There is a close association between infectious diseases, epidemics and war, and for many reasons. In history, soldiers and sailors have endured many hardships – wounds and death, exhaustion from battles and long marches, shortage of shelter, food and water, and sometimes they brought disease with them from their homeland or from other wars, all leaving them susceptible to the added mortality of contagion.1, 2 By the 18th century, many physicians and military surgeons realised the importance of preventing disease and improving the health of soldiers in winning war campaigns.3 Plague was particularly important because it was known to be highly contagious and caused severe epidemics that had high mortality, although until the discoveries made during the 1894 pandemic, its cause, means of transmission and prevention were not known. Bubonic plague is now a treatable and immunisable disease but it continues to have military significance, especially because of its virulence and infectivity in the pneumonic form, and is listed by the Centers for Disease Control and Prevention as a Category A bioterrorism agent.4
For many centuries infectious diseases such as bubonic plague, smallpox and cholera were thought to be due to ‘miasmas’, disease carrying vapours that emanated from corpses, putrescent matter, or the breath of a sick person. Others thought plagues such as the Black Death were due to earthquakes or comets, or were punishment from God for their sins and immoral behaviour. During times of plague, many people prayed to saints such as St Roch and St Sebastian for salvation or became penitents and roaming flagellants.5, 6 The advent of the microscope and the germ theory and the discoveries by scientists and doctors such as Louis Pasteur and Robert Koch that disease could be caused by micro-organisms changed the way we thought about disease and led to the development of the disciplines of bacteriology and preventive public health.7
Louis Pasteur was a French chemist and bacteriologist whose experiments supported the new germ theory of disease, countering the prevailing view of spontaneous generation of disease. He showed that the souring of wine and beer were due to micro-organisms, which he called ‘ferments’, and which were actually various types of cocci and bacilli, and proposed the idea that such micro-organisms could cause disease in humans. In 1863 he refined the process of pasteurisation of wine and later applied it to milk, heating milk to kill organisms to prevent the spread of diseases such as tuberculosis and typhoid. Pasteur also worked in developing vaccines, he successfully demonstrated the effectiveness of the anthrax vaccine in preventing anthrax and in 1885 developed the rabies vaccine.3, 7, 8
Robert Koch was a German physician who after serving in the Franco-Prussian War worked in the Royal Prussian Institute for Infectious Diseases in Berlin (now the Robert Koch Institute) and was instrumental in discovering the causes of many infectious diseases. In 1879 he published that traumatic wound infections were caused by bacteria. In 1882 he discovered the causative organism of tuberculosis, and of cholera in the following year. He showed that the anthrax bacillus, which was previously discovered by Franz Pollender, under certain conditions formed spores which could last for many years in soil and cause re-emergence of infection in animals. Koch also developed methods for staining histological specimens with dyes and the use of gelatine and later blood-serum and agar-agar in developing culture mediums that were more effective than the broth mediums. His students and his rivals used his methods to discover the causative organisms of many other diseases including typhoid, diphtheria, tetanus, leprosy, gonorrhoea, syphilis, and coccal infections such as pneumonia and meningitis.3, 7, 8 Koch was a pupil of Jakob Henle, also a German physician and pathologist, and together they developed the Henle-Koch postulates which are required for proof that a particular micro-organism causes a particular disease.9
Early in 1894 bubonic plague broke out in Canton and Hong Kong, the start of the third great plague pandemic. Two bacteriologists immediately began working independently from one another to isolate and culture the causative organism of the plague; Shibasaburo Kitasato, a previous pupil of Robert Koch, and Alexandre Yersin, from the Pasteur Institute.10, 11, 12
On June 12 a Japanese team of researchers led jointly by Shibasaburo Kitasato and Aoyama Tanemichi arrived in Hong Kong to try to identify the organism responsible for the plague. Kitasato was a renowned Japanese bacteriologist who worked with Emil von Behring and Robert Koch in Berlin where they developed antitoxins for tetanus and diphtheria.11, 12 James Lowson, the British physician in charge of the Hong Kong plague emergency, set up Kitasato’s team with a well furnished laboratory in Kennedy Town Hospital. Kitasato found bacilli in the bubo pus, blood and organs of a plague victim who had died. He cultured the bacillus on broth culture and inoculated mice and other animals who died with the same bacilli in their blood.13 On June 14 Kitasato informed Lowson that he had found the likely plague bacteria and Lowson immediately cabled The Lancet who published Kitasato’s findings in an editorial the next week, and his full research report in August, with great admiration from the Hong Kong and Japanese governments.11
