Tularemia

Diagnosis

Clinical diagnosis. A clue to the diagnosis of tularemia after a BW attack with F. tularensis might be a large number of temporally clustered patients presenting with similar nonspecific, febrile, systemic illnesses progressing rapidly to life-threatening pleuropneumonitis. Differential diagnoses include typhoidal syndromes (e.g., typhoid fever, rickettsia, or malaria) or pneumonic processes (e.g., plague, mycoplasma, influenza, Q-fever, staphylococcal enterotoxin B). Even after an aerosol BW attack, a percentage of patients should be expected to present with ulceroglandular disease. Some patients may exhibit a pulse-temperature mismatch (seen as often as 40 percent of the time in naturally acquired disease). The systemic symptoms and signs (fever) of tularemia classically respond quickly to appropriate antibiotics; patients typically improve dramatically within 24-48 hr of initiation of aminoglycosides (e.g. gentamicin), tetracyclines (e.g. doxycycline), or fluoroquinolones (e.g. ciprofloxacin). In contrast patients may remain febrile for weeks while on penicillin or cephalosporins alone.

Radiologic diagnosis. Chest radiographs should be performed if systemic tularemia disease is suspected but findings are often nonspecific. Atypical pneumonia accompanied by hilar adenopathy or pulmonary findings on CXR in the absence of clinical findings of pulmonary disease, could be clues to tularemia in some cases.

Laboratory diagnosis. Initial laboratory evaluations are generally nonspecific. Peripheral white blood cell counts usually range from 5,000 to 22,000 cells per microliter. Differential blood cell counts are normal with occasional lymphocytosis late in the disease process. Hematocrit, hemoglobin, and platelet levels are usually normal. Mild elevations in lactic dehydrogenase, serum transaminases, and alkaline phosphatase are common. Rhabdomyolysis may be associated with elevations in serum creatine kinase and urinary myoglobin levels. Cerebrospinal fluid is usually normal, although mild abnormalities in protein, glucose, and blood cell counts have been reported. Tularemia can be diagnosed by recovering the organism in culture from blood, ulcers, conjunctival exudates, sputum, gastric washings, and pharyngeal exudates. Recovery of organisms may even be possible after the institution of appropriate antibiotic therapy. However, unless tularemia is suspected, delays in diagnosis are probable as the organism does not grow well in standard clinical laboratory medium. F. tularensis produces small, smooth, opaque colonies after 24 to 48 hr on medium containing cysteine or other sulfhydryl compounds (e.g., glucose cysteine blood agar, thioglycollate broth). Isolation represents a clear hazard to laboratory personnel and culture should only be attempted in BSL-3 containment.

Most diagnoses of tularemia are made serologically using bacterial agglutination or enzyme-linked immunosorbent assay (ELISA). Antibodies to F. tularensis appear within the first week of infection but levels adequate to allow confidence in the specificity of the serologic diagnosis (titer > 1:160) do not appear until more than 2 weeks after infection. Because cross-reactions can occur with Brucella spp., Proteus OX19, and Yersinia organisms and because antibodies may persist for years after infection, diagnosis should be made only if a fourfold or greater increase in the tularemia tube agglutination or microagglutination titer is seen during the course of the illness. Titers are usually negative the first week of infection, positive the second week in 50-70 percent of cases, and reach a maximum in 4-8 weeks.

Differential Diagnosis

Differential Diagnosis for Glandular Tularemia

Conditiona,b

Distinguishing Features

Bubonic plague (Yersinia pestis)

—Clinical course often fulminant
—Systemic toxicity common

Cat-scratch disease (Bartonella henselae)

—History of contact with cats; usually history of cat scratch
—Indolent clinical course; progresses over weeks
—Primary lesion at site of scratch often present (small papule, vesicle)

Mycobacterial infection, including scrofula (Mycobacterium tuberculosis and other Mycobacterium species)

—With scrofula, adenitis occurs in cervical region
—Lymph nodes generally painless and nontender
—Infections with species other than M tuberculosis more likely to occur in immunocompromised patients

Sporotrichosis (Sporothrix schenckii)

—Lymph nodes generally painless and nontender
—Systemic symptoms absent
—Painless papulonodular cutaneous lesion usually present distal to involved lymph nodes; secondary cutaneous lesions may occur along lymphatic channels
—Patients often have history of contact with soil, plants, or plant products (eg, sphagnum moss, thorned plants such as rose bushes)

Streptococcal or staphylococcal adenitis (Staphylococcus aureus, Streptococcus pyogenes)

—Site of initiating infection often present distal to involved nodes (ie, pustule, infected traumatic lesion)
—Involved nodes more likely to be fluctuant

Chancroid (Haemophilus ducreyi)

—Adenitis occurs in inguinal region only
—Ulcerative lesion present
—History of sexual exposure or activity

Lymphogranuloma venereum (Chlamydia trachomatis)

—Adenitis occurs in inguinal region only
—Suppuration, fistula tracts common
—Although lymph nodes may be somewhat tender, exquisite tenderness usually absent
— History of sexual exposure 10-30 days prior

Primary genital herpes

—Herpes lesions in genital area
—Adenitis in inguinal region only
—History of sexual exposure or activity

Secondary syphilis (Treponema pallidum)

—Enlarged lymph nodes in inguinal region only
—Lymph nodes generally painless and nontender
—History of sexual exposure or activity

aSee References: Butler 1979, Cross 2000, Penn 2010.
bInfectious causes of generalized lymphadenopathy (eg, cytomegalovirus infection, toxoplasmosis, mononucleosis, lymphoma) also may be considered, depending on the clinical presentation.


