Tick-Borne Diseases, Tularemia
Jonathan A Edlow, MD, Associate Professor of Medicine, Department of Emergency Medicine, Harvard Medical School; Vice Chairman, Department of Emergency Medicine, Beth Israel Deaconess Medical Center
Updated: Dec 9, 2008
Introduction
Background
First described in Japan in 1837, tularemia is an infectious disease caused by the gram-negative pleomorphic bacterium, Francisella tularensis. The disease name relates to the description in 1911 of a plaguelike illness in ground squirrels in Tulare County, California, and the subsequent work performed by Dr Edward Francis. In 1928, Francis described his personal experience with more than 800 cases.
F tularensis is found worldwide in more than 100 species of wild animals, birds, and insects. This occurs in both terrestrial (rabbits, hares, ticks, and flies) and aquatic animals (muskrats and beavers). Four major strains, which differ in both virulence and geographic range, exist. The "tularensis" strain, found primarily in North America, is the most virulent.
The organism produces an acute febrile illness in humans. The route of transmission and factors relating to the host and the organism influence the presentation.
Clinical Image Atlas
Click to view clinical images on the features, causes, epidemiology, diagnosis, and treatment of Lyme disease.
Pathophysiology
Categories of tularemia
Some authorities classify tularemia into 2 groups, which include the far more common ulceroglandular form (in which local or regional symptoms and signs predominate) and the more lethal typhoidal form (in which systemic symptoms dominate the clinical picture). More commonly, however, tularemia is divided into 6 forms:
Ulceroglandular
Glandular
Oculoglandular
Oropharyngeal
Pneumonic
Typhoidal
Each form reflects the mode of transmission. The organism gains access to the host by means of inoculation into skin or mucous membrane, inhalation, or ingestion. Although person-to-person transmission does not occur with F tularensis, the organism is extremely infectious, with as few as 10-50 inhaled organisms producing disease. It is therefore an organism that can infect laboratory technicians working with the organism, making it a candidate for use as a biological weapon.
Ulceroglandular form (70-80% of cases): The organism enters through a scratch, abrasion, or tick or insect bite and spreads via the proximal lymphatic system. Within the ulceroglandular form, more differentiation exists. A subcutaneous inoculum of as few as 10 organisms can cause disease.
Glandular form (rare): No ulcer is present, and the organism is presumed to have gained access to the lymphatic system and/or bloodstream through clinically unapparent abrasions.
Oculoglandular form (1% of cases): The organism enters through the conjunctiva from either a splash of infected blood or rubbing the eyes after contact with infectious materials (eg, blood from a rabbit carcass).
Oropharyngeal form (rare): This form occurs after ingestion of eating undercooked rabbit meat containing the organism.
Pneumonic form (uncommon): This form occurs when the organism is inhaled. This form is observed in laboratory workers and occasionally occurs naturally. Pneumonia also occurs in 10-15% of patients with ulceroglandular tularemia and in one half of those patients with typhoidal tularemia.
Typhoidal (or septicemic) form (10-15% of cases): This form is more severe than the others and often includes pneumonia. Ingestion may be the mode of transmission; however, in most cases, the portal of entry remains unknown.
Incubation
After an incubation period of 3-4 days (range, 1-14 d), a papule develops, accompanied by a high fever. The papule evolves into an ulcer associated with regional lymphadenopathy. Some patients infected by a second, less virulent strain (type B) have less dramatic presentations.
Carriers
Although numerous animals and insects can carry F tularensis, rabbits and ticks (especially Dermacentor and Amblyomma species) most commonly are implicated in human cases. The deer fly is another classic, although less common, vector.
Frequency
United States
A few hundred cases of tularemia are reported annually in the United States. As with most such diseases, most cases are likely unreported or misdiagnosed. Although sporadic cases occur in all states, those with highest prevalence are Arkansas, Illinois, Missouri, Texas, Oklahoma, Utah, Virginia, and Tennessee. Some occupations confer risk for tularemia; they include laboratory workers, landscapers, farmers, veterinarians, hunters, trappers, cooks, and meat handlers.
The frequency of tularemia has decreased markedly over the last 50 years, and a shift from winter disease (usually from rabbits) to summer disease (more likely from ticks) has occurred. Although this decrease led to the Centers for Disease Control and Prevention (CDC) removing tularemia from its list of reportable diseases in 1994, it was reinstated in 2000 due to concerns about tularemia being used as a biological weapon.
International
Tularemia is found worldwide, but the incidence is unknown.
