by The Pandemic Century- One Hundred Years of Panic, Hysteria
After his death in 1885, Pasteur’s disciples, such as Emile Roux and Roux’s star pupil Charles Nicolle, continued these investigations. Dividing his time between biomedical research and administrative duties—it was Roux who created the Pasteur Institute—by 1902 Roux had identified ten diseases that he believed were due to filter-passing viruses. The same year, he persuaded Nicolle to join the Pasteur Institute in Tunis. Though greatly attracted by literature, Nicolle had bowed to the wish of his physician father to study medicine, but while practicing in Rouen had suffered a hearing loss that prevented him from effectively using a stethoscope—an accident that may have persuaded him to concentrate on bacteriology instead and accept the position in North Africa. Nicolle quickly showed himself worthy of Roux’s faith, and on arriving in Tunis launched a study of epidemic typhus. At the time, most doctors thought typhus, which tended to decimate armies at times of war and was a particular problem in prisons and other closed institutions, was a disease of filth and squalor. No one realized typhus was actually transmitted by the body louse (Pediculus humanis corporis), which infested unlaundered clothing, or that the agent was a tiny intracellular organism belonging to the Rickettsia family—the same family responsible for the tick-borne disease, Rocky Mountain spotted fever. Nicolle began by injecting guinea pigs with blood from patients with typhus, showing that, although they did not develop the disease, the inoculations resulted in transient fevers—evidence that they were subclinically, or as Nicole put it, “inapparently” infected by something in the blood. However, the crucial observation came when he was observing typhus patients entering the Sadiki Hospital in Tunis and realized that they ceased to be infectious as soon as their clothing was removed and they were bathed and dressed in hospital uniforms. Suspecting that lice, not dirt, was the cause, Nicolle requested a chimpanzee from Roux and injected the chimp with blood from a typhus patient. When the chimp developed fever and skin eruptions, he injected its blood into a macaque monkey, and when the macaque also fell ill he allowed lice to feed on it. In this way, he was able to transfer the infection to other macaques and, eventually, a chimp. In September 1909, he communicated his finding that lice were the carriers of typhus to the French Academy of Sciences—a discovery for which in 1928 he was awarded the Nobel Prize.
Although Nicolle’s efforts to develop a vaccine for typhus would be unsuccessful (this would be left to others), it was only natural that when the influenza epidemic struck he would want to study it using similar methods. There is no evidence that Nicolle had worked on influenza before or had tried to culture its putative bacillus, but by the summer of 1918 French bacteriologists raised in the Pasteurian tradition were finding it increasingly difficult to isolate Pfeiffer’s organism and were becoming increasingly skeptical of the German’s claims. Instead, Nicolle and his assistant, Charles Lebailly, began to suspect that, like the microbe of yellow fever, influenza might be a filter-passer.
By late August the flu had reached Tunis and there were signs of la grippe everywhere. Whether this was an extension of the same flu that had visited Europe in the spring and early part of the summer or a different strain, such as the more virulent strain seen at Devens in the fall of 1918, is difficult to say. The point is that rather than trying to cultivate the bacillus, Nicolle decided to use the same method he had used with typhus. Accordingly, in late August he and Lebailly requested more test animals and began monitoring patients with flu. Chimpanzees were now impossible to obtain, so once again Nicolle settled on macaques, a fortunate choice as it turned out. Nicolle and Lebailly then looked for a household afflicted by the epidemic to be sure that they were examining a definitive case of la grippe, and not some other disease. The patient they selected was a forty-four-year-old man, identified only as “M.M.,” who had fallen ill on August 24, together with his daughters. Six days later, M.M. was displaying classic symptoms of influenza—nasopharyngitis, a violent headache, and fever—and Nicolle and Lebailly drew some blood. The following day, September 1, they also collected bronchial expectorations. At this point, Nicolle and Lebailly had no idea if it was possible to transmit flu to a monkey or if the organism responsible for the disease was to be found in human blood, sputum, or other bodily fluids. However, while noting that M.M.’s sputum contained “diverse” bacteria, including B. influenzae, they observed that the bacillus was present in “minimal” amounts and did not attempt to prepare pure cultures of the bacillus. Instead, they removed B. influenzae and other bacteria from M.M.’s bronchial expectorations using a Chamberland filter and injected the filtrate directly into the eyes and nose of a Chinese bonnet monkey (Macacus sinicus). At the same time, they administered the filtrate to two human volunteers, a twenty-two-year-old who was inoculated under the skin, and a thirty-year-old who received the filtrate intravenously. Six days later, both the macaque and the first volunteer came down with symptoms highly suggestive of flu—the monkey developed a fever and marked depression with loss of appetite, while the twenty-two-year-old experienced rapid onset of fever, accompanied by a runny nose, headache, and generalized body aches. As no one else in the first volunteer’s living quarters developed influenza at the same time, Nicolle and Lebailly reasoned that the person had contracted flu from the filtrate. However, the second volunteer showed no signs of illness, even after fifteen days. Nicolle and Lebailly also attempted to infect other macaques by inoculating them with blood from M.M., but without success (the injections were given in either the monkeys’ peritoneal cavities or their brains). Using blood from the macaque, they also inoculated a third volunteer who had developed apparent symptoms of influenza, but this also proved unsuccessful. Finally, on September 15 they repeated the first experiment with a long-tailed macaque (Macacus cynomologus) and a fourth volunteer. This time the filtered expectorations resulted in only a slight rise in temperature in the monkey and induced mild symptoms of flu in the volunteer.
