Exogenous female sex steroid hormones and new-onset asthma in women: a matched case-control study.

BACKGROUND: Evidence on the role of exogenous female sex steroid hormones in asthma development in women remains conflicting. We sought to quantify the potential causal role of hormonal contraceptives and menopausal hormone therapy (MHT) in the development of asthma in women. METHODS: We conducted a matched case-control study based on the West Sweden Asthma Study, nested in a representative cohort of 15,003 women aged 16-75 years, with 8-year follow-up (2008-2016). Data were analyzed using Frequentist and Bayesian conditional logistic regression models. RESULTS: We included 114 cases and 717 controls. In Frequentist analysis, the odds ratio (OR) for new-onset asthma with ever use of hormonal contraceptives was 2.13 (95% confidence interval [CI] 1.03-4.38). Subgroup analyses showed that the OR increased consistently with older baseline age. The OR for new-onset asthma with ever MHT use among menopausal women was 1.17 (95% CI 0.49-2.82). In Bayesian analysis, the ORs for ever use of hormonal contraceptives and MHT were, respectively, 1.11 (95% posterior interval [PI] 0.79-1.55) and 1.18 (95% PI 0.92-1.52). The respective probability of each OR being larger than 1 was 72.3% and 90.6%. CONCLUSIONS: Although use of hormonal contraceptives was associated with an increased risk of asthma, this may be explained by selection of women by baseline asthma status, given the upward trend in the effect estimate with older age. This indicates that use of hormonal contraceptives may in fact decrease asthma risk in women. Use of MHT may increase asthma risk in menopausal women.

Sensitization to molecular dog allergens in an adult population: Results from the West Sweden Asthma Study.

BACKGROUND: As the prevalence of dog allergy rises, component resolved diagnosis might improve the diagnosis, understanding of the clinical outcomes and the effectiveness of immunotherapy. Considering the paucity of data in adults, the current study characterized the patterns of sensitization to dog molecular allergens in an adult population. METHODS: Data were derived from the West Sweden Asthma Study, a population-based and representative sample of adults from western Sweden. Of the 2006 subjects clinically examined, 313 participants sensitized to whole dog allergen extract were measured for specific immunoglobulin E (sIgE) levels to Can f 1, Can f 2, Can f 3, Can f 4, Can f 5 and Can f 6 using ImmunoCAP™. Polysensitization was defined as sensitization to ≥3 components. Overlapping sensitization was defined as having concomitant sensitization to at least two dog molecular allergen families (lipocalin, albumin or prostatic kallikrein). RESULTS: Of 313, 218 (70%) subjects tested positive to at least one dog allergen component. Sensitization to Can f 1 (43%) was the most common, followed by Can f 5 (33%) among molecular allergens, while sensitization to lipocalins (56%) was the most common among component families. Polysensitization was found in 22% of all participants and was more common in participants with than in those without asthma. Subjects with asthma were less likely to be monosensitized to Can f 5 than those without asthma. Subjects with asthma had higher IgE levels of Can f 3, Can f 4 and Can f 6 than those without asthma. Overlapping sensitizations also differed between those with asthma and allergic rhinitis and those without. CONCLUSION: Increased knowledge about the sensitization patterns of dog allergen components can aid in defining their role in asthma and rhinitis. In complex clinical cases of dog allergy, a detailed analysis of dog allergen components can provide additional information on the nature of sensitization.

Level of education and asthma control in adult-onset asthma.

OBJECTIVE: Education in itself and as a proxy for socioeconomic status, may influence asthma control, but remains poorly studied in adult-onset asthma. Our aim was to study the association between the level of education and asthma control in adult-onset asthma. METHODS: Subjects with current asthma with onset >15 years were examined within the Obstructive Lung Disease in Northern Sweden study (OLIN, n = 593), Seinäjoki Adult Asthma Study (SAAS, n = 200), and West Sweden Asthma Study (WSAS, n = 301) in 2009-2014 in a cross-sectional setting. Educational level was classified as primary, secondary and tertiary. Uncontrolled asthma was defined as Asthma Control Test (ACT) score ≤19. Altogether, 896 subjects with complete data on ACT and education were included (OLIN n = 511, SAAS n = 200 and WSAS n = 185). RESULTS: In each cohort and in pooled data of all cohorts, median ACT score was lower among those with primary education than in those with secondary and tertiary education. Uncontrolled asthma was most common among those with primary education, especially among daily ICS users (42.6% primary, 28.6% secondary and 24.2% tertiary; p = 0.001). In adjusted analysis, primary education was associated with uncontrolled asthma in daily ICS users (OR 1.92, 95% CI 1.15-3.20). When stratified by atopy, the association between primary education and uncontrolled asthma was seen in non-atopic (OR 3.42, 95% CI 1.30-8.96) but not in atopic subjects. CONCLUSIONS: In high-income Nordic countries, lower educational level was a risk factor for uncontrolled asthma in subjects with adult-onset asthma. Educational level should be considered in the management of adult-onset asthma.

