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Purpose: Asthma control is multifaceted, involving symptoms and risk of adverse outcomes. Emerging evidence suggests a bidirectional link between poor asthma control and severe COVID-19, but large studies addressing all components of asthma control in this context are lacking. Our aims were to evaluate if 1) uncontrolled asthma was a risk factor for COVID-19 hospitalization and death, 2) asthma control changed during the pandemic and 3) COVID-19 hospitalization was a risk factor for future uncontrolled asthma.

Methods: Patients with asthma (n = 125,362) were identified in the Swedish National Airway Register from January 2014 to 2020, whereof n = 2377 were hospitalized and n = 305 died due to COVID-19 during follow-up until December 2022. Asthma control was evaluated by symptoms (Asthma Control Test (ACT) ≥ 20: well controlled, ACT 16–19 not well-controlled and ACT < 16 very poorly controlled asthma), lung function (FEV1% predicted (pp)) and frequent and/or severe exacerbations (dispensed oral corticosteroids and asthma inpatient care).

Results: ACT 16–19 (RR 1.57, 95% CI 1.34–1.84), ACT < 16 (1.72, 1.46–2.02), FEV1 < 80pp (1.29, 1.13–1.48), frequent (1.99, 1.79–2.21) and severe exacerbations (2.54, 2.09–3.08) were associated with a higher risk for COVID-19 hospitalization. COVID-19 death was associated with ACT < 16, frequent and severe exacerbations. Overall, at follow-up, proportions of ACT < 20 (36.1%) and FEV1 < 80pp (48.3%) were stable, while exacerbations decreased (frequent; 7.9% to 6.8%, severe; 1.3% to 0.4%). COVID-19 hospitalization was a risk factor for frequent (1.35, 1.22–1.51) and severe (3.42, 1.22–1.51) future asthma exacerbations.

Conclusion: All dimensions of poor asthma control were associated with an increased risk of severe COVID-19. In contrast, only exacerbation risk was elevated following COVID-19.

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.

Background: Respiratory symptoms are common in the general adult population. Increased burden of respiratory symptoms may increase the risk of mortality. We assessed the association between respiratory symptom clusters and mortality.

Methods: Participants were derived from two population-based Swedish adult cohorts (N = 63,060). Cluster analysis was performed with Locality Sensitive Hashing (LSH)-k-prototypes in subjects with ≥ 1 self-reported respiratory symptom. Linked mortality register data (up to 21 years of follow-up, > 600,000 person-years) were used. Associations between clusters and all-cause/cause-specific mortality were assessed using asymptomatic subjects as reference.

Results: Over 60% reported ≥ 1 respiratory symptom and ~ 30% reported ≥ 5 respiratory symptoms. Five clusters were identified, partly overlapping with established respiratory disease phenotypes but many individuals were undiagnosed: (1) "low-symptomatic" (30.3%); (2) "allergic nasal symptoms" (10.7%); (3) "allergic nasal symptoms, wheezing, and dyspnea attacks" (4.7%); (4) "wheezing and dyspnea attacks" (6.6%); (5) "recurrent productive cough and wheezing" (4.1%). All but Cluster 2 were associated with all-cause mortality, highest risk for Cluster 3 (hazard ratio 1.4, 95% confidence interval 1.13–1.73) and Cluster 5 (1.4, 1.22–1.61). Comparable associations were seen for cardiovascular mortality. For respiratory mortality, Cluster 4 (2.02, 1.18–3.46) and Cluster 5 (1.89, 1.1–3.25) were most strongly associated.

Conclusions: Respiratory symptoms are common in the general adult population, with identifiable clusters. These clusters have clinical relevancy as they are differentially associated with mortality and relatively weakly correlated with diagnosed respiratory disease.

Aims: Patients with heart failure (HF) with reduced ejection fraction (HFrEF) and chronic obstructive pulmonary disease (COPD) are poorly represented in HFrEF trials testing beta-blockers. We assessed cardiovascular effectiveness and respiratory safety of beta-blockers in these patients.

Methods and results: Patients with HFrEF and COPD in the Swedish HF Registry (2006–2023) were included. Overlap-weighted models were used to assess associations between beta-blocker use and 5-year risk of outcomes, with cardiovascular death/total hospitalizations for HF (HHF) representing the primary cardiovascular effectiveness outcome, and total severe COPD exacerbations being the primary respiratory safety outcome. Of 5084 patients with HFrEF and COPD, median age was 75 years (interquartile range [IQR] 69–81), 68.3% were male, 36.9% were in GOLD group E, 91.5% used beta-blockers. Over a median follow-up of 2.5 years (IQR 1.0–4.8), beta-blocker users had lower crude risk of cardiovascular death/total HHF (rate ratio [RR] 0.66, 95% confidence interval [CI] 0.56–0.78) and total severe COPD exacerbations (RR 0.75, 95% CI 0.60–0.93). After overlap weighting, beta-blocker use was independently associated with lower risk of cardiovascular death/total HHF (RR 0.74, 95% CI 0.58–0.96) but not total severe COPD exacerbations (RR 0.99, 95% CI 0.73–1.35). These associations were consistent across subgroups (including GOLD groups), except for the greater magnitude of the association with lower risk of cardiovascular death/total HHF in patients with left ventricular ejection fraction <30% (p for interaction = 0.004). Falsification analyses suggested no influence from residual confounding.

