title: Temporal clustering of exacerbations in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Exacerbations 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.
  
  
  OBJECTIVE
  To assess whether exacerbations are random events, or cluster in time.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  Exacerbations 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.
authors.affiliation: Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, London, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Hurst
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Donaldson
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Quint
authors.forename: James J P
authors.initials: JJ
authors.lastname: Goldring
authors.forename: Ramin
authors.initials: R
authors.lastname: Baghai-Ravary
authors.forename: Jadwiga A
authors.initials: JA
authors.lastname: Wedzicha
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D016000:Cluster Analysis; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D016012:Poisson Distribution; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology*; D012044:Regression Analysis; D012141:Respiratory Tract Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D012307:Risk Factors; D012621:Seasons
chemical_list: D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents