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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  The Impact of Cigarette Smoking on Asthma: A Population-Based International Cohort Study 
Background
The prevalence rates of smoking in subjects with asthma have frequently been reported as similar to those in the general population; however, available data are not up-to-date. There is only limited and somewhat conflicting information on the long-term effects of smoking on health outcomes among population-based cohorts of subjects with asthma. We aimed to investigate changes in smoking habits and their effects on forced expiratory volume in 1 s (FEV1) in subjects with asthma in comparison with the rest of the population, focusing on the healthy smoker effect.
Methods
We studied 9,092 subjects without asthma and 1,045 with asthma at baseline who participated in both the European Community Respiratory Health Survey I (20–44 years old in 1991–1993) and II (1999–2002).
Results
At follow-up, smoking was significantly less frequent among subjects with asthma than in the rest of the population (26 vs. 31%; p < 0.001). Subjects with asthma who were already ex-smokers at the beginning of the follow-up in the 1990s had the highest mean asthma score (number of reported asthma-like symptoms, range 0–5), probably as a result of the healthy smoker effect (2.80 vs. 2.44 in never smokers, 2.19 in quitters and 2.24 in smokers; p < 0.001). The influence of smoking on FEV1 decline did not depend on asthma status. Smokers had the highest proportion of subjects with chronic cough/phlegm (p < 0.01).
Conclusion
One out of 4 subjects with asthma continues smoking and reports significantly more chronic cough and phlegm than never smokers and ex-smokers. This stresses the importance of smoking cessation in all patients with asthma, even in those with less severe asthma.
doi:10.1159/000330900
PMCID: PMC3696371  PMID: 22286571
Asthma; Cigarette smoking; Epidemiology
13.  Insomnia in untreated sleep apnea patients compared to controls 
Journal of Sleep Research  2011;21(2):131-138.
Insomnia and obstructive sleep apnea (OSA) often co-exist, but the nature of their relationship is unclear. The aims of this study were to compare the prevalence of initial and middle insomnia between OSA patients and controls from the general population as well as to study the influence of insomnia on sleepiness and quality of life in OSA patients.
Two groups were compared, untreated OSA patients (n=824) and controls ≥ 40 years from the general population in Iceland (n=762). All subjects answered the same questionnaires on health and sleep and OSA patients underwent a sleep study. Altogether, 53% of controls were males compared to 81% of OSA patients.
Difficulties maintaining sleep (DMS) were more common among men and women with OSA compared to the general population (52 vs. 31% and 62 vs. 31%, respectively, p<0.0001). Difficulties initiating sleep (DIS) and DIS+DMS were more common among women with OSA compared to women without OSA. OSA patients with DMS were sleepier than patients without DMS (Epworth Sleepiness Scale: 12.2 vs. 10.9, <0.001) while both DMS and DIS were related to lower quality of life in OSA patients as measured by the Short Form 12 (physical score 39 vs. 42 and mental score 36 vs. 41, p<0.001). DIS and DMS were not related to OSA severity.
Insomnia is common among OSA patients and has a negative influence on quality of life and sleepiness in this patient group. It is relevant to screen for insomnia among OSA patients and treat both conditions when they co-occur.
doi:10.1111/j.1365-2869.2011.00972.x
PMCID: PMC3258454  PMID: 21988168
Insomnia; sleep apnea; risk factors; population sample
14.  Higher Risk of Wheeze in Female than Male Smokers. Results from the Swedish GA2LEN Study 
PLoS ONE  2013;8(1):e54137.
Background
Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders.
Methods
In 2008 the Global Allergy and Asthma European Network (GA2LEN) questionnaire was mailed to 45.000 Swedes (age 16–75 years), and 26.851 (60%) participated. “Any wheeze”: any wheeze during the last 12 months. “Asthmatic wheeze”: wheeze with breathlessness apart from colds.
Results
Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56–2.19) vs. 1.60 (1.30–1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age ≥53 years.
Discussion
In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.
doi:10.1371/journal.pone.0054137
PMCID: PMC3554721  PMID: 23357876
15.  Clinical COPD Questionnaire score (CCQ) and mortality 
Introduction
The Clinical COPD Questionnaire (CCQ) measures health status and can be used to assess health-related quality of life (HRQL). We investigated whether CCQ is also associated with mortality.
Methods
Some 1111 Swedish primary and secondary care chronic obstructive pulmonary disease (COPD) patients were randomly selected. Information from questionnaires and medical record review were obtained in 970 patients. The Swedish Board of Health and Welfare provided mortality data. Cox regression estimated survival, with adjustment for age, sex, heart disease, and lung function (for a subset with spirometry data, n = 530). Age and sex-standardized mortality ratios were calculated.
