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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.

Background: The use of blood eosinophil count (BEC) as a prognostic biomarker in the management of conditions such as asthma and chronic obstructive pulmonary disease (COPD) may be complicated by factors such as atopy, age, sex, smoking, and comorbidities. Objective: We sought to produce reference values for BEC, considering age, asthma, COPD, and clinical allergy for the general adult population. Methods: The West Sweden Asthma Study constitutes a population-representative clinical epidemiological cohort of randomly selected adults in Western Sweden. From this cohort, 1145 individuals took part in clinical examinations, including skin prick testing, specific IgE, and BEC. Results: The upper limit (95th percentile) of BEC varied by age. It ranged from 400 to 500 cells/μL in the full sample and from 300 to 400 cells/μL in subjects without asthma, COPD, and clinical allergy (n = 710). Sex, smoking, atopy, clinical allergy, obesity, asthma, COPD, diabetes, and hypertension were statistically significantly associated with higher BEC levels. However, only asthma and clinical allergy in the full sample, and obesity and diabetes in those without asthma, COPD, or clinical allergy, remained statistically significant with higher BEC levels in multivariable regression analyses. Conclusions: In a population-representative sample, the upper limit of BEC in healthy adults ranged between 300 and 400 cells/μL, varying by age. Age, smoking, obesity, asthma, COPD, and clinical allergy influence BEC levels and should be considered in clinical interpretation.

Background: Individuals with a restrictive spirometric pattern have a high burden of cardiovascular and metabolic morbidity.

Objective: To assess prevalence of elevated cardiac biomarkers among individuals with a restrictive spirometric pattern compared to those with a normal lung function and to evaluate the association between cardiac biomarkers and mortality.

Methods: In 2002–04, individuals with airway obstruction were identified from population-based cohorts, together with age- and sex-matched non-obstructive referents. The analysis population consisted of the non-obstructive referents stratified according to whether they had a restrictive spirometric pattern or normal lung function in whom cardiac biomarkers were measured. Deaths were recorded until 31 December 2010.

Results: Participants with a restrictive spirometric pattern were older and more likely to be obese with a higher burden of cardiovascular risk factors than those with normal function. Elevated cardiac troponin but not natriuretic peptide levels were more common in those with a restrictive spirometric pattern independent of age, sex, BMI, or risk factors (adjusted OR 1.8, 95% CI 1.29–2.74). At 5 years, death occurred more frequently in participants with restrictive spirometric pattern compared to those with normal function (15.7% [31/197] versus 7.6% [57/751]), with highest mortality rate in those with restriction and elevated cardiac troponin (28.7% [27/94]). Cardiac troponin was independently associated with death among those with a restrictive spirometric pattern (HR 4.91, 95% CI 1.58–15.26) but not in those with normal lung function.

Conclusion: Cardiac troponin was elevated more often in people with a restrictive spirometric pattern in whom it was a strong independent predictor of death.

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: Physician diagnosed COPD with normal spirometry (dnsCOPD) (sometimes labeled pre-COPD) and Preserved Ratio Impaired Spirometry (PRISm) has been studied in population-based cohorts, but not in physician diagnosed COPD (dCOPD) patients from routine clinical practice. The Swedish National Airway Register (SNAR) is a large nationwide register including data from dCOPD patients from over 1000 clinics across all regions of Sweden and is representative of the COPD care in Sweden. We aimed to identify and characterize patients with dnsCOPD, PRISm and spirometrically confirmed COPD (sCOPD) from dCOPD patients in SNAR, stratify them further according to symptoms and exacerbations risk using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) A/B/E classification, and assess differences in risk for exacerbations, cause-specific hospitalisations and mortality.

Methods: We enrolled patients aged ≥30 years with dCOPD in the SNAR from 1 January 2014 to 30 June 2022 with complete spirometry i.e., postbronchodilator values for both forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (index date). Patients with concomitant asthma were excluded. Patients were stratified into dnsCOPD (FEV1/FVC ≥0.7 and FEV1 ≥80% predicted), PRISm (FEV1/FVC ≥0.7 and FEV1 <80% predicted) and sCOPD (FEV1/FVC <0.7). Further substratification was based on GOLD A/B/E (A: COPD assessment test (CAT) score <10 points and <2 moderate, 0 severe exacerbations within 1 year before the index date, B: CAT-score ≥10 points and <2 moderate, 0 severe exacerbations, E: ≥2 moderate or ≥1 severe exacerbation(s)). Patients were followed until 31 November 2022. Competing risk regression was used to calculate subdistribution hazard ratios (SHR)s with 95% confidence intervals (CIs) for exacerbation, hospitalisation and mortality.

