Tularemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has tularemia? What are the typical findings for this disease?

Tularemia is an infection caused by the Gram-negative bacteria Francisella tularensis.

Six clinical syndromes of tularemia are classified by the portal of entry of the infection:

1. Ulceroglandular tularemia (75% of cases)

Painful swollen papule, at the portal of entry of the infection, that becomes an ulcer

Tender lymphadenopathy proximal to the papule/ulcer – may suppurate

Fever, malaise

2. Glandular tularemia (15% of cases)

Tender lymphadenopathy – most commonly axillary, inguinal, or cervical- may suppurate

Fever, malaise

3. Oropharyngeal tularemia (<5% of cases)

Severe pharyngitis – may have oral ulcers and/or an oropharyngeal pseudomembrane

Cervical lymphadenitis

Fever

4. Oculoglandular tularemia

Nodular conjunctivitis – corneal ulcers may occur

Parinaud’s oculoglandular syndrome – conjunctivitis and (painful) ipsilateral preauricular lymphadenopathy

5. Typhoidal tularemia

Fever with no localizing signs

Sepsis

Headaches

Myalgias

Diarrhea

6. Pneumonic tularemia

Pneumonia – severe and with high mortality

Fever

Cough, chest pain, hilar adenopathy

Pleural effusions may be present

What other disease/condition shares some of these symptoms?

Depending upon the clinical syndrome, the following conditions may share the symptoms of tularemia:

Ulceroglandular and glandular tularemia – Lymphadenitis due to: Staphylococcus aureus, Streptococcus pyogenes, tuberculosis, non-tuberculous mycobacterium, or Bartonella, anthrax, HIV, infectious mononucleosis, sporotrichosis, or lymphogranuloma venereum, lymphoma.

Oropharyngeal tularemia – streptococcal pharyngitis, diphtheria, viral pharyngitis

Oculoglandular tularemia – Bartonella, sporotrichosis, tuberculosis, syphilis, coccidioidomycosis, herpes simplex virus (HSV)

Typhoidal tularemia – bacterial sepsis, malaria, brucellosis, Q fever, rickettsial diseases, ehrlichiosis, typhoid fever, disseminated tuberculosis, disseminated histoplasmosis.

Pneumonic tularemia- typical and atypical bacterial pneumonia, tuberculosis, Legionnaire’s disease, Q fever, fungal pneumonia, viral pneumonia, psittacosis, plague, lymphoma.

What caused this disease to develop at this time?

Individuals at risk for developing the infection include hunters, trappers, taxidermists, grounds maintenance workers, sheep herders/shearers, laboratory workers, those with tick exposure, and those living in or traveling to areas where tularemia is endemic.
The incubation period is 1-21 days (average 2-5 days)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

White blood cell count may be normal or elevated with a predominance of neutrophils
C-reactive protein and erythrocyte sedimentation rate are typically elevated
Liver function tests may be elevated
The diagnosis is typically made clinically but is confirmed by serologic testing.
Commercially available standard agglutination tests – however agglutinating antibodies usually are not detectable until the second week of illness. Acute and convalescent testing should be obtained at least 2 weeks apart.
Presumptive diagnosis can be made if a single serum antibody titer is greater than or equal to 1:160; however, this can also represent past infection
Diagnosis is confirmed if there is a four-fold or higher increase in titer between acute and convalescent serology.
Cross-reactivity may occur because of antibodies to Brucella,
Legionella, Salmonella, Yersinia or other Gram-negative bacteria.
Diagnosis is also confirmed by isolation of F. tularensis in blood, body fluids, or tissue
The bacteria rarely is seen on Gram staining
Health care providers should alert microbiology laboratory personnel if tularemia is suspected, as it highly infectious, and laboratory workers have a high risk of acquiring infection.
Culture of F. tularensis should be done only in a biosafety level 3 (BSL-3) laboratory.
Polymerase chain reaction (PCR) assays for the diagnosis of tularemia are very sensitive but are not commercially available.
In the United States, tularemia is a nationally notifiable disease, and cases should be reported to the local department of health

Would imaging studies be helpful? If so, which ones?

