A TOUCH OF FRANCE AND VIETNAM / Alexandre Yersin: plague, rubber, and cinchona




Alexandre Yersin: plague, rubber, and cinchona


by J . V. Hi r schmann, USA






Plague has occurred in three pandemics, causing staggering mortality and social disruption. The first began with the Plague of Justinian and lasted from 541 to about 750. The second started in 1346 and ended about 1750. The third, beginning in western China, appeared in Hong Kong in 1894. There, an obscure 30-year-old microbiologist, Alexandre Yersin, who had trained in Paris with Louis Pasteur and Emile Roux, discovered the cause of plague and identified its vector as rats. He developed an effective antiplague serum from injecting plague bacilli into horses. Earlier, Yersin had traveled to the Far East and had conducted four explorations into French Indochina, primarily in Vietnam, mapping the areas and studying their potential for mining, agriculture, and forestry. After his plague studies, he remained in Vietnam, except for brief trips abroad. He developed a laboratory there, planted rubber trees, and sold its latex to the Michelin Company. During World War I he planted cinchona trees to provide Vietnam with its own supply of quinine to combat malaria. He had widespread interests—astronomy, radio, photography, and French automobiles—that he pursued until his death at 77 in 1943..

Medicographia. 2014;36:528-539 (see French abstract on page 539)



Three pandemics of bubonic plague have ravaged mankind, causing horrific mortality and widespread social devastation. The first one began in Egypt with that portion of it known as the “Plague of Justinian” (541-543), so called because it started in the reign and territory of the Eastern Roman Emperor Justinian (482-565) and because he contracted the disease, which he luckily survived. The pandemic eventually spread to Europe and continued as periodic outbreaks until it ended and plague mysteriously vanished in the 8th century.

Of course this did not mean that the disease had disappeared entirely, and arguably one of the most famous early victims of the plague, according to his medieval chroniclers, was king Saint Louis, an icon to French schoolchildren who all recite: “Saint Louis died of the plague in 1270 in Tunis, during the 8th Crusade…” even though it is today recognized that the culprit was most probably dysentery. But plague is more the stuff of legend than dysentery….

Plague returned with ferocity in 1346, probably arising in central Asia, traveling along trade routes, and arriving in Crimea in 1347. From there the second pandemic spread to numerous seaports, such as Messina in Sicily, Venice, Genoa, and Marseille, and then throughout Europe, killing more than one-third of the population in five years.

Physicians during this pandemic used the Latin word pestis (“pestilence” in English) for the disease or “plague,” from a Greek word meaning “stroke” or “blow.” A common term was the “Great Mortality.” Only two centuries later was the illness first called the Black Death, not referring to the dark skin lesions that can occur, but apparently because of a Scandinavian mistranslation from the Latin of atra mors, for in its original source atra meant “terrible,” not “black.” Despite this error, the outbreak from 1346-1353 has been called the Black Death since. Further epidemics occurred intermittently, but frequently, in the succeeding years, until the second pandemic ended when plague disappeared from Europe in the 18th century. The third pandemic started in western China and spread to Canton and Hong Kong in 1894. Plague then disseminated to other Asian countries, Africa, and, apparently for the first time, to Australia and the Western Hemisphere. Between 1896 and 1910 an estimated 13 million people died in China and India alone.



Saint Louis dies of the plague on 25th August 1270 during the 8th and last Crusade,
against Tunis. From the Grandes Chroniques de France, a translation into French of the
Latin histories by the monks of Saint-Denis, official historiographers to the French kings.
The chronicle ends with the death of Charles V in 1380. Illuminated vellum, 14th century,
Musée Condé, Chantilly, France.
© Mithra-Index/Bridgeman Images.



