1918 Influenza, a Puzzle with Missing Pieces

hanks and Brundage offer thought-provoking hypotheses about infl uenza pathogenesis during the catastrophic 1918–1919 pandemic (1). Although we neither agree nor disagree with their views, its central hypothesis of T-cell–mediated immunopathogenesis begs examination of past events in light of modern immunologic and virologic understanding. We also emphasize that effects of the pandemic virus should not be measured only by illness and death in 1918–1919, but should also take into account disease caused by its descendent seasonal and pandemic infl uenza viruses up to the present (2). Thus, for human infl uenza history to be better understood, it must be continually reevaluated. Specifi cally, Shanks and Brundage hypothesize that high mortality rates in 1918 resulted from immunopathogenic effects of cell-mediated immune responses elicited by previously circulating infl uenza viruses. They also suggest that clues to immunopathogenic mechanisms are found in the unique, well-documented, W-shaped age-specifi c mortality curve of the 1918 pandemic (3) (Figure) in which the typical (U-shaped) curve of pandemic infl uenza, featuring mortality rate peaks in young and old persons, was augmented by an unprecedented third mortality rate peak in persons 20–40 years of age. A complicating fact about 1918–1919 mortality patterns and pathogenesis hypotheses is that for ≈98% of infected persons, infl uenza was clinically unremarkable in its traditional signs and symptoms (fever, cough, myalgia) and severity (4). Clinical and epidemiologic differences were confi ned to 2 aspects: higher frequency of its long-appreciated post-illness complication— bacterial pneumonia (5)—and an unusual peak in fatal or nonfatal pneumonia cases in persons 20–40 years of age. In 1918, a higher percentage of persons of all ages, and especially those 20–40 years old, experienced infl uenza that led to cases of secondary bacterial pneumonia, which were caused by highly prevalent pneumopathogenic bacteria (especially pneumococci, streptococci, and staphylococci). These bacteria had been continuously causing primary pneumonia and pneumonia after infl uenza and other respiratory illnesses, and had long been exacting a substantial death toll. These 1918 postinfl uenza cases of pneumonia produced case-fatality rates similar to those of noninfl uenza pneumonia caused by the same organisms. Moreover, antibacterial vaccines administered in 1918–1919 seem to have prevented postinfl uenza deaths (6). Infl uenza mortality rates in 1918–1919 were most strongly associated with increased case incidence of, not increased severity of, common complicating bacterial pneumonia, and this fi nding was seen especially in persons 20–40 years of age. The epidemiology of 1918 infl uenza …