By today’s standards the experiments were hardly ideal—for instance, Nicolle and Lebailly did not use other monkeys or humans as controls (presumably because macaques were in short supply), nor do they appear to have been “blinded” from their subjects, as would be required today. Moreover, they did not investigate the pathogenic effect of filtered sputum from noninfluenza cases, nor were they able to conduct passage experiments, as Pasteur had done with rabies in rabbits, to manipulate the virulence of the organism and reproduce the disease through several generations. Nevertheless, Nicolle and Lebailly concluded that the bronchial expectorations of influenza patients were virulent and that both the bonnet monkey and the long-tailed macaque were susceptible to subcutaneous inoculation with the filtered fluids. Flu therefore was an “organisme filtrant”—a filtered organism. They further concluded that the filtered virus had “reproduced the disease” in the two people inoculated subcutaneously.
Nicolle and Lebailly’s paper detailing their findings was read by Roux before the French Academy of Sciences in Paris on September 21. In other words, the day before Welch arrived at Devens and witnessed the carnage sweeping the camp. Ordinarily, such an announcement before a respected scientific body would make other researchers around the world sit up and take notice. But the world was in the midst of war and Welch and his colleagues had more pressing concerns. Besides, even if reports of Nicolle and Lebailly’s study had reached the surgeon general’s office in Washington, DC in time and the news had been communicated to Welch—and there is no evidence that at this stage it was—it is unlikely that he would have given it particular credence. After all, Nicolle and Lebailly’s investigations could hardly be considered conclusive. Moreover, before accepting their findings, Welch would have wanted other researchers—preferably American ones—to duplicate their experiments. The ideal place to do this was at the Rockefeller Institute, now an auxiliary laboratory of the US Army, or at nearby naval research laboratories in Boston and Rhode Island. The bacteriological paradigm of influenza could not be overturned on the basis of just a few experiments conducted in North Africa thousands of m
iles from the main theaters of war and the world’s preeminent medical research institutions.
Today, we know that Nicolle and Lebailly’s supposition was correct. Influenza is a virus. To be precise, it is composed of eight slender strands of ribonucleic acid (RNA)—by contrast the building blocks of human and other mammalian cells are comprised of double-stranded helix spirals of deoxyribonucleic acid (DNA). However, Nicolle and Lebailly were almost certainly not justified in reaching that conclusion based on their experiments. First, while it is possible they could have infected the human volunteers with influenza if they had dripped the filtrate directly into their noses, it is extremely unlikely they could have done so by injecting the filtrate under the skin. That is not to say that the volunteers did not have influenza, only that they probably did not get it the way that Nicolle and Lebailly thought they did. Second, although it is possible to infect a range of Old World monkeys with human flus (squirrel monkeys are particularly susceptible), macaques are a poor refractory species for human influenza and rarely develop visible respiratory symptoms or lung damage. It is also very difficult to get them to “take” the disease by dripping filtrate into their noses or by exposing them to aerosols containing the virus—indeed, in studies conducted in monkeys since 1918 researchers have reported far greater success with intravenous inoculations of the virus, somewhat ironic given Nicolle and Lebailly’s reported failure in this respect.
