AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Tularemia is an acute, febrile, granulomatous, infectious zoonosis caused by the aerobic gram-negative pleomorphic bacillus Francisella tularensis. Although the disease has likely existed since ancient times,¹ the disease was first described in Japan in 1837. In 1911, a plaguelike disease in ground squirrels was described in Tulare County, California (tulare is an Aztec word for the tule reed, a marsh plant commonly found in that area), and was later found to be caused by the bacterium now known as F tularensis. Edward Francis studied the causative organism further, named the disease, and, in 1928, described his experience.²

Worldwide, more than 100 species of animals, birds, amphibians, and arthropods host F tularensis. The bacillus may also be found in mud and water. The organism produces acute infectious illness in humans. The mode of transmission and factors related to the host and organism influence the clinical presentation (ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal).

Pathophysiology

Humans become infected after introduction of the bacillus by inhalation, intradermal injection, or oral ingestion. The clinical form of disease reflects the mode of transmission. Some authors classify the disease as typhoidal (predominance of systemic symptoms), pneumonic (pulmonary findings), or ulceroglandular (regional symptoms).

To cause the disease in humans via intradermal injection or inhalation, 10-50 bacilli are required. To transmit the disease orally, 100 million organisms are required.

Ulceroglandular tularemia (80% of reported cases) usually occurs after the organism enters through the skin. Reportedly, bacilli can penetrate intact skin, but an abrasion (which may be clinically inapparent), a tick bite, or an insect bite is more likely to allow entry. Inoculation of the oral mucosa or conjunctiva may follow contact with hands or fingers that are contaminated with tissue fluids or contact with infectious aerosols.

Following an incubation period of 3-5 days (range, 1-14 d), a papule develops. In 2-4 more days, the papule may ulcerate, usually accompanied by fever and regional lymphadenopathy. Humans are probably bacteremic during this phase. The bacilli become entrapped in the reticuloendothelial system, where they may survive for a prolonged period. Caseating granulomata, with or without multinucleated giant cells, may develop.

Many animals and arthropods may carry the organism; however, ticks (especially Dermatocentor and Amblyomma species) and rabbits are the most common vectors implicated in cases of human infection. Domestic cats are increasingly recognized as associated with human tularemia. The deer fly is also a classic vector, although a less commonly reported one.

Inhalation of the organism may lead to pulmonic tularemia, while oral ingestion may cause oropharyngeal tularemia. Conjunctival inoculation may follow after contact with contaminated tissue fluids. The portal of entry is unknown in most cases of typhoidal tularemia.

Frequency

United States

A few hundred cases are reported annually. Many cases are probably undiagnosed, misdiagnosed, or unreported. Infections occur in all states except Hawaii; however, most reported ones 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, recently, tularemia has been reported more frequently during warm-weather months (eg, tick-associated disease).

International

Tularemia infections occur 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. Tularemia has not been reported in Africa and South America.

Mortality/Morbidity

• Overall, the mortality rate for untreated tularemia is approximately 8%. The mortality rate for untreated typhoidal tularemia is 2-3 times higher. With early diagnosis and appropriate treatment, the mortality rate is less than 1%.

Race

• All races are equally susceptible.

Sex

• Both sexes are equally susceptible to disease; however, societal activities common to young men may predispose them to F tularensis exposure.

Age

• People of all ages are susceptible to the disease; however, young-to-middle-aged people are more likely to participate in activities that predispose them to exposure.

CLINICAL

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History

Most patients have abrupt onset of fever, chills, malaise, and fatigue and develop 1 of 6 well-recognized clinical forms: ulceroglandular tularemia, glandular tularemia, oculoglandular tularemia, oropharyngeal tularemia, pneumonic tularemia, and typhoidal (septicemic) tularemia.

