The Great Influenza: The Epic Story of the Deadliest Plague in History - John M. Barry (2004)

Part X. ENDGAME

Chapter 34

BY WORLD WAR I, the revolution in American medicine led by William Welch had triumphed. That revolution had radically transformed American medicine, forcing its teaching, research, art, and practice through the filter of science.

Those in the United States capable of doing good scientific research remained a small, almost a tiny, cadre. The group was large enough to be counted in the dozens, and, counting the most junior investigators, by the mid-1920s it reached several dozen dozens, but no more.

They all knew each other, all had shared experiences, and nearly all had at least some connection to the Hopkins, the Rockefeller Institute, Harvard, or to a lesser extent the University of Pennsylvania, the University of Michigan, or Columbia. The group was so small that it still included the first generation of revolutionaries, with Welch and Vaughan and Theobald Smith and a few others still active. Then came their first students, men only a few years younger: Gorgas, who had reached mandatory retirement age from the army days before the war ended—the army could have allowed him to remain but he had no friends among army superiors—and who then shifted to international public health issues for a Rockefeller-funded foundation; Flexner and Park and Cole in New York; Milton Rosenau in Boston; Frederick Novy at Michigan; and Ludwig Hektoen in Chicago. Then came the next half generation of protégés: Lewis in Philadelphia; Avery, Dochez, Thomas Rivers, and others at Rockefeller; George Whipple in Rochester, New York; Eugene Opie at Washington University in St. Louis; and a few dozen more. It was only in the next generation, and the next, that the numbers of true researchers began to multiply enormously and spread throughout the country.

The bonds that held these men together were not of friendship. Some of them—Park and Flexner, for example—had no love for each other, many had happily embarrassed a rival by finding flaws in his work, and they had no illusions about each other’s virtues. The profession had grown large enough for maneuvering within it. If one listened closely, one could hear: “The appointment of Dr. Opie as the primary key man in this plan would be a fatal mistake.” Or, “Jordan seems at first a rather dazzling possibility, but I am a little afraid…that he is not a man who can be absolutely certain to stand up for his convictions in a tight place.” Or, “Of the names you suggest, I would distinctly prefer Emerson but I fear he would be particularly unacceptable to Russell and Cole, and perhaps to the [Rockefeller] Foundation group in general, as I have the impression that he has been somewhat at outs with them.”

Yet these men also recognized that whatever each other’s flaws might be, each of them also had strengths, remarkable strengths. Their work was good enough that, even if in error, one could often find in that error something new, something important, something to build upon. It was an exclusive group and, despite rivalries and dislikes, almost a brotherhood, a brotherhood that included a very few women, literally a handful, and in bacteriology these very few women did not extend far beyond Anna Williams and Martha Wollstein.*

All of these scientists had worked frenetically in their laboratories from the first days of the disease, and none of them had stopped. In those most desperate of circumstances, the most desperate circumstances in which they—and arguably any scientist—ever worked, most of them had willingly, hopefully, accepted less evidence than they would normally have to reach a conclusion. For of course as Miguel de Unamuno said, the more desperate one is, the more one hopes. But for all their frenzy of activity, they had still always avoided chaos, they had always proceeded from well-grounded hypotheses. They had not, as Avery said with contempt, poured material from one test tube into another. They had not done the wild things that had no basis in their understanding of the workings of the body. They had not given quinine or typhoid vaccine to influenza victims in the wild hope that because it worked against malaria or typhoid it might work against influenza. Others had done these things and more, but they had not.

They also recognized their failures. They had lost their illusions. They had entered the first decades of the twentieth century confident that science, even if its victories remained limited, would triumph. Now Victor Vaughan told a colleague, “Never again allow me to say that medical science is on the verge of conquering disease.” With the contempt one reserves for one’s own failings, he also said, “Doctors know no more about this flu than 14th century Florentine doctors had known about the Black Death.”

But they had not quit. Now this scientific brotherhood was beginning its hunt. It would take longer than they knew.