Throughout these pandemics the clinical description and the human responses to the disease were strikingly similar despite the disparate cultures, countries, and times involved. The illness began suddenly with fever, usually followed shortly by the development in the groin, thigh, axilla, or neck of an excruciatingly painful swelling, called a “bubo” (Greek for “groin”). Sometimes, it drained pus, which was a favorable sign. Cough, dyspnea, and bloody sputum could occur and signified imminent demise. Cutaneous ulcers, carbuncles, or pustules might arise, but black spots (called “God’s tokens” during the Black Death) were especially ominous. Many victims reeked from the stench of their breath or because of putrid discharges from their sores or nasal cavities. Some became delirious or comatose. Death usually arrived within a few days, but it could be sudden. In Constantinople in 542, for example, people wore nametags for identification in case they should abruptly fall dead in the streets. Plague during pregnancy was particularly lethal. The overall case-fatality rate in the first two pandemics is impossible to determine, but among untreated patients in the third pandemic it ranged from about 40% to 80%. Its source was puzzling. A common explanation in most cultures— including Christian, Moslem, or Chinese—was that it was God’s vengeance for widespread human depravity. Some thought that it resulted from “miasma,” air polluted by noxious substances that could enter the human body through the skin or respiratory tract. A third concept was that it arose from a malign configuration of the planets. These three explanations often overlapped, as when Shakespeare alluded to “a planetary plague, when Jove/Will o’er some high-viced [ie, vice-ridden] city hang his poison/In the sick air” (Timon of Athens IV; iii: 110-112). Although the mechanisms were unclear, the disease seemed contagious, and a common response was to avoid the sick. One option, especially for the wealthy, was to flee. In The Decameron by Giovanni Boccaccio (1313-75), for example, the ten fictional characters abandon plague-infested Florence in 1348 to travel into the surrounding countryside, where they entertain themselves by telling ten stories daily for ten days. Many physicians approved: a late 15th-century German manuscript stated, “Clever doctors have three golden rules to keep us safe from pestilence: get out quickly, go a long way away, and don’t be in a hurry to come back.” [“Flüch bald, flüch ferr, kom spät herwieder, dann fürvar das sind drei nützere Krüter,” from the Büchlein der Ordnung der Pestilenz (1473), by Heinrich Steinhöwel, town doctor of Ulm from 1450 to 1482]. Because plague was also present in rural areas, however, traveling there did not necessarily avert infection. Indeed, evidence of widespread plague deaths was often apparent—farms deserted, crops abandoned, livestock unattended.








second response to the fear of contagion was the ruthless desertion of the afflicted by friends and families, who sometimes paid others to attend their sick relatives and bury them when they died. Another reaction was to isolate the ill. In some places guards were placed outside their dwellings to keep them incarcerated. In the London epidemic of 1665, Samuel Pepys (1633-1703) recorded in his diary how the doors of those houses were marked with a red cross and the words “Lord have mercy upon us.” Such imprisonment seemed inhumane: “This disease makes us more cruel to one another than if we are dogs.” In Germany, houses of inhabitants with the plague were marked with black crosses, and the word “Pest” (plague).



British soldiers from the Staffordshire Regiment cleaning plague-infested houses in
Hong Kong during the 1894 plague epidemic. © Wellcome Library, London.



Another attempt at preventing disease was to exclude potentially contagious outsiders from entering a community. For example, in 1383 travelers to Marseille and their goods were sequestered for 40 days (“quarantine” in Italian) before receiving permission to come into the city. The result of the staggering death rates, isolation of the sick, and flight from urban areas was that the streets of even large cities were largely deserted. Deserted, that is, of live bodies, but not necessarily dead ones, whose number and stench were overwhelming. Disposal of the corpses was challenging. Numerous accounts concur with Boccaccio’s description: “When all the graves were full, enormous trenches were dug… into which the new arrivals were put by the hundreds, stowed layer upon layer like merchandise in ships….”

