Tularemia

1. Overview
2. Causative Agent and Microbiology
3. Epidemiology and Reservoirs
4. Transmission Routes
5. Clinical Presentations
6. Ulceroglandular and Glandular Tularemia
7. Pneumonic and Typhoidal Tularemia
8. Diagnosis
9. Treatment
10. Bioterrorism Potential and Post-Exposure Prophylaxis
11. References
12. Connections
13. Featured Videos

Overview

Tularemia — commonly called rabbit fever or deer fly fever — is a serious bacterial zoonosis caused by Francisella tularensis, one of the most infectious bacteria known to science. A single exposure to as few as 10 organisms via skin or aerosol is sufficient to cause disease in a healthy adult; roughly 50 inhaled organisms can produce potentially fatal pneumonic tularemia. Because of this extreme infectivity and the severity of its aerosol form, F. tularensis is classified as a Biosafety Level 3 (BSL-3) agent and a Category A bioterrorism select agent by the Centers for Disease Control and Prevention.

The disease was first described in Tulare County, California in 1911, when George McCoy identified the bacterium in ground squirrels. Edward Francis later characterized its clinical spectrum in humans through the 1920s, and the organism now bears his name. Tularemia affects a wide range of mammals — particularly rabbits, hares, and rodents — and reaches humans through tick bites, deer fly bites, direct animal contact, inhalation, or ingestion. Outcomes range from a self-limited skin ulcer with swollen lymph nodes to rapidly progressive pneumonia with respiratory failure. With prompt antimicrobial therapy the prognosis is excellent; without treatment, mortality from pneumonic and typhoidal forms can reach 30–60%.

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Causative Agent and Microbiology

Francisella tularensis is a gram-negative, facultative intracellular coccobacillus. On Gram stain it appears as tiny, pleomorphic, poorly staining rods that are easily missed on routine examination. The organism is nonmotile and fastidious — it does not grow on standard laboratory media and requires cysteine-supplemented media such as buffered charcoal yeast extract (BCYE) or chocolate agar for isolation. It does not ferment lactose. Because the organism survives within macrophages and resists phagocytic killing, cell-mediated immunity is central to host defense, and antibody titers rise relatively slowly — often not reaching diagnostic levels until the second week of illness.

Two main subspecies are responsible for virtually all human disease:

• F. tularensis subspecies tularensis (Type A) — found almost exclusively in North America; considered the more virulent subspecies; responsible for the majority of disease in the United States; untreated pneumonic infection carries a 5–30% case fatality rate.
• F. tularensis subspecies holarctica (Type B) — distributed across Europe, Asia, and North America; causes milder illness; strongly associated with aquatic environments and waterborne transmission; rarely fatal even without treatment.

A third subspecies, mediasiatica, exists in Central Asia but is not a significant cause of human disease. The organism's virulence is mediated by its ability to evade phagosomal destruction, replicate within the cytoplasm of macrophages and dendritic cells, and suppress early innate immune responses — adaptations that account for its unusually low infectious dose and its persistence in the environment (it survives for weeks in soil, water, and animal carcasses under cool conditions).

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Epidemiology and Reservoirs

Tularemia is a zoonosis with a broad reservoir among wild mammals. The most epidemiologically important hosts in North America are lagomorphs — cottontail rabbits, jackrabbits, and snowshoe hares — along with rodents such as muskrats, squirrels, voles, prairie dogs, and beavers. The organism cycles through these populations largely via ticks, with periodic epizootics causing mass die-offs that can alert public health authorities to heightened human risk.

Approximately 100–200 cases per year are reported in the United States, though underreporting is likely. The four states with the highest burden are Missouri, Arkansas, Oklahoma, and Kansas, which together account for more than half of annual cases. Temporal patterns reflect transmission routes: a May–September peak corresponds to tick and deer fly activity, while a smaller November–December peak reflects hunting season — particularly rabbit and squirrel hunting. Occupational and recreational risk groups include hunters, trappers, farmers, landscapers, veterinarians, and laboratory workers. In Scandinavia and parts of Eastern Europe, Type B tularemia causes substantial outbreaks linked to hare hunting and contaminated surface water.

The bacterium persists in the environment beyond living hosts: it survives in soil, water, and carcasses for extended periods, particularly under cold conditions. This environmental persistence underlies waterborne outbreaks and the risk from landscape work (for example, lawnmowing over the carcass of an infected rabbit can aerosolize organisms sufficient to cause pneumonic disease).

