Continuing Education Activity

Tularemia is an acute febrile zoonotic illness caused by the highly infectious gram-negative organism Francisella tularensis. It is important to maintain a high degree of clinical suspicion for tularemia infections as symptoms can vary depending on the route of infection. This activity reviews the evaluation and management of tularemia and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Explain when the diagnosis of tularemia should be considered.
• Describe the population most at risk for developing tularemia.
• Explain how to manage a patient with tularemia.
• Employ interprofessional team strategies for improving coordination and communication to advance the care of patients with tularemia.

Introduction

Tularemia is an acute febrile zoonotic illness caused by the highly infectious Gram-negative organism Francisella tularensis. It is important to maintain a high degree of clinical suspicion for tularemia infections as symptoms can vary depending on the route of infection.[1][2][3]

F. Tularensis is one of the most infectious agents known; as few as 10-25 organisms can cause an infection in humans. Several subspecies of the bacteria are known and their virulence and geographical range also vary. In the US, tularemia is rare with most cases reported in the southern and central states. However, over the years cases have been reported in the Northern part of the country.

Etiology

Tularemia is caused by the highly infectious gram-negative coccobacillus Francisella tularensis. Infection can occur with a small number of organisms and through a variety of entry sites, including inhalation, direct contact with non-intact skin or mucous membranes, ingestion or via the bite of a tick or fly vector. There are four recognized subspecies of F. tularensis,  with F. tularensis type A causing the most severe disease and the most frequent disease in North America. A less severe disease is associated with F. tularensis subspecies holarctica (type B) in other parts of the northern hemisphere, including widespread disease in Europe. In addition to variations in disease severity associated with each subtype, there may also be differences in antibiotic susceptibility with a greater degree of fluoroquinolone susceptibility reported in F. tularensis subspecies holarctica (type B).

Tularemia has the following presentations:

1. Ulceroglandular disease that presents with cutaneous ulcerations and marked lymphadenopathy
2. Glandular disease that presents with no ulcers but marked lymphadenopathy
3. Oculoglandular disease that presents with preauricular lymphadenopathy and conjunctivitis
4. Oropharyngeal disease that presents with pharyngitis, stomatitis and cervical lymphadenopathy
5. GI treat disease that presents with vomiting, abdominal discomfort, and diarrhea
6. Respiratory disease that presents as pneumonia or pleuritis
7. Typhoid tularemia is a febrile illness without any early signs or symptoms

The type of tularemia one develops depends on the mode of transmission. In most cases, the organism is transmitted by inoculation into the skin or via inhalation/ingestion. Human to human spread is not likely. However, the transmission of infection can occur from an insect bite or contact with contaminated animal products. Thorough cooking can lessen the risk of transmission. The organism can survive extremes of cold, heat and even in animal carcasses. The organism has been found in many insects and animals. In Northern Europe, mosquitoes may serve as an insect vector. In North America, many ticks have been found to have tularensis.

F tularensis biovar tularensis is found in North American ticks and rabbits and known to cause severe infection in humans. F tularensis biovar holarctica is found in European and Asian rodents and causes a milder form of infection.

The risk of infection is increased in the following populations:

• Veterinarians
• Laboratory workers
• Farmers, landscappers
• People who work with animals, sheep
• People who handle meat

Epidemiology

Tularemia infections are reported throughout the northern hemisphere and occur in a wide variety of vertebrate reservoirs, with rabbits and hares the most classically associated. Infection occurs most often during warmer summer months and early fall via tick or fly bite or handling of infected animal tissue. Infection can also occur via inhalation, ingestion, and contact with mucous membranes. In the United States, infection is reported most frequently in the south-central states of Arkansas, Missouri, and Oklahoma although it is reported throughout the country sporadically. Tularemia is most commonly reported in children, with an increased rate of infection in males, particularly in adolescence and adulthood.

Pathophysiology

F. tularensis is capable of infecting a wide variety of immune and non-immune cells, leading to necrosis and microabscess development in multiple sites. Macrophages appear to be an important early target of infection and may spread the infection from the initial site of inoculation to the regional lymph nodes and beyond. Studies are underway to define the immune evasion mechanisms, such as caspase-3 mediated cell death, as these may provide targets for future therapy.

Inhalation of as few as ten organisms can lead to disease. Once inside the body, the organism rapidly multiplies. Ulceration is common at the site of entry and this is usually followed by local lymphadenopathy. Granuloma formation is very common and thus the organism is often mistaken for mycobacterium tuberculosis. 

F.tularensis can impair phagocytosis and survive for prolonged periods in the infected cells. The incubation period varies from 2-9 days. A few individuals are asymptomatic but in most people, it leads to an acute septic reaction followed by death.

Toxicokinetics

The organism is considered a category A biowarfare agent because of its high rate of infectivity, stability in a liquid environment, relative ease of growth, easy spread and ability to cause significant illness and morbidity. Because of its ability to remain viable in the environment, this can also lead to repeat outbreaks and relapses that can last many months. The infection must be reported to the local authorities ASAP.

