Tularemia

Practice Essentials

Tularemia is an acute, febrile, granulomatous, infectious zoonosis caused by Francisella tularensis, an aerobic, gram-negative, pleomorphic bacillus. F tularensis is one of the most infectious bacterial species known. See the image below.

View Image

Eschar on thumb and under thumbnail at the site of a rabbit bite in a patient with tularemia.

Signs and symptoms

The following are common findings in the various clinical forms of tularemia:

• Abrupt onset of fever and chills - These symptoms typically last for several days, remit for a brief interval, and then recur
• Pulse-temperature disassociation^[1]
• Headache
• Anorexia
• Malaise and fatigue or prostration
• Myalgias
• Cough
• Vomiting
• Pharyngitis
• Abdominal pain
• Secondary pneumonitis - May occur in 45-83% of patients with the typhoidal form of tularemia

As many as 20% of patients with tularemia have a rash, which may begin as blotchy, macular, or maculopapular and progress to pustular. Erythema nodosum and erythema multiforme are rare.

More specific signs and symptoms are as follows:

• Ulceroglandular tularemia - Includes painful regional lymphadenopathy and an ulcerated skin lesion
• Glandular tularemia - Tender lymphadenopathy without evidence of local cutaneous lesions
• Oculoglandular tularemia - Unilateral conjunctivitis, corneal ulceration, lymphadenopathy, photophobia, lacrimation, lid edema, vision loss (rare)
• Oropharyngeal tularemia - Stomatitis and exudative pharyngitis or tonsillitis; abdominal pain, nausea, and vomiting; cervical lymphadenopathy; diarrhea; gastrointestinal bleeding
• Intestinal tularemia - Abdominal pain, vomiting, and diarrhea
• Pneumonic tularemia - Dry cough, dyspnea, and pleuritic-type chest pain
• Typhoidal tularemia - Fever, chills, myalgias, malaise, and weight loss

Diagnosis

Serology

The diagnosis of tularemia is usually based on serology results. Tests vary from antibody detection (using latex agglutination or enzyme-linked immunosorbent assay [ELISA] testing) to the examination of a range of polymerase chain reaction (PCR) assay products.^{[2, 3, 4]}

An agglutination titer greater than 1:160 is considered presumptively positive, and treatment may be started if this result is obtained. A second titer, demonstrating a 4-fold increase after 2 weeks, confirms the diagnosis.

Indirect fluorescent antibody testing

Indirect fluorescent antibody testing of suppurative material is rapid and specific. Microscopic examination of tissue and smear specimens is possible using fluorescently labeled antibodies at reference laboratories, possibly providing rapid confirmation of disease.

Histologic studies

Early tularemic lesions may demonstrate areas of focal necrosis surrounded by neutrophils and macrophages. Later, the necrotic areas become surrounded by epithelioid cells and lymphocytes. Caseating granulomata with or without multinucleated giant cells develops in some lesions.

Bacterial culturing

Although F tularensis has been cultured from sputum, pleural fluid, wounds, blood, lymph node biopsy samples, and gastric washings, the yield is extremely low and culturing poses a danger to laboratory personnel.

Imaging

• Chest radiography - To evaluate for pneumonia; this is indicated in any patient in whom the diagnosis of tularemia is suspected
• Ultrasonography - To examine lymph nodes for findings suggestive of infection; however, these findings lack specificity

Management

Medical care in tularemia is directed primarily toward antibiotic eradication of F tularensis, with streptomycin being the drug of choice (DOC) for this treatment. Research increasingly supports the use of fluoroquinolones to treat the disease, but clinical experience and in vitro data regarding their efficacy are limited.^[5]

Symptomatic and supportive care is applied for accompanying conditions (eg, osteomyelitis, pericarditis, peritonitis) in patients with tularemia, as clinically indicated.

Vaccination

No tularemia vaccine is currently available. A vaccine based on a live strain of the bacterium was previously available but is no longer produced because of concerns about unknown attenuation, safety, and production.

Prevention

• Avoid tick-infested areas
• Wear trousers and long-sleeved shirts to avoid tick bites
• Use tick repellants
• Frequently inspect the body and clothing for evidence of ticks
• Avoid exposure to dead or wild mammals and wear gloves if such exposure is necessary; hands should be thoroughly washed afterwards

• References

Background

Tularemia is an acute, febrile, granulomatous, infectious zoonosis caused by Francisella tularensis, an aerobic, gram-negative, pleomorphic bacillus .F tularensis is one of the most infectious bacterial species known, as it can cause illness in humans with exposure to as few as 10-50 organisms. Four major subspecies, or biovars, exist; they differ in virulence and geographic range, with F tularensis biovar tularensis, found primarily in North America, being the most virulent. (See Pathophysiology and Etiology.)

Worldwide, more than 100 species of animals, including mammals, birds, amphibians, and arthropods, host F tularensis. The bacillus, which causes acute infectious illness in humans, may also be found in mud and water. (See Etiology.)

Although tularemia was quite common in the United States before World War II, incidence of the disease began a steady decline in the 1950s, falling to fewer than 0.15 cases per 100,000 population by 1965.^[6] As a result, tularemia was removed from the reportable disease list in 1995, although outbreaks and sporadic cases have continued to occur worldwide. The disease was again put on the reportable list in 2000, owing to its potential as a bioweapon.^{[7, 8]} (See Epidemiology.)