Mortality/Morbidity
Untreated, tularemia has a mortality rate of 5-15%; this rate is even higher with the typhoidal form. Appropriate antibiotics lower this rate to about 1%.
Sex
Biologically, no gender bias exists; however, young?to?middle-aged men may be more likely to engage in activities (eg, associated with tick bites, rabbit, and wild game exposure) that predispose them to tularemia. Recently, tularemia has been associated with the bite of a pet hamster.1
Clinical
History
The general history for tularemia may include fever, chills, myalgias, and malaise. Occasionally, patients with tularemic meningitis, pericarditis, peritonitis, endocarditis, and osteomyelitis have symptoms that correspond to the organ system or systems involved. However, the usual manifestations correlate with the pathophysiological form outlined above.
Ulceroglandular forms
Patients have ulcers at the site of inoculation.
In rabbit-associated cases, ulcers usually are on the fingers or hands.
In tick-associated cases, common sites include the groin, axillae, and trunk. Swollen regional glands reflect this same geographic pattern. Infected nodes are painful.
Glandular form
This form is distinguished from the ulceroglandular form by the absence of an ulcer.
The bacterium presumably gains entry via microscopic abrasions or potentially through intact skin.
Oculoglandular form
The patient has a painful, red eye, often with purulent exudate.
Swollen glands may occur in submandibular, preauricular, or cervical areas.
Oropharyngeal form
Produced from eating undercooked infected meat, this form is associated with a sore throat, abdominal pain, nausea, vomiting and diarrhea, and occasionally, GI bleeding.
Abdominal pain is caused by mesenteric adenopathy, and bleeding results from intestinal ulcerations.
Pneumonic form (Note: Considering tularemia in patients presenting with atypical pneumonia, especially with the epidemiologic profile as below, is important.
In this form, produced by inhalation of organisms or by hematogenous spread from ulceroglandular or typhoidal disease, patients have a dry cough, dyspnea, and pleuritic chest pain. Landscaping during the summer months, especially cutting grass with a power mower, which may aerosolize organisms, is another described risk.
Some patients with tularemic pneumonia have systemic symptoms without these respiratory complaints.
Typhoidal (septicemic) form
F tularensis bacteremia causes this form and produces fevers, chills, myalgias, malaise, and weight loss.
The absence of an ulcer or lymphadenopathy makes diagnosis difficult.
Physical
Physical findings in tularemia vary with the mode of presentation.
Findings common to most cases are fever, tender hepatosplenomegaly, and in about 20% of patients, a generalized maculopapular rash that occasionally becomes pustular.
In one series, erythema nodosum occurred in 4 of 88 cases.2
The ulcer forms at the site of skin entry of the organism. The location varies with the vector.
The lesion starts as a tender papule that evolves into an ulcer with sharply demarcated borders and exudate.
The base evolves from yellow to black.
Regional nodes are edematous and tender, can become fluctuant, and may drain spontaneously.
Ocular findings may include unilateral intensely injected conjunctiva with purulent exudate, ulcerations and nodules on the palpebral conjunctiva, preauricular and cervical adenopathy, and corneal ulceration.
Exudative and membranous pharyngitis with regional adenopathy may be observed with the oropharyngeal form.
In the pneumonia form, rales are sometimes heard, but normal findings at lung examination are not uncommon.
Physical findings associated with pericarditis, peritonitis, meningitis, and osteomyelitis can be observed.
Causes
Tularemia is caused by infection with the bacteria F tularensis. The 2 subspecies are A (tularensis) and B (holartica). In the western United States, type A infections may be less severe than type B infections.
Differential Diagnoses
Catscratch Disease
Rhabdomyolysis
CBRNE - Plague
Salmonella Infection
Legionnaires Disease
Tick-Borne Diseases, Colorado
Lymphogranuloma Venereum
Tick-Borne Diseases, Introduction
Malaria
Tick-Borne Diseases, Lyme
Mononucleosis
Tick-Borne Diseases, Q Fever
Mumps
Tick-Borne Diseases, Rocky Mountain Spotted Fever
Pharyngitis
Toxoplasmosis
Pneumonia, Viral
Other Problems to Be Considered
Psittacosis
Brucellosis
Q fever
Legionella pneumonia
Workup
Laboratory Studies
Results of standard blood tests are nondiagnostic.
WBC count usually is normal or elevated. No consistent abnormality is found in other components of the CBC count.
In one series, urinalysis revealed pyuria in nearly one quarter of the cases.2
Serum chemical analysis reveals elevation of at least 1 test of hepatic function in about 50% of patients. An elevated creatine kinase level is associated with rhabdomyolysis and is a poor prognostic sign.
