Tularemia: Causes, Symptoms, Treatment and Prevention

Tularemia, also known as rabbit fever or deer fly fever, is a rare but potentially serious infectious disease caused by the bacterium Francisella tularensis. This bacterium is highly infectious, meaning that even a small number of organisms can cause illness. It is considered a zoonotic disease, which means it can be transmitted from animals to humans. Tularemia primarily affects wild animals especially small mammals like rabbits, hares, voles, and rodents but can also spread to domestic animals such as cats and sheep.

Humans can become infected in several ways, including through the bite of an infected arthropod (such as a tick, deer fly, or mosquito), direct skin contact with infected animal tissues or fluids, drinking water contaminated with the bacteria, or inhaling dust or aerosols containing F. tularensis. Because the bacteria can survive in the environment for weeks or months, especially in soil, water, or animal carcasses, the risk of exposure is not limited to direct animal contact.

The symptoms of tularemia depend on the route of infection. Most commonly, people experience a sudden high fever, chills, fatigue, and a skin ulcer at the site of bacterial entry, often accompanied by swollen lymph nodes, which are part of the body’s immune system. Other forms of the disease may involve the eyes (oculoglandular tularemia), throat (oropharyngeal tularemia), or lungs (pneumonic tularemia), with the latter being the most serious and potentially life-threatening if not treated promptly.

Early diagnosis and treatment are essential to prevent severe complications, including pneumonia, sepsis, or organ damage. Tularemia is not spread from person to person, but its potential for airborne transmission in laboratory settings or through bioterrorism has led to its classification as a Category A bioterrorism agent by the U.S. Centers for Disease Control and Prevention (CDC).

People at higher risk include hunters, trappers, farmers, landscapers, and others who work or spend time in areas where wild animals or ticks are common.

Treatment involves the use of antibiotics, such as streptomycin, gentamicin, doxycycline, or ciprofloxacin. These may be administered by injection or taken orally, depending on the severity and form of the disease. With timely medical care, most people recover fully, though serious cases may require hospitalization and supportive treatments.

Epidemiology

Tularemia is primarily reported in North America, Europe, and parts of Asia. Endemic regions include the central United States, the Nordic countries of Northern Europe, Central Asia, and areas within the Balkans. In Europe, approximately 800 human cases are reported annually, with Sweden and Finland recording the highest incidence rates among European Union and European Economic Area countries.

In the World Health Organization’s Eastern Mediterranean Region, studies measuring antibodies in human populations suggest exposure rates of around 6.2%. Environmental monitoring in the region has detected Francisella tularensis in approximately 5–6% of samples from ticks and other sources, while lower detection rates have been observed in rodents and domestic animals. Tularemia has not been formally reported in Africa.

Tularemia has experienced periods of major outbreaks, particularly during the early to mid-20th century. For example, in 1939, the United States reported over 2,000 cases, while the Soviet Union recorded more than 100,000 cases in the same era. Following this period, the number of cases in the U.S. dropped significantly, reaching about 100 per year by 2010. However, recent years have seen a resurgence, with an average of 200 to 300 cases reported annually.

A nationwide analysis conducted by the U.S. Centers for Disease Control and Prevention covering 2011 to 2022 identified 2,462 cases, representing a 56% increase compared to the previous decade. Current figures show an average of approximately 205 cases per year, translating to an incidence rate of 0.064 per 100,000 people. The rise in reported cases is attributed in part to improved diagnostic techniques, such as enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), which have increased the identification of probable cases.

Outbreaks relate to seasonal insect activity and animal population dynamics. Regions with tick and deer fly prevalence have higher case numbers. The disease is rare or absent in tropical and southern hemisphere locations.

Certain population groups experience higher incidence rates, including children aged 5 to 9 years, older adult males especially those aged 65 to 84 and American Indian and Alaska Native communities. These demographic trends are thought to reflect variations in occupational and environmental exposure.

Causes and Transmission

Tularemia arises from a specific bacterial source and spreads through defined methods. Certain organisms and environments maintain this bacterium, which is distributed unevenly across regions.

