Plague (disease)

• 1. Introduction

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  Plague, the disease caused by the bacterium Yersinia pestis, killed more than 50 million people in Europe during the Black Death of the 14th century. Today the world records only about 600 cases a year. That gap raises questions. Where did the bacterium come from? Why is the rat, the animal everyone blames, not the true carrier? What does the infection do inside a human body, and why does one form of it travel through the air? And how did armies come to treat it as a weapon?

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• 2. Graves in Kyrgyzstan

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  Three graves in Kyrgyzstan, dated to 1338 and 1339, hold the oldest trace researchers have found of the bacterium's modern family. In 2022, DNA from human remains in those graves was identified as the possible origin of all modern strains of Yersinia pestis. That strain turned out to be the most recent common ancestor of the strains found in historic graves and the strains that exist today.

  Marmots in modern-day Kyrgyzstan carry bacteria that are closer to the grave strain than those of any other infected rodents sampled worldwide. That closeness suggests the region is where plague first crossed from animals to people.

  The first recorded outbreak of the Black Death came soon afterward, during the siege of Caffa in Crimea in 1346. People trying to escape the disease carried it into Europe by boat.

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• 3. The Starving Flea

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  The flea Xenopsylla cheopis, and not the rat, is the real engine of bubonic plague. Rats that host these fleas are the first victims, which makes them casualties rather than the cause. A person falls ill after being bitten by a flea that picked up the bacteria from an infected rodent. That rodent, in turn, caught the disease from a flea bite.

  A plug of clumped bacteria blocks the stomach of an infected flea, and the insect begins to starve. It keeps biting in a hunger it can never satisfy. Each time, it vomits bacteria-tainted blood back into the wound. The bacterium passes to a new host, and the flea eventually dies of starvation. Serious outbreaks usually start when some other disease sweeps through rodents, or when their numbers rise.

  The animal reservoirs of the bacterium, mostly rodents, sit in natural foci on every continent except Australia. Those foci form a broad belt through tropical, subtropical and warmer temperate latitudes, between 55 degrees north and 40 degrees south.

  In recent years, cases have split between small seasonal outbreaks, mainly in Madagascar, and isolated cases in endemic areas. In 2017, the countries with the most cases included the Democratic Republic of the Congo, Madagascar and Peru. In the United States, infections still turn up occasionally in rural areas, where the bacteria are believed to circulate among rodents.

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• 4. Three Forms

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  Black lips are among the signs of plague, alongside fever, weakness and headache. Symptoms usually begin one to seven days after exposure. The disease takes three main forms. Bubonic plague is the most common, followed by septicemic and then pneumonic. Rarer manifestations include plague meningitis, plague pharyngitis and ocular plague.

  In bubonic plague, the bacteria survive even when the body's cells swallow them, because Y. pestis can reproduce inside cells. They then travel along the lymphatic vessels until they reach a lymph node and cause acute lymphadenitis. The swollen nodes are the buboes that give the form its name. Autopsies have found them mostly hemorrhagic or necrotic. The bacteria also secrete several toxins, and one is known to cause beta-adrenergic blockade.

  When a lymph node is overwhelmed, the infection can spill into the bloodstream and become secondary septicemic plague. If the lungs are seeded, secondary pneumonic plague can follow.

  In septicemic plague, endotoxins trigger disseminated intravascular coagulation, or DIC. Tiny clots form throughout the body, and tissue can die for lack of blood, a process called ischemic necrosis. The body then runs out of clotting resources and can no longer control bleeding. Blood seeps into the skin and organs, producing a red or black patchy rash and bloody coughing and vomiting. Skin bumps resemble insect bites, red and sometimes white in the centre. Untreated, this form is usually fatal. Early antibiotics bring mortality down to between 4 and 15 per cent.

  Pneumonic plague has an incubation period of usually two to four days, and sometimes only a few hours. Its first signs, such as headache, weakness and spitting or vomiting blood, look like many other respiratory illnesses. Death can follow in one to six days unless treatment comes within hours. Untreated mortality is nearly 100 percent. Coughing from the infected lungs sends out droplets of bacteria, which infect anyone who breathes them in.

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• 5. The Village That Sealed Itself

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  In 1665, the village of Eyam in England's Derbyshire Dales cut itself off from the outside world during a plague outbreak. Because the village was isolated, researchers in the 21st century could study that outbreak closely. They concluded that about three-quarters of the cases were likely due to transmission between people, especially within families. That is a much larger share than had been thought.

  The list of ways Y. pestis can reach an uninfected person has six entries. Droplets spread when an infected person coughs or sneezes on someone. Direct physical contact counts, including sexual contact. Indirect contact usually means touching contaminated soil or a contaminated surface. Airborne spread is possible if the microorganism can stay in the air for long periods. Fecal-oral spread usually comes from contaminated food or water. The sixth route is carriage by insects or other animals.

