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Sofia Eriksson,1 Maaike Giezeman,2,3 Mikael Hasselgren,2,3 Christer Janson,4 Marta A Kisiel,5 Scott Montgomery,2,6,7 Anna Nager,8 Hanna Sandelowsky,7,9 Björn Ställberg,10 Josefin Sundh,11 Karin Lisspers10 1Region Dalarna, Falun, Sweden; 2School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 3Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden; 4Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 5Department of Medical Sciences, Occupational and Environment Medicine, Uppsala University, Uppsala, Sweden; 6Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 7Department of Epidemiology and Public Health, University College, London, UK; 8NVS, Section for Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden; 9Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden; 10Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 11Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, SwedenCorrespondence: Karin Lisspers, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Box 564, Uppsala, SE-75122, Sweden, Tel +46703524721, Email Karin.lisspers@regiondalarna.se; Karin.lisspers@uu.sePurpose: To study risk factors for uncontrolled asthma and insufficient quality of life (QoL) in patients with mild asthma, ie those without preventer treatment.Patients and Methods: Patients aged 18– 75 years with a doctor’s diagnosis of asthma randomly selected from primary and secondary care in Sweden. Mild asthma was defined as self-reported current asthma and no preventer treatment. Data were collected from self-completed questionnaires in 2012 and 2015. Well-controlled asthma was defined as Asthma Control Test (ACT) ≥ 20 points and no exacerbation and uncontrolled asthma as ACT< 20 points and/or at least one exacerbation in the previous six months. QoL was measured by the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ), where a total mean score of ≥ 6 indicated sufficient and < 6 insufficient QoL. Multivariate logistic regression analyses were performed using asthma control and Mini-AQLQ as dependent variables. Asthma control was dichotomized as controlled and uncontrolled asthma and the Mini-AQLQ as sufficient QoL (mean score ≥ 6) and insufficient QoL (mean score < 6).Results: Among 298 patients, 26% had uncontrolled asthma, 40% insufficient QoL and 20% both uncontrolled asthma and insufficient QoL. Age ≥ 60 years, obesity, daily smoking, rhinitis and inadequate knowledge of asthma self-management were independently associated with poor asthma control. Factors independently associated with insufficient QoL were age ≥ 60 years, overweight, obesity, rhinitis, sinusitis and inadequate knowledge of asthma self-management. Age ≥ 60 years, obesity, rhinitis and inadequate knowledge of asthma self-management were independently associated with both uncontrolled asthma and insufficient QoL.Conclusion: Among asthma patients without preventer medication, 26% had uncontrolled asthma and 40% had insufficient asthma-related QoL. Older age, obesity, and rhinitis were risk factors for both poor asthma control and a reduced QoL, but having good knowledge of asthma self-management reduced this risk. Our findings suggest that this group of patients requires further attention and follow-up.Plain Language Summary: Many patients with little symptoms of asthma do not take asthma-preventer medication as their asthma is recognized as mild. Still, it is well-known that in this group there are patients with frequent and severe symptoms and acute attacks of asthma, defined as uncontrolled asthma. Quality of life (QoL) is less studied in these patients. Our aim was to study patient characteristics and factors with a higher risk for uncontrolled asthma and insufficient QoL in patients with mild asthma.We studied patients with asthma diagnosis 18– 75 of age in Sweden who reported asthma and no asthma preventer medication. They answered questionnaires about characteristics, knowledge of asthma, asthma symptoms, acute asthma attacks and QoL. A test for asthma symptom control, the Asthma Control Test (ACT), was answered, where 20 points or more meant good asthma symptom control. Patients were regarded as having uncontrolled asthma if they had less than 20 points and/or at least one acute asthma attack the last six months. QoL was measured by the Mini Asthma Quality of Life Questionnaire. A mean score of 6 or more meant sufficient and less than 6 insufficient QoL.Of the 298 patients, 26% had uncontrolled asthma, 40% had insufficient QoL and 20% had both. Patients with risk for both uncontrolled asthma and insufficient QoL were 60 years and over, with obesity, rhinitis and those who reported insufficient knowledge of how to handle asthma. Our results suggest that patients with mild asthma need more attention, better management and follow-ups.Keywords: asthma, management, risk factors, asthma outcomes

Dennis Bouhuis,1 Maaike Giezeman,1,2 Mikael Hasselgren,1,2 Christer Janson,3 Marta A Kisiel,4 Karin Lisspers,5 Scott Montgomery,6– 8 Anna Nager,9 Hanna Sandelowsky,7,9,10 Björn Ställberg,5 Josefin Sundh11 1School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 2Centre for Clinical Research and Education, Karlstad, Sweden; 3Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 4Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden; 5Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 6Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro, Sweden; 7Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; 8Department of Epidemiology and Public Health, University College, London, UK; 9Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden; 10Academic Primary Health Care Centre, Stockholm, Sweden; 11Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, SwedenCorrespondence: Josefin Sundh, Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden, Tel +46702349517, Email josefin.sundh@regionorebrolan.seBackground: Patients with chronic obstructive pulmonary disease (COPD) and no exacerbations may need less maintenance treatment and follow-up. The aim was to identify factors associated with a non-exacerbator COPD phenotype.Methods: Cross-sectional analysis of 1354 patients from primary and secondary care, with a doctor’s diagnosis of COPD. In 2014, data on demographics, exacerbation frequency and symptoms using COPD Assessment Test (CAT) were collected using questionnaires and on spirometry and comorbid conditions by record review. The non-exacerbator phenotype was defined as having reported no exacerbations the previous six months. Multivariable logistic regression with the non-exacerbator phenotype as dependent variable was performed, including stratification and interaction analyses by sex.Results: The non-exacerbator phenotype was found in 891 (66%) patients and was independently associated with COPD stage 1 (OR [95% CI] 5.72 [3.30– 9.92]), stage 2 (3.42 [2.13– 5.51]) and stage 3 (2.38 [1.46– 3.88]) compared with stage 4, and with CAT score < 10 (3.35 [2.34– 4.80]). Chronic bronchitis and underweight were inversely associated with the non-exacerbator phenotype (0.47 [0.28– 0.79]) and (0.68 [0.48– 0.97]), respectively. The proportion of non-exacerbators was higher among patients with no maintenance treatment or a single bronchodilator. The association of COPD stage 1 compared with stage 4 with the non-exacerbator phenotype was stronger in men (p for interaction 0.048). In women, underweight and obesity were both inversely associated with the non-exacerbator phenotype (p for interaction 0.033 and 0.046 respectively), and in men heart failure was inversely associated with the non-exacerbator phenotype (p for interaction 0.030).Conclusion: The non-exacerbator phenotype is common, especially in patients with no maintenance treatment or a single bronchodilator, and is characterized by preserved lung function, low symptom burden, and by absence of chronic bronchitis, underweight and obesity and heart failure. We suggest these patients may need less treatment and follow-up, but that management of comorbid conditions is important to avoid exacerbations.Keywords: COPD, exacerbations, lung function, CAT, body mass index, chronic bronchitis, sex, heart failure

