Thorax

BackgroundIf lung cancer in never-smokers was a single disease entity, it would be the sixth most commonly occurring malignancy. Despite the population impact, its risk factors are poorly understood owing to a dearth of larger-scale, well-characterised studies. MethodsWe pooled individual-participant data from 18 prospective cohort studies comprising 91,588 never smokers (55,452 women) aged 16-102 years at study induction. Participants were linked to national death registries. ResultsA maximum of 17 years follow-up (mean 9.7) gave rise to 85 lung cancer deaths. Of the 19 potential determinants captured at baseline, only being older age (hazard ratio; 95% confidence interval per 10 year increase: 2.45; 2.11, 2.85), male (2.25; 1.46, 3.48), and having a high fruit and vegetable intake (2.29; 1.25, 4.17) were associated with elevated rates of lung cancer in this never-smoking group. No other substantial relationships were detected. ConclusionsDespite the number and breadth of potential risk factors featured in this multi-cohort study, there was no clear suggestion of new determinants of lung cancer in never-smokers. ImpactOur findings point to the need to explore the influence of risk factors additional to those included herein, particular in the field of genetics. Our unlikely finding for fruit and vegetable consumption warrants further testing.

BackgroundSmoking cessation is the only intervention known to affect disease progression in patients with COPD as measured by the rate of change in forced expiratory volume/1s (FEV1) over time. The need for new drugs to modify the progression of COPD is well recognised. We hypothesised that changes on CT in relation to smoking cessation may relate to changes in response to disease-modifying drugs, and therefore as a novel quantitative biomarker of drug efficacy. CT biomarkers of emphysema and airway wall thickness are increasingly used in research, but there has not been a systematic appraisal of the evidence to assess how these biomarkers evolve with a change in smoking exposure in COPD patients. MethodsWe searched MEDLINE, Embase, the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL)), and Web of Science to 10th September 2019. We included longitudinal studies of smoking COPD patients who had CT scans before and after smoking cessation. Two review authors (DC, SA) independently screened studies, extracted outcome data and assessed the risk of bias, with a third reviewer (JRH) arbitrating conflicts. ResultsFour studies were included in the final analysis. Three studies measured CT markers of lung density, which all, perhaps counter-intuitively, showed a significant decrease with smoking cessation. One study measured CT markers of airway wall thickness, which also significantly decreased with smoking cessation. Authors conclusionsSmoking cessation in COPD patients causes a fall in lung density, but the magnitude of the effect has not been rigorously assessed. One study has reported a decrease in airway wall thickness with smoking cessation. The number of studies is small, with some risk of bias. This question remains important for COPD researchers and requires further studies, in particular to assess whether changes with smoking cessation may model changes in response to novel pharmaceutical agents, and how to handle change in smoking status in relation to longitudinal observational imaging studies in COPD.

BackgroundThe imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described. MethodsWe conducted a population-based longitudinal study in 2,312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and moderate/severe asthma exacerbations were collected via monthly on-line questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders. ResultsRelaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and moderate/severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted odds ratio 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31). ConclusionsRelaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of moderate/severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant. FundingBarts Charity, UKRI

IntroductionHypersensitivity pneumonitis (HP), a common interstitial lung disease (ILD), comprises two distinct but related forms, acute and fibrotic (fHP). HP is classically described as a disease triggered by antigen exposure. However, a wide range of triggers are described and in [~]50% of cases no cause is identified, rendering observational studies challenging. The British Pigeon Fanciers Genetics of ILD (BPF-GILD) study aims to address this by studying a population with a clear history of exposure to a common trigger. MethodsParticipants were recruited from 2019 to 2023 at large UK Pigeon Fancier meetings. Each participant performed spirometry, completed a standardised questionnaire with a doctor, and provided blood samples. We present our baseline data in this manuscript. Results417 subjects were recruited from four shows. The median age of the cohort was 63 years, 95% were male and 94% self-reported white ethnicity. The median number of pigeons kept was 80 [range 4-800], with fanciers spending 14 hours per week [1-100] in their lofts. 52% of participants had occupational dust exposures. 49% of the cohort reported at least one respiratory symptom related to loft exposure. 14% had a history of ILD and these individuals had more loft-related respiratory symptoms, poorer lung function, and appeared more likely to wear a mask with their pigeons than those without (74% vs 57%). 41% of participants had positive responses to questions employed to detect occult connective tissue disease in ILD clinics. DiscussionOur well characterised cohort of pigeon fanciers commonly experience acute HP symptoms and are likely to be at increased risk of fHP. Subsequent work using stored samples will enable us to determine genetic risk factors and pathways relevant to the development of fHP.

IntroductionShared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection. MethodsThe UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam. ResultsA total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days from discharge; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants. ConclusionThese interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors.

