Yersinia pestis/Plague

The plague is a bacterial infection caused by Yersinia pestis (Y. pestis), which primarily infects rodents. The disease is transmitted to humans via a fleabite. Inhalation of infectious droplets and handling infected animals or laboratory specimens are other means of transmission. The plague has 3 forms: bubonic (most common form), septicemic, and pneumonic. Bubonic plague results in swollen and tender lymph nodes called buboes in the inguinal area. Pneumonic and septicemic plague can arise as the primary presentation, but also can result from hematogenous spread from the bubonic disease. Diagnosis includes clinical history and findings, culture, polymerase chain reaction (PCR), and serology. The mortality rate is high, so prompt diagnosis and treatment with antibiotics are necessary.

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General Characteristics

Basic features of Yersinia pestis

  • Structure: bacilli/rods
  • Gram stain: gram negative 
  • Other stain(s): 
    • Stains such as Wright’s, Giemsa’s, and Wayson’s
    • Bipolar staining (retain staining at the ends of the cells) or “safety pin” appearance 
  • Spore formation: non-spore forming
  • Invasion and replication in relation to the host cell(s): facultative intracellular
  • Oxygen requirement: facultative anaerobes
  • Enzymes/biochemical tests:
    • Oxidase negative
    • Lactose negative

Clinically relevant species and diseases

  • Associated species: Enteropathogenic Yersinia cause yersiniosis (discussed separately).
  • Associated disease: plague (“Black Death”)
    • Yersinia pestis (Y. pestis) predominantly cause disease in rodents; humans are usually incidental hosts.
    • Forms:
      • Bubonic plague (most common)
      • Pulmonic plague
      • Septicemic plague

Epidemiology

Worldwide cases of the plague:

  • Majority of cases are from Africa.
  • Countries with the most prevalent cases:
    • Democratic Republic of the Congo
    • Madagascar
    • Peru
World Plague Map 2009

World map of plague cases reported to the World Health Organization (WHO), 2000–2009

Image: “World Plague Map – 2000 to 2009 – CDC” by the CDC. License: Public domain.

Plague in the United States:

  • Locations:
    • “4 Corners” (the junction point of New Mexico, Arizona, Colorado, and Utah)
    • West: California, southern Oregon, and western Nevada
  • Period with the most cases: May to October (People are outdoors, and rodents are plenty.)

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Pathogenesis

Reservoir and transmission

  • Plague: zoonotic infection
  • Reservoir: rodents, prairie dogs
  • Transmission: 
    • In areas with poor sanitary conditions and infestations of rats, the infection is acquired by a fleabite (the most common route). 
    • Handling of living or dead mammals 
    • Post-mortem examination of an infected body or laboratory handling of a specimen
    • Inhalation of infectious droplets (such as in bioterrorism) can cause pneumonic plague.
  • Vector: Xenopsylla cheopis (the Oriental rat flea, the most efficient flea vector):
    • Y. pestis multiplies in the flea’s midgut after ingestion of a blood meal. 
    • Yersinia aggregates can block the flea’s intestine.
    • The flea then regurgitates the bacteria into the bite wound with each feeding.
    • In some cases, bacteria are transmitted right after feeding on an infected host.

Virulence factors

  • Lipopolysaccharide endotoxin: leads to systemic toxicity in bacteremia
  • Type III secretion system: 
    • Injects Yersinia outer membrane proteins (Yops) into the host cell
    • Yops trigger cytotoxic events and inhibit phagocytosis as well as biochemical pathways.
  • High-pathogenicity island (HPI)
    • Encodes for an iron-scavenging siderophore, yersiniabactin
    • Yersiniabactin provides the bacterium the ability to take iron molecules needed for growth and dissemination.
  • Virulence regulation by temperature and calcium: 
    • Expression of Yersinia virulence factors is affected by temperature and free calcium. 
    • Physiologically, the mammalian host temperature is different from that of an insect.
    • Likewise, the calcium concentration is different in intracellular fluid than in extracellular fluids. 
    • Yersinia: able to adjust virulence factors based on the above actions, with the life cycle continuing in the environment or host
  • Y. pestis:
    • pPCP1 (or pPst): plasmid with genes for enzymes with protease, coagulase, and fibrinolytic activity
    • pFra/pMT: encodes Fraction 1 capsular protein (has antiphagocytic function) and phospholipase D (facilitates survival in the flea’s midgut)

