Tularemia, Emergency Medicine

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Tularemia, Emergency Medicine

Basics

Description

Outpatient therapy: Oral or IM therapy for mild illness with close follow-up

Critical care and infectious disease consultation to assist in assessment of differential considerations and manage life-threatening complications

Infectious disease consultation to manage ongoing treatment and reduce subsequent exposures

Tularemia is an acute febrile illness caused by the small aerobic gram-negative pleomorphic intracellular coccobacillus Francisella tularensis:Organism is highly infectious.Person-to-person transmission has not been reported.
Humans become infected through different environmental exposures:Bites from infected tick, deerfly, mosquito, or other infected insectDirect contact with infectious animal tissue or fluidContact with or ingestion of contaminated food, water, or soilInhalation of infected aerosols (e.g., cutting grass with power mowers, which may aerosolize the organism)
The 4 major strains of the bacterium have different virulence and geographic location:2 subspecies cause human infection in North America: F. tularensis subspecies tularensis (type A, more virulent) and F. tularensis subspecies holartica (type B, less virulent)
Natural hosts:Lagomorphs and other rodentsFound in species of wild animals (insects, rabbits, hares, ticks, flies, muskrats, beavers, mice), domestic animals (sheep, cattle, cats), ticks, and water and soil contaminated by infected animals
Natural vectors:TicksBiting fliesMosquitoesWild rabbits
Weaponization of tularemia was accomplished during the Cold War:Because of its virulence and ability to be aerosolized, it remains a potential biologic agent for mass destruction.
Lab technicians handling culture specimens are at high risk:F. tularensis cultures should be manipulated only in a biosafety level 3 facility.
Also known as "rabbit fever " or "deerfly fever "

Organism is highly infectious.
Person-to-person transmission has not been reported.

Bites from infected tick, deerfly, mosquito, or other infected insect
Direct contact with infectious animal tissue or fluid
Contact with or ingestion of contaminated food, water, or soil
Inhalation of infected aerosols (e.g., cutting grass with power mowers, which may aerosolize the organism)

2 subspecies cause human infection in North America: F. tularensis subspecies tularensis (type A, more virulent) and F. tularensis subspecies holartica (type B, less virulent)

Lagomorphs and other rodents
Found in species of wild animals (insects, rabbits, hares, ticks, flies, muskrats, beavers, mice), domestic animals (sheep, cattle, cats), ticks, and water and soil contaminated by infected animals

Ticks
Biting flies
Mosquitoes
Wild rabbits

Because of its virulence and ability to be aerosolized, it remains a potential biologic agent for mass destruction.

F. tularensis cultures should be manipulated only in a biosafety level 3 facility.

Etiology

Individuals who spend time outdoors in endemic areas are at higher risk:FarmersHuntersForest workersThose who handle animal carcasses are at highest risk (taxidermists and butchers).Two-thirds of cases occur in males.
Although tularemia can occur worldwide, it is endemic in the northern hemisphere:Reported nationwide except in HawaiiStates with the highest incidence include Missouri, Arkansas, Kansas, South Dakota, and Oklahoma.Few hundred cases annually in US, although probably underreportedPeak season is June " October.
Mortality is 5 " 15%. Appropriately treated patients have mortality as low as 1%.

Farmers
Hunters
Forest workers
Those who handle animal carcasses are at highest risk (taxidermists and butchers).
Two-thirds of cases occur in males.

Reported nationwide except in Hawaii
States with the highest incidence include Missouri, Arkansas, Kansas, South Dakota, and Oklahoma.
Few hundred cases annually in US, although probably underreported
Peak season is June " October.

25% of cases occur in children 1 " 14 yr of age.
Children who spend time outdoors in endemic rural areas are at highest risk.