In a normal year, the fatal lung disease Idiopathic Pulmonary Fibrosis (IPF) accounts for [~]1% of UK deaths. Smoking is a recognised risk factor for IPF but the question of causality remains unanswered. Here, we used data from the UK Biobank (UKBB) and the well-established genetic technique of Mendelian randomisation (MR) methods to investigate whether smoking is causal for IPF compared with COPD, where causality is established. We looked at observational associations in unrelated Europeans, with 871 IPF cases, 11,413 COPD cases and 366,942 controls. We performed analyses using one-sample MR to test for inferred smoking causality in ever smokers using genetic variants that have a previously demonstrated association with smoking heaviness. Strong associations between disease status and ever having smoked were found in both IPF (OR = 1.52; 95%CI:1.32-1.74; P=2.4x10-8) and COPD (OR= 5.77; 95%CI:5.48-6.07; P<1x10-15). Using MR, a one allele increase in smoking volume genetic risk score was associated with higher odds of COPD in ever smokers, (OR = 4.32; 95%CI:3.37-5.54; P<1x10-15), but no association was seen in IPF (OR=0.55; 95%CI: 0.17-1.81; P=0.33). No association was found between the genetic risk score and disease prevalence in never smokers with IPF (OR = 1.00; 95%CI:0.98-1.02; P=1.00) or COPD (OR = 1.00; 95%CI:0.99-1.01; P=0.53). Although both IPF and COPD are observationally associated with smoking, our analysis provides evidence inferring that the association is causal in COPD but there is no such evidence in IPF. This suggests that other environmental exposures also need consideration in IPF.

Background: Heat exposure has been linked to chronic obstructive pulmonary disease (COPD) outcomes, but evidence on relative humidity and humidity-temperature interaction remains limited and inconsistent. Methods: We conducted a nationwide time-stratified case-crossover study of 473,494 COPD hospital admissions in England during the summer months (June-August) from 2003 to 2021. Case-control pairs were linked to high-resolution daily maximum temperature and relative humidity data derived from HadUK-Grid and ERA5-Land, respectively. Exposure-response relationships were modelled using distributed lag non-linear models. Joint effects were examined using interaction models, including linear interaction, temperature spline by humidity category, and fully categorical specifications. Analyses were stratified by age group, sex, and socioeconomic deprivation. Results: COPD admission risk increases steeply at higher temperatures following a J-shaped curve. The exposure-response for relative humidity is U-shaped with a relative risk of 1.08 (95% Confidence Intervals: 1.00 - 1.15) at the 99th relative humidity percentile. We find limited evidence of effect modification by socioeconomic deprivation for both exposures. An estimated 1,040 (95%CI: 820 - 1,270) summer COPD admissions per year are attributable to non-optimal temperatures and 910 (95%CI: 680 - 1,160) to relative humidity. Higher relative risks are observed with concurrent high temperature and high humidity, but the evidence is weak. Conclusion: High temperature and high relative humidity are associated with increased risk of COPD admission, with limited evidence of an interaction. Relative humidity should be considered alongside temperature in environmental risk assessment and targeted adaptation strategies, such as proactive heat-health advice for people living with COPD.

BackgroundTrials have not directly compared biologics for the treatment of asthma. ObjectiveTo comparative the relative efficacy of biologics in asthma. MethodsWe searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to May 31, 2022, for randomized trials addressing biologic therapies for asthma. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the GRADE approach. We present dichotomous outcomes as absolute risk differences per 1000 patients and relative risk (RR) with 95% confidence intervals (95% CI) and continuous outcomes as mean difference (MD) and 95% CI. ResultsWe identified 64 trials, including 26,630 patients. For patients with eosinophilic asthma, tezepelumab (329 fewer exacerbations per 1000 [95% CI 272.6 to 366.6 fewer]) and dupilumab (319.6 fewer exacerbations per 1000 [95% CI 272.6 to 357.2 fewer]) reduce exacerbations compared to placebo (high certainty). Tezepelumab (MD 0.24 L [95% CI 0.16 to 0.32]) and dupilumab (0.25 L (95% CI 0.21 to 0.29) improve lung function (FEV1) compared to placebo (high certainty). Both tezepelumab (110.97 fewer hospital admissions per 1000 (95% CI 94.53 to 120.56 fewer) and dupilumab (97.27 fewer hospitalizations [4.11 to 124.67 fewer]) probably reduce hospital admissions compared to placebo (moderate certainty). For patients with low eosinophils, biologics probably do not improve asthma outcomes. For these patients, tezepelumab (MD 0.1 L [95% CI 0 to 0.19]) and dupilumab (MD 0.1 L [95% CI 0 to 0.20)] may improve lung function (low certainty). ConclusionTezepelumab and dupilumab are effective at reducing exacerbations. For patients with low eosinophils, however, clinicians should probably be more judicious in use of biologics, including tezepelumab since they probably do not confer substantial benefit.