Chest X-ray findings in pneumonic tularemia may include: hilar lymphadenopathy, pulmonary infiltrates, pleural effusions, empyema

If you are able to confirm that the patient has tularemia, what treatment should be initiated?

Antibiotic therapy should be initiated as soon as tularemia is suspected rather than awaiting results of serologic testing.
Aminoglycosides are the drugs of choice for the treatment of tularemia:
gentamicin, streptomycin, amikacin.
Gentamicin dose: 5 mg/kg divided every 8 or 12 hours.
Aminoglycoside levels should be monitored.
The typical treatment course is 10 days.
Alternative antibiotic therapies include the following: doxycycline (may require a longer treatment course), ciprofloxacin (most studies on fluoroquinolone efficacy have been done in Europe where Francisella tularensis subspecies holarctica -type B predominates), chloramphenicol
Beta-lactams, clindamycin, and trimethoprim-sulfamethoxazole are not effective for the treatment of tularemia

Sepsis due to tularemia should be treated with fluid resuscitation, vasopressors, respiratory support, and other supportive measures as needed

What are the adverse effects associated with each treatment option?

Aminoglycosides – potential ototoxicity and nephrotoxicity; aminoglycoside levels should be monitored.

Doxycycline – relapse is more common in patients treated with tetracyclines; doxycycline should not be given to children younger than 8 years of age because of the potential for teeth staining, unless the benefits outweigh the risks.

Ciprofloxacin – not FDA approved for tularemia in children; in children younger than18 years of age there is the potential for joint/cartilage injury.

Jarisch-Herxheimer reactions can occur with antibacterial therapy,

What are the possible outcomes of tularemia?

Mortality is less than 1% for all types of tularemia except typhoidal and pneumonic.

Relapse is possible even after appropriate antibiotic therapy.

The illness may be prolonged if antibiotic therapy is delayed.

What causes this disease and how frequent is it?

Tularemia is a zoonotic infection caused by Francisella tularensis, a fastidious aerobic Gram-negative coccobacillus
There are four subspecies, but the disease is mainly caused by
Francisella tularensis subspecies tularensis (type A) and
Francisella tularensissubspecies holarctica (type B)
Type A is more virulent and is found in North America.
Type B is found in the northern hemisphere and often causes subclinical infection.
The organism is highly contagious; only a small inoculum is needed
Arkansas, Oklahoma, and Missouri account for 40 percent of the cases of tularemia reported in the United States each year.
Tularemia presents most commonly in the summer in the south central United States (high tick activity) and peaks in the winter in the northeastern United States (hunting season).
Males have a higher incidence of infection than females.
The highest incidence is in children and in adults greater than 75 years of age.
Francisella tularenis can survive in water and animal carcasses for long periods. Frozen rabbit meat has remained infective for greater than 3 years.
Tularemia tick vectors include: Amblyomma americanum (lonestar tick), Dermacentor andersoni (wood tick),
Dermacentor variabilis (dog tick).

How do these pathogens/genes/exposures cause the disease?

Disease transmission occurs via:

Handling the carcass of an infected animal (rabbits, hares, muskrats, prairie dogs, skunks, raccoons, rats, voles, squirrels, sheep, cattle, cats)

Tick or deer fly bite (infected when they feed on an infected animal or via transovarian passage)

Bite of a infected animal

Ingestion of food (diseased animal) or water contaminated with Francisella tularensis

Contact with aerosolized bacteria (lawn mowing, farm workers, laboratory workers)

There is no person to person transmission.

Portal of entry of the infection:

Ulceroglandular tularemia – skin.

Glandular tularemia – unknown portal of entry but likely through the skin

Oropharyngeal tularemia – oropharyngeal mucosa

Oculoglandular tularemia -conjunctiva

Typhoidal tularemia – oropharyngeal mucosa or respiratory tract

Pneumonic tularemia – respiratory tract

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

Lymph node suppuration with glandular or ulceroglandular tularemia is the most common complication. The risk of lymph node suppuration increases if there is a delay in beginning appropriate antibacterial therapy.