Maaike Giezeman,1,2 Josefin Sundh,3 Åsa Athlin,1 Karin Lisspers,4 Björn Ställberg,4 Christer Janson,5 Scott Montgomery,6– 8 Marta A Kisiel,9 Anna Nager,10 Hanna Sandelowsky,7,10,11 Mikael Hasselgren1,2 1School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 2Centre for Clinical Research and Education, Karlstad, Sweden; 3Department of Respiratory Medicine, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 4Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 5Department of Medical Sciences, Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden; 6Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 7Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; 8Department of Epidemiology and Public Health, University College London, London, UK; 9Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden; 10Division of Family Medicine and Primary Care, Inst NVS, Karolinska Institutet, Stockholm, Sweden; 11Academic Primary Health Care Centre, Region Stockholm, SwedenCorrespondence: Maaike Giezeman, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden, Email Maaike.giezeman@oru.sePurpose: The aim of this study was to examine the association of comorbid heart disease, defined as chronic heart failure or ischemic heart disease, on all-cause and cause-specific hospitalization and mortality in patients with COPD over a period of nearly 15 years.Materials and Methods: The cohort study included patients with COPD from primary and secondary care in 2005 with data from questionnaires and medical record reviews. The Swedish Board of Health and Welfare provided hospitalization and mortality data from 2005 through 2019. Cox regression analyses, adjusted for sex, age, educational level, smoking status, BMI, exacerbations, dyspnea score and comorbid diabetes or hypertension, assessed the association of comorbid heart disease with all-cause and cause-specific time to first hospitalization and death. Linear regression analyses, adjusted for the same variables, assessed this association with hospitalization days per year for those patients that had been hospitalized.Results: Of the 1071 patients, 262 (25%) had heart disease at baseline. Cox regression analysis showed a higher risk of hospitalization for patients with heart disease for all-cause (HR (95% CI) 1.55; 1.32– 1.82), cardiovascular (2.14; 1.70– 2.70) and other causes (1.27; 1.06– 1.52). Patients with heart disease also had an increased risk of all-cause (1.77; 1.48– 2.12), cardiovascular (3.40; 2.41– 4.78) and other (1.50; 1.09– 2.06) mortality. Heart disease was significantly associated with more hospitalization days per year of all-cause (regression coefficient 0.37; 95% CI 0.15– 0.59), cardiovascular (0.57; 0.27– 0.86) and other (0.37; 0.12– 0.62) causes. No significant associations were found between heart disease and respiratory causes of hospitalization and death.Conclusion: Comorbid heart disease in patients with COPD is associated with an increased risk for all-cause hospitalization and mortality, mainly due to an increase of hospitalization and death of cardiovascular and other causes, but not because of respiratory disease. This finding advocates the need of a strong clinical focus on primary and secondary prevention of cardiovascular disease in patients with COPD.Keywords: chronic obstructive pulmonary disease, comorbidity, chronic heart failure, ischemic heart disease, hospitalization, mortality

Johanna Heldin,1 Andrei Malinovschi,2 Ane Johannessen,3 Kjell Alving,4 Mathias Holm,5 Karl A Franklin,6 Bertil Forsberg,7 Vivi Schlünssen,8,9 Rain Jögi,10 Thorarinn Gislason,11,12 Bryndis Benediktsdottir,11,12 Cecilie Svanes,3,13 Christer Janson1 1Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Department of Medical Sciences: Clinical Physiology, Uppsala University, Uppsala, Sweden; 3Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 4Department of Women’s and Children’s Health, Paediatric Research, Uppsala University, Uppsala, Sweden; 5Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 6Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden; 7Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden; 8Department of Public Health, Unit for Environment, Occupation and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark; 9National Research Center for the Working Environment, Copenhagen, Denmark; 10Tartu University Hospital, Lung Clinic, Tartu, Estonia; 11The Medical Faculty, University of Iceland, Reykjavik, Iceland; 12Department of Sleep, Landspitali University Hospital Reykjavik, Reykjavik, Iceland; 13Department of Occupational Medicine, Haukeland University Hospital, Bergen, NorwayCorrespondence: Christer Janson, Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden, Email christer.janson@medsci.uu.seBackground: Although asthma and allergic rhinitis are chronic diseases, some patients experience periods of remission. Information on prognostic factors associated with the remission of asthma and allergic rhinitis is valuable in resource prioritization. This study investigated factors associated with the clinical remission of asthma and allergic rhinitis.Methods: In the Respiratory Health In Northern Europe (RHINE) study, data was collected with questionnaires in stage one (RHINE I, 1989– 1992) and two follow-ups (RHINE II, 1999– 2001 and RHINE III, 2010– 2012) from Sweden, Norway, Denmark, Iceland and Estonia. Clinical remission was defined as having reported asthma or allergic rhinitis in RHINE I or RHINE II but not in RHINE III.Results: Of 13,052 participants, 975 (7.5%) reported asthma in RHINE I or RHINE II, and 3379 (25.9%) allergic rhinitis. Clinical remission of asthma and allergic rhinitis was found in 46.4% and 31.8%, respectively. Living in Estonia (OR (95% CI) 2.44 (1.22– 4.85)) and living in an apartment (1.45 (1.06– 1.98)) were related to remission of asthma, while subjects reporting allergic rhinitis (0.68 (0.51– 0.90)), asthma onset ≤ 12 years of age (0.49 (0.35– 0.68)), receiving treatment with antibiotics for respiratory illness (0.64 (0.47– 0.87)) were less likely to have asthma remission. Factors related to a higher likelihood of remission of allergic rhinitis were no asthma at baseline, age ≥ 58 years in RHINE III, allergic rhinitis onset after 12 years of age, living in rural areas as a child, having only a primary school education and not being pregnant.Conclusion: Clinical remission was found in almost one-half of those with asthma and one-third of persons with allergic rhinitis. Coexisting allergic symptoms were associated with less clinical asthma remission. Age, asthma symptoms and environmental factors in childhood, such as living in a rural area, were found to influence the clinical remission of allergic rhinitis.Keywords: asthma, allergic rhinitis, remission, epidemiology

Hanna Sandelowsky,1– 3 Christer Janson,4 Fredrik Wiklund,5 Gunilla Telg,6 Sofie de Fine Licht,6 Björn Ställberg7 1Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden; 2Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Solna, Sweden; 3Academic Primary Health Care Centre, Region Stockholm, Stockholm, Sweden; 4Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 5Statisticon AB, Uppsala, Sweden; 6AstraZeneca Nordic, Stockholm, Sweden; 7Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, SwedenCorrespondence: Hanna Sandelowsky, Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden, Tel +46738902565, Email hannasandelowsky@gmail.comObjective: The Swedish guidelines recommend that patients with chronic obstructive pulmonary disease (COPD) on maintenance treatment are monitored annually, and within six weeks after an exacerbation. We describe the patterns of COPD-related visits in Sweden, both regular follow-up and post-exacerbation visits.Methods: Patients (> 40 years) with a first-time COPD diagnosis between 2006 and 2017 were identified in primary care medical records and linked to hospital contacts and administered drug data. The index date was defined as the first collection of inhaled COPD maintenance treatment after the diagnosis. Regular COPD visits within 15-months after the index, and post-exacerbation visits for COPD within six weeks and 15-months after an exacerbation were estimated using the cumulative incidence function adjusted for competing risk. Visits without a ICD code for COPD were not included in the analyses.Results: A total of 19,857 patients (mean age 69 years, 57% females) were included. The overall probability of having a regular follow-up visit for COPD within 15 months post-index was 39.1%. In total, 15,095 (76%) patients experienced at least one COPD exacerbation during the observation period. Among them, the probability of having a post-exacerbation visit was 7.0% within six weeks and 29.7% within 15-months. Patients without a regular COPD follow-up visit claimed significantly more oral corticosteroids (25.6% vs 15.6%), more respiratory antibiotics (39.1% vs 23.1%), and less maintenance treatment (10.9% vs 16.5%).Conclusion: Only 39% of COPD patients attended a regular follow-up visit within 15-months from the COPD diagnosis and one-third had a post-exacerbation visit. The adherence to guideline recommendations need to be improved.Keywords: COPD, follow-up visit, exacerbation, guidelines