  So many routes, and symptoms so often vague, mean that doctors cannot simply look at a patient and be sure.

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• 6. Proving the Diagnosis

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  Laboratory testing is the only definitive way to confirm plague, because its symptoms are usually non-specific. Y. pestis can be identified under a microscope and by culturing a sample, and culture serves as the reference standard. Samples can come from blood, sputum or fluid drawn from a bubo. A false negative is possible if antibiotics are given before the sample is taken, or if the sample is stored badly or reaches the laboratory late.

  Polymerase chain reaction, or PCR, looks for bacterial genes such as pla and caf1. It needs only a very small sample and detects both living and dead bacteria. A patient given antibiotics too early may therefore have a negative culture and a positive PCR result.

  Blood tests can detect antibodies against Y. pestis. They need samples taken at different times, to compare F1 antibody levels in the acute and convalescent phases.

  A 2020 study examined rapid tests for the F1 capsule antigen, using sputum or bubo fluid. These tests work for people with suspected pneumonic or bubonic plague, but not for people without symptoms. They are highly sensitive, which promises quick treatment and a fast public health response. Both positive and negative results still need confirmation.

  The study's numbers explain why. In a population of 1000, the test correctly identified all 40 people who had plague. It also wrongly flagged 317 people as positive.

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• 7. Vaccines and Antibiotics

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  In 1897, the bacteriologist Waldemar Haffkine developed the first plague vaccine. He ran a massive inoculation program in British India. An estimated 26 million doses were sent out from Bombay between 1897 and 1925, and plague mortality fell by 50-85 percent.

  As of 2023, human plague is rare in most places, so routine vaccination is not needed. The United States CDC recommends it only for three groups. They are laboratory and field staff working with antimicrobial-resistant Y. pestis, people running aerosol experiments with the bacterium, and people doing field work in areas with enzootic plague where exposure cannot be prevented. A Cochrane Collaboration review found no studies of high enough quality to judge how well the vaccine works.

  Preventive medication is a separate question. First responders and health care workers caring for pneumonic patients do not need it beforehand, provided standard and droplet precautions hold. Medication after exposure should be considered for people who spent sustained time within 6 feet of a pneumonic patient without adequate protective equipment. It can also be considered for laboratory workers accidentally exposed and for people in close contact with infected animals, such as veterinary staff, pet owners and hunters.

  Treated in time, plague usually responds well to antibiotics. Streptomycin, chloramphenicol and tetracycline are often used. Among newer drugs, gentamicin and doxycycline have worked as single treatments. A typical regimen pairs gentamicin with a fluoroquinolone. The risk of death is about 10 percent with treatment and about 70 percent without it. The CDC published guidelines on treatment and prophylaxis in 2021.

  The bacterium could still develop drug resistance and become a major threat again. One drug-resistant case was found in Madagascar in 1995. Further outbreaks there were reported in November 2014 and October 2017.

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• 8. Plague as a Weapon

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  Huo Qubing, a general of the Han dynasty, is recorded to have died from contaminated water while fighting the Xiongnu. Accounts from ancient China and medieval Europe describe the Xiongnu or Huns, Mongols, Turks and others fouling enemy water supplies with the carcasses of cows, horses and people. Plague victims were also reportedly thrown by catapult into besieged cities.

  In 1347, the Genoese possession of Caffa, a great trade emporium on the Crimean peninsula, was besieged by Mongol warriors of the Golden Horde under Jani Beg. The siege dragged on, and the Mongol army was reportedly withering from the disease. They decided to catapult infected corpses over the walls. The episode might explain how quickly the Black Death reached the south of Europe.

  During World War II, the Imperial Japanese Army developed weaponized plague, based on breeding and releasing large numbers of fleas. In occupied Manchuria, Unit 731 deliberately infected Chinese, Korean and Manchurian civilians and prisoners of war. The victims were called "maruta", or "logs". Some were studied by dissection, and others by vivisection while still conscious.

  Shirō Ishii, a member of the unit, was exonerated from the Tokyo tribunal by Douglas MacArthur. In 1949-12 other members were prosecuted at the Khabarovsk War Crime Trials. Some admitted spreading bubonic plague within a 36 km radius around the city of Changde.

  Ishii also innovated bombs holding live mice and fleas, with very small explosive loads. A ceramic casing, rather than metal, kept the blast from killing the animals and insects. No records survive of actual use, but prototypes exist and are believed to have been used in experiments.

  After the war, both the United States and the Soviet Union developed ways to weaponize pneumonic plague. Experiments covered delivery methods, vacuum drying, sizing the bacterium, antibiotic-resistant strains, combination with other diseases such as diphtheria, and genetic engineering. Scientists from the Soviet programs have said the effort was formidable and produced large stocks. Information on many of these projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat.

  Plague is easily treated with antibiotics, and countries such as the United States hold large supplies in case of an attack.

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