While most cases of tularemia in the United States have occurred in the south-central states of Arkansas, Kansas, Missouri, Nebraska, and Oklahoma, the incidence of cases occurring north of these states has been increasing.^{[9, 10, 11]}

Types of tularemia

Some authorities classify tularemia into 2 groups, which include the far more common ulceroglandular form (in which local or regional symptoms and signs predominate) and the more lethal typhoidal form (in which systemic symptoms dominate the clinical picture). More commonly, however, tularemia is divided into the following 7 forms:^[12]

• Ulceroglandular tularemia: Cutaneous ulcer with regional lymphadenopathy
• Glandular tularemia: Regional lymphadenopathy with no ulcer
• Oculoglandular tularemia: Conjunctivitis with preauricular lymphadenopathy
• Oropharyngeal tularemia: Stomatitis, pharyngitis, or tonsillitis with cervical lymphadenopathy
• Intestinal tularemia: Abdominal pain, vomiting, and diarrhea
• Pneumonic tularemia: Primary pleuropulmonary disease
• Typhoidal tularemia: Febrile illness without early localizing signs and symptoms

Each form reflects the mode of transmission. The organism gains access to the host by means of inoculation into skin or mucous membrane or through inhalation or ingestion. (See the image below.)

View Image

Ulceroglandular tularemia on an extremity. Courtesy of Dr Hon Pak.

Biovars of F tularensis

F tularensis is an aerobic, gram-negative, pleomorphic coccobacillus. It is capable of growing within several different cell types, including macrophages, endothelial cells, and hepatocytes.^{[13, 14]}

Four subspecies of F tularensis, all of which have been associated with human disease, have been described, but only the F tularensis biovar tularensis (Jellison type A) and F tularensis biovar holarctica (Jellison type B) are common causes. The 2 forms are serologically identical, differing primarily in their geographic distribution, fermentation reactions, and virulence.

F tularensis biovar tularensis is found predominantly in North America (although cases have been described in Europe) and is an extremely virulent organism. As few as 10-50 organisms may result in disease if inhaled or injected intradermally, although oral ingestion would require as many as 10⁸ organisms for disease to occur.

F tularensis biovar holarctica (also known as F tularensis biovar palearctica) is found primarily in Europe^[15] and Asia but has also been identified in cases of tularemia in North America. It is from this less-virulent subspecies that the live virus vaccine is derived. F tularensis biovars novicida and mediasiatica are of low virulence. A Japanese F tularensis biovar holarctica variant, japonica, has been more recently characterized.

Traditionally, Francisella subspecies have been characterized on the basis of biochemical reactions, growth characteristics, and virulence properties. However, biochemical methods for differentiating between the subspecies have been found to be imprecise; newer molecular typing methodology has advanced classification of these organisms.

Bioweapon potential

The species is considered a category A biowarfare agent due to its high infectivity, relative ease of growth and stability in liquid formulation, ease of dissemination, and ability to cause substantial illness and death.^{[16, 17]}

The World Health Organization (WHO) conducted modeling studies in 1970 on the possible use of F tularensis as an aerosolized bioweapon. The WHO estimated that an aerosol dispersal of 50 kg of virulent F tularensis over a metropolitan area with 5 million inhabitants would result in 250,000 incapacitating casualties, including 19,000 fatalities. This dispersal would also result in relapses occurring for many months after the initial exposure and the potential to establish enzootic reservoirs of tularemia in wild animals, leading to possible subsequent outbreaks.

A subsequent modeling study found that mitigation strategies will have to depend on the size of the release, the stockpile level of antibiotics, and the speed of antibiotic distribution. As previously mentioned, due to concerns regarding its potential use as a biowarfare agent, tularemia, which had been taken off the list of reportable diseases in 1995, was reinstated on the list in 2000.^{[18, 19]}

Patient education

Direct patient education at limiting tick and deer fly exposure. If the patient hunts, stress the importance of learning contact precautions and good hygiene for handling rabbits and other wild animals.

For patient education information, see Ticks.

• References

Pathophysiology

The cell wall of F tularensis possesses high levels of fatty acids, and wild strains have an electron-transparent, lipid-rich capsule. Loss of this capsule may result in loss of serum resistance and virulence; however, the capsule exhibits no innate immunogenicity or toxicity.

A subcutaneous inoculum of 10 organisms is sufficient to induce disease, whereas an inhalational exposure of 25 organisms may cause a severely debilitating or fatal disease. Over the first 3-5 days after cutaneous exposure, the organism multiplies locally and a papule forms.

During the next 2-4 days, the site ulcerates. Organisms spread from the entry site to regional lymph nodes and may disseminate lympho-hematogenously to involve multiple organs. Pulmonary findings may be primary after direct inhalation of aerosolized bacteria or may be present in up to half of all tularemia cases from hematogenous spread (secondary pneumonia). Patients are most likely bacteremic at this time, although this is not usually detected.