Kjell Larsson,1 Karin Lisspers,2 Björn Ställberg,2 Gunnar Johansson,2 Florian S Gutzwiller,3 Karen Mezzi,3 Bine Kjoeller Bjerregaard,4 Leif Jorgensen,4 Hyewon Koo,5 Christer Janson6 1Integrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Novartis Pharma AG, Basel, Switzerland; 4IQVIA Solutions, Copenhagen, Denmark; 5IQVIA Solutions, Solna, Sweden; 6Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, SwedenCorrespondence: Kjell Larsson, Integrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden, Tel +467 0582 0763, Email kjell.larsson@ki.seBackground: Patients with mild chronic obstructive pulmonary disease (COPD) account for more than half of the total COPD population but are often undiagnosed and sparsely studied. This real-world, longitudinal study compared the socioeconomic burden, clinical characteristics and treatment patterns in patients with mild COPD and age- and gender-matched controls.Patients and methods: Our population included mild COPD patients (forced expiratory volume in one second ≥ 80% of predicted value) and reference controls from 52 Swedish primary care centres over 15 years (2000– 2014). We linked electronic medical record (EMR) data to Sweden’s National Health Registries. The outcomes analyzed were socioeconomic status including annual income from work, presence of comorbidities and the use of medications.Results: 844 patients with mild COPD were included in this study and matched with 844 reference controls. Compared with the reference controls, mild COPD patients had a significantly lower annual income from work (mean difference, men: 12,559€ and women: 7143€) and were significantly less likely to be married or employed. The presence of comorbidities, including cardiovascular disease, anxiety and depression (only women) was significantly higher in mild COPD patients. The use of medications, such as proton pump inhibitors, antidepressants, central painkillers and sleep medications, was significantly higher in the mild COPD group.Conclusion: Mild COPD presents a considerable socioeconomic and clinical burden compared with reference controls The findings suggest that COPD constitutes a condition that influences health status even in mild disease clearly demanding an increased need for early detection and treatment.Keywords: chronic obstructive pulmonary disease, socioeconomic status, comorbidities, co-medications, annual income, exacerbation, Sweden

Hanna Sandelowsky,1– 3 Björn Ställberg,4 Fredrik Wiklund,5 Gunilla Telg,6 Sofie de Fine Licht,6 Christer Janson7 1Karolinska Institutet, Department of Medicine, Division of Clinical Epidemiology, Solna, Sweden; 2Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Solna, Sweden; 3Academic Primary Health Care Centre, Region Stockholm, Sweden; 4Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 5Statisticon AB, Uppsala, Sweden; 6AstraZeneca Nordic, Södertälje, Sweden; 7Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, SwedenCorrespondence: Hanna Sandelowsky, Karolinska Institutet, Department of Medicine, Division of Clinical Epidemiology, Solna, Sweden, Tel +46738902565, Email hanna.sandelowsky@ki.seBackground: Symptom control has not improved in Swedish asthma patients during the last two decades. Guidelines recommend annual reviews for asthma patients treated with maintenance inhaled corticosteroids (ICS). We aimed to describe how visit patterns in an ICS-treated asthma population in Sweden were related to applicable asthma guidelines.Methods: Swedish electronic health data for incident asthma patients, ≥ 18 years, with at least one ICS collection (index date) between 2006 and 2017 were included. Exacerbations were defined as hospitalizations, emergency visits, or collection of oral corticosteroids (OCS). Probability of an asthma-related regular follow-up visit and probability of a follow-up visit after an exacerbation, both within 15 months, were estimated using the cumulative incidence function, time-to-event analysis, and incident rate ratios.Results: In 51,349 asthma patients (mean age 47.6 years, 63% females), 17,573 had a regular asthma visit in primary or secondary care within 15 months after the index, yielding an overall probability of a visit of 37.4%. Patients with a follow-up visit had higher ICS collection and lower OCS collection than patients without regular visits. Among 22,097 patients with acute exacerbations, the probability of a visit within 15 months after an exacerbation was 31.0%. The probability of having a visit increased during the study period.Conclusion: Only one-third of ICS-treated asthma patients, regardless of asthma severity, had a regular or post-exacerbation follow-up visit within a 15-month period. The consequences of this lack of adherence to guidelines need further evaluation to secure optimal asthma management.Keywords: asthma, disease management, follow-up visit, exacerbation

Marta A Kisiel,1,&ast; Martin Jacobsson,2,&ast; Susann Järhult,3 Linda Ekerljung,4 Kjell Alving,5 Roelinde Middelveld,6 Karl Franklin,7 Christer Janson2 1Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden; 2Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 3Department of Medical Sciences, Emergency Department, Uppsala University, Uppsala, Sweden; 4Department of Internal Medicine and Clinical Nutrition, Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden; 5Department of Women’s and Children’s Health, Paediatric Research, Uppsala University, Uppsala, Sweden; 6Centre for Allergy Research and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 7Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden&ast;These authors contributed equally to this workCorrespondence: Marta A Kisiel, Dag Hammarskjölds väg 60, Uppsala, 751 85, Sweden, Tel +46704145919, Email marta.kisiel@medsci.uu.seBackground: Asthma is a common chronic disease presenting with airway symptoms such as wheezing, chest tightness and attacks of breathlessness. Underdiagnosis of asthma is common and correlates to negative outcomes such as a lower quality of life and reduced work capacity.Purpose: This study aims to identify factors for not being diagnosed with asthma if presenting with asthma symptoms.Patients and Methods: A questionnaire was sent to 45,000 subjects (age 16– 74 years) in Sweden. Subjects who reported both wheeze and breathlessness and wheeze when not having a cold were defined as having asthma-related symptoms. Data on demographics, educational level, smoking, physical activity, comorbidities, symptoms and asthma were collected. Logistic regression was used to identify risk factors for not being diagnosed with asthma.Results: Of the 25,391 who responded to the survey, 6.2% reported asthma-related symptoms. Of these, 946 had been diagnosed with asthma previously, while 632 had not. Independent risk factors for not being diagnosed with asthma were higher age (OR (95% CI) (2.17 (1.39– 3.40))), male sex (1.46 (1.17– 1.81)), current smoking (2.92 (2.22– 3.84)), low level of education (1.43 (1.01– 2.01)), low physical activity (1.36 (1.06– 1.74)), and hypertension (1.50 (1.06– 2.12)).Conclusion: Men, smokers, older subjects, and those with low educational level or low physical activity are less likely to be diagnosed with asthma despite presenting asthma-related symptoms.Keywords: asthma symptoms, no diagnosis despite symptoms of asthma

