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BACKGROUND: In COPD, the balance between matrix metalloproteinases (MMPs) and their natural inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] is shifted towards excessive degradation, reflected in bronchoalveolar lavage (BAL) as increased MMP concentrations. Because of their critical role in lung homeostasis, MMP activity is tightly regulated, but to what extent this regulation occurs through epigenetic mechanisms remains unknown.

METHODS: To explore the interplay between MMPs, TIMPs, and DNA methylation (DNAm) we (1) analysed MMP-9, -12, and TIMP-1 concentrations in BAL fluid, and profiled DNAm in BAL cells from 18 COPD and 30 control subjects, (2) estimated protein-COPD relationships using multivariable regression, (3) identified protein quantitative trait methylation loci (pQTMs) with COPD as a potential modifier in a separate interaction model, and (4) integrated significant interactions with a previous COPD GWAS meta-analysis.

RESULTS: COPD was associated with higher levels of BAL MMP-12 (p = 0.016) but not with MMP-9 or TIMP-1. Further examination of MMP-12 identified association with DNAm at 34 loci (pQTMs), with TGFBR2 (p = 2.25 × 10^-10) and THBS4 (p = 1.11 × 10^-9) among the top ten pQTM genes. The interaction model identified 66 sites where the DNAm-MMP-12 association was significantly different in COPD compared to controls. Of these, one was colocalized with SNPs previously associated with COPD.

CONCLUSIONS: Our findings indicate that airway MMP-12 may partially be regulated by epigenetic mechanisms and that this regulation is disrupted in COPD. Furthermore, integration with COPD GWAS data suggests that this dysregulation is influenced by a combination of environmental factors, disease processes, and genetics, with the latter potentially playing a lesser role.

Introduction: Computational sciences have significantly contributed to characterizing airway disease phenotypes, complementing medical expertise. However, comparing studies that derive phenotypes is challenging due to varying decisions made during phenotyping. We conducted a systematic review to describe studies that utilized unsupervised computational approaches for phenotyping obstructive airway diseases in children and adults.

Methods: We searched for relevant papers published between 2010 and 2020 in PubMed, EMBASE, Scopus, Web of Science, and Google Scholar. Additional sources included conference proceedings, reference lists, and expert recommendations. Two reviewers independently screened studies for eligibility, extracted data, and assessed study quality. Disagreements were resolved by a third reviewer. An in-house quality appraisal tool was used. Evidence was synthesized, focusing on populations, variables, and computational approaches used for deriving phenotypes.

Results: Of 120 studies included in the review, 60 focused on asthma, 19 on severe asthma, 28 on COPD, 4 on asthma-COPD overlap (ACO), and 9 on rhinitis. Among asthma studies, 31 focused on adults and 9 on children, with phenotypes related to atopy, age at onset, and disease severity. Severe asthma phenotypes were characterized by symptomatology, atopy, and age at onset. COPD phenotypes involved lung function, emphysematous changes, smoking, comorbidities, and daily life impairment. ACO and rhinitis phenotypes were mostly defined by symptoms, lung function, and sensitization, respectively. Most studies used hierarchical clustering, with some employing latent class modeling, mixture models, and factor analysis. The comprehensiveness of variable reporting was the best quality indicator, while reproducibility measures were often lacking.

Conclusion: Variations in phenotyping methods, study settings, participant profiles, and variables contribute to significant differences in characterizing asthma, severe asthma, COPD, ACO, and rhinitis phenotypes across studies. Lack of reproducibility measures limits the evaluation of computational phenotyping in airway diseases, underscoring the need for consistent approaches to defining outcomes and selecting variables to ensure reliable phenotyping.

Background: Chronic airway obstruction (CAO) and restrictive spirometry pattern (RSP) are associated with mortality, but sex-specific patterns of all-cause and specific causes of death have hardly been evaluated.

Objectives: To study the possible sex-dependent differences of all-cause mortality and patterns of cause-specific mortality among men and women with CAO and RSP, respectively, to that of normal lung function (NLF).

Design: Population-based prospective cohort study.

