Tularemia: Clinical manifestations, diagnosis, treatment, and prevention

INTRODUCTION — Tularemia is a zoonotic infection caused by Francisella tularensis, an aerobic and fastidious gram-negative bacterium. Human infection occurs following contact with infected animals or invertebrate vectors. Synonyms include Francis disease, deer-fly fever, rabbit fever, market men disease, water-rat trappers disease, wild hare disease (yato-byo), and Ohara disease [1]. The clinical manifestations of Francisella infection may range from asymptomatic illness to septic shock and death, in part depending on the virulence of the infecting strain, portal of entry, inoculum, and the immune status of the host [1].

The clinical manifestations, diagnosis, treatment, and prevention of tularemia will be reviewed here. The microbiology, pathogenesis, and epidemiology of infection due to F. tularensis are discussed separately. (See "Tularemia: Microbiology, epidemiology, and pathogenesis".)

CLINICAL MANIFESTATIONS

Initial nonspecific symptoms — Tularemia usually has an abrupt or rapid onset of nonspecific systemic symptoms, including fever, chills, anorexia, and malaise, which occur approximately three to five days (range 1 to 21 days) following exposure. Classically, the fever may abate after a few days but then quickly return. Other nonspecific symptoms include headache, fatigue, soreness in the chest or muscles, abdominal pain, emesis, or diarrhea. In some patients, these systemic symptoms may have waned by the time of evaluation.

When patients do come to medical attention, they usually have specific clinical manifestations associated with one of the six major clinical forms of tularemia, depending on the portal of entry [2]:

●Ulceroglandular tularemia

●Glandular tularemia

●Oculoglandular tularemia

●Pharyngeal (oropharyngeal) tularemia

●Pneumonic tularemia

●Typhoidal tularemia

These syndromes are discussed separately in detail below, although overlapping manifestations may be present.

Some features may depend on the infecting subtype. Pulse-temperature dissociation (eg, relative bradycardia in the setting of a fever) was reported in only 5 percent of patients in a series from Sweden, where F. tularensis subspecies holarctica predominates, but was reported in 42 percent of patients in a series from the United States, where F. tularensis subspecies tularensis predominates [2,3].

Clinical syndromes

Ulceroglandular disease — Ulceroglandular disease, characterized by a skin lesion and associated adenopathy, is the most common and most easily recognizable form of tularemia [1,2]. As an example, in a review of 190 tularemia cases in Missouri between 2000 and 2007, ulceroglandular tularemia was the most common clinical form overall and among adults; among children, it was the second most common form (glandular disease was the most common among children) [4]. Ulceroglandular disease was also among the most common forms of tularemia during 2015 in Colorado, Nebraska, South Dakota, and Wyoming: states with significantly increased numbers of cases during that time [5]. Among 177 tularemia patients identified in France between 2008 and 2017, ulceroglandular disease was the most common presentation; all were infected with F. tularensis subspecies holarctica [6]. (See "Tularemia: Microbiology, epidemiology, and pathogenesis".)

Patients with ulceroglandular disease usually report recent animal contact or exposure to potential insect vectors (particularly ticks). They typically present with fever and a single erythematous papulo-ulcerative lesion with a central eschar at the site of inoculation (eg, the site of a tick bite) (picture 1). Ulcers on the hands and arms are more common following animal exposures; ulcers on the head or neck, trunk, perineum, and legs are more common following tick exposures. Occasionally, more than one skin lesion may be present [2].

Affected patients also have tender regional lymphadenopathy, which can occur before, at the same time, or shortly after the appearance of the skin lesion. Adenopathy involving cervical or occipital nodes is more common in children than adults, and the associated ulcers may be hidden in the scalp. The overlying skin of the node can be erythematous, as observed in 19 percent of cases in a series of 215 Swedish patients with infection due to the less virulent F. tularensis subspecies holarctica [3]. A "sporotrichoid" presentation, or subcutaneous nodules along the draining lymphatics, has also been described in some patients with tularemia [7]. However, frank lymphangitis is not usually seen; its presence should suggest the uncommon complication of bacterial superinfection of the skin ulcer.

Suppuration of affected lymph nodes is a relatively common complication and may occur despite antibiotic therapy. In a review of tularemia cases in Missouri, 15 of 81 patients (19 percent) with lymphadenopathy required incision and drainage of suppurative nodes [8]. Recurrent lymph node suppuration despite treatment has been described in a patient with tularemia who had been treated with an anti-tumor necrosis factor (TNF) agent and methotrexate [9]. Suppurated, fluctuant nodes warrant surgical or needle drainage. (See 'Adjunctive management' below.)

Patients seeking medical attention relatively late in the course of disease may have adenopathy with little or no fever and only evidence of a healed skin lesion.

Glandular disease — Glandular tularemia refers to tender regional lymphadenopathy involving single or multiple nodes, in the absence of an identifiable skin lesion. It is a relatively common presentation of tularemia. Among 190 cases of tularemia in Missouri between 2000 and 2007, glandular disease was the most common presentation among children (44 percent of cases), and it was the second most common presentation overall (28 percent of cases); it was the third most common presentation in adults (16 percent of cases) [4]. Among 177 tularemia patients identified in France between 2008 and 2017, glandular disease was the second most common presentation [6].

Glandular disease is transmitted via the same mechanism as ulceroglandular disease, and the clinical features of the associated adenopathy are the same, but in glandular disease, there is no evident lesion at the site of inoculation. Suppurative lymph nodes can also occur with glandular disease. (See 'Ulceroglandular disease' above.)

Oculoglandular disease — Oculoglandular tularemia refers to infection involving the eye and accounts for a small percentage of tularemia cases.

It occurs when F. tularensis gains access to the conjunctiva, either via splashing infected material into the eye, rubbing the eyes with contaminated fingers, or by infected aerosols. Eye symptoms are usually unilateral and include pain, photophobia, and increased tearing. Eye examination demonstrates conjunctival erythema with edema and vascular engorgement. Some patients may have conjunctival purulence, small conjunctival ulcers or nodules, and periorbital erythema and/or edema [10]. Tender regional adenopathy may be present in the preauricular, postauricular, cervical, and submandibular regions. Parinaud's oculoglandular syndrome specifically refers to conjunctivitis in one eye and swollen lymph nodes in front of the ear on the same side; F. tularensis is one cause of this syndrome. (See 'Differential diagnosis' below.)