Menopausal hormone therapy and women's health: An umbrella review.

BACKGROUND: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). CONCLUSIONS: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Multimorbidity in asthma, association with allergy, inflammatory markers and symptom burden, results from the Swedish GA2 LEN study.

BACKGROUND: Asthma is common worldwide and a large part of subjects with asthma have concomitant allergic multimorbidity in the form of rhinitis and/or eczema. OBJECTIVE: The aim of this study is to investigate whether the presence of allergic multimorbidity in asthma relates to allergic sensitization, allergic and respiratory symptoms, quality of life, inflammatory markers, lung function, use of medication and background factors. METHODS: A total of 437 asthmatics from the (GA2 LEN) cross-sectional survey in Sweden were grouped depending on the presence of rhinitis and/or eczema. The impact of allergic multimorbidity was assessed in terms of allergic sensitization, allergic and respiratory symptoms, quality of life, type-2 inflammatory markers (exhaled nitric oxide, eosinophil activation markers, periostin), lung function, use of medication and background factors. RESULTS: Subjects with asthma, rhinitis and eczema were more likely to be sensitized to seasonal allergens (67% vs 32%, P < .001), food allergens (54% vs 18%, P < .001) and to have a higher degree of sensitization than subjects with only asthma (23% vs 10%, P < .001). Subjects with allergic multimorbidity more often had allergic reactions to food (28% vs 10%, P = .002), more respiratory symptoms and anxiety/depression (40% vs, 14%, P < .001) than subjects with only asthma, despite having similar levels of type 2 inflammatory markers. Individuals with allergic multimorbidity were more likely to be diagnosed with asthma before the age of 12 (48% vs 27%, P = .016) and to have maternal heredity for allergy (53% vs 33%, P = .011) than subjects with only asthma. CONCLUSION AND CLINICAL RELEVANCE: Asthmatics with allergic multimorbidity are more likely to be sensitized to seasonal aeroallergens, food allergens and they have a higher degree of sensitization compared with those with only asthma. Allergic multimorbidity is associated with respiratory and allergy symptoms, anxiety and/or depression.

Decreased COPD prevalence in Sweden after decades of decrease in smoking.

BACKGROUND: COPD has increased in prevalence worldwide over several decades until the first decade after the millennium shift. Evidence from a few recent population studies indicate that the prevalence may be levelling or even decreasing in some areas in Europe. Since the 1970s, a substantial and ongoing decrease in smoking prevalence has been observed in several European countries including Sweden. The aim of the current study was to estimate the prevalence, characteristics and risk factors for COPD in the Swedish general population. A further aim was to estimate the prevalence trend of COPD in Northern Sweden from 1994 to 2009. METHODS: Two large random population samples were invited to spirometry with bronchodilator testing and structured interviews in 2009-2012, one in south-western and one in northern Sweden, n = 1839 participants in total. The results from northern Sweden were compared to a study performed 15 years earlier in the same area and age-span. The diagnosis of COPD required both chronic airway obstruction (CAO) and the presence of respiratory symptoms, in line with the GOLD documents since 2017. CAO was defined as post-bronchodilator FEV1/FVC < 0.70, with sensitivity analyses based on the FEV1/FVC < lower limit of normal (LLN) criterion. RESULTS: Based on the fixed ratio definition, the prevalence of COPD was 7.0% (men 8.3%; women 5.8%) in 2009-2012. The prevalence of moderate to severe (GOLD ≥ 2) COPD was 3.5%. The LLN based results were about 30% lower. Smoking, occupational exposures, and older age were risk factors for COPD, whereof smoking was the most dominating risk factor. In northern Sweden the prevalence of COPD, particularly moderate to severe COPD, decreased significantly from 1994 to 2009, and the decrease followed a decrease in smoking. CONCLUSIONS: The prevalence of COPD has decreased in Sweden, and the prevalence of moderate to severe COPD was particularly low. The decrease follows a major decrease in smoking prevalence over several decades, but smoking remained the dominating risk factor for COPD.

Age-specific incidence of allergic and non-allergic asthma.