History and Physical

Patients with tularemia present with a variety of symptoms and physical exam findings, depending on the route of infection. It is important to obtain a detailed travel history, including any game or ground water ingestion, and participation in outdoor activities such as handling carcasses while hunting or potential tick bites. Importantly, lack of a history of tick bite or other definitive exposure does not exclude the diagnosis of tularemia as the tick or insect bite may be brief and unnoticed. Among all syndromes, fever, headache, and malaise are common. The most common syndromes are ulceroglandular, in which an ulcer forms at the site of inoculation in association with tender regional lymphadenopathy, and glandular tularemia, in which regional lymphadenopathy occurs in the area of inoculation, but no ulcer is identified. Tularemia may also present as an oculoglandular disease, with exudative conjunctivitis and regional lymphadenopathy, oropharyngeal tularemia, with exudative pharyngitis and regional lymphadenopathy, gastrointestinal tularemia, with abdominal pain, diarrhea, and vomiting, or pneumonic tularemia, a severe bilateral pneumonia with a mortality rate of 30% to 60% in some series. In all presentations with associated lymphadenopathy, the lymph node may develop fluctuance as the disease progresses even after the resolution of systemic symptoms. Systemic or typhoidal tularemia, with fever, septic shock, and hepatosplenomegaly can occur following any route of inoculation. While these are the most commonly reported clinical syndromes associated with tularemia, it has also been associated with meningitis, osteomyelitis and other infectious syndromes.

Evaluation

Diagnosis of tularemia requires a high degree of clinical suspicion as it may be difficult to confirm with laboratory testing. Serologic diagnosis, with either an initial titer > 1:160 or a four-fold rise between initial and convalescent serology, is most commonly used to confirm a diagnosis of tularemia. It is important to recognize that early testing may be negative as antibodies have not yet had time to form. Therefore, initial negative serology does not rule out tularemia infection. F. tularensis can also be cultured from blood, spinal fluid, lymphatic tissue and swabs of ulcer tissue for definitive diagnosis of tularemia infection. However, culturing F. tularensis should be done in highly controlled conditions as accidental inhalation of tularemia by laboratory workers presents a significant risk of pneumonic tularemia. If tularemia is suspected in any culture sample, the laboratory should be notified so that it can be handled in appropriate conditions. The laboratory should also be notified as a culture of tularemia requires specialized media and longer incubation times. On other laboratory evaluations, patients may have elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) or leukocytosis; however, these may also be normal and thus should not be considered definitive in excluding tularemia if negative.

Treatment / Management

To date, there have been no randomized controlled trials to define the optimal antibiotic management for tularemia infection. Currently, most sources recommend treatment with intravenous (IV) gentamicin for seven to 14 days, depending on the severity of illness. Fluoroquinolones, such as ciprofloxacin, may also play a role in mild disease although data supporting this approach in the more virulent type A tularemia infections in the United States is limited. It has been more widely used with success in Europe, where the less virulent strain of tularemia is more common. Caution should be used in the use of tetracyclines in the treatment of tularemia, as these agents are bacteriostatic and associated with a high rate of relapse after discontinuation of treatment of tularemia. In some cases, incision and drainage of affected lymph nodes may also be needed. [4][5][6]

Differential Diagnosis

• Chlamydial infections

• Diphtheria

• Endocarditis, bacterial

• Endocarditis, fungal

• Legionella infection

• Lyme disease

• Malaria

• Psittacosis

• Q-fever

Prognosis

If tularemia is not treated, it carries a mortality rate of 10-50%. Typhoid tularemia carries the highest mortality. Even those who survive are left with residual scars, lung and kidney damage and muscle loss.

Complications

• Lung abscess, pneumonia
• ARDS
• Rhabdomyolysis
• Renal failure
• Meningitis
• Peritonitis

Enhancing Healthcare Team Outcomes

Tularemia is best managed by an interprofessional team. Todate there is no proven agent to treat this infection. Currently, most sources recommend treatment with intravenous (IV) gentamicin for seven to 14 days, depending on the severity of illness. Fluoroquinolones, such as ciprofloxacin, may also play a role in mild disease although data supporting this approach in the more virulent type A tularemia infections in the United States is limited. It has been more widely used with success in Europe, where the less virulent strain of tularemia is more common. Caution should be used in the use of tetracyclines in the treatment of tularemia, as these agents are bacteriostatic and associated with a high rate of relapse after discontinuation of treatment of tularemia. In some cases, incision and drainage of affected lymph nodes may also be needed.

Tularemia is also considered a potential bioweapon given its high rate of infection with very small inoculating doses. In this setting, inhalational exposure, and thus pneumonic tularemia, would be the most likely presentation. A vaccine for tularemia is not routinely available, but studies are ongoing to develop effective preventative measures. Avoidance of exposures by using insect repellant, minimizing handling of carcasses with bare hands and avoiding ingestion of potentially contaminated game or water can decrease the chance of infection. Currently, there is no recommendation for antibiotic prophylaxis for tularemia after tick bites in endemic areas. [7][8][9]