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Rationale: Spirometry is essential for diagnosis and assessment of prognosis in patients with chronic obstructive pulmonary disease (COPD). Objectives: To identify FEV 1 trajectories and their determinants on the basis of annual spirometry measurements among individuals with and without airway obstruction (AO) and to assess mortality in relation to trajectories. Methods: From 2002 through 2004, individuals with AO (FEV 1 /VC < 0.70, n  = 993) and age- and sex-matched nonobstructive (NO) referents were recruited from population-based cohorts. Annual spirometry until 2014 was used in joint-survival latent-class mixed models to identify lung function trajectories. Mortality data were collected during 15 years of follow-up. Measurements and Main Results: Three trajectories were identified among the subjects with AO and two among the NO referents. Trajectory membership was driven by baseline FEV 1 % predicted (FEV 1 %pred) in both groups and also by pack-years in subjects with AO and current smoking in NO referents. Longitudinal FEV 1 %pred depended on baseline FEV 1 %pred, pack-years, and obesity. The trajectories were distributed as follows: among individuals with AO, 79.6% in AO trajectory 1 (FEV 1 high with normal decline), 12.8% in AO trajectory 2 (FEV 1 high with rapid decline), and 7.7% in AO trajectory 3 (FEV 1 low with normal decline) (mean, 27, 72, and 26 ml/yr, respectively) and, among NO referents, 96.7% in NO trajectory 1 (FEV 1 high with normal decline) and 3.3% in NO trajectory 2 (FEV 1 high with rapid decline) (mean, 34 and 173 ml/yr, respectively). Hazard for death was increased for AO trajectories 2 (hazard ratio [HR], 1.56) and 3 (HR, 3.45) versus AO trajectory 1 and for NO trajectory 2 (HR, 2.99) versus NO trajectory 1. Conclusions: Three different FEV 1 trajectories were identified among subjects with AO and two among NO referents, with different outcomes in terms of FEV 1 decline and mortality. The FEV 1 trajectories among subjects with AO and the relationship between low FVC and trajectory outcome are of particular clinical interest.

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV 1 /FVC ratios. The prevalence of postbronchodilator FEV 1 /FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV 1 /FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV 1 /FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P  < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P  < 0.001) than subjects with a postbronchodilator FEV 1 /FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV 1 /FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

DNA methylation patterns in chronic pulmonary obstructive disease (COPD) might offer new insights into disease pathogenesis. To assess methylation profiles in the main COPD target organ, we performed an epigenome-wide association study on BAL cells. Bronchoscopies were performed in 18 subjects with COPD and 15 control subjects (ex- and current smokers). DNA methylation was measured using the Illumina MethylationEPIC BeadChip Kit, covering more than 850,000 CpGs. Differentially methylated positions (DMPs) were examined for 1 ) enrichment in pathways and functional gene relationships using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, 2 ) accelerated aging using Horvath's epigenetic clock, 3 ) correlation with gene expression, and 4 ) colocalization with genetic variation. We found 1,155 Bonferroni-significant ( P  < 6.74 × 10 -8 ) DMPs associated with COPD, many with large effect sizes. Functional analysis identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. Strong correlation was found between DNA methylation and chronological age but not between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL cells. Thirty-nine percent of DMPs were colocalized with COPD-associated SNPs. To the best of our knowledge, this is the first epigenome-wide association study of COPD on BAL cells, and our analyses revealed many differential methylation sites. Integration with mRNA data showed a strong functional readout for relevant genes, identifying sites where DNA methylation might directly affect expression. Almost half of DMPs were colocated with SNPs identified in previous genome-wide association studies of COPD, suggesting joint genetic and epigenetic pathways related to disease.

Chronic airflow limitation (CAL) can be defined as fixed ratio of forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) < 0.70 after bronchodilation. It is unclear which is the most optimal ratio in relation to respiratory morbidity. The aim was to investigate to what extent different ratios of FEV 1 /FVC were associated with any respiratory symptom. In a cross-sectional general population study, 15,128 adults (50-64 years of age), 7,120 never-smokers and 8,008 ever-smokers completed a respiratory questionnaire and performed FEV 1 and FVC after bronchodilation. We calculated different ratios of FEV 1 /FVC from 0.40 to 1.0 using 0.70 as reference category. We analysed odds ratios (OR) between different ratios and any respiratory symptom using adjusted multivariable logistic regression. Among all subjects, regardless of smoking habits, the lowest odds for any respiratory symptom was at FEV 1 /FVC = 0.82, OR 0.48 (95% CI 0.41-0.56). Among never-smokers, the lowest odds for any respiratory symptom was at FEV 1 /FVC = 0.81, OR 0.53 (95% CI 0.41-0.70). Among ever-smokers, the odds for any respiratory symptom was lowest at FEV 1 /FVC = 0.81, OR 0.43 (95% CI 0.16-1.19), although the rate of inclining in odds was small in the upper part, that is FEV 1 /FVC = 0.85 showed similar odds, OR 0.45 (95% CI 0.38-0.55). We concluded that the odds for any respiratory symptoms continuously decreased with higher FEV 1 /FVC ratios and reached a minimum around 0.80-0.85, with similar results among never-smokers. These results indicate that the optimal threshold associated with respiratory symptoms may be higher than 0.70 and this should be further investigated in prospective longitudinal studies., (© 2020 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background: Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that-among COPD patients-the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV 1 ., Methods: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV 1  ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV 1  ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry., Results: The proportions of Tregs with regulatory function (FoxP3 + /CD4 + CD25 bright ) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function., Conclusions: COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV 1 . Trial registration Clinicaltrials.gov identifier NCT02729220.