Immune response

Infection produces an acute inflammatory response initially involving local macrophages, neutrophils, and fibrin. T lymphocytes, epithelioid cells, and giant cells then migrate into local necrotic tissue.^[20] As the area of necrosis expands, thrombosis of adjacent arteries and veins may occur. Granulomas develop, which may caseate and be mistaken for tuberculosis, and necrotic foci may coalesce to form abscesses. These changes occur in infected sites and have been demonstrated on autopsy in lymph nodes, the liver, the spleen, bone marrow, and the lungs.^[21] F tularensis may remain viable for prolonged periods. They may remain viable in the tissues, where they cause infection.

During the second to third week of Francisella infection, humoral immunity develops against the bacterium's carbohydrate antigens. Agglutinating immunoglobulin M (IgM), IgG, and IgA antibodies are seen at this time.^{[14, 22]} Opsonizing IgG and IgM antibodies are also produced; these act in conjunction with complement (C3).

B-cell ̶ deficient mice have been shown to have impaired clearance of organisms after primary infection with the less virulent vaccine strain of Francisella.^[23] In addition, alpha/beta T-cell ̶ dependent immunity, involving either CD4+ or CD8+ T cells and directed against protein antigens, has been demonstrated to be necessary for effective eradication of Francisella.^{[13, 14]}

It has also been found that in humans, tularemia antigens, whether introduced by natural exposure or vaccination, elicit a vigorous and long-lasting response by memory T cells (T_M cells). Some of these T_M cells have lytic potential, and they demonstrate the ability to enter intestinal mucosal and nonmucosal lung sites.^[24]

Preformed molecules on the surface of Francisella trigger rearrangements of the host cell cytoskeleton. Macrophage complement receptors interact with complement factor C3 fixed by molecules on the bacterial cell surface, and bacteria are internalized by looping phagocytosis.

Immediately after phagocytosis, the bacteria are housed in a nonacidified phagosome. Bacteria may degrade the phagosomal membrane and escape into the cytoplasm, where they actively multiply. This can lead to cell death and liberation of bacteria. In rodent macrophages, bacterial survival has been shown to be associated with failure of phagosome-lysosome fusion, phagosome acidification, and utilization of host iron.^[25]

It has also been found that a lack of CD14 on human dendritic cells in the lung, or the existence of just minimal amounts of it, appears to contribute to F tularensis evasion of the host’s immune response.^[26]

Interferon gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) activate macrophages to kill Francisella through the production of reactive nitrogen products such as nitric oxide (NO),^[27] while neutrophils and mononuclear cells have been demonstrated to accumulate at infected liver foci and lyse Francisella -containing hepatocytes, releasing organisms from their relatively protected, sequestered environment.^[28]

The ability of F tularensis to impair phagocyte function and survive in infected cells is central to its virulence. This intracellular life cycle has been shown to be related to the tightly regulated expression of a series of genes.^{[29, 30]}

In the unique environment of the lung, oxygen-dependent neutrophil killing of wild virulent strains appears to be only partially effective.^[31] Shortly after inhalation, Francisella are found inside cells that typically act as cytokine-producing first responders to infection, including airway macrophages and alveolar epithelial cells. Mouse experiments demonstrate lack of production of pro-inflammatory cytokines, including interleukin 12p40 (IL-12p40), TNF, IL-6, and IL-1 alpha. The exact mediators responsible for immunosuppression remain unclear; however, immunomodulatory factors, such as transforming growth factor-beta (TGF-beta) and prostaglandin E2 (PGE2), may be actively involved.

Approximately 48-72 hours postinfection, a number of cytokines and chemokines, such as IFN-gamma and TNF, are upregulated, and levels of proinflammatory mediators, such as RANTES (regulated on activation, normal T cell expressed and secreted), IL-6, and IL-1 beta, are detected. Unfortunately, the lung may contain more than 10⁸ colony-forming units (CFU) of F tularensis, and this upregulation may be too late to prevent death.^{[13, 32]} This late "cytokine storm," similar to that demonstrated in other instances of severe bacterial sepsis, may actually prove harmful to the host, causing capillary leakage, tissue injury, and lethal organ failure.^{[33, 34]}

The incubation period for tularemia depends on the size of the inoculum, but ranges from 1-21 days (average 2-6 days). Individuals with tularemia may be asymptomatic or acutely septic with rapid death. Six clinical forms of tularemia have been identified. Each form is influenced by factors related to the host, organism, route of transmission, and host entry site.

• References

Etiology

As previously mentioned, 4 subspecies of F tularensis have been described. Although all of them have been associated with human disease, however, only the F tularensis biovar tularensis (Jellison type A) and F tularensis biovar holarctica (Jellison type B) are common causes. The 2 forms are serologically identical, differing primarily in their geographic distribution, fermentation reactions, and virulence.

F tularensis biovar tularensis is generally found in North American rabbits and ticks and causes severe disease in humans. An inoculum of 10 organisms subcutaneously is sufficient to induce disease, while an inhalational exposure of only 25 organisms may cause disease.

F tularensis biovar holarctica is found primarily in Asian and European rodents and results in a milder form of disease in humans.

Methods of transmission include inhalation, ingestion, contact with an infected animal, and vector-associated exposure.

Transmission

Human-to-human spread of tularemia is not thought to occur. Transmission of disease to humans most often results from an insect bite or contact with contaminated animals or animal products.^{[35, 36]} Thorough cooking of meat before consumption is believed to lessen the likelihood of transmission.

