Tularemia Study Guide

Overview and Clinical Importance

Tularemia (also known as rabbit fever) is a highly infectious zoonotic disease caused by the gram-negative bacterium Francisella tularensis. This disease primarily affects lagomorphs (rabbits and hares) and rodents, often resulting in high mortality rates during outbreaks. Tularemia is considered a Category A bioterrorism agent and is a reportable disease in the United States due to its high infectivity, potential for airborne transmission, and significant public health implications.

Etiology and Microbiology

Causative Organism

Francisella tularensis is a small (0.2 x 0.2 μm), gram-negative coccobacillus that is nonmotile, nonspore-forming, and facultatively intracellular. The organism requires cysteine-enriched media for growth and is considered highly fastidious.

Subspecies Classification

Epidemiology

Geographic Distribution

Tularemia has been found in every U.S. state except Hawaii. The highest incidence occurs in Arkansas, Missouri, Oklahoma, and Kansas, which together account for more than half of reported cases. The disease is most commonly reported during late spring, summer, and early autumn when tick and deer fly vectors are most active.

Host Species and Reservoirs

Primary wildlife hosts: Cottontail rabbits, jackrabbits, snowshoe hares, beavers, muskrats, voles, ground squirrels, and prairie dogs

Domestic animals: Cats (most commonly affected), sheep, dogs, pigs, and horses. Cattle appear resistant to clinical disease.

Important note: Over 250 species including mammals, birds, reptiles, fish, and invertebrates can be infected.

Transmission and Pathogenesis

Routes of Transmission

Arthropod vectors: American dog tick (Dermacentor variabilis), Lone Star tick (Amblyomma americanum), Rocky Mountain wood tick (Dermacentor andersoni), and deer flies (Chrysops spp.)

Direct contact: Handling infected animals or carcasses, bites, scratches, or contact with contaminated tissues or fluids through broken skin or mucous membranes

Ingestion: Consumption of contaminated water, undercooked meat, or infected prey (important route for cats)

Inhalation: Aerosols from contaminated materials, disturbing carcasses during mowing, processing hay, or laboratory work

Pathogenesis

F. tularensis is a facultative intracellular pathogen that survives and replicates within macrophages. After entering the body, the organism:

• Is phagocytosed by macrophages at the entry site
• Escapes the phagosome into the cytoplasm within 30 minutes using acid phosphatase (AcpA) to prevent phagolysosome fusion
• Replicates rapidly in the cytosol, utilizing iron obtained via siderophores
• Causes macrophage lysis, releasing bacteria into bloodstream (bacteremia/septicemia)
• Disseminates hematogenously to liver, spleen, lymph nodes, lungs, and other organs
• Causes multifocal necrotizing lesions in affected organs

Clinical Signs in Rabbits and Small Mammals

Acute Presentation (Most Common)

The incubation period ranges from 1-10 days. Many rabbits and small mammals are found dead with no premonitory signs (peracute death). When clinical signs are observed, they include:

Fever: Acute onset, often greater than 40.5°C (105°F)

Depression and lethargy: Marked obtundation, reluctance to move

Anorexia: Complete loss of appetite with sharp decline in food and water intake

Respiratory signs: Dyspnea, tachypnea, nasal discharge

Lymphadenopathy: Enlarged, painful lymph nodes, particularly in head, neck, and mesenteric regions

Ataxia and incoordination: Progressive neurological signs may develop

Oral ulceration: Ulcers on tongue, oral mucosa, or pharynx

Chronic Presentation (Less Common)

Some animals may develop chronic infections with persistent lymphadenopathy, weight loss, and intermittent illness over weeks to months.

Pathologic Findings

Gross Necropsy Lesions

The most consistent and pathognomonic lesions are miliary white to tan foci of necrosis (1-2 mm diameter) scattered throughout multiple organs:

Liver: Multiple small white necrotic foci throughout parenchyma, mottled appearance with dark and light areas

Spleen: Splenomegaly with numerous white nodules, darker color than normal, extensive necrosis

Lungs: Multifocal pneumonia with necrotic foci, consolidated areas, possible hemorrhage

Lymph nodes: Marked enlargement with necrosis, particularly mesenteric, cervical, and mandibular nodes

Gastrointestinal tract: White foci in intestinal wall, ileus with gastric and intestinal distension, hemorrhage of serosa

Other findings: Fibrinous peritonitis, ascites, icterus, kidney lesions

Histopathologic Lesions

Multifocal necrotizing lesions: Acute, coagulative necrosis with pyogranulomatous inflammation in liver, spleen, lymph nodes, and lungs