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Transmission Routes

Tularemia reaches humans through several distinct routes, each producing somewhat different clinical patterns:

• Tick bite — the single most common route in the United States. The principal vectors are Dermacentor variabilis (American dog tick), Dermacentor andersoni (Rocky Mountain wood tick), and Amblyomma americanum (lone star tick). Ticks maintain F. tularensis transstadially (larva → nymph → adult) and transmit the organism through infected saliva during feeding. Unlike Lyme disease, tick transmission of tularemia can occur within a few hours of attachment.
• Deer fly bite — Chrysops discalis is the principal arthropod vector in the western United States, especially in Utah. Deer fly-associated tularemia tends to affect the face and upper extremities given fly feeding preferences.
• Direct contact — handling, skinning, or dressing infected animals (especially rabbits) allows entry through microabrasions in the skin. This route accounts for most hunter-associated cases and produces the classic ulceroglandular presentation.
• Inhalation — produces the most dangerous form: primary pneumonic tularemia. Sources of infectious aerosols include lawnmowing or brush-cutting over contaminated soil or carcasses, agricultural work with contaminated dust or hay, and laboratory manipulation of cultures (a serious occupational hazard). Weaponized aerosolized F. tularensis represents the primary bioterrorism concern.
• Ingestion — consumption of undercooked game meat (particularly rabbit) or drinking contaminated surface water produces oropharyngeal tularemia. Waterborne outbreaks have occurred in Europe and North America, particularly involving streams or ponds frequented by infected muskrats or beavers.
• Ocular inoculation — splashing infected material into the eye, or touching the conjunctiva after handling an infected animal, causes oculoglandular tularemia. Person-to-person transmission does not occur.

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Clinical Presentations

Tularemia is clinically diverse — the route of entry largely determines which of six recognized syndromes develops. All forms share a common prodrome following an incubation period of typically 3–5 days (range 1–14 days): abrupt onset of high fever (38–40°C), rigors, headache, myalgias, and malaise. Without these systemic features tularemia is easily dismissed as a localized skin or lymph node problem. The six forms are:

• Ulceroglandular (75–85% of cases) — the most common presentation; arises from skin inoculation.
• Glandular (5–10%) — regional lymphadenopathy without an identifiable skin lesion.
• Oculoglandular (1–2%) — conjunctival inoculation producing Parinaud's oculoglandular syndrome.
• Oropharyngeal (1–4%) — ingestion route producing pharyngitis and cervical adenopathy.
• Pneumonic (variable; 1–30%) — primary inhalation or secondary hematogenous spread; the most dangerous form.
• Typhoidal (rare) — systemic bacteremia without localizing signs; highest mortality.

Clinicians should maintain heightened suspicion whenever a febrile illness follows a tick bite, deer fly bite, animal contact, or outdoor exposure in an endemic region — particularly if accompanied by a skin ulcer, regional lymphadenopathy, or unexplained pneumonia.

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Ulceroglandular and Glandular Tularemia

Ulceroglandular tularemia is the prototypical presentation and the form most familiar to clinicians in endemic areas. After skin inoculation — most often a tick or deer fly bite site, or an abrasion sustained while handling an infected animal — the sequence of local findings is characteristic: an initial erythematous papule evolves over several days into a vesicle, then ruptures to form a painful ulcer with raised, indurated borders and a necrotic base. This "punched-out" ulcer typically measures 0.4–3 cm; it may be covered by a dark eschar resembling a tick bite reaction. The ulcer often heals very slowly over weeks to months even with treatment, though antimicrobials prevent progression and systemic complications.

Simultaneously, regional lymphadenopathy develops in the node group draining the inoculation site: inguinal nodes for lower extremity bites, axillary nodes for upper extremity, and cervical nodes for head and neck inoculations. Affected nodes are tender, firm, and enlarged — often dramatically so, reaching 8–10 cm. In 25–30% of untreated patients, nodes suppurate and may drain spontaneously through the skin. Suppurated nodes that are surgically incised rather than aspirated are prone to form chronic sinus tracts, so aspiration is strongly preferred.

Glandular tularemia presents with identical regional lymphadenopathy but without a primary skin ulcer. The portal of entry is not apparent — likely either a very small or healed skin break, or hematogenous seeding of nodes without a discernible local lesion. Clinically it closely resembles lymphoma, cat-scratch disease (caused by Bartonella henselae), or mycobacterial lymphadenitis, and tularemia serology is an essential part of the workup for unexplained lymphadenopathy in an endemic setting. Lymph node biopsy in both forms characteristically shows necrotizing granulomas with central necrosis surrounded by neutrophils — a pattern that, while not pathognomonic, narrows the differential considerably.