Background: Anxiety affects 22-56% of patients with COPD. It is independently associated with increased exacerbations, readmissions, and mortality. Medical hypnosis transiently alleviates state anxiety in severe COPD, and attenuates experimentally-induced dyspnoea in healthy volunteers. We aimed to assess the efficacy of hypnosis as adjunct therapy for anxiety during Pulmonary Rehabilitation (PR) versus an active comparator controlling for general motivation and relaxation. Methods. HYPNOBPCO_2 was a single-centre, phase 2, cluster-randomised, active-comparator, parallel-group, superiority trial done at Centre Hospitalier de Bligny, France. Adults +30 years with established COPD, mMRC dyspnoea grade +2, and +10 pack-years were eligible. Consecutive pulmonary rehabilitation cohorts (clusters) were randomly assigned (1:1) to medical hypnosis or structured relaxation, both adjunctive to a 4-week inpatient PR. The primary outcome was the six-item State-Trait Anxiety Inventory (STAI-6) at week 4, analysed in the intention-to-treat population. Secondary outcomes were sensory and affective dyspnoea (Multidimensional Dyspnea Profile sensory and affective sub-scales, COPD Assessment Test) and functional capacity (6-minute walk distance). A moderation analysis tested whether the hypnosis effect varied with baseline sensory and affective dyspnoea burden using Bayesian inference. This trial was registered prospectively (NCT04868357) and the protocol published. Findings. Between 27/09/2021 and 31/01/2024, 79 participants in 24 clusters were randomised (medical hypnosis n = 36, age 64.9 [8.3], 20 female; relaxation n = 43, age 67.4 [9.1], 23 female). Anxiety improved in both arms (deltaSTAI-6 = -5.72, posterior probability of reduction beyond MCID = 0.93). Medical hypnosis did not show an advantage over relaxation overall (deltaSTAI-6 = 0.95; posterior probability of reduction beyond MCID = 0.12). Medical hypnosis did show an advantage that scaled with baseline dyspnoea profile: in patients with high sensory and low affective burden, the predicted anxiety reduction relative to relaxation was larger and more probable (deltaSTAI-6 = -9.26; posterior probability of reduction beyond the 3-point MCID = 0.81). No clinically important safety issues were associated with either intervention and there were no deaths. Interpretation. Anxiety improved under both adjunctive mind-body interventions. The usefulness of hypnosis beyond relaxation was predicted by baseline dyspnoea profile, concentrating in patients with predominantly sensory burden. Future trials should focus on evaluating complementary interventions against burden phenotypes, ultimately paving the way for personalized interventions. Funding. Helebor Foundation; Agence Nationale de la Recherche.

IntroductionEpidemiological and laboratory research seems to suggest that smoking and perhaps nicotine alone could reduce the severity of COVID-19. Likewise, there is some evidence that inhaled corticosteroids could also reduce its severity, opening the possibility that nicotine and inhaled steroids could be used as treatments. MethodsIn this prospective cohort study, we will link English general practice records from the QResearch database to Public Health Englands database of SARS-CoV-2 positive tests, Hospital Episode Statistics, admission to intensive care units, and death from COVID-19 to identify our outcomes: hospitalisation, ICU admission, and death due to COVID. Using Cox regression, we will perform sequential adjustment for potential confounders identified by separate directed acyclic graphs to: O_LIAssess the association between smoking and COVID-19 disease severity, and how that changes on adjustment for smoking-related comorbidity. C_LIO_LIMore closely characterise the association between smoking and severe COVID-19 disease by assessing whether the association is modified by age (as a proxy of length of smoking), gender, ethnic group, and whether people have asthma or COPD. C_LIO_LIAssess for evidence of a dose-response relation between smoking intensity and disease severity, which would help create a case for causality. C_LIO_LIExamine the association between former smokers who are using NRT or are vaping and disease severity. C_LIO_LIExamine whether pre-existing respiratory disease is associated with severe COVID-19 infection. C_LIO_LIAssess whether the association between chronic obstructive pulmonary disease (COPD) and asthma and COVID-19 disease severity is modified by age, gender, ethnicity, and smoking status. C_LIO_LIAssess whether the use of inhaled corticosteroids is associated with severity of COVID-19 disease. C_LIO_LITo assess whether the association between use of inhaled corticosteroids and severity of COVID-19 disease is modified by the number of other airways medications used (as a proxy for severity of condition) and whether people have asthma or COPD. C_LI ConclusionsThis representative population sample will, to our knowledge, present the first comprehensive examination of the association between smoking, nicotine use without smoking, respiratory disease, and severity of COVID-19. We will undertake several sensitivity analyses to examine the potential for bias in these associations.