Complications include corneal ulceration and dacryocystitis. Tularemia also has been associated with other less common ocular manifestations, including a case of unilateral uveitis [11,12].

Suppurative lymph nodes can also occur with oculoglandular disease. (See 'Ulceroglandular disease' above.)

Pharyngeal (oropharyngeal) disease — Pharyngeal tularemia involves the mouth and throat and accounts for a small percentage of cases in the United States. However, pharyngeal disease accounts for a larger percentage of cases in other parts of the world, particularly in outbreaks in the setting of war or natural disaster [13].

It results from an oropharyngeal portal of infection, usually ingestion of contaminated food or water. Transmission can also occur from oral exposure to contaminated droplets or by hand-to-mouth exposure (eg, in the setting of finger contamination from crushing ticks or handling contaminated animals).

The major symptoms are fever, severe sore throat, and swelling in the neck [14]. Examination demonstrates an exudative pharyngitis and tonsillitis, cervical lymph node enlargement, and usually pharyngeal or tonsillar ulcers. Preparotid and retropharyngeal lymph nodes also may be enlarged and tender. In addition, a pharyngeal membrane mimicking diphtheria can occur [15].

Pneumonic disease — Pneumonic tularemia refers to a clinical presentation dominated by pulmonary involvement. Pneumonic disease is more common in adults but can affect any age group and has occurred with increasing frequency. Among 190 cases in Missouri between 2000 and 2007, pneumonic disease accounted for 39 percent of adult cases and 24 percent of tularemia cases overall [4]. Pneumonic and ulceroglandular tularemia were equally common in Colorado, Nebraska, South Dakota, and Wyoming during 2015, a year when there was a significant increase in the number of tularemia cases in these states [5]. Pneumonic disease caused by F. tularensis subspecies tularensis (prevalent in North America) is generally more severe than that caused by subspecies holarctica (prevalent in other parts of the world) [16,17]; however, subspecies holarctica may also cause severe pneumonia, particularly in immunocompromised patients [18].

Pneumonic disease can be categorized as primary or secondary, based on the route of transmission.

●Primary pneumonic disease results from direct inhalation of the organism into the lungs. Occupations at particular risk for primary disease include farmers, sheep shearers, landscapers, and laboratory workers.

Following the initial nonspecific symptoms (eg, fever, headache, malaise, myalgias, nausea, and anorexia), fevers, chest pain, and cough with scant sputum production become more pronounced [19,20]. Patients sometimes complain of substernal or pleuritic chest pain. Findings on chest examination include rales, signs of consolidation, and a friction rub or evidence of pleural fluid.

Early after inhalational exposure, the chest radiograph may be normal, but abnormalities usually develop as respiratory findings become more prominent [19]. Common radiographic changes include peribronchial infiltrates, lobar consolidation, pleural effusion, and hilar adenopathy. Rounded infiltrates and cavitation from pneumonic tularemia are uncommon, although the presence of nodular infiltrates with a pleural effusion should raise concern for tularemic pneumonia or pneumonic plague. (See "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)", section on 'Clinical manifestations'.)

●Secondary pneumonic disease results from hematogenous spread to the lung. Secondary pneumonic disease can complicate any of the major forms of tularemia but is most common with the typhoidal and ulceroglandular forms [2,21].

The clinical presentation of secondary pneumonic tularemia is varied. Secondary pneumonia can present with bilateral disease, involvement of the lower lobes, and/or with miliary disease. There can be pulmonary infiltrates, pleural effusion, or both. In one series, some patients with secondary lung involvement had abnormal chest radiographs but no clinical evidence of pneumonia [2]. Pulmonary nodules, pleural effusion, and mediastinal adenopathy have been described in a patient with typhoidal tularemia who had been treated with the anti-tumor necrosis factor agent infliximab [22].

Pleural effusions in pneumonic tularemia are exudative with a lymphocytic predominance and may have an elevated adenosine deaminase level [23]. Pleural or lung biopsies can demonstrate granuloma formation and therefore be confused with pulmonary tuberculosis [1,23]. Empyema requiring decortication has been reported [8].

Respiratory failure requiring mechanical ventilation and the adult respiratory distress syndrome can result from either primary or secondary pneumonic tularemia. In one series of 128 patients with tularemia, those with pneumonic disease were more likely to have underlying typhoidal illness, to recall no potential exposure, to require hospitalization, to have a longer hospital stay, to have positive cultures, and to have a higher mortality rate compared with those without pulmonary involvement [21].

Typhoidal disease — Typhoidal tularemia is a systemic febrile illness without prominent regional adenopathy or other localizing signs that does not fit another major form of the disease. Typhoidal disease is a common presentation in certain locations. As an example, in the United States, it was the most common tularemia presentation among cases reported in Arkansas from 2009 through 2013 and was particularly frequent among older patients [24], and it was among the most common forms during 2015 in Colorado, Nebraska, South Dakota, and Wyoming [5].

Typhoidal disease may result from any portal of entry, but the source is usually inapparent at the time of presentation. Affected patients often have chronic underlying conditions.

The clinical presentation ranges from acute sepsis to a chronic febrile illness. Major symptoms include fever, chills, anorexia, headache, myalgias, sore throat, cough, abdominal pain, and diarrhea. Prominent physical findings may include evidence of intravascular volume depletion, mild pharyngitis, and diffuse abdominal tenderness.

Occasionally, localizing findings can be present. A clinical presentation with predominant abdominal symptoms has been referred to as "abdominal tularemia," potentially from ingestion of the pathogen; mesenteric adenopathy can be present. Enlargement of the liver and spleen is more likely to be detectable with a longer duration of illness. Pulmonary involvement secondary to hematogenous spread is seen in up to 45 percent of cases [1]. (See 'Pneumonic disease' above.)