Examination of the spinal fluid occasionally reveals an elevated protein level or a mild pleocytosis.
Findings with routine blood cultures usually are normal because the organism has unique growth requirements. Similarly, while the organism is present in the ulcers, it rarely grows in cultures.
The sputum of patients with tularemic pneumonia usually is white and does not reveal the pathogen.
Imaging Studies
A chest radiograph is indicated, because roughly 30% of patients with tularemic pneumonia do not have respiratory symptoms. Overlap with other atypical pneumonias may exist.
Other Tests
Definitive diagnosis usually is established with serologic testing. This is in part because the organism is often not present in large numbers in blood or sputum and, in any case, may be difficult to cultivate.
Notifying the hospital laboratory staff is important if tularemia is a serious differential diagnostic possibility, because the organism can grow on normal culture media and many episodes of laboratory technician disease have been reported. The organism should only be worked with in culture in a Biosafety Level 3 facility.
A 4-fold increase in the titer or a single titer of 1:160 or more is the common threshold, although this varies with the laboratory. The methods also vary from antibody detection by latex agglutination or enzyme-linked immunosorbent assay (ELISA) testing to a range of polymerase chain reaction (PCR) products that directly measure DNA from the organisms.
One study revealed that no patient had a diagnostic titer before the 11th day of illness, but nearly all had one by day 16.2 Therefore, in interpreting the result, one must factor in the timing of the serologic test.
Rabbit handlers and others may have an asymptomatic elevation in antitularemic antibody titers without disease; thus, the elevated titer in the absence of clinical tularemia does not establish a diagnosis.
Treatment
Emergency Department Care
Consider tularemia in patients with fever and regional lymphadenopathy, particularly when an ulcer or conjunctivitis is present.
The typhoidal form presents as a nonspecific febrile illness with little to suggest tularemia in the absence of a careful epidemiologic history taking. In patients with this form of the disease, other potentially life-threatening infections should be considered and excluded or treated as appropriate.
Supportive care with fluids and antipyretics may be indicated.
Consultations
Consultation with an infectious diseases specialist often is indicated.
Discussion with public health authorities is important if a cluster of cases is seen, given that this could represent a biological attack.
Medication
The goal of therapy is eradication of tularemia with antibiotics.
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in context of the clinical setting. In treating tularemia, streptomycin is the drug of choice. Although less experience exists with other aminoglycosides, gentamicin also appears to be effective.
Although aminoglycosides are the drugs of choice, reports of patients who have responded well to fluoroquinolones (prior to tularemia being suspected) exist. In addition, in vitro susceptibility testing shows that the quinolones have great promise in treating tularemia. Thus, this class of drug may be an alternative in patients who cannot tolerate aminoglycosides. Also, many practitioners are using newer fluoroquinolones as monotherapy for community-acquired pneumonia.
Both levofloxacin and ciprofloxacin have been used clinically with success. In fact, in a large outbreak in Spain (142 cases), ciprofloxacin had the lowest treatment failure rate with the fewest side effects.3
While tetracycline and doxycycline have been used, both are bacteriostatic and not cidal for the organism. This is also true of chloramphenicol, relegating these 3 antibiotics to a third choice.
Streptomycin sulfate
Aminoglycoside antibiotic recommended when therapeutic agents with less potential hazard are ineffective or contraindicated.
Dosing
Adult
1-2 g IM divided bid for 7-14 d or until patient is afebrile for 5-7 d; not to exceed 2 g/d
Pediatric
20-40 mg/kg/d IM for 7-14 d or until patient is afebrile; not to exceed 0.75-1 g
Interactions
Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Contraindications
Documented hypersensitivity; non?dialysis-dependent renal insufficiency
Precautions
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 not treated with dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission
Gentamicin (Garamycin, Gentacidin)
Aminoglycoside used as an alternative to streptomycin. Less experience exists with this agent. Dosing regimens are numerous and adjusted based on creatinine clearance and changes in volume of distribution, as well as body space into which the agent must distribute. Follow each regimen by at least a trough level drawn on the third or fourth dose, 0.5 h before dosing; may draw a peak level 0.5 h after the 30-min infusion.