Conclusions: In patients with HFrEF and COPD, beta-blocker use was associated with lower risk of cardiovascular death/total HHF, without evidence of safety concerns for COPD exacerbations.

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.

During the last decades, there has been an accelerating development of diagnostic and treatment possibilities. This paper aims to remind readers of significant milestones in the medical history of asthma. In the early 1800s, important tools for auscultation of the lungs and assessment of vital capacity were developed when Laennec invented the stethoscope and Hutchinson the spirometer. Tests of allergic sensitisation were developed later; the skin prick test in the 1920s, while immunoglobulin E, IgE, was discovered in the 1960s. Dating back to ancient times, asthma has been treated using the sympathomimetic ephedrine and the anticholinergic belladonna. Asthma cigarettes act via anticholinergic effects of Datura stramonium (common name thorn apple), which contains hyoscyamine, scopolamine, and atropine. From the 1930s, ephedrine was replaced by adrenergic agents (e.g., adrenaline) and its further developments. The first selective β2-agonist, salbutamol, was introduced in 1969, followed by long-acting β2-agonists. From the 1920s until 1990, theophylline was frequently used as a bronchodilator, while cromolyn was used as a non-corticosteroid treatment of asthma in the 1970s and 1980s. Introducing inhaled corticosteroids (ICS) in the mid-1970s revolutionised asthma treatment. The use of ICS gathered momentum in the mid-1980s, with improved asthma morbidity and reduced need for hospital treatment. Recent introduction of ICS-formoterol in all treatment steps of asthma further contribute to improved adherence, asthma control and lower risk of exacerbations. At last, in management of severe asthma, monoclonal antibodies targeting IgE or different T2-cytokines, provide significant improvements in symptom control, exacerbation rate, and quality of life for patients.

Background: Airway obstruction is a characteristic spirometric finding in asthma but the clinical significance of other abnormal spirometric patterns is less well described. We aimed to explore pre-and post-bronchodilator (BD) prevalences and clinical characteristics of preserved ratio impaired spirometry (PRISm), dysanapsis and airflow obstruction with low forced expiratory volume in 1 s (FEV₁) in children diagnosed with asthma.

Methods: We extracted specialist care data (clinical and spirometry) from the Swedish National Airway Register (n=3301, age 5–17 years). Normal spirometry was defined as FEV₁⩾ lower limit of normal (LLN) and FEV₁/forced vital capacity (FVC)⩾LLN. PRISm was defined as forced FEV₁< LLN and FEV₁/FVC⩾LLN, dysanapsis as FEV₁/FVC<LLN and FEV₁⩾LLN, and airflow obstruction with reduced FEV₁ as FEV₁/FVC<LLN and FEV₁<LLN. The BD response (BDR) was calculated as ((post-BD(L)−pre-BD(L))/predicted (L))×100. Values >10% were considered positive (BDRpos). Groups were compared using parametric tests and associations were explored using logistic regression analysis.

Results: Pre-/post-BD PRISm, dysanapsis and obstruction with low FEV₁ were identified in 9%/7%, 10%/4% and 8%/2%, respectively. Compared with normal spirometry, all three groups were associated with older age and BDRpos in pre-BD analyses. Furthermore, dysanapsis was associated with overweight/ obesity and obstruction with low FEV1 with uncontrolled asthma and more treatment.

Interpretation: In this paediatric asthma cohort, PRISm and dysanapsis were associated with BDRpos and they were at least as common as airflow obstruction with reduced FEV₁. These spirometric phenotypes should be addressed in the management of childhood asthma and testing of BDR should be considered also in children with PRISm and dysanapsis.

Background: Preserved ratio impaired spirometry (PRISm) is a spirometry pattern of interest regarding incident airflow obstruction and higher mortality risk. We applied a proteomic approach to gain more insight into the biological mechanisms associated with PRISm.

Methods: From the population-based Swedish Cardiopulmonary Bioimage Study (SCAPIS), participants in the Main (n=4835) and Pilot (n=1054) studies, were included as discovery and replication cohorts. The lower limit of normal (LLN) of post-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC was defined as the fifth percentile in healthy, never-smoking SCAPIS participants. Participants were subdivided into five groups: reference: FEV1/FVC⩾LLN and FEV1⩾LLN and FVC⩾LLN (n=4084)); mild chronic airflow limitation (CAL): FEV1/FVC<LLN and FEV1⩾LLN (n=278); moderate–severe CAL: FEV1/FVC<LLN and FEV1<LLN (n=170); restrictive spirometric pattern (RSP): FEV1/FVC ⩾LLN and FVC<LLN (n=238); and PRISm: FEV1/FVC⩾LLN and FEV1<LLN (n=238). Proximity extension assays were used to measure 168 proteins. The associations of each standardised protein were assessed with each study group by multiple linear regression models, adjusting for age, sex, body mass index (BMI), smoking, physical activity and study centres, and corrected for multiple testing to control for a false discovery rate of 5%.

Results: Eight proteins were associated with PRISm and replicated: tumour necrosis factor receptor superfamily member 10A, interleukin-6, paraoxonase 3 (negative association), renin, urokinase plasminogen activator surface receptor (U-PAR), E-selectin, matrix metalloproteinase 7 and chitinase-3-like protein 1. Interleukin-6 and U-PAR were also associated with moderate–severe CAL and E-selectin with RSP. In addition, five other proteins were associated with moderate–severe CAL and three with RSP.

Conclusion: Protein profile in PRISm differs from other spirometric patterns suggesting specific disease mechanisms.