Plague


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 pestisYersinia 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. [1Three biovars (with minor genetic variations) have been identified within the Y pestis clone—Antiqua, Medievalis, and Orientalis. [1One 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. [3These 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. Dog-to-human transmission was reported in a 2014 outbreak in Colorado. [5Survival 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. [6The 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. [7]

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

Host fatality has been known to be the harbinger of an epidemic. [6Whether 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.

The prairie dog is a burrowing rodent of the genusThe 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 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.

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

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. [8The 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.

Pictured is a flea with a blocked proventriculus, 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.

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. [9In 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. [9This blockage causes the flea to die of starvation and dehydration. [10]

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. [11]

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. [12Involved 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: [13]

  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

Another potential cause of plague transmission in humans is contact with an infected dog. In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924. [5]

Epidemiology

Frequency

United States

Between 2010 and 2015, 39 cases of human plague were reported in the United States, resulting in 5 deaths. [14About half of human plague cases involve individuals aged 12-45 years, although it can affect people of all ages. The risk is slightly higher in men, probably owing to a higher likelihood of outdoor activities among males, increasing their risk of exposure to vectors. [14]

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. [15In 2006, 13 plague cases were reported among residents of New Mexico, Colorado, California, and Texas, two of which resulted in death. [16]

On average, 7 cases of human plague are reported annually in the United States, with a range of 1-17 cases per year. [14Over time, human cases of plague have moved from crowded cities to the rural West. This has paralleled the observed patterns of introduction of exotic plants and animals. [17The 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. From 1977-1998, 23 cases of human plague associated with cats were reported from the western states, representing 8% of all reported plague cases during that time. [7In 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. [7]

In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924. [5]

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.

1998 world distribution of plague. Image courtesy 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:

  • Pneumonic plague

    • Untreated - 100%

    • Treated - 50%

  • Bubonic plague

    • Untreated - 50%-90%

    • Treated - 10%-20%

  • Septicemic plague - 20%-25%

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.

CLINICAL PRESENTATION


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.

Bubonic plague

This is the most common presentation of plague.

The incubation period varies but usually ranges 2-6 days.

There is a sudden onset of high fever, chills, and headache.

Patients with this type experience body aches, extreme exhaustion, weakness, abdominal pain, and/or diarrhea.

Painful, swollen lymph glands (buboes) arise, usually in the groin (most common site), axilla, or neck.

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

Axillary, cervical, and epitrochlear buboes are almost always seen in cat-associated plague. [18]

Without intervention, this stage may lead to secondary pneumonic plague or meningitis or may disseminate and manifest as a sepsis picture.

Meningeal plague

This is characterized by fever, headache, and nuchal rigidity.

Buboes are common in meningeal plague.

Axillary buboes are associated with an increased incidence of meningeal plague.

Pharyngeal plague

Pharyngeal plague results from ingestion of the plague bacilli.

Patients experience sore throat, fever, and painful cervical lymph nodes. [19]

Marshall et al (1967) has described an asymptomatic pharyngeal carrier state of Y pestis infection in patients with bubonic plague. [20]

Pneumonic plague

Pneumonic plague is highly contagious and transmitted by aerosol droplets.

This is often secondary to bubonic or septicemic plague. However, primary pneumonic plague may be seen in laboratory workers, individuals exposed to an infected person, or those who have been exposed to a cat with pneumonic plague. [21]

There is an abrupt onset of fever and chills, accompanied by cough, chest pain, dyspnea, purulent sputum, or hemoptysis.

Buboes may or may not be associated with pneumonic plague.

The ability for plague to be spread by aerosols makes Y pestis a potential agent of bioterrorism.

Septicemic plague

Septicemic plague is observed in elderly patients and causes a rapid onset of symptoms.

Patients experience nausea, vomiting, abdominal pain, and diarrhea. (Diarrhea may be the predominant symptom.)

Patients exhibit a toxic appearance and soon become moribund.

Buboes are uncommon in septicemic plague, making the diagnosis elusive.

Septicemic plague carries a high mortality rate and is associated with disseminated intravascular coagulation (DIC), multiorgan failure, and profound hypotension.

Plague initially occurred as a flea-borne septicemic disease. However, over its evolutionary course, it acquired the plasminogen activator gene, giving rise to the bubonic form of disease. [22]

Genitourinary/gastrointestinal plague

This was reported as the sole presentation of Y pestis infection in 4 of 27 patients in a case series published in 1992. [13]

Cutaneous plague

This manifests as purpura. [19]

Physical

Bubonic plague

Vesicles may be observed at the site of the infected flea bite. With advanced disease, papules, pustules, carbuncles, or an eschar may be observed in areas of the skin drained by the involved lymph nodes. A generalized papular rash of the hands and feet may be observed.