BackgroundAsthma is the most common chronic disease in childhood and is a growing global concern. However, there are limited data regarding long-term asthma management in low-income countries (LIC), particularly for children. This study will assess the feasibility of recruitment and retention, the acceptability of an intervention and data collection methods, and baseline levels of asthma control and exacerbation rates in our target population of Malawian asthmatic children. Furthermore, we plan to; evaluate the effect of a package of enhanced asthma care, appropriate for a LIC, over a 3-month period; to describe clinical and airway inflammatory phenotypes; to identify clinical and laboratory features which might predict response to treatment in this population. MethodsWe will recruit 120 children aged 6-15 years, attending outpatient asthma follow-up at a tertiary government hospital in Malawi. Participants will be randomised, stratified by level of asthma control (Childhood Asthma Control Test (C-ACT) [&le;]19 or [&ge;]20), to receive standard care in the hospital clinic, or an enhanced care package comprising; detailed clinical assessment (including pre- and post-bronchodilator spirometry, exercise challenge, exhaled nitric oxide (FeNO) measurement and sputum induction), optimisation of inhaled asthma treatment, and asthma education delivered by non-healthcare workers. Feasibility outcomes will include recruitment and retention rates, data completeness for study procedures, and baseline asthma control and exacerbation rates. The primary clinical outcome is asthma control, measured by C-ACT at 3 months, with adjustment for baseline measurement and intervention as covariates in a regression model. Secondary clinical outcomes at 3 months include; asthma exacerbations (requiring emergency health care use, treatment with oral corticosteroids or hospital admission), school absence, lung function and FeNO levels. Participants will be described by clinical and inflammatory phenotypes, with the latter categorised as eosinophilic or non-eosinophilic based on sputum cytology results and FeNO levels. DiscussionIt is important to assess whether global treatment guidelines for long-term asthma management are appropriate for low-income settings. This study will provide key feasibility data, including baseline clinical characteristics of asthmatic Malawian children, to inform assessment of an asthma care package in a low-income setting, which includes task-shifting to non-healthcare workers. Trial registrationPan African Clinical Trials Registry: PACTR201807211617031. Registered 09/07/18, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=3468

BackgroundThe impact of climate change on health is increasing, as global warming continues to rise.1 Within the health and social care sector, pressurised metered dose inhalers (pMDIs) and breath-actuated pMDIs (BA-pMDIs) have been identified as a significant contributing factor to Englands National Health Service carbon footprint.2 MethodsA grounded theory study design was applied to formulate a process map and methodology for Inhaler carbon footprint estimation, utilising established inhaler carbon footprint values and pharmaceutical principles. ResultsA methodology has been developed to support estimation of inhaler carbon footprint values for those inhalers and refills, that do not have a manufacturers independently verified carbon footprint certificate. ConclusionDefinitive Inhaler carbon footprint values, such as those reported here, are required to enable analysis and monitoring of prescribing against Net Zero targets. Further application can also support sustainability assessment and formulary decision making.

Background and ObjectivePatients with COPD have elevated levels of airway glucose. This may increase the risk of bacterial infection leading to exacerbation and disease progression. We aimed to test whether treating COPD patients with metformin, an oral hypoglycaemic used in diabetes, reduced airway glucose. MethodsIn this randomized, double-blind, placebo-controlled crossover pilot study, we assigned patients with COPD to two 3-month periods of treatment with 1g metformin or placebo twice daily, followed by the alternate treatment after a 2-week washout period. Patients were required to be free of infection, antibiotic or oral steroid treatment in the 8 weeks prior to enrolment. The following were collected at baseline and monthly thereafter: sputum (lower airways sample), nasal/upper airway lining fluid samples using synthetic absorptive matrix (SAM), spirometry, and St Georges Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) scores. The primary outcome was a change in sputum glucose following 3 months treatment with metformin compared to 3 months of placebo. Results14 patients were randomised of whom 3 completed the study, mainly due to withdrawals for exacerbations (8/11 withdrawals). In the n=4 patients who completed 3 months metformin treatment, there were no significant changes in sputum or nasal glucose compared to baseline. Metformin did not affect COPD symptom scores or spirometry. ConclusionsTreatment with metformin in this underpowered pilot study did not significantly reduce airway glucose in COPD. Larger studies are required to definitively evaluate this. SUMMARY AT A GLANCEElevated airway glucose is associated with bacterial infection in chronic obstructive pulmonary disease (COPD) exacerbations. We tested whether metformin, a drug used to treat diabetes, reduced airway glucose in patients with COPD. Recruitment/retention difficulties led to an underpowered study, which observed no difference between metformin and placebo on airway glucose.

