Eye on ID

Plague: Blame the flea, not the rat

Plague is caused by Yersinia pestis, a gram-negative coccobacillus. HHS and the Department of Agriculture classify it as a Tier 1 select agent. Y. pestis exists in nature in rodent fleas. Periodically, the number of rodents and their fleas increase, presumably related to environmental factors. As rodents die from plague in increased numbers, the fleas abandon their preferred warm-blooded hosts to find others to feed on, such as humans. This is the most common manner by which humans become infected. Interestingly, in the infected flea, the midgut and the proventriculus (a valve-like area that keeps ingested mammalian blood from escaping) become blocked with aggregating Y. pestis. This causes the flea to bite more aggressively in an attempt to feed and in doing so, the flea delivers regurgitated Y. pestis with the feeding attempts. Therefore, not only does the rodent die, but ironically, the flea also eventually starves to death. Less commonly, infected rodents and other infected animals can infect humans by physical contact with their fluids or tissues through a break in the skin. Humans with pneumonic plague can cause infection by coughing infectious droplets. Because of the centrality of fleas as carriers of the disease, epidemics tend to occur in warm weather as opposed to cold weather. Y. pestis is very sensitive to sunlight and is rapidly killed outside the host.

Larry I. Lutwick
Donald Kaye

Epidemiology

There have been multiple pandemics of plague in the Old World with very high fatality rates. The one best known to most Americans was the “Black Death” of the 1340s. It started in China, where it killed half the population of about 120 million. Plague was brought to Europe from Asia by ships in 1347. Many of the sailors aboard those ships were dead on arrival in Sicily. Further spread is thought to have occurred primarily by ship. By the time the pandemic ended in the early 1350s, it had killed 20 to 50 million people — or 30% to 60% of the population of Europe — according to different accounts. It killed not only people but also cows, sheep and other domesticated animals.

Today, plague occurs in some countries in Central and Far East Asia, Africa and the Americas (the Western United States and several countries in South America). Most cases occur in rural sub-Saharan Africa and on the island of Madagascar. There have been about 2,000 cases reported annually in the world for many years. However, in 2017, an epidemic — unusually large for modern times — occurred in Madagascar. In previous years, there were about 400 cases of plague each year in Madagascar, typically the bubonic type and confined mainly to rural areas. The 2017 epidemic started early in the plague season, which normally runs September through April, and has involved 2,575 cases and 221 deaths as of Dec. 10, 2017. Over three-quarters of the cases have been pneumonic plague, and they occurred in large urban areas as well as rural areas. In relatively recent history, there have been several epidemics where pneumonic plague has been very prominent. Two of these occurred in Manchuria in 1910-1911 and 1920-1921.

In the U.S., there has been an average of seven cases per year (range, 1-17) over the past several decades. The great majority of these cases have been in the rural West (northern New Mexico, northern Arizona, southern Colorado, California, southern Oregon, and far western Nevada). The animal hosts include prairie dogs, squirrels and chipmunks. Cats and dogs have been implicated in the transmission of plague to humans in the U.S. as well. Cats eat infected rodents and then aerosolize respiratory droplets, and dogs can carry infected fleas into the house. In 2015, the first cases of plague ever diagnosed in Michigan and Georgia occurred in travelers who had returned from a festival in Colorado and a visit to Yosemite National Park in California, respectively.

Plague as a bioweapon

Plague is a disease that can cause terror in a population because of how quickly it can kill, along with the obvious signs of buboes and necrosis of distal extremities, nose and ears in some cases (hence, the “Black Death”). Plague was used as a bioweapon by the Mongols, who catapulted bodies of plague victims over the walls of a city, and by the Japanese in World War II who dropped infected fleas over China. Both the former Soviet Union and the U.S. developed Y. pestis to be used as an aerosolized bioweapon. The U.S. terminated the program in 1970 before a large quantity had been accumulated. However, the Soviet Union had acquired large stockpiles of Y. pestis and in fact developed multidrug-resistant (including fluoroquinolone-resistant) strains of the bacteria. WHO estimated that if 59 kg of Y. pestis aerosol were dropped over a city with 5 million inhabitants, plague pneumonia would occur in up to 150,000 people. WHO further estimated that the aerosolized Y. pestis would remain viable for up to 1 hour.

Principal clinical syndromes

There are three main presentations of plague: bubonic, septicemic and pneumonic.

