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1.  The relationship between exercise induced bronchial obstruction and health related quality of life in female and male adolescents from a general population 
Background
Previous studies have observed that exercise-induced bronchoconstriction (EIB) is more common and more strongly related to exercise related breathing problems in female adolescents than male adolescents. However, few studies have investigated the association between EIB and health related quality of life (HRQoL) from a gender perspective. The aim of this study was to examine the association between EIB and HRQoL and physical activity level in female and male adolescents with and without EIB.
Methods
From a population based study on exercise-induced breathing problems among adolescents (13–15 years, n = 3838) a cross sectional study with prospective data collection was carried out in a random subsample of 140 adolescents. The subjects in the sample were tested for EIB with a standardised exercise test, of which 49 adolescents were tested positive. HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) and the adolescents’ physical activity levels were measured objectively with accelerometer.
Results
The female subjects with EIB reported a lower HRQoL, both in total score (p = 0.03) and physical functioning score (p = 0.009) and had a lower baseline FEV1 compared to females without EIB (88 vs. 94 % predicted, p = 0.001). No differences were found in HRQoL or baseline lung function between males with or without EIB. There were no differences in minutes of moderate to vigorous physical activity per day between females or males with and without EIB.
Conclusion
In a general population, the female adolescents with EIB had lower HRQoL and poorer baseline lung function compared to counterparts without EIB. These differences were not observed in males. EIB does not appear to affect the level of daily physical activity neither in females nor males.
doi:10.1186/s12890-016-0226-0
PMCID: PMC4847200  PMID: 27117559
Adolescents; Exercise-induced bronchoconstriction; Health-related quality of life; Physical activity
2.  New data analysis in a population study raises the hypothesis that particle size contributes to the pro-asthmatic potential of small pet animal allergens 
Background
The size of inhaled particles influences where they deposit and theoretically should be important for the development of airway inflammation and responsiveness. Our aim was to assess if sensitization to smaller-sized aeroallergens relates to higher prevalence of treated asthma, increased airway responsiveness, and airway and systemic inflammation.
Methods
Molecular-based IgE antibody determination was done in 467 subjects. Sensitized subjects were grouped based on the particle size of the aeroallergen: (1) Large particles only (mainly pollen); (2) Medium-sized particles (sensitized to mainly mite and mold and possibly to large particles); and 3) Small particles (sensitized to pet allergens and possibly to medium- and/or large-sized particles). Airway responsiveness to methacholine, exhaled nitric oxide (FENO), and serum eosinophil cationic protein (S-ECP) were measured. Asthma and rhinitis were questionnaire-assessed.
Results
Subjects sensitized to small particles had higher prevalence of treated asthma (35% versus 10%, P < 0.001), higher FENO50 (32 versus 17 ppb, P < 0.001), higher S-ECP (10 versus 7.5 ng/mL, P = 0.04), and increased bronchial responsiveness (dose-response slope, 5.6 versus 7.5, P < 0.001) compared with non-atopics. This was consistent after adjusting for potential confounders. Sensitization to only large or to medium and possibly also large aeroallergen particles was not related to any of these outcomes after adjustments.
Conclusions
Sensitization to smaller particles was associated with a higher prevalence of asthma under treatment, higher airway responsiveness, and airway and systemic inflammation. Mapping of IgE sensitization to small particles might help to detect subjects having increased airway and systemic inflammation and bronchial responsiveness, indicating increased risk of developing asthma.
doi:10.3109/03009734.2015.1109569
PMCID: PMC4812054  PMID: 26610050
Asthma; components; inflammation; methacholine test; nitric oxide; particle size; respiratory medicine; S-ECP
3.  Sleep disturbances among Swedish soldiers after military service abroad 
Aims
Since 1956, more than 100,000 Swedish soldiers have served abroad on various international missions. The aim of this paper was to determine whether there was a connection between military service abroad and sleep disorders among Swedish soldiers.
Methods
The prevalence of sleep disturbances among 1,080 veterans from Kosovo and Afghanistan was compared with almost 27,000 Swedes from a general population sample, using propensity score matching and logistic regression. The sleep disturbances studied were habitual snoring, difficulty inducing sleep (DIS), difficulty maintaining sleep (DMS), early morning awakenings (EMA), and excessive daytime sleepiness (EDS). Insomnia was defined as having at least one of DIS, DMS, or EMA. The covariates used in the matching and adjustments were age, gender, smoking habits, BMI, education, ever having had asthma, moist snuff, and exercise habits.
Results
The veterans had a significantly lower prevalence of insomnia (26.2% versus 30.4%) and EDS (22.7% versus 29.4%) compared with a matched group from the reference population, using propensity score matching. Analyses with logistic regression showed that belonging to the military population was related to a lower risk of having DMS (adjusted OR (95% CI) 0.77 (0.64–0.91)), insomnia (OR 0.82 (0.71–0.95)), and EDS (OR 0.74 (0.63–0.86)), whereas no significant difference was found for snoring, DIS, and EMA.
Conclusion
Swedish veterans have fewer problems with insomnia and daytime sleepiness than the general Swedish population. The explanation of our findings may be the selection processes involved in becoming a soldier and when sampling personnel for military assignments abroad.
doi:10.3109/03009734.2016.1144663
PMCID: PMC4812060  PMID: 26959327
Anxiety; occupational medicine; sleep disturbances
4.  Early Life Origins of Lung Ageing: Early Life Exposures and Lung Function Decline in Adulthood in Two European Cohorts Aged 28-73 Years 
PLoS ONE  2016;11(1):e0145127.