Diagnosis

Signs and Symptoms

Tularemia has different presentations based on route of entry:Primary route of entry is through skin; most often a cutaneous ulcer develops.
Incubation is 3 " 5 days, range 1 " 14 days. Lesion usually begins as papule, often with fever.
6 forms of illness:Ulceroglandular:Most common presentation (70 " 80% of cases)Inoculated cutaneously (scratch, abrasion, insect bite) with as few as 50 organismsInitially, a local cutaneous papule at point of entryFollowed by tender regional adenopathy and constitutional symptoms to include fever, chills, myalgias, and headachesAssociated with pneumonia in 30% of casesGlandular:Rare formGains access to lymphatic system or bloodstream through inapparent abrasionTender regional lymphadenopathy with no local lesionsOculoglandular:Rare formOrganism enters through a splash of infected blood/fluid to the eye or is introduced by eye rubbing after handling infectious materials (e.g., rabbit carcass).Edema, conjunctivitis, injection, chemosis with periauricular, submandibular, or cervical lymphadenopathyPharyngeal:Rare formFrom ingestion of contaminated food or waterSevere throat pain with exudative pharyngitis and regional lymphadenitisPneumonic:Secondary to inhalationSeen in sheep shearers, farmers, landscapers, and lab techniciansFever, dry cough, and pleuritic chest pain develop.Pneumonia can occur in 30% of patients with ulceroglandular tularemiaTyphoidal:Historically, the typhoidal form defined as devoid of skin or mucous membrane lesion or remarkable lymph node enlargement.No known point of entry (probably oral or respiratory).Only when no route of infection can be established may the term still be acceptable.In North America, where type A is prevalent, fulminant manifestations are reported, including severe sepsis, meningitis, endocarditis, hepatic failure, and renal failure.Septicemia associated with type A tularemia is usually extremely severe and potentially fatal. High fever, abdominal pain, and diarrhea may occur early in the course of disease.

Primary route of entry is through skin; most often a cutaneous ulcer develops.

Ulceroglandular:Most common presentation (70 " 80% of cases)Inoculated cutaneously (scratch, abrasion, insect bite) with as few as 50 organismsInitially, a local cutaneous papule at point of entryFollowed by tender regional adenopathy and constitutional symptoms to include fever, chills, myalgias, and headachesAssociated with pneumonia in 30% of cases
Glandular:Rare formGains access to lymphatic system or bloodstream through inapparent abrasionTender regional lymphadenopathy with no local lesions
Oculoglandular:Rare formOrganism enters through a splash of infected blood/fluid to the eye or is introduced by eye rubbing after handling infectious materials (e.g., rabbit carcass).Edema, conjunctivitis, injection, chemosis with periauricular, submandibular, or cervical lymphadenopathy
Pharyngeal:Rare formFrom ingestion of contaminated food or waterSevere throat pain with exudative pharyngitis and regional lymphadenitis
Pneumonic:Secondary to inhalationSeen in sheep shearers, farmers, landscapers, and lab techniciansFever, dry cough, and pleuritic chest pain develop.Pneumonia can occur in 30% of patients with ulceroglandular tularemia
Typhoidal:Historically, the typhoidal form defined as devoid of skin or mucous membrane lesion or remarkable lymph node enlargement.No known point of entry (probably oral or respiratory).Only when no route of infection can be established may the term still be acceptable.In North America, where type A is prevalent, fulminant manifestations are reported, including severe sepsis, meningitis, endocarditis, hepatic failure, and renal failure.Septicemia associated with type A tularemia is usually extremely severe and potentially fatal. High fever, abdominal pain, and diarrhea may occur early in the course of disease.

Most common presentation (70 " 80% of cases)
Inoculated cutaneously (scratch, abrasion, insect bite) with as few as 50 organisms
Initially, a local cutaneous papule at point of entry
Followed by tender regional adenopathy and constitutional symptoms to include fever, chills, myalgias, and headaches
Associated with pneumonia in 30% of cases

Rare form
Gains access to lymphatic system or bloodstream through inapparent abrasion
Tender regional lymphadenopathy with no local lesions

Rare form
Organism enters through a splash of infected blood/fluid to the eye or is introduced by eye rubbing after handling infectious materials (e.g., rabbit carcass).
Edema, conjunctivitis, injection, chemosis with periauricular, submandibular, or cervical lymphadenopathy

Rare form
From ingestion of contaminated food or water
Severe throat pain with exudative pharyngitis and regional lymphadenitis

Secondary to inhalation
Seen in sheep shearers, farmers, landscapers, and lab technicians
Fever, dry cough, and pleuritic chest pain develop.
Pneumonia can occur in 30% of patients with ulceroglandular tularemia

Historically, the typhoidal form defined as devoid of skin or mucous membrane lesion or remarkable lymph node enlargement.
No known point of entry (probably oral or respiratory).
Only when no route of infection can be established may the term still be acceptable.
In North America, where type A is prevalent, fulminant manifestations are reported, including severe sepsis, meningitis, endocarditis, hepatic failure, and renal failure.
Septicemia associated with type A tularemia is usually extremely severe and potentially fatal. High fever, abdominal pain, and diarrhea may occur early in the course of disease.