Potential laboratory findings in severe typhoidal tularemia include elevated creatine phosphokinase (CPK), myoglobinuria, hyponatremia, and renal failure.

Presentation in immunocompromised patients — Immunocompromised patients with tularemia usually have fever with or without any of the nonspecific symptoms described above (see 'Clinical syndromes' above). They may be more likely to present with pneumonic or typhoidal illness.

A review of 17 immunocompromised individuals with tularemia reported fever in 94 percent, sweats or fatigue in 36 percent, respiratory symptoms in 41 percent, and abdominal symptoms in 24 percent [25]. Eight patients (48 percent) presented with pneumonic tularemia, five (29 percent) had typhoidal tularemia, and only four (24 percent) had ulceroglandular or glandular disease.

Other features

Secondary skin manifestations — Secondary skin changes are common in all forms of tularemia, reported in up to 50 percent in some series, and are often misdiagnosed or overlooked [3,26-28]. These secondary eruptions are usually maculopapular, vesiculopapular, erythema multiforme, erythema nodosum, or urticarial; some have been mistaken for varicella or drug eruptions [27]. Sweet syndrome also has been reported to occur with tularemia [28]. More than one type of eruption can occur in the same patient [29].

The character of the skin eruption may vary with the underlying type of tularemia. Patients with typhoidal tularemia can have erythema multiforme or erythema nodosum, whereas patients with pneumonic tularemia are more likely to have erythema nodosum. In Turkey, where oropharyngeal disease is common, erythema multiforme has been reported most often with oropharyngeal or glandular tularemia [30].

Laboratory findings — Routine laboratory tests are nonspecific. The white blood cell count may be low, normal, or elevated. Other nonspecific findings may include low platelet count, low serum sodium, abnormal liver enzymes, evidence of rhabdomyolysis or myoglobinuria, and pyuria.

Complications — If untreated, tularemia can cause prolonged fever, weight loss, adenopathy, and debility that can last for weeks or months [15]. Even with appropriate treatment, some patients will have a lengthy recovery following tularemia.

Patients with prolonged tularemia often complain of fatigue and lassitude, and may have anorexia, weakness, and weight loss. Neuropsychiatric complaints include headache, difficulty concentrating, and disturbed sleep [31]. Many of these patients have had suppurative lymph nodes, a common complication when lymph nodes are involved (see 'Ulceroglandular disease' above). Risk factors for a poor outcome include older age, serious underlying disease, a delay in correct diagnosis, prolonged symptoms prior to treatment, pneumonic or typhoidal disease, renal failure, and inadequate antibiotic treatment [21,32].

Other complications include sepsis, renal failure, rhabdomyolysis, and hepatitis [2,32]. Rarely, F. tularensis infection may cause otitis media and mastoiditis, endocarditis, pericarditis, myocarditis, meningitis, osteomyelitis, peritonitis, granulomatous hepatitis, splenic hematoma, spontaneous splenic rupture, aortitis, or prosthetic joint infection [1,6,33-38]. All four patients identified in one literature review of F. tularensis endocarditis initially presented with typhoidal disease [35]. F. tularensis subspecies holarctica infection of a bioprosthetic valve occurred in a patient presenting with prolonged fever and a resolving skin lesion [39,40]. Meningitis, reported with ulceroglandular and typhoidal disease, can develop 3 to 30 days after the onset of illness and cause a cerebrospinal fluid mononuclear cell pleocytosis with low glucose and high protein [41-43]. Meningitis developed in a patient with fever and rash after he ran his lawn mower over a dead rabbit [43]. Other rare neurological manifestations attributed to tularemia include Guillain-Barré syndrome and isolated cranial nerve abnormalities [44,45].

One report described a patient whose only manifestation of tularemia was pericarditis; the diagnosis was made serologically [46].

Potential bioterrorism use — F. tularensis is a category A bioterrorism agent (ie, of highest concern for bioterrorism use), as classified by the United States Centers for Disease Control and Prevention, in part because of its low infectious dose, high associated mortality, and potential for easy dissemination.

A bioterrorist attack with F. tularensis would most likely employ aerosolization of the organism to do the most harm to the most people [47]. Such an attack would most likely result in an outbreak of inhalational tularemia three to five days later, marked by an acute, undifferentiated febrile illness with predominant manifestations of pneumonia, pleuritis, and hilar lymphadenopathy [47]. Because an airborne organism could still invade through sites other than the lung and could contaminate food and water, other clinical forms of tularemia would also occur, including typhoidal, pharyngeal, and ocular tularemia [1,47].

Rapid recognition and reporting of a possible bioterrorist event due to tularemia is thus a difficult clinical challenge. The possibility should be suggested by clustered cases of pneumonic or typhoidal disease, particularly in urban areas in patients without the expected epidemiologic exposures to animals, insects, or environmental activities.

DIAGNOSIS

Clinical suspicion — Tularemia should be suspected in patients with a compatible clinical syndrome and epidemiologic risk factors. Because laboratory confirmation may be delayed, the initial diagnosis of tularemia is often made presumptively, when the patient's presentation is both clinically and epidemiologically consistent and there is no more likely cause.

Specific clinical features that should prompt consideration for tularemia include:

●Regional lymphadenopathy, particularly if associated with an inoculation site

●Conjunctivitis accompanied by local lymphadenopathy

●Severe pharyngitis that is unresponsive to penicillin and undiagnosed after routine testing

●Persistent systemic febrile illness that is undiagnosed after routine testing

●Community-acquired pneumonia that is unresponsive to standard antibiotic therapy and undiagnosed after routine testing

●Nodular infiltrates plus a pleural effusion on chest imaging

When these clinical features are observed in the setting of a history of animal (particularly wild animal) exposure or insect bites, the possibility of tularemia is greater, and making the presumptive diagnosis is reasonable. In particular, people who are farmers, veterinarians, hunters, national park service employees, landscapers, meat handlers, or laboratory workers are at increased risk for exposure. The patient's location, activities, and travel history also should inform the likelihood of tularemia. It has been reported globally, but is less common in Africa, South America, Australia, and England. In the United States, it is most commonly reported in the south-central states, the Pacific Northwest, and parts of Massachusetts (figure 1). Clusters of cases, particularly of infections consistent with pneumonic tularemia in the absence of typical exposures, should raise suspicion for the possibility of a bioterrorism event. (See "Tularemia: Microbiology, epidemiology, and pathogenesis", section on 'Epidemiology'.)