Transmission has also been described via ingestion of or contact with contaminated water, exposure to contaminated mud, animal bites,^{[37, 38]} and exposure to aerosolized water droplets or dust from contaminated soil or grains.

Francisella has been shown to survive for prolonged periods of time in frozen water, mud, and animal carcasses.^[8] Carnivores, such as domestic cats, may transiently harbor Francisella in their mouths or on their claws after killing or feeding on infected prey, regardless of whether they have actually become infected. Cases have developed in laboratory workers, who should be notified in advance to safely handle specimens when tularemia is suspected.

Animal hosts

F tularensis is capable of infecting hundreds of different invertebrate, aquatic, and terrestrial vertebrate species, including lagomorphs, rodents, ticks, mosquitos, and flies. In any geographic region, usually no more than a dozen mammals are important to its ecology. However, the overall ecology of F tularensis remains poorly characterized, particularly transmission cycles and specific differences between the 4 subspecies.^{[39, 40]}

Lagomorphs, including Sylvilagus and Lepus species, have been historically recognized as common sources of transmission (hence the common names wild hare disease and rabbit skinners' disease for tularemia). In North America, squirrels, muskrat, beavers, and voles have also been identified as natural reservoirs of F tularensis. In the former Soviet Union, in addition to hares, animal hosts include hamsters, voles, water rats and mice.^[37]

Tularemia has been recovered from over 54 species of arthropods.^[41] Blood-feeding flies and arthropods are the most important vectors for tularemia in the United States. Biting flies, such as deer flies (Chrysops discalis), are the predominant vectors in the far western states, while ticks, primarily Amblyomma americanum, Dermacentor andersoni, and D variabilis, are important vectors from the Rocky Mountains eastward. In Northern Europe and the former Soviet Union, mosquitos serve as the most important insect vector.

Ticks are a particularly important reservoir and vector because at least 13 different species have been found to be infected with F tularensis. In addition, vertical transmission of the bacterium transovarially has been demonstrated. F tularensis may be present in tick feces or saliva and can be inoculated directly or indirectly into the bite wound. Tick colonization by the organism may be enhanced, as intraerythrocytic F tularensis are protected from the acidic pH in the tick gut.^[42]

Specific etiologies

Ulceroglandular form

This form occurs in 70-80% of cases. The organism enters through a scratch, abrasion, or tick or insect bite and spreads via the proximal lymphatic system. Within the ulceroglandular form, more differentiation exists. A subcutaneous inoculum of as few as 10 organisms can cause disease. (See the image below.)

View Image

Ulceroglandular type of tularemia on the hand. Courtesy of Dr Hon Pak.

Glandular form

This form of the disease is rare. No ulcer is present, and the organism is presumed to have gained access to the lymphatic system and/or bloodstream through clinically unapparent abrasions.

Oculoglandular form

In this form of tularemia, which makes up 1% of cases, the organism enters through the conjunctiva from either a splash of infected blood or rubbing the eyes after contact with infectious materials (eg, blood from a rabbit carcass).

Oropharyngeal form

This form of the disease, which is also rare, occurs after ingestion of undercooked rabbit meat containing the organism or consumption of contaminated water.

Pneumonic form

This uncommon form of tularemia occurs when the organism is inhaled via aerosols of water or dust from soil, grains, or pelts or arises secondary to hematogenous spread of the bacterium. It is observed in laboratory workers and occasionally occurs naturally. Pneumonia also occurs in 10-15% of patients with ulceroglandular tularemia and in 50% of those with typhoidal tularemia. The mortality rate can reach 60% if untreated.

Typhoidal (or septicemic) form

This form, which occurs in 10-15% of cases, is more severe than the others and often includes pneumonia. Ingestion may be the mode of transmission; in most cases, however, the portal of entry remains unknown.

• References

Epidemiology

Tularemia is widely distributed; however, it is found largely in the northern hemisphere from 30-71° north latitude. The disease is most commonly described in the western and south-central regions of the United States and in continental Europe and Asia.

Occurrence in the United States

A few hundred cases of tularemia are reported annually in the United States, Most reported cases occur in Arkansas, Tennessee, Texas, Oklahoma, Kansas, Utah, and Missouri.

In the past, tularemia infections reportedly occurred more frequently during the cold-weather months (eg, rabbit-associated disease); however, the infections are now being reported more frequently during warm-weather months (eg, tick-associated disease).

Approximately 200 cases of tularemia are reported annually in the United States, although many cases are probably undiagnosed, misdiagnosed, or unreported. The disease has been reported in all states except Hawaii.

Transmission of tularemia was previously most frequent from June through August and in December. The summer peak was thought to be due to insect bites, while the winter peak was attributed to hunting-associated cases. Peak reporting now occurs in late spring and early summer.^[6] From 1990-2000, 56% of cases reported in the United States were from Arkansas, Missouri, Oklahoma, and South Dakota, with high numbers of cases also reported in Massachusetts, Kansas, and Montana.^[25] High incidence rates among indigenous Alaskans and Native Americans have also been reported.^{[6, 43]}

Occupations and avocations associated with an increased risk of tularemia include the following:

• Laboratory work
• Veterinary practice
• Farming
• Landscaping
• Working with sheep
• Hunting and trapping
• Meat handling

International occurrence

Tularemia occurs throughout the Northern Hemisphere, except for in the United Kingdom. Cases have been reported in the United States, the former Soviet Union, Japan, Canada, Mexico, and Europe.^{[35, 40, 43]} Tularemia has not been reported in Africa and South America.