Objectives
Early life environment is essential for lung growth and maximally attained lung function. Whether early life exposures impact on lung function decline in adulthood, an indicator of lung ageing, has scarcely been studied.
Methods
Spirometry data from two time points (follow-up time 9–11 years) and information on early life exposures, health and life-style were available from 12862 persons aged 28–73 years participating in the European population-based cohorts SAPALDIA (n = 5705) and ECRHS (n = 7157). The associations of early life exposures with lung function (FEV1) decline were analysed using mixed-effects linear regression.
Results
Early life exposures were significantly associated with FEV1 decline, with estimates almost as large as personal smoking. FEV1 declined more rapidly among subjects born during the winter season (adjusted difference in FEV1/year of follow-up [95%CI] -2.04ml [-3.29;-0.80]), of older mothers, (-1.82 ml [-3.14;-0.49]) of smoking mothers (-1.82ml [-3.30;-0.34] or with younger siblings (-2.61ml [-3.85;-1.38]). Less rapid FEV1-decline was found in subjects who had attended daycare (3.98ml [2.78;5.18]), and indicated in subjects with pets in childhood (0.97ml [-0.16;2.09]). High maternal age and maternal smoking appeared to potentiate effects of personal smoking. The effects were independent of asthma at any age.
Conclusion
Early life factors predicted lung function decline decades later, suggesting that some mechanisms related lung ageing may be established early in life. Early life programming of susceptibility to adult insults could be a possible pathway that should be explored further.
doi:10.1371/journal.pone.0145127
PMCID: PMC4728209  PMID: 26811913
5.  The Association of Gum Bleeding with Respiratory Health in a Population Based Study from Northern Europe 
PLoS ONE  2016;11(1):e0147518.
Background
There is little knowledge about how oral and respiratory health is interrelated even though the mucosa of the oral cavity and airways constitutes a continuum and the exposures to these are partly similar.
Aims
To investigate whether gum bleeding is related to asthma, respiratory symptoms and self-reported COPD.
Methods
A postal questionnaire including questions about respiratory and oral health was sent to general population samples in seven Northern European centres. In 13,409 responders, gum bleeding when brushing teeth was reported always/often by 4% and sometimes by 20%. Logistic regressions accounted for age, smoking, educational level, centre and gender. Effects of BMI, cardio-metabolic diseases, early life factors, gastro-oesophageal reflux, dental hygiene, nasal congestion, and asthma medication were addressed.
Results
Gum bleeding always/often was significantly associated with ≥3 asthma symptoms (OR 2.58, 95% CI 2.10–3.18), asthma (1.62 [1.23–2.14]) and self-reported COPD (2.02 [1.28–3.18]). There was a dose-response relationship between respiratory outcomes and gum bleeding frequency (≥3 symptoms: gum bleeding sometimes 1.42 [1.25–1.60], often/always 2.58 [2.10–3.18]), and there was no heterogeneity between centres (pheterogeneity = 0.49). None of the investigated risk factors explained the associations. The observed associations were significantly stronger among current smokers (pinteraction = 0.004).
Conclusions
A consistent link between gum bleeding and obstructive airways disease was observed, not explained by common risk factors or metabolic factors. We speculate that oral pathogens might have unfavourable impact on the airways, and that the direct continuity of the mucosa of the oral cavity and the airways reflects a pathway that might provide novel opportunities for interventions.
doi:10.1371/journal.pone.0147518
PMCID: PMC4725728  PMID: 26808490
6.  Sex differences in reported and objectively measured sleep in COPD 
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<0.001), while no corresponding difference was found in women. In men with COPD, those with reported sleep disturbances had lower forced vital capacity, higher C-reactive protein, myeloperoxidase, and higher prevalence of chronic bronchitis.
Conclusion
The COPD was associated with impaired sleep in men while the association was less clear in women. This was also confirmed by recorded longer sleep latency in male subjects with COPD compared with controls.
doi:10.2147/COPD.S94268
PMCID: PMC4734736  PMID: 26869781
chronic obstructive pulmonary disease; sleep; polysomnography; quality of sleep; sex
7.  The Urban-Rural Gradient In Asthma: A Population-Based Study in Northern Europe 
The early life environment appears to have a persistent impact on asthma risk. We hypothesize that environmental factors related to rural life mediate lower asthma prevalence in rural populations, and aimed to investigate an urban-rural gradient, assessed by place of upbringing, for asthma. The population-based Respiratory Health In Northern Europe (RHINE) study includes subjects from Denmark, Norway, Sweden, Iceland and Estonia born 1945–1973. The present analysis encompasses questionnaire data on 11,123 RHINE subjects. Six categories of place of upbringing were defined: farm with livestock, farm without livestock, village in rural area, small town, city suburb and inner city. The association of place of upbringing with asthma onset was analysed with Cox regression adjusted for relevant confounders. Subjects growing up on livestock farms had less asthma (8%) than subjects growing up in inner cities (11%) (hazard ratio 0.72 95% CI 0.57–0.91), and a significant urban-rural gradient was observed across six urbanisation levels (p = 0.02). An urban-rural gradient was only evident among women, smokers and for late-onset asthma. Analyses on wheeze and place of upbringing revealed similar results. In conclusion, this study suggests a protective effect of livestock farm upbringing on asthma development and an urban-rural gradient in a Northern European population.
doi:10.3390/ijerph13010093
PMCID: PMC4730484  PMID: 26729146
asthma; early life environment; farming; microbial exposure; urban-rural gradient; hygiene hypothesis; RHINE
8.  The phenotype of concurrent chronic bronchitis and frequent exacerbations in patients with severe COPD attending Swedish secondary care units 
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.
doi:10.2147/COPD.S91362
PMCID: PMC4630179  PMID: 26604732
lung function; smoking; chronic obstructive lung disease; musculoskeletal symptoms
9.  Respiratory Health in Cleaners in Northern Europe: Is Susceptibility Established in Early Life? 
PLoS ONE  2015;10(7):e0131959.