BackgroundThe predominant airway inflammation in chronic obstructive pulmonary disease (COPD) is neutrophilic, although numerous studies have shown that eosinophilic inflammation contributes significantly to COPD. Eosinophilic COPD patients are characterized by a greater number of total exacerbations and higher hospitalization rates. Biological therapy targets multiple steps in eosinophilic inflammation, providing a promising approach to reduce exacerbation frequency and mortality. ObjectiveTo provide a timely, rigorous, and continuously updated summary of the evidence available on the role of biological therapy for the treatment of patients with COPD. DesignThis is a Living Evidence synthesis, that starts with a baseline synthesis report of the effects of the intervention on the main predefined outcomes. Based on its conclusions, we will set up the living evidence approach, and the evidence monitoring will begin. MethodsO_ST_ABSEvidence identification, screening, and selectionC_ST_ABSAutomated living searches were performed in relevant databases following the Epistemonikos procedures. Results were incorporated into the Epistemonikos "Living OVerview of Evidence (L.OVE)" platform which was used for evidence screening, and selection. Two reviewers screened all titles and abstracts supported by the platform automated classifiers that excluded references with a low probability of being relevant. For this baseline report we included randomized trials that evaluated the use of biological therapy compared to the use of standard-of-therapy alone in adult patients with COPD. Main outcomes defined as critical or important for decision making include exacerbation rate, exacerbation-free time, lung function and quality of life. Two reviewers independently screened each study for eligibility, extract data, and assess its methodological quality using appropriate tools. We performed meta-analyses of the studys results when pertinent. We applied the GRADE approach to assess the certainty of the evidence found for each outcome. We will continuously monitor the evidence by performing daily searches and monthly screening of the retrieved references. Additionally, each three months we will manually search for ongoing studies in the International Clinical Trials Registry Platform trial registries. The evidence monitoring, including decisions to incorporate evidence and withdraw the question from the living mode will follow the process proposed by the Living Evidence to Inform Health Decisions framework (ref) as stated in our protocol. A living, web-based version of this review will be openly available during the next year at https://livingevidenceihd.com/lesrepo/. We will resubmit it every time the conclusions change or whenever there are substantial updates. ResultsInitial searches retrieved 24 systematic reviews, 2 evaluating the use of biologics on COPD, which included 6 randomized control trials. Additional searches retrieved 125 randomized controlled trials (RCTs). Of these, 31 RCTs were deemed potentially eligible and were reviewed in full text. Ultimately, 9 RCTs evaluating the use of biological therapies (MEDI8968, benralizumab, mepolizumab, dupilumab, astegolimab, and itepekimab) compared to placebo in COPD patients were included. The GRADE quality of evidence for the main outcomes was assessed as intermediate. ConclusionsThe evidence suggests that biological therapies may reduce the risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, the overall impact on lung function and quality of life remains inconclusive. The variability in study outcomes, particularly concerning SGRQ scores and FEV1, emphasizes the need for continuing monitoring evidence. PROSPERO /OSF Protocol Registration DOI: 10.17605/OSF.IO/SUYD2 STRUCTURED ABSTRACTO_ST_ABSObjectiveC_ST_ABSTo synthesize and update evidence on the efficacy and safety of biological therapy for chronic obstructive pulmonary disease (COPD). MethodsThis living evidence synthesis included systematic reviews (SRs) and randomized controlled trials (RCTs) comparing biological therapies (e.g., benralizumab, mepolizumab, dupilumab) with placebo or standard care in adults with moderate to severe COPD. Automated searches were conducted using the Epistemonikos "Living Overview of Evidence" (L.OVE) platform, supplemented by manual searches. Two reviewers independently screened studies, extracted data, and assessed risk of bias using Cochrane RoB2 for RCTs and AMSTAR II for SRs. Meta-analyses were performed, and the certainty of evidence was evaluated using the GRADE approach. ResultsNine RCTs were included. Biological therapy probably reduces annual exacerbation rates (moderate certainty; MD -0.12, 95% CI -0.23 to 0.00). The evidence is very uncertain about its effect on quality of life (SGRQ score: MD 0.05, 95% CI -0.04 to 0.14; very low certainty) due to serious inconsistency (I{superscript 2} = 95.5%) and imprecision. Biological therapy may result in little to no difference in lung function (FEV1: MD 0.02, 95% CI -0.02 to 0.06; low certainty), with serious inconsistency (I{superscript 2} = 76.8%) and imprecision. Biological therapy probably results in no difference in total adverse events (moderate certainty; RR 1.02, 95% CI 0.99 to 1.05) but likely reduces severe adverse events (high certainty; RR 0.84, 95% CI 0.77 to 0.93). ConclusionsCurrent evidence suggests that biological therapies for COPD provide little to no clinical benefit over standard care in terms of exacerbation rates, lung function, or safety, with uncertain effects on quality of life. Biological therapy probably has little to no effect on annual exacerbations compared with standard care. There is likely no meaningful difference in lung function (FEV1) compared with standard care. Biologicals probably result in no difference in the number of total adverse events. Regarding the effect on quality of life, measured by the SGRQ compared with standard care, the evidence is very uncertain; therefore, no conclusions can be drawn. Overall, the certainty of the evidence supporting these statements is generally moderate, but is particularly limited by imprecision in estimates when considering thresholds for the minimal important difference (MID).