Björn Ställberg,1 Karin Lisspers,1 Kjell Larsson,2 Christer Janson,3 Mario Müller,4 Mateusz Łuczko,5 Bine Kjøller Bjerregaard,6 Gerald Bacher,7 Björn Holzhauer,7 Pankaj Goyal,7 Gunnar Johansson1 1Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 2Integrative Toxicology, Karolinska Institutet, Stockholm, Sweden; 3Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 4Department of Data Science and Advanced Analytics, IQVIA, Frankfurt Am Main, Germany; 5Department of Data Science and Advanced Analytics, IQVIA, Warsaw, Poland; 6Department of Real World Evidence Solutions, IQVIA, Copenhagen, Denmark; 7Department of Clinical Development and Analytics, Novartis Pharma AG, Basel, SwitzerlandCorrespondence: Björn StällbergDepartment of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Box 564, Uppsala, SE-75122, SwedenTel +46-070-3149944Email b.stallberg@telia.comPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations can negatively impact disease severity, progression, mortality and lead to hospitalizations. We aimed to develop a model that predicts a patient’s risk of hospitalization due to severe exacerbations (defined as COPD-related hospitalizations) of COPD, using Swedish patient level data.Patients and Methods: Patient level data for 7823 Swedish patients with COPD was collected from electronic medical records (EMRs) and national registries covering healthcare contacts, diagnoses, prescriptions, lab tests, hospitalizations and socioeconomic factors between 2000 and 2013. Models were created using machine-learning methods to predict risk of imminent exacerbation causing patient hospitalization due to COPD within the next 10 days. Exacerbations occurring within this period were considered as one event. Model performance was assessed using the Area under the Precision-Recall Curve (AUPRC). To compare performance with previous similar studies, the Area Under Receiver Operating Curve (AUROC) was also reported. The model with the highest mean cross validation AUPRC was selected as the final model and was in a final step trained on the entire training dataset.Results: The most important factors for predicting severe exacerbations were exacerbations in the previous six months and in whole history, number of COPD-related healthcare contacts and comorbidity burden. Validation on test data yielded an AUROC of 0.86 and AUPRC of 0.08, which was high in comparison to previously published attempts to predict COPD exacerbation.Conclusion: Our work suggests that clinically available information on patient history collected via automated retrieval from EMRs and national registries or directly during patient consultation can form the basis for future clinical tools to predict risk of severe COPD exacerbations.Keywords: COPD, machine learning, exacerbation, hospitalization

Åsa Athlin,1 Maaike Giezeman,1,2 Mikael Hasselgren,1 Scott Montgomery,3– 5 Karin Lisspers,6 Björn Ställberg,6 Christer Janson,7 Josefin Sundh8 1School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 2Centre for Clinical Research, Region Värmland, Karlstad, Sweden; 3Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, S-701 82, Sweden; 4Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Epidemiology and Public Health, University College, London, UK; 6Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 7Department of Medical Sciences, Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden; 8Department of Respiratory Medicine, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, SwedenCorrespondence: Åsa Athlin Vallgatan 17, Fjugesta, S-716 31, SwedenTel +4670 2265976Email asa.athlin@regionorebrolan.sePurpose: A multidimensional approach in the risk assessment of chronic obstructive pulmonary disease (COPD) is preferable. The aim of this study is to compare the prognostic ability for mortality by different COPD assessment systems; spirometric staging, classification by GOLD 2011, GOLD 2017, the age, dyspnea, obstruction (ADO) and the dyspnea, obstruction, smoking, exacerbation (DOSE) indices.Patients and Methods: A total of 490 patients diagnosed with COPD were recruited from primary and secondary care in central Sweden in 2005. The cohort was followed until 2017. Data for categorization using the different assessment systems were obtained through questionnaire data from 2005 and medical record reviews between 2000 and 2003. Kaplan-Meier survival analyses and Cox proportional hazard models were used to assess mortality risk. Receiver operating characteristic curves estimated areas under the curve (AUC) to evaluate each assessment systems´ ability to predict mortality.Results: By the end of follow-up, 49% of the patients were deceased. The mortality rate was higher for patients categorized as stage 3– 4, GOLD D in both GOLD classifications and those with a DOSE score above 4 and ADO score above 8. The ADO index was most accurate for predicting mortality, AUC 0.79 (95% CI 0.75– 0.83) for all-cause mortality and 0.80 (95% CI 0.75– 0.85) for respiratory mortality. The AUC values for stages 1– 4, GOLD 2011, GOLD 2017 and DOSE index were 0.73, 0.66, 0.63 and 0.69, respectively, for all-cause mortality.Conclusion: All of the risk assessment systems predict mortality. The ADO index was in this study the best predictor and could be a helpful tool in COPD risk assessment.Keywords: chronic obstructive pulmonary disease, GOLD classification, ADO index, DOSE index, prediction, mortality

Kjell Larsson,1 Christer Janson,2 Karin Lisspers,3 Björn Ställberg,3 Gunnar Johansson,3 Florian S Gutzwiller,4 Karen Mezzi,4 Bine Kjoeller Bjerregaard,5 Leif Jorgensen5 1Integrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; 2Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 3Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 4Novartis Pharma AG, Global Patient Access, Basel, Switzerland; 5IQVIA Solutions, Real World Evidence Solutions, Copenhagen, DenmarkCorrespondence: Kjell LarssonIntegrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institute, Stockholm, SE-171 77, SwedenTel +467 0582 0763Email kjell.larsson@ki.sePurpose: The aim of this study was to assess the association between exacerbation frequency and clinical and economic outcomes in patients with COPD.Patients and Methods: Electronic medical record data linked to National Health Registries were collected from COPD patients at 52 Swedish primary care centers (2000– 2014). The outcomes analyzed were exacerbation rate, mortality, COPD treatments, lung function and healthcare costs during the follow-up period. Based on the exacerbation rate two years before index date, the patients were initially classified into three groups, either 0, 1 or ≥ 2 exacerbations per year. After the index date, the classification into exacerbation groups was updated each year based on the exacerbation rate during the last year of follow-up. A sensitivity analysis was conducted excluding patients with asthma diagnosis from the analysis.Results: In total 18,586 COPD patients were analyzed. A majority of the patients (60– 70%) who either have had no exacerbation or frequent exacerbations (≥ 2/year) during the pre-index period remained in their group (ie, with 0 or ≥ 2 annual exacerbations) during up to 11 years of follow-up. Compared with having no exacerbation, mortality was higher in patients having 1 (HR; 2.06 [1.93– 2.20]) and ≥ 2 (4.58 [4.33– 4.84]) exacerbations at any time during the follow-up. Lung function decline was more rapid in patients with frequent exacerbations and there was an almost linear relationship between exacerbations frequency and mortality. Total healthcare costs were higher in the frequent exacerbation group (≥ 2/year) than in patients with no or one exacerbation annually (p< 0.0001 for both). The results did not differ from the main analysis after exclusion of patients with a concurrent asthma diagnosis.Conclusion: In addition to faster lung function decline and increased mortality, frequent exacerbations in COPD patients imply a significant economic burden.Keywords: chronic obstructive pulmonary disease, exacerbations, mortality, lung function, healthcare cost, Sweden

