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Division of Infectious Diseases

Tularemia: Natural Disease vs. Act of Bioterrorism

 

RabbitAgent: Francisella tularensis

Common name: rabbit fever, deer fly fever, Ohara's disease

History
Microbiology
Natural Epidemiology
Potentials as Biological Weapon
Pathogenesis
Clinical Features
Mortality
Laboratory Diagnosis
Radiology
Diagnosis of tularemia as bioterrorism
Treatment
Prevention
Reporting/ Appropriate action
Selected References
View Dr. Janak Koirala's Presentation on Tularemia (Adobe Acrobat Reader required)

 

History

  • First described in US by McCoy as a plague like disease of rodents in 1911 followed by recognition of severe, fatal human illness with isolation of organism in 1912 [1-3]
  • Previously described as hare associated illness in Japan in 1818
  • Originally named Bacterium tularense as the original work took place in Tulare County, CA, but later changed to Francisella tularensis after Edward Francis to recognize his lifetime achievements in understanding the disease

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Microbiology

  • Francisella tularensis is a small, aerobic, pleomorphic, gram-negative coccobacillus
  • Bipolar staining with Gram or Giemsa stains give coccoidal appearance
  • Virulence has been associated with capsule and citrulline ureidase activity (4)
  • 2 major biogroups identified: F. tularensis (type A) N. America high virulence F. palearctica (type B) Asia, Europe, N. America low virulence

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Natural Epidemiology

  • RESERVOIRS: small mammals including voles, mice, water rats, squirrels, rabbits and hares. Recovered also from water, soils, vegetation.
  • VECTORS / VEHICLES: ticks, flies, mosquitoes, contaminated environment
  • MODES OF TRANSMISSION: insect bites, handling infectious animal tissues or fluids, contact or ingestion of contaminated materials, inhalation of infective aerosols. No human to human transmission.
  • DISTRIBUTION: Almost entirely a rural disease with few exceptions of outbreaks in urban and suburban areas. It is a disease of Northern hemisphere with remarkable absence from the south.
    • N. America: most US states except Hawaii highest rates- Missouri, Arkansas, Oklahoma, S. Dakota Incidence in USA- 0.05 cases per 100,000 population [15]
    • Europe: Spain, Sweden, Finland, Russia, Czech Republic, Kosovo, Slovakia
    • Asia: Japan, Turkey, Kazakhstan, Afghanistan
    • South America, Africa, Australia: none reported
  • HIGH RISK GROUPS: hunters, meat handlers, farmers, lab workers
  • OUTBREAKS: largest recorded airborne outbreak occurred in Sweden in 1966-67 in which F. tularensis biovar palaearctica (type B) affected 600 farmers [5]

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Potentials as Biological Weapon

  • F. tularensis was studied as a potential warfare agent in Japan (1932-1945) and in USA (1950's and 60's) [6-7], whereas Russia is believed to have strains resistant to antibiotics and vaccines [8].
  • aerosol dispersal of 50 kg of virulent F. tularensis over a metropolitan area with 5 million inhabitants would result in 250,000 incapacitating casualties, including 19,000 deaths (WHO expert committee) [9].
  • an aerosol release in a densely populated area would result in a febrile illness in 3-5 days followed by pleuropneumonitis and systemic infection [8]
  • slower progression and case fatality than anthrax or plague but illness would be expected to persist for several weeks with relapses.
  • virulence and resistance to antibiotics can be potentially enhanced to transform the bacteria into a more lethal agent [8, 10]
  • CDC estimates an aerosol attack with Tularemia would cost $5.4 billion per 100,000 persons exposed [11].

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Pathogenesis

  • Routes of infection: skin and mucous membranes, gastrointestinal tract, respiratory tract.
  • After inoculation, F. tularensis multiplies in the local tissue, spreads into the regional lymph nodes, multiplies in macrophages, and disseminate to various organs.
  • Suppurative lesions are formed at the site of inoculation, which later change into granulomas with central necrosis.
  • Inhalational exposure may result in bronchiolitis, bronchopneumonia and hemorrhagic inflammation of the airways, leading to pleuritis and hilar adenopathy.