• Ulceroglandular tularemia  
• • This form accounts for approximately 80% of tularemia cases.
  • The organism usually gains entry into the body via a scratch or abrasion and then spreads lymphatically, usually causing painful regional lymphadenopathy and an ulcerated skin lesion. Rarely, lymphangitis or nodular sporotrichoid lesions develop proximal to the ulcer.
  • In rabbit-associated disease, the ulcer is located on a finger or hand in more than 90% of patients.
  • In tick-borne disease, the ulcer is found on a lower extremity or the perineal area in 50% of patients, the trunk in 30%, and the head in 5-10%.
• Glandular tularemia
• • This form is similar to the ulceroglandular form except for the absence of the characteristic skin lesion.
  • The organism is presumed to enter via an inapparent abrasion and then to spread lymphatically or via the bloodstream.
• Oculoglandular tularemia
• • In this form (1-2% of patients), the organism enters via the conjunctivae after inoculation from either splashing of blood or rubbing of eyes after contact with contaminated tissue fluids.
  • Clinical manifestations are usually unilateral.
  • Painful purulent conjunctivitis with preauricular or cervical lymphadenopathy may develop. Some patients experience chemosis, periorbital edema, and small nodular or ulcerative lesions of the palpebral conjunctivae.
• Oropharyngeal tularemia
• • This is a rare form that may occur after consumption of poorly cooked meat of an infected rabbit.
  • Patients usually report a sore throat, abdominal pain (from mesenteric lymphadenopathy), nausea, vomiting, diarrhea, and, occasionally, frank gastrointestinal bleeding (from intestinal ulcerations).
• Pneumonic tularemia
• • Primary tularemia pneumonia is uncommon and occurs after inhalation of the organism.
  • Rarely acquired naturally, it may develop in laboratory workers.
  • Pneumonia may develop after hematogenous spread in 10-15% of patients with ulceroglandular tularemia and in 30-80% of those with typhoidal tularemia.
  • Patients usually report a dry cough, dyspnea, and pleuritic-type chest pain.
  • Chest radiographs may reveal patchy ill-defined infiltrates in one or more lobes. Frank lobar pneumonia may also develop. Bilateral hilar adenopathy may be present. Bloody pleural effusions are characteristic and demonstrate a mononuclear cellular response.
  • Adult respiratory distress syndrome (ARDS) develops in some patients.
• Typhoidal (septicemic) tularemia
• • This form accounts for 10-15% of tularemia cases.
  • It is more severe and probably represents bacteremia with the organism.
  • Patients present with fever, chills, myalgias, malaise, and weight loss. They often have pneumonia.
  • Diagnosis is difficult because ulcers and lymphadenopathy are usually absent.
• Clinical symptoms
• • Clinical symptoms correspond to the type of tularemia.
  • As many as 20% of patients may have a blotchy, macular, maculopapular, or pustular rash.
  • Erythema nodosum or erythema multiforme is rare.
• Other forms
• • Rare manifestations include osteomyelitis, pericarditis, peritonitis, endocarditis, and nervous system abnormalities, including meningitis, abscesses,³ and optic neuritis.⁴
  • Other possible manifestations include acute renal failure, hepatomegaly, abnormal liver function test results, and rhabdomyolysis.

Physical

Physical findings vary based on the clinical form disease presentation. Patients have fever and possibly tender hepatosplenomegaly.

• Ulceroglandular tularemia
• • This form is characterized by an ulcer at the site of the organism's 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 that turns to black.
  • Regional lymphadenopathy develops. The lymph nodes are usually edematous and tender. They can become fluctuant and may drain spontaneously.
• Oculoglandular tularemia
• • Ocular findings are usually unilateral.
  • 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.
• Clinical symptoms: As many as 20% of patients have a rash that may begin as blotchy, macular, or maculopapular and that may progress to pustular lesions. Erythema nodosum and erythema multiforme rarely occur.
• Less-common clinical forms: In these forms of the disease (eg, meningitis, pericarditis, peritonitis, osteomyelitis), physical findings are the same as those commonly found in the clinical forms described above.

