Tularemia¶

Chapter 175 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 175

Key Clinical Points¶

Tularemia is a zoonotic disease caused by Francisella tularensis, a small (0.2–0.7 × 0.2 μm), facultatively intracellular, aerobic, gram-negative, pleomorphic bacterium.
Two clinically significant subspecies exist: F. tularensis s.l. tularensis (Type A) and F. tularensis s.l. holarctica (Type B).
Clinical recognition can be challenging; patients often present with acute fever and influenza-like illness, potentially mimicking malignancy or other infections like tuberculosis.
The incubation period is typically 3–5 days but can range from 1 to 21 days.
Serology is the mainstay diagnostic tool, requiring a significant (fourfold) increase in antibody titers between samples taken 2–4 weeks apart.
Culture of F. tularensis requires BSL-3 containment and is associated with significantly reduced odds of survival (OR, 0.1).
Early specific antimicrobial treatment (ciprofloxacin, levofloxacin, gentamicin, or doxycycline) is essential to prevent complications.
Treatment duration is typically at least 10 days; relapse occurs in up to 30% of poorly compliant patients.
Postexposure prophylaxis is recommended for high-risk exposures, such as aerosol-generating procedures with F. tularensis cultures outside a BSL-3 cabinet.
Historically, case fatality rates were 5–15%, and up to 60% for respiratory/pneumonic tularemia; recent data show a 3.0% death rate.

1. DEFINITION & OVERVIEW¶

Tularemia is a zoonotic disease transmitted from vertebrate animals to humans, causing a febrile illness.

Synonyms: Deer-fly fever, rabbit fever, market men’s disease, water-rat trappers’ disease, wild hare disease (yato-byo), Francis’ disease, and Ohara’s disease.

Historical Context: Described in 1911 as a 'plage-like disease of rodents.' The bacterium was originally named Bacterium tularense after Edward Francis.

1.1 Biosafety & Laboratory Handling¶

• Pathogen Characteristics: F. tularensis is a small (0.2–0.7 × 0.2 μm), facultatively intracellular, aerobic, gram-negative, pleomorphic bacterium.

• Risk Level: Highly virulent for humans and mammals; known to cause airborne laboratory-acquired infection. It is a U.S. Department of Health and Human Services (HHS) Tier 1 Select Agent.

• Containment: Culturing and handling must be performed by trained staff in biologic safety cabinets under Biosafety Level 3 (BSL-3) conditions.

2. EPIDEMIOLOGY¶

Transmission Routes: • Arthropod bites (mosquitoes, ticks, tabanid flies). • Inhaling infectious aerosols. • Handling infected animals or contaminated material. • Ingestion of contaminated water/food.

Dynamics: Cases often represent 'bridging' between environmental maintenance and spillover from animal populations (e.g., rodents, hares, rabbits) during epizootics.

2.1 Maintenance in Nature¶

• Environmental Persistence: Potential survival in decaying tissues of dead animals or in water with protozoa (e.g., amoeba) serving as host cells.

• Subspecies Ecology: ◦ Type A (F. t. tularensis): Associated with rabbits, ticks, domestic cats, and sheep in dry environments; primarily North American. ◦ Type B (F. t. holarctica): Associated with water sources (streams, ponds, lakes) and semi-aquatic animals (muskrats, beavers); found globally (e.g., Finland, Sweden, Turkey).

3. ETIOLOGY & PATHOPHYSIOLOGY¶

Pathogen Diversity: • Type A (F. t. tularensis): Human disease documented exclusively in North America. • Type B (F. t. holarctica): Human disease documented in North America and other parts of the world. • Type C (F. t. mediasiatica): Isolated from animals in Central Asia/Russia; no documented human disease.

3.1 Immune Response¶

• Immune Evasion: The bacterium delays the immune response to permit rapid systemic distribution.

• Cellular Response: Requires both B and T cells; antigen-specific recall T cell responses persist 25–30 years after infection or vaccination.

• Mediators: Involves complement, antibodies, neutrophils, inducible NO synthase, phagocyte oxidase, and cytokines (IFN-γ, TNF-α, IL-12).

4. CLINICAL FEATURES¶

Clinical Recognition: Often difficult; may be misdiagnosed as lung cancer, head/neck cancer, lymphoma, or tuberculosis due to lack of overt fever or similarity in imaging.

4.1 Clinical Forms¶

• Ulceroglandular or glandular: Skin inoculation via arthropods or direct contact → local ulcer and regional lymphadenopathy.

• Oropharyngeal: Ingestion of contaminated food/water.

• Oculoglandular: Contact with eyes via contaminated fingers or aerosol exposure.

• Respiratory/pneumonic: Inhalation of contaminated aerosols.

• Typhoidal: Likely inhalation; rarely ingestion.

• Other Manifestations: Primary tularemia meningitis, endocarditis, and bone/joint infections.