Exposure and epidemiologic risk factors can be helpful.
Sudden fever, chills, headaches
Progression of components of signs and symptoms may be useful in defining form of illness.

Fever
Tender, well-demarcated cutaneous ulcer
Tender regional lymphadenopathy; lymph nodes can develop fluctuance and spontaneously drain.
Exudative pharyngitis (with pharyngeal tularemia)
Ulcerations of the conjunctiva with pronounced chemosis (with oculoglandular tularemia)

Diagnosis Tests & Interpretation

No rapid diagnostic test available
Routine lab studies nonspecific:CBC can be normal.ESR might be slightly elevated.CSF: May have increased protein or mild pleocytosisLFTs are often abnormal.
Gram stain, cultures, and tissue biopsies:Often negative
Blood cultures usually negative because of specific growth requirements
Enzyme-linked immunosorbent assay and polymerase chain reaction are available through reference labs.
Serum antibody titers:Typically do not reach diagnostic levels until ≥10 days after the onset of illnessA single titer of at least 1:160 for tube agglutination is diagnostic for F. tularensis infection.May not be elevated before day 11 of illness and generally are diagnostic after 16th day.

CBC can be normal.
ESR might be slightly elevated.
CSF: May have increased protein or mild pleocytosis
LFTs are often abnormal.

Often negative

Typically do not reach diagnostic levels until ≥10 days after the onset of illness
A single titer of at least 1:160 for tube agglutination is diagnostic for F. tularensis infection.
May not be elevated before day 11 of illness and generally are diagnostic after 16th day.

Chest radiograph for:Consolidative process, pleural effusions, and hilar adenopathy
CT scan of chest for:Severe pulmonary symptomsOther possible etiologies of atypical pneumonia

Consolidative process, pleural effusions, and hilar adenopathy

Severe pulmonary symptoms
Other possible etiologies of atypical pneumonia

Differential Diagnosis

Ulceroglandular tularemia mimics include:TuberculosisCatscratch diseaseSyphilisChancroidLymphogranuloma venereumToxoplasmosisSporotrichosisRat-bite feverAnthrax
Oculoglandular tularemia mimics include:Adenoviral infection
Pharyngeal tularemia mimics include:DiphtheriaBacterial pharyngitisInfectious mononucleosisAdenoviral infection
Typhoidal tularemia mimics include:SalmonellosisBrucellosisLegionnaire diseaseQ feverMalariaDisseminated fungal or mycobacterial infections
Pulmonary tularemia mimics include:Mycoplasmal infectionLegionnaire diseaseChlamydial infectionTuberculosis

Tuberculosis
Catscratch disease
Syphilis
Chancroid
Lymphogranuloma venereum
Toxoplasmosis
Sporotrichosis
Rat-bite fever
Anthrax

Adenoviral infection

Diphtheria
Bacterial pharyngitis
Infectious mononucleosis
Adenoviral infection

Salmonellosis
Brucellosis
Legionnaire disease
Q fever
Malaria
Disseminated fungal or mycobacterial infections

Mycoplasmal infection
Legionnaire disease
Chlamydial infection
Tuberculosis

Treatment

Pre-Hospital

Universal precautions
Management of ABCs
Treat dehydration/hypotension with boluses of normal saline.