Dosing
Adult
5 mg/kg/d IV/IM q6-8h
Pediatric
<5 years with normal renal function: 2.5 mg/kg/dose IV/IM q8h
>5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d with adjustments for renal function prn
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents (prolonged respiratory depression may occur); coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Contraindications
Documented hypersensitivity; non?dialysis-dependent renal insufficiency
Precautions
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 not treated with dialysis, myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment
Tetracycline (Sumycin)
Third-line drug, tetracyclines being only bacteriostatic. Duration of treatment of <2 wk is associated with greater risk of relapse. Only potential advantage is its ability to cover other coexisting tick-borne pathogens. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Dosing
Adult
500 mg PO bid or 250 mg PO qid for 7-14 d
Pediatric
<9 years: Not recommended
>9 years: 10-20 mg/lb/d (25-50 mg/kg) PO divided qid
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Chloramphenicol (Chloromycetin)
Insufficient data exist on use of chloramphenicol in tularemia. This agent is a distant third choice. Binds to 50S bacterial ribosomal subunit and interferes with or inhibits protein synthesis. Is effective against gram-negative and gram-positive bacteria.
Dosing
Adult
50-100 mg/kg/d PO/IV divided q6h; not to exceed 4 g/d
Pediatric
50-75 mg/kg/d PO/IV divided q6h
Interactions
Concurrently with barbiturates, chloramphenicol serum levels may decrease, while barbiturate levels may increase, causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; 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
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use only for indicated infections or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; perform baseline and periodic blood studies approximately every 2 d during therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)
Levofloxacin (Levaquin)
May be a useful agent to treat tularemia.
Dosing
Adult
500 mg PO qd
Pediatric
<18 years: Not recommended
>18 years: 250-500 mg PO qd
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy
Ciprofloxacin (Cipro)
Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Has no activity against anaerobes. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared.
Second DOC; in one study, was associated with lowest rate of treatment failure.
Dosing
Adult
750 mg PO bid
Pediatric
<18 years: Not recommended
>18 years: Administer as in adults
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Dosage adjustments (adult adjustments)
CrCl (mL/min) <10: 50% of PO or IV dose q12h
HD: 0.25-0.5 g PO or 0.2-0.4 g IV q12h
During peritoneal dialysis: 0.25-0.5 g PO or 0.2-0.4 g IV q8h
In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; not drug of first choice in pediatric patients because of increased incidence of adverse events compared to controls, including arthropathy; no data exist for dose for pediatric patients with renal impairment (ie, CrCl <50 mL/min)
Doxycycline (Doryx, Bio-Tab, Vibramycin)
Broad-spectrum, synthetically derived bacteriostatic antibiotic in tetracycline class. Almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Third-line drug; bacteriostatic.
Dosing
Adult
100 mg PO/IV bid
Pediatric
<9 years: Not recommended
>9 years and <45 kg: 2-5 mg/kg (1-2 mg/lb) PO q12h
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Follow-up
Further Outpatient Care
Any patient being treated as an outpatient for tularemia should undergo close follow-up, preferably with his or her primary care physician.
Deterrence/Prevention
When hunting rabbits or skinning or preparing rabbit carcasses, great care must be taken to avoid touching the rabbit blood and flesh. Touching one's eyes should be avoided while performing these activities. Hands should be washed thoroughly afterwards.
For other suggestions for avoiding tick bites, see Tick-borne Diseases, Introduction.
Complications
Complications of tularemia may include the following:
Pneumonia
Hemoptysis
Lung abscess
Respiratory failure
Rhabdomyolysis
Renal failure requiring dialysis
Prognosis
Roughly 5-15% of untreated patients die of the disease.
Factors associated with increased mortality include typhoidal presentation, elevated creatine kinase levels, renal failure, late diagnosis, or other serious comorbidities.
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
Medicolegal Pitfalls
Failure to consider this treatable and potentially fatal infection is a major pitfall.
When the ulceroglandular form is present, the physician is more likely to consider tularemia.
The typhoidal form, which is more deadly, is usually accompanied by few clues and is therefore difficult to diagnose unless the physician routinely searches for the epidemiologic clues.
Special Concerns
Because F tularensis is so infectious, it has been considered as a biological weapon. In fact, some have speculated that the tularemia outbreak prior to the Battle of Stalingrad in 1942, was the result of weaponized tularemia developed by the Soviets. While not person-to-person transmissible, tularemia organisms delivered by aerosol could infect a large number of individuals. Being alert to an outbreak of pneumonia that is consistent with tularemia or an outbreak in which tularemia turns out to be the cause should suggest a possible biological attack. This is especially true if such a cluster of cases were to occur in urban or suburban environments, where the natural exposure to the organism is much less common.
