Table 1.

Important questions posed by the 1918 pandemic

Where did the 1918 virus originate?	An unknown source; unlike H5N1, from an avian influenza-like lineage genetically distinct from those currently known
What was the pathogenesis and why did so many people die?	Different pathogenesis in 1918 not documented: causes of death in 1918 similar to other pandemics; most fatalities had secondary pneumonias caused by common bacteria, ARDS-like syndromes in a minority of cases; higher proportion of severe cases at all ages seen; 1918 virus virulence determinants not yet fully mapped
Why were there so many deaths among the young and healthy?	Unknown; unappreciated host or environmental variables possible, such as a robust immunologic response to the virus in younger individuals resulting in enhanced tissue damage
Why was mortality among the elderly lower than expected?	Unknown; evidence is consistent with previous exposure to a virus eliciting protective immunity, conceivably the virus associated with the 1847 pandemic
Why were there three pandemic waves in 1918 to 1919, and what are the implications for predicting future pandemic spread?	Unknown; at least two virus variants in second wave; identity of viruses in first and third waves not known; epidemiology of rapidly recurrent waves not understood
Do influenza pandemics occur in predictable cycles?	Insufficient evidence for pandemic cyclicity; steps in pandemic emergence not fully understood
Are we better able to prevent morbidity and mortality today?	Yes, in developed world with advanced medical care, antibiotics, antivirals, and effective public health; preventive vaccines would be critical if available in time, but developing world still at great risk

ARDS, acute respiratory distress syndrome.