4.2 Laboratory Findings¶

• Routine Biochemistry: Generally unspecific (may show elevated liver enzymes or RBCs in urine).

• C-reactive protein (CRP): ◦ Outpatients (Type B): Median 78 mg/L (range 30–130) at peak (days 7–9). ◦ Severe Respiratory (Bacteremic): 100–400 mg/L. ◦ Severe Respiratory (Nonbacteremic): 50–220 mg/L.

5. DIFFERENTIAL DIAGNOSIS¶

• Malignancy: Lung cancer, head and neck cancer, lymphoma.

• Infectious Diseases: Tuberculosis (TB), other diseases with lymphoid tissue engagement, common community-acquired pneumonia, or undifferentiated fever/sepsis.

6. INVESTIGATIONS & DIAGNOSIS¶

Laboratory confirmation may be based on recovery of an F. tularensis isolate, specific antigens, nucleic acids, or serology.

6.1 Specimen Collection¶

• Ulcer specimens: Sample from the edge of the wound; remove scabs before sampling.

• Lower respiratory tract: Sputum, tracheal washing, or bronchoalveolar lavage (BAL).

• Other sites: Lymph node biopsies/aspirates and blood cultures.

6.2 Imaging Findings¶

• Chest X-ray: Useful for respiratory tularemia; shows consolidation, pleural effusion, and hilar/mediastinal lymphadenopathy.

• CT Scan: May reveal multiple rounded subpleural consolidations with inclusion necrosis and a distinct marginal zone.

7. MANAGEMENT & TREATMENT¶

Early specific antimicrobial treatment is essential to avoid complications.

7.1 Pharmacologic Treatment¶

• Ciprofloxacin: 400 mg every 8 hrs IV or 750 mg every 12 hrs PO for 10–21 days.

• Levofloxacin: 750 mg every 24 hrs IV or PO for 10–21 days.

• Gentamicin: 5–7 mg/kg IV or IM per day (every 12 or 24 hours) for 7–14 days; avoid in renal impairment.

• Doxycycline: 200 mg loading dose, then 100 mg every 12 hrs IV or PO for 10–21 days.

7.2 Postexposure Prophylaxis¶

• Doxycycline: 100 mg PO twice daily for 14 days.

• Ciprofloxacin: 500 mg every 12 hrs PO for 10 days.

• Indication: Recommended for high-risk exposures, such as aerosol-generating procedures with F. tularensis cultures outside a BSL-3 cabinet.

8. PROGNOSIS & COMPLICATIONS¶

• Historical Mortality: 5–15% overall; up to 60% for respiratory/pneumonic tularemia.

• Recent Data (2006–2021): 3.0% death rate among 903 patients.

• Culture Correlation: Culture of F. tularensis from clinical specimens is associated with significantly reduced odds of survival (OR, 0.1).

9. SPECIAL CONSIDERATIONS¶

• High-Risk Exposure: Postexposure prophylaxis is required for personnel performing aerosol-generating procedures with F. tularensis cultures outside a BSL-3 cabinet.

10. KEY PEARLS & CLINICAL TRAPS¶

• Clinical Mimicry: Tularemia can mimic malignancy on imaging (e.g., lung cancer).

• Serology Requirement: Diagnosis requires paired sera to confirm a significant (fourfold) increase in antibody titers.

• Culture Risk: Culture is not routinely feasible due to high virulence and BSL-3 requirements; positive cultures are associated with poorer outcomes.

Reference Tables¶

TABLE 175-1 Clinical Forms of Tularemia FORM a Ulceroglandular or glandular Oropharyngeal Oculoglandular…¶

Harrison's 22e, p.1338

FORMa	F. TULARENSIS INFECTION ROUTE
Ulceroglandular or glandular	Skin inoculation by blood-feeding arthropods or direct contact (touching infected animal or F. tularensis contaminated material)
Oculoglandular	Touching the eye with contaminated fingers or exposure to contaminated aerosol
Typhoidal	Unknown (likely by inhalation, rarely by ingestion)

TABLE 175-2 Treatment and Postexposure Prophylaxis Recommendations for Adult Patients with Tularemia or with…¶

Harrison's 22e, p.1340

ADULTS, INCLUDING PREGNANT WOMEN
	DRUG	DOSEa	DURATION (DAYS)
Preferred choices	Ciprofloxacin	400 mg every 8 hrs IV or 750 mg every 12 hrs PO	10
	Levofloxacin	750 mg every 24 hrs IV or PO	10
	Gentamicin	5–7 mg/kg IV or IM per day, given every 12 hrs or 24 hrs	10
	Doxycyclinec	200 mg loading dose, then 100 mg every 12 hrs IV or PO
Postexposure prophylaxisd	Doxycycline	100 mg PO twice daily	14
	Ciprofloxacin	500 mg every 12 hrs PO	10