Sex- and age-related demographics

Although both sexes are equally susceptible to tularemia, males are more frequently affected than females. This primarily results from increased exposure to specific activities (eg, hunting and skinning animals) and increased occupational vulnerability among males.

People of all ages are susceptible to the tularemia; however, young to middle-aged people are more likely to participate in activities that predispose them to exposure.^[6]

• References

Prognosis

Untreated tularemia has a mortality rate of 5-15%; if treated, the disease carries a mortality rate of 1-3%. The mortality rate is 2-3 times higher in patients with typhoidal tularemia than in those with other forms.

Other factors associated with increased mortality include elevated creatine kinase levels, renal failure, and other serious comorbidities, as well as late diagnosis. The mortality rate also depends on the subspecies involved; F tularensis biovar tularensis is significantly more virulent than the others and is responsible for almost all reported deaths.

• References

Complications

Complications of tularemia include the following:

• Pneumonia
• Lung abscess
• Respiratory failure, including possible acute respiratory distress syndrome (ARDS)
• Rhabdomyolysis
• Renal failure with possible hemodialysis
• Hemoptysis
• Meningitis
• Endocarditis
• Suppurative lymphadenitis
• Pericarditis
• Peritonitis
• Appendicitis
• Perisplenitis
• Osteomyelitis
• Guillain-Barré syndrome
• Hepatitis
• Sepsis

• References

History

As previously discussed, 6 clinical forms of tularemia have been described; ie, ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, and typhoidal. These forms are not necessarily distinct entities and may have overlapping features.^[44]

As with many other tick-borne diseases, tularemia may, early in its course, have a nonspecific presentation. Moreover, many individuals may not be aware of or recall having been bitten by a tick or fly. These factors illustrate the importance of routinely including queries regarding travel, work, and animal and arthropod exposure in the history when presented with a patient who potentially has tularemia.

Delayed diagnosis and late administration of effective antibiotic therapy may result in increased morbidity and a greater risk of mortality in patients with the disease. Atypical or particularly severe presentations of common illnesses may provide clues to the presence of relatively rare diseases.^{[45, 46, 47, 48]}

Children infected with tularemia typically have a clinical presentation similar to that of adults. However, children have been reported to have fever, pharyngitis, hepatosplenomegaly, and constitutional symptoms more often than do adult patients.

The following are common findings in the various clinical forms of tularemia:

• Abrupt onset of fever and chills - These symptoms typically last for several days, remit for a brief interval, and then recur
• Pulse-temperature disassociation^[1]
• Headache
• Anorexia
• Malaise and fatigue or prostration
• Myalgias
• Cough
• Vomiting
• Pharyngitis
• Abdominal pain
• Secondary pneumonitis - May occur in 45-83% of patients with the typhoidal form

As many as 20% of patients with tularemia have a rash, which may begin as blotchy, macular, or maculopapular and progress to pustular. Erythema nodosum and erythema multiforme are rare.

Ulceroglandular tularemia

In this form of tularemia, F tularensis usually enters the body via a scratch or abrasion and then spreads lymphatically, typically causing painful regional lymphadenopathy and an ulcerated skin lesion.

In most cases, 2-5 days following exposure to the disease bacterium (but with a range of 1-10 days) a small, erythematous, tender or pruritic papule occurs at the site of inoculation; the papule enlarges and becomes ulcerated 2-3 days later. Gradually, the tender necrotic base develops with a black eschar, often concomitantly with tender regional adenopathy. (See the image below.)

View Image

Eschar on thumb and under thumbnail at the site of a rabbit bite in a patient with tularemia.

The tick-borne form usually involves inguinal or femoral adenopathy, while the rabbit (animal)-associated form usually involves axillary or epitrochlear adenopathy. (See the image below.)

View Image

Axillary bubo in a patient with tularemia.

Systemic adenopathy may also occur. Some patients will exhibit a sporotrichoid picture of ascending, tender subcutaneous nodules. Lymphadenopathy, lymphadenitis, or both may occur, with tender, suppurative, local enlargement reflecting the site of entry. More than 20% of lymph nodes will suppurate if left untreated or treatment is delayed longer than 2 weeks.^{[1, 49]}

The ulcer, which has raised edges and a jagged floor, is located on a finger or hand in more than 90% of patients with rabbit-associated disease. In tick-borne tularemia, the ulcer is found on a lower extremity or the perineal area in 50% of patients, on the trunk in 30% of cases, and on the head in 5-10% of patients. (See the images below.)

View Image

Ulceroglandular type of tularemia on the face. Courtesy of Dr Hon Pak.

View Image

Ulceroglandular tularemia on an extremity. Courtesy of Dr Hon Pak.

View Image

Ulceroglandular type of tularemia on the hand. Courtesy of Dr Hon Pak.

Glandular tularemia

In the glandular form of tularemia, tender lymphadenopathy occurs without evidence of local cutaneous lesions. The bacterium presumably gains entry via microscopic abrasions or potentially through intact skin. It then spreads lymphatically or via the bloodstream. (See the image below.)