Causative Agent

The disease is caused by Francisella tularensis, a highly infectious, gram-negative coccobacillus. It is known for its ability to cause disease even at very low exposure levels—fewer than 10 organisms may be sufficient to initiate infection in humans. The bacterium is resilient in nature, capable of surviving in cold temperatures, moist environments, and slightly acidic conditions for extended periods.

There are four recognized subspecies of F. tularensis. The two most relevant to human disease are:

Subspecies tularensis (Type A): This is the most virulent form and is found almost exclusively in North America. It is associated with more severe clinical outcomes and is often carried by terrestrial mammals such as rabbits and hares.
Subspecies holarctica (Type B): This form is less virulent and has a wider geographic distribution, particularly across Europe and parts of Asia. It is commonly associated with aquatic environments and animals such as beavers and muskrats.

The remaining two subspecies mediasiatica and novicida are less commonly implicated in human disease and are typically isolated in restricted geographic areas.

Modes of Transmission

Tularemia can be transmitted to humans through several routes:

Arthropod bites: Ticks (especially Dermacentor and Amblyomma species), deer flies (Chrysops spp.), and occasionally mosquitoes serve as vectors. These insects acquire the bacterium from infected animals and can transmit it to humans through bites. Tick bites are the most common transmission route in the United States.
Direct contact with infected animals: Handling infected wildlife, particularly rabbits, hares, and rodents, can lead to infection through skin abrasions or mucous membranes. Hunters, trappers, and individuals who handle carcasses are at elevated risk.
Inhalation: Breathing in aerosolized bacteria, especially during farming, landscaping, mowing, or brush clearing in areas where infected animals live, can lead to respiratory tularemia. Laboratory workers are also at risk if exposed to airborne particles in clinical or research settings.
Ingestion: Consuming contaminated water or undercooked meat from infected animals can lead to oropharyngeal or gastrointestinal tularemia, although these forms are less common.
Exposure through contaminated objects: Rare cases have involved contact with contaminated tools, animal fur, or soil, particularly when protective gear is not used.

Human-to-human transmission has not been documented.

Natural Reservoirs

Francisella tularensis is maintained in nature through a complex cycle involving animals, insects, and environmental sources.

Animal reservoirs: Small to medium-sized mammals, especially rabbits, hares, squirrels, muskrats, and beavers, serve as primary reservoirs. These animals may harbor the bacterium without displaying severe symptoms, facilitating silent transmission within wildlife populations.
Environmental reservoirs: The bacterium can survive for weeks to months in water, moist soil, decaying vegetation, and mud. This environmental persistence supports outbreaks in endemic regions and allows for indirect transmission even in the absence of direct animal contact.
Arthropod vectors: Insects such as ticks not only transmit the bacteria but can also maintain it across generations through transstadial (across life stages) and possibly transovarial (from adult to egg) transmission. This ability contributes to the seasonal and geographic patterns of tularemia.

Signs and Symptoms

Tularemia presents in multiple clinical forms, each corresponding to the route of transmission, bacterial strain, and host factors. While the infection may begin with non-specific systemic symptoms, the disease often localizes based on the site where Francisella tularensis enters the body. The incubation period typically ranges from 3 to 5 days but may vary from 1 to 14 days.

Major Forms of Tularemia

Tularemia manifests primarily in six clinical forms: ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, and typhoidal.

Ulceroglandular is the most common. Usually resulting from arthropod bites or direct skin contact with infected animals. It is characterized by a painful skin ulcer at the point of entry and regional lymphadenopathy (swollen lymph nodes).
Glandular involves lymph node enlargement in the absence of a visible skin lesion. This form also typically arises from tick or fly bites but without the development of a cutaneous ulcer.
Oculoglandular occurs when the bacterium enters through the eye, often by touching the eyes after handling contaminated material or infected animals. It manifests as conjunctivitis along with swelling of the preauricular or cervical lymph nodes.
Oropharyngeal results from ingesting contaminated water or undercooked meat from infected animals. Symptoms include severe sore throat, mouth ulcers, difficulty swallowing, and cervical lymphadenopathy.
Pneumonic occurs when F. tularensis is inhaled in aerosolized form, typically during farming, landscaping, or handling infected animal materials. It presents with respiratory symptoms such as cough, chest pain, difficulty breathing, and can rapidly progress to pneumonia or respiratory failure. This form is associated with a higher risk of complications and mortality if not treated promptly.
Typhoidal is a rare and severe form, thought to result from either high-dose exposure or hematogenous spread of the bacteria. It lacks localized signs and presents with systemic symptoms such as prolonged high fever, fatigue, weight loss, and multi-organ involvement. The route of infection is often unclear in these cases.

