Temporal clustering of exacerbations in chronic obstructive pulmonary disease.

RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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

Serum IP-10 as a Biomarker of Human Rhinovirus Infection at Exacerbation of COPD

BACKGROUND: Human rhinovirus (HRV) is the most frequent virus associated with COPD exacerbations. Viral infections increase exacerbation severity and likelihood of hospitalization. As ease of sampling blood makes serum a more practical marker than sputum, we investigated whether changes in serum interferon-gamma-inducible protein 10 (IP-10) from baseline to exacerbation were higher in airway HRV-positive exacerbations and whether IP-10 levels related to HRV load. METHODS: One hundred thirty-six patients with COPD and 70 controls were included over 2 years and 72 exacerbations sampled. HRV positivity and load were determined by reverse transcriptase-polymerase chain reaction in nasopharyngeal swabs and/or sputum at baseline and exacerbation. IP-10 was measured by enzyme-linked immunosorbent assay in serum and compared with HRV load. RESULTS: At baseline, serum IP-10 was higher in patients with COPD than controls; medians were 149.4 pg/mL (103-215) and 111.7 pg/mL (82-178), P = .02. The presence of HRV at baseline did not increase IP-10: patients with COPD, 166.9 pg/mL (110-240) and 149.4 pg/mL (103-215), P = .30; controls, 136.4 pg/mL (77-204) and 111.7 pg/mL (82-178), P = .53. IP-10 increased significantly from baseline to exacerbation in HRV-positive exacerbations: 154.9 pg/mL (114.0-195.1) to 207.5 pg/mL (142.1-333.5), P = .009. There was no change in IP-10 between baseline and exacerbation in HRV-negative exacerbations: 168.3 pg/mL (94.3-249.8) and 175.6 pg/mL (107.2-290.4), P = .49. At exacerbation, IP-10 correlated with sputum viral load: rho = 0.48; P = .02. In receiver operating characteristics analysis, the combination of IP-10 and coryzal symptoms gave an area under the curve of 0.82 (95% CI, 0.74-0.90). CONCLUSIONS: IP-10 increases from baseline to exacerbation in HRV-positive exacerbations and correlates with sputum HRV load. Serum IP-10 may be useful as a novel marker for these events