Oculoglandular tularemia

In this form, F tularensis enters via the conjunctivae after the patient is either splashed with blood or rubs his or her eyes following contact with contaminated tissue fluids. Clinical manifestations are usually unilateral; they include the following:

• Unilateral conjunctivitis - Painful, purulent conjunctivitis; some patients experience chemosis, periorbital edema, and small, nodular or ulcerative lesions of the palpebral conjunctivae
• Corneal ulceration
• Lymphadenopathy - Most commonly cervical, but preauricular and submandibular also observed
• Photophobia
• Lacrimation
• Lid edema
• Vision loss (rare)

Oropharyngeal tularemia

This is a rare form that may occur after consumption of infected, undercooked meat or contaminated water. Manifestations of oropharyngeal tularemia include the following:

• Stomatitis and exudative pharyngitis or tonsillitis - The patient may occasionally develop a yellow-white pseudomembrane resembling diphtheria
• Abdominal pain (due to mesenteric lymphadenopathy), nausea, and vomiting
• Cervical lymphadenopathy, including deep neck infection^[50]
• Diarrhea
• Gastrointestinal bleeding - Occasionally; caused by intestinal ulcerations

Pneumonic tularemia

Primary tularemia pneumonia, an uncommon condition, occurs after inhalation of F tularensis.^[51] Rarely acquired naturally, pneumonic tularemia may develop in laboratory workers.

Secondary pneumonic tularemia may result from hematogenous spread and may complicate any form of tularemia, but is most common with the ulceroglandular or typhoidal forms.^{[1, 52]}

Patients with pneumonic tularemia usually report a dry cough, dyspnea, and pleuritic-type chest pain. Chest radiography may reveal patchy, ill-defined infiltrates in 1 or more lobes. Frank lobar pneumonia may also develop, and bilateral hilar adenopathy may be present. Bloody pleural effusions are characteristic and demonstrate a mononuclear cellular response. ARDS develops in some patients.^{[51, 53]}

Typhoidal tularemia

This form of tularemia is particularly severe; it probably represents F tularensis bacteremia. Patients with this disease present with the following:

• Fever
• Chills
• Myalgias
• Malaise
• Weight loss

Patients often have pneumonia. Diagnosis is difficult because ulcers and lymphadenopathy are usually absent.

Additional manifestations

Rare manifestations of tularemia include the following:

• Osteomyelitis
• Pericarditis
• Peritonitis
• Endocarditis
• Nervous system abnormalities - Including meningitis, abscesses,^[54] and optic neuritis.^[55]

Other possible manifestations include acute renal failure, hepatomegaly, abnormal liver function, and rhabdomyolysis.

• References

Physical Examination

Patients with tularemia have fever and possibly tender hepatosplenomegaly. As many as 20% of patients have a rash, which may begin as blotchy, macular, or maculopapular and progress to pustular. Erythema nodosum and erythema multiforme rarely occur.

Ulceroglandular tularemia

This form is characterized by an ulcer at the site of F tularensis entry through the skin. The ulcer varies with the vector. It usually begins as a tender papule that eventually ulcerates and has a sharply demarcated border with a yellowish exudate. Initially, the base of the ulcer also has a yellowish exudate, but this subsequently turns black.

Regional lymphadenopathy develops, and the lymph nodes are usually edematous and tender. They can become fluctuant and may drain spontaneously.

Oculoglandular tularemia

Ocular findings are usually unilateral. Clinical presentation includes the following:

• Painful conjunctivitis with purulent exudate may be present
• Nodules or ulcerations may develop on the palpebral conjunctivae
• Submandibular, preauricular, and cervical adenopathy are common
• Corneal ulcerations may develop

Oropharyngeal tularemia

Exudative or membranous pharyngotonsillitis with regional adenopathy may be observed.

Pneumonic tularemia

Chest examination findings may be normal in tularemic pneumonia, or rales may be present in the affected lung fields.

• References

Approach Considerations

Consider tularemia in patients with fever and regional lymphadenopathy, particularly when an ulcer or conjunctivitis is present.

Routine laboratory testing is generally not helpful in tularemia, except to aid in excluding other diseases from the differential diagnoses. The following lab results may be seen in patients infected with F tularensis, but these are not specific to tularemia:

• Serum transaminase levels are mildly elevated in about one half of patients
• Urinalysis may show sterile pyuria in as many as one fourth of patients
• The complete blood count (CBC) may reveal an elevated white blood cell (WBC) count in about one half of patients
• Mild thrombocytopenia may be present
• Hyponatremia is occasionally present
• Elevation of creatine kinase values may be observed and is associated with rhabdomyolysis
• Cerebrospinal fluid (CSF) may show hypoglycorrhachia, a mild elevation of protein concentration, and, almost always, a mononuclear cell pleocytosis

Updated (2014) guidelines on the diagnosis and treatment of tularemia have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).^[57]

Indirect fluorescent antibody test

Indirect fluorescent antibody testing of suppurative material is rapid and specific. Microscopic examination of tissue and smear specimens is possible using fluorescently labeled antibodies at reference laboratories, possibly providing rapid confirmation of disease.

