Questioning the Salicylates and Influenza Pandemic Mortality Hypothesis in 1918–1919

To the Editor—Starko [1] presented an original and creative idea to explain a continuing medical mystery, the extreme virulence of the 1918–1919 influenza pandemic. Her hypothesis, that the use of salicylates exacerbated the tendency of the infection to produce fluid in the lungs, has face validity and is supported by anecdotal evidence of widespread use of aspirin in the United States during the pandemic. The international characteristics of the pandemic make the salicylate hypothesis difficult to sustain as the primary explanation for the unusual virulence of the 1918–1919 influenza pandemic. Worldwide, an estimate of the mortality of the 1918–1919 pandemic is 50 million deaths, with a range of up to 100 million deaths [2]. Taking the 50 million figure, this was about 2.5% of the world population. By contrast, in the United States, mortality was on the order of 0.5%. Clearly, the rest of the world was struck more severely, on average, than the United States. India serves as a useful vignette. Mortality in India was staggering, with estimates of 18.5 million persons dead [3] and higher [4]. Indeed, the Indian peasant population was so severely affected that economics Nobel laureate Theodore W. Schultz used the pandemic as a natural experiment in per capita agricultural output [5]. Given the huge number of deaths in India and the burden among subsistence agricultural workers, it is extremely implausible that salicylates played an exacerbating role in anything other than a trivial percentage of Indian mortality. Thus, Starko’s intriguing hypothesis fails the test of dose-response. That is to say, in countries such as the United States, where salicylates were more available, mortality was much lower compared with regions where salicylates were less readily available. These observations are at the ecological level, and such comparisons are notoriously susceptible to confounding. However, if the salicylate hypothesis applies universally, then the ecological confounding would have to operate such that the salicylate-influenza connection is stronger in countries with less access to aspirin, which seems a priori unlikely. Indeed, the overwhelming majority of the millions of Indian peasants who were killed by the flu certainly had no access to salicylates whatsoever. If the salicylate hypothesis only works in the United States and in similar settings, then we question its validity given the worldwide scope of severe mortality in 1918–1919.