To determine if fatal infections caused by different highly virulent infl uenza A viruses share the same pathogenesis, we compared 2 different infl uenza A virus subtypes, H1N1 and H5N1. The subtypes, which had shown no pathogenicity in laboratory mice, were forced to evolve by serial passaging. Although both adapted viruses evoked diffuse alveolar damage and showed a similar 50 % mouse lethal dose and the same peak lung concentration, each had a distinct pathologic signature and caused a different course of acute respiratory distress syndrome. In the absence of any virus labeling, a histologist could readily distinguish infections caused by these 2 viruses. The different histologic features described in this study here refute the hypothesis of a single, universal cytokine storm underlying all fatal infl u-enza diseases. Research is thus crucially needed to identify sets of virulence markers and to examine whether treatment should be tailored to the infl uenza virus pathotype. According to the World Health Organization, influenza annually infects 5%–15 % of the global population, causing 3–5 million cases of severe illness and ≈500,000 reported deaths. The persistence of influenza A virus (H5N1) in poultry populations over the past 6 years and the ability of those viruses to cause fatal infections in humans, along with the recent pandemic (H1N1) 2009 outbreaks, have raised fears of a renewed catastrophic influenza outbreak comparable to that of 1918, which caused death in 0.2%–8 % of those infected in various countrie
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