Using Clinical Research Networks to Assess Severity of an Emerging Influenza Pandemic

Abstract

Background: Early clinical severity assessments during the 2009 influenza A H1N1 pandemic (pH1N1) overestimated clinical severity due to selection bias and other factors. We retrospectively investigated how to use data from the International Network for Strategic Initiatives in Global HIV Trials, a global clinical influenza research network, to make more accurate case fatality ratio (CFR) estimates early in a future pandemic, an essential part of pandemic response.

Methods: We estimated the CFR of medically attended influenza (CFRMA) as the product of probability of hospitalization given confirmed outpatient influenza and the probability of death given hospitalization with confirmed influenza for the pandemic (2009-2011) and post-pandemic (2012-2015) periods. We used literature survey results on health-seeking behavior to convert that estimate to CFR among all infected persons (CFRAR).

Results: During the pandemic period, 5.0% (3.1%-6.9%) of 561 pH1N1-positive outpatients were hospitalized. Of 282 pH1N1-positive inpatients, 8.5% (5.7%-12.6%) died. CFRMA for pH1N1 was 0.4% (0.2%-0.6%) in the pandemic period 2009-2011 but declined 5-fold in young adults during the post-pandemic period compared to the level of seasonal influenza in the post-pandemic period 2012-2015. CFR for influenza-negative patients did not change over time. We estimated the 2009 pandemic CFRAR to be 0.025%, 16-fold lower than CFRMA.

Conclusions: Data from a clinical research network yielded accurate pandemic severity estimates, including increased severity among younger people. Going forward, clinical research networks with a global presence and standardized protocols would substantially aid rapid assessment of clinical severity.

Clinical trials registration: NCT01056354 and NCT01056185

Figure 1.

Map of International Network for Strategic Initiatives in Global HIV Trials influenza protocol patient intake sites. Blue markers indicate FLU002 outpatient sites and red markers indicate FLU003 inpatient sites.

Figure 2.

A schematic representation of the pyramid modeling approach used to estimate the 2009 pandemic case fatality ratio among medically attended cases from probabilities of disease progression from International Network for Strategic Initiatives in Global HIV Trials outpatient (FLU002) and inpatient (FLU003) data. Modeling was also done for 18–64 and 65+ year age groups separately due to known differences in attack rates and preexisting immunity. Abbreviations: AR, all infected persons; CFR, case fatality ratio; ILI, influenza-like illness; MA, medically attended; P (D|H), probability of death given hospitalization; P (H|ILI) , probability of hospitalization given influenza-like illness.