Anders Andersson

Background: Sleep disturbances are highly prevalent in chronic obstructive pulmonary disease (COPD) but are not incorporated into current phenotypic classifications. We examined whether multidimensional sleep data identify clinically relevant patterns in COPD and whether these patterns are associated with all-cause mortality. Methods: In a clinical cohort of 205 patients with COPD, home-based sleep assessment was performed using the WatchPAT™ device. Fifteen complementary variables reflecting sleep duration and architecture, nocturnal oxygenation, sleep-disordered breathing, and daytime sleepiness were analysed using Partitioning Around Medoids clustering. The resulting phenotypes were characterised by pulmonary function, gas exchange, functional capacity, systemic biomarkers, and comorbidity burden. Longitudinal follow-up was available for 199 participants; survival was assessed using Kaplan-Meier analysis and Cox regression adjusted for age, sex, post-bronchodilator FEV₁ and positive airway pressure (PAP) treatment. Results: Five distinct sleep phenotypes were identified: preserved sleep physiology (good sleepers, 20.5%), curtailed sleep duration (short sleepers, 33%), altered sleep architecture with REM suppression (light sleepers, 18.5%), predominant nocturnal hypoxaemia (hypoxic sleepers, 20%), and severe sleep-disordered breathing (apnoeic sleepers, 8%). Despite similar airflow limitation and COPD symptom burden, phenotypes differed in gas exchange, functional capacity, systemic inflammation, and cardiometabolic comorbidities. During a median follow-up of 4.2 years, 56 participants (28.1%) died. Compared with good sleepers, hypoxic sleepers had a higher hazard of death after adjustment for age, sex, and FEV₁ (HR 2.80, 95% CI 1.05– 7.44). Following adjustment for PAP treatment, a higher mortality hazard was also observed among untreated apnoeic sleepers (HR 6.16, 95% CI 1.56– 24.38). Conclusion: Multidimensional sleep phenotyping identified clinically distinct clusters of patients with COPD beyond conventional spirometric severity and apnoea–hypopnoea index (AHI)-defined sleep-disordered breathing. These findings support sleep as a clinically relevant dimension of COPD heterogeneity, and warrant prospective validation of sleep-related traits and their clinical outcomes.

Background: There is published evidence that a modest increase in blood eosinophils during stable COPD indicates future risk for exacerbations and a potential utility of inhaled corticosteroids. This has been perceived as an argument for targeting systemic eosinophil mobilization to prevent exacerbations in COPD, but there are no published data on systemic eosinophil mobilization during exacerbations in patients without allergy.Methods: We investigated long-term tobacco smokers (LTS: ≥10 pack-years) with COPD and chronic bronchitis (COPD-CB; GOLD stage 1–4; n = 47) but no allergy; LTS without COPD and CB (LTS; n = 10), and healthy never-smokers (HNS; n = 10) during stable disease for cross-sectional comparisons. For longitudinal comparisons, we followed the COPD-CB group for 15 months during stable disease and exacerbations, excluding samples affected by systemic corticosteroids. We quantified blood concentrations of eosinophils, the activity marker eosinophilic cationic protein (ECP) and the chemokine interleukin (IL)-4.Results: During stable disease, the concentrations of eosinophils were similar for the COPD-CB and the LTS group, although higher than in the HNS group. The concentrations of ECP and IL-4 were not markedly different in the COPD-CB and LTS groups either. During exacerbations, the concentrations of eosinophils, ECP and IL-4 were not further increased, and there was even a mathematical trend towards a decrease for these concentrations.Conclusion: The clinical evidence presented here suggests that, by average, there is no additional mobilization of eosinophils during exacerbations in patients with COPD and chronic bronchitis but no allergy. Thus, in this common phenotype, the immunological rationale for targeting systemic eosinophils during exacerbations remains unaccounted for, which motivates verification studies in large cohorts stratified for allergy and chronic bronchitis.