Symptoms

Regardless of form, the onset of tularemia is usually sudden and characterized by:

Fever and Chills: A hallmark of infection, often exceeding 38.5°C.
Malaise and Fatigue: Generalized weakness and discomfort.
Headache and Myalgia: Common systemic features, especially in typhoidal or pneumonic forms.

Symptoms then vary based on the clinical presentation:

Ulceroglandular: Skin ulcers with a necrotic center and tender, swollen lymph nodes, usually in the groin or axilla.
Glandular: Enlarged, sometimes suppurating lymph nodes without visible skin involvement.
Oculoglandular: Redness, tearing, photophobia, and mucopurulent discharge from the eye, along with preauricular node enlargement.
Oropharyngeal: Severe pharyngitis, tonsillar inflammation, and painful swallowing.
Pneumonic: Cough, pleuritic chest pain, dyspnea, and possible hemoptysis.
Typhoidal: High-grade fever, abdominal pain, vomiting, and signs of systemic toxicity.

Complications

Complications are more common in untreated or severe cases.

Suppurative Lymphadenitis: Abscess formation within lymph nodes, which may require surgical drainage.
Pneumonic Progression: Severe respiratory compromise, including pleural effusion, respiratory failure, and secondary bacterial infections.
Septicemia: Disseminated infection leading to multi-organ failure.
Rare Manifestations: Meningitis, endocarditis, osteomyelitis, and pericarditis, particularly in immunocompromised individuals or in typhoidal cases.

Delayed treatment increases risk of fatal outcomes, particularly in typhoidal and pneumonic forms. Long-term disability is uncommon but can occur from extensive tissue damage.

Diagnosis of Tularemia

Diagnosing tularemia involves several approaches to identify the bacterium Francisella tularensis. Clinical findings must be supported by laboratory evidence and distinguished from other diseases with similar symptoms.

Diagnostic Methods

The diagnostic process begins with a thorough patient history, including recent outdoor activities, occupational risks, and contact with known animal reservoirs or vectors. Exposure to ticks, deer flies, rabbits, or contaminated water sources—common transmission pathways of F. tularensis should prompt consideration of tularemia, especially in endemic areas.

Physical examination may reveal hallmark signs such as skin ulcers, regional lymphadenopathy, or conjunctivitis, depending on the route of infection. For suspected pneumonic tularemia, which may result from inhalation of contaminated aerosols during farming, landscaping, or laboratory work, chest radiographs are typically performed to assess pulmonary involvement.

Because tularemia presents with non-specific symptoms, such as fever and malaise, a high index of clinical suspicion is necessary, particularly in patients who live in or have traveled to areas where the bacterium is endemic. These include the central United States, Northern Europe, and parts of Central Asia. Awareness of natural reservoirs including rodents, hares, and contaminated environments such as moist soil or water also aids in assessing patient risk.

Laboratory Testing

Laboratory confirmation is critical for definitive diagnosis and involves several methods:

Culture: Isolation of F. tularensis from clinical specimens such as blood, lymph node aspirates, or respiratory secretions provides definitive diagnosis. However, due to the bacterium’s high infectivity and potential for aerosol transmission, culturing requires biosafety level 3 (BSL-3) laboratory facilities.
Serologic Testing: Antibody detection using microagglutination tests or enzyme-linked immunosorbent assay (ELISA) is widely used. These tests are most reliable after 2–3 weeks post-exposure when antibody levels rise, and are especially useful in areas without access to advanced molecular diagnostics.
Polymerase Chain Reaction (PCR): PCR assays allow for rapid and sensitive detection of bacterial DNA directly from patient samples. This method is particularly valuable for early diagnosis and in severe forms such as pneumonic or typhoidal tularemia, though it is typically available only in reference or specialized laboratories.