Rationale
There is some evidence that maternal smoking increases susceptibility to personal smoking’s detrimental effects. One might question whether early life disadvantage might influence susceptibility to occupational exposure.
Objectives
In this cross-sectional study we investigated respiratory symptoms, asthma and self-reported chronic obstructive pulmonary disease (COPD) as related to working as a cleaner in Northern European populations, and whether early life factors influenced susceptibility to occupational cleaning’s unhealthy effects.
Methods
The RHINE III questionnaire study assessed occupational cleaning in 13,499 participants. Associations with respiratory symptoms, asthma and self-reported COPD were analysed with multiple logistic regressions, adjusting for sex, age, smoking, educational level, parent´s educational level, BMI and participating centre. Interaction of occupational cleaning with early life disadvantage (maternal smoking, severe respiratory infection <5 years, born during winter months, maternal age at birth >35 years) was investigated.
Main Results
Among 2138 ever-cleaners the risks of wheeze (OR 1.4, 95% CI 1.3–1.6), adult-onset asthma (1.5 [1.2–1.8]) and self-reported COPD (1.7 [1.3–2.2]) were increased. The risk increased with years in occupational cleaning (adult-onset asthma: ≤1 year 0.9 [0.7–1.3]; 1–4 years 1.5 [1.1–2.0]; ≥4 years 1.6 [1.2–2.1]). The association of wheeze with cleaning activity ≥4 years was significantly stronger for those with early life disadvantage than in those without (1.8 [1.5–2.3] vs. 1.3 [0.96–1.8]; pinteraction 0.035).
Conclusions
Occupational cleaners had increased risk of asthma and self-reported COPD. Respiratory symptom risk was particularly increased in persons with factors suggestive of early life disadvantage. We hypothesize that early life disadvantage may increase airway vulnerability to harmful exposure from cleaning agents later in life.
doi:10.1371/journal.pone.0131959
PMCID: PMC4500550  PMID: 26168149
10.  Ambient Air Pollution and Adult Asthma Incidence in Six European Cohorts (ESCAPE) 
Environmental Health Perspectives  2015;123(6):613-621.
Background
Short-term exposure to air pollution has adverse effects among patients with asthma, but whether long-term exposure to air pollution is a cause of adult-onset asthma is unclear.
Objective
We aimed to investigate the association between air pollution and adult onset asthma.
Methods
Asthma incidence was prospectively assessed in six European cohorts. Exposures studied were annual average concentrations at home addresses for nitrogen oxides assessed for 23,704 participants (including 1,257 incident cases) and particulate matter (PM) assessed for 17,909 participants through ESCAPE land-use regression models and traffic exposure indicators. Meta-analyses of cohort-specific logistic regression on asthma incidence were performed. Models were adjusted for age, sex, overweight, education, and smoking and included city/area within each cohort as a random effect.
Results
In this longitudinal analysis, asthma incidence was positively, but not significantly, associated with all exposure metrics, except for PMcoarse. Positive associations of borderline significance were observed for nitrogen dioxide [adjusted odds ratio (OR) = 1.10; 95% CI: 0.99, 1.21 per 10 μg/m3; p = 0.10] and nitrogen oxides (adjusted OR = 1.04; 95% CI: 0.99, 1.08 per 20 μg/m3; p = 0.08). Nonsignificant positive associations were estimated for PM10 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 10 μg/m3), PM2.5 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 5 μg/m3), PM2.5absorbance (adjusted OR = 1.06; 95% CI: 0.95, 1.19 per 10–5/m), traffic load (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 4 million vehicles × meters/day on major roads in a 100-m buffer), and traffic intensity (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 5,000 vehicles/day on the nearest road). A nonsignificant negative association was estimated for PMcoarse (adjusted OR = 0.98; 95% CI: 0.87, 1.14 per 5 μg/m3).
Conclusions
Results suggest a deleterious effect of ambient air pollution on asthma incidence in adults. Further research with improved personal-level exposure assessment (vs. residential exposure assessment only) and phenotypic characterization is needed.