So far each laboratory had been working in isolation, barely communicating with the others. Investigators had to meet, to trade ideas, to trade laboratory techniques, to discuss findings not yet published or that one investigator thought unimportant that might mean something to another. They had to try to piece together some way to make concrete progress against this pestilence. They had to sift through the detritus of their failures for clues to success.

On October 30, 1918, with the epidemic on the East Coast fading to manageable proportions, Hermann Biggs organized an influenza commission of leading scientists. Biggs had a proud history, having made the New York City municipal health department the best in the world, but, fed up with Tammany politics, had left to become state commissioner of public health. His commission included Cole, Park, Lewis, Rosenau, epidemiologists, and pathologists. Welch, still recovering in Atlantic City, was too ill to attend. Biggs opened the first meeting by echoing Vaughan: “[T]here has never been anything which compares with this in importance…in which we were so helpless.”

But unlike Vaughan he was angry, declaring their failures “a serious reflection upon public health administration and work and medical science that we should be in the situation we now are.” They had seen the epidemic coming for months. Yet public health officials and scientists both had done nothing to prepare. “We ought to have been able to obtain all the scientific information available now or that can be had six months from now before this reached us at all.”

He was determined that they would now address this problem, and solve it.

It would not be so easy. And even in that first meeting the problems presented themselves. They knew virtually nothing about this disease. They could not even agree upon its nature. The pathology was too confusing. The symptoms were too confusing.

Even this late Cole still wondered if it was influenza at all: “All who have seen cases in the early stage think we are dealing with a new disease…. One great difficulty for us is to find what influenza is and how to make the diagnosis…. We have been going over all case histories during this epidemic and it is almost as difficult to see which is influenza—a very complex picture.”

A navy scientist observed, “In several places there has been a similarity of symptoms with the bubonic plague.”

A Harvard investigator dismissed their observations: “It is the same old disease and does not change a bit in its character.”

But it did change, changed constantly, from mild cases of influenza from which victims recovered quickly to cases with strange symptoms never associated with influenza, from sudden violent viral pneumonias or ARDS to secondary invaders causing bacterial pneumonias. All these conditions were being seen. Lewellys Barker, Cole’s mentor at the Hopkins, noted, “The pneumonia specimens which came in from different areas are very different. Those from Devens are entirely different from those from Baltimore and they differ from several other camps. The lesions are quite different in different localities.”

They reached no consensus about the disease and moved on to discuss the likely pathogen. There too they could reach not even a tentative conclusion. Investigators had found Pfeiffer’s influenza bacillus, yes, but Cole reported that Avery had also discovered B. influenzae in 30 percent of healthy people at the Rockefeller Institute. That proved nothing. It might be commonly found now because of the epidemic and be an unusual finding in nonepidemic times. Besides, as they all knew, many healthy people carried pneumococci in their mouths and did not get pneumonia. And in the lungs of epidemic victims they had also found pneumococci, streptococci, staphylococci, and other pathogens. Park asked about the chances that a filterable virus caused the disease. Rosenau was conducting experiments pursuing that question.

They knew so little. So little. They knew only that isolation worked. The New York State Training School for Girls had quarantined itself, even requiring people delivering supplies to leave them outside. It had had no cases. The Trudeau Sanatorium in upstate New York had similar rules. It had no cases. Across the continent, a naval facility in San Francisco on an island that enforced rigid quarantine. It had no cases. All that proved was that the miasma theory, which none of them believed in anyway, could not account for the disease.

Yet they ended with agreement. They agreed on lines of approach, on the work that needed to be done. Only on that—in effect on how little they knew—they could agree.

They intended to proceed down two paths: one exploring the epidemiology of the disease, the other tracing clues in the laboratory. The first task in both lines of attack was to cut through the fog of data that was coming in.

They planned precise epidemiological investigations: correlating public health measures and deaths; performing extremely detailed studies in selected areas, for example, isolating small communities where they would account for the seventy-two hours before every single person who suffered from influenza felt the first symptoms; taking detailed personal histories of both victims and those who had not been attacked; looking for linkages with other diseases, with earlier influenza attacks, with diet.