Differential Diagnosis

Tularemia shares clinical and epidemiologic features with several other infectious diseases, making differential diagnosis essential:

Ulceroglandular and Glandular Forms: These must be distinguished from cat scratch disease (caused by Bartonella henselae), staphylococcal or streptococcal lymphadenitis, and sporotrichosis. The presence of a necrotic skin ulcer and exposure to wild animals or insect vectors supports tularemia.
Oculoglandular Form: Resembles viral or bacterial conjunctivitis but should raise suspicion in individuals with direct contact with infected animal material or contaminated hands.
Pneumonic Tularemia: This form must be differentiated from community-acquired pneumonia caused by Legionella pneumophila, Mycoplasma pneumoniae, or other atypical pathogens. A relevant exposure history such as lawn mowing in endemic areas or laboratory aerosol exposure may point toward tularemia.
Typhoidal Form: As a systemic illness without localized signs, typhoidal tularemia may be confused with enteric fever, leptospirosis, or rickettsial infections. Laboratory testing is essential to confirm the diagnosis.

In all forms, consideration of the bacterium’s transmission routes, environmental reservoirs, and patient exposure history enhances diagnostic accuracy and helps prevent misdiagnosis, particularly in areas where tularemia is uncommon or under-reported.

Treatment Options

Effective management of tularemia relies on prompt use of appropriate antibiotics, alongside supportive care to address symptoms. Treatments vary depending on the severity and form of the infection, while some challenges can complicate therapy and recovery.

Antibiotic Therapy

Tularemia is primarily treated with specific antibiotics that target Francisella tularensis. The bacterium is known for its high infectivity and ability to persist in host cells and harsh environments such as soil and water. As a result, antibiotic selection must ensure strong intracellular penetration to effectively eradicate the organism. The first-line medications include streptomycin and gentamicin, both aminoglycosides, known for their effectiveness. Streptomycin is usually given intramuscularly for 10 days, while gentamicin may be preferred if streptomycin is unavailable. These are especially used in severe cases or systemic forms such as pneumonic or typhoidal tularemia, which can result from inhalation of contaminated aerosols or ingestion of contaminated food or water.

Alternative drugs include doxycycline and ciprofloxacin, which are oral options often used for milder cases or for patients unable to tolerate aminoglycosides. Doxycycline is typically administered for 14–21 days to prevent relapse. These alternatives are useful in ulceroglandular or glandular forms often resulting from tick bites or contact with infected animals like rabbits and rodents.

Early administration of antibiotics is critical to reduce complications and mortality. Delayed treatment can lead to prolonged illness and more severe disease forms.

Supportive Care

Supportive care includes:

Hydration and electrolyte balance, especially important in typhoidal and oropharyngeal forms
Analgesics and antipyretics for pain and fever control
Oxygen supplementation or ventilatory support in pneumonic tularemia
Topical and wound care for skin ulcers in cutaneous forms (ulceroglandular or oculoglandular)

Patients infected through inhalation (e.g., mowing contaminated grass) or animal handling may experience more aggressive disease requiring hospitalization and intensive supportive interventions.

Treatment Challenges

Several challenges complicate the treatment of tularemia:

Diagnostic delays are common due to non-specific symptoms and the disease’s rarity in many areas. Because F. tularensis is transmitted through varied routes (vector bites, aerosol inhalation, ingestion, or direct contact), symptoms often resemble more common illnesses.
The bacterium’s intracellular niche limits antibiotic access, necessitating drugs with good cell penetration.
Relapse can occur, particularly when using oral antibiotics or when treatment is initiated late. Doxycycline, while effective, requires a longer treatment duration to minimize this risk.
Limited availability of first-line drugs like streptomycin in some countries may force clinicians to use second-line options, which may be less effective for severe forms.
Special populations, such as immunocompromised individuals or children, may experience more severe infections or drug side effects, necessitating customized therapy plans.

Although antibiotic resistance in F. tularensis remains rare, inappropriate antibiotic use—such as monotherapy with beta-lactams, which are ineffective—can contribute to treatment failure.