The most common type of plague is bubonic plague, accounting for about 85% of cases. This usually occurs following a bite from an infected flea, but it also can occur when infected tissue or secretions from an infected animal or fomites contaminated with Y. pestis come into contact with a break in a person’s skin. The bacteria are transported to regional lymph nodes, where they multiply and cause the node to become inflamed, necrotic and rapidly enlarged, forming what is called a bubo. The bubo is very tender and is accompanied by high fever. Bacteremia is common and, if untreated, can result in pneumonia and disseminated intravascular coagulation and shock. It is of note that bacteremia from Y. pestis is classically low grade in humans, so it is unusual for fleas to become infected from feeding on people with plague.

Humans most frequently acquire plague after being bitten by a rodent flea that is carrying the bacterium Yersinia pestis or by handling an animal infected with plague, according to the CDC.

Source: Shutterstock

Septicemic plague occurs in 10% to 15% of cases and presents with high fever and no localizing signs or symptoms. Disseminated intravascular coagulation, shock and multiorgan failure follow. It kills rapidly in 2 to 3 days if not treated.

Pneumonic plague occurs most commonly because of bacteremic spread in untreated bubonic plague (secondary pneumonic plague). In less than 5% of cases, Y. pestis is inhaled, causing primary pneumonic plague. If left untreated, pneumonic plague is rapidly lethal. It is much less common than bubonic plague. However, in the 2017 Madagascar epidemic, for unknown reasons, it was the most common form of the disease. Droplets from the cough of a patient with pneumonic plague can be inhaled and infect other people who are in close contact. Death occurs in 2 to 6 days if untreated. The cough in pneumonic plague begins as a dry cough, and when sputum production begins, there is no blood and few plague bacilli. In the few hours before death, the affected individual produces large amounts of bloody sputum with large amounts of organisms. It is during this final period that aerosol transmission is most likely. The bacteria are transmitted by droplets traveling no more than 4 feet from the patient source.

Meningitis can result from localization in patients with bacteremia, and Y. pestis pharyngitis can occur following ingestion or inhalation of the organism. It is associated with cervical adenopathy.

Therapy

Early treatment is very important in reducing mortality associated with plague. Y. pestis is generally susceptible to aminoglycosides, tetracyclines, chloramphenicol, trimethoprim/sulfamethoxazole and fluoroquinolones. For many years, streptomycin was the drug of choice. Currently, gentamicin or doxycycline, alone or in combination, are commonly used. Chloramphenicol is probably the best option for Y. pestis meningitis.

Antibiotic resistance is unusual in nature, but in 1995, an outbreak of plague in Madagascar was caused by a multidrug-resistant strain of Y. pestis mediated by a transferable plasmid. This has not been reported in subsequent outbreaks. Also, unrelated to the natural outbreak in Madagascar, it is worth remembering that the Soviets developed a weaponized strain of Y. pestis that was resistant to multiple antimicrobials.

Prevention

There is no FDA-approved vaccine available in the U.S. There was a U.S.-licensed formaldehyde-killed whole bacilli vaccine until 1999, when it was discontinued. This killed vaccine helped prevent bubonic plague but was ineffective in preventing primary pneumonic plague. Subunit vaccines are being evaluated, but they result in inconsistent protection in different primates and do not generate a cell-mediated response. Recent research suggests that to protect against pneumonic plague, cell- and antibody-mediated immunity are required. Live-attenuated vaccines produce both humoral- and cell-mediated immune responses. There is a live-attenuated vaccine used in China and other countries that has been demonstrated to provide protection against both bubonic and pneumonic plague in humans. However, attenuated strains may cause disease in people who are immunocompromised or have certain diseases. An investigator in the U.S. working with a pigmentation (pgm) locus-attenuated strain of Y. pestis died from septicemic plague. The pgm locus is an area of the Y. pestis chromosome composed of a segment of iron acquisition linked to a pigmentation segment. He was discovered to have hemochromatosis post-mortem. Those with hemochromatosis are especially susceptible to infection with Vibrio vulnificus, Listeria monocytogenes, Y. enterocolitica and Y. pseudotuberculosis. Animal studies have shown that the virulence of pgm locus-attenuated Y. pestis strains can be enhanced by the simultaneous injection of iron into experimental animals.

In the absence of a safe and reliable vaccine, the only option for prevention in those who have been or may be exposed to plague, either naturally or from aerosolization as a biowarfare weapon, is use of antimicrobial agents, which are extremely effective in preventing plague. With exposure of large numbers of people via aerosolization in biowarfare, prevention with an oral agent would be required, and because of the possibility of induced resistance, two agents such as doxycycline plus a fluoroquinolone would make most sense.

It is worth noting that the FDA recently granted orphan drug designation to an investigational plague vaccine that is being developed by DynPort Vaccine Company LLC in Maryland. It is a recombinant subunit vaccine.

Disclosures: Kaye and Lutwick report no relevant financial disclosures.