The traditional rituals surrounding death were commonly abandoned or curtailed. The historian Procopius (500-565), who was in Constantinople when the plague struck in 542, wrote, “All the customary rites of burial were overlooked… it was sufficient if one carried… the body of one of the dead to the parts of the city which bordered on the sea and flung him down; and there the corpses would be thrown upon skiffs in a heap, to be conveyed wherever it might chance.”

The plague had other effects on human behavior. Procopius described how some previously licentious people became suddenly religious…until the danger passed and they returned to their prior villainy. Boccaccio wrote that many lived moderately and abstemiously, but others “maintained that the surest medicine for such an evil disease was to drink heavily, enjoy life’s pleasures…satisfying their appetites by any means available….” Searching for causes, some blamed the disease on others. Accused of poisoning wells and rivers, nearly 1000 Jews were burned in Strasbourg in 1349, and other Jewish communities in the Rhineland were almost completely annihilated. At about the same time, flagellants, condemning them- selves, Jews, and humanity in general, traveled through Europe exhorting repentance and beating themselves bloody with knotted whips to propitiate God’s anger. Many people, undoubtedly, were courageous and humane, but most probably became inured to death. Pepys, noticing a corpse being carried away, responded, “Lord, to see what custom is, that I am come almost to think nothing of it.” These reactions of fear, flight, indifference, bizarre behavior, and inhumanity arose primarily because the cause of plague remained unknown. In 1894, an obscure microbiologist in Hong Kong finally eliminated that uncertainty.

Alexandre Yersin (1863-1943) was born in a Swiss village on the shores of Lake Geneva, three weeks after his father’s death.His 25-year-old mother movedher children to the nearby town of Morges, where she started a finishing school for girls that emphasized household skills and elegant French manners. Yersin, who was quite misogynistic, regarded the girls with contempt, but he did remain close to his mother and his sister, writing nearly 1000 letters to them until their deaths in 1905 and 1933, respectively. In 1883, he began his medical studies in Lausanne, but after one year went to Marburg Germany. In 1885, he transferred his medical education to Paris, where he became a student at Hôtel-Dieu, a large public hospital dedicated to treating the poor. Shy, solitary, and intensely private, Yersin found himself more interested in pathology than patient care. He began work in the laboratory of the eminent pathologist Andre Cornil (1837-1908), where he translated German articles for the Professor and performed dissections, including autopsies of rabies victims. After meeting Emile Roux (1853-1933), who had developed an antirabies vaccine with Louis Pasteur (1822-1895), Yersin was hired as an assistant in Pasteur’s laboratory. In 1888, he became a citizen of France, a requirement to practice medicine there. In 1889, he completed research on an experimental form of septicemic tuberculosis for his doctoral thesis, winning a bronze medallion from the Faculty of Medicine of the University of Paris.

Earlier, in 1886, he and Roux began to study Corynebacterium diphtheriae, the recently identified cause of diphtheria. They demonstrated that the disease’s clinical manifestations arose from a toxin, which they identified in the urine of infected patients. It was the first isolation of a bacterial exotoxin, and they proposed using it to develop a vaccine. They also showed that humans could be asymptomatic pharyngeal carriers of C diphtheriae. Pasteur was impressed with Yersin’s great scientific qualities, characterizing his habits of silent labor as almost ascetic.



Alexandre Yersin in 1893. Photo by
Pierre Petit. © Institut Pasteur – Musée Pasteur.



In 1888, Roux, organizing a bacteriology curriculum for presentation at the newly constructed Pasteur Institute, sent Yersin to Berlin to attend a two-month program conducted by the great German microbiologist Robert Koch (1843-1910), who had earlier discovered the bacteria responsible for anthrax and tuberculosis. On his return, Yersin taught five consecutive courses, but he disliked teaching.

Uninterested in Parisian life and imbued with enthusiasm for adventure, he resigned from the Pasteur Institute in 1890 to fulfill his inmost dream of emulating the Scottish explorer David Livingstone (1813-1873) by traveling to other continents. Furthermore, as he once wrote to his mother, he was unsettled about a career in microbiology: “Scientific research is very interesting, but Mr Pasteur is quite right when he said that, unless he is a genius, a man must be wealthy to work in a laboratory and risk leading a miserable existence, even if it does win him a certain scientific renown.”