Methods: Individuals with CAO [FEV1/vital capacity (VC) < 0.70], RSP [FEV₁/VC ⩾ 0.70 and forced vital capacity (FVC) < 80% predicted] and NLF (FEV₁/VC ⩾ 0.70 and FVC ⩾ 80% predicted) were identified within the Obstructive Lung Disease in Northern Sweden (OLIN) studies in 2002–2004. Mortality data were collected through April 2016, totally covering 19,000 patient-years. Cox regression and Fine–Gray regression accounting for competing risks were utilized to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, body mass index, sex, smoking habits and pack-years.

Results: The adjusted hazard for all-cause mortality was higher in CAO and RSP than in NLF (HR, 95% CI; 1.69, 1.31–2.02 and 1.24, 1.06–1.71), and the higher hazards were driven by males. CAO had a higher hazard of respiratory and cardiovascular death than NLF (2.68, 1.05–6.82 and 1.40, 1.04–1.90). The hazard of respiratory death was significant in women (3.41, 1.05–11.07) while the hazard of cardiovascular death was significant in men (1.49, 1.01–2.22). In RSP, the higher hazard for respiratory death remained after adjustment (2.68, 1.05–6.82) but not for cardiovascular death (1.11, 0.74–1.66), with a similar pattern in both sexes.

Conclusion: The higher hazard for all-cause mortality in CAO and RSP than in NLF was male driven. CAO was associated with respiratory death in women and cardiovascular death in men, while RSP is associated with respiratory death, similarly in both sexes.

INTRODUCTION: How e-cigarette use relates to changes in smoking status and respiratory symptoms in the population remains controversial. The aim was to study the association between e-cigarette use and, changes in smoking status and changes in respiratory symptoms.

METHODS: A prospective, population-based study of random samples of the population (age 16–69 years) was performed within The Obstructive Lung Disease in Northern Sweden (OLIN) study and West Sweden Asthma Study (WSAS). A validated postal questionnaire containing identical questions was used in OLIN and WSAS at baseline in 2006–2008 and at follow-up in 2016. In total, 17325 participated on both occasions. Questions about respiratory symptoms and tobacco smoking were included in both surveys, while e-cigarette use was added in 2016.

RESULTS: In 2016, 1.6% used e-cigarettes, and it was significantly more common in persistent tobacco smokers (10.6%), than in those who quit smoking (2.1%), started smoking (7.8%), or had relapsed into tobacco smoking at follow-up (6.4%) (p<0.001). Among current smokers at baseline, tobacco smoking cessation was less common in e-cigarette users than e-cigarette non-users (14.2% vs 47.6%, p<0.001) and there was no association with a reduction in the number of tobacco cigarettes smoked per day. Those who were persistent smokers reported increasing respiratory symptoms. In contrast, the symptoms decreased among those who quit tobacco smoking, but there was no significant difference in respiratory symptoms between quitters with and without e-cigarette use.

CONCLUSIONS: E-cigarette use was associated with persistent tobacco smoking and reporting respiratory symptoms. We found no association between e-cigarette use and tobacco smoking cessation, reduction of number of tobacco cigarettes smoked per day or reduction of respiratory symptoms.

Background: Acute exacerbations (AEs) of COPD are increasingly recognized as episodes of heightened risk of cardiovascular events. It is not known whether exacerbation history is differentially associated with future myocardial infarction (MI) or pulmonary embolism (PE).

Research Question: Is the number and severity of AEs of COPD associated with increased risk of MI or PE in a real-life cohort of patients with COPD?

Study Design and Methods: We identified a cohort of 66,422 patients (≥ 30 years of age) with a primary diagnosis of COPD in the Swedish National Airway Register from January 2014 to June 2022, with complete data on lung function. Patients were classified by moderate (prescription of oral corticosteroids) and severe (hospitalization) exacerbations the year before index date and were followed until December 2022 for hospitalization or death from MI or PE, corresponding to > 265,000 patient-years, with a maximum follow-up time of 9 years. Competing risk regression, according to the Fine-Gray model, was used to calculate subdistribution hazard ratios with 95% CIs.

