Plague

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Background

Plague is an acute, contagious, febrile illness transmitted to humans by the bite of an infected rat flea. Human-to-human transmission is rare except during epidemics of pneumonic plague. The disease is caused by the plague bacillus, rod-shaped bacteria referred to as Yersinia pestis. Yersinia is named in honor of Alexander Yersin, who successfully isolated the bacteria in 1894 during the pandemic that began in China in the 1860s.

Plague is worldwide in distribution, with most of the human cases reported from developing countries.

Three studies have shown that this bacterium emerged from the gut pathogen Yersinia pseudotuberculosis shortly after the first epidemic.[1] Three biovars (with minor genetic variations) have been identified within the Y pestis clone—Antiqua, Medievalis, and Orientalis.[1] One theory is that these biovars emerged before any of the plague epidemics. In fact, as reported by Drancourt et al (2004), genotyping performed on bacteria derived from the remains of plague victims of the first two epidemics revealed sequences similar to that of Orientalis.[2]

The virulence of this bacterium results from the 32 Y pestis chromosomal genes and two Y pestis –specific plasmids, constituting the only new genetic material acquired since its evolution from its predecessor.[3] These acquired genetic changes have allowed the pathogen to colonize fleas and to use them as vectors for transmission.[4]

Plague is a zoonotic disease that primarily affects rodents; humans are incidental hosts. Survival of the bacillus in nature depends on flea-rodent interaction, and human infection does not contribute to the bacteria's persistence in nature. Of the 1500 flea species identified, only 30 of them have been shown to act as vectors of plague.[5] The most prominent of these vectors is Xenopsylla cheopis (oriental rat flea); however, Oropsylla montana has been incriminated as the primary vector for this disease in North America.[6]


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Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Preventio....

Host fatality has been known to be the harbinger of an epidemic.[5] Whether susceptibility and fatality are related is unknown. However, ground squirrels and prairie dogs have been known to be highly susceptible to plague, whereas others have been known to be either moderately susceptible or absolutely resistant to infection.


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The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of ....


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Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Preve....

Plague was first described in the Old Testament and has persisted into the modern era. Plague has caused large-scale epidemics, thereby changing the course of history in many nations. The first pandemic was believed to have started in Africa and killed 100 million people over a span of 60 years. In the Middle Ages, plague killed approximately one fourth of Europe's population. The pandemic that began in China in the 1860s spread to Hong Kong in the 1890s and was subsequently spread by rats transported on ships to Africa, Asia, California, and port cities of South America. In the early twentieth century, plague epidemics accounted for about 10 million deaths in India. As reported in National Geographic, mass graves of plague victims were recently discovered in an area of Venice called "Quarantine Island."

Pathophysiology

Y pestis is a nonmotile, pleomorphic, gram-negative coccobacillus that is nonsporulating. The bacteria elaborate a lipopolysaccharide endotoxin, coagulase, and a fibrinolysin, which are the principal factors in the pathogenesis of plague. The pathophysiology of plague basically involves two phases—a cycle within the fleas and a cycle within humans.

The key to the organism’s virulence is the phenomenon of "blockage," which aids the transmission of bacteria by fleas. After ingestion of infected blood, the bacteria survive in the midgut of the flea owing to a plasmid-encoded phospholipase D that protects them from digestive juices.[7] The bacteria multiply uninhibited in the midgut to form a mass that extends from the stomach proximally into the esophagus through a sphincterlike structure with sharp teeth called the proventriculus.


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Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ....

It has been shown that this property requires the presence of hemin-producing genes, which are needed for the formation of a biofilm that permits colonization of the proventriculus.[8] In fact, as described by Jarrett et al (2004), this mutation in hemin genes allows colonization in the midgut without extension to the proventriculus. Consequently, the "blockage phenomenon" does not occur, thereby leading to failure of transmission.[8] This blockage causes the flea to die of starvation and dehydration.[9]

As a desperate measure, the flea then repeatedly tries to obtain a meal by biting a host, managing only to regurgitate the infected mass into host's bloodstream. However, the concept that the flea must be engorged before becoming infectious loses support when trying to explain the rapid rate of spread of disease during a plague epidemic. Studies of vectors such as O montana clearly indicate the redundancy of the aforementioned hypothesis, since this vector does not die of blockage and remains infectious for a long period, unlike its counterpart.[10]

Once the flea bites a susceptible host, the bacilli migrate to the regional lymph nodes, are phagocytosed by polymorphonuclear and mononuclear phagocytes, and multiply intracellularly. Survival and replication within macrophages is probably of greatest importance in early stages of the disease.[11] Involved lymph nodes show dense concentrations of plague bacilli, destruction of the normal architecture, and medullary necrosis. With subsequent lysis of the phagocytes, bacteremia can occur and may lead to invasion of distant organs in the absence of specific therapy.

The following are the modes of plague transmission in humans:[12]

  1. Bites by fleas
  2. Exposure to humans with pneumonic plague
  3. Handling of infected carcasses
  4. Scratches or bites from infected domestic cats
  5. Exposure to aerosols containing plague-causing bacilli

Epidemiology

Frequency

United States

A few natural plague foci are located in the western United States. From the states of Arizona, California, Colorado, New Mexico, and Utah, 49 cases of plague and 3 attributed deaths were reported from 1994-1999.[13] In 2006, 13 plague cases were reported among residents of New Mexico, Colorado, California, and Texas, two of which resulted in death.[14]

On average, 10-15 cases of human plague are reported annually in the United States. The rate of plague in the United States is low, since most of the endemic areas are rural and largely uninhabited, thereby limiting human exposure. In recent years, and with the potential threat for bioterrorism, the Centers for Disease Control and Prevention (CDC) has specified Y pestis as a Category A bioterrorism agent.

Animal reservoirs in America mostly include squirrels, rabbits, and prairie dogs. However, there has been an established role of domestic cats in the transmission of plague since the late 1970s. Since 1977-1998, 23 cases of human plague associated with cats have been reported from the western states, representing 8% of all reported plague cases during that time.[6] In this scenario, transmission via inhalation was more common than in any other form of plague.

In a study of cat-related plague, mortality was associated with misdiagnosis or delay in treatment. Of the 23 cases from 1977-1998, 5 of 17 bubonic plague cases resulted in death.[6]

International

Most cases of plague reported outside of the United States are from developing countries in Africa and Asia. During 1990-1995, a total of 12,998 cases of plague were reported to the World Health Organization (WHO), particularly from countries such as India, Zaire, Peru, Malawi, and Mozambique. The following countries reported more than 100 cases of plague: China, Congo, India, Madagascar, Mozambique, Myanmar, Peru, Tanzania, Uganda, Vietnam, and Zimbabwe. Several foci are located in the semi-arid regions of northeastern Brazil, and outbreaks have also been reported from Malawi and Zambia. Australia is the only continent that is considered free of plague. The largest enzootic plague area is in North America—the southwestern United States and the Pacific coastal area.

The WHO reports that, in 2003, 9 countries reported a total of 2118 plague cases and 182 deaths, 98.7% and 98.9% of which were reported from Africa, respectively.


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1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Mortality/Morbidity

The risk of plague-related death depends on the type of plague and whether the infected individual receives appropriate treatment.[4]

The following are the mortality rates associated with the different types of plague:

Race

In the United States, most cases of plague occur in whites. Native Americans living in endemic areas of Arizona, New Mexico, and Utah have a 10-fold greater risk of acquiring the disease than non–Native Americans.

Humans are exposed in the domestic or outdoor environment. Infections in the wild are usually isolated or sporadic, causing infections in Indians, hunters, miners, and tourists in the United States and Brazil.

Sex

Plague has no sexual predilection.

Age

Most cases of plague occur in persons younger than 20 years.

History

Travel to endemic areas within and outside the United States, history of a flea bite, close contact with a potential host, or exposure to dead rodents or rabbits should raise suspicion for plague.

Physical

Causes

Y pestis is the cause of plague.

Laboratory Studies

The possibility of plague should be strongly considered in febrile patients from endemic areas who have history of exposure to rodents. Rapid recognition of the classic symptoms of this disease and laboratory confirmation are essential to instituting lifesaving therapy.

Expertise in testing for plague bacilli is limited to reference laboratories in plague-endemic states and the CDC.

Leukocytosis with a predominance of neutrophils is observed, and the degree of leukocytosis is proportional to the severity of illness.

Peripheral blood smear shows toxic granulations and Dohle bodies.

Thrombocytopenia is common, and levels of fibrin degradation products may be elevated.

Serum transaminase and bilirubin levels may be elevated.

Proteinuria may be present, and renal function test findings may be abnormal.

Hypoglycemia may be observed.

Twenty-seven percent to 96% of blood cultures are positive for Y pestis in patients with bubonic plague and septicemic plague.[18] Microbiology staff should be informed of the possibility of Y pestis agents in samples so that they can take adequate precautions when handling specimens.

Y pestis may be observed on a peripheral blood smear. Smear stained with Wright-Giemsa reveals rod-shaped bacteria. A Wayson stain demonstrates the typical "safety pin" appearance (bipolar staining) of the bacterium. Gram stain shows small gram-negative coccobacilli.


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Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control....

Lymph node aspirates often demonstrate Y pestis. In patients with pharyngeal plague, Y pestis is cultured from throat swabs.

Cerebrospinal fluid (CSF) analysis in meningeal plague may show pleocytosis with a predominance of polymorphonuclear leukocytes.[20] Gram stain of CSF may show plague bacilli. Limulus test of CSF demonstrates the presence of endotoxin.

Gram stain of sputum often reveals Y pestis.