• References

Histology

Early tularemic lesions may demonstrate areas of focal necrosis surrounded by neutrophils and macrophages. Later, the necrotic areas become surrounded by epithelioid cells and lymphocytes. Caseating granulomata with or without multinucleated giant cells develops in some lesions.

• References

Serology

The diagnosis of tularemia is usually based on serology results. Tests vary from antibody detection (using latex agglutination or enzyme-linked immunosorbent assay [ELISA] testing) to the examination of a range of polymerase chain reaction (PCR) assay products.^{[2, 3, 4]}

An agglutination titer greater than 1:160 is considered presumptively positive, and treatment may be started if this result is obtained.

A second titer, demonstrating a 4-fold increase after 2 weeks, confirms the diagnosis. Note that, although titers begin to rise within 7-10 days after exposure, early titers in the first 2 weeks of illness may be negative in the setting of infection. Detectable titers are identified in the second week of infection in more than 50% of cases.

Titers achieve maximum levels between 4-8 weeks and may remain elevated for years after infection, causing an uncertainty in individuals with a remote history of tularemia exposure.

Titers of 1:10-80 occur in 1% of the American population, especially in persons with long-term exposure to rabbits. Thus, an elevated titer in the absence of clinical tularemia does not establish a diagnosis. Moreover, tularemia serologic tests may cross-react with Salmonella, Brucella, Yersinia, Burkholderia, Pseudomonas, and Legionella species, as well as the Proteus strain OX19.

PCR assay

PCR assay tests may provide rapid and specific confirmation that tularemia is present, and may demonstrate the disease phase.^[3] Real-time PCR assay for genetic typing of clinical and environmental isolates of F tularensis has been developed.^{[58, 59]} A study on wound swabs from 40 patients with ulceroglandular tularemia found that PCR assay using 17-kDa primers was 75% sensitive, while culture was 62% sensitive.^[60]

However, while PCR assay is very sensitive in artificial media, it is less sensitive when applied to biologic specimens, and false negatives may occur. Although it has been used to detect F tularensis after initiation of antibiotic therapy, it is not yet available in most laboratories.

Capture ELISA

Capture ELISA is an advancement based on monoclonal antibodies specific for lipopolysaccharide of the virulent forms of F tularensis. In animal studies, capture ELISA was more sensitive and specific than routine ELISA.

• References

Bacterial Culture

Although F tularensis has been cultured from sputum, pleural fluid, wounds, blood, lymph node biopsy samples, and gastric washings, the yield is extremely low and culturing poses a danger to laboratory personnel. The plates must be sealed and handled by a biosafety level-2 (BSL-2) facility, with further testing at a BSL-3 facility after a presumptive identification of F tularensis.^[61]

Specimens should be maintained for at least 10 days because the slow growth of the culture may require 48-72 hours to be identified.

Blood cultures have poor sensitivity, which is probably due to the specific medium (cysteine-glucose-blood agar) needed to culture this organism.

• References

Imaging Studies

C hest Radiography

Chest radiography is indicated in any patient in whom the diagnosis of tularemia is suspected, to evaluate for pneumonia. As many as 30% of patients with tularemic pneumonia have no physical findings or respiratory tract symptoms.

Common findings in tularemia pneumonia include bilateral patchy infiltrates or lobar infiltrates (74%); cavitary lesions, which may be better visualized on chest computed tomography (CT) scans; hilar lymphadenopathy (32%); and a pleural effusion (30%).

The triad of oval opacities, hilar lymphadenopathy, and pleural effusion is more likely with tularemia than with other tick-borne diseases.

Ultrasonography

Ultrasonograms of infected lymph nodes may reveal findings suggestive of infection; however, these findings lack specificity.

• References

Approach Considerations

Medical care in tularemia is directed primarily toward antibiotic eradication of F tularensis. Symptomatic and supportive care is applied for accompanying conditions (eg, osteomyelitis, pericarditis, peritonitis) in patients with tularemia, as clinically indicated.

Updated (2014) guidelines on the diagnosis and treatment of tularemia have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).^[57]

Inpatient care

Treatment for patients with tularemia includes supportive and general medical care for manifestations that require hospitalization (eg, ARDS, pneumonia, lung abscess, renal insufficiency).

Surgical care

Surgical care is not needed in tularemia management unless an ulcerative lesion develops a superinfection and requires debridement or drainage is required for empyema or a fluctuant lymph node.

Consultations

Consider consultation with an infectious diseases specialist to help determine the diagnosis and treatment plan. In patients with pneumonia or ARDS, assistance from a pulmonologist may be necessary.

Reporting

Tularemia is currently a reportable disease in the United States. Contact your local public health department if you suspect a case of tularemia. Contact local or federal law enforcement agencies and the Centers for Disease Control and Prevention if multiple cases occur, which would suggest biologic or terrorist attack.

• References

Antibiotic Therapy

Streptomycin is considered the drug of choice (DOC) to treat tularemia. Less experience has been reported with other aminoglycosides; gentamicin and amikacin are effective, have been used successfully, and are more generally available.

While chloramphenicol and tetracycline are clinically useful, relapse rates of up to 50% have been reported in patients treated with these agents.

