• John R Hurst, Gavin C Donaldson, Jennifer K Quint, James J P Goldring, Ramin Baghai-Ravary, and Jadwiga A Wedzicha.
• Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, London, United Kingdom.
• Am. J. Respir. Crit. Care Med. 2009 Mar 1; 179 (5): 369-74.

RationaleExacerbations are important events in chronic obstructive pulmonary disease. Preventing exacerbations is a key treatment goal. Observational data suggest that after a first exacerbation, patients may be at increased risk of a second exacerbation, but this has not been specifically studied. We hypothesized that exacerbations may cluster together in time, a finding that would have important implications for targeting preventative interventions and the analysis of clinical trial data.ObjectivesTo assess whether exacerbations are random events, or cluster in time.MethodsA total of 297 patients in the London chronic obstructive pulmonary disease cohort recorded daily symptoms and were assessed for a total of 904 patient-years. The observed timing of second exacerbations after an initial exacerbation was compared with that expected should exacerbations occur randomly.Measurements And Main ResultsThe observed timing distribution of second exacerbations differed significantly (P < 0.001) from the expected exponential function (shape parameter of the fitted Weibull function, 0.966 [95% confidence interval, 0.948-0.985]), suggesting that more second exacerbations occurred sooner than later and that exacerbations cluster together in time. Twenty-seven percent of first exacerbations were followed by a second recurrent event within 8 weeks. Approximately one third of exacerbations were recurrent exacerbations. Although initial exacerbations were milder than isolated events, they were not less likely to receive treatment, and under-treatment of initial events is not a plausible explanation for exacerbation recurrence. Recurrent exacerbations contribute significantly to overall exacerbation frequency (rho = 0.81; P < 0.0001).ConclusionsExacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial excerbation.

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