Updated (2014) guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[21]

Imaging Studies

Other Tests

Procedures

Medical Care

Updated (2014) guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[21]

Precautions

All patients with suspected plague and signs of pneumonia should be placed in strict respiratory isolation for 48-72 hours after antibiotic therapy is initiated and kept there until pneumonia has been ruled out or until sputum culture have shown negative findings.

Report patients thought to have plague to the local health department and to the WHO.

Alert laboratory personnel to the possibility of the diagnosis of plague. All fluid specimens must be handled with gloves and mask to prevent aerosolization of the infected fluids.

Supportive therapy

Hemodynamic monitoring and ventilatory support are performed as appropriate.

Intravenous fluids, epinephrine, and dopamine are implemented as necessary for correction of dehydration and hypotension.

Postexposure prophylaxis

Presumptive therapy consists of a 7-day course of oral doxycycline and ciprofloxacin. Chloramphenicol may be used as an alternative. Levofloxacin may be prescribed as a 10-14 day regimen for either treatment or postexposure prophylaxis.

In a community experiencing a pneumonic plague epidemic, individuals with a temperature of 38.5°C or higher or newly onset cough should promptly receive parenteral antimicrobial therapy.[24]

Surgical Care

Consultations

Medication Summary

Streptomycin

Clinical Context:  Aminoglycoside antibiotic recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Gentamicin (Garamycin)

Clinical Context:  Aminoglycoside antibiotic for gram-negative coverage.

Doxycycline (Bio-Tab, Doryx, Doxy, Vibramycin, Vibra-Tabs

Clinical Context:  Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Chloramphenicol (Chloromycetin)

Clinical Context:  Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin has been approved to treat and reduce the risk of getting plague after exposure to Yersinia pestis, the bacterium that causes the disease.

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.

Transfer

Deterrence/Prevention

Complications

Prognosis

Author

Siddharth Wayangankar, MD, MPH, Resident Physician, Department of Internal Medicine, Oklahoma University Health Sciences Center

Disclosure: Nothing to disclose.

Coauthor(s)

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Disclosure: Nothing to disclose.

Rhett L Jackson, MD, Associate Professor and Vice Chair for Education, Department of Medicine, Director, Internal Medicine Residency Program, University of Oklahoma College of Medicine; Assistant Chief, Medicine Service, Oklahoma City Veterans Affairs Hospital

Disclosure: Nothing to disclose.

Venkat R Minnaganti, MD, Consulting Staff, Department of Medicine, Winthrop University Hospital; Clinical Instructor, Department of Internal Medicine, Division of Infectious Disease, State University of New York School of Medicine at Stony Brook

Disclosure: Nothing to disclose.

Specialty Editors

Thomas J Marrie, MD, Dean of Faculty of Medicine, Dalhousie University Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Disclosure: Nothing to disclose.

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Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.

Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ravenous hunger because of its inability to digest the fibrinoid mass of blood and bacteria. If this flea were to bite a mammal, the proventriculus would be cleared, and thousands of bacteria would be regurgitated into the bite wound. Courtesy of the United States Army Environmental Hygiene Agency.

1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Swollen lymph glands, termed buboes, are a hallmark finding in bubonic plague. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Acral necrosis of the nose, the lips, and the fingers and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC, US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Acral necrosis of the toes and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Ulcerated flea bite caused by Yersinia pestis bacteria. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Swollen lymph glands, termed buboes, are a hallmark finding in bubonic plague. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Fluorescence antibody positivity is observed as bright, intense green staining around the cell wall of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of lung in fatal human plague–fibrinopurulent pneumonia. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of lung showing pneumonia with many Yersinia pestis organisms (the plague bacillus) on a Giemsa stain. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of spleen in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of lymph node showing medullary necrosis and Yersinia pestis, the plague bacillus. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of liver in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Focal hemorrhages in islet of Langerhans in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Bioterrorist Agents. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/bioterrorism.html.

Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ravenous hunger because of its inability to digest the fibrinoid mass of blood and bacteria. If this flea were to bite a mammal, the proventriculus would be cleared, and thousands of bacteria would be regurgitated into the bite wound. Courtesy of the United States Army Environmental Hygiene Agency.

After the femoral lymph nodes, the next most commonly involved regions in plague are the inguinal, axillary, and cervical areas. This child has an erythematous, eroded, crusting, necrotic ulcer at the presumed primary inoculation site in the left upper quadrant. This type of lesion is uncommon in patients with plague. The location of the bubo is primarily a function of the region of the body in which an infected flea inoculates plague bacilli. Courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.

Ecchymoses at the base of the neck in a girl with plague. The bandage is over the site of a prior bubo aspirate. These lesions are probably the source of the line from the children's nursery rhyme, "ring around the rosy." Courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.

Acral necrosis of the nose, the lips, and the fingers and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC, US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Acral necrosis of the toes and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.