The epidemiological studies would have the ancillary benefit of exciting and transforming another emerging field of medicine. In November 1918 the American Public Health Association created a Committee on Statistical Study of the Influenza Epidemic, funded largely by the Metropolitan Life Insurance Company. One committee member called this “an opportunity to show what statistics, especially vital statistics, and its methods can do for preventive medicine,” while a colleague saw it as the “possible vindication of the theory of probabilities and the method of random sampling.” In January 1919 the surgeons general of the army, the navy, and the Public Health Service also joined with the Census Bureau to form an influenza committee that grew into a permanent statistical office. Yet at the same time, an epidemiologist present at the first meeting of the Biggs group said, “I realize the problem has got to be solved ultimately in the laboratory.”

Gorgas had had one goal: to make this war the first one in American history in which battle killed more troops than disease. Even with one out of every sixty-seven soldiers in the army dying of influenza, and although his superiors largely ignored his advice, he just barely succeeded—although when navy casualties and influenza deaths were added to the totals, deaths from disease did exceed combat deaths.

Gorgas had largely triumphed over every other disease. U.S. soldiers almost entirely escaped malaria, for example, even while it struck down tens of thousands of French, British, and Italians.

Now two million men were returning from Europe. After other wars, even in the late nineteenth century, returning troops had carried diseases home. British, French, and Russian troops had spread cholera after the Crimean War; Americans troops had spread typhoid, dysentery, and smallpox after the Civil War; Prussians had brought smallpox home from the Franco-Prussian War; and Americans had returned from the Spanish-American War carrying typhoid.

One of Gorgas’s last acts was to set in motion plans to prevent any such happenings this time. Soldiers were kept isolated for seven days before they boarded ships home, and were deloused before embarking. Soldiers would be bringing no disease home.

Meanwhile, the most massive scientific inquiry ever undertaken was taking shape. Biggs’s commission met three more times. By the last meeting, every member would be serving on other commissions as well. The American Medical Association, the American Public Health Association, the army, the navy, the Public Health Service, the Red Cross, and the Metropolitan Life Insurance Company all launched major studies in addition to those already begun, each of them designed to complement and not overlap with the others. At every meeting of every medical specialty, of every public health organization, in every issue of every medical journal, influenza dominated the agenda. In Europe it was the same.

Every major laboratory in the United States continued to focus on the disease. Lewis in Philadelphia kept after it, as did others at the University of Pennsylvania. Rosenau in Boston led a team of Harvard researchers. Ludwig Hektoen and Preston Kyes at the University of Chicago stayed after it. Rosenow at the Mayo Clinic in Minnesota continued to work on it. Every member of the army’s pneumonia commission returned to civilian research and continued to investigate influenza. The Metropolitan Life Insurance Company gave grants to university scientists and actually subsidized both the city of New York and the federal government, giving grants for research by Park and Williams in their New York laboratories and by George McCoy of the Public Health Service’s Hygienic Laboratory.

The army also made “every effort to collect…specimens representing pulmonary lesions due to the present influenza epidemic,” not only from army camps but from civilian sources. These specimens would prove enormously important more than three-quarters of a century later, when Jeffrey Taubenberger would extract the 1918 influenza virus from them and successfully sequence its genome.

At the Rockefeller Institute, Cole put “every available man” to work on it. He also put Martha Wollstein on it. When Captain Francis Blake, who had been part of the army’s pneumonia commission, visited his old colleagues at the institute at Christmas, he found everyone “working tooth and nail on this influenza business with monkeys and everything else.” A week later, out of the army and back at Rockefeller, he said, “I shall be so glad when we can get all this business off our hands and finished up and I can to something else for a change, as it seems as though I have done nothing but work on, and eat, and dream about and live with pneumonia and influenza for six months.”

He would not be free of it any time soon.

Slowly, over a period of months, a body of knowledge began to form. Investigators began to learn about the firestorm that had roared around the world and was continuing to smolder.