Citation
Jacquemin B, Siroux V, Sanchez M, Carsin AE, Schikowski T, Adam M, Bellisario V, Buschka A, Bono R, Brunekreef B, Cai Y, Cirach M, Clavel-Chapelon F, Declercq C, de Marco R, de Nazelle A, Ducret-Stich RE, Ferretti VV, Gerbase MW, Hardy R, Heinrich J, Janson C, Jarvis D, Al Kanaani Z, Keidel D, Kuh D, Le Moual N, Nieuwenhuijsen MJ, Marcon A, Modig L, Pin I, Rochat T, Schindler C, Sugiri D, Stempfelet M, Temam S, Tsai MY, Varraso R, Vienneau D, Vierkötter A, Hansell AL, Krämer U, Probst-Hensch NM, Sunyer J, Künzli N, Kauffmann F. 2015. Ambient air pollution and adult asthma incidence in six European cohorts (ESCAPE). Environ Health Perspect 123:613–621; http://dx.doi.org/10.1289/ehp.1408206
doi:10.1289/ehp.1408206
PMCID: PMC4455584  PMID: 25712593
11.  Perceived Food Hypersensitivity Relates to Poor Asthma Control and Quality of Life in Young Non-Atopic Asthmatics 
PLoS ONE  2015;10(4):e0124675.
Background
The relationship between perceived food hypersensitivity in asthmatics, food allergen sensitization, asthma control and asthma-related quality of life has not been studied.
Objective
Our aim was to study the prevalence of perceived food hypersensitivity in a cohort of young asthmatics, its relation to food allergen sensitization, and any correlation to asthma control and asthma-related quality of life.
Methods
Perceived food hypersensitivity, as well as IgE sensitization to common food allergens, levels of exhaled nitric oxide (FeNO), and blood eosinophil counts (B-Eos) were assessed in 408 subjects (211 women) with asthma, aged (mean ± SEM) 20.4 ± 0.3 years. Subjects filled out the Asthma Control Test (ACT) and the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ). Inflammation was assessed by means of FeNO and B-Eos.
Results
Fifty-three per cent of subjects reported food hypersensitivity. A corresponding food allergen sensitization was found in 68% of these subjects. Non-atopic subjects with perceived food hypersensitivity (n = 31) had lower ACT (19 (15 - 22) vs. 21 (20 - 23), p < 0.001) and Mini-AQLQ -scores (5.3 (4.3 - 6.1) vs. 6.1 (5.5 - 6.5), p < 0.001) than subjects with no food hypersensitivity (n = 190), despite lower levels of FeNO and B-Eos (p < 0.05).
Conclusions and Clinical Relevance
Food hypersensitivity was commonly reported among young asthmatics. In a majority of cases, a corresponding food allergen sensitization was found. A novel and clinically important finding was that non-atopic subjects with perceived food hypersensitivity were characterized by poorer asthma control and asthma-related quality of life.
doi:10.1371/journal.pone.0124675
PMCID: PMC4414584  PMID: 25923451
12.  Idiopathic fibrotic lung disease at a university hospital setting: management and prognostic factors 
European Clinical Respiratory Journal  2015;2:10.3402/ecrj.v2.26915.
Background
Idiopathic fibrosing interstitial pneumonia consists of many subtypes, most associated with a poor prognosis. The aim of the study was to evaluate diagnostic procedures and treatment as well as survival in patients with idiopathic fibrosing interstitial pneumonia.
Methods
This study comprised 175 patients with idiopathic fibrosing interstitial pneumonia (ICD 10 code J84) that had been diagnosed at Uppsala University Hospital, during 2005 to 2012. Patient records were reviewed concerning: gender, age, smoking, occupational exposure, comorbidities, procedures, lung function, and treatment. Information on survival and cause of death was collected.
Results
A total of 98% had been examined with computed tomography, 93% with spirometry, 49% with measurement of diffusion capacity, 48% with bronchoalveolar lavage, and 23% with lung biopsy. Prednisolone had been prescribed to 74% while N-acetylcysteine (NAC) and omeprazole were prescribed to 54%, respectively. Five-year survival was 46%. Mortality was associated with high age, low diffusion capacity, and the use of NAC.
Conclusion
High age and a low diffusion capacity are related to shorter survival in idiopathic fibrosing interstitial pneumonia. We also unexpectedly found that the use of NAC was related to shorter survival. A relatively low proportion of the patients were examined with diffusion capacity measurement. Thus, there is a possibility to improve diagnostic procedures and thereby improve estimation of prognosis in fibrotic lung disease.
doi:10.3402/ecrj.v2.26915
PMCID: PMC4629758  PMID: 26557254
fibrotic lung disease; idiopathic pulmonary fibrosis; diagnostics; prognosis; survival
13.  Effect of physical training on fat-free mass in patients with chronic obstructive pulmonary disease (COPD) 
Background
Weight loss and depletion of fat-free mass are common problems in patients with chronic obstructive pulmonary disease (COPD) and are related to muscular weakness and exercise intolerance. Physical training of COPD patients has good effect on exercise tolerance and quality of life. The aim of this study was to examine factors that affect change in fat-free mass after physical training, in patients with COPD.
Patients
Patients were examined before and after a 4-month exercise period. Weight and height were measured, and bioelectrical impedance was performed. Fat-free mass (FFM) was calculated, by a three-compartment model, and fat-free mass index (FFMI) was calculated as FFM kg/m2 and body mass index (BMI) as kg/m2. A symptom-limited ramp ergometer test and 12-minute walk test (12MWT) were performed. Dyspnoea score of daily activities was determined by Chronic Respiratory Disease Questionnaire (CRDQ). Blood was taken for analyses of C-reactive protein (CRP) and fibrinogen. Patients with a BMI <21 kg/m2 were given nutritional support during the training period.