Results
Over 5 years, 220 patients (22.7%) died. Mortality risk was higher for mean CCQ ≥ 3 (37.8% died) compared with mean CCQ < 1 (11.4%), producing an adjusted hazard ratio (HR) (and 95% confidence interval [CI]) of 3.13 (1.98 to 4.95). After further adjustment for 1 second forced expiratory volume (expressed as percent of the European Community for Steel and Coal reference values ), the association remained (HR 2.94 [1.42 to 6.10]). The mortality risk was higher than in the general population, with standardized mortality ratio (and 95% CI) of 1.87 (1.18 to 2.80) with CCQ < 1, increasing to 6.05 (4.94 to 7.44) with CCQ ≥ 3.
Conclusion
CCQ is predictive of mortality in COPD patients. As HRQL and mortality are both important clinical endpoints, CCQ could be used to target interventions.
doi:10.2147/COPD.S38119
PMCID: PMC3532021  PMID: 23277739
health status; Health Related Quality of Life (HRQL); Standardized Mortality Ratios (SMR)
16.  Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function 
Hancock, Dana B. | Artigas, María Soler | Gharib, Sina A. | Henry, Amanda | Manichaikul, Ani | Ramasamy, Adaikalavan | Loth, Daan W. | Imboden, Medea | Koch, Beate | McArdle, Wendy L. | Smith, Albert V. | Smolonska, Joanna | Sood, Akshay | Tang, Wenbo | Wilk, Jemma B. | Zhai, Guangju | Zhao, Jing Hua | Aschard, Hugues | Burkart, Kristin M. | Curjuric, Ivan | Eijgelsheim, Mark | Elliott, Paul | Gu, Xiangjun | Harris, Tamara B. | Janson, Christer | Homuth, Georg | Hysi, Pirro G. | Liu, Jason Z. | Loehr, Laura R. | Lohman, Kurt | Loos, Ruth J. F. | Manning, Alisa K. | Marciante, Kristin D. | Obeidat, Ma'en | Postma, Dirkje S. | Aldrich, Melinda C. | Brusselle, Guy G. | Chen, Ting-hsu | Eiriksdottir, Gudny | Franceschini, Nora | Heinrich, Joachim | Rotter, Jerome I. | Wijmenga, Cisca | Williams, O. Dale | Bentley, Amy R. | Hofman, Albert | Laurie, Cathy C. | Lumley, Thomas | Morrison, Alanna C. | Joubert, Bonnie R. | Rivadeneira, Fernando | Couper, David J. | Kritchevsky, Stephen B. | Liu, Yongmei | Wjst, Matthias | Wain, Louise V. | Vonk, Judith M. | Uitterlinden, André G. | Rochat, Thierry | Rich, Stephen S. | Psaty, Bruce M. | O'Connor, George T. | North, Kari E. | Mirel, Daniel B. | Meibohm, Bernd | Launer, Lenore J. | Khaw, Kay-Tee | Hartikainen, Anna-Liisa | Hammond, Christopher J. | Gläser, Sven | Marchini, Jonathan | Kraft, Peter | Wareham, Nicholas J. | Völzke, Henry | Stricker, Bruno H. C. | Spector, Timothy D. | Probst-Hensch, Nicole M. | Jarvis, Deborah | Jarvelin, Marjo-Riitta | Heckbert, Susan R. | Gudnason, Vilmundur | Boezen, H. Marike | Barr, R. Graham | Cassano, Patricia A. | Strachan, David P. | Fornage, Myriam | Hall, Ian P. | Dupuis, Josée | Tobin, Martin D. | London, Stephanie J.
PLoS Genetics  2012;8(12):e1003098.
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
Author Summary
Measures of pulmonary function provide important clinical tools for evaluating lung disease and its progression. Genome-wide association studies have identified numerous genetic risk factors for pulmonary function but have not considered interaction with cigarette smoking, which has consistently been shown to adversely impact pulmonary function. In over 50,000 study participants of European descent, we applied a recently developed joint meta-analysis method to simultaneously test associations of gene and gene-by-smoking interactions in relation to two major clinical measures of pulmonary function. Using this joint method to incorporate genetic main effects plus gene-by-smoking interaction, we identified three novel gene regions not previously related to pulmonary function: (1) DNER, (2) HLA-DQB1 and HLA-DQA2, and (3) KCNJ2 and SOX9. Expression analyses in human lung tissue from ours or prior studies indicate that these regions contain genes that are plausibly involved in pulmonary function. This work highlights the utility of employing novel methods for incorporating environmental interaction in genome-wide association studies to identify novel genetic regions.
doi:10.1371/journal.pgen.1003098
PMCID: PMC3527213  PMID: 23284291
17.  Occupational Exposure and New-onset Asthma in a Population-based Study in Northern Europe (RHINE) 
Annals of Occupational Hygiene  2012;57(4):482-492.
