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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

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