The diagnosis of tularemia requires a high index of suspicion, as the exposure history or epidemiologic risk may not be evident, and certain signs, such as fever or lesions around an inoculation site, may have abated by the time of presentation.

Meningitis is a rare complication of tularemia. Patients with suspected tularemia who have progressive headache, signs of meningeal irritation, or altered mental status warrant evaluation for meningitis with lumbar puncture. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Cerebrospinal fluid examination'.)

Microbiologic diagnosis

Approach — When tularemia is clinically suspected, serology for F. tularensis should be submitted at the time of presentation and again at least two to four weeks after presentation. This is because it takes at least two weeks after infection for antibodies to Francisella to be detectable, and diagnostic rises in convalescent antibody titers do not appear until at least two to four weeks after the onset of symptoms. The diagnosis is confirmed with a fourfold or greater change in titer from the initial to convalescent serology. Relevant patient specimens (such as ulcer exudate, blood, specimens from fluctuant or necrotic lymph nodes, sputum, and tissue biopsies) should also be sent for culture with specific instructions to the laboratory that tularemia is suspected; cultures are diagnostic if positive, but do not rule out the possibility of tularemia if negative. Molecular, direct fluorescent antibody, and immunohistochemical tests on such specimens could rapidly identify F. tularensis while awaiting serologic confirmation, but these tests are not widely available for routine use. (See 'Serology' below and 'Culture' below and 'Molecular and other novel testing' below.)

In the event of a suspected bioterrorist event using F. tularensis, steps to alert the appropriate authorities should be taken. These include immediate activation of local emergency response systems, immediate notification of infection control personnel and health care facility administration, and prompt notification of local and state health departments [48].

In the United States, the Federal Bureau of Investigation field office, local police, the Centers for Disease Control and Prevention (CDC), and medical emergency services should be informed in accordance with the local emergency response plan [48]. Specimens can be submitted to a specialized laboratory in the Laboratory Response Network for direct visualization of the organism and other rapid diagnostic tests. (See "Tularemia: Microbiology, epidemiology, and pathogenesis".)

Serology — The diagnosis of tularemia is usually confirmed serologically by detecting a fourfold or greater change in titers of antibodies to F. tularensis between acute and convalescent serum specimens [49]. Tube agglutination titers of 1:160 or higher or microagglutination titers of 1:128 or higher are considered positive [49]. The results of serologic testing should always be interpreted in the context of the clinical suspicion for tularemia. Serologic studies should be performed only in patients in whom tularemia is a realistic possibility; they should not be used as a screening test among febrile patients.

A diagnostic increase in antibody titer generally occurs two to four weeks after the onset of symptoms. Antibody titers are not reliably positive until after at least two weeks of infection, so they are rarely helpful in the acute setting. Both IgM and IgG antibodies appear together following the initial infection, and both antibody titers may remain elevated for years after an infection. Thus, a single positive titer is supportive of the diagnosis, but may also result from an old infection [50]. Serologic assays for tularemia can cross-react with heterophile antibodies and antibodies to other gram-negative organisms such as Brucella or Legionella, but cross-reactions are typically positive at a low, non-diagnostic titer [1,51].

In the United States, serologic studies are typically performed using a tube agglutination or microagglutination assay; commercially available enzyme-linked immunosorbent assays (ELISAs) have been used more commonly in Europe than in the United States. Serologic tests cannot identify the specific infecting F. tularensis subspecies. Investigational methods to improve serodiagnostic testing are being pursued [52,53].

Culture — Gram stain and culture are rarely positive for F. tularensis, but positive cultures can confirm the diagnosis, allow subspecies identification, and permit antibiotic susceptibility testing. Thus, it is appropriate to submit relevant specimens for culture when tularemia is suspected. Depending on the clinical presentation, relevant specimens include blood, lymph node drainage or biopsy specimens, skin lesion drainage or biopsy specimens, pleural fluid, sputum, and pharyngeal or ocular swabs. The laboratory should be notified prior to obtaining specimens for culture to optimize growth conditions as well as to take proper precautions to reduce the risk of infection among laboratory personnel. (See "Tularemia: Microbiology, epidemiology, and pathogenesis", section on 'Laboratory precautions'.)

When F. tularensis is seen on Gram stain of clinical specimens, it appears as weakly stained, tiny gram-negative coccobacilli. Routine cultures are frequently negative because the organism is quite fastidious. In addition, most routine solid media do not contain cysteine, which many Francisella strains require for growth. Culture growth is facilitated by use of supportive media. Other details regarding the growth and identification of F. tularensis are found elsewhere. (See "Tularemia: Microbiology, epidemiology, and pathogenesis", section on 'Laboratory features'.)

Molecular and other novel testing — Polymerase chain reaction (PCR) assays can be performed on human specimens for the rapid presumptive diagnosis of tularemia while awaiting serologic confirmation, but these tests are generally not yet available for routine testing in most hospital or clinical labs. Appropriate samples may include ulcer exudates, lymph node aspirates, blood, respiratory secretions, pleural fluid, spinal fluid, or tissue biopsies. Francisella PCR assays offer the potential advantages of a more rapid diagnosis than serologic tests or cultures, a greater sensitivity than smears or cultures, a more limited exposure of laboratory personnel to the potential hazards of processing cultures, and the availability of the basic methodology in many clinical laboratories. PCR may also eventually prove useful for the diagnosis of patients with prolonged illness and in those already given antibiotic treatment.

Real-time PCR assays have been developed that can distinguish between F. tularensis subspecies tularensis types A1 and A2, as well as among F. tularensis subspecies [54,55]. A sensitive, cartridge-based, automated PCR assay is able to detect F. tularensis bacteremia in a primate model, and a commercially available multiplex PCR system has been used successfully to diagnose tularemia [56,57].

