Rationale: Unrecognized coronary artery disease (CAD) may contribute to adverse outcomes in chronic obstructive pulmonary disease (COPD). Improved identification of at-risk groups could inform better preventive care. Objectives: We aimed to evaluate the burden and relationships of radiologically detectable CAD in COPD, establish the frequency of occult disease, and examine potential cardiovascular screening methods. Methods: Using computed tomography (CT) coronary angiography, we prospectively evaluated CAD in 50 patients with COPD compared with age- and sex-matched controls. In those with COPD, the relationship of CAD to cardiac symptoms (chest pain, dyspnea), functional capacity (6-minute-walk distance), exacerbations, and inflammation was assessed. The performance of screening tests (cardiovascular risk scores, biomarkers, and thoracic CT-derived coronary artery calcium score) were evaluated using receiver operating characteristic curves. Measurements and Main Results: CAD was present in 88% of patients with COPD (42% had obstructive [⩾50% stenosis of any vessel] and 28% severely obstructive [⩾70%] disease). Rates of obstructive (OR, 3.1; 95% CI, 1.1-8.9; P = 0.037) and severely obstructive CAD (OR, 10.1; 95% CI, 1.9-52.7; P = 0.006) were higher in those with COPD than in controls. In the COPD group, those with CAD had greater functional impairments but not greater dyspnea scores, and 75% reported no chest pain or prior ischemic heart disease. CAD was more extensive in those with increased systemic inflammation (fibrinogen, C-reactive protein, and leukocyte and neutrophil counts), bronchial wall thickening, and sputum bacterial growth but bore no relation to exacerbation frequency. The thoracic CT-derived coronary artery calcium score was an effective screening tool, with areas under the curve of 0.98 (95% CI, 0.95-1.00) for CAD and 0.89 (95% CI, 0.79-1.00) for obstructive CAD. Conclusions: CT coronary angiography-detected CAD is common in patients with COPD but correlates poorly with symptoms and conventional risk scores. Radiological screening with standard (non ECG-gated) CT of the thorax might improve detection and outcome in this patient group.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Rationale: Progressive lung function loss is recognized in chronic obstructive pulmonary disease (COPD); however, no study concurrently evaluates how accelerated lung function decline relates to mucus properties and the microbiome in COPD. Objectives: Longitudinal assessment of mucus and microbiome changes accompanying accelerated lung function decline in patients COPD. Methods: This was a prospective, longitudinal assessment of the London COPD cohort exhibiting the greatest FEV1 decline (n = 30; accelerated decline; 156 ml/yr FEV1 loss) and with no FEV1 decline (n = 28; nondecline; 49 ml/yr FEV1 gain) over time. Lung microbiomes from paired sputum (total 116 specimens) were assessed by shotgun metagenomics and corresponding mucus profiles evaluated for biochemical and biophysical properties. Measurements and Main Results: Biochemical and biophysical mucus properties are significantly altered in the accelerated decline group. Unsupervised principal component analysis showed clear separation, with mucus biochemistry associated with accelerated decline, whereas biophysical mucus characteristics contributed to interindividual variability. When mucus and microbes are considered together, an accelerated decline mucus-microbiome association emerges, characterized by increased mucin (MUC5AC [mucin 5AC] and MUC5B [mucin 5B]) concentration and the presence of Achromobacter and Klebsiella. As COPD progresses, mucus-microbiome shifts occur, initially characterized by low mucin concentration and transition from viscous to elastic dominance accompanied by the commensals Veillonella, Gemella, Rothia, and Prevotella (Global Initiative for Chronic Obstructive Lung Disease [GOLD] A and B) before transition to increased mucus viscosity, mucins, and DNA concentration together with the emergence of pathogenic microorganisms including Haemophilus, Moraxella, and Pseudomonas (GOLD E). Conclusions: Mucus-microbiome associations evolve over time with accelerated lung function decline, symptom progression, and exacerbations affording fresh therapeutic opportunities for early intervention.

Rationale: Respiratory syncytial virus (RSV) is a common global respiratory virus that is increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults that has acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. Objectives: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. Methods: Participants were recruited at specialist clinics in London, United Kingdom, and Groningen, the Netherlands, beginning in 2017 and observed for three consecutive RSV seasons, during exacerbations, and at least twice yearly. RSV infections were detected by RT-PCR and serologic testing. Measurements and Main Results: A total of 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8.7% of the total); of these, seven were detected only by PCR, 16 only by serology, and four by both methods. Increases in RSV-specific Nucleoprotein antibody were as sensitive as those in the antibody to Pre-Fusion or Post-Fusion for serodiagnosis of RSV-related exacerbations. Conclusions: RSV is associated with 8.7% of outpatient- managed COPD exacerbations in this study. Antibodies to RSV Nucleoprotein may have diagnostic value and are potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD.