Pneumonia: Necrotizing bronchopneumonia with PMN infiltration in alveolar ducts and airways

Vasculitis: Pulmonary arteritis is a prominent feature

Hepatic lesions: Multifocal necrotizing hepatitis with bacterial colonies visible in areas of necrosis

Diagnosis

Clinical Diagnosis

Tularemia should be suspected in rabbits or small mammals presenting with:

• Sudden death or peracute illness in endemic areas
• History of tick exposure or outdoor access
• Characteristic gross lesions (miliary necrosis in liver/spleen)
• Multiple animals affected in a die-off scenario

Laboratory Diagnosis

CRITICAL BIOSAFETY: Always notify diagnostic laboratories when tularemia is suspected. Do NOT perform necropsy outside of BSL-3 containment. Submission of intact carcass to diagnostic laboratory is strongly recommended to prevent human exposure.

Treatment

General Principles

Early treatment is critical to minimize mortality and decrease zoonotic risk. Suspected tularemia cases should be isolated immediately with strict biosafety protocols. Healthcare workers must wear N95 masks if pneumonia is suspected and take extreme care to avoid bites and needle-stick injuries.

Antimicrobial Therapy

Supportive Care

• Intravenous fluid therapy for dehydration and shock
• Nutritional support via syringe feeding or feeding tube
• Oxygen supplementation if respiratory compromise present
• Surgical drainage of abscesses may be required (use extreme caution)
• Pain management as appropriate

Prognosis

Prognosis for rabbits and wild lagomorphs is grave. Type A F. tularensis is particularly virulent in rabbits, with high mortality rates even with treatment. Most affected rabbits die within 3-10 days of infection. Domestic animals (cats, dogs, sheep) have better survival rates with early, aggressive treatment. Without treatment, tularemia is fatal in approximately 30-60% of cases in susceptible species; with appropriate antimicrobial therapy, mortality decreases to less than 5%.

Public Health and Zoonotic Significance

Human Infection

Tularemia is a serious zoonotic disease with approximately 126 cases reported annually in the United States. The infectious dose for humans is extremely low - as few as 10 organisms via inhalation or 25-50 organisms via skin inoculation can cause disease.

Clinical Forms in Humans

Ulceroglandular (most common, 75-85%): Skin ulcer at inoculation site with regional lymphadenopathy

Glandular: Lymphadenopathy without skin ulcer

Pneumonic: From inhalation; most severe form with high mortality if untreated

Oculoglandular: Conjunctivitis with preauricular lymphadenopathy

Oropharyngeal: Pharyngitis with cervical lymphadenopathy from ingestion

Typhoidal: Systemic disease without localizing signs; difficult to diagnose

Transmission to Humans

From infected animals: Cat bites or scratches, handling rabbits during hunting or necropsy, contact with contaminated tissues or fluids

Vector-borne: Tick bites (most common route in south-central U.S.), deer fly bites

Environmental: Inhalation during lawn mowing, handling contaminated hay, drinking contaminated water

Note: Human-to-human transmission has NOT been documented

Prevention and Biosafety

• Use BSL-3 practices for culture and necropsy of suspected cases
• Wear protective equipment: gloves, gowns, N95 masks, eye protection
• Avoid aerosol generation during necropsy or sample processing
• Always notify laboratory personnel when submitting specimens
• Educate clients about risks of handling wild rabbits and rodents
• Implement tick control measures for pets and livestock
• Cook wild game meat thoroughly (internal temperature greater than 165°F)
• Report all cases to state/federal health authorities as required

Exam Focus: Tularemia is a REPORTABLE disease in all U.S. states and is classified as a Category A Select Agent. Veterinarians are legally required to report confirmed or suspected cases to public health authorities. Failure to report can result in serious consequences. This is high-yield for NAVLE.

Differential Diagnoses

When evaluating a rabbit or small mammal with acute septicemia and necrotizing lesions, consider:

Plague (Yersinia pestis): Also causes acute septicemia with lymphadenopathy; geographic distribution differs; plague causes hemorrhagic lymphadenitis

Tyzzer disease (Clostridium piliforme): Causes multifocal hepatic necrosis but typically affects young animals; linear necrotic streaks in liver

Listeriosis: Can cause hepatic necrosis; more common in ruminants; neurologic signs prominent

Salmonellosis: Septicemic form causes multifocal necrosis; diarrhea more prominent

Pasteurellosis: Respiratory signs predominate; less likely to cause miliary hepatic/splenic lesions

Hepatic coccidiosis (Eimeria stiedae): Causes hepatic lesions but appears as linear, branching yellow-white lesions following bile ducts; may occur concurrently with tularemia