Christer Janson,1 Bright I Nwaru,2,3 Fredrik Wiklund,4 Gunilla Telg,5 Magnus Ekström6 1Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 3Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; 4Statisticon AB, Uppsala, Sweden; 5AstraZeneca Nordic-Baltic, Södertälje, Sweden; 6Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund, SwedenCorrespondence: Christer JansonDepartment of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Akademiska Sjukhuset, Uppsala 751 85, SwedenTel +4618-6114115Email christer.janson@medsci.uu.seBackground: Reducing the need for hospitalisation in patients with chronic obstructive pulmonary disease (COPD) is an important goal in COPD management. The aim of this study was to evaluate re-hospitalisation, treatment, comorbidities and mortality in patients with COPD who were hospitalised for the first time due to a COPD exacerbation.Methods: This was a retrospective, population-based observational cohort study of Swedish patients using linked data from three mandatory national health registries to assess re-hospitalisation rates, medication use and mortality. Rate of hospitalisation was calculated using the number of events divided by the number of person-years at risk; risk of all-cause and COPD-related mortality were assessed using Cox proportional hazard models.Results: In total, 51,247 patients were identified over 10 years; 35% of patients were not using inhaled corticosteroid, long-acting muscarinic antagonist or long-acting β2-agonist treatment prior to hospitalisation, 38% of whom continued without treatment after being discharged. Re-hospitalisation due to a second severe exacerbation occurred in 11.5%, 17.8% and 24% of the patients within 30, 90 and 365 days, respectively. Furthermore, 24% died during the first year following hospitalisation and risk of all-cause and COPD-related mortality increased with every subsequent re-hospitalisation. Comorbidities, including ischaemic heart disease, heart failure and pneumonia, were more common amongst patients who were re-hospitalised than those who were not.Conclusion: Following hospitalisation for first severe COPD exacerbation, many patients did not collect the treatment recommended by current guidelines. Risk of mortality increased with every subsequent re-hospitalisation. Patients with concurrent comorbidities had an increased risk of being re-hospitalised.Keywords: COPD, re-hospitalisation, management, mortality

Jens Ellingsen, 1 Gunnar Johansson, 2 Kjell Larsson, 3 Karin Lisspers, 2 Andrei Malinovschi, 4 Björn Ställberg, 2 Marcus Thuresson, 5 Christer Janson 1 1Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Integrative Toxicology, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden; 5Statisticon AB, Uppsala, SwedenCorrespondence: Jens EllingsenDepartment of Medical Sciences, Respiratory, Allergy and Sleep Research, Akademiska Sjukhuset, Uppsala SE-751 85, SwedenTel +46 18 611 13 93Fax +46 18 611 02 28Email jens.ellingsen@medsci.uu.seBackground: Life expectancy is significantly shorter for patients with chronic obstructive pulmonary disease (COPD) than the general population. Concurrent diseases are known to infer an increased mortality risk in those with COPD, but the effects of pharmacological treatments on survival are less established. This study aimed to examine any associations between commonly used drugs, comorbidities and mortality in Swedish real-world primary care COPD patients.Methods: Patients with physician-diagnosed COPD from a large primary care population were observed retrospectively, utilizing primary care records and mandatory Swedish national registers. The time to all-cause death was assessed in a stepwise multiple Cox proportional hazards regression model including demography, socioeconomic factors, exacerbations, comorbidities and medication.Results: During the observation period (1999– 2009) 5776 (32.5%) of 17,745 included COPD patients died. Heart failure (hazard ratio [HR]: 1.88, 95% confidence interval [CI]: 1.74– 2.04), stroke (HR: 1.52, 95% CI: 1.40– 1.64) and myocardial infarction (HR: 1.40, 95% CI: 1.24– 1.58) were associated with an increased risk of death. Use of inhaled corticosteroids (ICS; HR: 0.79, 95% CI: 0.66– 0.94), beta-blockers (HR: 0.86, 95% CI: 0.76– 0.97) and acetylsalicylic acid (ASA; HR: 0.87, 95% CI: 0.77– 0.98) was dose-dependently associated with a decreased risk of death, whereas use of long-acting muscarinic antagonists (LAMA; HR: 1.33, 95% CI: 1.14– 1.55) and N-acetylcysteine (NAC; HR: 1.26, 95% CI: 1.08– 1.48) were dose-dependently associated with an increased risk of death in COPD patients.Conclusion: This large, retrospective, observational study of Swedish real-world primary care COPD patients indicates that coexisting heart failure, stroke and myocardial infarction were the strongest predictors of death, underscoring the importance of timely recognition and treatment of comorbidities. A decreased risk of death associated with the use of ICS, beta-blockers and ASA, and an increased risk associated with the use of LAMA and NAC, was also found.Keywords: observational, LAMA, inhaled corticosteroids, beta-blockers, acetylsalicylic acid, chronic obstructive pulmonary disease

Johanna Sulku,1,2 Christer Janson,3 Håkan Melhus,4 Andrei Malinovschi,5 Björn Ställberg,6 Kristina Bröms,2,6 Marieann Högman,3 Karin Lisspers,6 Margareta Hammarlund-Udenaes,1 Elisabet I Nielsen1 1Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; 2Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden; 3Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 4Department of Medical Sciences, Clinical Pharmacogenomics and Osteoporosis, Uppsala University, Uppsala, Sweden; 5Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden; 6Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, SwedenCorrespondence: Johanna SulkuDepartment of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Box 591, Uppsala SE-751 24, SwedenTel +46 73 635 7075Fax +46 26 531 237Email johanna.sulku@farmbio.uu.sePurpose: Inhaled corticosteroids (ICS) are often more widely prescribed in the treatment of chronic obstructive pulmonary disease (COPD) than what is recommended in the guidelines. The aim of this study was to evaluate the appropriateness of ICS treatment in COPD patients using the algorithm proposed by the International Primary Care Respiratory Group (IPCRG) and to identify factors associated with ICS treatment.Patients and methods: Appropriateness of ICS therapy was studied with respect to concomitant asthma, history of exacerbations and blood eosinophils (B-Eos) in a Swedish cohort of primary and secondary care patients with COPD. Factors associated with ICS were investigated using multivariable logistic regression.Results: Triple treatment was found to be the most common treatment combination, used by 46% of the 561 included patients, and in total 63% were using ICS. When applying the IPCRG algorithm, there was a possible indication for discontinuation of ICS in 55% of the patients with ICS treatment. Of the patients not using ICS, 18% had an indication for starting such treatment. The strongest factors associated with ICS therapy were frequent exacerbations (aOR 8.61, 95% CI 4.06, 20.67), secondary care contacts (aOR 6.99, 95% CI 2.48, 25.28) and very severe airflow limitation (aOR 5.91, 95% CI 1.53, 26.58).Conclusion: More than half of the COPD patients on ICS met the criteria where withdrawal of the treatment could be tried. There was, however, also a subgroup of patients not using ICS for whom there was an indication for starting ICS treatment. Patients using ICS were characterized by more frequent exacerbations and lower lung function.Keywords: ICS, pharmacological management, inappropriate therapy, chronic obstructive pulmonary disease, IPCRG

Kjell Larsson,1 Christer Janson,2 Björn Ställberg,3 Karin Lisspers,3 Petter Olsson,4 Konstantinos Kostikas,5 Jean-Bernard Gruenberger,5 Florian S Gutzwiller,5 Milica Uhde,6 Leif Jorgensen,7 Gunnar Johansson31Work Environment Toxicology, Karolinska Institutet, Stockholm, Sweden; 2Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 3Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 4Novartis AB, Täby, Sweden; 5Novartis Pharma AG, Basel, Switzerland; 6IQVIA, Solna, Sweden; 7IQVIA, Copenhagen, DenmarkPurpose: Assess the clinical and economic consequences associated with an early versus late diagnosis in patients with COPD.Patients and methods: In a retrospective, observational cohort study, electronic medical record data (2000–2014) were collected from Swedish primary care patients with COPD. COPD indicators (pneumonia, other respiratory diseases, oral corticosteroids, antibiotics for respiratory infections, prescribed drugs for respiratory symptoms, lung function measurement) registered prior to diagnosis were applied to categorize patients into those receiving early (2 or less indicators) or late diagnosis (3 or more indicators registered >90 days preceding a COPD diagnosis). Outcome measures included annual rate of and time to first exacerbation, mortality risk, prevalence of comorbidities and health care utilization.Results: More patients with late diagnosis (n=8827) than with early diagnosis (n=3870) had a recent comorbid diagnosis of asthma (22.0% vs 3.9%; P

