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

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.

Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations.

BACKGROUND: Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD. OBJECTIVE: To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes. METHODS: We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes. RESULTS: The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis. CONCLUSIONS: Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient. TRIAL REGISTRATION NUMBER: Results, NCT01360398.

Impact and associations of eosinophilic inflammation in COPD: analysis of the AERIS cohort.

Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) predicts response to treatment, especially corticosteroids. We studied the nature of eosinophilic inflammation in COPD prospectively to examine the stability of this phenotype and its dynamics across exacerbations, and its associations with clinical phenotype, exacerbations and infection.127 patients aged 40-85 years with moderate to very severe COPD underwent repeated blood and sputum sampling at stable visits and within 72 h of exacerbation for 1 year.Blood eosinophils ≥2% was prevalent at baseline, and predicted both predominantly raised stable-state eosinophils across the year (area under the curve 0.841, 95% CI 0.755-0.928) and increased risk of eosinophilic inflammation at exacerbation (OR 9.16; p<0.001). Eosinophils ≥2% at exacerbation and eosinophil predominance at stable visits were associated with a lower risk of bacterial presence at exacerbation (OR 0.49; p=0.049 and OR 0.25; p=0.065, respectively). Bacterial infection at exacerbation was highly seasonal (winter versus summer OR 4.74; p=0.011) in predominantly eosinophilic patients.Eosinophilic inflammation is a common and stable phenotype in COPD. Blood eosinophil counts in the stable state can predict the nature of inflammation at future exacerbations, which when combined with an understanding of seasonal variation provides the basis for the development of new treatment paradigms for this important condition.