Background: To date, no study has used quantitative CT to study whether radiological abnormalities seen in established COPD occur in younger smokers with a normal FEV1, at risk of subsequently developing COPD. Methods: Participants in the BLF Early COPD multi-centre cohort (smokers, aged 30-45 yrs, with >10 pack-yrs tobacco history and normal (>80% predicted) FEV1) (NCT03480347) were compared to aged-matched healthy never smoking controls. Quantitative CT was performed to assess radiological COPD features: emphysema, functional small airways dysfunction, and airway wall thickness. Results: Disease Probability Measure (DPM) of the thoracic CTs demonstrated that, compared to never smoking controls, the Early COPD cohort participants had a higher percentage of fSAD (DPM Airtrap) (7.3% (IQR 5.3 – 12.5) for Early COPD cohort vs. 4.7% (IQR 4.2 – 5.5); Mann-Whitney, P<0.001), emphysema (0.05% (IQR 0.01 – 0.20) vs. 0.03% (IQR 0.01 – 0.07)); P=0.049), and a greater Pi10 (3.87 (IQR 3.82 – 3.94) vs. 3.78 (IQR 3.73 – 3.83), P=0.002)(figure 1A-C). There were no differences in age, gender, BMI and spirometry between 421 BLF cohort participants and 67 never-smoking healthy controls. We found that the extent of air trapping on CT related weakly to lower FEV1/FVC and higher RV/TLC ratios (figure 1E-F) whilst quantifiable emphysema also related positively to an increase in RV/TLC. Conclusion: For the first time we show the presence of functional small airways disease, emphysema and increased bronchial wall thickness is detectable in early disease and is increased compared to non-smoking controls with similar clinical characteristics. Radiological abnormalities relate to lung function abnormalities.

Background: Blood eosinophil counts (BEC) are elevated in a subgroup of COPD patients. Higher BEC demonstrate greater temporal variability in COPD. Variability of BEC in smokers at risk of developing COPD is currently unknown. Methods: BEC were obtained at baseline and 6 months from younger smokers (S) (NCT03480347). Subjects were aged <45 years, with a pack year history of ≥ 10 and normal FEV1 (>80%). At baseline, 534 BEC were obtained, with 266 repeat counts at 6 months. Low, intermediate and high BEC were defined by thresholds of <100, 100-300 and >300 cells/µL respectively. Results: Median baseline BEC was 180cells/µL, with low, intermediate and high groups represented by 10, 76 and 14% of S respectively (n=534). A good correlation was observed between repeated BEC (r=0.65, p<0.0001, Figure 1A, n=266), with ICC= 0.79. Intermediate BEC were most stable, with 90% remaining in the same category upon repeat testing, in comparison to low and high groups; 52 and 47% remained stable respectively (Figure 1B, C & D). Bland-Altman analysis revealed greater variability at higher BEC (mean difference: 2.29, LOA: -203.7 - 208.3 cells/µL). Figure 1: Association between repeat BEC (A), baseline and 6-month measures of BEC for low (B), intermediate (C) and high (D) groups. n=266. Conclusion: We demonstrate excellent overall short-term stability of BEC in S, with the greatest temporal variability observed in those with BEC >300 cells/µL.

Progressive lung function decline is a hallmark of chronic obstructive pulmonary disease (COPD). Airway dysbiosis occurs in COPD, but whether it contributes to disease progression remains unknown. Here, we show, through a longitudinal analysis of two cohorts involving four UK centers, that baseline airway dysbiosis in COPD patients, characterized by the enrichment of opportunistic pathogenic taxa, associates with a rapid forced expiratory volume in 1 s (FEV1) decline over 2 years. Dysbiosis associates with exacerbation-related FEV1 fall and sudden FEV1 fall at stability, contributing to long-term FEV1 decline. A third cohort in China further validates the microbiota-FEV1-decline association. Human multi-omics and murine studies show that airway Staphylococcus aureus colonization promotes lung function decline through homocysteine, which elicits a neutrophil apoptosis-to-NETosis shift via the AKT1-S100A8/A9 axis. S. aureus depletion via bacteriophages restores lung function in emphysema mice, providing a fresh approach to slow COPD progression by targeting the airway microbiome.