Objectives:
In a large population-based study among adults in northern Europe the relation between occupational exposure and new-onset asthma was studied.
Methods:
The study comprised 13 284 subjects born between 1945 and 1973, who answered a questionnaire 1989–1992 and again 1999–2001. Asthma was defined as ‘Asthma diagnosed by a physician’ with reported year of diagnose. Hazard ratios (HR), for new-onset adult asthma during 1980–2000, were calculated using a modified job-exposure matrix as well as high-risk occupations in Cox regression models. The analyses were made separately for men and women and were also stratified for atopy.
Results:
During the observation period there were 429 subjects with new-onset asthma with an asthma incidence of 1.3 cases per 1000 person-years for men and 2.4 for women. A significant increase in new-onset asthma was seen for men exposed to plant-associated antigens (HR = 3.6; 95% CI [confidence interval] = 1.4–9.0), epoxy (HR = 2.4; 95% CI = 1.3–4.5), diisocyanates (HR = 2.1; 95% CI = 1.2–3.7) and accidental peak exposures to irritants (HR = 2.4; 95% CI = 1.3–4.7). Both men and women exposed to cleaning agents had an increased asthma risk. When stratifying for atopy an increased asthma risk were seen in non-atopic men exposed to acrylates (HR = 3.3; 95% CI = 1.4–7.5), epoxy compounds (HR = 3.6; 95% CI = 1.6–7.9), diisocyanates and accidental peak exposures to irritants (HR = 3.0; 95% CI = 1.2–7.2). Population attributable risk for occupational asthma was 14% for men and 7% for women.
Conclusions:
This population-based study showed that men exposed to epoxy, diisocyanates and acrylates had an increased risk of new-onset asthma. Non-atopics seemed to be at higher risk than atopics, except for exposure to high molecular weight agents. Increased asthma risks among cleaners, spray painters, plumbers, and hairdressers were confirmed.
doi:10.1093/annhyg/mes083
PMCID: PMC3622438  PMID: 23204511
Atopics and non-atopics; high molecular weight agent; high-risk occupations; irritating agents;  job-exposure matrix; low molecualr weight agent; occupational asthma;  population attributable risk
18.  Can spirometric norms be set using pre- or post- bronchodilator test results in older people? 
Respiratory Research  2012;13(1):102.
Background
Chronic Obstructive Pulmonary Disease (COPD) is defined by post-bronchodilator spirometry. Data on “normal values” come predominantly from pre-bronchodilator spirometry. The effects of this on diagnosis are unknown.
Methods
Lower limits of normal (LLN) were estimated from “normal” participants in the Burden of Obstructive Lung Disease (BOLD) programme. Values separately derived using pre- and post-bronchodilator spirometry were compared. Sensitivity and specificity of criteria derived from pre-bronchodilator spirometry and pre-bronchodilator spirometry adjusted by a constant were assessed in the remaining population. The “gold standard” was the LLN for the post-bronchodilator spirometry in the “normal population”. For FEV1/FVC, sensitivity and specificity of criteria were also assessed when a fixed value of < 70% was used rather than LLN.
Results
Of 6,600 participants with full data, 1,354 were defined as “normal”. Mean differences between pre- and post- bronchodilator measurements were small and the Bland-Altman plots showed no association between difference and mean value. Compared with using the gold standard, however, tests using pre-bronchodilator spirometry had a sensitivity and specificity of detecting a low FEV1 of 78.4% and 100%, a low FVC of 99.8% and 99.1% and a low FEV1/FVC ratio of 65% and 100%. Adjusting this by a constant improved the sensitivity without substantially altering the specificity for FEV1 (99%, 99.8%), FVC (97.4%, 99.9%) and FEV1/FVC (98.7%, 99.5%).
Conclusions
Using pre-bronchodilator spirometry to derive norms for lung function reduces sensitivity compared to a post-bronchodilator gold standard. Adjustment of these values by a constant can improve validity of the test.
doi:10.1186/1465-9921-13-102
PMCID: PMC3570335  PMID: 23157675
Normal values; BOLD study; European population
19.  Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA 
PLoS ONE  2012;7(9):e44008.