Results: Compared with no AEs of COPD in the baseline period, AE of COPD number and severity were associated with increased long-term risk of both MI and PE in a gradual fashion, ranging from a subdistribution hazard ratio of 1.10 (95% CI, 0.97-1.24) and 1.33 (95% CI, 1.11-1.60), respectively, for one moderate exacerbation, to 1.82 (95% CI, 1.36-2.44) and 2.62 (95% CI, 1.77-3.89), respectively, for two or more severe exacerbations. In a time-restricted follow-up sensitivity analysis, the associations were stronger during the first year of follow-up and diminished over time.

Interpretation: The risk of MI and PE increased with the frequency and severity of AEs of COPD in this large, real-life cohort of patients with COPD.

Background and Aim: The relationship between socioeconomic status (SES), asthma and mortality is complex and multifaceted, and it is not established if educational level modifies the association between asthma and mortality. The aim was to study the association between asthma and mortality in Sweden and Norway and to what extent educational level modifies this association.

Participants and Methods: Within the Nordic EpiLung Study, >56,000 individuals aged 30–69 years participated in population-based surveys on asthma and associated risk factors in Sweden and Norway during 2005–2007. Data on educational level and 10-year all-cause mortality were linked by national authorities. The fraction of mortality risk attributable to asthma was calculated, and Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for mortality related to asthma, stratified by educational level.

Results: In total, 5.5% of all deaths was attributed to asthma. When adjusted for potential confounders, the HR for mortality related to asthma was 1.71 (95% CI 1.52–1.93). Those with primary level of education had higher hazard of all-cause death related to asthma than those with tertiary level (HR 1.80, 95% CI 1.48–2.18, vs HR 1.39, 95% CI 0.99–1.95).

Conclusion: Asthma was associated with an overall 71% increased all-cause mortality and 5.5% of deaths can be attributed to asthma. Educational levels modified the risk of mortality associated with asthma, with the highest risk among those with primary education.

Rationale: Knowledge regarding the prevalence and shared and unique characteristics of the restrictive spirometric pattern (RSP) and preserved ratio impaired spirometry (PRISm) is lacking for a general population investigated with post-bronchodilator spirometry and computed tomography of the lungs.

Objectives: To investigate shared and unique features for RSP and PRISm.

Methods: In the Swedish CArdioPulmonary bioImage Study (SCAPIS), a general population sample of 28,555 people aged 50-64 years (including 14,558 never-smokers) was assessed. The participants answered a questionnaire and underwent computed tomography of the lungs, post-bronchodilator spirometry, and coronary artery calcification score. Odds ratios with 95% confidence intervals (CIs) were calculated using adjusted logistic regression. RSP was defined as forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) ≥0.70 and FVC <80%. PRISm was defined as FEV₁/FVC ≥0.70 and FEV₁ <80%. A local reference equation was applied.

Results: The prevalence of RSP and PRISm were 5.1% (95% CI, 4.9-5.4) and 5.1% (95% CI, 4.8-5.3), respectively, with similar values seen in never-smokers. For RSP and PRISm, shared features were current smoking, dyspnea, chronic bronchitis, rheumatic disease, diabetes, ischemic heart disease, bronchial wall thickening, interstitial lung abnormalities, and bronchiectasis. Emphysema was uniquely linked to PRISm (odds ratio, 1.69; 95% CI, 1.36-2.10) versus 1.10 (95% CI, 0.84-1.43) for RSP. Coronary artery calcification score ≥300 was related to PRISm, but not among never-smokers.

Conclusions: PRISm and RSP have respiratory, cardiovascular, and metabolic conditions as shared features. Emphysema is only associated with PRISm. Coronary atherosclerosis may be associated with PRISm. Our results indicate that RSP and PRISm may share more features than not.

Highlights:

• Severe obesity strongly associates to blood neutrophils in adult-onset asthma.
• B-neutrophils may partly mediate associations between obesity and asthma control.
• Clinical evaluation of adult-onset asthma should include assessing B-neutrophils.