Scientists and public health officials, wary that the H5N1 avian influenza virus could trigger an influenza pandemic, have looked to past pandemics, including the 1918 ?Spanish Flu,? for insight into pandemic planning. However, in a Journal of Infectious Diseases review article now posted online, David M. Morens, M.D., and Anthony S. Fauci, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, conclude that studies of the 1918 influenza pandemic, which killed some 50 to 100 million people around the globe, have so far raised more questions than they answer.

?Today, nearly a century after the 1918 influenza pandemic, its mysteries remain largely unexplained,? says Dr. Fauci, NIAID director. ?Much work remains to be done, by scientists as well as by historians and other scholars, with regard to the many unanswered questions surrounding this historic pandemic. These studies must be part of our preparedness efforts as we face the prospect of a future influenza pandemic.?

Dr. Morens adds, ?In addition to ongoing laboratory studies, we feel that much can be learned from examining the vast scientific literature related to the 1918 influenza pandemic and previous influenza pandemics. A treasure trove of journal articles and other materials exists in many languages that can be mined for novel information with practical applications relevant to the threat of pandemic influenza we face.?

In their article, Drs. Morens and Fauci review several topics, including the origins of the 1918 pandemic influenza virus, the excess mortality of the pandemic, the predilection to kill the young and healthy, the lower-than-expected mortality among the elderly, and the cyclicity of influenza pandemics over the past 100 years. Such topics are relevant today as highly pathogenic H5N1 avian influenza viruses have spread from Asia to the Middle East, Europe and Africa.

One of the great unsolved mysteries surrounding the 1918 pandemic is why it tended to kill the young and healthy. Unlike yearly influenza epidemics, in which death rates are highest among infants, the elderly and those with chronic health conditions, the 1918 influenza pandemic took its greatest toll on healthy adults between the ages of 20 and 40. One possible explanation, supported by recent studies in mice with a reconstructed version of the 1918 virus, is that an over-responsive immune system may release a ?cytokine storm,? or excessive amount of immune system proteins that trigger inflammation and harm the patient in the process. Of note, most deaths among humans infected with the H5N1 avian influenza virus have occurred in individuals under the age of 40. However, as the authors point out, it is not yet known whether there is a higher percentage of young people in the affected populations compared to older people, whether younger people are more susceptible to infection or whether they have more exposure to infected birds.