Infectious Diseases

Tularemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has tularemia? What should you expect to find?

  • Patients usually present with the abrupt onset of fever, chills, malaise, myalgias, chest discomfort vomiting, abdominal pain and diarrhea. A severe generalized headache is often present.

  • Ulcero-glandular fever - In the most common form of tularemia; in this form of tularemia22, a painful ulcer is observed with raised borders at the site where the bacteria were first inoculated into the skin. The lymph nodes draining this region are swollen and painful.

  • Glandular fever- Less commonly lymphadenopathy is observed without an ulcerative skin lesion.

  • Oculoglandular fever - if contaminated fluid splashes the eye or the eyes are rubbed with contaminated fingers conjunctivitis can develop that can be accompanied by conjunctival ulcers along with lymphadenopathy in the periauricular, submandibular and cervical areas.

  • Pharyngeal - contracted during ingestion of contaminated food. Pharyngitis is exudative and extremely painful, accompanied by regional lymphadenopathy.

  • Typhoidal form - high fever, hypotension and diarrhea is a third constellation of symptoms and signs. This form of tularemia is frequently mistaken for Salmonella typhoid fever.

  • Pneumonic tularemia - is rare in natural disease being rarely seen in sheep shearers, farmers and laboratory workers. Pneumonia caused by Francisella tularensis should always raise the possibility of an aerosol bioterrorist attack. Cough is usually dry, hacking and nonproductive. Respiratory complaints may not be present and the clinical picture may mimic the typhoidal form of disease.

How did the patient develop tularemia? What was the primary source from which the infection spread?

  • F. tularensis is a zoonotic pathogen and only incidentally infects humans. The disease is contracted through contact with animals, including rabbits, beaver, muskrats, squirrels, and birds. A case was reported following a hamster bite.

    • Hunters develop skin infections after skinning, dressing or eating an infected animal, Rabbits are the most commonly reported animal to spread the infection to humans

  • Infection less commonly can be transmitted by ticks, biting flies, and mosquitoes.

  • Aerosol droplets from contaminated water or mud can be created by using a lawn mower or while gardening. The organism is able to survive in water for long periods by taking up residence in Acanthamoeba castellanii.

  • This infection is seen in temperate climates during the summer months and during hunting season. This infection is most commonly reported in Arkansas, Missouri, Kansas, South Dakota, Oklahoma and Cailfornia. Outside the US it is seen in all of Europe except Great Britain, and also in the former Soviet Union, Turkey, Tunisia, Iran, Israel, China and Japan.

Which individuals are at greater risk of developing tularemia?

  • Occupational history is important to obtain along with animal exposures and outdoors activities. Hunters are at highest risk, along with sheep herders and shearers, farmers, landscapers and those spending time in the wilderness.

  • No known host defense defect is known to specifically predispose to tularemia.

  • Outcome is worse in the elderly and in those with underlying diseases.

Beware: there are other diseases that can mimic tularemia:

  • Ulcero-glandular and glandular fever can be mistaken for cat scratch disease, malignancy, atypical and typical mycobacterial infection, toxoplasmosis, fungal infection, herpes simplex infection, syphilis, bubonic plague, anthrax, and rat-bite fever,

  • Oculoglandular disease can be misdiagnosed as cat scratch disease, herpes simplex, adenovirus infection, or other forms of pyogenic conjunctivitis.

  • Pharyngeal disease can be misdiagnosed as Group A streptococcal pharyngitis, mononucleosis, adenoviral pharyngitis, or diphtheria.

  • Typhoidal disease - in addition to mimicking Salmonella tularemia can be mistaken for brucellosis, Q fever and endocarditis.

  • Pneumonic disease can be mistaken for Q fever, psittacosis, tuberculosis, pneumonic plague, pulmonary fungal infection, as well as community-acquired pneumonia.

  • A failure to respond to conventional antibiotics should raise the possibility of tularemia.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Routine diagnostic testing is usually not helpful.

    • The peripheral WBC can be elevated, normal or low in this disease.

    • The platelet count is depressed in some patients,

    • A low serum sodium may be observed.

