Читать книгу To Catch a Virus - John Booss - Страница 23

The influenza pandemic of 1918–1919 is one of the greatest natural disasters of recorded history. First recorded at an Army Camp in Kansas in 1918 toward the conclusion of World War I, influenza killed more people worldwide than did that conflict. The exact number will never be known because of incomplete global health records, inaccurate records of death, and censorship associated with the war. One analysis estimated that between 24.7 and 39.3 million lives were lost to the pandemic worldwide (46). The war facilitated the pandemic in concentrating and moving troops and disrupting the civilian populations. Reciprocally, conduct of the conflict was hampered on both sides by disabled troops (Fig. 5). Rail travel and transoceanic steamships took the pandemic to all but a few remote locations. In other influenza epidemics, it has been the very young and the elderly who have suffered the brunt of the mortality. However, the unique feature of the 1918–1919 pandemic of influenza was the predilection for killing previously healthy young adults. It now seems likely that such mortality resulted from an overexuberant host response, with the body’s own defenses turning against the body in an attempt to ward off infection.

Figure 5 “Coughs and Sneezes Spread Diseases,” a slogan and poster campaign that was designed to cut down on the spread of respiratory diseases in the United Kingdom in World War II. Disease was portrayed as hampering the war effort at home. No doubt lurking in the minds of the Ministry of Health officials were the devastating effects of the 1919 influenza pandemic. (Courtesy of Yale University, Harvey Cushing/John Whitney Medical Library.)

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The effects on society and on individuals are poignantly described in Katherine Anne Porter’s story Pale Horse, Pale Rider (49). The medical historian Alfred W. Crosby said of Porter’s story, “It is the most accurate depiction of American society in the fall of 1918 in literature” (10). Porter was herself desperately ill and lost her lover, an Army lieutenant, to influenza. In the fictionalized account in Pale Horse, Pale Rider, the lover of the protagonist, Miranda, describes the effects of the disease on the city: “‘It’s as bad as anything can be,’ said Adam, ‘all the theaters and nearly all the shops and restaurants are closed, and the streets have been full of funerals all day and ambulances all night. . . .’” Miranda is taken to the hospital while Adam is out getting them ice cream and hot coffee. She never sees him again, for he was not allowed to visit her. Tragically, she learned of Adam’s death in an army camp hospital upon her recovery. Crosby reports that Porter said of the effect of the pandemic on her life, “It just simply divided my life, cut across it like that.” (10). It was true, commented Crosby, for many of her generation. He dedicated his account of the pandemic, America’s Forgotten Pandemic, “To Katherine Anne Porter, who survived” (10).

Although the pandemic of 1918–1919 was shattering on a global scale, “The first pandemic of influenza in the bacteriological era,” according to Richard Shope, “was that of 1889–1890” (56) (Fig. 6). During that epidemic, R. Pfeiffer isolated the bacillus Haemophilus influenzae (48). Pfeiffer held that the bacillus was present in cases associated with influenza but not in other individuals. John R. Mote reviewed the literature disputing this view but nonetheless assented that “. . . Pfeiffer’s bacillus was for years considered by many workers to be the cause of epidemic influenza” (42). As Patrick Playfair Laidlaw described in his Linacre lecture, H. influenzae “. . . had held an almost undisputed position since the end of the pandemic 1899–1890” (31).

Figure 6 L’influenza à Paris. This cover is from a Parisian weekly in 1890 during the influenza pandemic of 1889–1890. Originating in Russia and spreading westward, influenza became known as “Russian flu.” The cover depicts four scenes relating to the epidemic in Paris (clockwise from top left): a tent set up in a hospital courtyard, the interior of tent ward for the sick, the distribution of clothes to families of victims, and two men singing a new song, “L’influenza, tout l’monde l’a!” (“Influenza, Everyone Has It!”). (Courtesy of the National Library of Medicine.)