Results
A total of 27 patients completed the training (64 years, FEV1 31% of predicted). Patients with low FFMI gained 1.2 kg, whereas those with normal FFMI lost 0.7 kg (p = 0.04). In multivariate analyses high age (p = 0.03), low FEV1 (p = 0.02), and a high level of dyspnoea (p = 0.01) at baseline were found to be negative predictors for increase in FFM.
Conclusions
Difficulties in increasing the fat-free mass in COPD patients by physical training seem to be associated with dyspnoea in daily life and impaired lung function (FEV1).
doi:10.3109/03009734.2014.990124
PMCID: PMC4389008  PMID: 25430624
Chronic obstructive pulmonary disease; dyspnoea; exercise training; fat-free mass; nutrition
14.  Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units 
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) <50% of predicted value from 27 secondary care respiratory units in Sweden. Correlation analyses and multiple linear regression models were performed using EQ-5D index, EQ-5D visual analog scale (VAS), and CAT scores as response variables.
Results
Having more comorbid conditions was associated with a worse HRQL as assessed by all instruments. Chronic bronchitis was significantly associated with a worse HRQL as assessed by EQ-5D index (adjusted regression coefficient [95% confidence interval] −0.07 [−0.13 to −0.02]), EQ-5D VAS (−5.17 [−9.42 to −0.92]), and CAT (3.78 [2.35 to 5.20]). Musculoskeletal symptoms were significantly associated with worse EQ-5D index (−0.08 [−0.14 to −0.02]), osteoporosis with worse EQ-5D VAS (−4.65 [−9.27 to −0.03]), and depression with worse EQ-5D index (−0.10 [−0.17 to −0.04]). In stratification analyses, the associations of musculoskeletal symptoms, osteoporosis, and depression with HRQL were limited to female patients.
Conclusion
The instruments EQ-5D and CAT complement each other and emerge as useful for assessing HRQL in patients with COPD. Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL. We conclude that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD.
doi:10.2147/COPD.S74645
PMCID: PMC4310343  PMID: 25653516
chronic bronchitis; EQ-5D; CAT; osteoporosis; depression; musculoskeletal symptoms
15.  Determinants of uncontrolled asthma in a Swedish asthma population: cross-sectional observational study 
European Clinical Respiratory Journal  2014;1:10.3402/ecrj.v1.24109.
Background
Asthma control is achieved in a low proportion of patients. The primary aim was to evaluate risk factors for uncontrolled asthma. The secondary aim was to assess quality of life associated with asthma control.
Methods
In a cross-sectional study, asthma patients aged 18–75 were randomly selected from primary and secondary health care centers. Postal questionnaires were sent to 1,675 patients and the response rate was 71%. A total of 846 patients from primary and 341 patients from secondary care were evaluated. Data were collected using a questionnaire and review of medical records. The questionnaire included questions about asthma control and a quality-of-life questionnaire, the mini-AQLQ, with four domains (symptoms, activity limitation, emotional function, and environmental stimuli). The mean score for each domain and the overall score were calculated. Asthma control was divided into three levels according to the GINA guidelines and partly and uncontrolled asthma were combined into one group – poorly controlled asthma.
Results
Asthma control was achieved in 36% of the sample: 38% in primary and 29% in secondary care. In primary and secondary care, 35 and 45% had uncontrolled asthma, respectively. Risk factors for poorly controlled asthma were female sex [OR 1.31 (1.003–1.70)], older age [OR 2.18 (1.28–3.73)], lower educational level [OR 1.63 (1.14–2.33)], and current smoking [OR 1.68 (1.16–2.43)]. Older age and lower educational level remained statistically significantly associated with poorly controlled asthma when the analyses were limited to never-smokers. Depression was an independent risk factor for poorly controlled asthma in men [OR 3.44 (1.12–10.54)]. The mini-AQLQ scores and the mean overall score were significantly lower in uncontrolled asthma.
Conclusion
Risk factors for poorly controlled asthma were female sex, older age, low educational level, and smoking. Uncontrolled asthma was significantly associated with lower quality of life.
doi:10.3402/ecrj.v1.24109
PMCID: PMC4629716  PMID: 26557235
asthma; uncontrolled; risk factors; quality of life; cross-sectional study
16.  Quality of life in relation to the traffic pollution indicators NO2 and NOx: results from the Swedish GA2LEN survey 
BMJ Open Respiratory Research  2014;1(1):e000039.
Background
Asthma is a chronic disease that may affect daily activities and quality of life. Asthmatics have higher incidence of chronic rhinosinusitis (CRS) and asthma is associated with sinonasal inflammation and nasal symptoms, that all impair quality of life. Worsening of asthma has been found associated with levels of nitrogen dioxide as traffic indicator.
Aims
The aim of the study was to evaluate the impact of traffic pollution indicated by nitrogen oxides (NO2 and NOx) on quality of life in asthmatic persons, individuals with CRS and controls.
Methods
Within the Swedish Ga2len (Global Allergy and Asthma European Network), 605 asthmatics with and without CRS, 110 individuals with CRS only and 226 controls from four cities were surveyed. The mini Asthma Quality of life Questionnaire (mAQLQ) and the Euro Quality of Life (EQ-5D) health questionnaire were used. Air pollution concentrations at the home address were modelled using dispersion models.