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Clinical Features

  • Incubation period: 2-10 days
  • Abrupt onset of fever with chills/ rigors, headache, body aches, upper respiratory symptoms, pulse-temperature dissociation.
  • Clinical Forms:
    • Ulceroglandular (45-80%)- cutaneous ulcer with regional lymphadenopathy
    • Glandular- regional lymphadenopathy with no skin lesion
    • Oculoglandular- purulent conjunctivitis plus periauricular lymphadenopathy
    • Oropharyngeal- stomatitis, pharyngitis or tonsillitis with cervical lymphadenopathy
    • Pneumonic- pleuropulmonary disease
    • Typhoidal- systemic illness with fever and without signs of local disease
    • Septicemia- severe form with nonspecific fever, abdominal pain, diarrhea, and vomiting, with toxic appearing confused patient; may rapidly lead to septic shock, DIC, ARDS and death.

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Mortality

  • case fatality rate for F. tularensis (type A)
    • without antibiotics:
      • overall 5-15%
      • severe forms 30-60% (pneumonic, septic)
    • with antibiotics
      • overall < 2% (in USA)
  • case fatality rate for F. tularensis (type B)- rarely fatal

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Laboratory Diagnosis [8,12,13]

Physician suspecting a case of tularemia should collect respiratory and blood samples, and send them to lab with alert promptly. F. tularensis should be processed following BSL-2 microbiology laboratory procedures. Also, see Figure 1.

  • Gram stain: small, gram-negative coccobacilli
  • DFA (direct fluorescent antibody) stain, PCR or antigen detection can be used for rapid identification- DFA is recommended as the preferred method.
  • Culture: requires cysteine-enriched medium. It can be grown from pharyngeal and other respiratory secretions, and occasionally from blood.
  • Antimicrobial susceptibility: E-test
  • Microaggluttination assay can detect antibodies beginning 10 days. A 4-fold rise or a single titer of >1:128 is diagnostic.
  • Virulence testing and molecular genetic characterizations are available in specialized labs
  • Histopathology: acute suppurative necrosis followed by granulomatous reactions may be present in skin, lungs, lymph nodes, spleen, liver and kidneys.

Limitations:

1. F. tularensis should not be identified with commercial systems as it can generate aerosols.
2. Commercial systems may lead to misidentification of F. tularensis. The most common misidentifications are Haemophilus influenzae (satellite or XV positive) and Actinobacillus species (beta-lactamase negative). [12]

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Radiology

  • Peribronchial infiltrates, bronchopneumonia of one or more lobes, pleural effusion and hilar lymphadenopathy
  • Infiltrates may range from small discrete pulmonary lesions to scattered granulomatous lesions of lung parenchyma or pleura.

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Diagnosis of tularemia as bioterrorism [8,13]

  • Clinical suspicion of inhalational tularemia: sudden onset of acute febrile illness progressing to pharyngitis, bronchiolitis, pneumonitis, pleuritis and hilar lymphadenitis, which may lead to sepsis and septic shock
  • Epidemic setting: point-source outbreak in an urban / nonagricultural setting; unexpected severe respiratory illness in otherwise healthy persons, risk related to degree of exposure with no difference in susceptibility by age or other risk factors.
  • Presumptive Diagnosis:
    • detection of elevated serum antibody titers to F. tularensis in a patient with no history of immunization against tularemia
    • detection of confirmed detection of F. tularensis on DFA assay
  • Confirmatory diagnosis:
    • isolation and identification of F. tularensis
    • a 4-fold rise in antibody titer

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Treatment

  • Preferred Agents: Aminoglycosides for 10 days.
    • Streptomycin 1 gram twice daily, IM, or
    • Gentamicin 5 mg/kg/day, IM or IV
  • Alternative Agents:
    • use of bacteriostatic drugs, such as tetracyclines or chloramphenicol, may result in higher rates of relapses. Treat for 14-21 days with these agents.
    • ciprofloxacin for 10 days (only in vitro and animal data, not approved for human)
  • Children: same as adults
  • Pregnancy: gentamicin or ciprofloxacin
  • Mass Casualty Situation: treat with oral agents for 14 days
    • Doxycycline:
      • adults 100 mg, PO, twice daily
      • children <45 kg 2.2 mg/kg, PO, twice daily
    • Ciprofloxacin:
      • adults 500 mg, PO, twice daily
      • children 15 mg/kg, PO, twice daily

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Prevention

  • Immunization:
    • a live attenuated vaccine is available for lab workers as an investigational new drug, which is now under FDA review
    • During 1960's, live attenuated vaccine reduced inhalational tularemia in lab workers from 5.7 cases to 0.27 cases per 1000 person-years [14]
  • Post-exposure prophylaxis: doxycycline or ciprofloxacin for 14 days
  • Infection control:
    • Standard precautions
    • Isolation not required as there is no human-to human transmission
    • Microbiology Lab personnel should be alerted as they require BSL-2 precautions
    • Procedures potentially resulting in aerosol or droplet production need BSL-3 lab conditions
    • Autopsy procedures likely to cause aerosols, e.g. bone sawing, should be avoided
    • Exposed person should wash with soap and plenty of water
    • In case of environmental contamination, e.g. a lab spill, etc, 10% bleach solution can be used for spraying or cleaning. Further decontamination or cleaning can be done by using alcohol 10 minutes after using bleach.
    • Standard chlorine level in municipal water should be sufficient to protect against waterborne disease.