Differential Diagnosis for Ulceroglandular Tularemia

Condition

Distinguishing Features

Anthrax (Bacillus anthracis)

—Painless ulcer that develops into black eschar over several days
—Extensive non-pitting edema around lesion may occur

Orf (orf virus, a parapox virus)

—Occurs in farm workers
—Characterized by pustule that progresses to weeping nodule
—Regional adenitis may occur, but not common

Pasteurella infections (Pasteurella multocida)

—History of dog or cat exposure (animal bite or licking of open wound)
—Regional lymphadenopathy occurs in 30%-40% of cases

Primary syphilis (Treponema pallidum)

—Characterized by painless ulcer (chancre) in genital area
—Lymph nodes generally painless and nontender

Rat-bite fever (Spirillum minus)a

—Infection caused by S minus occurs in Asia
—Maculopapular rash over palms, soles, and extremities 2-4 days after onset of fever

Rickettsialpox (Rickettsia akari)

—Initial presentation involves painless papule which forms black eschar
—Generalized maculopapular rash appears 2-3 days later
—Regional lymphadenopathy usually present but nontender

Scrub typhus (Orientia tsutsugamushi; formerly Rickettsia tsutsugamushi)

—Zoonotic infection from chigger bites
—Occurs in endemic areas (Asia and Western Pacific)
—Often associated with a generalized maculopapular rash

Staphylococcal or streptococcal cellulitis (Staphylococcus aureus, Streptococcus pyogenes)

—May be history of trauma or preexisting lesion at site of infection

aRat-bite fever caused by Streptobacillus moniliformis (type found in North America and Europe) generally does not result in ulceration at site of bite, is not associated with regional lymphadenopathy, and therefore is not considered in differential diagnosis of ulceroglandular tularemia.


Differential Diagnosis for Pneumonic Tularemia

Conditiona,b

Distinguishing Features

Community-acquired bacterial pneumonia
—Mycoplasmal pneumonia (Mycoplasma pneumoniae)
—Pneumonia caused by Chlamydia pneumoniae
—Legionnaires' disease (Legionella pneumophila or other Legionella species)
—Psittacosis (Chlamydia psittaci)
—Other bacterial agents (eg, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis)

—Legionellosis and many other bacterial agents (S aureus, S pneumoniae, H influenzae, K pneumoniae, M catarrhalis) usually occur in persons with underlying pulmonary or other disease or in elderly
—Bird exposure with psittacosis
—Community outbreaks caused by other etiologic agents less likely to suggest point-source outbreak (as would be seen with intentional release of Francisella tularensis)
—Outbreaks of S pneumoniae usually institutional
—Community outbreaks of legionnaires' disease often involve exposure to cooling towers
—Gram stain of sputum may be useful in distinguishing agents

Inhalational anthrax (Bacillus anthracis)

—Widened mediastinum and pleural effusions seen on CXR or chest CT
—Not true pneumonia; minimal sputum production
—Severe and rapidly progressive course; often fulminant and fatal

Pneumonic plague (Yersinia pestis)

—Hemoptysis commonly occurs
—Consolidation often noted on CXR early in clinical course (radiographic evidence of pneumonia in patients with tularemia generally not as pronounced early in clinical course)
—Severe and rapidly progressive course; often fulminant and fatal

Q fever (Coxiella burnetii)

—Exposure to infected parturient cats, cattle, sheep, goats
—May be difficult to distinguish clinically from pneumonic tularemia

Tuberculosis (Mycobacterium tuberculosis)

—More common among elderly or among persons who have lived in tuberculosis-endemic countries (ie, developing world, countries of the former Soviet Union)

Viral pneumonia
—Influenza
—Hantavirus
—RSV
—CMV

—Influenza generally seasonal (October-March in United States) or involves history of recent cruise ship travel or travel to tropics
—Exposure to excrement (urine and feces) of mice with hantavirus
—RSV usually occurs in children (although may be cause of pneumonia in elderly); tends to be seasonal (winter/spring)
—CMV usually occurs in immunocompromised patients

Abbreviations: CMV, cytomegalovirus; CT, computed tomography; CXR, chest x-ray; RSV, respiratory syncytial virus.

aOther causes of pneumonia (eg, fungal infections) also may be considered, depending on the clinical presentation and setting.
bSee References: Butler 1979, Cross 2000, Penn 2010.


