The effect of influenza on mortality is much greater in Japan than in the United States and can be measured about equally well in terms of deaths from all causes and deaths attributed to pneumonia or influenza. Vaccinating schoolchildren against influenza provides protection and reduces mortality from influenza among older persons.

In economically developed countries, mortality increases distinctly during winter. Many causes have been suggested, including light-dark cycles, temperature/weather, and infectious agents. The authors analyzed monthly mortality in the United States during the period 1959-1999 for four major disease classes. The authors isolated the seasonal component of mortality by removing trends and standardizing the time series. They evaluated four properties: coincidence in mortality peaks, autocorrelation structure and autoregressive integrated moving average (ARIMA) models, magnitude, and age distribution. Peak months of mortality for ischemic heart disease, cerebrovascular disease, and diabetes mellitus coincided appropriately with peaks in pneumonia and influenza, and coefficients of autocorrelation and ARIMA models were essentially indistinguishable. The magnitude of the seasonal component was highly correlated with traditional measures of excess mortality and was significantly larger in seasons dominated by influenza A(H2N2) and A(H3N2) viruses than in seasons dominated by A(H1N1) or B viruses. There was an age shift in mortality during and after the 1968/69 pandemic in each disease class, with features specific to influenza A(H3N2). These findings suggest that the cause of the winter increase in US mortality is singular and probably influenza. Weather and other factors may determine the timing and modulate the magnitude of the winter-season increase in mortality, but the primary determinant appears to be the influenza virus.

There is an ongoing threat of epidemic or pandemic diseases that could be caused by influenza, Ebola or other emerging viruses. It will be difficult and costly to develop new drugs that target each of these viruses. Statins and angiotensin receptor blockers (ARBs) have been effective in treating patients with sepsis, pneumonia and influenza, and a statin/ARB combination appeared to dramatically reduce mortality during the recent Ebola outbreak. These drugs target (among other things) the endothelial dysfunction found in all of these diseases. Most scientists work on new drugs that target viruses, and few accept the idea of treating the host response with generic drugs. A great deal of research will be needed to show conclusively that these drugs work, and this will require the support of public agencies and foundations. Investigators in developing countries should take an active role in this research. If the next Public Health Emergency of International Concern is caused by an emerging virus, a "top down" approach to developing specific new drug treatments is unlikely to be effective. However, a "bottom up" approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could reduce mortality in any country with a basic health care system. In doing so, it would make an immeasurable contribution to global equity and global security.

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Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat patients with severe COVID-19 infection.