Disease process

Bubonic plague:

  • When a flea bites a human and contaminates the wound with regurgitated blood, the bacteria are passed into the tissue.
  • Bacteria enter the dermal lymphatic system.
  • Subsequent effects of the infection: 
    • Replication of Yersinia → lymph node swelling → hemorrhage or necrosis → suppurative lymphadenitis (bubo)
    • Axillary and groin lymph nodes often affected
  • Lymph nodes get overwhelmed and the infection passes to the bloodstream.

Pneumonic plague:

  • Arises from inhalation of highly contagious infected droplets
  • Can result from hematogenous spread of bubonic plague
  • Rapidly progressive pneumonia with bacteria prominent in the air spaces (segmental → lobar → bilateral lung involvement)

Septicemic plague:

  • Bacteria replicate in the bloodstream, spreading to other organs.
  • Travel to the lungs produces secondary plague pneumonia. (Initially, the bacteria are more prominent in the interstitium than in the air spaces.) 
  • Infection of the meninges (meningitis) and gastrointestinal tract can occur.
  • Progresses to:
    • Bacterial endotoxic shock
    • Disseminated intravascular coagulation (DIC): clotting cascade, thrombosis with eventual bleeding from depletion of the clotting factors and platelets 
    • Ischemic necrosis from poor perfusion 
    • Death
Transmission of Y. pestis

The transmission of Yersinia pestis
Direct contact with rodents or flea bites give rise to bubonic plague while airborne transmission (human-to-human), either by coughing or sneezing, gives rise to pneumonic plague.

Image by Lecturio.

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Clinical Presentation

Bubonic plague

  • Symptoms start within 1 week of inoculation:
    • Headache, malaise, myalgia
    • Fever, chills
    • Painful, swollen, and some suppurative lymph nodes (buboes)
    • Inguinal (most frequent) and axillary lymph nodes often affected
  • Without treatment, serious illness follows from hematogenous spread.
Plague buboes

Bubonic plague: swollen inguinal lymph nodes on a person infected with the bubonic plague

Image: “Plague buboes” by the CDC. License: Public domain.

Pneumonic plague

  • In primary plague pneumonia, symptoms start within 2–3 days of exposure.
  • The initial signs are indistinguishable from several other respiratory illnesses: 
    • Fever
    • Headache
    • Weakness
  • After 24 hours, cough, hemoptysis, and shortness of breath follow. 

Septicemic plague

  • The initial presentation in a minority of cases: septic shock without lymphadenopathy/bubo
  • Risk factors for septicemia (for all Yersinia spp.):
    • Diabetes mellitus
    • Iron overload or hemochromatosis
  • Hemorrhage occurs in other organs, with tissue vasculature occluded by thrombi:
    • Purpuric lesions
    • Hemoptysis/hematemesis 
    • Gangrene in ears, fingers, and toes
  • Difficult to diagnose, especially in a sporadic presentation without bubo

Diagnosis

Diagnostic tools

  • Clinical history and findings:
    • Travel to endemic areas
    • Animal contact
    • Occupational exposure
    • Suggestive symptoms and examination
  • Smear and culture:
    • Specimens:
      • Buboes: needle aspiration of affected lymph node(s)
      • Lungs: sputum, bronchial/tracheal aspirate 
      • Blood
      • Cerebrospinal fluid
    • Bipolar staining (“safety pin” shape) in Wright’s, Giemsa’s, or Wayson’s stains 
    • Fluorescent antibody stains targeting the capsular F1 antigen
    • Specimen cultured in blood agar, MacConkey agar plates, and brain–heart infusion broth
    • Yersinia-specific culture medium: cefsulodin, irgasan, and novobiocin (CIN) agar
  • Serology: A titer of > 1:16 is suggestive of the plague.
  • Specific polymerase chain reaction (PCR)
Yersinia pestis fluorescent

Yersinia pestis: under microscopy, dyed with fluorescent stain

Image: “Yersinia pestis fluorescent” by the CDC/Courtesy of Larry Stauffer, Oregon State Public Health Laboratory. License: Public domain.