    • Abnormal liver function tests

    • Elevated CPK may be seen as a consequence of rhabdomyolysis.

    • Pyuria can also be observed.

  • Aspiration of pleural fluid usually reveals lymphocytes suggesting the diagnosis of tuberculosis.

  • Gram stains of the sputum and skin lesions are usually unrevealing.

Results that confirm the diagnosis

  • Blood cultures are almost always negative because the organism does not grow on routine media, requiring either cysteine orcystine for growth.

    • This organism is dangerous for laboratory workers because an inoculum of 10-50 organisms is all that is required to cause disease.

    • When sending samples that may contain this organism the laboratory should be warned.

  • Organisms may be identified following sliver staining of lymph node biopsies

  • Diagnosis is usually made by testing for anti F. tularensis serum antibody. One of two tests is recommended

    • Tube agglutination - requires two weeks to become positive. A single titer of 1:160 or higher is supportive of the diagnosis, but could represent old disease. A rise in titer of 4-fold are greater in convalescent serum is considered diagnostic

    • Microagglutination assay - A titer of 1:128 or higher supports the diagnosis and a 4-fold or greater rise in titer in covalescent serum is felt to be diagnostic.

    • These tests should only be ordered if tularemia is a strong possibility and should not be used for routine screening.

  • A rapid, sensitive and specific PCR test has been reported, but is not widely available.

What imaging studies will be helpful in making or excluding the diagnosis of tularemia?

  • CXR may reveal a bronchopneumonia pattern of opacification in 50% of inhalation cases. Pleural effusions are noted in 15% of cases. $

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What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Given the fact that tularemia can mimic many infectious diseases, an infectious disease consultation will generally be helpful. Surgery may be consulted in some cases to obtain a lymph node biopsy.

If you decide the patient has tularemia, what therapies should you initiate immediately?

Key principles of therapy:

F. tularensis is not sensitive to cephalosporins or penicillins. In patients who fail to respond to these empiric antibiotics the possibility of tularemia should be considered. Aminoglycosides are the treatment of choice. Most experience is with streptomycin and many regard this antibiotic as the treatment of choice. However, in most developed countries gentamicin is more readily available. For mild disease oral doxycycline is recommended. Because the organism grows within cells, relapse is quite common following doxycycline treatment. Usually a more prolonged course of doxycycline for 21 days will prove effective. Alternatively treatment with an aminoglycoside can be initiated. There is less experience with the use of fluoroquinolones for the treatment of tularemia; however, of 14 cases recently treated in Missouri with ciprofloxacin, 86% were cured.

Delay in therapy worsens the prognosis. Untreated patients suffer continued weight loss, lassitude and often have prominent lymphadenopathy.

1. Anti-infective agents

Treatment for Tularemia

See Table I.

Table I.

Treatment for Tularemia.
Moderate to severe disease Dosage Duration Comments
StreptomycinGentamicinChloramphenicol 10 mg/kg IM Q12h 5 mg/kg IV Q24h15-25 mg/kg IV q6h 7-10 days7-10 days14-21 days streptomycin preferred if available. Aminoglycosides need to be adjusted for renal insufficiency
Mild diseases
DoxycyclineCiprofloxacin 100 mg po Q12h500-750 mg Q12h po 14 days
Meningitis
combine an aminoglycoside and chloramphenicol doses above

2. Other key therapeutic modalities.

  • Suppurative lymph nodes may require surgical drainage

What complications could arise as a consequence of tularemia?

Severe cases may result in

  • Sepsis

  • Renal failure

  • Rhabdomyolysis

  • Hepatitis

In pneumonic disease, empyema can develop and require surgical decortication

Other rarer complications include:

  • Osteomyelitis and prosthetic joint infections

  • Pericarditis

  • Endocarditis

  • Meningitis - may occur 3-30 days after the onset of illness. Lymphs and monocytes seen in the CSF with a low glucose and increased protein.

  • Peritonitis

What should you tell the family about the patient's prognosis?

Usually patients with tularemia respond to antibiotics and are cured. When lymph nodes are draining large amounts of pus we usually recommend surgical drainage.

We find patients do worse when they are:

  • elderly

  • have an underlying disease.

