A Correction to this paper has been published: https://doi.org/10.1038/s41746-020-00360-w

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.

COPD patients have increased risk of developing pneumonia, which is associated with poor outcomes. It can be symptomatically indistinguishable from exacerbations, making diagnosis challenging. Studies of pneumonia in COPD have focused on hospitalised patients and are not representative of the ambulant COPD population. Therefore, we sought to determine the incidence and aetiology of acute exacerbation events with evidence of pneumonic radiographic infiltrates in an outpatient COPD cohort.

Background Exacerbations of COPD are one of the commonest causes of admission to hospital in the UK. Re-admission is also a significant problem and is currently the fifth most common cause of hospitalisation. Self-management interventions have shown benefits in improving health related quality of life and reducing hospital admissions. We explored the potential for an online self-management system to improve outcomes for COPD patients recently admitted to hospital with an exacerbation. Methods We conducted a feasibility randomised controlled trial of a digital health platform 'myCOPD'. 41 Patients were recruited following an admission to hospital with an acute exacerbation of COPD. Patients gave written informed consent and were randomised to either receive usual care (n=21) (including written self-management plan) or the myCOPD app (n=20) for 3 months. Patients attended 2 visits and received monthly telephone contacts to capture AEs. Exacerbations, readmission, CAT and PAM scores were captured. Inhaler technique was assessed for critical errors, pre and post intervention by a blinded team. Analysis was performed by an independent blinded statistician to an a priori SAP. Results The overall cohort had a mean (SD) age of 66.6 (7) years, and had moderate to very severe disease FEV1 44 (17.6)% predicted. Exacerbations were less frequent in the digital arm compared to usual care over 3 m; 18 vs 34, p=0.047 for mean difference. Hospital readmissions were lower in the digital intervention arm than in usual care 4 vs 13. Patients' inhaler technique (total critical error count) improved in the digital intervention arm (101 improving to 20 errors) compared to usual care (100 and 72) p=0.008.As did CAT scores, with a differential improvement of −4.8 (CI −8.8 to −0.7) p=0.021 in favour of digitally enhanced care. No differences were seen between treatment arms for HAD, MRC, SGRQ or PAM scores. Conclusion In this early clinical study of the digital self- management platform myCOPD, its use has been shown to significantly improve exacerbation rates, lower re-admission numbers, improve symptom control and reduce the number of critical errors in inhaler technique compared to usual written self-management. This provides a strong basis for the design of a large multicentred trial.

COPD is a complex, heterogeneous disease characterised by progressive development of airflow limitation. Spirometry provides little information about key aspects of pathology and is poorly related to clinical outcome, so other tools are required to investigate the disease. We sought to explore the relationships between quantitative CT analysis with functional, inflammatory and infective assessments of disease to identify the utility of imaging to stratify disease to better predict outcomes and disease response.

Introduction: The six-minute walk test (6MWT) is used to assess functional status in COPD with both distance walked (6MWD) and oxygen desaturation important predictors of mortality. This study aims to identify CT-quantified features that predict poor performance at the 6MWT. Methods: AERIS is a longitudinal study where patients with COPD were followed for 2 years. At enrolment 127 subjects had CT, spirometry and 6MWT. Emphysema was defined as the % of lung with attenuation below -950 Hounsfield Units (%LAA). Airway wall dimensions were assessed using the standardised measure Pi10. Small airways disease was measured using the ratio of inspiratory/expiratory mean lung density (E/I MLD). Results: 119 subjects had complete data. There were no associations between 6MWD and CT measures (Table 1). %LAA was significantly higher (16.0 v 9.7) and FEV1% significantly lower (40.0 v 53.4) in subjects who walked <350m compared to those who walked further. On multivariate analysis FEV1% was the only one of these variables that significantly predicted the chance of being able to walk >350m. There were significant associations between desaturation during the 6MWT and %LAA and E/I MLD (Table 1). Subjects who desaturated by >5% had lower FEV1% (36.5 v 52.7) and higher %LAA (24.9 v 8.2) and E/I MLD (0.94 v 0.91). On multivariate analysis %LAA was the only variable that significantly predicted desaturation on exertion. Conclusion: Emphysema severity is associated with desaturation on exertion independently of FEV1% and other CT parameters, whereas no CT parameters influenced the distance walked.

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.

BACKGROUND:The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood. Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these events. METHODS:In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40-85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses. Results are presented for subjects in the full cohort, followed for 1 year. Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses. FINDINGS:The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50). At AECOPD, the most common bacterial species were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, and the most common virus was rhinovirus. Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when M. catarrhalis was detected regardless of season (5.09 (95% CI 2.76 to 9.41)). When NTHi was detected, the increased risk of exacerbation was greater in high season (October-March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)). Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%). A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031). CONCLUSIONS:AECOPD aetiology varies with season. Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection. TRIAL REGISTRATION NUMBER:Results, NCT01360398.