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The accepted ethical norms of disease investigation in humans seemed to be suspended when the influenza pandemic of 1918–1919 came toward the end of World War I. Historically, wartime overthrew many usual constraints on the study of illness. As the science writer Gina Kolata put it, “But in 1918, such ethical arguments were rarely considered. Instead, the justification for a risky study with human beings was that it was better to subject a few to a great danger in order to save the many” (30). Negative studies with sailors in Boston, MA, and San Francisco, CA, were recounted by Kolata: intense exposure of presumed susceptible subjects to infected persons and their mucus, blood, exhalations, and coughs failed to induce the disease. While other groups of investigators appeared to have some success, the results were not consistent enough to reach a conclusion. As expressed by Laidlaw, one of the investigators who successfully transmitted influenza to ferrets, “One can never be sure that the experimental subject is susceptible and therefore negative results can be discounted; while positive results, though perhaps more significant, are always open to the suspicion that infection was picked up in some accidental manner” (31).

Attempts to transfer the illness to animals that had proven susceptible to other human viral pathogens were inconclusive (42). Monkeys, rabbits, guinea pigs, and mice were among those tested. Mote’s compilation serves to emphasize the importance of at least three experimental variables: the material transmitted, blood versus sputum or throat washings; the site of transmission, intraperitoneal versus intranasal; and the susceptibility of the host. No clear etiological agent emerged from the 1918–1919 influenza pandemic. It was not until the study of swine influenza in two epizootics in 1928 and 1929 in Iowa by Richard Shope and Paul Lewis of the Department of Animal Pathology of the Rockefeller Institute at Princeton, NJ (36, 54, 55), that a new story began to emerge.

Swine influenza had been recognized during 1918–1919 by J. S. Koen of the U.S. Bureau of Animal Industry. According to Richard Shope’s review in 1958, Koen recognized in swine similarities in prevalence and symptoms to human influenza, but he was criticized for calling it “flu” (56). The objections were economic and arose from a fear that the swine-flu connection would turn away the public from the consumption of pork. The epizootic in pigs was massive, with millions becoming sick and thousands dying. Recognizing the annual recurrence and enormity of the epizootics with such devastating economic consequences, Shope and Lewis began in earnest their investigations in 1928.

What they uncovered, reported in 1931 in a series of three articles in the Journal of Experimental Medicine, was quite remarkable (36, 54, 55). They discovered two agents working synergistically to produce the disease, with neither producing severe disease on its own. The first organism, very much like the Pfeiffer bacillus, was named Haemophilus influenzae suis and failed to induce experimental disease by itself. The second organism, a newly recognized filterable virus, induced a milder disease in experimental pigs than seen on pig farms. The more severe disease in swine resulted when the two agents were administered simultaneously. It later emerged in the report by Wilson Smith, C. H. Andrewes, and Patrick Playfair Laidlaw that the human and swine influenza viruses were antigenically closely related (57). As Shope put it, “. . . despite the failure of human investigators of the 1918 influenza pandemic to discover the cause of the outbreak, Mother Nature, using swine as her experimental animals, had done so” (56). Shope reported that he and Laidlaw independently reached the conclusion of the “. . . likelihood that swine had indeed acquired their infection from man in 1918. . . .”

Prior to his work with Smith and Andrewes in which the virus of human influenza was isolated in ferrets, Laidlaw had collaborated with S. W. Dunkin on the experimental study of canine distemper in ferrets (13–15). The work was conducted at the National Institute for Medical Research Farm Laboratories, Mill Hill, London, United Kingdom, where thorough procedures were employed to prevent exogenous infection of experimental animals. The reasons to use the ferret were that it could “be confined in a small space with ease and comfort” and that keepers claimed that ferrets were very susceptible to dog distemper, which could wipe out an entire breeding colony. Hence, special buildings, cages, personnel practices, and experimental procedures to study ferrets were well established at Mill Hill by the 1920s. In developing the ferret model under such controlled conditions, Laidlaw and Dunkin successfully showed experimental transmission of canine distemper virus to the ferret with overt expression of clinical and pathological features of disease. They demonstrated the disease to be caused by a filterable virus, not by the bacterium Bacillus bronchisepticus (Bordetella bronchiseptica), which they characterized as a secondary invader (15). When influenza appeared again in London in 1933, “The ferret obviously was the animal to test for susceptibility to influenza. . . .” (6). Laidlaw’s team was the right group to perform the studies to isolate a filterable agent.