Results
Levels of NO2 (geometric mean 10.1 μg/m3 (95% CI 9.80 to 10.5) and NOx (12.1 μg/m3, 11.7 to 12.6) were similar among conditions (controls, asthmatics, individuals with CRS and asthmatics with CRS). The mAQLQ overall score was not found associated with levels of NO2 or NOx, with or without adjustments, and neither was scores within each of the four domains of mAQLQ: symptoms, activity limitations, emotional functions and effects of environmental stimuli. The mean EQ-5D index value, based on the five dimensions mobility, self-care, usual activities, pain/discomfort and anxiety depression, was also found unrelated to NO2 and NOx.
Conclusions
At moderate exposure levels traffic pollution appears not to affect quality of life.
doi:10.1136/bmjresp-2014-000039
PMCID: PMC4212716  PMID: 25478186
Asthma Epidemiology
17.  Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe 
European Journal of Epidemiology  2014;29(6):429-437.
Background The two inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease, has increased rapidly during the twentieth century, but the aetiology is still poorly understood. Impaired immunological competence due to decreasing biodiversity and altered microbial stimulation is a suggested explanation. Objective Place of upbringing was used as a proxy for the level and diversity of microbial stimulation to investigate the effects on the prevalence of IBD in adulthood. Methods Respiratory Health in Northern Europe (RHINE) III is a postal follow-up questionnaire of the European Community Respiratory Health Survey (ECRHS) cohorts established in 1989–1992. The study population was 10,864 subjects born 1945–1971 in Denmark, Norway, Sweden, Iceland and Estonia, who responded to questionnaires in 2000–2002 and 2010–2012. Data were analysed in logistic and Cox regression models taking age, sex, smoking and body mass index into consideration. Results Being born and raised on a livestock farm the first 5 years of life was associated with a lower risk of IBD compared to city living in logistic (OR 0.54, 95 % CI 0.31; 0.94) and Cox regression models (HR 0.55, 95 % CI 0.31; 0.98). Random-effect meta-analysis did not identify geographical difference in this association. Furthermore, there was a significant trend comparing livestock farm living, village and city living (p < 0.01). Sub-analyses showed that the protective effect was only present among subjects born after 1952 (OR 0.25, 95 % CI 0.11; 0.61). Conclusion This study suggests a protective effect from livestock farm living in early childhood on the occurrence of IBD in adulthood, however only among subjects born after 1952. We speculate that lower microbial diversity is an explanation for the findings.
doi:10.1007/s10654-014-9922-3
PMCID: PMC4065648  PMID: 24916994
Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Microbial exposure; Rural/urban environments; Hygiene hypothesis
18.  Longterm follow-up in European respiratory health studies – patterns and implications 
Background
Selection bias is a systematic error in epidemiologic studies that may seriously distort true measures of associations between exposure and disease. Observational studies are highly susceptible to selection bias, and researchers should therefore always examine to what extent selection bias may be present in their material and what characterizes the bias in their material. In the present study we examined long-term participation and consequences of loss to follow-up in the studies Respiratory Health in Northern Europe (RHINE), Italian centers of European Community Respiratory Health Survey (I-ECRHS), and the Italian Study on Asthma in Young Adults (ISAYA).
Methods
Logistic regression identified predictors for follow-up participation. Baseline prevalence of 9 respiratory symptoms (asthma attack, asthma medication, combined variable with asthma attack and/or asthma medication, wheeze, rhinitis, wheeze with dyspnea, wheeze without cold, waking with chest tightness, waking with dyspnea) and 9 exposure-outcome associations (predictors sex, age and smoking; outcomes wheeze, asthma and rhinitis) were compared between all baseline participants and long-term participants. Bias was measured as ratios of relative frequencies and ratios of odds ratios (ROR).
Results
Follow-up response rates after 10 years were 75% in RHINE, 64% in I-ECRHS and 53% in ISAYA. After 20 years of follow-up, response was 53% in RHINE and 49% in I-ECRHS. Female sex predicted long-term participation (in RHINE OR (95% CI) 1.30(1.22, 1.38); in I-ECRHS 1.29 (1.11, 1.50); and in ISAYA 1.42 (1.25, 1.61)), as did increasing age. Baseline prevalence of respiratory symptoms were lower among long-term participants (relative deviations compared to total baseline population 0-15% (RHINE), 0-48% (I-ECRHS), 3-20% (ISAYA)), except rhinitis which had a slightly higher prevalence. Most exposure-outcome associations did not differ between long-term participants and all baseline participants, except lower OR for rhinitis among ISAYA long-term participating smokers (relative deviation 17% (smokers) and 44% (10–20 pack years)).
Conclusions
We found comparable patterns of long-term participation and loss to follow-up in RHINE, I-ECRHS and ISAYA. Baseline prevalence estimates for long-term participants were slightly lower than for the total baseline population, while exposure-outcome associations were mainly unchanged by loss to follow-up.
doi:10.1186/1471-2466-14-63
PMCID: PMC4021078  PMID: 24739530
19.  BPIFB1 IS A LUNG-SPECIFIC AUTOANTIGEN ASSOCIATED WITH INTERSTITIAL LUNG DISEASE** 
Science translational medicine  2013;5(206):10.1126/scitranslmed.3006998.
Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes (1). Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. Here, we utilized a severe form of autoimmune disease, Autoimmune Polyglandular Syndrome Type 1 (APS1), to establish a strong link between an autoimmune response to the lung-specific protein BPIFB1 and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies specifically present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. Utilizing the animal model for APS1 to examine the mechanism of ILD pathogenesis, we found that Aire−/− mice harbor autoantibodies to a similar lung antigen named BPIFB9 that are a marker for ILD, and determined that a defect in thymic tolerance is responsible for the production of BPIFB9 autoantibodies and the development of ILD. Importantly, we also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also leads to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may be important to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.
doi:10.1126/scitranslmed.3006998
PMCID: PMC3882146  PMID: 24107778
20.  Natural History of Perceived Food Hypersensitivity and IgE Sensitisation to Food Allergens in a Cohort of Adults 
PLoS ONE  2014;9(1):e85333.
Background
No longitudinal studies exist on the natural history of food hypersensitivity and IgE sensitisation to food allergens in adults.
Objective
To examine the natural history of food hypersensitivity, the natural history of IgE sensitisation to food allergens and to investigate the risk factors for new onset food hypersensitivity.
Methods
Food hypersensitivity was questionnaire-assessed in 2307 individuals (aged 20–45 years) from Iceland and Sweden during the European Community Respiratory Health Survey both at baseline and follow-up 9 years later. IgE food and aeroallergen sensitisation were assessed in a subgroup of these individuals (n = 807). Values of 0.35 kU/L and above were regarded as positive sensitisation.
Results
Food hypersensitivity was reported by 21% of the subjects and this proportion remained unchanged at follow-up (p = 0.58). Fruits, nuts and vegetables were the three most common causes of food hypersensitivity, with a similar prevalence at baseline and follow-up. The prevalence IgE sensitisation to food allergens decreased in general by 56% (p<0.001) and IgE sensitisation to peanut decreased in particular by 67% (p = 0.003). The prevalence of timothy grass IgE sensitisation decreased by 15% (p = 0.003) while cat, mite and birch IgE sensitisation did not decrease significantly. Female sex, rhinitis, eczema and presence of IgE sensitisation to aeroallergens were independently associated with new onset food hypersensitivity.
Conclusion
The prevalence of food hypersensitivity remained unchanged while the prevalence of IgE sensitisation to food allergens decreased in adults over a 9-year follow-up period. The decrease in prevalence of IgE sensitisation to food allergens was considerably larger than the change in prevalence of IgE sensitisation to aeroallergens.
doi:10.1371/journal.pone.0085333
PMCID: PMC3888405  PMID: 24427301
21.  Physical activity level and its clinical correlates in chronic obstructive pulmonary disease: a cross-sectional study 
Respiratory Research  2013;14(1):128.
Background
Decreased physical activity is associated with higher mortality in subjects with COPD. The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.
Methods
Seventy-three subjects with COPD (67 ± 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV1%) predicted values of 43 ± 16 were included. The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR). TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry. Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics. Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL.
Results
The mean PAL was 1.47 ± 0.19, and 92% of subjects were classified as physically very inactive or sedentary. The walking speed was 1.02 ± 0.23 m/s, the quadriceps strength was 31.3 ± 11.2 kg, and the fat-free mass index (FFMI) was 15.7 ± 2.3 kg/m2, identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted. The regression model explained 45.5% (p < 0.001) of the variance in PAL. The FEV1% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%). Neither age, gender nor systemic inflammation contributed to the model.
Conclusions
Apart from lung function, walking speed and muscle strength are important correlates of physical activity. Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted.
doi:10.1186/1465-9921-14-128
PMCID: PMC3832683  PMID: 24237876
Physical activity; Activity monitor; COPD; Physical function; Body composition
22.  The influence of sensitisation to pollens and moulds on seasonal variations in asthma attacks 
The European Respiratory Journal  2013;42(4):935-945.
No large study has described the seasonal variation in asthma attacks in population-based asthmatics in whom sensitisation to allergen has been measured.
2637 young adults with asthma living in 15 countries reported the months in which they usually had attacks of asthma and had skin-prick tests performed. Differences in seasonal patterns by sensitisation status were assessed using generalised estimating equations.
Most young adults with asthma reported periods of the year when their asthma attacks were more common (range: 47% in Sweden to 86% in Spain). Seasonal variation in asthma was not modified by sensitisation to house dust mite or cat allergens. Asthmatics sensitised to grass, birch and Alternaria allergens had different seasonal patterns to those not sensitised to each allergen, with some geographical variation. In southern Europe, those sensitised to grass allergens were more likely to report attacks occurred in spring or summer than in winter (OR March/April 2.60, 95% CI 1.70–3.97; OR May/June 4.43, 95% CI 2.34–8.39) and smaller later peaks were observed in northern Europe (OR May/June 1.25, 95% CI 0.60–2.64; OR July/August 1.66, 95% CI 0.89–3.10). Asthmatics reporting hay fever but who were not sensitised to grass showed no seasonal variations.
Seasonal variations in asthma attacks in young adults are common and are different depending on sensitisation to outdoor, but not indoor, allergens.
Seasonal variation in asthma attacks is associated with sensitisation to pollens and moulds, but not indoor allergens http://ow.ly/nsuRS
doi:10.1183/09031936.00097412
PMCID: PMC3787817  PMID: 23471350
23.  Association of biomarkers of inflammation and cell adhesion with lung function in the elderly: a population-based study 
BMC Geriatrics  2013;13:82.
Background
Low lung function is associated with increased morbidity and mortality. It is therefore of interest to identify biomarkers that are associated with impaired lung function. The aim of the study was to analyse associations of biomarkers and combinations of biomarkers with lung function in an elderly general population.