Purpose: Chronic rhinosinusitis (CRS) is related to asthma and chronic obstructive pulmonary disease (COPD). However, combined data on CRS, pulmonary function, lower airway symptoms, and cigarette smoking from the general population are lacking. The current study investigates the relationships between CRS and chronic airflow limitation (CAL), lower airway symptoms and COPD in a middle-aged population of ever-smokers and never-smokers. Patients and Methods: All subjects from the Swedish CArdioPulmonary bioImage Study (SCAPIS) were included. Subjects underwent spirometry after bronchodilation. Chronic airflow limitation was defined as FEV₁/FVC ratio < 0.7. Computed tomography imaging of the thorax was performed to detect the presence of emphysema, and the subjects answered a comprehensive questionnaire on CRS, lower airway symptoms, asthma, chronic bronchitis, and cigarette smoking habits. Results: In total, 30,154 adult subjects in the age range of 50– 64 years were included. The prevalence of CRS was 5.6%. CRS was more-prevalent among subjects in the following categories: CAL (7.6%), lower airway symptoms (15.7%), current smokers (8.2%), asthma (13.6%), never-smokers and ever-smokers with COPD (17.6% and 15.3%, respectively), emphysema (6.7%), and chronic bronchitis (24.5%). In the adjusted regression model, CRS was significantly associated with CAL (OR 1.40), lower airway symptoms (OR 4.59), chronic bronchitis (OR 6.48), asthma (OR 3.08), and COPD (OR 3.10). Conclusion: In this national, randomly chosen population sample of more than 30,000 middle-aged men and women, CRS is associated with CAL, lower airway symptoms, chronic bronchitis, asthma, and COPD. In patients with CRS and in patients with lower airway inflammation, it is important to consider the inflammatory status of the entire airway system.

Background: Chronic rhinosinusitis (CRS) is a common disease of the upper airways causing nasal obstruction, loss of smell, facial pain and poor quality of life. Studies on CRS in COPD are scarce. Aims: To study the impact of CRS in COPD in terms of risk of exacerbations. Methods: We identified patients with COPD, aged ≥ 30 years, registered in the Swedish National Airway Register between January 2017 and August 2020. Patients were stratified for the absence or presence of CRS, defined as ≥2 prescriptions of nasal corticosteroids within one year before inclusion, and followed until January 2021 for moderate (prescription of oral corticosteroids) and severe (hospital admission for respiratory cause) exacerbations in national registries. A sensitivity analysis excluding patients with allergic rhinosinusitis (defined as additional prescription of antihistamins) was done. Results: Of the 45350 eligible COPD patients, 2539 (5.6%) had CRS. Patients with and without CRS respectively had similar age (71±9 vs 72±9 years), sex (male: 41% vs. 44%), BMI (28±13 vs. 27±13), CAT score (14±8 vs 13±7) and FEV1 % pred. (62±18 vs 60±18), while those with CRS were less often active smokers (28% vs 38%). Patients with CRS had an elevated hazard ratio (HR) for moderate exacerbations (HR 1.74; (95% CI:1.61-1.88), but not for severe exacerbations (HR 1.01, 95% CI: 0.95–1.08), adjusted for age, sex, smoking and FEV1. Most CRS patients (n=1622 (64%)) did not use antihistamins and those patients had similar results. Conclusion: In this nationwide cohort study, CRS was associated with a higher risk of moderate exacerbations in COPD and should be considered in the management of COPD.

Chronic obstructive pulmonary disease (COPD) kills millions of people annually and patients suffering from exacerbations of this disorder display high morbidity and mortality. The clinical course of COPD is associated with dysbiosis and infections, but the underlying mechanisms are poorly understood. Glycosylation of proteins play roles in regulating interactions between microbes and immune cells, and knowledge on airway glycans therefore contribute to the understanding of infections. Furthermore, glycans have biomarker potential for identifying smokers with enhanced risk for developing COPD as well as COPD subgroups. Here, we characterized the N-glycosylation in the lower airways of healthy never-smokers (HNS, n = 5) and long-term smokers (LTS) with (LTS+, n = 4) and without COPD (LTS−, n = 8). Using mass spectrometry, we identified 57 highly confident N-glycan structures whereof 38 oligomannose, complex, and paucimannose type glycans were common to BAL samples from HNS, LTS− and LTS+ groups. Hybrid type N-glycans were identified only in the LTS+ group. Qualitatively and quantitatively, HNS had lower inter-individual variation between samples compared to LTS− or LTS+. Cluster analysis of BAL N-glycosylation distinguished LTS from HNS. Correlation analysis with clinical parameters revealed that complex N-glycans were associated with health and absence of smoking whereas oligomannose N-glycans were associated with smoking and disease. The N-glycan profile from monocyte-derived macrophages differed from the BAL N-glycan profiles. In conclusion, long-term smokers display substantial alterations of N-glycosylation in the bronchoalveolar space, and the hybrid N-glycans identified only in long-term smokers with COPD deserve to be further studied as potential biomarkers.