Rationale
Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.
Objectives
To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.
Methods
The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.
Main Results
We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.
Conclusions
Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
doi:10.1371/journal.pone.0044008
PMCID: PMC3461045  PMID: 23028483
20.  Long-term survival in patients hospitalized for chronic obstructive pulmonary disease: a prospective observational study in the Nordic countries 
Background and aim
Mortality rate is high in patients with chronic obstructive pulmonary disease (COPD). Our aim was to investigate long-term mortality and associated risk factors in COPD patients previously hospitalized for a COPD exacerbation.
Methods
A total of 256 patients from the Nordic countries were followed for 8.7 ± 0.4 years after the index hospitalization in 2000–2001. Prior to discharge, the St George’s Respiratory Questionnaire was administered and data on therapy and comorbidities were obtained. Information on long-term mortality was obtained from national registries in each of the Nordic countries.
Results
In total, 202 patients (79%) died during the follow up period, whereas 54 (21%) were still alive. Primary cause of death was respiratory (n = 116), cardiovascular (n = 43), malignancy (n = 28), other (n = 10), or unknown (n = 5). Mortality was related to older age, with a hazard risk ratio (HRR) of 1.75 per 10 years, lower forced expiratory volume in 1 second (FEV1) (HRR 0.80), body mass index (BMI) <20 kg/m2 (HRR 3.21), and diabetes (HRR 3.02). Older age, lower BMI, and diabetes were related to both respiratory and cardiovascular mortality. An association was also found between lower FEV1 and respiratory mortality, whereas mortality was not significantly associated with therapy, anxiety, or depression.
Conclusion
Almost four out of five patients died within 9 years following an admission for COPD exacerbation. Increased mortality was associated with older age, lower lung function, low BMI, and diabetes, and these factors should be taken into account when making clinical decisions about patients who have been admitted to hospital for a COPD exacerbation.
doi:10.2147/COPD.S34466
PMCID: PMC3459657  PMID: 23055707
acute exacerbation; long-term mortality; co-morbidity; diabetes; lung function
21.  Lung Function before and Two Days after Open-Heart Surgery 
Reduced lung volumes and atelectasis are common after open-heart surgery, and pronounced restrictive lung volume impairment has been found. The aim of this study was to investigate factors influencing lung volumes on the second postoperative day. Open-heart surgery patients (n = 107, 68 yrs, 80% male) performed spirometry both before surgery and on the second postoperative day. The factors influencing postoperative lung volumes and decrease in lung volumes were investigated with univariate and multivariate analyses. Associations between pain (measured by numeric rating scale) and decrease in postoperative lung volumes were calculated with Spearman rank correlation test. Lung volumes decreased by 50% and were less than 40% of the predictive values postoperatively. Patients with BMI >25 had lower postoperative inspiratory capacity (IC) (33 ± 14% pred.) than normal-weight patients (39 ± 15% pred.), (P = 0.04). More pain during mobilisation was associated with higher decreases in postoperative lung volumes (VC: r = 0.33, P = 0.001; FEV1: r = 0.35, P ≤ 0.0001; IC: r = 0.25, P = 0.01). Patients with high BMI are a risk group for decreased postoperative lung volumes and should therefore receive extra attention during postoperative care. As pain is related to a larger decrease in postoperative lung volumes, optimal pain relief for the patients should be identified.
doi:10.1155/2012/291628
PMCID: PMC3423658  PMID: 22924127
22.  Bronchial Responsiveness Is Related to Increased Exhaled NO (FENO) in Non-Smokers and Decreased FENO in Smokers 
PLoS ONE  2012;7(4):e35725.
Rationale
Both atopy and smoking are known to be associated with increased bronchial responsiveness. Fraction of nitric oxide (NO) in the exhaled air (FENO), a marker of airways inflammation, is decreased by smoking and increased by atopy. NO has also a physiological bronchodilating and bronchoprotective role.
Objectives
To investigate how the relation between FENO and bronchial responsiveness is modulated by atopy and smoking habits.
Methods
Exhaled NO measurements and methacholine challenge were performed in 468 subjects from the random sample of three European Community Respiratory Health Survey II centers: Turin (Italy), Gothenburg and Uppsala (both Sweden). Atopy status was defined by using specific IgE measurements while smoking status was questionnaire-assessed.