Prevention and Control

Effective prevention and control of tularemia rely on minimizing exposure to infected animals and contaminated environments. Protective behaviors, scientific advancements in vaccines, and managing animal hosts and vectors are essential components.

Personal Protection Measures

Wear long-sleeved clothing, long pants, and gloves during outdoor activities in endemic areas to prevent arthropod bites and contact with infected animals.
Apply insect repellents containing DEET to exposed skin and permethrin to clothing to deter ticks and deer flies.
Avoid direct contact with wild animals—especially rabbits, hares, and rodents, which are key natural reservoirs of Francisella tularensis.
Use protective gear (e.g., masks and gloves) when handling animal carcasses or cleaning game, particularly in hunting or farming settings.
Thoroughly cook game meat to eliminate potential bacterial contamination and avoid ingesting raw or undercooked meat from wild animals.
Perform routine tick checks and promptly remove attached ticks after outdoor activities, especially during peak vector season (May to September).
Wash hands thoroughly and disinfect equipment and clothing after potential exposure to vectors or animal tissue.
Avoid mowing over animal carcasses or nesting areas in endemic zones to prevent inhalation of aerosolized bacteria.
Use clean, treated water sources, as F. tularensis can be transmitted through ingestion of contaminated water, especially in rural or wildlife areas.

Vaccination Research

Currently, no licensed vaccine for tularemia is publicly available. Research focuses on developing safe and effective vaccines using live attenuated strains and subunit technologies. Studies aim to induce robust immunity against Francisella tularensis without adverse effects.

Experimental vaccines have shown promise in animal models, but human trials remain limited. Challenges include balancing immune protection and vaccine safety. Continued investment in vaccine research seeks to improve prevention, particularly for high-risk groups like laboratory workers and military personnel.

Environmental Control

Reduce tick and deer fly populations in endemic zones through habitat modification and strategic insecticide use.
Implement rodent control programs to limit the spread from reservoir species like rabbits, hares, and small mammals.
Remove and properly dispose of animal carcasses to minimize environmental contamination and reduce transmission risks to humans and pets.
Restrict access to areas with recent animal die-offs or known tularemia outbreaks to limit human and pet exposure.
Use public health advisories to inform communities and outdoor workers about elevated risks following detection of tularemia in animal or vector populations.
Maintain environmental surveillance by monitoring ticks, water sources, and small mammals for F. tularensis, allowing early intervention.
Encourage collaboration between wildlife management, veterinary services, and public health agencies to track outbreaks and apply integrated control measures.

Tularemia in Animals

Tularemia affects a variety of animal species, ranging from small mammals to large wildlife. The disease’s impact varies by species and environment, with several animals acting as reservoirs for the bacteria. It also poses risks for humans through direct or indirect contact with infected animals.

Animal Hosts

Tularemia primarily infects small mammals such as rabbits, hares, and rodents. These species often harbor F. tularensis with minimal symptoms, functioning as natural reservoirs that sustain the bacterium in the environment. Outbreaks in these populations often go unnoticed until human cases are reported.

Rabbits (particularly cottontail rabbits in North America) are among the most commonly affected species and frequently implicated in zoonotic transmission.
Rodents such as voles, mice, and lemmings also play a key role in maintaining the disease cycle.

Insect vectors like ticks (especially Dermacentor, Amblyomma, and Ixodes spp.) and deer flies (Chrysops spp.) facilitate transmission between animals and from animals to humans.

Domestic animals, including cats and dogs, can acquire tularemia through ingestion of infected prey or contact with contaminated environments. Infected cats may present with high fever, lethargy, and lymphadenopathy, while dogs are generally more resistant but can still act as mechanical vectors or develop mild illness.

Large mammals such as squirrels, muskrats, beavers, and even opossums can also contract tularemia, with some species developing systemic illness. Mortality rates may vary based on the bacterial subspecies and host susceptibility.

In rare cases, birds, including waterfowl and game birds, have been found infected, though they are not primary reservoirs. Reptiles and amphibians are considered largely resistant but may carry infected ticks.

Subspecies-specific patterns of F. tularensis influence host range:

*F. tularensis subsp. tularensis (Type A) is associated with severe disease in lagomorphs and higher mortality in animals.
*F. tularensis subsp. holarctica (Type B) is more often found in aquatic environments and associated with muskrats and beavers.