Accordingly, he became a ship’s doctor, initially traveling between Saigon and Manila. He learned Vietnamese in order to communicate with the crew, and to allay the monotony of his trips, he also studied navigation and cartography. After a year, he began sailing between Saigon and Haiphong along the coast of Vietnam. It was then part of French Indochina, formed in 1887 as a federation of three Vietnamese regions—Tonkin in the North, Annam in the Central area, and Cochin China in the South—as well as Cambodia, with Laos being annexed in 1893. Recognizing that no European had visited much of this territory, he conducted four explorations into the interior from 1891-1894. Although small in stature, he possessed the extraordinary stamina and tenacity required to confront the challenges of these hazardous and physically demanding journeys. Travel was often on foot, and he had to contend with rugged terrain, heat, rain, leeches, tigers, mosquitoes, tropical diseases, and, sometimes, unscrupulous guides and interpreters. He also encountered hostility from some village chiefs, who denied passage through their territories. He took chronometers, altimeters, and compasses to map the areas and wrote detailed notes about the geography, flora, fauna, and people seen along the way. From these experiences, he made recommendations for road building, mining, and agriculture.

His first trip, in July 1891, was an ambitious attempt to journey from the coast southwest across the Annamite mountain range to Saigon 500 km away. Travelling through heavy rain, he only reached the plateau of Djiring, where he first met the Montagnards, the inhabitants of the Vietnam highlands. Suffering from a severe attack of malaria and unable to find further guides, he abandoned his trip, returning to the coast disheveled, his feet bare and bleeding.



The Bay of Nha Trang, at the turn of the 19th century. All rights reserved.


Albert Calmette (1863-1933), later famous for developing a vaccine against tuberculosis (Bacillus-Calmette-Guerin [BCG]), had been sent from the Pasteur Institute in Paris to found a branch in Saigon. He persuaded Yersin to join the French Colonial Health Service, which, he argued, would help support further explorations. In March 1892, Yersin began an officially authorized trip of three months from the coast at Nha Trang—a region he was to fall in love with and settle at permanently— west through the Central Highlands into Cambodia, reaching the Mekong River. His interpreter stole a large share of his goods and deserted. Yersin then traveled south on a river boat to Phnom Penh before returning to Saigon. During his trip, he mapped the area around the Mekong River, made observations about the natives, and took many illuminating photographs. Quinine prevented malaria, but he suffered a severe attack of dysentery.

In October 1892, Yersin returned to Paris, where, with Pasteur’s help, he obtained funding for his next expedition. In February1893, he began a seven-month trip from Saigon to explore the southern part of the Central Highlands, heading northeast and discovering along the way the fertile plateau of Lang Bian. Admiring its tall trees, lakes, waterfalls, and temperate climate, he recommended building a holiday resort there for French civil servants. The result was the charming village of Dalat, which also became a source of vegetables and fruits for the Vietnamese lowlands.

Other major accomplishments during this trip were developing accurate maps, including the height and configuration of its mountains; recording the customs of its inhabitants; and calculating its potential for commerce, livestock, mining, and forestry. In June, he caught up with some escaped prisoners and their five rebel chiefs, whom he fought alone, sustaining a saber wound to his right hand and the blow of a rifle butt to his right leg that incapacitated him for several days. When the main rebel chief was later arrested, Yersin witnessed his execution, admiring the impassivity of the victim, who sustained four blows with a sword before decapitation finally occurred.

His last exploration was a three-month trip in 1894 from the sea westward to the Central Highlands, following a varying northward course that finally ended at the coast in Da Nang. This time he had guards accompany him. Once again, he made detailed geographic observations and accurate maps of the significant villages and landmarks, but had to abandon nearly all his equipment because of unspecified difficulties.