Case reports indicate a potential role for erythromycin and fluoroquinolones (ciprofloxacin, levofloxacin); however, clinical experience and in vitro data supporting their use are limited.

F tularensis is naturally resistant to penicillins and first-generation cephalosporins. Ceftriaxone, a third-generation cephalosporin, has been examined in the treatment of tularemia and, although it was found to have good in vitro MICs (minimal inhibitory concentrations), a number of therapeutic failures occurred.^{[62, 63]}

Prophylaxis

Postexposure prophylaxis is recommended within 24 hours of airborne exposure to F tularensis using either ciprofloxacin or doxycycline for 2 weeks. It is unlikely that aerosolized exposure to F tularensis will be identified within 24 hours, so standard treatment is recommended within 14 days of exposure.

• References

Vaccination

No tularemia vaccine is currently available. A vaccine based on a live strain of the bacterium was previously available but is no longer produced because of concerns about unknown attenuation, safety, and production.

• References

Prevention

Tick bites can be prevented by avoiding tick-infested areas, wearing trousers and long-sleeved shirts, and using tick repellants and by frequent inspection of the body and clothing for evidence of ticks. Ticks should be promptly removed by grasping the tick near the mouthparts and pulling upward. Care should be taken to not squeeze the body, because tick secretions may be infectious.

Exposure to dead or wild mammals should be avoided, if possible. When exposure is necessary (eg, skinning or eviscerating a rabbit carcass), gloves should be worn, especially if abrasions are on the hands. Hands should be washed thoroughly afterwards.

• References

Surgical Care

Surgical or needle drainage of suppurated fluctuant nodes may be necessary.^[64] Recurrent suppuration of lymph nodes despite treatment has been described in patients with prior receipt of immunosuppressive medications.^[65]

• References

Medication Summary

Medical therapy in tularemia is directed at antibiotic eradication of the bacterium F tularensis. Streptomycin is the drug of choice (DOC) for this treatment; although less experience exists with other aminoglycosides, gentamicin also appears to be effective. In addition, although tetracyclines are acceptable alternatives, increasing research supports the use of fluoroquinolones in the treatment of tularemia.^[5]

In vitro susceptibility testing has shown that the quinolones have great promise in treating tularemia, and reports exist of patients who responded well to fluoroquinolones prior to tularemia being suspected. Thus, these drugs may be an alternative for treating patients who cannot tolerate aminoglycosides. Also, many practitioners are using newer fluoroquinolones as monotherapy for community-acquired pneumonia.

Levofloxacin and ciprofloxacin have been used clinically with success. In fact, in a large tularemia outbreak in Spain (142 cases), ciprofloxacin had a lower treatment failure rate and fewer side effects than did streptomycin and doxycycline.^[66]

• References

Streptomycin

• Dosing, Interactions, etc.

Clinical Context:  Streptomycin is an aminoglycoside antibiotic traditionally considered to be the DOC for tularemia. It has been administered safely intravenously but is usually administered intramuscularly.

• References

Gentamicin

• Dosing, Interactions, etc.

Clinical Context:  This aminoglycoside may be used as an alternative to streptomycin, although there has been less clinical experience with gentamicin than with streptomycin in the treatment of tularemia. The drug may be administered intravenously or intramuscularly. Many dosing schedules are based on creatinine clearance (CrCl), volume of distribution, site of infection, and type of infection. Monitor serum levels after steady state is reached (usually after 3-4 doses). Trough levels are usually obtained 0.5 hour before the dose; peak levels are usually obtained 1 hour after the dose is infused.

• References

Doxycycline (Adoxa, Alodox, Doxy 100, Doryx, Vibramycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is a broad-spectrum, synthetically derived, bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. The drug inhibits protein synthesis (and thus bacterial growth) by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Doxycycline may block dissociation of peptidyl transfer ribonucleic acid (t-RNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. It may eradicate not only F tularensis, but also other tick-related co-pathogens. Doxycycline should be used for a full 14 days to prevent risk of relapse.

• References

Chloramphenicol (Chloromycetin)

• Dosing, Interactions, etc.

Clinical Context:  Chloramphenicol binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.

There is insufficient data on chloramphenicol's use in the treatment of tularemia. It is a distant third or possibly fourth choice for tularemia therapy given growing evidence supporting the use of fluoroquinolones.

• References

Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Tetracycline is a third-line drug for the treatment of tularemia, since the tetracyclines are only bacteriostatic. Treatment that lasts less than 2 weeks is associated with a greater risk of relapse. The only potential advantage to the use of tetracycline is its ability to cover other, coexisting tick-borne pathogens.

The drug inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.

• References

Levofloxacin (Levaquin)

• Dosing, Interactions, etc.

Clinical Context:  This agent may be useful to treat tularemia.

• References

Ciprofloxacin (Cipro)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms but no activity against anaerobes. Continue treatment for at least 2 days (7-14 days are typical) after signs and symptoms disappear.

• References

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens for the clinical presentation. Streptomycin is considered the antimicrobial of choice in tularemia therapy.

While chloramphenicol and tetracycline are also clinically useful against tularemia, relapse rates of up to 50% have been reported with these agents.

Research increasingly supports the use of fluoroquinolones to treat the disease, but clinical experience and in vitro data regarding their efficacy are limited.^[5]

• References