Methods
Lung function (FEV1 and FVC) and a panel of 15 inflammatory markers from blood samples were analysed in 888 subjects aged 70 years. Biomarkers included cytokines, chemokines, adhesion molecules, C-reactive protein (CRP) and leukocyte count.
Results
Leukocyte count and CRP were independently associated with FEV1 after adjustments for other inflammatory markers, sex, BMI, current smoking and pack-years of smoking. In a similar model, leukocyte count and vascular cell adhesion protein 1 (VCAM-1) were the biomarkers that were significantly associated with FVC. Subjects that had both leukocyte count and CRP in the lowest tertile had a FEV1 that was 9% of predicted higher than subjects with leukocyte count and CRP in the highest tertile (103±16 vs. 94±21% of predicted, p=0.0002) (mean±SD). A difference of 8% of predicted in FVC was found between subjects with leukocyte count and VCAM-1 in the lowest and highest tertiles, respectively (106±18 vs. 98±19% of predicted, p=0.002).
Conclusion
Leucocyte count, CRP and VCAM-1 were found to relate to poorer lung function. A dose related association was found for the combination leukocyte count and CRP towards FEV1 and leukocyte and VCAM-1 towards FVC. This indicates that combination of two biomarkers yielded more information than assessing them one by one when analysing the association between systemic inflammation and lung function.
doi:10.1186/1471-2318-13-82
PMCID: PMC3750696  PMID: 23924044
Lung function; FEV1; FVC; COPD; Biomarkers; Gender
24.  Nocturnal sweating—a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort 
BMJ Open  2013;3(5):e002795.
Objectives
To estimate the prevalence and characteristics of frequent nocturnal sweating in obstructive sleep apnoea (OSA) patients compared with the general population and evaluate the possible changes with positive airway pressure (PAP) treatment. Nocturnal sweating can be very bothersome to the patient and bed partner.
Design
Case–control and longitudinal cohort study.
Setting
Landspitali—The National University Hospital, Iceland.
Participants
The Icelandic Sleep Apnea Cohort consisted of 822 untreated patients with OSA, referred for treatment with PAP. Of these, 700 patients were also assessed at a 2-year follow-up. The control group consisted of 703 randomly selected subjects from the general population.
Intervention
PAP therapy in the OSA cohort.
Main outcome measures
Subjective reporting of nocturnal sweating on a frequency scale of 1–5: (1) never or very seldom, (2) less than once a week, (3) once to twice a week, (4) 3–5 times a week and (5) every night or almost every night. Full PAP treatment was defined objectively as the use for ≥4 h/day and ≥5 days/week.
Results
Frequent nocturnal sweating (≥3× a week) was reported by 30.6% of male and 33.3% of female OSA patients compared with 9.3% of men and 12.4% of women in the general population (p<0.001). This difference remained significant after adjustment for demographic factors. Nocturnal sweating was related to younger age, cardiovascular disease, hypertension, sleepiness and insomnia symptoms. The prevalence of frequent nocturnal sweating decreased with full PAP treatment (from 33.2% to 11.5%, p<0.003 compared with the change in non-users).
Conclusions
The prevalence of frequent nocturnal sweating was threefold higher in untreated OSA patients than in the general population and decreased to general population levels with successful PAP therapy. Practitioners should consider the possibility of OSA in their patients who complain of nocturnal sweating.
doi:10.1136/bmjopen-2013-002795
PMCID: PMC3657640  PMID: 23674447
Hypertension < Cardiology
25.  Sensitization to pets is a major determinant of persistent asthma and new asthma onset in Sweden 
Upsala Journal of Medical Sciences  2013;118(2):111-121.
Introduction
Our knowledge about atopy as a longitudinal predictor of asthma is limited. The purpose of this study was to investigate the prognosis of asthma and risk factors for asthma onset, especially sensitization of specific allergens in a population sample.
Material and methods
A cohort responded to a respiratory questionnaire in 1990 and 2003. At baseline, 2,060 subjects who, in the screening questionnaire, reported respiratory symptoms and 482 controls were investigated with interviews, spirometry, and skin-prick test. A total of 721 asthmatics and 976 subjects without respiratory disease were clinically verified. At follow-up in 2003, 340 subjects with persistent asthma and 186 subjects with asthma remission were identified, while 76 subjects reported new asthma onset.
Results
Sensitization to pets and a high symptom score were significant determinants of persistent asthma (odds ratio (OR) 3.2 (95% CI 1.9–5.6) and 5.7 (2.5–13.3), respectively) and onset of asthma (OR 2.6 (1.1–6.0), and 1.7 (1.2–2.3)). A high self-reported responsiveness to airway irritants (OR 1.6 (1.1–2.2)), and more asthma medications (OR 2.0 (1.3–2.9)) were additional indicators of persistent asthma at the follow-up. Belonging to the older age group decreased the risk both of having persistent asthma and asthma onset.
Discussion
Asthmatics sensitized to pets have a more severe outcome than asthmatics not sensitized to pets. Sensitization to pets was also a strong predictor for onset of asthma. Special attention should be given to asthmatics who report having severe symptoms and problems with airway irritants as such patients are more likely to have persistent problems.
doi:10.3109/03009734.2012.752772
PMCID: PMC3633326  PMID: 23339512
Allergens; allergy tests; asthma; longitudinal study; prognosis; skin-prick test

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