Causes

• Tularemia is caused by infection with the bacterium F tularensis.

DIFFERENTIALS

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Other Problems to be Considered

CBRNE - Plague
Diphtheria
Tick-borne Diseases, Colorado
Tick Bite
Mycotic infections

WORKUP

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Lab Studies

• Routine laboratory testing is generally not helpful, except to aid in excluding other diseases from the differential diagnoses.
• Hematologic values are usually within the reference range. The WBC count may be slightly elevated. Occasionally, the WBC differential may demonstrate lymphocytosis.
• In 20-30% of patients, urinalysis reveals sterile pyuria.
• Liver function is usually normal. An elevated creatine phosphokinase (CPK) level may be associated with rhabdomyolysis and is a poor prognostic sign. High CPK values are more common in the typhoidal form of tularemia.
• Examination of spinal fluid may demonstrate a slightly elevated protein value or a few WBCs; however, this is nonspecific.
• Routine blood culture results are usually negative for tularemia. Successful cultivation requires media that contains cysteine for growth. Cultivation in the laboratory poses a hazard for workers; thus, laboratory personnel should always be advised if tularemia is suspected so that they may take appropriate precautions.
• A Gram stain of sputum from a patient with pneumonic tularemia usually does not demonstrate the organism.

Imaging Studies

• Obtain a chest radiograph to evaluate for pneumonia. As many as 30% of patients with tularemic pneumonia have no physical findings or respiratory tract symptoms.

Other Tests

• Diagnosis is usually based on serology results. Tularemia tube agglutination testing is the most commonly used serological test.⁵
  
  
  • Diagnosis is confirmed by a 4-fold increase in titer.
  • An acute-phase titer of 1:160 is suggestive, but such titers seldom develop until 11-21 days after onset of illness.
  • Titers of 1:10-80 occur in 1% of the American population, especially those with long-term exposure to rabbits. A titer result may positive in absence of clinical disease.
  • Tularemia serologic tests may cross-react with Salmonella, Brucella, Yersinia, and Legionella species.
• Skin testing may reveal a cellular immune response and is both sensitive and specific; however, skin test antigens are not commercially available.
• Lymph node biopsy is generally not needed for diagnosis.
• Polymerase chain reaction on material from wounds is being studied in some centers and appears promising as a means of earlier and easier diagnosis.⁶ This diagnostic modality is also being evaluated for potential use on other body substances.

Histologic Findings

Early 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 may develop in some lesions.

TREATMENT

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Medical Care

• Direct medical care primarily toward antibiotic eradication of the organism. Provide symptomatic and supportive care for accompanying conditions (eg, osteomyelitis, pericarditis, peritonitis) as clinically indicated.
• Streptomycin is considered the drug of choice (DOC). Less experience has been reported with other aminoglycosides, but gentamicin and amikacin are also effective.
• Chloramphenicol and tetracycline are clinically useful; however, relapse rates of up to 50% are reported when these agents are used.
• Case reports indicate a potential role for erythromycin or fluoroquinolones (ciprofloxacin, levofloxacin); however, clinical experience and in vitro data supporting their use are limited.
• In vitro susceptibility data support the possible role of third-generation cephalosporins (cefotaxime, ceftriaxone) and rifampin. However, failures occur with attempted third-generation therapy, and these agents should not be used for known or suspected tularemia.
• F tularensis is naturally resistant to penicillins and first-generation cephalosporins.

Surgical Care

• Surgical care is not needed unless an ulcerative lesion develops a superinfection and requires debridement or unless a lymph node requires drainage.

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 pulmonary specialist may be necessary.

Diet

• No special diet is required.

Activity

• Activity should not be restricted.