Similarly, if a laboratory technician were to present with tularemia or a syndrome suggesting it, steps should be taken to ensure that no safety breaches occur in the laboratory in order to prevent subsequent cases.
http://emedicine.medscape.com/article/787109-print
Jonathan A Edlow, MD, Associate Professor of Medicine, Department of Emergency Medicine, Harvard Medical School; Vice Chairman, Department of Emergency Medicine, Beth Israel Deaconess Medical Center
Updated: Dec 9, 2008
Introduction
Background
First described in Japan in 1837, tularemia is an infectious disease caused by the gram-negative pleomorphic bacterium, Francisella tularensis. The disease name relates to the description in 1911 of a plaguelike illness in ground squirrels in Tulare County, California, and the subsequent work performed by Dr Edward Francis. In 1928, Francis described his personal experience with more than 800 cases.
F tularensis is found worldwide in more than 100 species of wild animals, birds, and insects. This occurs in both terrestrial (rabbits, hares, ticks, and flies) and aquatic animals (muskrats and beavers). Four major strains, which differ in both virulence and geographic range, exist. The "tularensis" strain, found primarily in North America, is the most virulent.
The organism produces an acute febrile illness in humans. The route of transmission and factors relating to the host and the organism influence the presentation.
Clinical Image Atlas
Click to view clinical images on the features, causes, epidemiology, diagnosis, and treatment of Lyme disease.
Pathophysiology
Categories of tularemia
Some authorities classify tularemia into 2 groups, which include the far more common ulceroglandular form (in which local or regional symptoms and signs predominate) and the more lethal typhoidal form (in which systemic symptoms dominate the clinical picture). More commonly, however, tularemia is divided into 6 forms:
Ulceroglandular
Glandular
Oculoglandular
Oropharyngeal
Pneumonic
Typhoidal
Each form reflects the mode of transmission. The organism gains access to the host by means of inoculation into skin or mucous membrane, inhalation, or ingestion. Although person-to-person transmission does not occur with F tularensis, the organism is extremely infectious, with as few as 10-50 inhaled organisms producing disease. It is therefore an organism that can infect laboratory technicians working with the organism, making it a candidate for use as a biological weapon.
Ulceroglandular form (70-80% of cases): The organism enters through a scratch, abrasion, or tick or insect bite and spreads via the proximal lymphatic system. Within the ulceroglandular form, more differentiation exists. A subcutaneous inoculum of as few as 10 organisms can cause disease.
Glandular form (rare): No ulcer is present, and the organism is presumed to have gained access to the lymphatic system and/or bloodstream through clinically unapparent abrasions.
Oculoglandular form (1% of cases): The organism enters through the conjunctiva from either a splash of infected blood or rubbing the eyes after contact with infectious materials (eg, blood from a rabbit carcass).
Oropharyngeal form (rare): This form occurs after ingestion of eating undercooked rabbit meat containing the organism.
Pneumonic form (uncommon): This form occurs when the organism is inhaled. This form is observed in laboratory workers and occasionally occurs naturally. Pneumonia also occurs in 10-15% of patients with ulceroglandular tularemia and in one half of those patients with typhoidal tularemia.
Typhoidal (or septicemic) form (10-15% of cases): This form is more severe than the others and often includes pneumonia. Ingestion may be the mode of transmission; however, in most cases, the portal of entry remains unknown.
Incubation
After an incubation period of 3-4 days (range, 1-14 d), a papule develops, accompanied by a high fever. The papule evolves into an ulcer associated with regional lymphadenopathy. Some patients infected by a second, less virulent strain (type B) have less dramatic presentations.
Carriers
Although numerous animals and insects can carry F tularensis, rabbits and ticks (especially Dermacentor and Amblyomma species) most commonly are implicated in human cases. The deer fly is another classic, although less common, vector.
Frequency
United States
A few hundred cases of tularemia are reported annually in the United States. As with most such diseases, most cases are likely unreported or misdiagnosed. Although sporadic cases occur in all states, those with highest prevalence are Arkansas, Illinois, Missouri, Texas, Oklahoma, Utah, Virginia, and Tennessee. Some occupations confer risk for tularemia; they include laboratory workers, landscapers, farmers, veterinarians, hunters, trappers, cooks, and meat handlers.
The frequency of tularemia has decreased markedly over the last 50 years, and a shift from winter disease (usually from rabbits) to summer disease (more likely from ticks) has occurred. Although this decrease led to the Centers for Disease Control and Prevention (CDC) removing tularemia from its list of reportable diseases in 1994, it was reinstated in 2000 due to concerns about tularemia being used as a biological weapon.
International
Tularemia is found worldwide, but the incidence is unknown.
Mortality/Morbidity
Untreated, tularemia has a mortality rate of 5-15%; this rate is even higher with the typhoidal form. Appropriate antibiotics lower this rate to about 1%.