Main Results
Increased bronchial responsiveness was associated with increased FENO levels in non-smokers (p = 0.02) and decreased FENO levels in current smokers (p = 0.03). The negative association between bronchial responsiveness and FENO was seen only in the group smoking less <10 cigarettes/day (p = 0.008). Increased bronchial responsiveness was associated with increased FENO in atopic subjects (p = 0.04) while no significant association was found in non-atopic participants. The reported interaction between FENO and smoking and atopy, respectively were maintained after adjusting for possible confounders (p-values<0.05).
Conclusions
The present study highlights the interactions of the relationship between FENO and bronchial responsiveness with smoking and atopy, suggesting different mechanisms behind atopy- and smoking-related increases of bronchial responsiveness.
doi:10.1371/journal.pone.0035725
PMCID: PMC3338521  PMID: 22563393
23.  Hypertension, Systemic Inflammation and Body Weight in Relation to Lung Function Impairment—An Epidemiological Study 
COPD  2009;6(4):250-255.
Recent reports on the simultaneous occurrence of systemic inflammation and airflow obstruction are usually based on a highly selective patient population, but their importance warrants further evaluation in the general population. The objectives were to study the interrelationship between airflow obstruction, smoking, hypertension, obesity and CRP as a marker of systemic inflammation in a randomly selected sample of the general Icelandic population (n = 939). This study comprised 758 randomly selected men and women 40 years and older living in Reykjavik, Iceland, and who were participating in the Burden of Obstructive Lung Disease (BOLD) study (81% response rate). In addition to the BOLD protocol, which included post-bronchodilator spirometry, they answered questions about general health and medication. Serum samples were taken for measurement of C-reactive protein (CRP). In the sample—245 individuals (33%) reported having hypertension. Subjects with hypertension were older, had a higher BMI and higher CRP levels. Subjects with hypertension had lower values of FEV1 than predicted (89.9 ± 18.5 vs. 94.5 ± 14.4%) (p < 0.001) and FVC (92.2 ± 15.1 vs. 95.3 ± 12.3%) (p = 0.002). These differences remained significant after adjusting for age, BMI, CRP and smoking. Hypertension and CRP levels above the median were both independently and additively associated with lower FEV1 and FVC. In addition a lower FVC% was also associated with a higher BMI (> 30 mg/m2). Use of betablocking antihypertensives was not related to lung function. Hypertension, BMI and systemic inflammation affect lung function independently of each other. All three variables have a negative effect on FVC, while hypertension and high CRP were independently associated with impaired FEV1.
PMCID: PMC3334274  PMID: 19811383
Airflow obstruction; hypertension; obesity; systemic inflammation; cytokines
24.  Chronic airflow obstruction and markers of systemic inflammation: Results from the BOLD study in Iceland 
Respiratory medicine  2009;103(10):1548-1553.
Summary
Background
Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible chronic airflow obstruction and by an accelerated decline in lung function. Elevated circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both markers of systemic inflammation, have been found in COPD. Their possible associations with chronic airflow obstruction have mostly been evaluated in highly selected patient samples. Our objective was to evaluate the association between postbronchodilator lung function CRP and IL-6 in a randomly selected sample of the Icelandic population, 40 years and older, while adjusting for gender, age, smoking, and body weight.
Methods
Serum CRP and IL-6 values were measured among participants in the Burden of Obstructive Lung Disease (BOLD) study.
Results
Of the 938 subjects invited a total of 403 men and 355 women participated (response rate 81%) in the study. Their mean age (±SD) was 57.7 (±12.7) years. Both CRP and IL-6 were independently related to lower FEV1 and FVC values. Individuals in the highest quartiles of CRP and IL-6 had a 7.5% and 3.9%, respectively, lower FEV1% than predicted after adjustment for smoking, age, and body weight. High CRP levels were more strongly related to lower FEV1 levels in men (−11.4%) than in women ( −0.4%).
Conclusions
In a random population-based sample both CRP and IL-6 were significantly related to lower spirometric values. The association with CRP was stronger in men than in women. This finding underscores the possible importance of systemic inflammation in irreversible airflow limitation.
doi:10.1016/j.rmed.2009.04.005
PMCID: PMC3334275  PMID: 19427181
Airflow obstruction; Systemic inflammation; Cytokines; C-reactive protein; IL-6
25.  Transient receptor potential genes, smoking, occupational exposures and cough in adults 
Respiratory Research  2012;13(1):26.
Background
Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough.
Methods
Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model.
Results
Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05).
Conclusions
TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures.
doi:10.1186/1465-9921-13-26
PMCID: PMC3342106  PMID: 22443337
Asthma; Gene-environment interaction; Irritant exposure; Smoking; TRP channel

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