Objective To obtain evidence whether the online pulmonary rehabilitation(PR) programme 'my-PR' is non-inferior to a conventional face-to-face PR in improving physical performance and symptom scores in patients with COPD. Design A two-arm parallel single-blind, randomised controlled trial. Setting The online arm carried out pulmonary rehabilitation in their own homes and the face to face arm in a local rehabilitation facility. Participants 90 patients with a diagnosis of chronic obstructive pulmonary disease (COPD), modified Medical Research Council score of 2 or greater referred for pulmonary rehabilitation (PR), randomised in a 2:1 ratio to online (n=64) or face-to-face PR (n=26). Participants unable to use an internet-enabled device at home were excluded. Main outcome measures Coprimary outcomes were 6 min walk distance test and the COPD assessment test (CAT) score at completion of the programme. Interventions A 6-week PR programme organised either as group sessions in a local rehabilitation facility, or online PR via log in and access to 'myPR'. Results The adjusted mean difference for the 6 min walk test (6MWT) between groups for the intention-to-treat (ITT) population was 23.8 m with the lower 95% CI well above the non-inferiority threshold of -40.5 m at -4.5 m with an upper 95% CI of + 52.2 m. This result was consistent in the per-protocol (PP) population with a mean adjusted difference of 15 m (-13.7 to 43.8). The CAT score difference in the ITT was -1.0 in favour of the online intervention with the upper 95% CI well below the non-inferiority threshold of 1.8 at 0.86 and the lower 95% CI of -2.9. The PP analysis was consistent with the ITT. Conclusion PR is an evidenced-based and guideline-mandated intervention for patients with COPD with functional limitation. A 6-week programme of online-supported PR was non-inferior to a conventional model delivered in face-to-face sessions in terms of effects on 6MWT distance, and symptom scores and was safe and well tolerated.

Introduction: Understanding of COPD is limited by the heterogeneity of the condition and FEV1 provides limited information about this. CT analysis allows the quantification of key features and this study aims to assess the association of these with clinical and biological measures in COPD. Methods: AERIS is a study where patients with COPD were followed for 2 years. At enrolment 127 subjects had CT, pulmonary function tests (PFTs) and sputum/blood sampling. Emphysema was defined as the % of lung with attenuation < -950 Hounsfield Units (%LAA). Airway walls were assessed using the measure Pi10. Small airways disease was measured using the ratio of expiratory/inspiratory mean lung density (E/I MLD). Results: 122 subjects had complete data. %LAA and E/I MLD had significant associations with all PFTS, while Pi10 did not show any associations (Table 1). In multivariate analysis, %LAA and E/I MLD had independent associations with FEV1%, while %LAA had independent associations with TLCO% and E/I MLD with RV%. All CT measures had significant associations with CRP, but on multivariate analysis only the relationship with %LAA was significant. Exacerbation rate and annual FEV1 decline showed no associations with CT measures. Conclusion: %LAA and E/I MLD had associations with FEV1%, suggesting they both contribute to airflow obstruction. Structural changes identified on CT did not seem to influence disease activity.

Introduction The importance of eosinophilic inflammation in COPD is in its ability to predict an enhanced response to treatment, such as corticosteroids. However, little is know about the persistence of higher eosinophils, or its associations with infectious aetiology during clinical stability and exacerbation. We investigated the natural history of eosinophilic inflammation over time and studied eosinophil-associated acute exacerbations of COPD and the impact of seasonality in a cohort of COPD patients. Methods 127 subjects with moderate to very severe COPD were enrolled into the AERIS cohort (NCT01360398) and were reviewed monthly for scheduled visits and during exacerbations. Blood sampling was performed quarterly and at exacerbations. Higher blood eosinophils (BE) were defined as ≥2%. Based on frequency of higher BE over the study, subjects were divided into predominantly (PE), intermittent (IE) and rarely eosinophilic (RE) groups. Results Blood eosinophil levels ≥2% were prevalent at baseline (68.3%) and at exacerbations (51.1%). Over the study 57.6% of subjects had predominantly, 16.16% intermittently and 26.26% rarely ≥2% blood eosinophils. Higher BE at enrolment was strongly associated with a predominantly high BE profile for the year (AUC 0.841 p < 0.001) and with greater odds of ≥2% eosinophils at exacerbation (OR 9.60 p < 0.001). The odds of ≥2% BE at exacerbation were higher in the PE group compared to the rarely group (OR 12.00, p < 0.001). A larger proportion of exacerbations were eosinophilic in the Summer than Winter (OR 2.57, p = 0.001). The odds of bacterial presence at exacerbation was higher in Winter than Summer among those in the PE group (OR 4.74, CI: 1.43; 15.71, p = 0.011), but not among those in the RE group (OR 1.15, CI: 0.29; 4.56, p = 0.838). Conclusion Our data suggests that it is possible to stratify COPD patients by stable state blood eosinophil levels. This measure is easily accessible and provides important insights into the longitudinal inflammatory phenotype of COPD. Persistent higher blood eosinophil levels were associated with risk of bacterial infection at exacerbation, and seasonality of exacerbation. Intervention studies are required to establish clear treatment algorithms utilising this measure to stratify therapy.