Other possible complications include: sepsis, disseminated intravascular coagulation, renal failure, acute respiratory distress syndrome (ARDS), rhabdomyolysis, jaundice, hepatitis, meningitis, encephalitis,endocarditis, pericarditis, peritonitis, osteomyelitis, splenic rupture, rashes (maculopapular, erythema, erythema multiforme, pustular lesions) and thrombophlebitis.

Are additional laboratory studies available; even some that are not widely available?

N/A

How can tularemia be prevented?

Avoid areas that are tick infested.

Wear appropriate clothing that protects from tick and deer fly bites (long pants, long sleeves, tuck pants into long socks).

Insect repellents that contain DEET (diethyltoluamide) provide protection against ticks but need to be reapplied frequently.

Check for ticks frequently and remove any ticks as soon as possible using tweezers (not fingers). Grab the tick as close to the skin surface as possible and pull straight up. Wash hands immediately afterwards.

Avoid dead or sick animals.

Animals should not be skinned with bare hands – use gloves. Eye protection is also indicated.

All wild game should be cooked thoroughly before eating.

Do not drink untreated water.

When mowing, do not mow over any sick or dead animals.

There is no need for isolation in the hospital because there is no evidence for person-to-person transmission; standard precautions only.

What is the evidence?

Enderlin, G, Morales, L, Jacobs, RF. “Streptomycin and alternative agents for the treatment of tularemia: review of the literature”. Clin Infect Dis. vol. 19. 1994. pp. 42-7. (Literature review of in vitro susceptibilities, cure rates, and relapse rates of antibiotics used to treat tularemia. Cure rates were highest and relapse rates lowest for streptomycin. Gentamicin was noted to have similar efficacy to streptomycin. The reviewed studies included both adult and pediatric cases of tularemia.)

Cross, JT, Jacobs, RF. “Tularemia: treatment failures with outpatient use of ceftriaxone”. Clin Infect Dis. vol. 17. 1993. pp. 976-80. (This study showed that although ceftriaxone was effective in treating tularemia in vitro, it was associated with treatment failure when used in children with various types of tularemia. The study reaffirmed that aminoglycosides are the treatment of choice for tularemia.)

Jacobs, RF, Condrey, YM, Yamauchi, T. “Tularemia in adults and children: A changing presentation”. Pediatrics. vol. 76. 1985. pp. 818-22. (An excellent summary of the clinical characteristics of tularemia from a state with a high incidence of tularemia. Includes a comparison of the signs and symptoms of tularemia seen in children versus adults.)

Johansson, A, Berglund, L, Gothefors, L. “Ciprofloxacin for treatment of tularemia in children”. Pediatr Infect Dis J. vol. 19. 2000. pp. 449-53. (A study of 12 children with ulceroglandular tularemia successfuly treated with oral ciprofloxacin. The study was done in Sweden, where Francisella tularensis holarctica causes the majority of tularemia. F. tularensis holarctica causes far less severe disease than Francisella tularensis tularensis, the major causative agent of tularemia in North America.)

Tärnvik, A, Chu, MC. “New approaches to diagnosis and therapy of tularemia”. Ann N Y Acad Sci. vol. 1105. 2007. pp. 378-404. (Excellent review of techniques available for the diagnosis of tularemia, with an in-depth section on molecular methods of detection.)

Snowden, J, Stovall, S. “Tularemia: retrospective review of 10 years' experience in Arkansas”. Clin Pediatr (Phila). vol. 50. 2011. pp. 64-8. (Recent review of 30 cases of pediatric tularemia from 1996 through 2006 from a state with endemic tularemia. The majority of children were younger than 6 years of age and had ulceroglandular or glandular disease. Diagnosis was most commonly made serologicaly. Ninety-three percent of the patients were treated with gentamicin.)

Ongoing controversies regarding etiology, diagnosis, treatment

N/A

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