To be fair, in the absence of a reliable animal model for human influenza and a means of propagating the virus in living cells, in 1918 no researcher stood much chance of demonstrating that influenza was a virus. That only became possible after 1933, when a team of British researchers studying canine distemper demonstrated that ferrets were highly sensitive to influenza and could be inoculated simply by introducing filtered sputum into their nasal passages. When, soon after, one of the ferrets sneezed on a scientist who was handling it and the scientist went on to develop flu, the viral etiology of flu was considered proven. This was followed in 1934 by the discovery that influenza viruses could be cultivated in chick egg embryos, freeing researchers from the need to collect samples from patients during an outbreak or forcing them to abandon their research when epidemics ended and the supply of flu patients dried up. With chick embryo cultivation, the virus could now be propagated continuously in the laboratory, and scientists could be sure that they were performing experiments with the same strain of virus, something that had not been possible in 1918. By passaging flu viruses through embryonated hen’s eggs, scientists could also attenuate the viruses and manufacture vaccines, thereby providing protection against whichever type of flu happened to be circulating that season.‡
UNLIKE AIDS AND SMALLPOX, influenza is not a particularly disfiguring disease; for the most part, it does not leave visible marks or scars on the body. Nor does it cause victims to retch black fluids from their stomachs as yellow fever does, or induce uncontrollable diarrhea as cholera does. But for those who witnessed the disturbing cyanotic end stages of the disease, when victims’ lungs were compromised by pneumonia and their cheeks and lips turned blue then dark purple, Spanish flu was shocking to behold. This was not only the case at Devens and other US Army camps, but on the transatlantic troopships that conveyed American soldiers to Europe. On the Leviathan, a massive transport that set sail from New York at the end of September, eyewitnesses described having to step through “pools of blood from severe nasal hemorrhages.” At first men were confined to steel cabins below deck in the hope of containing the infection, but within days of leaving New York so many were ill and the stench below decks was so overpowering that they were brought outside to breathe the sea air. In an era before antibiotics, and with no vaccine, doctors were powerless to heal the afflicted. Instead, they distributed fresh fruit and water. Sadly, like the bloody discharges, these also soon ended up on the floor, so that the decks became “wet and slippery, [with the] groans and cries of the terrified added to the confusion of the applicants clamoring for treatment.” By the time the Leviathan arrived at Brest on October 8, some 2,000 soldiers were ill and eighty had died, the majority of their bodies having been disposed of at sea.
New Yorkers were unaware of the dreadful scenes on the Leviathan. When the vessel set sail, most New Yorkers still thought of Spanish influenza as an exotic foreign disease. Public health officials, keen to contribute to the war effort, colluded in the deception, downplaying the flu’s impact on American servicemen even as they talked up the toll it was exacting on German troops. “You haven’t heard of our doughboys getting it, have you?” queried New York’s Commissioner of Health Royal S. Copeland. “You bet you haven’t, and you won’t.” Slowly but surely, however, the virus was swimming closer to shore, conveyed in the bodies of the passengers and crew of returning troopships and commercial liners. And all the while, as it passaged through more and more bodies, it was growing in virulence. The result was that when it made landfall soldiers would not be the only casualties.
It is difficult to say how and where the second wave broke. Perhaps the fall outbreak began at Commonwealth Pier, in Boston, before spreading to Ayer and other towns in Massachusetts. Or perhaps there were several simultaneous introductions of the virus. New York, for instance, saw a marked increase in influenza deaths, particularly in middle age groups, in February–April 1918, though the first cases in the second wave were associated with passengers alighting from a Norwegian steamer in the middle of August. By the end of September, cases in New York were running at eight hundred a day, and Copeland took the unusual step of ordering quarantines (wealthy patients were allowed to remain in their homes, but those living in boarding houses or tenements were removed to city hospitals where they were kept under strict observation). Quarantines were something new and unprecedented for influenza—before the war, flu had not even been a notifiable disease—and New Yorkers could not help but be reminded of the polio epidemic two years earlier. Then, officials had gone door-to-door rounding up children with symptoms of “infantile paralysis,” spreading terror in neighborhoods like Brooklyn where recent Italian immigrants were suspected of harboring the disease. However, the Spanish flu was as likely to visit a Park Avenue brownstone as a Brooklyn tenement, and as each day brought new reports of sickness, the city grew increasingly uneasy. Copeland tried to reassure New Yorkers by explaining that influenza was only communicable “in the coughing and sneezing of one who actually has influenza,” not from someone living in the same household as someone stricken with flu but who did not show symptoms. He also insisted that a vaccine was imminent. He was referring to the efforts by scientists like Park and Williams at the New York public health laboratory who were experimenting with vaccines using mixed strains of B. influenzae. By the middle of October, Park was reporting that animals immunized with a heat-killed vaccine made from these bacterial cocktails showed specific antibodies against the bacillus. Scientists at Tufts Medical School in Boston and the University of Pittsburgh’s medical school were reporting similar progress with their own version of heat-killed bacterial vaccines. But while Park was having more success culturing B. influenzae and getting it to agglutinate to antibodies in serum, privately he was beginning to worry that the results might be a reflection of improved culture techniques rather than proof of the bacillus’s etiological role. “There is of course the possibility that some unknown filterable virus may be the starting point,” he wired a colleague. In spite of these misgivings, Park’s vaccine was eventually released to the military. It was also used to immunize 275,000 employees of the US Steel Company. There is no evidence that these primitive vaccines and serums had any effect on influenza whatsoever.