Military doctors at the Saigon
Hospital, in 1893.
Yersin is the first
from left, back row (his name is
written over his white uniform jacket).
Albert Calmette is seated, first from
left, front row. © Institut Pasteur.



After Yersin returned, Calmette asked him to travel to the British colony of Hong Kong to investigate the outbreak of plague there, which heralded the third pandemic. He arrived on June 15, 1894, with a staff of only two untrained people, one who quickly absconded with Yersin’s money.Yersin’sonly equipment was a microscope, an autoclave, and culture supplies. His arrival in Hong Kong was three days after that of Shibasaburo Kitasato (1852-1931), whom the Japanese government had sent to investigate the epidemic as well. Kitasato was a famed microbiologist who spent seven years in Robert Koch’s Berlin laboratory, where he developed anaerobic techniques that allowed him to isolate the cause of tetanus (Clostridium tetani) in pure culture for the first time. In addition, he discovered and characterized its exotoxin and, with Emil Behring (1854-1917), produced tetanus antitoxin. Kitasato came to Hong Kong with six assistants and received gracious hospitality from the Scottish doctor James Lowson (1866-1935), who was Superintendent of the Government Civil Hospital. He provided Kitasato with laboratories and facilities for autopsies. On June 14, Kitasato detected a bacillus in postmortem specimens. He inoculated a mouse and saw a similar bacterium in another patient. Lowson was confident Kitasato had found the cause of plague and wired the British journal Lancet with that claim.



Japanese microbiologist
Shibasaburo Kitasato (1852-1931).
© Institut Pasteur – Musée Pasteur.




Superintendents House and Government Civil Hospital in Hong Kong ca 1893.
Colonial Office Photographic Collection. The picture is likely taken from Bonham Road looking
toward the harbor, with Stonecutter’s Island in the background. © National Archives, UK.



Lowson was less enthusiastic about Yersin, who was unprepossessing, unable to speak English, shy, and, in contrast to Kitasato, unrenowned. Lowson refused Yersin access to autopsies. Yersin did manage to get a straw-covered bamboo hut constructed on the grounds of a recently converted hospital, where he established his laboratory. On June 20, at the advice of an Italian missionary, he bribed some English sailors in charge of the hospital mortuary to allow him to excise some buboes from the corpses before burial. Hurrying to his laboratory with the specimens, he made slides and discovered masses of very small, thick bacilli with rounded ends. The bacteria were Gram-negative and exhibited bipolar staining with aniline dyes. He inoculated agar, and the isolates, when injected into mice and rats, produced plague. On June 23, he demonstrated that rats dying in the streets of Hong Kong, like humans, had buboes filled with enormous numbers of the same bacilli. Yersin concluded that rats were the principal vector of plague.

Although Yersin clearly identified the plague bacillus, Kitasato had apparently discovered it six days earlier. The slides that Lowson and Kitasato sent to The Lancet and British Medical Journal, however, seemed to show two organisms: small bacilli, but also diplococci. Moreover, Kitasato was unable to state whether the bacillus was Gram-positive or Gram-negative, and he erroneously suggested that it was slightly motile. A probable explanation for Kitasato’s confusing initial reports is that another bacterium, possibly Streptococcus pneumoniae, contaminated his cultures. The question of priority for first finding the cause of plague generated considerable controversy, exacerbated by false claims and contradictory statements that Kitasato and his colleagues made afterwards, with Kitasato sometimes insisting that the microbe that he identified was different from Yersin’s isolate. The definitive resolution of this debate is reflected by the nomenclature of the plague bacillus. It was called Bacterium pestis before 1900, Bacillus pestis until 1923, and Pasteurella pestis up to 1970, when it received its final name, Yersinia pestis.



Yersinia
pestis
,
discovered
by
Yersin
during
the Hong
Kong
plague
epidemic
in 1894.
© Institut
Pasteur.




