Tularemia


Article Author:
Jessica Snowden


Article Editor:
Kari Simonsen


Editors In Chief:
Evelyn Metz
Julie Sewell
Aditya Arya


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
4/21/2019 11:20:06 AM

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]

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).

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.

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]

Enhancing Healthcare Team Outcomes

Tularemia is best managed by a multidisciplinary 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]


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Tularemia - Questions

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What is the cause of ulceroglandular fever?



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A patient returns from a hunting trip and complains of not feeling well. He says there were many insects and ticks in the woods, and he was bitten by several unknown insects. He now presents with fever, an ulcerated lesion on his right forearm, and painful axillary nodes ipsilaterally. Infection with which of the following organisms is most likely?



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A 14-year-old boy develops severe conjunctivitis with pain followed by the development of enlarged painful preauricular lymph nodes. He reveals that 1 week ago he went hunting with his father and killed a number of squirrels. Which of the following should be considered in the differential diagnosis of the adolescent's illness?



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Which of the following is not commonly seen in patients with tularemia?



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Which of the following is true regarding Francisella tularensis infections and treatment?



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Which of the following is responsible for the virulence of Francisella tularensis?



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Which of the signs or symptoms listed below is not characteristic of tularemia?



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A 65-year-old Vietnam veteran with no medical comorbidities was admitted to intensive care unit in a tertiary care center following the sudden onset of high-grade fever, intense headache, cough, and hemoptysis. He was profoundly hypoxic at admission needing intubation and mechanical ventilation. Inotropes were needed for septic shock. Bloodwork showed leukocytosis with 13% bands, hemoglobin 12.4 g/dL, mild thrombocytopenia, serum creatinine, electrolytes, and blood urea were normal. Liver enzymes included aspartate aminotransferase 70 U/L, alanine aminotransferase 85 U/L, alkaline phosphatase and serum total bilirubin were normal. CT chest with contrast revealed multilobar infiltrates, most pronounced in the right middle and lower lobes, associated with a moderate sized effusion. A week ago he returned from a week-long stay in Martha's Vineyard at his son's house, where he also mowed the lawn for one full day and pulverized a rabbit. Blood cultures were drawn and he was started on vancomycin, cefepime, and azithromycin. In 48 hours his FiO2 was increased from 40% to 70%, platelet counts were 42,000/microliter and infiltrates increased on chest x-ray. What is the most appropriate next step?



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Multiple patients present due to an outbreak of tularemia. Which of the following is correct?



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Tularemia - References

References

Frischknecht M,Meier A,Mani B,Joerg L,Kim OC,Boggian K,Strahm C, Tularemia: an experience of 13 cases including a rare myocarditis in a referral center in Eastern Switzerland (Central Europe) and a review of the literature. Infection. 2019 Jan 17;     [PubMed]
Kopping EJ,Doyle CR,Sampath V,Thanassi DG, Contributions of TolC orthologs to {i}Francisella tularensis{/i} Schu S4 multidrug resistance, modulation of host cell responses, and virulence. Infection and immunity. 2019 Jan 22;     [PubMed]
Kervyn A,Le Guern A,Gillard M,Bataille M,Modiano P, [Tularemia: A case report]. Annales de dermatologie et de venereologie. 2019 Jan 8;     [PubMed]
Balestra A,Bytyci H,Guillod C,Braghetti A,Elzi L, A case of ulceroglandular tularemia presenting with lymphadenopathy and an ulcer on a linear morphoea lesion surrounded by erysipelas. International medical case reports journal. 2018;     [PubMed]
Donate-Pérez-Molino P,Castelló-Abietar C,Fernández-Suárez J,de Vicente JC, Tularemia: diagnosis of an unexpected oculoglandular case in a non-endemic area by universal PCR. Enfermedades infecciosas y microbiologia clinica. 2018 Dec 27;     [PubMed]
Kwit NA,Schwartz A,Kugeler KJ,Mead PS,Nelson CA, Human tularaemia associated with exposure to domestic dogs-United States, 2006-2016. Zoonoses and public health. 2018 Dec 16;     [PubMed]
O'Malley KJ,Bowling JL,Stinson E,Cole KS,Mann BJ,Namjoshi P,Hazlett KRO,Barry EM,Reed DS, Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis. PloS one. 2018;     [PubMed]
Waits A,Emelyanova A,Oksanen A,Abass K,Rautio A, Human infectious diseases and the changing climate in the Arctic. Environment international. 2018 Dec;     [PubMed]
Rojas-Moreno C,Bhartee H,Vasudevan A,Adiga R,Salzer W, Tetracyclines for Treatment of Tularemia: A Case Series. Open forum infectious diseases. 2018 Sep;     [PubMed]

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