Plague is caused by Yersinia pestis, a gram-negative coccobacillus. HHS and the Department of Agriculture classify it as a Tier 1 select agent. Y. pestis exists in nature in rodent fleas. Periodically, the number of rodents and their fleas increase, presumably related to environmental factors. As rodents die from plague in increased numbers, the fleas abandon their preferred warm-blooded hosts to find others to feed on, such as humans. This is the most common manner by which humans become infected. Interestingly, in the infected flea, the midgut and the proventriculus (a valve-like area that keeps ingested mammalian blood from escaping) become blocked with aggregating Y. pestis. This causes the flea to bite more aggressively in an attempt to feed and in doing so, the flea delivers regurgitated Y. pestis with the feeding attempts. Therefore, not only does the rodent die, but ironically, the flea also eventually starves to death. Less commonly, infected rodents and other infected animals can infect humans by physical contact with their fluids or tissues through a break in the skin. Humans with pneumonic plague can cause infection by coughing infectious droplets. Because of the centrality of fleas as carriers of the disease, epidemics tend to occur in warm weather as opposed to cold weather. Y. pestis is very sensitive to sunlight and is rapidly killed outside the host.

Larry I. Lutwick
Donald Kaye

Epidemiology

There have been multiple pandemics of plague in the Old World with very high fatality rates. The one best known to most Americans was the “Black Death” of the 1340s. It started in China, where it killed half the population of about 120 million. Plague was brought to Europe from Asia by ships in 1347. Many of the sailors aboard those ships were dead on arrival in Sicily. Further spread is thought to have occurred primarily by ship. By the time the pandemic ended in the early 1350s, it had killed 20 to 50 million people — or 30% to 60% of the population of Europe — according to different accounts. It killed not only people but also cows, sheep and other domesticated animals.

Today, plague occurs in some countries in Central and Far East Asia, Africa and the Americas (the Western United States and several countries in South America). Most cases occur in rural sub-Saharan Africa and on the island of Madagascar. There have been about 2,000 cases reported annually in the world for many years. However, in 2017, an epidemic — unusually large for modern times — occurred in Madagascar. In previous years, there were about 400 cases of plague each year in Madagascar, typically the bubonic type and confined mainly to rural areas. The 2017 epidemic started early in the plague season, which normally runs September through April, and has involved 2,575 cases and 221 deaths as of Dec. 10, 2017. Over three-quarters of the cases have been pneumonic plague, and they occurred in large urban areas as well as rural areas. In relatively recent history, there have been several epidemics where pneumonic plague has been very prominent. Two of these occurred in Manchuria in 1910-1911 and 1920-1921.

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In the U.S., there has been an average of seven cases per year (range, 1-17) over the past several decades. The great majority of these cases have been in the rural West (northern New Mexico, northern Arizona, southern Colorado, California, southern Oregon, and far western Nevada). The animal hosts include prairie dogs, squirrels and chipmunks. Cats and dogs have been implicated in the transmission of plague to humans in the U.S. as well. Cats eat infected rodents and then aerosolize respiratory droplets, and dogs can carry infected fleas into the house. In 2015, the first cases of plague ever diagnosed in Michigan and Georgia occurred in travelers who had returned from a festival in Colorado and a visit to Yosemite National Park in California, respectively.

Plague as a bioweapon

Plague is a disease that can cause terror in a population because of how quickly it can kill, along with the obvious signs of buboes and necrosis of distal extremities, nose and ears in some cases (hence, the “Black Death”). Plague was used as a bioweapon by the Mongols, who catapulted bodies of plague victims over the walls of a city, and by the Japanese in World War II who dropped infected fleas over China. Both the former Soviet Union and the U.S. developed Y. pestis to be used as an aerosolized bioweapon. The U.S. terminated the program in 1970 before a large quantity had been accumulated. However, the Soviet Union had acquired large stockpiles of Y. pestis and in fact developed multidrug-resistant (including fluoroquinolone-resistant) strains of the bacteria. WHO estimated that if 59 kg of Y. pestis aerosol were dropped over a city with 5 million inhabitants, plague pneumonia would occur in up to 150,000 people. WHO further estimated that the aerosolized Y. pestis would remain viable for up to 1 hour.

Principal clinical syndromes

There are three main presentations of plague: bubonic, septicemic and pneumonic.

