"Results of this review point to possible improvements in future studies of the case fatality risk. First, there is a problem in using confirmed cases as the denominator of CFR for influenza, given that most infections are mild and do not present for medical attention. Because it is not feasible to diagnose all suspected cases with laboratory testing except at the very beginning of a pandemic, it is unrealistic that risk estimates based on confirmed cases can be consistently calculated and remain directly comparable over time, age groups, and location. We suggest avoiding entirely the use of case fatality risk based on confirmed cases. The case fatality risk based on symptomatic cases would provide a more reliable early assessment of seriousness for seasonal influenza or the next influenza pandemic. Second, estimation of seriousness in real-time is complicated by delays in reporting and analysis. Estimation of the case fatality risk based on confirmed deaths and symptomatic cases may be possible if relevant models can be prepared in advance and quickly fitted to available data during the pandemic. We have previously discussed real-time estimation of the cumulative incidence of infection based on serologic data. This would form the denominator of the infection fatality risk, but, as noted previously, this is unlikely to be available early in the pandemic. In preparation for the next influenza pandemic, it is essential to reach a consensus on how to define and measure the seriousness of infection (an important indicator of the severity of the pandemic), and whether the analysis can be based entirely on estimates of age-specific risk of death among cases. The consistent estimates of the infection fatality risk at around 1 to 10 deaths per 100,000 infections identified in our review may represent the seriousness of H1N1pdm09 in developed countries where data were available. Similar estimates for seasonal influenza viruses, however, are not available for comparison, and neither are estimates from less developed countries in which the seriousness profile would likely be higher."