Yersin standing in front of the straw-covered bamboo hut in Hong Kong in 1894 where
he made his landmark discovery of the plague bacillus. Yersin Photograph Collection.
© Institut Pasteur – Musée Pasteur.


Yersin’s involvement with plague did not end with discovering its cause. In 1895, he was back in Paris working with Calmette on an antiplague serum obtained by injecting bacilli into horses. He returned to Nha Trang later that year, and when plague recurred in 1896, he tried the therapy on an 18-year-old Chinese seminary student on June 26. It was the first recorded use of antiplague serum, and the patient survived, as did 21 of 23 other victims who received his remaining supply. Soon, he set up serum production in Nha Trang, where he built another Pasteur Institute, comprising a hospital, vaccination center, laboratory, and observatory. He lived there most of the remainder of his life. In 1897, plague erupted in India, and Yersin introduced his treatment there. Yersin’s antiserum and other similar formulations, employed until the advent of antimicrobial agents, reduced the mortality rate of plague from about 80% to about 35%. With streptomycin use, beginning in 1947, it was about 5% to 10%, which remains the current rate with gentamicin or doxycycline therapy.

Yersin had always been ambivalent about medical practice. In a letter, he wrote: “I take great pleasure in treating those who come to me, but I should not like to make medicine my living. I could never ask a patient to pay me for the treatment…. I regard medicine as a sacerdotal office, like the priesthood. Demanding payment for treating an invalid is rather like saying, ‘Your money or your life.’” Accordingly, after his work with plague, he became involved in other pursuits. In 1899, he established the first nursery for rubber trees in Vietnam, having imported the plants from Brazil, and he sold the first collection of latex to the Michelin Company in 1904. Asked by the French government to help found a medical school in Hanoi, he acted as its director from 1902-1904. He was appointed as the overall director of the Pasteur Institutes in Indochina. In 1915, after the outbreak of World War I, he determined to have Indochina make its own quinine, which comes from the bark of cinchona trees. Finding the appropriate growing conditions was challenging, but, using seeds that he had acquired in Java, his efforts eventually succeeded.

In1919, he became Inspector of the Pasteur Institutes of Indochina and in 1923, received the honorary title of Inspector General upon his retirement. He became interested in astronomy, radio, photography, and French automobiles, buying successive models, which he drove in Vietnam. In 1933, he was appointed a member of the Scientific Council of the Pasteur Institute in Paris, where he traveled annually to attend its meetings. On May 30, 1940, at the end of his last visit, he took a midnight plane destined for Saigon just six hours before the invading German army closed the Paris airport. Back in Nha Trang, where he witnessed the Japanese occupation of Indochina, he died peacefully on February 27, 1943, at the age of seventy-seven. On his tombstone is the inscription, “Benefactor and humanist, venerated by the Vietnamese people.” Indeed, he remains renowned in Vietnam, where streets bear his name, his burial site is honored, and his dwelling in Nha Trang is a museum. The Linh Son Phap Pagoda, in the village of Suôi Cat, some 20 km from the Nha Trang Bay, contains a shrine to Yersin, whith his portrait, the object of a fervent cult.



Yersin’s house and the cupola of his observatory, in Nha Trang.
© Institut Pasteur – Musée Pasteur




Yersin shrine at the Buddhist Lihn Son Phap Pagoda near Nha Trang.
All rights reserved.