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Reporting/ Appropriate action

Clinicians: Following steps are recommended by The Working Group on Civilian Biodefense [8]:

  • Clinicians caring for patients with suspected tularemia should immediately contact:
    1. Hospital epidemiologist or infection control practitioner and
    2. Local or state health departments
  • Consult your local telephone operator, the telephone directory under "governmental listings," or the Internet at http://www.cdc.gov/other.htm#states or http://www.astho.org/state.html
  • If the local and state health departments are unavailable, contact the Centers for Disease Control and Prevention at (970) 221-6400 or http://www.cdc.gov/ncidod/dvbid/dvbid.htm

Labs: Following steps are recommended in the Laboratory Protocol developed by CDC, ASM and APHL [12]:

  • Level A laboratories should consult with state public health laboratory director (or designate) prior to or concurrent with testing if F. tularensis is suspected by the physician.
  • Immediately notify state public health laboratory director (or designate) and state public health department epidemiologist/health officer if F. tularensis cannot be ruled out and a bioterrorist event is suspected. The state public health laboratory/ state public health department will notify local FBI agents as appropriate.
  • Immediately notify physician/infection control according to internal policies if F. tularensis cannot be ruled out.
  • Preserve original specimens pursuant to a potential criminal investigation and possible transfer to an appropriate Laboratory Response Network (LRN) laboratory. FBI and state public health laboratory/state public health department will coordinate the transfer of isolates/specimens to a higher-level LRN laboratory as appropriate. Start chain of custody documentation if appropriate.
  • Obtain guidance from the state public health laboratory as appropriate (e.g., requests from local law enforcement or other local government officials).
  • If F. tularensis is ruled out, proceed with efforts to identify using established procedures. Figure 1.

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Selected References

  1. Francis E., Tularemia. JAMA.1925;84:1243-1250.
  2. McCoy GW. A plague-like disease of rodents. Public Health Bull. 1911;43:53-71.
  3. McCoy GW, Chapin CW. Bacterium tularense, the cause of a plaguelike disease of rodents. Public Health Bull. 1912;53:17-23.
  4. Tärnvik A. Nature of protective immunity to Francisella tularensis. Rev Infect Dis. 1989;11:440-450.
  5. Dahlstrand S, Ringertz O, Zetterberg. Airborne tularemia in Sweden. Scand J Infect Dis. 1971;3:7-16.
  6. Harris S. Japanese biological warfare research on humans: a case study of microbiology and ethics. Ann N Y Acad Sci. 1992;666:21-52.
  7. Christopher GW, Cieslak TJ, Pavlin JA, Eitzen EM. Biological warfare: a historical perspective. JAMA. 1997;278:412-417.
  8. Dennis DT, Inglesby TD, Henderson DA, et al. Tularemia as a biological weapon: medical and pubic health management. JAMA. 2001;285:2763-2773.
  9. Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland: World Health Organization; 1970:105-107.
  10. Pavlov VM, Mokrievich, Volkovoy K. Cryptic plasmid pFNL10 from Francisella novicida-like F6168: the base of plasmid vectors for Francisella tularensis. FEMS Immunol Med Microbiol. 1996;13:253-256.
  11. Kaufmann AF, Meltzer MI, Schmid GP. The economic impact of a bioterrorist attack: are prevention and post-attack intervention programs justifiable? Emerg Infect Dis. 1997;3:83-94.
  12. CDC, ASM, APHL Basic Protocols For Level A Laboratories for the Presumptive Identification of Francisella Tularensis. Dec. 2001; 1-13.
  13. Miller JM. Agents of bioterrorism. Preparing for bioterrorism at the community health care level. Infect Dis Clin North Am. 2001;15(4):1127-56.
  14. Burke DS. Immunization against tularemia: analysis of the effectiveness of live Francisella tularensis vaccine in prevention of laboratory-acquired tularemia. J Infect Dis. 1977 Jan;135(1):55-60.
  15. CDC. Tularemia- United States, 1990-2000. MMWR 2002;51(09):182-84.

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