Findings: Of 45,653 patients with dCOPD, 5.4% had dnsCOPD, 11.4% had PRISm and 83.3% had sCOPD. Smoking history was similar between groups (ever smoker: dnsCOPD: 79% PRISm: 82% sCOPD: 86%) and inhalation therapy was common in all groups (any inhaler: 75%, 80% and 80%, triple combination: 22%, 28% and 35%). Patients with PRISm had a high prevalence of obesity (dnsCOPD: 30%, PRISm: 43%, COPD: 22%), cardiovascular disease (dnsCOPD: 39%, PRISm: 48%, COPD: 41%) and diabetes (dnsCOPD: 10%, PRISm: 17%, COPD: 9%). Baseline GOLD group B or E were highly prevalent in dnsCOPD (B: 54%, E: 11%), PRISm (B: 59%, E: 14%), as well as in COPD (B: 54%, E: 17%). DnsCOPD and PRISm patients had lower risk of exacerbations (SHR 0.69, 95%CI 0.64–0.74 and 0.85, 95%CI 0.81–0.89), respiratory hospitalisation (0.40, 95%CI 0.34–0.46 and 0.68, 95%CI 0.62–0.73), and respiratory mortality (0.22, 95%CI 0.13–0.37 and 0.60, 95%CI 0.48–0.75) compared to sCOPD. Cardiovascular mortality was lower in dnsCOPD (0.41, 95%CI 0.19–0.86), but similar in PRISm (0.73, 95%CI 0.49–1.08) compared to sCOPD. The A/B/E classification was predictive for all outcomes in dnsCOPD and PRISm. DnsCOPD and PRISm group E patients had higher risks for all outcomes than sCOPD group A or B.

Interpretation: DnsCOPD and PRISm are prevalent in a real-life cohort of patients with a physician diagnosis of COPD. These patients are symptomatic, might suffer from exacerbations and are commonly treated with inhaled therapy, equally to sCOPD. Patients with PRISm had a high prevalence of obesity, diabetes and cardiovascular disease. DnsCOPD and PRISm had generally lower overall risks of exacerbation or respiratory events, although PRISm patients showed similar cardiovascular risk to sCOPD. The A/B/E classification predicted future events, even in dnsCOPD and PRISm patients.

Funding: This study is performed with support from The Swedish Heart-Lung Foundation ( 20200150) and the Swedish government and country council ALF grant ( ALFGBG-824371).

Background: The link between the use of oral corticosteroids (OCS) and adverse events (AEs) in asthma is well described. In contrast, whether the use of high-dose inhaled corticosteroids (ICS) poses a risk to these is unknown.

Objective: To examine the association between ICS exposure and corticosteroid (CS)-related AEs.

Methods: We conducted an observational cohort study using nationwide Swedish registry data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration. We included patients with asthma aged ≥18 years between 2009 and 2019 and calculated their current ICS exposure and average daily ICS dose (budesonide equivalent) in follow-up. The association between ICS exposure and CS-related AEs was analyzed using Cox proportional hazards models adjusting for age, sex, and OCS dose.

Results: We included 529,203 patients with asthma. Overall, we observed increased hazard ratios (HRs) in those exposed to high-dose (≥800-1599 μg) and very high dose (≥1600 μg) ICS for several AEs, including cardiovascular disease, type 2 diabetes mellitus (T2DM), osteoporosis, and pneumonia compared with those not exposed to ICS. HRs for the current use of high-dose ICS ranged from 1.11 (95% confidence interval [CI]: 1.06-1.16) for T2DM to 1.65 (95% CI: 1.58-1.72) for pneumonia. Likewise, HRs linked to average daily high-dose ICS ranged from 1.16 (95% CI: 1.02-1.33) for pneumonia to 1.70 (95% CI: 1.38-2.08) for osteoporosis. Sensitivity analysis excluding patients using OCS showed that high-dose ICS was still associated with an increased risk of CS-related AEs. Overall, ICS <800 μg per day had no increased risk, except for cataract.

Conclusion: High-dose ICS is associated with an increased risk of several CS-related AEs. This highlights the importance of clinicians considering this risk in patients treated with high-dose and very high dose ICS.

Objective: To study whether worsening asthma at school was related to generic health-related quality of life (HRQoL) and asthma-related impact and worry among 15-year-olds with current asthma in Sweden. In addition, we studied the association between worsening asthma at school at age 15 and the change in the degree to which asthma interfered with daily activities between ages 15 and 19 years.

Methods: Within the Obstructive Lung Disease in Northern Sweden (OLIN) studies, a cohort of schoolchildren has been followed from age 8 years until 19 years of age. In the current study, the sample included 266 adolescents with physician-diagnosed asthma, and either wheeze or use of asthma medication during the last 12 months at age 15 years.

Results: At age 15, HRQoL scores were lower among those who reported worsening asthma at school (standardised beta (β) = −0.18, p = 0.003), they had more asthma-related worries (β = −0.33, p < 0.001) and asthma impacted their life during activities more (β = −0.46, p < 0.001) than those whose asthma did not worsen. Furthermore, the more adolescents reported that asthma worsened at school at age 15, the more it was associated with the increase in the degree to which asthma interfered with their activities between 15 and 19 years (β = 0.14, p = 0.038).

Conclusions: Worsening asthma at school was associated with lower generic health-related quality of life, higher asthma-related worry and impact on daily activities among teenagers with asthma.