Other specific techniques for the rapid presumptive diagnosis of tularemia have been developed, including direct fluorescent antibody (DFA) staining of clinical specimens and immunohistochemical staining of tissue [1,49]. However, these methods are not commercially available. In the United States, DFA and PCR assays can be obtained through state public health laboratories and the Laboratory Response Network.

Rapid tests to detect multiple potential bioterrorism pathogens simultaneously are being explored, as are genomic, proteomic, metabolomic, and immunologic methods for diagnosis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of tularemia is broad and depends on the predominant clinical syndrome.

●Fever and lymph node enlargement (ulceroglandular and glandular disease) – Many other infectious and non-infectious etiologies can cause fever and regional lymphadenopathy. Important infectious etiologies include streptococcal or staphylococcal lymphadenitis, cat scratch disease (Bartonella infection), sporotrichosis, toxoplasmosis, fungal or mycobacterial infection, Spirillum minus rat bite fever, anthrax, plague, syphilis, and other sexually transmitted infections [1]. Staphylococcal and streptococcal infections are more common than tularemia and often include frank cellulitis and perhaps purulence.

As with tularemia, cat scratch disease, sporotrichosis, toxoplasmosis, S. minus rat bite fever, anthrax, and plague are also associated with recent exposure to the outdoors, animals, or insects; all are uncommon infections. Skin ulcers are more common with tularemia and anthrax than with cat scratch disease or plague, a necrotic ulcer with surrounding induration and edema strongly favors anthrax, and the rapid onset of tender buboes suggests plague.

Non-infectious causes, such as malignancy or a necrotic spider bite, can also cause similar symptoms [58].

The evaluation of regional lymphadenopathy is discussed elsewhere. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Evaluation' and "Peripheral lymphadenopathy in children: Etiology", section on 'Localized lymphadenopathy'.)

●Conjunctival disease (oculoglandular disease) – When patients present with unilateral conjunctivitis associated with swollen lymph nodes in front of the ear on the same side (Parinaud's oculoglandular syndrome), other potential etiologies include cat scratch disease (Bartonella infection) and herpes simplex infection. Other more common causes of conjunctivitis include adenoviral infection and pyogenic bacterial infection. (See "Conjunctivitis", section on 'Classification and epidemiology'.)

●Severe pharyngitis (pharyngeal disease) – More common causes of pharyngitis are adenovirus, infectious mononucleosis, and streptococcal pharyngitis. (See "Evaluation of acute pharyngitis in adults", section on 'Infectious causes'.)

●Pneumonia, pulmonary infiltrates (pneumonic disease) – Clinical symptoms and radiographic findings are not sufficiently specific to distinguish tularemic pneumonia from other causes of community-acquired pneumonia. Among patients with apparent community-acquired pneumonia who have negative cultures and fail to respond to routine therapy, other diagnoses to consider include Coxiella infection, psittacosis, mycobacterial infection, pulmonary mycoses, and pneumonic plague [1]. (See "Nonresolving pneumonia", section on 'Misdiagnosis of pathogens'.)

Pneumonic tularemia may also be mistaken for lung cancer, particularly when infectious causes are not considered and positron emission tomography (PET)/computed tomography (CT) scans are positive [59].

●Fever of unknown origin (typhoidal disease) – The differential diagnosis of fever of unknown origin is broad. Other culture-negative systemic infections without localizing features include typhoid fever, brucellosis, Coxiella infection, tick-born relapsing fever, culture-negative endocarditis, malaria, rickettsioses, anaplasmosis, ehrlichiosis, and viral illnesses. (See "Fever of unknown origin in adults: Etiologies".)

TREATMENT — Antimicrobial therapy (table 1) should be administered promptly to all patients with suspected or confirmed tularemia. Although spontaneous resolution of infection in the absence of specific treatment has been recorded [2], early effective treatment is associated with less morbidity. Since the introduction of effective antibiotics (in particular streptomycin), historical mortality rates from tularemia have decreased from as high as 60 percent in severely ill patients with pneumonic or typhoidal disease to less than 5 percent overall [16,21,47,50].

Effective antibiotics — Antimicrobials with well-established clinical efficacy include the aminoglycosides streptomycin and gentamicin, tetracycline, doxycycline, the fluoroquinolones, and chloramphenicol. These agents exhibit achievable minimal inhibitory concentrations (MICs) when tested using a standardized in vitro method against F. tularensis [60-62]. Resistance to aminoglycosides, fluoroquinolones, or tetracycline in human isolates has been uncommon [63]. However, the majority of 29 human isolates of F. tularensis subspecies holarctica in Spain were resistant to tigecycline [63]. In a study from France, there was no fluoroquinolone resistance among 42 F. tularensis subspecies holarctica isolates and no molecular evidence of DNA gyrase mutations (which would confer fluoroquinolone resistance) among 82 tissue samples from patients with tularemia, including those who had a suboptimal outcome with fluoroquinolone treatment [64].

Beta-lactams have been associated with clinical failure despite favorable in vitro susceptibilities [65]. Although successful use of erythromycin has been reported, it is not considered reliable therapy and resistant strains are prevalent in parts of Europe and Russia [1,50,66,67].

Regimen selection — Our approach to regimen selection depends on the severity of infection, as below. In general, this treatment approach is based on observational data evaluating the frequency of cure and relapse with different antimicrobial agents [68]. No prospective controlled clinical trials have compared the efficacy of different drug regimens or defined the optimal duration of therapy for tularemia.

Severe infection — For patients with severe infection, we suggest gentamicin (given intramuscularly or intravenously) or streptomycin (given intramuscularly). Aminoglycosides are the drugs of choice for such patients, as there is the most successful clinical experience with these agents. Severe infection includes prolonged or extensive systemic symptoms prior to therapy, sepsis with or without renal failure in any form of tularemia, typhoidal tularemia, and symptomatic pneumonic tularemia. We also use an aminoglycoside when empiric treatment for tularemia is indicated in patients with an uncertain diagnosis who require hospitalization. Patients with rare complications, such as meningitis or endocarditis, are treated initially with combination therapy, ideally in consultation with an expert in infectious diseases; this is discussed separately. (See 'Meningitis or endocarditis' below.)