BackgroundAsthma is an umbrella diagnosis encompassing distinct pathophysiological mechanisms. While a global problem, our understanding of the interplay between respiratory microbiology and airway inflammation is largely from populations in high income settings. As a result, treatment approaches align poorly with asthma characteristics in less studied populations. ObjectiveTo identify conserved and geographically distinct relationships between airway inflammation and microbiota characteristics in young people with asthma. MethodsWe conducted a cross-sectional study performing inflammatory phenotyping, microbiota analysis, and enumeration of total bacteria, Haemophilus influenzae and Moraxella catarrhalis on 488 induced sputum samples from Brazil (n=68), Ecuador (n=119), Uganda (n=69), New Zealand (n=187), and the United Kingdom (n=45). Microbiological characteristics were compared by country, asthma status, and inflammatory characteristics, adjusting for age and sex. ResultsInflammatory phenotypes and airway microbiota differed between countries, with Uganda characterised by greater neutrophil%, microbial diversity, and bacterial load. Across all countries, microbiota similarity differed by asthma status (P=0.012). Within participants with asthma, microbiota similarity for neutrophilic and eosinophilic phenotypes differed from paucigranulocytic (P<0.001 and P=0.020, respectively) and from each other (P<0.001). Neutrophil% was strongly associated with microbiota composition (P<0.001) and positively associated with bacterial load and opportunistic pathogens (P<0.05). In contrast, eosinophil% was less strongly associated with microbiota similarity (P=0.033), positively associated with Streptococcus (P=0.0009), but not associated with bacterial load (P=0.787). Country-specific associations between sputum inflammation and microbiology were evident. ConclusionBoth airway inflammation and microbiology varied geographically in young people with asthma. Associations between microbiota characteristics and neutrophilic phenotype were conserved. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIAsthma treatment response and severity are associated with airway inflammation and microbiology. C_LIO_LIMost asthma research is performed in high income countries and the generalisability in other settings is unclear. C_LI What this study addsO_LIAsthma inflammatory phenotypes and airway microbiota vary across high income (New Zealand and the United Kingdom) and low to middle income (Brazil, Ecuador, Uganda) countries. C_LIO_LIThe association between airway microbiota and neutrophilic and eosinophilic inflammation is complex and varied between countries. C_LI How this study might affect research, practice or policyO_LIUnderstanding variation in underlying pathophysiology between countries can inform improved deployment of maintenance asthma therapies, such as macrolides and inhaled corticosteroids, that target specific inflammatory pathways. C_LI

IntroductionAlthough temporal variation is the hallmark of asthma, recommended diagnostic approaches largely rely on single clinic-based measurements. Ambulatory monitoring captures diurnal and day-to-day variability and may therefore enhance diagnostic accuracy. We evaluated the clinical feasibility and potential utility of home spirometry and fractional exhaled nitric oxide (FeNO) monitoring in asthma diagnosis. MethodsSymptomatic, untreated adults with GP-suspected asthma underwent diagnostic tests including bronchodilator reversibility, in-clinic FeNO, blood eosinophil counts and bronchial challenge. Participants measured spirometry and FeNO four times daily over one week; during the second week spirometry were measured twice daily. The reference standard was provided (asthma/not-asthma) by an expert panel of at least two asthma specialists based on clinical history and the results of all in-clinic testing; home spirometry (except for peak expiratory flow) and FeNO measurements were blinded to the panel. ResultsOf 67 eligible participants, 51(76%) were recruited, and 38 had asthma confirmed or excluded by the panel. 1058 home spirometry measurements were obtained from 37(73%) participants; 848 home FeNO readings were obtained from 39(76%) participants. Among those completing at least one home measurement, median (IQR) adherence was 66.7(58.6-97.6)% for spirometry and 78.5(51.8-103.6)% for FeNO. Collection of health impact data for economic evaluation was feasible. In participants with a confirmed diagnostic outcome who completed home measurements (FeNO: n=32; spirometry: n=28), the putative home-testing metrics demonstrated high sensitivities at [&ge;]90% specificity, and outperformed peak expiratory flow diurnal variability. Incorporating home testing into the BTS/NICE/SIGN 2024 diagnostic pathway had the potential to reduce reliance on bronchial challenge testing by 57%. ConclusionsHome spirometry and FeNO testing and the prospective collection of health-economic data in the diagnostic setting were feasible. Home-based testing strategy showed early potential to improve asthma diagnosis and pathway efficiency. These findings support further evaluation through an adequately powered diagnostic accuracy study and health-economic assessment. Key messagesO_LIWhat is already known on this topic: Asthma can be difficult to diagnose, as objective tests may be normal when assessments are performed during periods of minimal or intermittent symptoms. C_LIO_LIWhat this study adds: Our data suggest that home spirometry and FeNO monitoring could be successfully implemented within a diagnostic accuracy trial. Participants were able to perform these tests reliably in the home environment. C_LIO_LIHow this study might affect research, practice or policy: The early findings suggest that home-based physiological monitoring may offer additive diagnostic value beyond standard clinic-based assessments and could reduce reliance on bronchial challenge testing. These results provide a clear rationale for larger diagnostic accuracy trials and for undertaking early health-economic modelling to assess the potential impact on clinical pathways and resource utilisation. C_LI