Background: The diagnosis of chronic obstructive pulmonary disease is based on the presence of persistent respiratory symptoms and chronic airflow limitation (CAL). CAL is based on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV 1 :FVC) after bronchodilation, and FEV 1 :FVC less than the fifth percentile is often used as a cut-off for CAL. The aim was to investigate if increasing percentiles of FEV 1 :FVC were associated with any respiratory symptom (cough with phlegm, dyspnoea or wheezing) in a general population sample of never-smokers and ever-smokers., Methods: In a cross-sectional study comprising 15 128 adults (50-64 years), 7120 never-smokers and 8008 ever-smokers completed a respiratory questionnaire and performed FEV 1 and FVC after bronchodilation. We calculated their z -scores for FEV 1 :FVC and defined the fifth percentile using the Global Lung Function Initiative (GLI) reference value, GLI 5 and increasing percentiles up to GLI 25 . We analysed the associations between different strata of percentiles and prevalence of any respiratory symptom using multivariable logistic regression for estimation of OR., Results: Among all subjects, regardless of smoking habits, the odds of any respiratory symptom were elevated up to the GLI 15-20 strata. Among never-smokers, the odds of any respiratory symptom were elevated at GLI <5 (OR 3.57, 95% CI 2.43 to 5.23) and at GLI 5-10 (OR 2.57, 95% CI 1.69 to 3.91), but not at higher percentiles. Among ever-smokers, the odds of any respiratory symptom were elevated from GLI <5 (OR 4.64, 95% CI 3.79 to 5.68) up to GLI ≥25 (OR 1.33, 95% CI 1.00 to 1.75)., Conclusions: The association between percentages of FEV 1 :FVC and respiratory symptoms differed depending on smoking history. Our results support a higher percentile cut-off for FEV 1 :FVC for never-smokers and, in particular, for ever-smokers., Competing Interests: Competing interests: AA reports personal fees from Novartis and AstraZeneca, outside this work. AL reports personal fees from Boehringer Ingelheim, AstraZeneca, Novartis and Active Care, outside the submitted work. JV reports personal fees from Boehringer Ingelheim, outside the submitted work. PW reports personal fees from AstraZeneca and Chiesi Pharmaceuticals, outside the submitted work. CMS reports personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, AstraZeneca, Roche and Genzyme, outside the submitted work. PW has a patent device and method for pulmonary capacity measurements issued. MS reports personal fees from AstraZeneca, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cytotoxic lymphocytes are increased in the airways of COPD patients. Whether this increase is driven primarily by the disease or by smoking is not clear, nor whether it correlates with the rate of decline in lung function., Methods: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study according to pre-determined criteria; 12 with COPD and a rapid decline in lung function (loss of FEV 1  ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV 1  ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry., Results: In BAL fluid, the proportions of NK, iNKT and NKT-like cells all increased with pack-years. Within the COPD group, NK cells - but not iNKT or NKT-like cells - were significantly elevated also in subjects that had quit smoking. In contrast, current smoking was associated with a marked increase in iNKT and NKT-like cells but not in NK cells. Rate of lung function decline did not significantly affect any of the results., Conclusions: In summary, increased proportions of NK cells in BAL fluid were associated with COPD; iNKT and NKT-like cells with current smoking but not with COPD. Interestingly, NK cell percentages did not normalize in COPD subjects that had quit smoking, indicating that these cells might play a role in the continued disease progression seen in COPD even after smoking cessation., Trial Registration: Clinicaltrials.gov identifier NCT02729220 .

Background : Chronic obstructive pulmonary disease (COPD) is a largely underdiagnosed disease including several phenotypes. In this report, the design of a study intending to evaluate the pathophysiological mechanism in COPD in relation to the specific phenotypes non-rapid and rapid decline in lung function is described together with the recruitment process of the study population derived from a population based study. Method : The OLIN COPD study includes a population-based COPD cohort and referents without COPD identified in 2002-04 ( n  = 1986), and thereafter followed annually since 2005. Lung function decline was estimated from baseline in 2002-2004 to 2010 (first recruitment phase) or to 2012/2013 (second recruitment phase). Individuals who met the predefined criteria for the following four groups were identified; group A) COPD grade 2-3 with rapid decline in FEV 1 and group B) COPD grade 2-3 without rapid decline in FEV 1 (≥60 and ≤30 ml/year, respectively), group C) ever-smokers, and group D) non-smokers with normal lung function. Groups A-C included ever-smokers with >10 pack years. The intention was to recruit 15 subjects in each of the groups A-D. Results : From the database groups A-D were identified; group A n  = 37, group B n  = 29, group C n  = 41, and group D n  = 55. Fifteen subjects were recruited from groups C and D, while this goal was not reached in the groups A ( n  = 12) and B ( n  = 10). The most common reasons for excluding individuals identified as A or B were comorbidities contraindicating bronchoscopy, or inflammatory diseases/immune suppressive medication expected to affect the outcome. Conclusion : The study is expected to generate important results regarding pathophysiological mechanisms associated with rate of decline in lung function among subjects with COPD and the in-detail described recruitment process, including reasons for non-participation, is a strength when interpreting the results in forthcoming studies., Competing Interests: No potential conflict of interest was reported by the authors.