Introduction : Progressive loss of lung function is recognized in COPD, however, remains heterogenous between individuals. No study concurrently evaluates mucus properties, the lung microbiome and lung function decline in COPD. METHODS: Prospective longitudinal assessment (up to 11 years) of n=58 individuals from the London COPD cohort were assessed using "paired" sputum (total 116 specimens) and categorised into "Fast decliners" (>50 mL/year FEV1 loss; n= 30) and "control-COPD" (physiological airflow decline; n=28). Lung microbiomes were assessed by shotgun metagenomics and corresponding mucus profiles evaluated for biochemical and biophysical properties at both time points. RESULTS: Increased MUC5AC / MUC5B concentrations (p<0.001) and mucus elasticity (p<0.001) associate with "Fast decliners". Lung microbiomes demonstrate no compositional difference between the initial and follow-up timepoints, however, longitudinal change is observed between "Fast decliners" and "Control-COPD" characterized by increases in Haemophilus, Pseudomonas, and Moraxella (PPMs) and loss of Streptococcus, Prevotella, and Rothia. Strong correlations between PPMs and mucus biochemical profile are evident, while upper airway commensals negatively correlate with mucus biochemistry. No association between microbes and mucus biophysical profile were detected. CONCLUSION: Key relationships between airflow decline, biochemical and biophysical components of mucus and the lung microbiome exist in COPD, features providing novel insight to inform therapeutic development targeting the mucus-microbiome interface. FUNDING: LKCMedicine–ICL Fellowship (#020458-00001) (O.W.M) and Singapore MOH NMRC under its Clinician Scientist Award (MOH-000710) (S.H.C).

Background Early and accurate identification of acute exacerbations of COPD may lead to earlier treatment and prevent hospital admission. Electronic diaries have been developed for symptom monitoring and accelerometers to monitor activity. However, it is unclear whether this technology is usable in the COPD population. This study aimed to assess the feasibility of an electronic diary (eDiary) for symptom reporting using the MoreCare app and activity monitoring with the Garmin Vivofit 2 in COPD. Methods Participants were recruited from the London COPD Cohort. Participants were provided a Garmin Vivofit 2 activity monitor and an android tablet with the MoreCare app for a period of 3 months. Results 25 COPD patients were recruited (mean±sd age 70.8±7.1 years, forced expiratory volume in 1 s (FEV1) 49.8±14.8% predicted). Age, gender, disease severity and exacerbation frequency had no impact on eDiary compliance. There was a moderate positive correlation between median daily very active minutes and FEV1 % pred (ρ=0.62, p=0.005). Daily step counts decreased during the initial 7 days of exacerbation and recovery compared to a pre-exacerbation baseline. A decision-tree model identified change in sputum colour, change in step count, severity of cold, exacerbation history and use of rescue medication as the most important predictors of acute exacerbations of COPD in this cohort. Conclusions Symptom and activity monitoring using digital technology is feasible in COPD. Further large-scale digital health studies are needed to assess whether eDiaries can be used to identify patients at risk of exacerbation and guide early intervention.

Early and accurate identification of acute exacerbations of COPD may lead to earlier treatment and prevent hospital admission. Electronic diaries have been developed for symptom monitoring and accelerometers to monitor activity. However, it is unclear whether this technology is usable in the COPD population. This study aimed to assess the feasibility of an electronic diary (eDiary) for symptom reporting using the MoreCare app and activity monitoring with the Garmin Vivofit 2 in COPD.Participants were recruited from the London COPD Cohort. Participants were provided a Garmin Vivofit 2 activity monitor and an android tablet with the MoreCare app for a period of 3 months.25 COPD patients were recruited (mean±sd age 70.8±7.1 years, forced expiratory volume in 1 s (FEV1) 49.8±14.8% predicted). Age, gender, disease severity and exacerbation frequency had no impact on eDiary compliance. There was a moderate positive correlation between median daily very active minutes and FEV1 % pred (ρ=0.62, p=0.005). Daily step counts decreased during the initial 7 days of exacerbation and recovery compared to a pre-exacerbation baseline. A decision-tree model identified change in sputum colour, change in step count, severity of cold, exacerbation history and use of rescue medication as the most important predictors of acute exacerbations of COPD in this cohort.Symptom and activity monitoring using digital technology is feasible in COPD. Further large-scale digital health studies are needed to assess whether eDiaries can be used to identify patients at risk of exacerbation and guide early intervention.