BACKGROUND:Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function.METHODS:Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types.RESULTS:The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs.CONCLUSION:Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism.TRIAL REGISTRATION:Trial registration number NCT01701869 .

Eosinophilic inflammation (EI) in COPD may be associated with a greater response to steroid treatment, whilst bacterial exacerbations respond to antibiotics. This subanalysis aimed to evaluate the prevalence of EI in stable COPD and at exacerbation (AECOPD). We studied the relationship between blood and sputum biomarkers, and between EI and bacterial infection at AECOPD. Methods: We assessed EI on preliminary data from 127 COPD subjects (baseline sputum n=79; and blood n=126) recruited into the AERIS study (NCT01360398) including 355 AECOPD (sputum n=239; blood n=338). EI was defined as sputum eosinophils (SE) >3% or blood eosinophils (BE) ≥2%. The presence of sputum potential pathogenic microorganisms (PPM) at AECOPD was evaluated by culture. Results: Prevalence of SE was 35.4% and BE 68.3% at enrolment, and 24.7% and 49.7% at AECOPD. BE (count and %) was a significant predictor of SE at both baseline (AUC 0.73 and 0.81, p<0.01) and AECOPD (AUC 0.72 and 0.72, p<0.01). In individuals with SE, blood neutrophils were lower at enrolment, and both CRP and neutrophils were lower at AECOPD (p<0.01). 59% of all AECOPD had PPM present. PPMs were more prevalent in AECOPD with lower blood and sputum eosinophils (OR 1.85, 95% CI 1.17 to 2.94 and OR 4.00, 95% CI 2.14 to 7.50 respectively). Conclusion: Airway and systemic EI was highly prevalent during clinical stability and at AECOPD. Airway EI was associated with lower systemic inflammation. Sputum and blood eosinophils seem to be associated with a lower probability of airway bacterial infection and this would require further investigation to aid clinical management of AECOPD.

Background: Bronchiectasis prevalence in COPD is variable and the role and clinical features of concomitant bronchiectasis is poorly understood. This study aims to assess the frequency of bronchiectasis in a COPD cohort and assess its relationship with clinical and laboratory parameters. Methods: In the AERIS study 127 patients with moderate-very severe COPD were followed for 2 years. Subjects with prior bronchiectasis were excluded. Each had lung function, sputum/blood sampling and HRCT at enrolment. CT scans were reported by a radiologist and bronchiectasis was identified and visual scoring quantified this (range 0-12). Results: 10 subjects had bronchiectasis. Of these median bronchiectasis score was 2. Bronchiectasis subjects had raised blood and sputum neutrophils. 7 subjects with bronchiectasis had potentially pathogenic microorganisms (PPM) in their sputum. Conclusion: There was a low prevalence of bronchiectasis in this cohort. It was associated with worse lung function, increased airway and systemic neutrophilic inflammation. Use of CT imaging is able to identify this potentially high-risk population.

Introduction and objectives Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extra-cellular matrix (ECM) and drive tissue remodelling, key processes in the pathogenesis of COPD. The development of small airway disease and emphysema have been identified as critical mechanisms in the development of airflow obstruction but the contribution of MMPs in human disease is poorly characterised. We investigated the role of MMPs in the lung by quantifying levels and determining relationships with the key pathological components of COPD, measured by CT, in patients and healthy controls. Methods 24 mild and moderate COPD and 8 control subjects were enrolled onto the study and underwent bronchoalveolar lavage (BAL) and high resolution CT. We analysed levels of MMPs in BAL using a Luminex immunoassay. Image analysis, performed using VIDA Apollo software, quantitatively assessed emphysema, bronchial wall thickening and small airways disease. Results Multiple MMPs (MMP-1, -2, -3, -8, -9 and -10) were significantly elevated in the lungs of COPD subjects. MMP -3, -7, -8, -9, -10, and -12 concentrations were closely associated with CT markers of small airways disease (Table 1). Emphysema severity was also associated with MMP-3, -7, -8 and -10. However there were no strong relationships between MMPs and bronchial wall thickness of the larger airways. Stepwise linear regression analysis identified MMP-10 to be the only significant predictor of emphysema (R2 0.34, p 0.001) that was independent of each of the other MMPs while MMP-8 was the only significant predictor of small airways disease (R2 0.56, p < 0.001) independent of each of the other MMPs. Conclusion Pulmonary MMP concentrations are directly associated with the extent of gas trapping and small airways disease identified on CT scan. This suggests that MMPs may play a significant role in the pathogenesis of COPD by causing breakdown of the pulmonary ECM leading to abnormal remodelling in both the small airways and lung parenchyma. Whilst most previous work has focused on MMPs and emphysema, this study shows the strongest associations were with small airways disease.