Streptomycin has traditionally been the preferred aminoglycoside because of extensive experience supporting its use, its high efficacy, and the fact that, in the United States, it is approved for the treatment of tularemia by the US Food and Drug Administration [68]. However, gentamicin is more readily available than streptomycin. In addition, timely blood levels are usually more readily obtained for gentamicin than streptomycin, and gentamicin has less vestibular toxicity. Gentamicin is the preferred aminoglycoside for the treatment of tularemia in children for these reasons [51].

The doses are outlined in the table (table 1). The duration of aminoglycoside treatment is generally 7 to 10 days; in children, the usual duration is 10 days [51]. However, the duration should be tailored to clinical signs and symptoms, including resolution of fever, and should be extended (eg, to 14 days) for especially severe cases or for patients whose response to treatment is delayed.

Streptomycin has been associated with high cure rates and minimal relapses. As an example, in a review of case reports and series, the cure rate among 244 patients who received streptomycin for tularemia was 97 percent, with no relapses (table 1) [68]. Among the 36 patients who received gentamicin, the cure rate was 86 percent, and there were two relapses. Subsequent case series have reported similar or higher cure rates with gentamicin [8,69]. Once-daily gentamicin dosing has been used successfully and is a more convenient option for outpatient therapy of adults [19,70,71].

Some experts have recommended that severe disease be managed with a combination of an aminoglycoside and a fluoroquinolone, although this has not been proven to be superior to an aminoglycoside alone [72].

Mild or moderate infection

Adults — Initial oral treatment is reasonable for adult patients who can be managed reliably as outpatients and for hospitalized patients without severe disease. We suggest an oral fluoroquinolone (eg, ciprofloxacin) for adults with mild or moderate infection. Doxycycline is an alternative. An oral agent may also be appropriate to complete treatment in patients who responded to initial parenteral therapy. Doses are listed in the table (table 1).

We prefer fluoroquinolones to a tetracycline as oral treatment of tularemia in appropriate adults given their efficacy with lower likelihood of relapse [13,72]. The fluoroquinolones have been used successfully to treat F. tularensis subspecies holarctica infections, including in immunocompromised patients, although a higher rate of relapse was found in one small Spanish series [13,73,74]. There is less published clinical experience with using the fluoroquinolones for documented F. tularensis subspecies tularensis infections, although reports are emerging. In one series from Missouri, ciprofloxacin, given as monotherapy or combined with inactive agents for at least 10 days, cured 9 of 10 cases of tularemia [8]. Additionally, subspecies tularensis is susceptible to fluoroquinolones in vitro [60,62]. Ciprofloxacin and levofloxacin are the most active fluoroquinolones in vitro; both agents have been used successfully, although there is more published experience with ciprofloxacin.

Most published data on the use of tetracyclines in tularemia have evaluated tetracycline; doxycycline is now more commonly used because it is given only twice daily and likely has similar efficacy. In a review of case reports and series, the cure rate among 50 patients who received tetracycline was 88 percent; 12 percent relapsed [68]. Human inhalational challenge studies from the 1960s suggested that tetracycline (started early after the onset of fever) was most effective when given in a dose of 2 g daily for at least 14 days [20]. In a series that included 13 patients treated with at least 14 days doxycycline (alone or in combination with ineffective agents), 15 percent had treatment failure [8]. In contrast, a subsequent retrospective series of 16 patients treated with doxycycline monotherapy reported that all were cured with no relapses [75]. However, three of the nine patients who underwent drainage of suppurative lymph nodes prior to starting doxycycline required a repeat drainage procedure while receiving doxycycline (one patient after one week and two patients after two weeks of treatment) [75].

Children — We suggest gentamicin for treatment of children with mild or moderate infection [51]. The usual duration of gentamicin is 10 days, although in children with mild disease and no complications, it can be shortened to five to seven days if there is an adequate clinical response [51]. Oral ciprofloxacin is an appropriate alternative regimen for children with mild illness who would be expected to complete the recommended 10- to 14-day course of treatment [51]; doses are listed in the table (table 1).

Doxycycline is not recommended for treatment of tularemia in children because it is associated with higher relapse rates and must be given for a longer course [51].

Historically, there is the most clinical experience with the aminoglycosides to treat tularemia; they are highly effective, and gentamicin is readily available (see 'Severe infection' above). Although tetracyclines and fluoroquinolones are effective against tularemia, relapses with the tetracyclines are more frequent, and there are less data regarding fluoroquinolone use in children, particularly for documented F. tularensis subspecies tularensis infections.

Most of the reported successful experience with the fluoroquinolones in children has been from countries other than the United States and has usually involved infections with F. tularensis subspecies holarctica. Ciprofloxacin 7.5 mg/kg to 10 mg/kg twice daily was shown to be effective for the treatment of ulceroglandular tularemia among 12 children ages 1 to 10 years [76], and its successful use has been reported in more recent cases [8,27].

Meningitis or endocarditis — Meningitis and endocarditis are rare complications of tularemia. Both should be managed in consultation with an expert in infectious diseases.

●For adults and children with tularemic meningitis, we suggest an aminoglycoside combined with doxycycline or ciprofloxacin [51]. A combination regimen is preferred because cerebrospinal fluid levels of aminoglycosides may be erratic [51]. In general, the duration of treatment for tularemic meningitis is 14 to 21 days but should be tailored to clinical signs and symptoms, including resolution of fever.

Studies have reported successful treatment of tularemic meningitis with streptomycin plus chloramphenicol as well as streptomycin plus doxycycline, gentamicin plus doxycycline, and gentamicin plus ciprofloxacin [41,77,78]. However, chloramphenicol should only be used if ciprofloxacin or doxycycline cannot be given and it is available for immediate use. Chloramphenicol should not be used to treat other forms of tularemia because safer alternatives are available with greater efficacy.

