Francisella tularensis

Francisella tularensis is a cause of potentially severe zoonotic disease in humans; sometimes referred to as rabbit fever or deer-fly fever.

Epidemiology

Incidence – <1/100,000 in the U.S.
- Most cases occur in the west central and mountain regions (56% of total cases from 1990 – 2000 occurred in Arkansas, Oklahoma, Missouri, and South Dakota)
Transmission – blood-sucking arthropods or contact with infected animals via inapparent abrasions or consumption of contaminated water
- Primarily a disease of wild animals, especially rabbits
- In U.S., human vectors are primarily ticks and deer flies
  - Tick vectors include Amblyomma americanum, Dermacentor andersoni, Dermacentor variabilis
- Peak seasons – spring and summer
  - Historical peaks during fall and early winter (hunting season)

Organism

Gram-negative, aerobic, non-spore forming, fastidious coccobacillus
- Two main biovars are F. tularensis subsp. tularensis (type A) and F. tularensis subsp. holarctica (formerly subsp. palearctica, type B)
  - Type A is found predominantly in the U.S.
  - Type B is found predominantly in Europe and Asia
- F. tularensis subsp. novicida (type C) is a low-virulence strain in North America

Clinical Presentation

Incubation is generally 2-10 days
Disease often begins with the sudden onset of flu-like symptoms, including chills, fever, headache and generalized aches
Forms of tularemia
- Ulceroglandular (21-85%)
  - Direct contact with animal or insect bite
  - Most common form of tularemia
  - Starts as small, painful papule that becomes an ulcer at entry portal with associated lymphadenopathy (glandular tularemia [3-20%] similar presentation but lacking ulcer)
  - Progresses to fever, chills, myalgia, possibly septicemia
- Oculoglandular (2-5%) – Parinaud syndrome
  - Direct contact with animal
  - Conjunctival entry via contaminated fingers, splashes, aerosols
  - Unilateral intense conjunctivitis, preauricular, submandibular, cervical lymphadenopathy
    - Sequelae of corneal perforation and iris prolapse
- Oropharyngeal and gastrointestinal (2-12%)
  - Follows ingestion of contaminated food or water
  - Oral – exudative pharyngitis; deep, cervical lymphadenopathy
  - Gastrointestinal – ulcerative GI lesions, diarrhea
- Pneumonic (8-20%)
  - Inhalational exposure or extension from systemic disease (typically ulceroglandular form)
  - Pneumonia with dry cough, pleuritic chest pain
  - Often occupational exposure (sheep shearing, animal husbandry, farming, lawn/brush cutting, laboratory workers)
- Typhoidal (5-30%)
  - Rare in U.S.
  - Usually associated with bacteremic gastrointestinal or pneumonic disease and consumption of poorly cooked wild game
  - High fever, headache, diarrhea, shock
Complications – septicemia, meningitis, endocarditis, hepatitis, renal failure

Treatment and Prevention

Antibiotic treatment is necessary and is generally started prior to confirmation of disease
- Relapses may occur with certain therapies
Vaccination available for at-risk individuals

Indications for Testing

A history of contact with rabbits, ticks, dogs, cats or skunks along with nonspecific febrile illness with prominent lymphadenopathy (negative history of animal contact does not rule out diagnosis)

Laboratory Testing

Serology – may require acute and convalescent phase titers
- Preferred means of confirmation but is retrospective in nature
- Fourfold increase between acute and convalescent serology or >1:160 on acute titer
- Cross-reactivity between Brucella, Salmonella, Yersinia, and Legionella antigens
Culture – frequently negative
- Difficult to culture – fastidious organism
- Select agents; confirmed positive culture requires approval before transfer
PCR – not widely available but very sensitive
- Tissue samples (respiratory specimens, blood, or exudate) can be sent for PCR

Imaging Studies

Chest x-ray for patients presenting with signs and symptoms of pneumonia; demonstrates infiltrates

Differential Diagnosis

Ulceroglandular
- Streptococcal/staphylococcal skin infection
  - Staphylococcal disease
  - Streptococcal disease, Group B
- B. anthracis (anthrax)
- P. multocida (pasteurellosis)
- Atypical mycobacteria
- HIV
- Cytomegalovirus
- Epstein-Barr virus
- Rickettsia
  - Rickettsia rickettsii (Rocky Mountain spotted fever)
  - Rickettsia typhi (typhus fever)
- Y. pestis (plague)
- Lymphoma (B-cell)
Pneumonic
- Hantavirus
- Influenza virus
- Mycoplasma pneumoniae
- Brucella spp
- Legionella pneumophila
- B. anthracis
- Severe acute respiratory syndrome (SARS)
- Chlamydophila pneumoniae or psittaci
- Coxiella burnetii (Q–fever)
- Mycobacterium tuberculosis
- Acute respiratory distress syndrome
- Streptococcus pneumoniae
- Respiratory syncytial virus
Oropharyngeal
- Streptococcal disease, Group A
- Epstein-Barr virus
- HIV
Typhoidal
- Sepsis
Oculoglandular
- Viral or bacterial conjunctivitis

Tests generally appear in the order most useful for common clinical situations

Test name: Francisella tularensis Antibodies, IgG and IgM

ARUP #: 2005350

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Diagnose F. tularensis as agent of infection

Limitations:

Cross-reactions with Brucella or Yersinia antibodies may occur; results should be interpreted with caution and correlated with clinical information; the best evidence for current infection is significant change on two appropriately timed specimens

Additional Tests Available

Test name: Organism Identification by 16S rDNA Sequencing

ARUP #: 0060720

Methodology: 16S rDNA Sequencing

Comments:

If suspected, notify laboratory to rule out F. tularensis

Test name: Aerobic Organism Identification

ARUP #: 0060115

Methodology: Identification methods including Biochemical, MALDI TOF and/or 16S rDNA sequencing.

Comments:

If suspected, notify laboratory to rule out F. tularensis

For suspected agents of bioterrorism, notify state department of health and refer isolates to state laboratory for identification

Susceptibilities on agents of bioterrorism are not performed at ARUP

Test name: Rickettsia typhi (Typhus Fever) Antibody, IgM by IFA

ARUP #: 0050383

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Rickettsia rickettsii (Rocky Mountain Spotted Fever) Antibody, IgG

ARUP #: 0050369

Methodology: Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Brucella Antibody (Total) by Agglutination

ARUP #: 0050135

Methodology: Semi-Quantitative Bacterial Agglutination

Comments:

Cross-reactions may occur between Brucella and F.tularensis antigens and antisera; therefore, parallel tests should be run with these antigens; a fourfold rise in titer is considered diagnostic

Test name: Francisella tularensis Antibody, IgG

ARUP #: 2005353

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Cross-reactions with Brucella or Yersinia antibodies may occur; results should be interpreted with caution and correlated with clinical information; the best evidence for current infection is significant change on two appropriately timed specimens

Test name: Francisella tularensis Antibody, IgM

ARUP #: 2005354

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Cross-reactions with Brucella or Yersinia antibodies may occur; results should be interpreted with caution and correlated with clinical information; the best evidence for current infection is significant change on two appropriately timed specimens