Background: Respiratory syncytial virus (RSV) is a common global respiratory pathogen increasingly recognised in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. Vaccine candidates have recently registered excellent safety and efficacy against RSV in older adults. This prospective study aimed to establish the frequency and burden of RSV-related exacerbations of COPD in two well-characterised patient cohorts.Methods: Participants were recruited at specialist clinics in London, UK and Groningen, NL from 2017 and observed for three consecutive RSV seasons, during exacerbations and at least twice yearly. RSV infections were detected by reverse transcription-polymerase chain reaction (RT-PCR) and serology testing.Findings: 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations.There were 27 RSV-related exacerbations (8·7% of the total), of which 15 were identified by PCR and 16 by a four-fold rise in virus-specific serum antibody; four were identified by both PCR and serology.Adding additional serological testing in London to also include missed exacerbation events as per diary card, RSV infection was identified in 32 exacerbations (7·4% of the total). PCR also detected 51 exacerbations related to other viruses, 24 bacterial-related, and no pathogen was identified in 64 attended exacerbations.Interpretation: RSV is an important cause of COPD exacerbation, comparable to rhinovirus or influenza. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD.Funding: Innovative Medicines Initiative 2 Joint Undertaking, from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations.Declaration of Interest: JAW has received speaker fees from Astra Zeneca, GSK, Boehringer, Recipharm, Novartis and Fees for Advisory Boards from Astra Zeneca, Epiendo, GSK, Gilead, Novartis, Pieris, Pulmatrix Research grants to the Institution from Astra Zeneca, Boehringer, Chiesi, GSK, Novartis, Genentech, 37Clinical. PO has received consulting and / or speaker fees from GSK, Moderna, Janssen, Seqirus, Pfizer, Moderna and Medscape. DW has received consulting and / or speaker fees from Janssen, GSK, Pfizer and Sanofi. DO and JA were employees of Janssen Pharmaceutica nv during the study period.Ethical Approval: All relevant Research Ethics Committee (REC) and ethics permissions were obtained prior to the start of this project. The United Kingdom arm of this study was approved by the Harrow REC reference: 17/LO/1424 (date of REC approval 18/10/2017), while the Netherlands arm was approved by the local medical ethics committee (University of Groningen, Groningen, the Netherlands: METc 2017/015).

Introduction: Respiratory symptoms predict accelerated lung function decline, COPD development & radiological changes among smokers without COPD.1,2 We hypothesised CAT scores would be higher among young adult smokers with accelerated decline in FEV1. Methods: The Early COPD cohort (NCT03480347) is a multicentre, prospective study of smokers aged 30-45 years with >10 pack years history & FEV1≥80% predicted. FEV1 decline (ml/yr) was estimated using random effects linear regression. The relationship between baseline CAT score & accelerated (>60ml/yr) vs. non-accelerated (<60ml/yr) FEV1 decline was tested using the Mann-Whitney U test. Results: 368 participants (59% male, median age 38 years). Median follow-up time: 32 months (Interquartile range: 24.2 to 41.5). Mean FEV1 decline rate was -35.8ml/yr (95%CI:-45.2 to -27.1;P<0.001). The 103 (28%) participants with accelerated FEV1 decline had higher baseline CAT scores than those without: 12.1 (IQR 8-16) vs.10.4 (IQR 6-14);P=0.026). Mucus production (P<0.001) & activity limitation (P<0.01) was greater among those with accelerated FEV1 decline (Fig 1). Discussion Total CAT score was greater in those with accelerated lung function decline, relative to those without, driven by differences in mucus production & activity limitation. References 1. Allinson J et al. AJRCCM. 2016;193(6):662-72 2. Woodruff P et al. NEJM. 2016;374(19):1811-21

Background: Cardiovascular disease (CVD) is responsible for up to a third of deaths in patients with COPD1. Fibrinogen predicts mortality in COPD2 but is also a well-known marker of CVD. The extent to which it reflects cardiovascular risk in COPD is uncertain. Aims: We investigated how plasma fibrinogen level predicted future risk of cardiovascular event (CVE) among patients with COPD. Methods: We included subjects enrolled in the London COPD exacerbation cohort from 1995-2022. Follow-up was from first baseline fibrinogen measurement until last recorded study interaction. Archived records identified baseline characteristics and incidence of CVE (myocardial infarction (MI) or stroke/transient ischaemic attack (TIA)). We used Kaplan-Meier curves and Cox proportional hazards models to compare event free survival in subjects with a fibrinogen level of ≥3.5g/L versus <3.5g/L. Results: 437 subjects were followed for a median of 1140 days (IQR 416-2159). 116 (27%) had known CVD. During follow-up MI and stroke/TIA occurred in 16(4%) and 10(2%) subjects respectively. Those with fibrinogen ≥3.5g/L had a shorter CVE-free survival on log-rank test (all CVE P=0.001, MI P=0.009, stroke/TIA P=0.03). From Cox proportional hazards model adjusted for age, smoking and sex, acute CVE risk was higher among those with baseline fibrinogen ≥3.5g/L relative to <3.5g/L (HR 4.46, 95%CI:1.63-12.25, P=0.004). Conclusions: In patients with COPD an elevated plasma fibrinogen level indicated higher future CVE risk. Known links between fibrinogen and mortality in COPD might, in part, be driven by this. Fibrinogen could be a useful biomarker for cardiovascular risk in COPD. 1. Berry, C.E. et al. COPD 2010;7(5):375-82 2. Mannino, D.M. et al. COPD 2015;2(1):23-34