Alexandre Yersin, a Franco-Swiss physician, was the assistant of Emile Roux, director of the Pasteur Institute, a fellow colleague of Pasteur, and a member of the Pasteur Institute, a Pastorien. He had also studied under Robert Koch in Germany and in 1888 was awarded the Paris Medical Faculty bronze medal for his work on animal tuberculosis and the diphtheria exotoxin. In 1890 Yersin decided to leave his work at the Pasteur Institute to go to French Vietnam, earning his passage on the way as a ship’s physician for the Messageries Maritimes company.14 He arrived in Saigon and joined the French colonial health service as a missionary doctor. After plague had broken out in Hong Kong in 1894 he was asked by the Pasteur Institute to leave Vietnam and go to Hong Kong to try to isolate the plague organism, taking with him a microscope and an incubator as his only equipment. Yersin arrived in Hong Kong in June 1984 three days after Kitasato, Kitasato was already at work, but with a sophisticated laboratory and a staff of twenty or so.10, 11, 12, 15
Yersin was not able to either obtain hospital laboratory facilities or to be able to work alongside Kitasato, and instead set up a rudimentary laboratory in a hut near the Hong Kong Hospital and had to make do with working on hospital patient corpses. A week into his stay, one of the mice he had inoculated with pus taken from a bubo on a corpse, died. Its spleen contained “very small, stocky, round tipped bacilli which could be stained only with difficulty”. In the following week he successfully obtained pure cultures of the bacillus on medium. He also demonstrated for the first time that the same bacillus was present in the rat as well as in the human disease, indicating its possible means of transmission.11, 12, 14, 15
During June 1984 both Kitasato and Yersin announced isolation and culture of the plague bacillus. Although Kitasato was initially credited with the discovery for some years, it is now considered Yersin’s description of the bacillus to have been the more accurate. Yersin’s experiments satisfied Koch’s postulates for plague infection, his descriptions of the bacillus were more accurate and consistent than Kitasato’s, and he more accurately described the aniline dye and non-Gram staining of the bacillus. In addition, Kitasato’s cultures were probably contaminated by a gram-positive pneumococcus that was the cause of a secondary septicaemia in plague patients.10, 11, 13, 16 Yersin published his report in the Annales de l’Institut Pasteur with a paper titled La peste bubonique á Hong Kong and the bacillus was named Bacterium pestis. A few months after his return to France, Yersin was awarded the Légion d’honneur by Delcasse, the French Minister of Colonies.14, 15
Following is a description of the plague from his 1894 paper :
“The onset is rapid, with an incubation of 4½ to 6 days. The patient is prostrated. Abruptly, a high fever sets in, often accompanied by delirium. On the very first day a discrete bubo usually appears. In 75% of the cases it is located in the inguinal region, in 10% of the cases in the axillary region, and occasionally at the back of the neck and in other regions. The nodule rapidly reaches the size of an egg. Death occurs after 48 hours and often sooner. If the patient manages to survive 5 to 6 days, the prognosis is better, the bubo softens and one can operate to aspirate the pus. In a few cases, the bubo does not form, and one will note in such cases haemorrhages in the mucous membranes or petechial spots on the skin. Mortality is high; 95% in the hospitals.”13
While working on the bacillus Yersin had also noticed that the streets of Hong Kong were littered with dead rats. It had been observed throughout history, such as by Avicenna in Persia in the 11th century and by Nathaniel Hodges in 1665 in his work Loimographia, or an historical Account of the Plague in London in 1665, With precautionary Directions against the like Contagion that a plague of dead rats often heralded an epidemic in people.10 It is now known that epizootic infection in rats precedes a human epidemic of plague and that rats have just as great a mortality as humans. When all the rats die the fleas actively seek new hosts, people and their domestic animals being the closest, thus propagating an epidemic. Yersin suspected that there was a connection between rats, the bacillus, and epidemics, but didn’t know how the rats transmitted the bacillus if they were the vector.10, 17
In 1895 on his return to the Pasteur Institute, Yersin, in collaboration with Amedee Borrel and Albert Calmette, both Pastorien bacteriologists, began experimenting with an anti-plague serum and in 1897 Yersin went to back Bombay to continue trialling his antiserum, although he had poor success as only half of his patients survived.14 Yersin had a falling out with the local authorities and left Bombay to return to Nha Trang in Vietnam. In 1902 he founded a medical school in Hanoi and in 1924 was made Honorary Inspector General for Indochina’s Pasteur Institutes. Yersin died in his home in Nha Trang in 1943 where his grave is honoured as that of a national hero.14, 15 In 1900 the bacillus, Bacterium pestis, was renamed Bacillus pestis, then renamed again in 1923 as Pasteurella pestis after Pasteur. In 1970 the bacillus was reclassified as a different genus to Pasteurella and was renamed Yersinia pestis.13, 16