The most common type of plague is bubonic plague, accounting for about 85% of cases. This usually occurs following a bite from an infected flea, but it also can occur when infected tissue or secretions from an infected animal or fomites contaminated with Y. pestis come into contact with a break in a person’s skin. The bacteria are transported to regional lymph nodes, where they multiply and cause the node to become inflamed, necrotic and rapidly enlarged, forming what is called a bubo. The bubo is very tender and is accompanied by high fever. Bacteremia is common and, if untreated, can result in pneumonia and disseminated intravascular coagulation and shock. It is of note that bacteremia from Y. pestis is classically low grade in humans, so it is unusual for fleas to become infected from feeding on people with plague.

PAGE BREAK
Humans most frequently acquire plague after being bitten by a rodent flea that is carrying the bacterium Yersinia pestis or by handling an animal infected with plague, according to the CDC.

Source: Shutterstock

Septicemic plague occurs in 10% to 15% of cases and presents with high fever and no localizing signs or symptoms. Disseminated intravascular coagulation, shock and multiorgan failure follow. It kills rapidly in 2 to 3 days if not treated.

Pneumonic plague occurs most commonly because of bacteremic spread in untreated bubonic plague (secondary pneumonic plague). In less than 5% of cases, Y. pestis is inhaled, causing primary pneumonic plague. If left untreated, pneumonic plague is rapidly lethal. It is much less common than bubonic plague. However, in the 2017 Madagascar epidemic, for unknown reasons, it was the most common form of the disease. Droplets from the cough of a patient with pneumonic plague can be inhaled and infect other people who are in close contact. Death occurs in 2 to 6 days if untreated. The cough in pneumonic plague begins as a dry cough, and when sputum production begins, there is no blood and few plague bacilli. In the few hours before death, the affected individual produces large amounts of bloody sputum with large amounts of organisms. It is during this final period that aerosol transmission is most likely. The bacteria are transmitted by droplets traveling no more than 4 feet from the patient source.

Meningitis can result from localization in patients with bacteremia, and Y. pestis pharyngitis can occur following ingestion or inhalation of the organism. It is associated with cervical adenopathy.

Therapy

Early treatment is very important in reducing mortality associated with plague. Y. pestis is generally susceptible to aminoglycosides, tetracyclines, chloramphenicol, trimethoprim/sulfamethoxazole and fluoroquinolones. For many years, streptomycin was the drug of choice. Currently, gentamicin or doxycycline, alone or in combination, are commonly used. Chloramphenicol is probably the best option for Y. pestis meningitis.

Antibiotic resistance is unusual in nature, but in 1995, an outbreak of plague in Madagascar was caused by a multidrug-resistant strain of Y. pestis mediated by a transferable plasmid. This has not been reported in subsequent outbreaks. Also, unrelated to the natural outbreak in Madagascar, it is worth remembering that the Soviets developed a weaponized strain of Y. pestis that was resistant to multiple antimicrobials.

Prevention

There is no FDA-approved vaccine available in the U.S. There was a U.S.-licensed formaldehyde-killed whole bacilli vaccine until 1999, when it was discontinued. This killed vaccine helped prevent bubonic plague but was ineffective in preventing primary pneumonic plague. Subunit vaccines are being evaluated, but they result in inconsistent protection in different primates and do not generate a cell-mediated response. Recent research suggests that to protect against pneumonic plague, cell- and antibody-mediated immunity are required. Live-attenuated vaccines produce both humoral- and cell-mediated immune responses. There is a live-attenuated vaccine used in China and other countries that has been demonstrated to provide protection against both bubonic and pneumonic plague in humans. However, attenuated strains may cause disease in people who are immunocompromised or have certain diseases. An investigator in the U.S. working with a pigmentation (pgm) locus-attenuated strain of Y. pestis died from septicemic plague. The pgm locus is an area of the Y. pestis chromosome composed of a segment of iron acquisition linked to a pigmentation segment. He was discovered to have hemochromatosis post-mortem. Those with hemochromatosis are especially susceptible to infection with Vibrio vulnificus, Listeria monocytogenes, Y. enterocolitica and Y. pseudotuberculosis. Animal studies have shown that the virulence of pgm locus-attenuated Y. pestis strains can be enhanced by the simultaneous injection of iron into experimental animals.

In the absence of a safe and reliable vaccine, the only option for prevention in those who have been or may be exposed to plague, either naturally or from aerosolization as a biowarfare weapon, is use of antimicrobial agents, which are extremely effective in preventing plague. With exposure of large numbers of people via aerosolization in biowarfare, prevention with an oral agent would be required, and because of the possibility of induced resistance, two agents such as doxycycline plus a fluoroquinolone would make most sense.

It is worth noting that the FDA recently granted orphan drug designation to an investigational plague vaccine that is being developed by DynPort Vaccine Company LLC in Maryland. It is a recombinant subunit vaccine.

Disclosures: Kaye and Lutwick report no relevant financial disclosures.

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