Yersin’s discovery of the plague bacillus and its presence in rats left several issues unanswered. It was unclear how rats or humans acquired the bacteria. Paul-Louis Simond (1858- 1947), another Pasteur-trained microbiologist, noticed that people could safely handle rats that had died of the plague several hours earlier, but not when the animals had just expired. He proposed that there must be an intermediary between the rat and humans, suggesting the rat flea (Xenopsylla cheopsis) as the culprit. When a rat corpse cools, the fleas seek another warm-bodied animal, preferentially another rat, but if none is available, humans suffice. While studying the disease in India, he found plague bacilli in the intestines of fleas from infected rats, but not in those from healthy ones. Simond placed a rat suffering from plague into a jar and housed a healthy one above him on a screen, close enough for fleas to jump, but far enough to avoid direct contact between the animals. The healthy rat contracted plague. When a rat with plague, but no fleas, was similarly housed with healthy rats, no infection occurred. When fleas were added, however, plague developed. Subsequent studies, many conducted by the Indian Plague Commission formed in 1905 and comprising both British and Indian investigators, resolved several others issues about the source and transmission of plague. Y pestis enters X cheopsis when it sucks blood from infected rats, which have high-level bacteremia. When they next feed, infected fleas regurgitate the bacteria into the bite site, transmitting the bacilli to a new host.

Foci of plague currently exist in all continents except Australia and Antarctica. The reservoir for the organism is a chronic carrier state in various wild rodents—such as gerbils, marmots, field mice, and ground squirrels—which, unlike rats, remain relatively healthy despite prolonged bacteremia. These mammals typically acquire Y pestis through bites from fleas, including species other than X cheopsis. Y pestis, however, can also survive for months in soil, which, if contaminated, could cause infection when rodents inhale or ingest it. Modern observations have confirmed the clinical features described in the earlier pandemics. Disease occurs primarily in three forms: 1) bubonic plague, with fever and swollen, tender, necrotic, and hemorrhagic lymph nodes; 2) septicemic plague, in which bacteremia occurs, but no bubo develops; 3) pneumonic plague, either as a complication of bacteremia or from inhalation of aerosolized bacteria from people with plague pneumonia or from respiratory secretions of infected mammals. In addition to transmission via fleas and inhalation of Y pestis, plague can occur from direct handling of infected animal tissues or by ingesting the organism. The incubation period is 2-10 days, and in the bubonic form Y pestis travels from site of inoculation to the regional lymph nodes, where buboes form. The pustules, carbuncles, and ulcers described in older accounts were probably infection by Y pestis at the site of the flea bite. The ominous black spots (“tokens”) may also have been primary infections, but some were probably cutaneous hemorrhages and gangrene produced by disseminated intravascular coagulation. Finally, studies of DNA isolated from the teeth of plague victims in ancient grave sites have demonstrated that the first two pandemics were indeed caused by Y pestis, although they appear to be from different strains. These investigations confirm that the tiny bacillus that Alexandre Yersin discovered has, over many centuries, killed tens of millions of people, making it the most lethal bacterium in human history. ■



Xenopsylla cheopsis, the common rat flea,
vector of the plague and murine (endemic)
typhus. © Institut Pasteur


Further reading
– Benedictow OJ. The Black Death 1346-1353: The Complete History. Woodbridge, UK: Boydell; 2004.
– Boccaccio G. The Decameron. New York, NY: W.W. Norton; 2014.
– Butler T. Plague and Other Yersinia Infections. New York, NY: Plenum Medical Books; 1983.
– Butler T. Plague gives surprises in the first decade of the 21st century in the United States and worldwide. Am J Trop Med Hyg. 2013;89:788-793.
– Defoe D. A Journal of the Plague Year. New York, NY: W.W. Norton; 1992.
– Deville P. Plague and Cholera. London, UK: Little, Brown; 2014.
– Hawgood BJ: Alexandre Yersin (1863-1943): discoverer of the plague bacillus, explorer and agronomist. J Med Biog. 2008;16:167-172.
– Horrox R, ed. The Black Death. Manchester, UK: Manchester University Press; 1994.
– Slack P. Plague. A Very Short Introduction. Oxford: Oxford University Press; 2012.
– Wagner DM, Klunk J, Harbeck M, et al: Yersinia pestis and the Plague of Justinian 541-543 AD: a genomic analysis. Lancet Infect Dis. 2014;14:319-326.