●Endocarditis should also be managed initially with a combination regimen of an aminoglycoside plus a fluoroquinolone. Studies informing the optimal treatment of F. tularensis endocarditis are extremely limited, but case reports, including cases of prosthetic valve endocarditis, have documented favorable outcomes with two weeks of gentamicin plus a fluoroquinolone followed by another two to four weeks of a fluoroquinolone [35,39,40].

Specific circumstances

Pregnancy — The optimal therapy for tularemia in pregnant patients is undefined. Tularemia in pregnancy may lead to prematurity or fetal loss, although the extent of the risk is unknown and healthy newborns without adverse effects from maternal tularemia also have been reported [15,79-84]. Gentamicin and ciprofloxacin have been effective in a small number of recently reported cases [80,82]. Azithromycin was effective in a pregnant patient in Arkansas, and a prolonged course of azithromycin was effective in a patient in France where erythromycin-sensitive strains of F. tularensis subspecies holarctica predominate [67,81]. Exposure to these antibiotics early in pregnancy has been associated with an increased risk of spontaneous abortion [85]. Antibiotic use in pregnancy is discussed in detail elsewhere. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

Immunosuppression — Immunosuppressed patients with tularemia have an increased risk of treatment failure or relapse, and their optimal antibiotic management is unknown. We prefer an aminoglycoside for treatment of tularemia in immunocompromised patients, as used in patients with severe infection (see 'Severe infection' above). Case reports of tularemia patients with various underlying immunosuppressing conditions have documented successful treatment with gentamicin, a fluoroquinolone, or doxycycline, alone or in combination (table 1) [9,22,25,73,86-92]. Treatment may need to be prolonged beyond the usual recommended duration in patients who are slow to respond.

Bioterrorism event — Treatment of tularemia from a bioterrorism event depends on the numbers of ill patients [47]. Contained attacks generally allow individual medical management, whereas resources may be more constrained in the setting of mass casualties.

●Contained casualties – Affected individuals can be managed using the same aminoglycoside or oral regimens discussed above (table 1) (see 'Severe infection' above and 'Mild or moderate infection' above). In addition, the Working Group for Civilian Biodefense also includes ciprofloxacin for children and chloramphenicol for both adults and children as recommended treatment options [47]. The Working Group recommends durations of 10 days for an aminoglycoside or ciprofloxacin and 14 to 21 days for doxycycline or chloramphenicol [47]. Gentamicin is preferred by the Working Group for pregnant patients, and streptomycin or gentamicin is preferred for immunosuppressed patients.

●Mass casualties – For mass casualties, the Working Group recommends 14 days of either oral ciprofloxacin or doxycycline for most individuals [47]. Oral ciprofloxacin is preferred for pregnant patients; either streptomycin or gentamicin is preferred for immunosuppressed patients.

Adjunctive management — Even with appropriate antibiotic therapy, enlarged lymph nodes can progress to fluctuance and suppuration. In such cases, incision and drainage of the lymph node are warranted.

Debridement and drainage are also warranted for empyema in the setting of pneumonic tularemia. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

Relapses — Relapses can occur following any regimen but are more common when tetracyclines (bacteriostatic antimicrobials) are used for fewer than 14 days. Retreatment with the initial agent used is reasonable since resistance in clinical isolates has not been reported. If doxycycline was used initially, it can be used again but for a longer time (such as 21 days); alternatively, the patient can be retreated with an aminoglycoside or a fluoroquinolone.

This approach may not be effective for bioterrorism strains, however, since organisms can be engineered for resistance to commonly used agents [47].

PREVENTION

Minimizing exposure — Preventive measures include behavioral strategies to minimize the risk of exposure to the organism:

●Not using bare hands to skin or dress wild animals

●Avoiding sick or dead animals

●Wearing masks, eye protection, and gloves when disposing of dead animals, including those brought home by cats and other pets

●Wearing clothing that covers exposed skin and that is tight at the wrists and ankles

●Using insect repellents that are also effective against ticks

●Removing ticks promptly

●Only drinking potable water

●Adequately cooking wild meats

Institutional infection control — Standard precautions are adequate for hospitalized patients with tularemia; person-to-person transmission does not occur. Whenever tularemia is suspected or proven, microbiology laboratory and autopsy personnel handling patient specimens should be notified so that they can take precautions to minimize the likelihood of exposure to F. tularensis. (See "Tularemia: Microbiology, epidemiology, and pathogenesis", section on 'Laboratory precautions'.)

Post-exposure prophylaxis — The type of exposure, the length of time since the exposure, and the patient's concerns should be considered when making the decision about giving post-exposure prophylaxis. The approach also differs between adults and children.

●Adults – Antibiotic prophylaxis for tularemia is warranted in adults who have a suspected or proven high-risk exposure to tularemia and are identified early in the incubation period. This includes laboratory workers, autopsy personnel, and others exposed through nonintact skin, mucosal surfaces, or aerosols to materials contaminated with F. tularensis, as well as persons exposed to F. tularensis in a bioterrorism event.

Watchful waiting without antibiotics while monitoring for fever or other symptoms of tularemia is an appropriate strategy for individuals with lower-risk exposures, those identified later in the incubation period (eg, more than a week after exposure), and in vaccinated individuals. As examples, prophylaxis is not indicated following a tick bite [1,2] or if the only risk was close contact with a patient with tularemia [1,47]. Management without antibiotics following exposure to a bioterrorism event is also recommended for persons identified after others have become symptomatic (ie, later in the incubation period) [47].

Additionally, individuals who have had tularemia in the past do not require antibiotic prophylaxis with subsequent exposures, other than in a bioterrorism event. Although recurrent infections have been documented (despite the understanding that recovery from tularemia results in lifelong protective immunity), most recurrences have been clinically mild ulceroglandular disease. Regimens for post-exposure prophylaxis of adults are oral ciprofloxacin 500 mg or doxycycline 100 mg, each twice daily for 14 days [47,93].