Joakim Åberg,1 Mikael Hasselgren,1 Scott Montgomery,2–4 Karin Lisspers,5 Björn Ställberg,5 Christer Janson,6 Josefin Sundh71School of Medical Sciences, Örebro University, Örebro 70185, Sweden; 2Clinical Epidemiology and Biostatistics, Örebro University, Örebro 70182, Sweden; 3Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Epidemiology and Public Health, University College, London, UK; 5Department of Public Health and Caring Sciences, Family Medicine and Preventive medicine, Uppsala University, Uppsala 75122, Sweden; 6Department of Medical Sciences, Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala 75105, Sweden; 7Department of Respiratory Medicine, School of Medical Sciences, Örebro University, Örebro 70185, SwedenPurpose: Women with chronic obstructive pulmonary disease (COPD) have more symptoms, more exacerbations, lower health status scores, and more comorbidity. However, it is unclear whether management of COPD differs by sex. The aim of the study was to investigate differences by sex in the care of patients with COPD.Patients and methods: The population included 1329 primary and secondary care patients with a doctor´s diagnosis of COPD in central Sweden. Data were obtained from patient questionnaires and included patient characteristics and data on achieved COPD care. Analyses included cross-tabulations, chi-squared test and multiple logistic regression using several measures in COPD management as dependent variables, female sex as independent variable, and with adjustment for age groups, previous exacerbations, COPD Assessment Test, level of dyspnea assessed by the modified Medical Research Council scale, comorbid conditions, self-rated moderate/severe disease, level of education and body mass index.Results: Women were more likely to receive triple therapy (OR 1.86 (95% CI 1.38–2.51)), to have any maintenance treatment (OR 1.82 (95% CI 1.31–2.55)), to be on sick leave (OR 2.16 (95% CI 1.19–3.93)), to have received smoking cessation support (OR 1.80 (95% CI 1.18–2.75)) and to have had pneumococcal vaccination (OR 1.82 (95% CI 1.37–2.43)), all independently of age, severity of disease or other potential confounders.Conclusion: Management of COPD differs by sex, with women being more actively managed than men. It is unclear whether this is due to patient- or care-related factors.Keywords: gender, triple inhaled therapy, maintenance treatment, sick leave, smoking support, pneumococcal vaccination

Maaike Giezeman,1,2 Mikael Hasselgren,1 Karin Lisspers,3 Björn Ställberg,3 Scott Montgomery,4–6 Christer Janson,7 Josefin Sundh8 1School of Medical Sciences, Örebro University, Örebro, Sweden; 2Centre for Clinical Research, County Council of Värmland, Karlstad, Sweden; 3Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 4Clinical Epidemiology and Biostatistics, Örebro University, Örebro, Sweden; 5Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 6Department of Epidemiology and Public Health, University College, London, UK; 7Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 8Department of Respiratory Medicine, School of Medical Sciences, Örebro University, Örebro, Sweden Purpose: The aim of this study was to examine the changing influence over time of comorbid heart disease on symptoms and health status in patients with COPD. Patients and methods: This is a prospective cohort study of 495 COPD patients with a baseline in 2005 and follow-up in 2012. The study population was divided into three groups: patients without heart disease (no-HD), those diagnosed with heart disease during the study period (new-HD) and those with heart disease at baseline (HD). Symptoms were measured using the mMRC. Health status was measured using the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT; only available in 2012). Logistic regression with mMRC ≥2 and linear regression with CCQ and CAT scores in 2012 as dependent variables were performed unadjusted, adjusted for potential confounders, and additionally adjusted for baseline mMRC, respectively, CCQ scores. Results: Mean mMRC worsened from 2005 to 2012 as follows: for the no-HD group from 1.8 (±1.3) to 2.0 (±1.4), (P=0.003), for new-HD from 2.2 (±1.3) to 2.4 (±1.4), (P=0.16), and for HD from 2.2 (±1.3) to 2.5 (±1.4), (P=0.03). In logistic regression adjusted for potential confounding factors, HD (OR 1.71; 95% CI: 1.03–2.86) was associated with mMRC ≥2. Health status worsened from mean CCQ as follows: for no-HD from 1.9 (±1.2) to 2.1 (±1.3) with (P=0.01), for new-HD from 2.3 (±1.5) to 2.6 (±1.6) with (P=0.07), and for HD from 2.4 (±1.1) to 2.5 (±1.2) with (P=0.57). In linear regression adjusted for potential confounders, HD (regression coefficient 0.12; 95% CI: 0.04–5.91) and new-HD (0.15; 0.89–5.92) were associated with higher CAT scores. In CCQ functional state domain, new-HD (0.14; 0.18–1.16) and HD (0.12; 0.04–0.92) were associated with higher scores. After additional correction for baseline mMRC and CCQ, no statistically significant associations were found. Conclusion: Heart disease contributes to lower health status and higher symptom burden in COPD but does not accelerate the worsening over time. Keywords: COPD Assessment Test, CAT, Clinical COPD Questionnaire, CCQ, modified Medical Research Council dyspnea score, mMRC, ischemic heart disease, heart failure

Martin Sandelin,1 Stéphanie Mindus,1 Marcus Thuresson,2 Karin Lisspers,3 Björn Ställberg,3 Gunnar Johansson,3 Kjell Larsson,4 Christer Janson1 1Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Statisticon AB, Uppsala, Sweden; 3Department of Public Health and Caring Science, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 4Lung and Allergy Research Unit, National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden Background: The risk of dying of lung cancer is up to eightfold higher in patients with COPD than in age- and gender-matched controls. The aim of this study was to investigate the factors associated with lung cancer in a large cohort of COPD patients from primary care centers. Methods: To analyze whether age, gender, socioeconomic factors, comorbidity, and medication affect the risk of lung cancer in COPD, we used a COPD cohort of primary care patients. Data from primary care medical records and mandatory Swedish national registers were collected and linked in this population-based, retrospective observational registry study (NCT01146392). Results: Of the total cohort, 19,894 patients were included in the study. Five hundred and ninety-four lung cancer cases were diagnosed, corresponding to 3.0% of the studied population. In a multivariate analysis, the risk of lung cancer was lower if the COPD patients had a concurrent asthma diagnosis (HR: 0.54, CI: 0.41–0.71), while the risk of lung cancer increased with increasing age. A decreased lung cancer risk was observed in an exposure-dependent manner in patients who were prescribed inhaled corticosteroids (HR: 0.52, CI: 0.37–0.73), while the opposite was found for the use of acetylsalicylic acid (HR: 1.58, CI: 1.15–2.16). Conclusion: In this large population-based cohort, a concurrent asthma diagnosis and use of inhaled corticosteroids were independently related to decreased risk of lung cancer in COPD patients, while the use of acetylsalicylic acid was associated with an increased risk. The findings of the present study should be seen as hypothesis generating and need to be confirmed in prospective studies. Keywords: asthma, NSCLC, risk factor, ACO, inhaled corticosteroids