  • have pneumonic or typhoidal disease.

  • have renal failure

  • if antibiotic therapy was delayed or inadequate

What pathogens are responsible for this disease?

Francisella tularensis

  • is a small aerobic Gram negative cocco-bacillus

  • requires either cysteine or cystine for growth.

  • is able to be grown on glucose–cystine blood agar

Selective medium is often required to isolate this pathogen from normal skin and mouth flora.

How does F. tularnesis cause disease ?

  • Pathogenesis

    • The cell wall of this bacterium has a capsule with high fatty acid content that resists serum bactericidal activity.

    • Produces no known exotoxins

    • Expresses a lipopolysaccharide (LPS) endotoxin that is 1/1000th as potent as LPS from E. coli.

    • Tularemia usually begins when the organism gains entry to the body through a small break in the skin.

      • Phagocytosed by monocytes, where it is able to survive intracellularly

        • Escapes from the phagolysosome into the cytoplasm where it readily multiplies.

        • F. tularensis can also grow in hepatocytes and endothelial cells.

      • As the organisms grow and lyse cells, they induce an acute inflammatory reaction, and tissue necrosis is followed by granuloma formation.

      • Cell-mediated immunity plays a critical role in controlling this intracellular pathogen.

      • Only 10 to 50 bacteria are required to cause skin and pulmonary infection, making this organism extremely dangerous to laboratory workers.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Conlan, JW. "Tularemia vaccines: recent developments and remaining hurdles". Future Microbiol.. vol. 6. 2011. pp. 391-405.

(Reviews the recently developed vaccines and the hurdles they face before reaching the public.)

Eliasson, H, Back, E. "Tularaemia in an emergent area in Sweden: an analysis of 234 cases in five years". Scand J Infect Dis.. vol. 39. 2007. pp. 880-889.

(A retrospective study. About half of patients had skin lesions in addition to the primary lesion. Cough was a frequent complaint in all forms of tularemia. Diagnosis and treatment were often delayed. No cases were fatal.)

Kugeler, KJ, Mead, PS, Janusz, AM. "Molecular Epidemiology of Francisella tularensis in the United States". Clin Infect Dis. vol. 48. Apr 1 2009. pp. 863-870.

(Francisella tularensis subtypes A1a,b and A2 cause most of the disease in the U.S.A. A1b strains are more virulent in humans than A1a, A2 or type B strains.)

Matyas, BT, Nieder, HS, Telford, SR. "Pneumonic tularemia on Martha's Vineyard: clinical, epidemiologic, and ecological characteristics". Ann N Y Acad Sci.. vol. 1105. 2007. pp. 351-377.

(The site of the only two recognized outbreaks of primary pneumonia tularemia in the United States. 60% of cases of tularemia were pneumonic. Landscaping activities were the major risk factor for inhalation disease The main host was found to be dog ticks, skunks and raccoons.)

Santic, M, Al-Khodor, S, Abu Kwaik, Y. "Cell biology and molecular ecology of Francisella tularensis". Cell Microbiol.. vol. 12. 2010. pp. 129-139.

(Once within the macrophage phagolysosome the organism escapesinto the cytosol within 30-60 minutes. Intracellular bacteria trigger interferon release and the generation of inflammasomes.)

Thomas, LD, Schaffner, W. "Tularemia pneumonia". Infect Dis Clin North Am.. vol. 24. 2010. pp. 43-55.

(In addition to inhalation, pneumonia can be a secondary manifestation of ulceroglandular or typhoidal disease. This is the expected primary manifestation of bioterrorist attack resulting from aerosolized F. tularensis.)

Weber, IB, Turabelidze, G, Patrick, S, Griffith, KS, Kugeler, KJ, Mead, PS. "Clinical recognition and management of tularemia in Missouri: a retrospective records review of 121 cases". Clin Infect Dis.. vol. 55. 2012. pp. 1283-1290.

(A retrospective review of cases from 2000-2007. The majority of cases were attributed to tick bites. Systemic disease occurred more frequently in elderly patients. Oral ciprofloxacin was found to be efficacious in 9 of 10 patients who received this agent.)
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