Influenza Mixes Its Pitches: Lessons Learned to Date from the Influenza A (H1N1) Pandemic

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This note will appear towards the end of the 2009 baseball season, and the authors may perhaps be excused for resorting to a metaphor derived from that game. As Mike Stadler notes in The Psychology of Baseball (1), one of the fascinations of baseball to fans relates to the fact that professional players literally achieve the impossible on a daily basis. Major league pitchers throw a ball so hard, and have the ability to make the ball ‘break’ or swerve so sharply, that it is actually impossible for the eye of a batter to follow as it crosses the plate. As such, batters actually need to make decisions about whether or not to swing, and where to swing, before the ball has even left the pitcher’s hand. If the pitcher’s delivery didn’t vary from pitch to pitch, presumably a good hitter would learn to anticipate the ball’s placement, and would hit successfully often. But good pitchers mix their pitches: change the speed, change the degree to which they break or slide across the plate, and change the placement. No wonder the best hitters succeed only three times out of 10. A reader who has been paying attention to both the baseball season and the almost perfectly coincident influenza pandemic, which emerged following the occurrence of disease caused by a novel swine-origin influenza A (H1N1) virus in Mexico in April 2009 (2), will anticipate what we are about to say next. Influenza, as an RNA virus with a segmented genome (3), accumulates mutations and recombines freely with other strains (eg, the current pandemic strain is a mixture of known swine, avian and human strains) (4). As such, the virological and epidemiological characteristics of a novel influenza strain represent the infectious disease equivalent of a well-thrown knuckleball, a pitch whose movements may be unpredictable even to the pitcher. As the infectious disease specialist ‘batters’, we nonetheless need to make rapid decisions about our actions regarding influenza: how and when should nonpharmaceutical mitigation strategies be used? How should the public be informed of risk? How should our limited supplies of antiviral drugs be allocated? This problem is further compounded by our remarkably limited knowledge of the genesis and behaviour of influenza pandemics. Indeed, there are only three pandemics (including the present one) during which viruses were actually identifiable using laboratory diagnostic methods (with the characterization of earlier pandemics based largely on serological testing) (5). The degree to which prior influenza pandemics and epidemics were identified ‘indirectly’ is exemplified by the work of Robert Graves, an eminent 19th century clinician (he of “Graves’ disease” fame), who documented the presence of an influenza epidemic in 19th century Dublin by counting over 700 excess burials in that city’s Prospect Cemetary (6). Infectious disease trivia buffs will know that Haemophilus influenzae is so named because it was mistakenly believed (as Pfeiffer’s bacillus) to be the etiological agent of the 1918 influenza pandemic (7). In the 1957 and 1968 pandemics, diagnosis was achieved through culture and serological testing. Our current testing methods, which are largely based on nucleic acid amplification techniques, far exceed earlier methods in sensitivity, which reduces our ability to compare the epidemiology of earlier pandemics to the current pandemic directly. Our gap in understanding with respect to the molecular epidemiology of earlier pandemics and shift events is even greater: the number of influenza sequences available in the United States National Institutes of Health decreases markedly with time. For example, a July 31, 2009, search of the Genbank flu sequence archive (8) retrieved 1008 sequences for the influenza A HA genes from 2009 alone; by contrast, only 98 sequences for viruses circulating during the four decades between 1918 and 1957.