ObjectiveCirculating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis. MethodsWe tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospective observational study of pulmonary fibrosis (PROFILE; NCT01134822). A subset of recruited participants had blood samples processed for fibrocyte measurement, with flow cytometry based on CD45 and collagen-I gating. Associations were tested using univariable and multivariable generalised linear models. Mortality data were subsequently combined with an independent cohort in a mixed-effect multilevel analysis. ResultsIn 102 participants with idiopathic pulmonary fibrosis, an empirically defined cutpoint of 2.22% was associated with a greater risk of overall mortality in adjusted analysis (Hazard Ratio 2.24 95% CI 1.06-4.72). A 2.5 fold greater risk of mortality was supported in a pooled analysis with a historic cohort for a larger sample of 162 participants of idiopathic pulmonary fibrosis, specifically (Hazard Ratio 2.49 95% CI 2.41-2.56). A previously defined mortality risk threshold of 5% circulating fibrocytes was not reproducible in this cohort, circulating fibrocytes were not significantly elevated above non-specific interstitial pneumonia or healthy controls.. We found no association of fibrocytes with lung function or disease progression. ConclusionsIn a prospective clinical cohort of idiopathic pulmonary fibrosis, circulating fibrocytes of 2.22% or above are associated with greater mortality, but do not associate with disease related decline in lung function. What is the key question?Can circulating fibrocytes provide reproducible prognostic biomarker value in fibrotic lung disease? What is the bottom line?Greater proportions of fibrocytes isolated from circulating leukocyte populations are associated with an increase risk of mortality in idiopathic pulmonary fibrosis, but no association was observed with disease related decline in lung function. Why read on?We present associations and limitations of circulating fibrocytes in the largest sample of individuals with pulmonary fibrosis, recruited into a prospective observational study, and replicate prognositic insights from a historic cohort.

In pharmacoepidemiologic studies of COVID-19, there were concerns about bias from residual confounding. We applied high-dimensional propensity scores (HDPS) to a case study investigating the role of inhaled corticosteroids (ICS) in COVID-19 to adjust for unmeasured confounding. We selected patients with chronic obstructive pulmonary disease on 01 March 2020 from Clinical Practice Research Datalink (CPRD) Aurum, comparing ICS/LABA/(+-LAMA) and LABA/LAMA users. ICS effects on the outcomes COVID-19 hospitalisation and death were assessed through weighted and unweighted Cox proportional hazards models. HDPS were estimated from primary care clinical records, prescriptions and hospitalisations. SNOMED-CT codes and dictionary of medicines and devices codes from CPRD Aurum were mapped to International Classification of Disease 10th revision codes and British National Formulary paragraphs respectively. We estimated propensity scores (PS) combining prespecified and HDPS covariates, selecting the top 100, 250, 500, 750 and 1000 covariates ranked by confounding potential. When excluding triple therapy users, the conventional PS-weighted estimates showed weak evidence of increased risk of COVID-19 hospitalisation among ICS users (HR 1.19 (95% CI 0.92-1.54)). Results varied slightly based on the number of covariates included in HDPS (HR using 100 HDPS covariates 1.01 (95% CI 0.76-1.33), HR using 250 HDPS covariates 1.24 (95% CI 0.83-1.87)). For COVID-19 death, conventional PS-weighted models showed weak evidence of harm of ICS when excluding triple therapy users (HR 1.24 (95% CI 0.87-1.75)). HDPS-weighting moved estimates toward the null, suggesting no effect of ICS (HR using 250 HDPS covariates excluding triple therapy 1.08 (95% CI 0.73- 1.59)). HDPS may have provided better confounding control for COVID-19 deaths and may be able to partially compensate for suboptimal comparison groups. HDPS results can be sensitive to the number of covariates included, highlighting the importance of sensitivity analyses. Key pointsO_LIResidual confounding, including residual confounding by indication, is a major concern in pharmacoepidemiologic studies of COVID-19 outcomes. C_LIO_LIWe apply high-dimensional propensity scores (HDPS) to adjust for residual confounding in a case study of inhaled corticosteroids (ICS) on COVID-19 hospitalisation and death in CPRD Aurum. C_LIO_LIConventional PS-weighted analyses suggested harmful effects of ICS on COVID-19 hospitalisation and, to a lesser extent, deaths. C_LIO_LIHDPS weighted analyses of COVID-19 hospitalisations were sensitive to the number of covariates included, with results moving towards the null for smaller number of covariates and away from the null when including more covariates, while for deaths, estimates moved towards the null consistently. C_LIO_LIHDPS demonstrated promise in addressing confounding even when comparison groups are suboptimal, but its performance depends on the careful selection and ranking of covariates. C_LI Plain Language SummaryA key challenge when researching the effects of medications using electronic health records is accounting for the fact that people who receive different medications often differ in important ways. Such differences, called confounding, is typically accounted for using statistical methods which require researchers to pre-specify all important confounders. A newer method, called high-dimensional propensity scores (HDPS), uses a data-driven approach to select what confounders to account for instead. These methods have not yet been applied to studies of inhaled corticosteroids and COVID-19 outcomes, an area where studies have found conflicting findings. We used electronic health records from the UK to compare the risk of COVID-19 hospitalisation and death among patients with chronic obstructive pulmonary disease taking two different treatments (ICS/LABA and LABA/LAMA) using both conventional and HDPS methods. Our findings showed that HDPS can reduce important differences between patients (confounding), but that the results can be sensitive to the number of covariates included. This demonstrates the value of HDPS and the need for researchers to run their analysis using several different assumptions.