●Children – In general, children with exposures other than a bioterrorism event should be observed for fever or other signs of illness without prophylactic antibiotics [93]. Post-exposure prophylaxis in children is indicated following exposure to an F. tularensis bioweapon. The recommended doses are ciprofloxacin 15 mg/kg orally twice daily (not to exceed 1 gram daily) or doxycycline 2.2 mg/kg orally twice daily (for those <45 kg) and 100 mg orally twice daily (for those ≥45 kg) [47,51]. Antibiotics should be given as early as possible in the incubation period following the bioweapon exposure and continued for 14 days.

Investigational vaccines — No tularemia vaccine is currently available. A vaccine prepared from the live vaccine strain (LVS) of F. tularensis subspecies holarctica that was previously used is no longer available because of concerns about its unknown mechanisms of attenuation, stability, and production. Research to develop a new vaccine is actively investigating subunit vaccines, new live strains with defined attenuation, and an improved LVS vaccine [63,94-97].

SUMMARY AND RECOMMENDATIONS

●Microbiology and transmission – Tularemia is a zoonotic infection caused by Francisella tularensis, an aerobic and fastidious gram-negative bacterium. Human infection occurs following contact with infected animals or invertebrate vectors. (See "Tularemia: Microbiology, epidemiology, and pathogenesis".)

●Clinical syndromes – Tularemia usually has an abrupt onset of nonspecific symptoms, such as fever, chills, headache, and malaise following an incubation period of three to five days. Patients usually present with clinical features associated with one of six major syndromes (with occasional overlap) depending on the portal of entry:

•Ulceroglandular tularemia – This is the most common manifestation. Affected patients present with fever and a single erythematous papulo-ulcerative lesion with a central eschar (picture 1) accompanied by tender regional lymphadenopathy. They usually report recent animal handling or exposure to potential insect vectors (particularly ticks). (See 'Ulceroglandular disease' above.)

•Glandular tularemia – This manifests as enlargement of a single or multiple regional lymph nodes in the absence of an identifiable skin lesion. It occurs more often in children than adults. (See 'Glandular disease' above.)

•Oculoglandular and pharyngeal tularemia – These are less common forms of tularemia that result from organism invasion through the conjunctivae and oral mucosa, respectively. Eye findings are usually unilateral and include pain, photophobia, and conjunctival erythema with regional adenopathy; the major features of pharyngeal tularemia are an exudative pharyngitis and tonsillitis with cervical node enlargement. (See 'Oculoglandular disease' above and 'Pharyngeal (oropharyngeal) disease' above.)

•Pneumonic tularemia – This can result from direct inhalation of F. tularensis (primary) or bacteremic spread to the lung (secondary). In primary disease, cough is typically nonproductive. Common findings on chest imaging include peribronchial infiltrates, lobar consolidation, pleural effusion, and hilar adenopathy. Rounded infiltrates and cavitation are uncommon. (See 'Pneumonic disease' above.)

•Typhoidal tularemia – This is a systemic febrile illness without prominent regional adenopathy or other clear localizing signs that does not fit another major form of the disease. The clinical presentation ranges from acute sepsis to a chronic febrile illness. (See 'Typhoidal disease' above.)

●Skin findings – Secondary skin rashes are an underappreciated and relatively common manifestation in all forms of tularemia. These secondary eruptions are usually maculopapular, vesiculopapular, erythema multiforme, erythema nodosum, or urticarial; some have been mistaken for varicella or drug eruptions. (See 'Secondary skin manifestations' above and 'Complications' above.)

●When to suspect tularemia – Tularemia should be suspected in patients with features compatible with one of these clinical syndromes and epidemiologic risk factors. A history of animal (particularly wild animal) exposure or insect bites should heighten suspicion for tularemia; the patient's location (figure 1), activities, and travel history should also inform the likelihood of tularemia. Because laboratory confirmation may be delayed, the initial diagnosis is often made presumptively. Clusters of cases, particularly of infections consistent with pneumonic tularemia in the absence of typical exposures, should raise suspicion for the possibility of a bioterrorism event. (See 'Clinical suspicion' above.)

●Diagnosis – When tularemia is clinically suspected, serology for F. tularensis should be submitted at the time of presentation and again at least two to four weeks later. A single tube agglutination titer of 1:160 or higher or a single microagglutination titer of 1:128 or higher is supportive of the diagnosis; a fourfold or greater change in titer between acute and convalescent serum specimens is confirmatory. Specimens should also be sent for culture with specific instructions to the laboratory that tularemia is suspected; cultures are diagnostic if positive but do not rule out the possibility of tularemia if negative. (See 'Microbiologic diagnosis' above.)

●Treatment – Antibiotics are the cornerstone of therapy and should be administered promptly to patients with documented or suspected tularemia. Adjunctive management includes incision and drainage of suppurated lymph nodes. (See 'Treatment' above.)

•Severe infection – For adults and children with severe infection, we suggest gentamicin or streptomycin (Grade 2C). Streptomycin has traditionally been the preferred aminoglycoside because of greater experience with this agent, but gentamicin is also effective, is more readily available, and has less associated vestibular toxicity. (See 'Severe infection' above.)

•Mild infection – For adults with mild or moderate infection, we suggest an oral fluoroquinolone (eg, ciprofloxacin) (Grade 2C). Doxycycline is an acceptable alternative oral agent. For children with mild or moderate infection, we suggest gentamicin (Grade 2C). An oral fluoroquinolone is an acceptable alternative for children with mild disease. (See 'Mild or moderate infection' above.)

•Doses and durations – These are listed in the table (table 1).

●Prevention – Preventive measure include behavioral strategies to minimize the risk of exposure (eg, avoiding sick or dead animals, not using bare hands to skin game, tick or insect bite prevention). We suggest antibiotic prophylaxis for adults with nonintact skin, mucosal surface, or inhalational exposure to materials contaminated with F. tularensis and for individuals exposed to F. tularensis in a bioterrorism event (Grade 2C). Either oral ciprofloxacin or doxycycline can be used for post-exposure prophylaxis. (See 'Prevention' above.)