Impact on Wildlife

Tularemia outbreaks can cause sudden and large-scale die-offs in wildlife populations, especially among rabbits and rodents. These mass mortalities can significantly disrupt local ecosystems.

Carcasses from die-offs serve as amplifying sources for the bacterium, increasing environmental contamination and risk to other animals and humans.
Predator-prey dynamics may be altered as infected prey become slower and more susceptible to predation, potentially impacting predator health if consumed.
Scavenger species, including foxes, coyotes, and raptors, may also be exposed through consumption of infected carcasses.

In aquatic environments, tularemia outbreaks in beavers and muskrats have been linked to contaminated water sources, leading to bacterial persistence in rivers, ponds, or lakes. This can affect fish, amphibians, and aquatic birds indirectly by altering habitat conditions and prey availability.

Zoonotic Risk

Animals infected with tularemia pose a direct and indirect risk to humans. Human cases are frequently preceded by outbreaks or clusters in animal populations.

Direct contact with infected animals through skinning, butchering, or handling carcasses can lead to infection.
Bites or scratches from infected animals, especially domestic cats or wildlife, are known routes of transmission.
Hunters, trappers, veterinarians, and wildlife workers are at heightened risk due to occupational or recreational exposure.
Ticks and deer flies feeding on infected animals can transmit the bacterium to humans, often in endemic areas.

Consumption of undercooked or raw meat, especially from wild rabbits or rodents, may result in oropharyngeal tularemia. Waterborne transmission has also been documented when people swim, fish, or drink from water contaminated by infected animals.

Public Health and Bioterrorism Concerns

Tularemia is closely monitored due to its potential impact on public health and its classification as a possible bioterrorism agent.

Notifiable Disease Status

Tularemia is a notifiable disease in many countries, including the United States, Canada, members of the European Union, and parts of Asia. Under national disease surveillance systems, healthcare providers, laboratories, and veterinarians must report suspected and confirmed cases to local or national public health agencies.

This mandatory reporting ensures accurate tracking of disease incidence and supports coordinated public health responses.
Real-time surveillance facilitates contact tracing, environmental investigations, and identification of animal or vector sources.
In addition to human cases, animal tularemia outbreaks (especially in rabbits or rodents) may also be reportable in some jurisdictions, serving as early warning signals for public health authorities.
Public health data is used to monitor geographic spread, identify seasonal trends, and detect unusual patterns that may suggest environmental contamination or a deliberate event.

In the U.S., the National Notifiable Diseases Surveillance System (NNDSS) collects data on tularemia, and the disease is also tracked through Zoonotic and Vectorborne Disease programs at the state level.

Bioterrorism Potential

Tularemia is classified as a Category A bioterrorism agent by the Centers for Disease Control and Prevention (CDC)—indicating the highest level of concern. This classification is shared with other high-threat pathogens such as anthrax (Bacillus anthracis), smallpox (Variola virus), and plague (Yersinia pestis).

Key reasons for this classification include:

Low infectious dose: As few as 10–50 organisms can cause disease when inhaled.
Aerosol stability: F. tularensis can be weaponized as an aerosol, making it suitable for airborne dissemination in a biological attack.
Non-specific early symptoms: Inhalational tularemia initially mimics influenza or pneumonia, delaying diagnosis and increasing transmission risk.
Lack of vaccine in general use: Although vaccines are in development and stockpiled for emergency use, none are currently approved for general public immunization.

In the context of bioterrorism preparedness:

Governments have developed response protocols for deliberate release scenarios, including rapid identification, quarantine guidelines, and emergency medical countermeasures.
Stockpiling of antibiotics like streptomycin, gentamicin, doxycycline, and ciprofloxacin ensures readiness for mass post-exposure prophylaxis.
Healthcare providers and emergency responders receive specialized training to recognize potential bioterrorism cases and implement protective measures.
Ongoing research focuses on the development of rapid diagnostic assays, environmental detection systems, and more effective vaccines.

Agencies such as the CDC, WHO, and U.S. Department of Homeland Security monitor global tularemia activity and maintain contingency plans as part of broader biosecurity strategies.