Initial Stabilization/Therapy

ABCs
Supplemental oxygen for hypoxia
Fluid resuscitation with normal saline for intravascular volume depletion or septic shock
Central line access for unstable patients
Vasopressors for persistent hypotension

Ed Treatment/Procedures

Fever control with acetaminophen
Early administration of antibiotic therapy after obtaining cultures
Antibiotic options:1st-line agents: Streptomycin or gentamicin continued for 10 daysCiprofloxacin if community-acquired pneumonia is in the differential diagnosis of patients ≥18 yr of ageTetracycline or doxycycline in those >8 yr of age; or chloramphenicol:Continue for 14 days, since these drugs are only bacteriostatic.Associated with a higher rate of treatment failures than the previously mentioned antibiotics3rd tier of treatment, since they are static
F. tularensis is resistant to ²-lactam drugs and carbapenems

1st-line agents: Streptomycin or gentamicin continued for 10 days
Ciprofloxacin if community-acquired pneumonia is in the differential diagnosis of patients ≥18 yr of age
Tetracycline or doxycycline in those >8 yr of age; or chloramphenicol:Continue for 14 days, since these drugs are only bacteriostatic.Associated with a higher rate of treatment failures than the previously mentioned antibiotics3rd tier of treatment, since they are static

Continue for 14 days, since these drugs are only bacteriostatic.
Associated with a higher rate of treatment failures than the previously mentioned antibiotics
3rd tier of treatment, since they are static

Medication

Gentamicin: 5 mg/kg IV or IM q24h (peds: 2.5 mg/kg IV or IM q8h) 10 days
Streptomycin: 1 g IM (peds: 15 mg/kg, not to exceed 2 g/d) q12h 10 days

Ciprofloxacin: 400 mg IV q12h 10 days
Doxycycline: 100 mg (peds: If weight ≥45 kg and child >8 yr, 100 mg; if weight ≤45 kg and child >8 yr, 2.2 mg/kg) IV q12h for at least 14 days (longer treatment needed since doxycycline is bacteriostatic); max. 200 mg/d
Chloramphenicol is usually avoided due to the possibility of adverse reactions. However, chloramphenicol may be considered in cases of tularemic meningitis due to its ability to cross the blood " brain barrier and reach higher concentrations in the CSF.

Follow-Up

Disposition

ICU admission for advanced age, neutropenia, severe hypoxemia, hemodynamic instability, or patients presenting with typhoidal tularemia
Inpatient floor bed admission for mild to moderate illness:Isolation bed required only for the purpose of ruling out other etiology (e.g., tuberculosis)

Isolation bed required only for the purpose of ruling out other etiology (e.g., tuberculosis)

Followup Recommendations

Pearls and Pitfalls

Patients presenting with high fever and regional lymphadenopathy, especially if there is an ulcer or conjunctivitis, should have tularemia in the differential.
Epidemiology may be useful in pointing to this diagnosis.
Definitive diagnosis ultimately based upon serology, which usually isnt positive until >10 days of infection.
Vaccine currently under review by FDA; not currently available in US
Currently listed as category A (critical agent of concern) bioterrorism agent because of pathogenicity. It can be disseminated via dispersal in food, water, or air.

Additional Reading

American Academy of Pediatrics. Red Book 2012 Report of the Committee on Infectious Diseases. Elk Grove, IL: AAP; 2012.
Centers for Disease Control and Prevention. Available at www.cdc.gov/tularemia. Accessed on January 2011.
Hofinger DM, Cardona L, Mertz GJ, et al. Tularemic meningitis in the United States. Arch Neurol. 2009;66(4):523 " 527.
Snowden J, Stovall S. Tularemia: Retrospective review of 10 years ' experience in Arkansas. Clinical Pediatrics. 2011;50(1):64 " 68.
Treat JR, Hess SD, McGowan KL, et al. Ulceroglandular tularemia. Pediatr Dermatol. 2011;28(3):318 " 320.
World Health Organization Guidelines on Tularemia, 2007.

Codes

ICD9

021.0 Ulceroglandular tularemia
021.3 Oculoglandular tularemia
021.9 Unspecified tularemia
021.2 Pulmonary tularemia
021.1 Enteric tularemia
021.8 Other specified tularemia
021 Tularemia

ICD10

A21.0 Ulceroglandular tularemia
A21.1 Oculoglandular tularemia
A21.9 Tularemia, unspecified
A21.2 Pulmonary tularemia
A21.3 Gastrointestinal tularemia
A21.7 Generalized tularemia
A21.8 Other forms of tularemia
A21 Tularemia

SNOMED

19265001 Tularemia (disorder)
37722001 Ulceroglandular tularemia (disorder)
73363000 Oculoglandular tularemia (disorder)
45556008 Pulmonary tularemia
34023009 Generalized tularemia (disorder)
398599000 Enteric tularemia