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 FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/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 FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/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.

Background: In patient care, demand is growing for digital health tools to enable remote services and enhance patient involvement. People with chronic conditions often have multiple health problems, and long-term follow-up is recommended to meet their needs and enable access to appropriate support. A digital tool for previsit preparation could enhance time efficiency and guide the conversation during the visit toward the patient’s priorities. Objective: This study aims to develop a digital previsit tool and explore potential end user’s perceptions, using a participatory approach with stroke as a case example. Methods: The digital tool was developed and prototyped according to service design principles, informed by qualitative participant data and feedback from an expert panel. All features were processed in workshops with a team that included a patient partner. The resulting tool presented questions about health problems and health information. Study participants were people with stroke recruited from an outpatient clinic and patient organizations in Sweden. Development and data collection were conducted in parallel. For conceptualization, the initial prototype was based on the Post-Stroke Checklist and research. Needs and relevance were explored in focus groups, and we used a web survey and individual interviews to explore perceived utility, ease of use, and acceptance. Data were thematically analyzed following the Framework Method. Results: The development process included 22 participants (9 women) with a median age of 59 (range 42-83) years and a median of 51 (range 4-228) months since stroke. Participants were satisfied or very satisfied with using the tool and recommended its use in clinical practice. Three main themes were constructed based on focus group data (n=12) and interviews (n=10). First, valuable accessible information illuminated the need for information to confirm experiences, facilitate responses, and invite engagement in their care. Amendments to the information in turn reconfigured their expectations. Second, utility and complexity in answering confirmed that the questions were relevant and comprehensible. Some participants perceived the answer options as limiting and suggested additional space for free text. Third, capturing needs and value of the tool highlighted the tool’s potential to identify health problems and the importance of encouraging further dialog. The resulting digital tool, Strokehälsa [Strokehealth] version 1.0, is now incorporated into a national health platform. Conclusions: The participatory approach to tool development yielded a previsit digital tool that the study group perceived as useful. The holistic development process used here, which integrated health information, validated questions, and digital functionality, offers an example that could be applicable in the context of other long-term conditions. Beyond its potential to identify care needs, the tool offers information that confirms experiences and supports answering the questions in the tool. The tool is freely shared for adaptation in different contexts. Trial Registration: researchweb 236341; https://www.researchweb.org/is/vgr/project/236341

BACKGROUND In patient care, demand is growing for digital health tools to enable remote services and enhance patient involvement. People with chronic conditions often have multiple health problems, and long-term follow-up is recommended to meet their needs and enable access to appropriate support. A digital tool for previsit preparation could enhance time efficiency and guide the conversation during the visit toward the patient’s priorities. OBJECTIVE This study aims to develop a digital previsit tool and explore potential end user’s perceptions, using a participatory approach with stroke as a case example. METHODS The digital tool was developed and prototyped according to service design principles, informed by qualitative participant data and feedback from an expert panel. All features were processed in workshops with a team that included a patient partner. The resulting tool presented questions about health problems and health information. Study participants were people with stroke recruited from an outpatient clinic and patient organizations in Sweden. Development and data collection were conducted in parallel. For conceptualization, the initial prototype was based on the Post-Stroke Checklist and research. Needs and relevance were explored in focus groups, and we used a web survey and individual interviews to explore perceived utility, ease of use, and acceptance. Data were thematically analyzed following the Framework Method. RESULTS The development process included 22 participants (9 women) with a median age of 59 (range 42-83) years and a median of 51 (range 4-228) months since stroke. Participants were satisfied or very satisfied with using the tool and recommended its use in clinical practice. Three main themes were constructed based on focus group data (n=12) and interviews (n=10). First, valuable accessible information illuminated the need for information to confirm experiences, facilitate responses, and invite engagement in their care. Amendments to the information in turn reconfigured their expectations. Second, utility and complexity in answering confirmed that the questions were relevant and comprehensible. Some participants perceived the answer options as limiting and suggested additional space for free text. Third, capturing needs and value of the tool highlighted the tool’s potential to identify health problems and the importance of encouraging further dialog. The resulting digital tool, Strokehälsa [Strokehealth] version 1.0, is now incorporated into a national health platform. CONCLUSIONS The participatory approach to tool development yielded a previsit digital tool that the study group perceived as useful. The holistic development process used here, which integrated health information, validated questions, and digital functionality, offers an example that could be applicable in the context of other long-term conditions. Beyond its potential to identify care needs, the tool offers information that confirms experiences and supports answering the questions in the tool. The tool is freely shared for adaptation in different contexts. CLINICALTRIAL researchweb 236341; https://www.researchweb.org/is/vgr/project/236341