Differential Diagnosis for Oculoglandular Tularemia

Conditiona,b

Distinguishing Features

Adenoviral infection (adenovirus)

—Generally not associated with regional lymphadenopathy
—Systemic symptoms absent
—Commonly hemorrhagic

Cat-scratch disease (Bartonella henselae)

—Watery discharge, granulomatous conjunctival nodule, chemosis
—Lymph nodes nontender
—Mild systemic toxicity may be present but usually less severe than that seen with tularemia

Coccidioidomycosis (Coccidioides immitis)

—Granulomatous conjunctival nodule with small areas of necrosis
—Lymph nodes may be tender and some systemic toxicity may be present

Herpes infection (herpes simplex virus)

—Causes characteristic dendritic keratitis in addition to conjunctivitis

Pyogenic bacterial infections

—Mild cases not associated with regional lymphadenopathy
—Systemic symptoms usually absent

Sporotrichosis (Sporothrix schenckii)

—Firm chancre in skin of eyelid, yellow conjunctival nodules, subcutaneous nodules along lymphatics
—Lymph nodes nontender
—Systemic symptoms absent

Syphilis (Treponema pallidum)

—Conjunctival ulcer with indurated margin and gray base
—Lymph nodes nontender
—Systemic symptoms absent

Tuberculosis (Mycobacterium tuberculosis)

—Small conjunctival ulcer embedded in nodule
—Lymph nodes nontender
—Systemic symptoms generally absent

aSee References: Halperin 1985.
bOther rare causes of oculoglandular syndrome include actinomycosis, blastomycosis, yersiniosis, listeriosis, mumps, lymphogranuloma venereum, and chancroid.


Differential Diagnosis for Oropharyngeal Tularemia

Conditiona

Distinguishing Features

Streptococcal pharyngitis (Streptococcus pyogenes)

—Responds to penicillin therapy

Infectious mononucleosis (Epstein-Barr virus)

—Most common in young adults
—Splenomegaly commonly occurs

Adenoviral infection (adenovirus)

—Occurs mostly in children and young adults
—Often associated with rhinorrhea

Diphtheria (Corynebacterium diphtheriae)

—Primarily occurs in nonimmune children under 15 yr of age
—Removal of pharyngeal membrane often causes bleeding of submucosa (unlike tularemia)

aSee References: Cross 2000, Penn 2010, Tyson 1976.


Differential Diagnosis for Typhoidal Tularemia

Condition

Distinguishing Features

Typhoidal tularemia without sepsisa

Brucellosis (Brucella abortus and other Brucella species)

—Usually history of contact with tissues, blood, aborted fetuses of infected animals (cattle, swine, goats, sheep)
—Occupational disease

Disseminated mycobacterial or fungal infection

—Underlying illness usually present

Endocarditis

—Features of endocarditis (eg, cardiac murmur, embolic phenomenon) often present
—Risk factors may be present (underlying cardiac abnormality, prosthetic valve, injecting drug use)

Leptospirosis (Leptospira interrogans)

—History of exposure to infected animals or to water or soil contaminated with urine from infected animals
—Characteristic features (in addition to acute onset of febrile illness) include conjunctival suffusion, severe myalgias, and pretibial maculopapular eruption

Pontiac fever (Legionella pneumophila)

—Often mild clinical illness; does not require antibiotic therapy

Malaria (Plasmodium species)

—History of travel to malaria-endemic area is typical
—Cyclic fevers (every 48 hr for P vivax or P ovale; every 72 hr for P malariae) or continuous fever with intermittent spikes (most common pattern for P falciparum)
—Parasites may be seen on microscopic examination of thick or thin smears

Q fever (Coxiella burnetii)

—Exposure to infected parturient cats, cattle, sheep, goats

Typhoid fever (Salmonella typhi)

—Symptoms of enterocolitis and abdominal pain may be more prominent with typhoid fever than with typhoidal tularemia
—Bloody diarrhea may be present (not usually seen with tularemia)

Typhoidal tularemia with sepsis

Meningococcemia (Neisseria meningitidis)

—Rapid progression to shock and often death

Septicemic plague (Yersinia pestis)

—Often secondary to bubonic plague (characteristic bubo present in groin, axilla, or cervical region)
—Fulminant, often fatal course

Septicemia caused by other gram-negative bacteria

—Underlying illness usually present
—Fulminant course

Staphylococcal or streptococcal TSS (Staphylococcus aureus, Streptococcus pyogenes)

—Streptococcal TSS may be associated with necrotizing fasciitis
—Staphylococcal TSS often associated with characteristic epidemiologic features (eg, tampon use in menstruating women, antecedent trauma)

Abbreviation: TSS, toxic shock syndrome.

aSee References: Cross 2000, Penn 2005.

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