Oculoglandular tularemia (Parinaud's oculoglandular syndrome) results from conjunctival inoculation — usually from splashing infected water or blood into the eye, or from touching the conjunctiva after handling an infected animal. The conjunctiva becomes intensely inflamed, producing painful purulent conjunctivitis, chemosis, and eyelid edema. The pathognomonic accompanying finding is preauricular lymphadenopathy (the preauricular node drains the conjunctiva). Without treatment, corneal ulceration can occur. This syndrome should trigger immediate testing for tularemia in anyone with unilateral follicular conjunctivitis and a preauricular node.

Oropharyngeal tularemia follows ingestion of undercooked rabbit or contaminated water. Patients develop a severe exudative tonsillitis or pharyngitis — often with a pseudomembrane indistinguishable from diphtheria or severe streptococcal pharyngitis — accompanied by painful cervical lymphadenopathy. The lack of response to standard streptococcal therapy is an important clue. Dysphagia and odynophagia may be prominent. A careful dietary and exposure history (recent consumption of game meat, drinking from streams) is essential to considering this diagnosis.

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Pneumonic and Typhoidal Tularemia

Pneumonic tularemia is the most clinically severe form and carries the highest mortality if untreated. It occurs in two settings:

Primary pneumonic tularemia results from inhalation of infectious aerosols — the route of greatest bioterrorism concern. After an incubation period of 3–5 days, patients develop an abrupt febrile illness with nonproductive cough, pleuritic chest pain, and progressive dyspnea. Unlike typical community-acquired pneumonia, auscultatory findings may be subtle despite severe radiographic involvement. Chest radiography and CT characteristically show bilateral bronchopneumonia, mediastinal lymphadenopathy, and pleural effusions — this combination in a febrile patient with an appropriate exposure history should raise immediate suspicion for inhalation tularemia or bioterrorism event. Respiratory failure requiring mechanical ventilation develops in a minority but accounts for most deaths. Historically, the Martha's Vineyard outbreak of 2000 (described by Feldman et al.) demonstrated that landscape work — mowing over infected rabbit carcasses — can generate aerosols sufficient to cause primary pneumonic tularemia in people with no direct animal contact.

Secondary pneumonic tularemia arises from hematogenous seeding of the lungs during any form of untreated or inadequately treated tularemia. Approximately 30% of untreated ulceroglandular patients develop secondary pneumonia. Clinically the picture is a biphasic illness: initial skin ulcer and adenopathy followed by worsening systemic illness with new respiratory symptoms. CT findings overlap with primary disease: patchy bronchopneumonia, mediastinal adenopathy, and pleural effusion.

Typhoidal tularemia is a systemic illness characterized by high fever, profound prostration, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), and frank bacteremia — but without the localizing features that distinguish the other forms. Patients may appear toxic and septic. Because there is no skin ulcer, no lymphadenopathy, and no respiratory complaint to guide the differential, typhoidal tularemia is commonly misidentified as enteric fever (typhoid), brucellosis, Q fever, or culture-negative sepsis. The absence of localizing signs combined with a relevant exposure history is the key diagnostic clue. This form carries the highest untreated case fatality rate of all tularemia presentations.

Any form of tularemia that is not recognized and treated promptly can progress through bacteremic dissemination to involve the central nervous system (meningitis, encephalitis), pericardium, kidneys, liver, and bone marrow, though such complications are uncommon in the antibiotic era.

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Diagnosis

Tularemia is frequently underdiagnosed because clinicians in non-endemic areas do not consider it, and because laboratory methods require specific expertise and precautions. The following diagnostic tools are available:

• Clinical suspicion and exposure history — the most important diagnostic step. Key epidemiological clues include: tick or deer fly bite, rabbit hunting or skinning, outdoor work in an endemic area, consumption of wild game, fever plus painful skin ulcer plus regional lymphadenopathy. Without a targeted history, tularemia is easily missed.
• Serology (tube agglutination or microagglutination) — the most widely used confirmatory test. Antibody titers typically begin rising by the end of the second week. A single titer of ≥1:160 is presumptive evidence; a 4-fold or greater rise between acute and convalescent sera (collected 2–4 weeks apart) is confirmatory. An important limitation: F. tularensis agglutinins cross-react with Brucella antigens, so reciprocal false-positive results can occur — interpret in clinical context. Titers may persist elevated for years after infection.
• Polymerase chain reaction (PCR) — the most sensitive method early in illness before antibody titers rise, and the most useful when a rapid definitive answer is needed. Appropriate specimens include ulcer swabs, lymph node aspirates, sputum, and broncheoalveolar lavage fluid. PCR is not yet universally available and is primarily performed at state public health laboratories and the CDC.
• Culture — definitive but requires BSL-3 containment. Laboratory personnel must be notified before submitting specimens, because the risk of laboratory-acquired tularemia is substantial: even routine processing of an unidentified specimen can cause infection. F. tularensis fails to grow on standard blood or MacConkey agar; it requires cysteine-supplemented media (BCYE, chocolate agar, or Thayer-Martin). Colonies are tiny, gray, and mucoid; growth is slow (48–72 hours minimum). Identification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) is reliable in properly equipped BSL-3 facilities.
• Direct fluorescent antibody (DFA) staining and immunohistochemistry — applied to tissue sections or touch preparations; rapid results but requires specific reagents available at public health reference laboratories.
• Lymph node biopsy histopathology — shows necrotizing granulomas with central necrosis and neutrophilic infiltrate, a pattern seen also in cat-scratch disease, plague, and some mycobacterial infections. Histology narrows the differential and supports empirical treatment while serology matures.
• Complete blood count and metabolic panel — nonspecific but characteristically show a relative lymphopenia early in illness, elevated liver enzymes (particularly with typhoidal form), and elevated inflammatory markers. Blood cultures are positive in bacteremic typhoidal and pneumonic forms but require BSL-3 processing and prior laboratory notification.

Because tularemia serology takes weeks to become positive, empirical antibiotic treatment is appropriate whenever clinical and epidemiological suspicion is high — do not wait for laboratory confirmation in a patient with a compatible illness and exposure history.

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Treatment

Aminoglycosides are bactericidal against F. tularensis and are the cornerstone of treatment for moderate-to-severe disease. Bacteriostatic agents (tetracyclines) are effective but carry a higher relapse rate and require longer courses. No vaccine is approved for civilian use in the United States.

• Streptomycin 7.5–10 mg/kg IM every 12 hours for 10 days — the traditional gold standard, with a cure rate exceeding 99%. Highly effective for all forms including pneumonic and typhoidal. Limitations include the intramuscular route, monitoring for ototoxicity and nephrotoxicity, and significant availability issues: streptomycin is no longer commercially available in many countries and must be obtained through compounding pharmacies or the CDC Strategic National Stockpile in mass casualty scenarios.
• Gentamicin 5 mg/kg IV once daily (or 3–5 mg/kg/day in divided doses) for 10 days — now the preferred agent in most treatment centers due to comparable efficacy, easier dosing, wider availability, and an established intravenous formulation. Efficacy has been demonstrated in multiple clinical series. Nephrotoxicity and ototoxicity monitoring apply.
• Doxycycline 100 mg orally twice daily for 14–21 days — appropriate oral therapy for mild-to-moderate ulceroglandular tularemia in non-pregnant adults. The bacteriostatic mechanism results in a relapse rate of 10–20% — substantially higher than aminoglycosides — necessitating a full extended course and close follow-up. Patients who relapse require aminoglycoside re-treatment.
• Ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10–14 days — bactericidal fluoroquinolone with good intracellular penetration; relapse rates are lower than with doxycycline, making it a preferred oral alternative in practice. Used for mild-to-moderate disease, post-exposure prophylaxis, and in mass casualty scenarios where aminoglycosides cannot be administered to large numbers of people.
• Suppurated lymph nodes — surgical management is sometimes necessary for fluctuant, large, or spontaneously draining nodes. Needle aspiration is strongly preferred over incision and drainage because incision creates a wound that frequently develops a chronic sinus tract and delayed healing. Aspirated material is infectious and requires BSL-3 precautions.
• Pregnancy — doxycycline is contraindicated in the second and third trimesters due to fetal skeletal and dental effects. Gentamicin is the preferred agent in pregnant women, with careful monitoring of renal function and fetal wellbeing. Ciprofloxacin is a second-line option; the risk-benefit calculation favors treatment over untreated tularemia in pregnancy.
• Children — gentamicin is preferred; doxycycline is relatively contraindicated under age 8 (tooth discoloration) except when no alternative exists; ciprofloxacin is used when aminoglycosides cannot be given.

Patients with pneumonic or typhoidal tularemia require hospitalization, intravenous aminoglycoside therapy, and supportive care including supplemental oxygen or mechanical ventilation as clinically indicated. Defervescence typically occurs within 24–72 hours of starting effective therapy. Standard contact and droplet precautions are adequate for hospitalized patients — person-to-person transmission does not occur.