IntroductionGrowing evidence suggests that biological sex influences the incidence, presentation, diagnosis and outcomes of many lung diseases. Understanding these differences is the first step towards precision medicine to improve patient care. MethodsIn this cross-sectional study IPF patients enrolled in a national, multicentre registry (UK BTS-ILD) were categorised by sex and analysed for differences in demographics, pulmonary function tests, HRCT radiological pattern, eligibility/uptake of antifibrotics and survival. ResultsOf 7177 cases, 77.8% (n=5587) were male, median age 75 years (IQR 69.5-80.5) for both sexes (p=0.83). Males were more likely to have a history of smoking (p<0.001) and lower baseline median FVC % predicted (males 76.4%, IQR 66.2-86.7 vs females 78.8%, IQR 68.6-89.1, p<0.001). Diabetes, cardiovascular disease and gastro-oesophageal reflux disease were statistically more common in males (p<0.001), whilst major depressive illness was more common in females (p<0.001). Significantly more females experienced symptoms for >24 months prior to first clinic appointment (females 40.1% vs males 36.6%, p=0.028). Whilst more males in the cohort met eligibility criteria for antifibrotics at baseline (p<0.001), a larger proportion chose not to commence antifibrotic treatment (males 47.0% vs females 29.6%, p<0.001). Female sex was associated with longer mean survival (female 9.99 years (95% CI 9.18-10.79) vs males 8.57 years (95% CI 8.15-8.99), p<0.001). Male sex, higher age, lower baseline FVC % predicted and co-existent lung cancer were all independently associated with worse survival (p<0.001). ConclusionThis is the first UK study to use national registry data to systematically evaluate IPF disease characteristics stratifying by biological sex and highlights distinct characteristics between groups. Future clinical trials should explicitly explore sex-specific targeted interventions and analyses, to optimise future IPF patient care. What is already known about this topic?Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung condition with a poor prognosis. There are established sex differences in the incidence and prevalence of IPF, and reports of differing lived experience. What this study adds?This study is the first to report on UK real-world registry dataset to systematically evaluate sex differences in clinical disease characteristics, treatments and outcomes. The results of this study suggest that IPF has distinct characteristics depending on biological sex. How this study might affect research, practice or policy?These findings highlight key areas that could be addressed to improve patient outcomes and care within the UK. It creates the opportunity to explore tailored approaches to care.

RATIONALEImpaired lung function predicts mortality and is a diagnostic criterion for chronic obstructive pulmonary disease (COPD). Proteins are often the target of pharmacological interventions, therefore identifying causal links between proteins and lung function could inform understanding of COPD pathophysiology and suggest therapeutic targets. We aim to infer the potential impact of circulating protein levels on lung function, using strictly defined cis protein quantitative trait loci (cis-pQTLs) as genetic instrumental variables for Mendelian randomisation (MR). METHODSWe applied two-sample MR by integrating protein GWAS data (2,923 proteins, 48,195 UK Biobank European participants) with lung function GWAS data (four lung function traits, 149,166 European participants from 36 non-UK Biobank cohorts). We selected strictly defined cis-pQTLs, within 100 kilobase pairs of a transcription start site and strongly associated (P[&le;]5x10-9) with protein levels, and applied single-cis-MR analysis (Wald ratio method). Sensitivity analyses included colocalization analysis (to distinguish causal effects from genomic confounding by linkage disequilibrium), and bidirectional MR to explore possible reverse causation. Replication analysis was conducted where possible. We used the Drug-Gene Interaction Database and phenome-wide association studies (PheWAS) to inform biological and clinical interpretation of identified proteins. RESULTSWe curated 1,841 proteins with a suitable cis-pQTL instrument, and evaluated evidence for causal effects of these proteins on four lung function traits. The single-cis MR analysis implicated 16 proteins for lung function at a Bonferroni-corrected threshold (Wald ratio estimator P<1.71x10-5), with evidence from colocalization. Of these, 10 proteins have been previously implicated either by lung function GWAS, or from other MR analyses with colocalization. Surfactant protein D (SFTPD) has been highlighted in previous respiratory MR analyses and variants in SFTPD have been previously reported to be associated with emphysema; our PheWAS suggested that this variant has a relatively specific effect on lung function as it was associated with no non-respiratory traits at a FDR<1%. In contrast to previous expression QTL evidence, our study suggested that ITGAV inhibition could reduce FEV1/FVC; we note that reduced lung function was also seen in a recent trial of an ITGAV inhibitor (NCT01371305). Our MR analysis implicated six proteins not implicated by previous lung function GWAS or MR (DTD1, PILRA, PTPRK, TDPRK, GRHPR, NUDT5). CONCLUSIONSOur protein-based approach identified proteins that may be causally related for lung function variability. We highlight known protein drug targets, and identify several new proteins which are potentially therapeutic targets but warrant further follow up for potential utility and safety.