Drivers of year-to-year variation in exacerbation frequency of COPD: analysis of the AERIS cohort

Abstract

The association between exacerbation aetiology and exacerbation frequency is poorly understood. We analysed 2-year follow-up data from a prospective observational study of patients with chronic obstructive pulmonary disease (COPD) (www.clinicaltrials.gov identifier number NCT01360398) to evaluate year-to-year variation in exacerbation frequency and related aetiology. A total of 127 patients underwent blood and sputum sampling monthly and at exacerbation to detect respiratory infections and eosinophilic inflammation; 103 continued into year 2 and 88 completed both years. The most common bacterial species at stable state and exacerbation was Haemophilus influenzae. Among infrequent exacerbators (one exacerbation per year), the incidence of viral infection at exacerbation was high (60.0% (95% CI 35.1-81.7%) in year 1 and 78.6% (53.4-94.2%) in year 2). Those with more frequent exacerbations tended to have higher relative incidence of bacterial than viral infection. Patients with at least two additional exacerbations in year 2 versus year 1 had a higher risk of H. influenzae colonisation at stable state than those with at least two fewer exacerbations, as detected by culture (OR 1.43 (95% CI 0.71-2.91) versus 0.63 (0.40-1.01), p=0.06) and PCR (1.76 (95% CI 0.88-3.51) versus 0.56 (0.37-0.86), p<0.01). This was not seen with other infection types or eosinophilic inflammation. Analysis of the same cohort over 2 years showed, for the first time, that changes in yearly COPD exacerbation rate may be associated with variations in H. influenzae colonisation.

FIGURE 1

Focus on the patient.

FIGURE 2

Flow chart of patients and sputum sampling in the study.

FIGURE 3

Distribution of patients in the first- or second-year follow-up according to the number of acute exacerbations of chronic obstructive pulmonary disease presented and their severity (full cohort, year 1 or year 2). The “any” category indicates overall classification; patients could experience exacerbations in one or more severity category.

FIGURE 4

Percentage of culture-positive or PCR-positive sputum samples at stable state and exacerbation in year 1 and year 2 (full cohort, year 1 or year 2). a) Percentage culture-positive for bacteria. b) Percentage PCR-positive for bacteria. c) Percentage PCR-positive for virus. Error bars represent 95% confidence intervals. HRV: human rhinovirus.

FIGURE 5

Percentage of chronic obstructive pulmonary disease patients with culture- or PCR-positive sputum samples for bacterial or viral pathogens or eosinophilic sputum samples (presence of eosinophils >3%) at a) exacerbation and b) stable visits, by frequency of exacerbations reported during year 1 or year 2 (completer cohort). Exacerbation frequency in specified year: infrequent, one or (for stable visits) none; frequent, two to four; very frequent, more than four. Error bars represent 95% confidence intervals.

FIGURE 6

Effect of the presence of aetiological factors (bacterial or viral infection, or eosinophilic inflammation) at stable visits on the odds of experiencing a change in number of exacerbations in year 2 relative to year 1 (completer cohort). a) Haemophilus influenzae detected by PCR or culture. Comparison of ≤ −2 and ≥2 groups, p=0.006 (PCR) and p=0.060 (culture). b) Moraxella catarrhalis detected by PCR or culture. Comparison of ≤ −2 and ≥2 groups, p=0.068 (PCR) and 0.673 (culture). c) Viruses and eosinophils. Comparison of ≤ −2 and ≥2 groups, p=0.052 (viruses) and p=0.669 (eosinophils). ≤ −2: at least two fewer exacerbations in year 2 than in year 1; −1: one fewer exacerbation; 0: no change; 1: one more exacerbation; ≥2: at least two more exacerbations. Error bars represent 95% confidence intervals. p-values were estimated using the Wald test.