil, hay, straw, or decaying animal carcasses.
    • Bacteria are not destroyed by freezing; may remain viable in a frozen carcass for up to 3 years
    • Growth requires cysteine or sulfhydryl compounds
    • Killed readily by heat (56°C for 10 minutes)
    • Killed by disinfectants, such as 1% hypochlorite, 70% ethanol, glutraldehyde, and formaldehyde
    • The bacteria are generally susceptible to aminoglycosides (streptomycin, gentamicin) tetracyclines, chloramphenicol, and fluoroquinolones but are generally resistant to beta-lactam antibiotics.
Tularemia and Bioterrorism
  • F. tularensis has been considered for use as a biological weapon since the 1940s.
    • During WWII, the Japanese conducted research on F. tularensis as a biological weapon
    • 1940s to early 1990s - the former Soviet Union weaponized F. tularensis, the Soviet program included development of antibiotic- and vaccine-resistant strains
    • 1950s and 1960s - the United States developed weapons that could deliver aerosolized F. tularensis organisms
    • In 1969, the WHO estimated that an aerosol dispersal of 50 kg of virulent F. tularensis over a metropolitan area with 5 million inhabitants in a developed country would result in 250,000 illnesses and 19,000 deaths.
    • Aerosol release of F. tularensis would be expected to cause the following clinical syndromes:
      • Primary pneumonic tularemia
      • Oculoglandular tularemia
      • Glandular or ulcerglandular disease could occur through exposure of broken skin
      • Oropharyngeal disease
    • Characteristics of F. tularensis that make it suitable for weaponization:
      • Grown relatively easily
      • Relatively stable in liquid form
      • Highly stable in a dry formulation (If the bacteria were to be used as a weapon, it would most likely be made airborne for human exposure by inhalation)
      • Appropriate particle size
      • Low LD50 for humans (10-50 cells)
      • Capable of forming secondary foci of infection via infected rodents
      • Can persist in nature for long periods of time
  • Click here for more information on the use of tularemia as a biological weapon published by JAMA.10
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Outbreaks
  • 2003: F. tularensis was identified on several filters from a biodetection air-monitoring system in Houston, Texas (the environmental reservoir was not definitively determined)
  • 2002: An outbreak of tularemia in commercially distributed prairie dogs occurred in the U.S. Infected animals had been shipped to AR, FL,IL, MI, MS, NV, OH, TX, WA, and WV in the U.S.; Belgium, Czech Republic; Japan; Netherlands; and Thailand
  • 2000: Martha's Vineyard - Fifteen cases of tularemia were reported; 11 patients had primary pneumonic disease and one patient died. Exposure - aerosols due mowing the lawn and brush cutting.12
  • 1984: South Dakota - Twenty cases of glandular tularemia were reported on Crow Creek Indian reservations. Exposure - ticks
  • 1971: Utah - Thirty-nine cases of tularemia were reported. Exposure - infected deerflies
  • 1968: Forty-seven cases of tularemia were diagnosed in persons who had handled muskrats. Exposure - muskrats
  • 1930s: 2,000 cases were reported annually
  • Click here for more information on tularemia outbreaks in the U.S. between 1990 and 2000 published by the CDC.8
  • Click on the following hyperlink for the most recent outbreak information located at the Office International des Epizooties Website. http://www.oie.int/eng/info/hebdo/A_DSUM.htm.
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Sources and Related Articles
Sources
  1. CDC, February 1, 2001. Tularemia Case Definition. Available at http://www.bt.cdc.gov/Agent/Tularemia/CaseDef.asp.
  2. CFSPH, October 26, 2005. Tularemia. Available at http://www.cfsph.iastate.edu/Factsheets/pdfs/tularemia.pdf.
  3. CIDRAP, April 13, 2006. Tularemia: Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis. Available at http://www.cidrap.umn.edu/cidrap/content/bt/tularemia/biofacts/....
  4. FAS. Fact Sheet - Tularemia. Available at http://www.fas.org/main/content.jsp?formAction=297&contentId=524.
  5. The Merck Veterinary Manual, 2006. Tularemia: Introduction. Available at http://www.merckvetmanual.com/mvm/htm/bc/52400.htm.
  6. NIAID, April 2005. Tularemia. Available at http://www.niaid.nih.gov/factsheets/tularemia.htm.
  7. UAB: Bioterrorism and Emerging Infections Education. Tularemia. Available at http://bioterrorism.uab.edu/CategoryA/tularemia/tularemia.pdf.←
    8. Related Articles
  8. Anonymous, March 8, 2002. Tularemia---United States, 1990 - 2000. MMWR. 51(9):182-184. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5109a1.htm. ←
  9. Chu, M. C., R. B. Carey, and D. F. Welch, December 13, 2001. Basic Protocols for Level A Laboratories: For the Presumptive Identification of Francisella tularensis. Published on the CDC Website. Available at http://www.asm.org/ASM/files/LEFTMARGINHEADERLIST/DOWNLOADFILENAME/.... ←
  10. Dennis, D. T., T. V. Inglesby, D. A. Henderson, J. G Bartlett, M. S. Ascher, et. al., June 6, 2001. Tularemia as a Biological Weapon: Medical and Public Health Management. JAMA. 285(21):2763-2773. Available at http://jama.ama-assn.org/cgi/reprint/285/21/2763.pdf. ←
  11. Ellis, J., P. C. F. Oyston, M. Green, and R. W. Tidball, October 2002. Tularemia. Clinical Microbiology Reviews. 15(4):631-646. Available at http://cmr.asm.org/cgi/reprint/15/4/631. ←
  12. Feldman, K. A., D. Stiles-Enos, K. Julian, B. T. Matyas, S. R. Telford, et. al., March 2003. Tularemia on Martha's Vineyard: Seroprevalence and Occupational Risk. Emerg Infect Dis. 9(3):350-354. Available at http://www.cdc.gov/ncidod/EID/vol9no3/pdfs/02-0462.pdf. ←
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