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Bioterrorism Potential and Post-Exposure Prophylaxis

Francisella tularensis has been categorized as a Category A select agent — the highest-priority bioterrorism threat category — by the CDC and Department of Homeland Security. The combination of extreme low-dose infectivity by aerosol (approximately 50 organisms inhaled can cause fatal pneumonia), high case fatality rates for pneumonic disease without treatment, potential for large-scale aerosol release over populated areas, and the absence of an approved civilian vaccine makes weaponized tularemia one of the most concerning biological threats. Both the United States and the former Soviet Union developed aerosol-deliverable tularemia weapons during the Cold War. The Soviet program produced strains resistant to first-line antibiotics, a concern that informs current preparedness planning.

In a suspected bioterrorism release, public health response priorities include:

• Early recognition — clusters of febrile pneumonia in otherwise healthy adults, particularly with mediastinal lymphadenopathy on chest imaging, should trigger immediate bioterrorism notification to local and state public health authorities and the CDC Emergency Operations Center.
• Post-exposure prophylaxis (PEP) — individuals known or suspected to have been exposed to aerosolized F. tularensis but not yet symptomatic should receive doxycycline 100 mg orally twice daily for 14 days or ciprofloxacin 500 mg orally twice daily for 14 days. These agents are preferred for mass casualty prophylaxis because of their oral bioavailability and feasibility of mass dispensing; aminoglycosides cannot practically be administered to large populations.
• Treatment of confirmed cases — aminoglycosides (gentamicin or streptomycin) remain standard for treatment of established disease; ciprofloxacin or doxycycline can be used if aminoglycosides are unavailable or contraindicated.
• Laboratory notification — any suspected tularemia specimen must be processed under BSL-3 conditions; sentinel clinical laboratories should immediately refer suspicious cultures to their state public health laboratory rather than attempting identification.

Vaccine status — a live attenuated vaccine (derived from the Czechoslovak LVS strain) was used for decades to protect laboratory workers in the United States, but it was never formally licensed by the FDA due to incomplete safety and efficacy data. Research into next-generation vaccines (subunit and attenuated mutants) is ongoing. No approved vaccine is currently available for general civilian or military use in the United States.

For routine clinical encounters — hunters, farmers, veterinarians, landscapers, and others at occupational or recreational risk — the most effective preventive measures remain tick and deer fly avoidance (repellents, protective clothing, prompt tick removal), wearing gloves when handling wild animals, thoroughly cooking all game meat, and not drinking untreated surface water in endemic areas.

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References

1. Dennis DT, et al. Tularemia as a biological weapon: medical and public health management. JAMA. 2001;285(21):2763–2773. PMID: 11386933. DOI: 10.1001/jama.285.21.2763
2. Tärnvik A, Berglund L. Tularaemia. Eur Respir J. 2003;21(2):361–373. PMID: 12608453. DOI: 10.1183/09031936.03.00088903
3. Feldman KA, et al. An outbreak of primary pneumonic tularemia on Martha's Vineyard. N Engl J Med. 2001;345(22):1601–1606. PMID: 11757506. DOI: 10.1056/NEJMoa011374
4. Johansson A, et al. Ciprofloxacin for treatment of tularemia. Clin Infect Dis. 2002;35(4):433–438. PMID: 12145726. DOI: 10.1086/341889
5. Eliasson H, et al. Tularemia: current epidemiology and disease management. Infect Dis Clin North Am. 2006;20(2):289–311. PMID: 16762741. DOI: 10.1016/j.idc.2006.03.002
6. Ellis J, et al. Tularemia. Clin Microbiol Rev. 2002;15(4):631–646. PMID: 12364373. DOI: 10.1128/CMR.15.4.631-646.2002
7. Penn RL. Francisella tularensis (tularemia) as an agent of bioterrorism. Semin Respir Crit Care Med. 2004;25(2):221–228. PMID: 16088481. DOI: 10.1055/s-2004-818272
8. Snowden J, Simonsen KA. Tularemia. In: StatPearls. PMID: 28846365.
9. Maurin M, Gyuranecz M. Tularaemia: clinical aspects in Europe. Lancet Infect Dis. 2016;16(1):113–124. PMID: 26738826. DOI: 10.1016/S1473-3099(15)00355-2
10. Thomas LD, Schaffner W. Tularemia pneumonia. Infect Dis Clin North Am. 2010;24(1):43–55. PMID: 20171547. DOI: 10.1016/j.idc.2009.10.012
11. Tärnvik A, et al. New approaches to diagnosis and therapy of tularemia. Ann N Y Acad Sci. 2007;1105:378–404. PMID: 17435132. DOI: 10.1196/annals.1409.017
12. McLendon MK, et al. Francisella tularensis: taxonomy, genetics, and immunopathogenesis of a potential agent of biowarfare. Ann N Y Acad Sci. 2006;1078:244–255. PMID: 17114714. DOI: 10.1196/annals.1374.042

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Connections

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