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease defined by airflow limitation and characterized by a spectrum of treatable and untreatable pulmonary and extra-pulmonary disease characteristics. Nonpharmacological management related to physical activity, physical capacity, body composition, breathing and energy-saving techniques, coping strategies, and self-management is as important as its pharmacological management. Most patients with COPD carry other chronic diagnoses and this poses a key challenge, as it lowers the quality of life, increases mortality, and impacts healthcare consumption. A personalized, multi-, and interprofessional approach is key. Today, healthcare is poorly organized to meet this complexity with the isolation between care levels, logic silos of the different healthcare professions, and lack of continuity of care along the patient’s journey with the healthcare system. In order to meet the criteria for integrated, personalized care for COPD, the structural capabilities of healthcare to support a comprehensive approach and continuity of care needs improvement. COPD is preeminently a disease that requires a transition from a reactive single-specialty approach to a proactive interprofessional approach. In this study, we discuss the issues that need to be addressed when moving from current health care practice to a person-centered model where the care processes and information are aligned to the individual personal needs of the patient.

Background: Long-term exposure to tobacco smoke causes local inflammation in the airways that involves not only innate immune cells, including NK cells, but also adaptive immune cells such as cytotoxic (CD8⁺) and helper (CD4⁺) T-cells. We have previously demonstrated that long-term tobacco smoking increases extracellular concentration of the CD4⁺-recruiting cytokine interleukin (IL)-16 locally in the airways. Here, we hypothesized that tobacco smoking alters IL-16 biology at the systemic level and that this effect involves oxygen free radicals (OFR). Methods: We quantified extracellular IL-16 protein (ELISA) and intracellular IL-16 in NK cells, T-cells, B-cells, and monocytes (flow cytometry) in blood samples from long-term tobacco smokers with and without chronic obstructive pulmonary disease (COPD) and in never-smokers. NK cells from healthy blood donors were stimulated with water-soluble tobacco smoke components (cigarette smoke extract) with or without an OFR scavenger (glutathione) in vitro and followed by quantification of IL-16 protein. Results: The extracellular concentrations of IL-16 protein in blood did not display any substantial differences between groups. Notably, intracellular IL-16 protein was detected in all types of blood leukocytes. All long-term smokers displayed a decrease in this IL-16 among NK cells, irrespective of COPD status. Further, both NK and CD4⁺ T-cell concentrations displayed a negative correlation with pack-years. Moreover, cigarette smoke extract caused release of IL-16 protein from NK cells in vitro, and this was not affected by glutathione, in contrast to the decrease in intracellular IL-16, which was prevented by this drug. Conclusion: Long-term exposure to tobacco smoke does not markedly alter extracellular concentrations of IL-16 protein in blood. However, it does decrease the intracellular IL-16 concentrations in blood NK cells, the latter effect involving OFR. Thus, long-term tobacco smoking exerts an impact at the systemic level that involves NK cells; innate immune cells that are critical for host defense against viruses and tumors – conditions that are overrepresented among smokers.