Sex
Biologically, no gender bias exists; however, young?to?middle-aged men may be more likely to engage in activities (eg, associated with tick bites, rabbit, and wild game exposure) that predispose them to tularemia. Recently, tularemia has been associated with the bite of a pet hamster.1
Clinical
History
The general history for tularemia may include fever, chills, myalgias, and malaise. Occasionally, patients with tularemic meningitis, pericarditis, peritonitis, endocarditis, and osteomyelitis have symptoms that correspond to the organ system or systems involved. However, the usual manifestations correlate with the pathophysiological form outlined above.
Ulceroglandular forms
Patients have ulcers at the site of inoculation.
In rabbit-associated cases, ulcers usually are on the fingers or hands.
In tick-associated cases, common sites include the groin, axillae, and trunk. Swollen regional glands reflect this same geographic pattern. Infected nodes are painful.
Glandular form
This form is distinguished from the ulceroglandular form by the absence of an ulcer.
The bacterium presumably gains entry via microscopic abrasions or potentially through intact skin.
Oculoglandular form
The patient has a painful, red eye, often with purulent exudate.
Swollen glands may occur in submandibular, preauricular, or cervical areas.
Oropharyngeal form
Produced from eating undercooked infected meat, this form is associated with a sore throat, abdominal pain, nausea, vomiting and diarrhea, and occasionally, GI bleeding.
Abdominal pain is caused by mesenteric adenopathy, and bleeding results from intestinal ulcerations.
Pneumonic form (Note: Considering tularemia in patients presenting with atypical pneumonia, especially with the epidemiologic profile as below, is important.
In this form, produced by inhalation of organisms or by hematogenous spread from ulceroglandular or typhoidal disease, patients have a dry cough, dyspnea, and pleuritic chest pain. Landscaping during the summer months, especially cutting grass with a power mower, which may aerosolize organisms, is another described risk.
Some patients with tularemic pneumonia have systemic symptoms without these respiratory complaints.
Typhoidal (septicemic) form
F tularensis bacteremia causes this form and produces fevers, chills, myalgias, malaise, and weight loss.
The absence of an ulcer or lymphadenopathy makes diagnosis difficult.
Physical
Physical findings in tularemia vary with the mode of presentation.
Findings common to most cases are fever, tender hepatosplenomegaly, and in about 20% of patients, a generalized maculopapular rash that occasionally becomes pustular.
In one series, erythema nodosum occurred in 4 of 88 cases.2
The ulcer forms at the site of skin entry of the organism. The location varies with the vector.
The lesion starts as a tender papule that evolves into an ulcer with sharply demarcated borders and exudate.
The base evolves from yellow to black.
Regional nodes are edematous and tender, can become fluctuant, and may drain spontaneously.
Ocular findings may include unilateral intensely injected conjunctiva with purulent exudate, ulcerations and nodules on the palpebral conjunctiva, preauricular and cervical adenopathy, and corneal ulceration.
Exudative and membranous pharyngitis with regional adenopathy may be observed with the oropharyngeal form.
In the pneumonia form, rales are sometimes heard, but normal findings at lung examination are not uncommon.
Physical findings associated with pericarditis, peritonitis, meningitis, and osteomyelitis can be observed.
Causes
Tularemia is caused by infection with the bacteria F tularensis. The 2 subspecies are A (tularensis) and B (holartica). In the western United States, type A infections may be less severe than type B infections.
Differential Diagnoses
Catscratch Disease
Rhabdomyolysis
CBRNE - Plague
Salmonella Infection
Legionnaires Disease
Tick-Borne Diseases, Colorado
Lymphogranuloma Venereum
Tick-Borne Diseases, Introduction
Malaria
Tick-Borne Diseases, Lyme
Mononucleosis
Tick-Borne Diseases, Q Fever
Mumps
Tick-Borne Diseases, Rocky Mountain Spotted Fever
Pharyngitis
Toxoplasmosis
Pneumonia, Viral
Other Problems to Be Considered
Psittacosis
Brucellosis
Q fever
Legionella pneumonia
Workup
Laboratory Studies
Results of standard blood tests are nondiagnostic.
WBC count usually is normal or elevated. No consistent abnormality is found in other components of the CBC count.
In one series, urinalysis revealed pyuria in nearly one quarter of the cases.2
Serum chemical analysis reveals elevation of at least 1 test of hepatic function in about 50% of patients. An elevated creatine kinase level is associated with rhabdomyolysis and is a poor prognostic sign.
