on 27-Aug-2023 (Sun)

Tularemia is a zoonotic infection caused by Francisella tularensis, an aerobic and fastidious gram-negative bacterium.

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].

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].

Ulceroglandular disease, characterized by a skin lesion and associated adenopathy, is the most common and most easily recognizable form of tularemia [1,2].

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].

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].

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 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 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.

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.

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].

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 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 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.

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 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.

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.

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].

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]

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].

Other rare neurological manifestations attributed to tularemia include Guillain-Barré syndrome and isolated cranial nerve abnormalities [44,45].

Meningitis developed in a patient with fever and rash after he ran his lawn mower over a dead rabbit [ 43].

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].

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.

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.

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.

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.

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].

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.

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

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.

PCR may also eventually prove useful for the diagnosis of patients with prolonged illness and in those already given antibiotic treatment.

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]

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].

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.

Severe pharyngitis (pharyngeal disease) – More common causes of pharyngitis are adenovirus, infectious mononucleosis, and streptococcal pharyngitis.

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].

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.

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].

Antimicrobials with well-established clinical efficacy include the aminoglycosides streptomycin and gentamicin, tetracycline, doxycycline, the fluoroquinolones, and chloramphenicol.

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].

No prospective controlled clinical trials have compared the efficacy of different drug regimens or defined the optimal duration of therapy for tularemia.