Additional tests

  • Laboratory tests:
    • Complete blood count: may show leukocytosis with left shift; in some, may have leukopenia; thrombocytopenia in DIC
    • Metabolic panel: Multi-organ involvement may show renal and hepatic function abnormalities.
    • Elevated fibrin degradation products and prolonged prothrombin times in septicemia
  • Imaging studies: chest X-ray in pneumonic plague
Chest X-ray pneumonic plague

A patient with pneumonic plague
A chest X-ray shows increased pulmonary markings, with thick interlobar pleura in a patient who presented with fever, cough, and dyspnea after exposure to a herding dog.

Image: “PMC4759734_12879_2016_1403_Fig2_HTML” by Li YF, Li DB, Shao HS, Li HJ, Han YD. License: CC BY 4.0.

Management

Treatment

  • High mortality rate with delay of or without treatment
  • Antibiotics: aminoglycosides (gentamicin)
  • Alternatives:
    • Doxycycline/tetracycline
    • Streptomycin (ototoxic and nephrotoxic; not widely available) 
    • Levofloxacin, moxifloxacin, ciprofloxacin
    • Chloramphenicol
  • Droplet isolation of the infected patient (until pneumonia has been ruled out or > 48 hours of treatment)
  • Post-exposure prophylaxis:
    • Exposure to plague: close contact with a patient who has pneumonic plague or direct contact with infected tissue/fluids
    • Give doxycycline or levofloxacin. 
    • For pregnant women or children: Give trimethoprim-sulfamethoxazole.

Prevention

  • Vaccine: 
    • Not available in the United States
    • Used in military personnel deployed in endemic areas
  • Use of proper personal protective equipment in high-risk occupations
  • Sanitation measures and rodent control
  • In outdoor activities: use of insect repellent, insecticide, and protective clothing

Differential Diagnosis

  • Anthrax: an infection caused by Bacillus anthracis. Cutaneous anthrax presents with small blisters that become ulcers with a black eschar. In inhalational anthrax, chest pain and dyspnea occur. Bloody diarrhea, abdominal pain, and vomiting are noted in gastrointestinal anthrax. History, PCR, and culture help with the diagnosis. Antimicrobial treatment and antitoxin are given for systemic anthrax.
  • Cat scratch disease: an infection caused by Bartonella henselae, a gram-negative bacillus. Patients usually present with fever, weight loss, and tender lymphadenopathy after being bitten or scratched by a cat. Symptomatic treatment is recommended, with azithromycin given for severe illness.
  • Tularemia: a rare infection caused by Francisella tularensis acquired by contact with animal tissue, from ticks, or from biting flies. Infection manifests as a papule, followed by fever, headache, and suppurative lymphadenopathy. Tularemia may have multi-organ involvement. Diagnosis is by the culture of blood and infected tissue. Treatment is with antibiotics.
  • Pneumonia: an infection of the lung parenchyma most commonly caused by bacteria (most common: Streptococcus pneumoniae) or viruses. Pneumonia is community acquired (CAP) in 80% of the cases. Diagnosis is based on a clinical presentation of fever, cough, dyspnea, rales, and consolidation on chest X-ray. Atypical pneumonia may present with milder symptoms and less remarkable imaging. 

References

  1. Prentice, M.B. (2018). Plague and other yersinia infections. In Jameson J, et al. (Ed.)  Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
  2. Stout, J., Sexton, D., & Bloom, A. (2020). Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection). UpToDate. Retrieved Jan 5, 2021, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-plague-yersinia-pestis-infection
  3. Stout, J., Sexton, D., & Bloom, A. (2020). Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection). UpToDate. Retrieved Jan 6, 2021, from https://www.uptodate.com/contents/epidemiology-microbiology-and-pathogenesis-of-plague-yersinia-pestis-infection

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