MEDICATION

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Medical therapy is directed at antibiotic eradication of the bacterium F tularensis.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Gentamicin (Gentacidin, Garamycin)
Description	Aminoglycoside that may be used as an alternative to streptomycin. Less clinical experience with gentamicin than streptomycin in treatment of tularemia. May be administered IV/IM. Many dosing schedules based on 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 h before dose; peak levels are usually obtained 1 h after dose is infused.
Adult Dose	5 mg/kg/d IV/IM divided bid/tid; adjust dose in patients with renal insufficiency
Pediatric Dose	<5 y with normal renal function: 2.5 mg/kg IV/IM q8h; not to exceed 300 mg/d >5 y with normal renal function: 1.5-2 mg/kg IV/IM q8h or 6-7.5 mg/kg/d divided tid IV/IM; not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Aminoglycosides enhance effects of neuromuscular-blocking agents (thus, prolonged respiratory depression may occur); coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (patient not taking dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Doxycycline (Bio-Tab, Doryx, Vibramycin)
Description	Preferred therapy. Also may eradicate other tick-related copathogens. Should be used for a full 14 d to avoid risk of relapse.
Adult Dose	100 mg PO/IV bid
Pediatric Dose	<8 years: Not recommended >8 years: 2-4 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability minimally affected with antacids that contain aluminum, calcium, magnesium, iron, or bismuth subsalicylate
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur (rare) with prolonged exposure to sunlight or tanning equipment; tetracycline use during tooth development (last half of pregnancy and children <8 y) can cause permanent discoloration of teeth

Drug Name	Chloramphenicol (Chloromycetin)
Description	Use only if tetracyclines or aminoglycosides cannot be used. Use if meningeal involvement is possible. Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.
Adult Dose	50-100 mg/kg/d PO/IV divided qid; not to exceed 4 g/d
Pediatric Dose	50-75 mg/kg/d PO/IV divided qid
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, serum levels may decrease while barbiturate levels may increase, causing toxicity; rifampin may reduce serum levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; levels may be increased or decreased when taken concurrently with hydantoins
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Use only for indicated infections; serious or fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

FOLLOW-UP

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Further Inpatient Care

• Care primarily involves supportive and general medical care for manifestations that require hospitalization (eg, ARDS, pneumonia, lung abscess, renal insufficiency).

Further Outpatient Care

• Observe patients for resolution of clinical manifestations and potential toxicities of antibiotics.
• Relapses are common and may be retreated with the same medication because recurrence is usually due to incomplete treatment rather than antimicrobial resistance.

In/Out Patient Meds

• Administer antibiotics for 7-14 days to complete a course of treatment (see Medication).

Transfer

• Transfer patients if complications require therapeutic options (eg, ventilator management, cerebrospinal fluid examination, hemodialysis) unavailable at the initial facility.
• Consider transfer if evaluation by a subspecialist (eg, infectious diseases, pulmonary, nephrology) is needed and those subspecialists are not available at the initial facility.
  

Deterrence/Prevention

• Avoid tick bites, if possible, by avoiding tick-infested areas, wearing trousers and long-sleeved shirts, using tick repellants, and by frequently inspecting clothing and bodies for evidence of ticks. Remove ticks promptly by grasping the tick near the mouthparts and pulling upward, taking care to not squeeze the body because tick secretions may be infectious.
• Avoid exposure to dead or wild mammals if possible. When exposure is necessary (eg, skinning or eviscerating a rabbit carcass), gloves should be worn, especially if abrasions are on the hands.
• Frequent and thorough hand washing is also advised.
• A live attenuated vaccine is available. Although it does not provide complete protection against development of disease, it reduces the severity of disease in vaccinated people. Consider it only in people who may have repeated exposure because of vocation (eg, laboratory workers, wild-animal veterinarians, taxidermists).

Complications

• Pneumonia
• Lung abscess
• Respiratory failure, including possible ARDS
• Rhabdomyolysis
• Renal failure with possible hemodialysis
• Hemoptysis
• Meningitis
• Endocarditis

Prognosis

• The mortality rate in untreated patients is 5-15%.
• The mortality rate in treated patients is 1-3%.
• The mortality rate is 2-3 times higher in patients with the typhoidal form of the disease than in those with other forms.

