Clinical diagnosis. Diagnosis of plague is based primarily on clinical suspicion. A patient with a painful bubo accompanied by fever, severe malaise and possible rodent exposure in an endemic area should raise suspicion of bubonic plague. The sudden appearance of large numbers of previously healthy patients with severe, rapidly progressive pneumonia with hemoptysis strongly suggests pneumonic plague as a result of an intentional aerosolization.

Laboratory diagnosis. A presumptive diagnosis can be made microscopically by identification of the coccobacillus in Gram (negative), Wright, Giemsa, Wayson's, or more specific immunofluorescent antibody stained smears from lymph node needle aspirate, sputum, blood, or cerebrospinal fluid samples. Bubo aspirates can be obtained by inserting a 20 gauge needle on a 10ml syringe containing 1ml of sterile saline; saline is injected and withdrawn until blood tinged. Definitive diagnosis relies on culturing the organism from clinical specimens. The organism grows slowly at normal incubation temperatures (optimal growth at 25-28 C), and may be misidentified by automated systems (often as Y. pseudotuberculosis) because of delayed biochemical reactions. It may be cultured on blood agar, MacConkey agar, or infusion broth. It will also grow in automated culture systems. Any patient with suspected plague should have blood cultures performed; as bacteremia can be intermittent, multiple cultures should be obtained, preferably prior to receipt of antibiotics (clinical severity permitting). Confirmatory diagnosis via culture commonly takes 48-72 hours (cultures should be held 5-7 days); thus specific antibiotic therapy for plague must not be withheld pending culture results. Confirmative culture-based diagnosis is conducted via specific bacteriophage lysis of the organism, which is available at reference laboratories.

Most naturally occurring strains of Y. pestis produce an F1-antigen in vivo, which can be detected in serum samples by specific immunoassay. A single anti-F1 titer of >1:10 by agglutination testing is suggestive of plague, while a single titer of >1:128 in a patient who has not previous been exposed to plague or received a plague vaccine is more specific; a fourfold rise in acute vs. convalescent antibody titers in patient serum is probably the most specific serologic method to confirm diagnosis, but results are available only retrospectively. Most patients will seroconvert to plague within 1-2 weeks of disease onset, but a minority require 3 or more weeks.

PCR (using specific primers), is not sufficiently developed yet for routine use but it is a very sensitive and specific technique, currently able to identify as few as 10 organisms per ml.

Most clinical assays can be performed in biosafety level 2 (BSL-2) laboratories, whereas procedures producing aerosols or yielding significant quantities of organisms require BSL-3 containment.

Differential Diagnosis

Differential Diagnosis for Bubonic, Septicemic, and Pneumonic Plague


Distinguishing Features


Streptococcal or staphylococcal adenitis (Staphylococcus aureus, Streptococcus pyogenes)

—Purulent or inflamed lesion often noted distal to involved nodes (eg pustule, infected traumatic lesion)
—Involved nodes more likely to be fluctuant
—Associated ascending lymphangitis or cellulitis may be present (generally not seen with plague)

Tularemia (Francisella tularensis)b

—Ulcer or pustule often present distal to involved nodes
—Clinical course rarely as fulminant as in plague
—Systemic toxicity uncommon

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)
—Systemic toxicity not present

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

—With scrofula, adenitis occurs in cervical region
—Usually painless
—Indolent clinical course
—Infections with species other than M tuberculosis more likely to occur in immunocompromised patients

Lymphogranuloma venereum (Chlamydia trachomatis)

—Adenitis occurs in the inguinal region
—History of sexual exposure 10-30 days previously
—Suppuration, fistula tracts common
—Although LGV buboes may be somewhat tender, exquisite tenderness usually absent
—Although patients may appear ill (headache, fever, myalgias), systemic toxicity not present

Chancroid (Haemophilus ducreyi)

—Adenitis occurs in the inguinal region
—Ulcerative lesion present
—Systemic symptoms uncommon; toxicity does not occur

Primary genital herpes

—Herpes lesions present in genital area
—Adenitis occurs in the inguinal region
—Although patients may be ill (fever, headache), severe systemic toxicity not present

Primary or secondary syphilis (Treponema pallidum)

—Enlarged lymph nodes in the inguinal region
—Lymph nodes generally painless
—Chancre may be noted with primary syphilis

Strangulated inguinal hernias

Evidence of bowel involvement



More likely to have evidence of meningitis (but not always present)

Septicemia caused by other gram-negative bacteria

Underlying illness usually present


Inhalational anthrax (Bacillus anthracis)

—Widened mediastinum and pleural effusions seen on CXR or chest CT
—Not true pneumonia; minimal sputum production
—Hemoptysis uncommon (if present, suggests diagnosis of plague)

Tularemia (F tularensis)

Clinical course not as fulminant as pneumonic plague

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, S aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis)

—Rarely as fulminant as pneumonic plague
—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 the elderly
—Bird exposure with psittacosis
—Gram stain of sputum may be useful
—Community outbreaks caused by other etiologic agents not likely to be as explosive as pneumonic plague outbreak
—Outbreaks of S pneumoniae usually institutional
—Community outbreaks of legionnaires' disease often involve exposure to cooling towers

Viral pneumonia

—Influenza generally seasonal (October-March in United States) or involves history of recent cruise ship travel or travel to tropics
—Exposure to excrement (urine or 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

Q fever (Coxiella burnetii)

—Exposure to infected parturient cats, cattle, sheep, goats
—Severe pneumonia not prominent feature

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

aInfectious causes of generalized lymphadenopathy (eg, CMV infection, toxoplasmosis, mononucleosis) also may be considered, depending on the clinical presentation.
bSee References: Butler 1979, Cleri 1997.
cOther causes of pneumonia also may be considered, depending on the clinical presentation and setting (eg, tuberculosis, fungal infections).

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