First, they confirmed what they had suspected: the lethal fall disease was a second wave of the same disease that had hit in the spring. They based their conclusion on the fact that those exposed to the spring wave had substantial immunity to the later one. The army had the best records. These records involved chiefly young men, so they were not useful in answering some questions. But they could speak to immunity, and clearly demonstrated it. Camp Shelby, for example, was home to the only division in the United States that remained in the United States from March through the fall. In April 1918 influenza sickened 2,000 of 26,000 troops there enough to seek treatment, many more probably had lesser or subclinical infections, and all 26,000 men were exposed to the disease. During the summer, 11,645 new recruits arrived. In October influenza “scarcely touched” the old troops but decimated the recruits. In Europe in the spring, influenza hit the Eleventh Regiment Engineers, making 613 men out of a command of 1,200 ill and killing two, but protecting them from the lethal wave: in the fall the regiment suffered only 150 “colds” and a single death. Camp Dodge had two units of seasoned troops; influenza had struck one group in the spring, and only 6.6 percent of this organization caught influenza in the fall; the other group escaped the spring wave, but 48.5 percent of them had influenza in the fall. And there were many other examples.

Statistics also confirmed what every physician, indeed every person, already knew. In the civilian population as well, young adults had died at extraordinary, and frightening, rates. The elderly, normally the group most susceptible to influenza, not only survived attacks of the disease but were attacked far less often. This resistance of the elderly was a worldwide phenomenon. The most likely explanation is that an earlier pandemic (later analysis of antibodies proved it was not the 1889–90 one), so mild as to not attract attention, resembled the 1918 virus closely enough that it provided protection.

Finally, a door-to-door survey in several cities also confirmed the obvious: people living in the most crowded conditions suffered more than those with the most space. It also seemed—although this was not scientifically established—that those who went to bed the earliest, stayed there the longest, and had the best care also survived at the highest rates. Those findings meant of course that the poor died in larger numbers than the rich. (Questions about race and the epidemic yielded contradictory information.)

But nearly everything else about the disease remained unsettled. Even the interplay between the germ theory of disease and other factors was at issue. As late as 1926, a respected epidemiologist still argued a version of the miasma theory, claiming “a correlation between…influenza and cyclic variation in air pressure.”

In the laboratory, however, the fog remained dense. The pathogen remained unknown. Enormous resources were being poured into this research everywhere. In Australia, Macfarlane Burnet lived through the epidemic as a teenager, and it burned itself into his consciousness. As he said soon after receiving the Nobel Prize, “For me as for many others interested in bacteriology and infectious disease, the outstanding objective in medicine for years was…influenza.”

Yet all this work had not penetrated the fog.

The problem did not lie in any lack of clues. The problem lay in distinguishing the few clues that led in the right direction from all those that led in the wrong direction. This was not bubonic plague. That was among the easiest pathogens to discover: the bacteria that caused it swarmed in the buboes. This was only influenza.

As the second wave of influenza had broken upon the world, thousands of scientists had attacked the problem. In Germany and France they had attacked it, in Britain and Italy, in Australia and Brazil, in Japan and China. But as 1919 wore away, then 1920, as the disease drifted toward mildness, one at a time these thousands began to peel off. They found the problem too difficult to conceptualize—to figure out a way to address it—or the techniques seemed too inadequate to address it, or it lay too far from their old interests or knowledge base. After two years of extraordinary—and continuing—efforts by many of the world’s best investigators, in 1920 Welch made a frustrating prediction: “I think that this epidemic is likely to pass away and we are no more familiar with the control of the disease than we were in the epidemic of 1889. It is humiliating, but true.”

Hundreds of investigators did continue to pursue the question but they could agree on little. Everything was in dispute. And central to those disputes were the old team of William Park and Anna Williams on one side, Paul Lewis and many of those at the Rockefeller Institute on another.

Lewis’s research would end in irony and tragedy. The Rockefeller Institute would discover most of its own investigators in error.

But Oswald Avery would not be in error. Avery would make the most profound discovery of them all.