Buboes are unilateral, oval, extremely tender lymph nodes and can vary from 2-10 cm in size. Femoral lymph nodes are most commonly involved. Patients with an inguinal bubo walk with a limp, and the affected limb may be in a position of flexion, abduction, and external rotation. Patients resist any attempt to examine the involved lymph nodes. Enlargement of the buboes leads to rupture and discharge of malodorous pus.

Hepatomegaly and splenomegaly often occur and may be tender.

Pharyngeal plague

Pharyngeal plague causes pharyngeal erythema and painful and tender anterior cervical nodes.

Pneumonic plague

Pneumonic plague causes fever, lymphadenopathy, productive sputum, and/or hemoptysis.

Septicemic plague

Because of an overwhelming infection with the plague bacillus, patients with septicemic plague have a toxic appearance and may present with tachycardia, tachypnea, and hypotension. Hypothermia is common.

Generalized purpura may be observed and can progress to necrosis and gangrene of the distal extremities.

Acral necrosis of the nose, the lips, and the fingAcral 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 ecchymosesAcral 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.

No evidence of lymphadenitis or bubo formation is apparent. Patients may die of a high-grade bacteremia.

Causes

Y pestis is the cause of plague.

Risk factors include the following:

  • Flea bite

  • Contact with a patient or a potential host

  • Contact with sick animals or rodents

  • Residence in an endemic area of plague (eg, southwestern United States)

  • Presence of a food source for rodents in the immediate vicinity of the home

  • Camping, hiking, hunting, or fishing

  • Occupational exposure (eg, researchers, veterinarians)

  • Direct handling or inhalation of contaminated tissue or tissue fluids

  • Contact with a dog infected with Y pestis [5]

DDx

Diagnostic Considerations

In 2014, an automated system in a Colorado hospital laboratory mistakenly identified a serum isolate as Pseudomonas luteola. Upon further examination, the organism was correctly identified as Y pestis. [5]

Differential Diagnoses

TREATMENT & MANAGEMENT

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). [24]

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 care to prevent aerosolization of the infected fluids. Gowns, gloves, and masks should be worn at all times, and strict infection control is of utmost importance.

Supportive therapy

Hemodynamic monitoring and ventilatory support are performed as appropriate.

Management of sepsis associated with plague requires aggressive intravenous hydration. Norepinephrine and other vasopressors may be required to manage hypotension and to improve hemodynamic status.

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. [27]

Surgical Care

Enlarging or fluctuant buboes require incision and drainage.

Consultations

The following specialists may be consulted:

  • Infectious disease specialist

  • Pulmonary and critical care specialist

  • General surgeon

  • Neurologist

MEDICATION

Medication Summary

Untreated plague can progress to a fulminant illness with a high risk of mortality. Thus, early and appropriate antibiotic treatment is essential.

Historically, streptomycin (15 mg/kg, up to 1 g intramuscularly every 12 h) has been the drug of choice. [27However, in the United States, supplies of streptomycin are scarce.

An in vitro comparison [28and a murine model trial [29demonstrated that gentamicin (5 mg/kg intravenously or intramuscularly once daily) is comparable to or superior than streptomycin. Gentamicin has been used successfully in the treatment of human plague, [13is inexpensive, and can be dosed once daily.

Doxycycline (as dosed for anthrax) is a recommended alternative in patients who cannot take aminoglycosides or in the event of a mass casualty scenario, making parenteral therapy unachievable. [27]

Because chloramphenicol attains high CSF concentrations, [27it has been used to treat meningeal plague, although no studies have been conducted for substantiation. [30]

Studies in murine models have shown that fluoroquinolones demonstrate efficacy similar to that of the aminoglycosides. [29Fluoroquinolones are a reasonable alternative therapy. However, no clinical trials of fluoroquinolone therapy in human plague have been conducted. [30]

The FDA has approved levofloxacin and moxifloxacin for the treatment of plague. These have also been approved for use as prophylaxis following exposure to Yersinia pestis.

Trimethoprim-sulfamethoxazole has been used to treat bubonic plague; however, it is not considered first-line therapy.

Beta-lactam antibiotics and macrolides should not be used.

Patients with advanced plague have a presentation of typical gram-negative sepsis and need antibiotic treatment for 10-14 days, along with other supportive measures. [30]

Antibiotics

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.

Levofloxacin (Levaquin)

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerases type II), enzymes required for DNA replication, transcription, repair, and recombination. It is indicated for treatment and prophylaxis of plague, including pneumonic and septicemic plague, caused by Yersinia pestis in adults and pediatric patients, aged 6 months or older.

Moxifloxacin (Avelox)

Moxifloxacin is a fluoroquinolone antibiotic that inhibits A subunits of DNA gyrase (topoisomerase type II) and topoisomerase IV, resulting in inhibition of bacterial DNA replication and transcription. It is indicated in adults for treatment and prophylaxis of pneumonic or septicemic plague caused by Yersinia pestis.

Streptomycin

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

Gentamicin (Garamycin)

Aminoglycoside antibiotic for gram-negative coverage.

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

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

Chloramphenicol (Chloromycetin)

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