Are You Confident of the Diagnosis?

Characteristic findings on physical examination

Bubonic plague presents with suppurative lymphadenitis in the form of enlarged, tender lymph nodes. Fever, chills and prostration are common. Pneumonic plague presents primarily wth fever, chills, cough and dyspnea. Patients may experience shock and death if the diagnosis is not considered and the disease is not treated early with an appropriate antibiotic.

Septicemic plague presents with fever, chills, and prostration. Abdominal pain is often prominent and shock and bleeding may be seen, producing significant clinical overlap with viral hemorrhagic fevers, particularly dengue and hantavirus. The diagnosis should be considered if exposure was possible. The local health department and Centers for Disease Control should be notified for suspected or confirmed disease. Case report forms are available on-line.

The National Notifiable Disease Surveillance System (NNDSS) is the primary reporting system for animal-related plague surveillance. They can assist with laboratory testing of fleas, animal tissues or serum specimens. The Centers for Disease Control (CDC) office at Fort Collins, CO is a World Health Organization (WHO) Collaborating Center for Reference and Research on Plague Control, and reports human plague cases to the WHO.

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Diagnostic studies

Specimens intended for culture should be taken before antibiotic treatment is initiated. The preferred material for microscopic examination and isolation from bubonic plague is material from the affected bubo. Blood cultures should also be obtained. A series of blood specimens taken 10-30 minutes apart is considered optional. Sputum and throat smears from patients with pneumonic plague should be sent for fluorescent-antibody testing. Bronchial/tracheal washing may be required to obtain an adequate specimen. Throat specimens are not ideal as they often contain many other bacteria. F1 antigen detection by immunofluorescent assay has also been used as a diagnostic test.

Who is at Risk for Developing this Disease?

People usually acquire plague by being bitten by a rodent flea. Such patients present with suppurative lymphadenitis as well as systemic symptoms. Pneumonic plague is highly infectious and is thought to be responsible for much of the death from disease during the great epidemics of the Middle Ages.

While it has been suggested that the Black Death in the middle ages may have represented viral hemorrhagic fever rather than plague, but other data suggest that specific strains of Y pestis were associated with each of the great plagues with transmission changing from rat flea, to human flea, to droplet as the epidemic progressed. In terms of subtypes, the Antiqua type has been implicated as the cause of the plague pandemic in the sixth century, Medievalis as the cause of the second pandemic wave, and Orientalis recently.

Zoonotic disease remains endemic in the western United States, with most cases occurring in New Mexico, northern Arizona, southern Colroado, California, southern Oregon and western Nevada. The last large urban epidemic occurred in Los Angeles in 1924. Zoonotic plague also exists in Africa, Asia, and South America. The organism is also a prime candidate for germ warfare attacks, which would result primarily in pneumonic disease.

What is the Cause of the Disease?

Plague is a zoonotic disease caused by a bacterium named Yersinia pestis, a Gram-negative coccobacillus with characteristic “safety pin” bipolar staining.


Temperature-dependent virulence factors are not produced in the flea (26°C), but these genes are upregulated when the temperature increases to 37°C (human or rodent body temperature). The temperature-dependent plasmid-encoded virulence factor Pla is expressed as a surface protease and activates human plasminogen. It appears to be a key virulence factor in bubonic and pneumonic plague. Pla is a transmembrane β-barrel protease which requires bound lipopolysaccharide in order to be proteolytically active. The resulting cascade involves complex interactions of lipopolysaccharide endotoxin, coagulase, and fibrinolysin.

Systemic Implications and Complications

With progression of the disease, patients may experience high fever, chills, malaise, cough, dyspnea and hemoptysis. If plague patients do not receive appropriate antibiotic therapy, the disease can progress rapidly to sepsis, disseminated intravascular coagulation, and death.

Treatment Options

For adults with pneumonic disease, gentamicin 5mg/kg IM or IV once daily or 2mg/kg loading dose followed by 1.7mg/kg IM or IV three times daily is now preferred by some authorities. The traditional treatment for adults was Streptomycin 1g IM twice daily, but other active antibiotics include , doxycycline 100mg twice daily (severe disease may require parenteral dosing), ciprofloxacin 400mg IV twice daily, and chloramphenicol 25mg/kg IV 4 times daily.

Prophyaxis after exposure in adults has been accomplished with doxycycline 100mg orally twice daily . For specific dosing regimens, pediatric dosing and prophylactic regimens, phyicians should consult their local health department or an infectious disease specialist.

Optimal Therapeutic Approach for this Disease

When plague is suspected, the local health department should be notified immediately. They can provide guidance for collection of specimens and treatment as outlined above.

Patient Management

Patients should be treated in conjunction with an infectious disease specialist, as progression to severe systemic illness is possible.

Unusual Clinical Scenarios to Consider in Patient Management

Herd immunity could have a benefit for weaponized plaque. Work is ongoing to produce a commercially available vaccine. In the meantime, rodent control, early recognition, isolation of patients with pneumonic disease, and prophylactic antibiotics play roles in containment of the disease. Lovastatin can help prevent disease in an animal model.

What is the Evidence?

Ramasamy, S, Liu, CQ, Tran, H, Gubala, A, Gauci, P, McAllister, J, Vo, T. “Principles of antidote pharmacology: an update on prophylaxis, post-exposure treatment recommendations and research initiatives for biological agents”. Br J Pharmacol. vol. 161. 2010 Oct. pp. 721-48. (Good overview of postexposure regimens for biologic agents.)

Cantwell, AM, Bubeck, SS, Dube, PH. “YopH inhibits early pro-inflammatory cytokine responses during plague pneumonia”. BMC Immunol. vol. 11. 2010 Jun. pp. 29(YopH can inhibit the early pro-inflammatory response in the lungs. This appears to be an important step in the pathogenesis of the infection.)

Ayyadurai, S, Lepidi, H, Nappez, C, Raoult, D, Drancourt, M. “Lovastatin protects against experimental plague in mice”. PLoS One. vol. 5. 2010 Jun. pp. e10928(In a mouse model, lovostatin prevents death from plague.)

Pages, F, Faulde, M, Orlandi-Pradines, E, Parola, P. “The past and present threat of vector-borne diseases in deployed troops”. Clin Microbiol Infect. vol. 16. 2010 Mar. pp. 209-24. (A good overview of regional endemic vector-borne disease.)

Rubin, GJ, Dickmann, P. “How to reduce the impact of “low-risk patients” following a bioterrorist incident: lessons from SARS, anthrax, and pneumonic plague”. Biosecur Bioterror. vol. 8. 2010 Mar. pp. 37-43. (In epidemics, hospitals become important sites of contagion. Strategies to reduce spread include disseminating information about who should not go to a hospital, using telephone services to provide information and initial screening, employing triage at hospital entrances, and follow-up by telephone.)

Yamanaka, H, Hoyt, T, Yang, X, Bowen, R, Golden, S, Crist, K, Becker, T, Maddaloni, M, Pascual, DW. “A parenteral DNA vaccine protects against pneumonic plague”. Vaccine. vol. 28. 2010 Apr. pp. 3219-30. (No commercial vaccine is currently available.)

Welford, M, Bossak, B. “Body lice, Yersinia pestis Orientalis, and Black Death [letter]”. Emerg Infect Dis [serial on the Internet]. 2010 Oct. (The authors suggest that viral hemorrhagic fevers caused the great plagues.)