Examination of the spinal fluid occasionally reveals an elevated protein level or a mild pleocytosis.
Findings with routine blood cultures usually are normal because the organism has unique growth requirements. Similarly, while the organism is present in the ulcers, it rarely grows in cultures.
The sputum of patients with tularemic pneumonia usually is white and does not reveal the pathogen.
Imaging Studies
A chest radiograph is indicated, because roughly 30% of patients with tularemic pneumonia do not have respiratory symptoms. Overlap with other atypical pneumonias may exist.
Other Tests
Definitive diagnosis usually is established with serologic testing. This is in part because the organism is often not present in large numbers in blood or sputum and, in any case, may be difficult to cultivate.
Notifying the hospital laboratory staff is important if tularemia is a serious differential diagnostic possibility, because the organism can grow on normal culture media and many episodes of laboratory technician disease have been reported. The organism should only be worked with in culture in a Biosafety Level 3 facility.
A 4-fold increase in the titer or a single titer of 1:160 or more is the common threshold, although this varies with the laboratory. The methods also vary from antibody detection by latex agglutination or enzyme-linked immunosorbent assay (ELISA) testing to a range of polymerase chain reaction (PCR) products that directly measure DNA from the organisms.
One study revealed that no patient had a diagnostic titer before the 11th day of illness, but nearly all had one by day 16.2 Therefore, in interpreting the result, one must factor in the timing of the serologic test.
Rabbit handlers and others may have an asymptomatic elevation in antitularemic antibody titers without disease; thus, the elevated titer in the absence of clinical tularemia does not establish a diagnosis.
Treatment
Emergency Department Care
Consider tularemia in patients with fever and regional lymphadenopathy, particularly when an ulcer or conjunctivitis is present.
The typhoidal form presents as a nonspecific febrile illness with little to suggest tularemia in the absence of a careful epidemiologic history taking. In patients with this form of the disease, other potentially life-threatening infections should be considered and excluded or treated as appropriate.
Supportive care with fluids and antipyretics may be indicated.
Consultations
Consultation with an infectious diseases specialist often is indicated.
Discussion with public health authorities is important if a cluster of cases is seen, given that this could represent a biological attack.
Medication
The goal of therapy is eradication of tularemia with antibiotics.
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in context of the clinical setting. In treating tularemia, streptomycin is the drug of choice. Although less experience exists with other aminoglycosides, gentamicin also appears to be effective.
Although aminoglycosides are the drugs of choice, reports of patients who have responded well to fluoroquinolones (prior to tularemia being suspected) exist. In addition, in vitro susceptibility testing shows that the quinolones have great promise in treating tularemia. Thus, this class of drug may be an alternative in patients who cannot tolerate aminoglycosides. Also, many practitioners are using newer fluoroquinolones as monotherapy for community-acquired pneumonia.
Both levofloxacin and ciprofloxacin have been used clinically with success. In fact, in a large outbreak in Spain (142 cases), ciprofloxacin had the lowest treatment failure rate with the fewest side effects.3
While tetracycline and doxycycline have been used, both are bacteriostatic and not cidal for the organism. This is also true of chloramphenicol, relegating these 3 antibiotics to a third choice.
Streptomycin sulfate
Aminoglycoside antibiotic recommended when therapeutic agents with less potential hazard are ineffective or contraindicated.
Dosing
Adult
1-2 g IM divided bid for 7-14 d or until patient is afebrile for 5-7 d; not to exceed 2 g/d
Pediatric
20-40 mg/kg/d IM for 7-14 d or until patient is afebrile; not to exceed 0.75-1 g
Interactions
Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Contraindications
Documented hypersensitivity; non?dialysis-dependent renal insufficiency
Precautions
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 not treated with dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission
Gentamicin (Garamycin, Gentacidin)
Aminoglycoside used as an alternative to streptomycin. Less experience exists with this agent. Dosing regimens are numerous and adjusted based on creatinine clearance and changes in volume of distribution, as well as body space into which the agent must distribute. Follow each regimen by at least a trough level drawn on the third or fourth dose, 0.5 h before dosing; may draw a peak level 0.5 h after the 30-min infusion.