Marieann Högman,1 Johanna Sulku,2,3 Björn Ställberg,4,5 Christer Janson,1 Kristina Bröms,3,4 Hans Hedenström,6 Karin Lisspers,4,5 Andrei Malinovschi6 1Department of Medical Sciences, Respiratory, Allergy and Sleep Research, 2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, 3Center for Research & Development, Uppsala University/Region Gävleborg, Gävle, 4Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, 5Center for Clinical Research, Uppsala University, County Council Dalarna, Falun, 6Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden Background: Unlike the 2014 guidelines, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines have removed lung function from the risk assessment algorithm of patients with COPD. The aim of this investigation was to analyze the proportion of subjects who would change to a lower risk group when applying GOLD2017 and determine if they exhibit different characteristics in terms of inflammation, symptoms and comorbidity compared to the subjects who would remain in a high-risk group. Subjects and methods: A total of 571 subjects with physician-diagnosed and spirometry-verified COPD were included in the present study. The data consisted of measurements of lung function, inflammatory markers, together with questionnaires that covered comorbidities, COPD symptoms and medication. Results: From group C, 53% of the subjects would be reclassified to the lower risk group A, and from group D, 47% of the subjects would be reclassified to the lower risk group B when using GOLD2017 instead of GOLD2014. Compared to the subjects who would remain in group D, those who would change to group B were more often men (56% vs 72%); of an older age, mean (SD), 71 (8) years vs 68 (7) years; had more primary care contact (54% vs 33%); had lower levels of blood neutrophils, geometrical mean (95% CI), 5.3 (5.0, 5.7) vs 4.6 (4.3, 4.9); reported less anxiety/depression (20% vs 34%); experienced less asthma (29% vs 46%) and had fewer symptoms according to the COPD assessment test,16 (5) vs 21 (7). All p-values were

Karin Lisspers,1 Kjell Larsson,2 Gunnar Johansson,1 Christer Janson,3 Madlaina Costa-Scharplatz,4 Jean-Bernard Gruenberger,5 Milica Uhde,6 Leif Jorgensen,7 Florian S Gutzwiller,5 Björn Ställberg1 1Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, 2Department of Work Environment Toxicology, The National Institute of Environmental Medicine, Karolinska Institute, Solna, 3Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, 4Novartis AB, Täby, Sweden; 5Novartis, Basel, Switzerland; 6IQVIA, Solna, Sweden; 7IQVIA, Copenhagen, Denmark Background: We assessed direct and indirect costs associated with COPD in Sweden and examined how these costs vary across time, age, and disease stage in a cohort of patients with COPD and matched controls in a real-world, primary care (PC) setting.Patients and methods: Data from electronic medical records linked to the mandatory national health registers were collected for COPD patients and a matched reference population in 52 PC centers from 2000 to 2014. Direct health care costs (drug, outpatient or inpatient, PC, both COPD related and not COPD related) and indirect health care costs (loss of income, absenteeism, loss of productivity) were assessed.Results: A total of 17,479 patients with COPD and 84,514 reference controls were analyzed. During 2013, direct costs were considerably higher among the COPD patient population (€13,179) versus the reference population (€2,716), largely due to hospital nights unrelated to COPD. Direct costs increased with increasing disease severity and increasing age and were driven by higher respiratory drug costs and non-COPD-related hospital nights. Indirect costs (~€28,000 per patient) were the largest economic burden in COPD patients of working age during 2013.Conclusion: As non-COPD-related hospital nights represent the largest direct cost, management of comorbidities in COPD would offer clinical benefits and relieve the financial burden of disease. Keywords: COPD, direct cost, indirect cost, burden, Sweden

Christer Janson,1 Georgios Stratelis,1,2 Anna Miller-Larsson,3 Tim W Harrison,4 Kjell Larsson5 1Respiratory, Allergy and Sleep Research Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 2Respiratory, Inflammation and Autoimmunity, AstraZeneca Nordic, Södertälje, Sweden; 3Respiratory GMed, AstraZeneca Gothenburg, Mölndal, Sweden; 4Nottingham Respiratory Research Unit, City Hospital Campus, University of Nottingham, Nottingham, UK; 5Lung and Airway Research, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Abstract: Inhaled corticosteroids (ICSs) treatment combined with long-acting β2-adrenoceptor agonists (LABAs) reduces the risk of exacerbations in COPD, but the use of ICSs is associated with increased incidence of pneumonia. There are indications that this association is stronger for fluticasone propionate than for budesonide. We have examined systematic reviews assessing the risk of pneumonia associated with fluticasone propionate and budesonide COPD therapy. Compared with placebo or LABAs, we found that fluticasone propionate was associated with 43%–78% increased risk of pneumonia, while only slightly increased risk or no risk was found for budesonide. We have evaluated conceivable mechanisms which may explain this difference and suggest that the higher pneumonia risk with fluticasone propionate treatment is caused by greater and more protracted immunosuppressive effects locally in the airways/lungs. These effects are due to the much slower dissolution of fluticasone propionate particles in airway luminal fluid, resulting in a slower uptake into the airway tissue and a much longer presence of fluticasone propionate in airway epithelial lining fluid. Keywords: COPD, pneumonia, inhaled corticosteroids, budesonide, fluticasone

Josefin Sundh,1 Helena Lindgren,2 Mikael Hasselgren,2 Scott Montgomery,3–5 Christer Janson,6 Björn Ställberg,7 Karin Lisspers7 1Department of Respiratory Medicine, School of Medical Sciences, 2Medical Programme, School of Medical Sciences, 3Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, 4Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Epidemiology and Public Health, University College, London, UK; 6Department of Medical Sciences, Respiratory, Allergy and Sleep Research, 7Department of Public Health and Caring Science, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden Introduction: Pulmonary rehabilitation is effective in all stages of COPD. The availability and utilization of pulmonary rehabilitation resources, and the characteristics of COPD patients receiving rehabilitation, were investigated in primary and secondary care in central Sweden. Materials and methods: Data on available pulmonary rehabilitation resources were collected using questionnaires, to 14 hospitals and 54 primary health care centers, and information on utilization of different rehabilitation professionals was obtained from questionnaires completed by 1,329 COPD patients from the same centers. Multivariable logistic regression examined associations with having received rehabilitation in the previous year. Results: In primary care, nurse-based asthma/COPD clinics were common (87%), with additional separate access to other rehabilitation professionals. In secondary care, rehabilitation was more often offered as part of a multidisciplinary teamwork (71%). In total, 36% of the patients met an asthma/COPD nurse in the previous year. Utilization was lower in primary than in secondary care for physiotherapists (7% vs 16%), occupational therapists (3% vs 10%), nutritionists (5% vs 13%), and counselors (1% vs 4%). A higher COPD Assessment Test score and frequent exacerbations were associated with higher utilization of all rehabilitation professionals. Conclusion: Pulmonary rehabilitation resources are available but underutilized, and receiving rehabilitation is more common in severe COPD. Treatment recommendations need to be better implemented, especially in mild and moderate COPD. Keywords: multidisciplinary, asthma/COPD nurse, physiotherapist, occupational therapist, nutritionist, counselor