Patient Education

• See Deterrence/Prevention.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider tularemia in the differential diagnosis may lead to death if the patient is not treated properly.
• Typical presentation with the ulceroglandular form of the disease is more likely to be diagnosed than the typhoidal form. When the typhoidal form is present, epidemiologic information must be carefully obtained from the history to provide clues for the diagnosis.

Special Concerns

• Because of the risk to laboratory workers, routine culturing of this organism is discouraged. If tularemia is suspected in a specimen, notify laboratory workers so that they can take appropriate precautions.
• F tularensis is a possible agent of bioterrorism. Diagnosis of this disease, especially in the setting of unusual clinical or epidemiological aspects of the presentation, should prompt timely contact with the appropriate public health authorities.^{7, 8}

MULTIMEDIA

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Media file 1:  Eschar on thumb and under thumbnail at the site of a rabbit bite in a patient with tularemia.
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Media type:  Photo

Media file 2:  Axillary bubo in a patient with tularemia.
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REFERENCES

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1. Trevisanato SI. The 'Hittite plague', an epidemic of tularemia and the first record of biological warfare. Med Hypotheses. May 11 2007;[Medline].
2. Francis E. A summary of present knowledge of Tularaemia. Medicine. 1928;7:411-32.
3. van de Beek D, Steckelberg JM, Marshall WF, Kijpittayarit S, Wijdicks EF. Tularemia with brain abscesses. Neurology. Feb 13 2007;68(7):531. [Medline].
4. Mitchell LA, Bradsher RW Jr, Paden TC, Malak SF, Warmack TS, Nazarian SM. Tularemia induced bilateral optic neuritis. J Ark Med Soc. Mar 2006;102(9):246-9. [Medline].
5. Gelfand MS, Slade W, Abolnik IZ. Tularemia serology: Differentiating true-positive and false-positive titers. Inf Dis Clin Pract. 1992;1:105-8.
6. Tärnvik A, Chu MC. New approaches to diagnosis and therapy of tularemia. Ann N Y Acad Sci. Apr 27 2007;[Medline].
7. Cronquist SD. Tularemia: the disease and the weapon. Dermatol Clin. Jul 2004;22(3):313-20, vi-vii. [Medline].
8. Gallagher-Smith M, Kim J, Al-Bawardy R, Josko D. Francisella tularensis: possible agent in bioterrorism. Clin Lab Sci. 2004;17(1):35-9. [Medline].
9. Choi E. Tularemia and Q fever. Med Clin North Am. Mar 2002;86(2):393-416. [Medline].
10. Cunha BA. Tularemia. In: Tickborne Infectious Diseases: Diagnosis and Management. Marcel Dekker; 2000:251-68.
11. Dienst FT. Tularemia: a perusal of three hundred thirty-nine cases. J La State Med Soc. Apr 1963;115:114-27. [Medline].
12. Ellis J, Oyston PC, Green M, Titball RW. Tularemia. Clin Microbiol Rev. Oct 2002;15(4):631-46. [Medline].
13. Evans ME, Gregory DW, Schaffner W, McGee ZA. Tularemia: a 30-year experience with 88 cases. Medicine (Baltimore). Jul 1985;64(4):251-69. [Medline].
14. Farlow J, Wagner DM, Dukerich M, Stanley M, Chu M, Kubota K. Francisella tularensis in the United States. Emerg Infect Dis. Dec 2005;11(12):1835-41. [Medline].
15. Markowitz LE, Hynes NA, de la Cruz P, et al. Tick-borne tularemia. An outbreak of lymphadenopathy in children. JAMA. Nov 22-29 1985;254(20):2922-5. [Medline].
16. Penn RL, Kinasewitz GT. Factors associated with a poor outcome in tularemia. Arch Intern Med. Feb 1987;147(2):265-8. [Medline].

Article Last Updated: Aug 3, 2007