Case-fatality of COPD exacerbations: a meta-analysis and statistical modeling approach Short title: Case-fatality of COPD exacerbations

Objective of the study was to estimate the case-fatality of a severe exacerbation from longterm survival data presented in the literature. A literature search identified studies reporting at least 1.5 year survival after a severe COPD exacerbation resulting in hospitalization. Each study’s survival curve was divided into a critical and a stable period. Mortality during the stable period was then estimated by extrapolating the survival curve during the stable period back to the time of exacerbation onset. Case-fatality was defined as the excess mortality that results from an exacerbation and was calculated as 1 minus the (backwardly) extrapolated survival during the stable period at the time of exacerbation onset. The 95% confidence intervals of the estimated case-fatalities were obtained by bootstrapping. A random effect model was used to combine all estimates into a weighted average with 95%-confidence interval. The meta-analysis based on six studies that fulfilled the inclusion criteria resulted in a weighted average case-fatality rate of 15.6% (95%CI:10.9%-20.3%), ranging from 11.4% to 19.0% for the individual studies. A severe COPD exacerbation requiring hospitalization not only results in higher mortality risks during hospitalization, but also in the time period after discharge and contributes substantially to total COPD mortality. Word count abstract: 198