Yersin’s position in Bombay was taken over by Paul- Louis Simond, a young doctor in the French Navy, and like Yersin, was a fellow Pastorien. Simond earned his medical doctorate in 1887 and was awarded the Godard prize for his dissertation on leprosy in French Guyana. Simond joined the French Naval Medical Corps, the Médecin de première class, and was posted to French Guyana and the Far East, until in 1895 he returned to Paris and joined the Pasteur Institute to study the biology of coccidians and Plasmodium protozoa. In 1897 he was sent to India by the Institute to replace Yersin and continue his work on the antiserum for plague.18, 19
In Bombay, Simond continued with Yersin’s hypothesis about there being a vector for the bacillus. He noticed tiny fluid filled vesicles, phlyctene precoce, on the legs and feet of plague patients which he found to be swarming with plague bacilli.10, 18 He considered these to be the primary lesion preceding formation of a bubo and that it may be caused by an insect bite, and in particular, the flea. He also noted, like Yersin in Hong Kong, that the streets of Bombay were littered with dead rats. He wrote as one of his observations:
“On the rats captured alive, and on the rats which had just died, the fleas were thicker than I have ever seen them… We have to assume there must be an intermediary between a dead rat and a human. This intermediary might be the flea.”10
In 1898 in Karachi Simond, using a very simple experiment with an infected rat and its fleas and a healthy rat, showed that the bacillus was transmitted by the fleas, and that the brown sewer rats were the main host of the bacillus. He published his experiment and findings in the Annales de l’Institut Pasteur with his paper La Propagation de la Peste and was awarded the Barbier Prize from the French Academy of Medicine for his work. Unfortunately Simond’s theory and his experiments about a flea vector were met with great scorn from the European medical authorities despite evidence for some decades that insects were known to be a vector for several epidemic diseases such as filariasis and yellow fever. In 1901 Simond was awarded the Légion d’honneur in Paris and went on to study yellow fever in Brazil but was not given credit for his flea discovery until many years later.15, 18, 19
In 1906 Simond became professor at the Graduate School of the French Colonial Health Service and continued his work on the prevention of mosquito transmission of yellow fever and the development of a vaccine for typhus. In 1913 he became a corresponding member of the French Society of Biology for his passion and work with classifying orchids in Indochina. During the first world war he was Director of the Colonial Health Service and Inspector of Hygiene and Health Services in Indochina. From 1919 he worked in public health and prevention of tuberculosis in Valence where he died in 1947.19
In 1902 in the Sydney outbreak of plague, John Ashburton-Thompson, the chief medical officer, embraced the hypothesis of the rat flea as the plague vector and identified the fleas Pulex pallidus and Pulex fasciatus as the main vectors in the outbreak20. He confirmed that there was a close association between rats and plague in humans and that an epizootic in rats always preceded an epidemic, and also made the observation that rats during a plague epizootic harboured more fleas than at other times.21
The flea vector hypothesis was also confirmed by Masanori Ogata in 1898, G. Zirolia in 1902, and J-C. Gauthier and A. Raybaud in 1902 and 1903 in similar experiments to Simond’s. In 1903 Nathaniel Charles Rothschild, a British entomologist, identified specimens of the Indian rat flea found during a plague outbreak in Egypt and Sudan as Pulex cheopis (named by Rothschild after the pharaoh Cheops, and renamed Xenopsylla cheopis by Rothschild and Karl Jordan in 1911) which was later considered to be identical to the Pulex pallidus in the plague outbreaks that occurred in Sydney and other places throughout Australia.17, 20, 22
Around 1900, Waldemar Haffkine, a Russian physician working for the Indian government during the epidemic, developed a killed plague vaccine. This work was continued in the 1920’s and 1930’s by Albert Calmette, Kiyoshu Shiga, and Alexandre Besredka who developed reasonably effective killed vaccines, and by George Girard and Jean-Marie Robic who developed a live vaccine from a non-virulent strain of the bacillus.3, 7, 15
Plague continued on as a world pandemic until 1959 and in that time many physicians and scientists made important contributions to our knowledge of plague. The early discoveries in particular by two French physicians, Alexandre Yersin and Paul- Louis Simond, gave medicine the beginnings of a long sought after insight into the bubonic plague – the nature of the bacterium that caused it, the relationship between the bacillus and the primary hosts, the urban and sewer rats, and its transmission to humans by the bite of the rat flea.
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