K Torén,1 B Bake,1 A-C Olin,1 G Engström,2 A Blomberg,3 J Vikgren,4 J Hedner,5 J Brandberg,4 HL Persson,6,7 CM Sköld,8 A Rosengren,9 G Bergström,9 C Janson10 1Section of Occupational and Environmental Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 2Department of Clinical Science, Lund University, Malmö, 3Division of Medicine/Respiratory Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, 4Department of Radiology, Institute of Clinical Sciences, 5Department of Internal Medicine/Lung Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 6Department of Respiratory Medicine, 7Department of Medicine and Health Sciences, Linköping University, Linköping, 8Respiratory Medicine Unit, Department of Medicine Solna, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, 9Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 10Department of Medical Sciences, Clinical Physiology and Lung, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden Background: Data are lacking from general population studies on how to define changes in lung function after bronchodilation. This study aimed to analyze different measures of bronchodilator response of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and slow vital capacity (SVC). Materials and methods: Data were derived from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) Pilot study. This analysis comprised 1,050 participants aged 50–64 years from the general population. Participants were investigated using a questionnaire, and FEV1, FVC and SVC were recorded before and 15 minutes after inhalation of 400 µg of salbutamol. A bronchodilator response was defined as the relative change from baseline value expressed as the difference in units of percent predicted normal. Predictors of bronchodilator responses were assessed using multiple linear regression models. Airway obstruction was defined as FEV1/FVC ratio below lower limit of normal (LLN) before bronchodilation, and COPD was defined as an FEV1/FVC ratio below LLN after bronchodilation. Physician-diagnosed asthma was defined as an affirmative answer to “Have you ever had asthma diagnosed by a physician?”. Asymptomatic never-smokers were defined as those not reporting physician-diagnosed asthma, physician-diagnosed COPD or emphysema, current wheeze or chronic bronchitis and being a lifelong never-smoker.Results: Among all subjects, the greatest bronchodilator responses (FEV1, FVC and SVC) were found in subjects with asthma or COPD. The upper 95th percentile of bronchodilator responses in asymptomatic never-smokers was 8.7% for FEV1, 4.2% for FVC and 5.0% for SVC. The bronchodilator responses were similar between men and women. In a multiple linear regression model comprising all asymptomatic never-smokers, the bronchodilator response of FEV1 was significantly associated with airway obstruction and height. Conclusion: When the bronchodilator response in asymptomatic never-smokers is reported as the difference in units of predicted normal, significant reversibility of FEV1, FVC and SVC to bronchodilators is ~9%, 4% and 5%, respectively. Keywords: spirometry, reversibility, COPD, epidemiology

Kjell Torén,1 Anna-Carin Olin,1 Anne Lindberg,2 Jenny Vikgren,3 Linus Schiöler,1 John Brandberg,3 Åse Johnsson,3 Gunnar Engström,4 H Lennart Persson,5 Magnus Sköld,6 Jan Hedner,7 Eva Lindberg,8 Andrei Malinovschi,8 Eeva Piitulainen,9 Per Wollmer,9 Annika Rosengren,10 Christer Janson,8 Anders Blomberg,2 Göran Bergström10 1Section of Occupational and Environmental Medicine, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 2Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, 3Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 4Department of Clinical Science, Malmö, Lund University, Lund, 5Department of Respiratory Medicine and Department of Medicine and Health Sciences, Linköping University, Linköping, 6Respiratory Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 7Department of Internal Medicine/Lung Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 8Department of Medical Sciences, Clinical Physiology and Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, 9Department of Translational Medicine, Lund University, Malmö, 10Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Background: Spirometric diagnosis of chronic obstructive pulmonary disease (COPD) is based on the ratio of forced expiratory volume in 1 second (FEV1)/vital capacity (VC), either as a fixed value

Jenny Theorell-Haglöw,1 Inga Sif Ólafsdóttir,1–3 Bryndís Benediktsdóttir,2,3 Thórarinn Gíslason,2,3 Eva Lindberg,1 Christer Janson1 1Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Department of Respiratory Medicine and Sleep, Landspitali University Hospital, 3Medical Faculty, University of Iceland, Reykjavík, Iceland Background: The aim was to assess and compare reported sleep disturbances and objectively measured sleep in men and women with COPD compared with controls and also explore sex differences. Methods: A total of 96 patients with COPD and 90 age- and sex-matched controls answered a sleep questionnaire, underwent ambulatory polysomnography, a post-bronchodilatory spirometry, and blood sampling. Results: Of the patients with COPD, 51% reported sleep disturbances as compared with 31% in controls (P=0.008). Sleep disturbances were significantly more prevalent in males with COPD compared with controls, whereas there was no significant difference in females. The use of hypnotics was more common among patients with COPD compared with controls, both in men (15% vs 0%, P=0.009) and women (36% vs 16%, P=0.03). The men with COPD had significantly longer recorded sleep latency than the male control group (23 vs 9.3 minutes, P

Josefin Sundh,1 Gunnar Johansson,2 Kjell Larsson,3 Anders Lindén,3 Claes-Göran Löfdahl,4 Thomas Sandström,5 Christer Janson6 1Department of Respiratory Medicine, Örebro University, Örebro, Sweden; 2Department of Public Health and Caring Science, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 5Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, Sweden; 6Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden Background: Chronic bronchitis and previous exacerbations are both well-known risk factors for new exacerbations, impaired health-related quality of life, and increased mortality in COPD. The aim of the study was to characterize the phenotype of concurrent chronic bronchitis and frequent exacerbation in severe COPD. Methods: Information on patient characteristics, comorbidity, and exacerbations from the previous year (total number and number requiring hospitalization) was collected from 373 patients with stage III and IV COPD attending 27 secondary care respiratory units in Sweden. Logistic regression used chronic bronchitis and frequent exacerbations (≥2 exacerbations or ≥1 hospitalized exacerbations in the previous year) as response variables. Stratification and interaction analyses examined effect modification by sex. Results: Chronic bronchitis was associated with current smoking (adjusted odds ratio [OR] [95% CI], 2.75 [1.54–4.91]; P=0.001), frequent exacerbations (OR [95% CI], 1.93 [1.24–3.01]; P=0.004), and musculoskeletal symptoms (OR [95% CI], 1.74 [1.05–2.86]; P=0.031), while frequent exacerbations were associated with lung function (forced expiratory volume in 1 second as a percentage of predicted value [FEV1% pred]) (OR [95% CI] 0.96 [0.94–0.98]; P=0.001) and chronic bronchitis (OR [95% CI] 1.73 [1.11–2.68]; P=0.015). The phenotype with both chronic bronchitis and frequent exacerbations was associated with FEV1% pred (OR [95% CI] 0.95 [0.92–0.98]; P=0.002) and musculoskeletal symptoms (OR [95% CI] 2.55 [1.31–4.99]; P=0.006). The association of smoking with the phenotype of chronic bronchitis and exacerbations was stronger in women than in men (interaction, P=0.040). Conclusion: Musculoskeletal symptoms and low lung function are associated with the phenotype of combined chronic bronchitis and frequent exacerbations in severe COPD. In women, current smoking is of specific importance for this phenotype. This should be considered in clinical COPD care. Keywords: lung function, smoking, chronic obstructive lung disease, musculoskeletal symptoms

Josefin Sundh,1 Gunnar Johansson,2 Kjell Larsson,3 Anders Lindén,3 Claes-Göran Löfdahl,4 Christer Janson,5 Thomas Sandström6 1Department of Respiratory Medicine, Örebro University, Örebro, Sweden; 2Department of Public Health and Caring Science, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 5Department of Medical Sciences: Respiratory Medicine and Allergology, Uppsala University, Uppsala, Sweden; 6Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, Sweden Introduction: Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of improvement. The aim of this study was to examine the associations between comorbidities and HRQL as measured by the instruments EuroQol-5 dimension (EQ-5D) and the COPD Assessment Test (CAT). Methods: Information on patient characteristics, chronic bronchitis, cardiovascular disease, diabetes, renal impairment, musculoskeletal symptoms, osteoporosis, depression, and EQ-5D and CAT questionnaire results was collected from 373 patients with Forced Expiratory Volume in one second (FEV1)