Isolation of human influenza virus in ferrets, reported in the 8 July 1933 issue of The Lancet by Smith, Andrewes, and Laidlaw, was a signal event in the history of human influenza (57). The article described work that was fastidious in the care to exclude exogenous infection and elegant in the clarity of its results. It also demonstrated the experimental serendipity of susceptibility to various viral infections by different species of animals, so-called “species specificity.” Although the possibility of influenza being a viral disease had been raised in about 1914 (31), ambiguous results had been obtained in humans, and unsuccessful attempts were made in other species. Smith et al. commented that “The filtrates, proved to be bacteriologically sterile, were used in attempts to infect many different species. All such attempts were entirely unsuccessful until the ferret was used . . .” (57).

The report in 1933, which the investigators termed “a preliminary communication,” detailed a number of critical parameters for experimentation. These included the source and nature of the inoculum, throat washings from people sick with influenza. Experimental manipulation and important clinical observations in ferrets included intranasal instillation, the biphasic clinical course, the nasal histopathology in infected ferrets, and serial passage. Finally, the characteristics of the agent were documented, including filterability, the absence of bacterial growth, and the neutralization of the virus by serum taken from people who had recovered from clinical influenza and from ferrets that had recovered from experimental infection. Smith and colleagues also studied the relationship to the virus of swine influenza received from Richard Shope; they found “a close antigenic relationship” (57). However, “[i]n striking contrast to swine influenza,” there was no synergistic role for H. influenzae suis in the production of experimental disease in ferrets.

The Mill Hill investigators’ report on the successful use of the ferret as an animal model received prompt confirmation from investigators on other continents. For example, T. Francis, at the Rockefeller Institute in New York City, working with sputum obtained from patients in a 1934 influenza epidemic in Puerto Rico, transmitted the disease to ferrets (18). F. M. Burnet reported the experimental transmission of influenza to ferrets from a 1935 epidemic in Melbourne, Australia (4).

The successful isolation of human influenza virus in the ferret in several laboratories triggered the exploration of other biological systems. Andrewes et al. reported the successful transmission of ferret-passed virus to mice (1), which was also reported in the following month by Francis (18). Reports of the successful cultivation of the virus in minced chicken embryo soon emerged (19, 58). Smith concluded that the egg membrane technique was “unsuitable for the study of this virus” (58). However, further studies would show that this biological system, the embryonated egg of chickens, was remarkably productive for the understanding of human influenza infection.

There are parallels between the yellow fever story and the study of the cause of human influenza. Noguchi claimed to have isolated a bacterial cause of yellow fever, Leptospira icteroides, in guinea pigs. The bacterium, while causing symptoms in guinea pigs similar to those of yellow fever, turned out not to be the cause of yellow fever, and the guinea pig turned out not to be a susceptible host of yellow fever. As noted above, Pfeiffer in 1893 reported the isolation of a gram-negative bacterium as the cause of human influenza (48). Haemophilus influenzae, or Pfeiffer’s bacillus, as it came to be known, was for some time thought to be the cause of influenza (42). Richard Shope and Paul Lewis found Haemophilus influenzae suis to be associated with swine influenza (36, 54, 55). It was to be shown that the ferret was the model of choice to study human influenza and that a synergistic bacterial infection was not present (57).

There was also a tragic link to three of the diseases discussed in this chapter. Paul A. Lewis was one of the first to transmit poliovirus serially in monkeys (16) and to identify it as a filterable agent in his work with Flexner (17). He had collaborated with Shope on his studies of swine influenza (70), only to later succumb to yellow fever while studying it in Brazil.