Dosing
Adult
5 mg/kg/d IV/IM q6-8h
Pediatric
<5 years with normal renal function: 2.5 mg/kg/dose IV/IM q8h
>5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d with adjustments for renal function prn
Interactions
Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents (prolonged respiratory depression may occur); coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Contraindications
Documented hypersensitivity; non?dialysis-dependent renal insufficiency
Precautions
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 not treated with dialysis, myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment
Tetracycline (Sumycin)
Third-line drug, tetracyclines being only bacteriostatic. Duration of treatment of <2 wk is associated with greater risk of relapse. Only potential advantage is its ability to cover other coexisting tick-borne pathogens. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Dosing
Adult
500 mg PO bid or 250 mg PO qid for 7-14 d
Pediatric
<9 years: Not recommended
>9 years: 10-20 mg/lb/d (25-50 mg/kg) PO divided qid
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Chloramphenicol (Chloromycetin)
Insufficient data exist on use of chloramphenicol in tularemia. This agent is a distant third choice. Binds to 50S bacterial ribosomal subunit and interferes with or inhibits protein synthesis. Is effective against gram-negative and gram-positive bacteria.
Dosing
Adult
50-100 mg/kg/d PO/IV divided q6h; not to exceed 4 g/d
Pediatric
50-75 mg/kg/d PO/IV divided q6h
Interactions
Concurrently with barbiturates, chloramphenicol serum levels may decrease, while barbiturate levels may increase, causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; 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
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use only for indicated infections or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; perform baseline and periodic blood studies approximately every 2 d during therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)
Levofloxacin (Levaquin)
May be a useful agent to treat tularemia.
Dosing
Adult
500 mg PO qd
Pediatric
<18 years: Not recommended
>18 years: 250-500 mg PO qd
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy
Ciprofloxacin (Cipro)
Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Has no activity against anaerobes. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared.
Second DOC; in one study, was associated with lowest rate of treatment failure.
Dosing
Adult
750 mg PO bid
Pediatric
<18 years: Not recommended
>18 years: Administer as in adults
Interactions
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Dosage adjustments (adult adjustments)
CrCl (mL/min) <10: 50% of PO or IV dose q12h
HD: 0.25-0.5 g PO or 0.2-0.4 g IV q12h
During peritoneal dialysis: 0.25-0.5 g PO or 0.2-0.4 g IV q8h
In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; not drug of first choice in pediatric patients because of increased incidence of adverse events compared to controls, including arthropathy; no data exist for dose for pediatric patients with renal impairment (ie, CrCl <50 mL/min)
Doxycycline (Doryx, Bio-Tab, Vibramycin)
Broad-spectrum, synthetically derived bacteriostatic antibiotic in tetracycline class. Almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Third-line drug; bacteriostatic.
Dosing
Adult
100 mg PO/IV bid
Pediatric
<9 years: Not recommended
>9 years and <45 kg: 2-5 mg/kg (1-2 mg/lb) PO q12h
Interactions
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Contraindications
Documented hypersensitivity; severe hepatic dysfunction
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Follow-up
Further Outpatient Care
Any patient being treated as an outpatient for tularemia should undergo close follow-up, preferably with his or her primary care physician.
Deterrence/Prevention
When hunting rabbits or skinning or preparing rabbit carcasses, great care must be taken to avoid touching the rabbit blood and flesh. Touching one's eyes should be avoided while performing these activities. Hands should be washed thoroughly afterwards.
For other suggestions for avoiding tick bites, see Tick-borne Diseases, Introduction.
Complications
Complications of tularemia may include the following:
Pneumonia
Hemoptysis
Lung abscess
Respiratory failure
Rhabdomyolysis
Renal failure requiring dialysis
Prognosis
Roughly 5-15% of untreated patients die of the disease.
Factors associated with increased mortality include typhoidal presentation, elevated creatine kinase levels, renal failure, late diagnosis, or other serious comorbidities.
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
Medicolegal Pitfalls
Failure to consider this treatable and potentially fatal infection is a major pitfall.
When the ulceroglandular form is present, the physician is more likely to consider tularemia.
The typhoidal form, which is more deadly, is usually accompanied by few clues and is therefore difficult to diagnose unless the physician routinely searches for the epidemiologic clues.
Special Concerns
Because F tularensis is so infectious, it has been considered as a biological weapon. In fact, some have speculated that the tularemia outbreak prior to the Battle of Stalingrad in 1942, was the result of weaponized tularemia developed by the Soviets. While not person-to-person transmissible, tularemia organisms delivered by aerosol could infect a large number of individuals. Being alert to an outbreak of pneumonia that is consistent with tularemia or an outbreak in which tularemia turns out to be the cause should suggest a possible biological attack. This is especially true if such a cluster of cases were to occur in urban or suburban environments, where the natural exposure to the organism is much less common.
Similarly, if a laboratory technician were to present with tularemia or a syndrome suggesting it, steps should be taken to ensure that no safety breaches occur in the laboratory in order to prevent subsequent cases.
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