BACKGROUND: Onset of allergic asthma has a strong association with childhood but only a few studies have analyzed incidence of asthma from childhood to late adulthood in relation to allergy. The purpose of the study was to assess age-specific incidence of allergic and non-allergic asthma. METHODS: Questionnaires were sent to 8000 randomly selected recipients aged 20-69 years in Finland in 2016. The response rate was 52.3% (n = 4173). The questionnaire included questions on e.g. atopic status, asthma and age at asthma diagnosis. Asthma was classified allergic if also a physician-diagnosed allergic rhinitis was reported. RESULTS: The prevalence of physician-diagnosed asthma and allergic rhinitis were 11.2 and 17.8%, respectively. Of the 445 responders with physician-diagnosed asthma, 52% were classified as allergic and 48% as non-allergic. Median ages at diagnosis of allergic and non-allergic asthma were 19 and 35 years, respectively. Among subjects with asthma diagnosis at ages 0-9, 10-19, 20-29, 30-39, 40-49, 50-59 and 60-69 years, 70, 62, 58, 53, 38, 19 and 33%, respectively, were allergic. For non-allergic asthma, the incidence rate was lowest in children and young adults (0.7/1000/year). It increased after middle age and was highest in older age groups (2.4/1000/year in 50-59 years old). CONCLUSIONS: The incidence of allergic asthma is highest in early childhood and steadily decreases with advancing age, while the incidence of non-allergic asthma is low until it peaks in late adulthood. After approximately 40 years of age, most of the new cases of asthma are non-allergic.

Characterization of sensitization to furry animal allergen components in an adult population.

BACKGROUND: There are paucity of data on sensitization to furry animal allergen components in adults. Furry animals are major sensitizers and contributors to asthma burden in northern Europe and North America. OBJECTIVE: To characterize sensitization patterns to furry animal allergen components in Swedish adults. METHODS: Based on the West Sweden Asthma Study, a random population (n = 1103) and an asthma sample (n = 769) were tested for allergen sensitization using Phadiatop® . Those with IgE ≥ 0.35 kUA /L were tested for cat (Fel d 1, 2, and 4), dog (Can f 1, 2, 3, and 5), and horse (Equ c 1) allergen component sensitization. We defined allergen component poly-sensitization patterns, identified data-driven sensitization clusters, described component sensitization overlaps, and assessed determinants of sensitization patterns. RESULTS: The prevalence of allergen component sensitization ranged from 0.8% for Fel d 2 and Can f 3 to 8.9% for Fel d 1. The most common dog component was Can f 5 (3.6%); 2.1% were sensitized to Equ c 1. Those sensitized to Fel d 2 and Fel d 4 were commonly sensitized to Fel d 1. The most common dog component overlap was between Can f 1/Can f 2 and Can f 5. Mono-sensitization was 5.6%, double sensitization 1.5% and poly-sensitization 2.1%. Sensitization was always higher in the asthma than in the random sample. Three sensitization clusters were derived, namely non-sensitized (90% in random vs 66% in asthma sample); Fel d 1-driven sensitized (7% vs 19%); and multi-sensitized (3% vs 15%). Key determinants of sensitization were gender, age, raised on a farm, family history of allergy or asthma, smoking, and occupational exposure to dust or fumes. CONCLUSIONS & CLINICAL RELEVANCE: Fel d 1 and Can f 5 are the most common cat and dog components sensitization in this adult Swedish population. Mono-sensitization is more common than poly-sensitization. This detailed characterization highlights the current distribution of furry animal allergen components in Swedish adults, and their impact on clinical outcomes of asthma will be further explored.

Severe asthma-A population study perspective.

BACKGROUND: Severe asthma is a considerable challenge for patients, health-care professionals and society. Few studies have estimated the prevalence of severe asthma according to modern definitions of which none based on a population study. OBJECTIVE: To describe characteristics and estimate the prevalence of severe asthma in a large adult population-based asthma cohort followed for 10-28 years. METHODS: N = 1006 subjects with asthma participated in a follow-up during 2012-14, when 830 (mean age 59 years, 56% women) still had current asthma. Severe asthma was defined according to three internationally well-known criteria: the ATS workshop definition from 2000 used in the US Severe Asthma Research Programme (SARP), the 2014 ATS/ERS Task force definition and the GINA 2017. All subjects with severe asthma according to any of these criteria were undergoing respiratory specialist care and were also contacted by telephone to verify treatment adherence. RESULTS: The prevalence of severe asthma according to the three definitions was 3.6% (US SARP), 4.8% (ERS/ATS Taskforce), and 6.1% (GINA) among subjects with current asthma. Although all were using high ICS doses and other maintenance treatment, >90% did not have controlled asthma according to the asthma control test. Severe asthma was related to age >50 years, nasal polyposis, impaired lung function, sensitization to aspergillus, and tended to be more common in women. Further, neutrophils in blood significantly discriminated severe asthma from other asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Severe asthma differed significantly from other asthma in terms of demographic, clinical and inflammatory characteristics, results suggesting possibilities for improved treatment regimens of severe asthma. The prevalence of severe asthma in this asthma cohort was 4%-6%, corresponding to approximately 0.5% of the general population.

Changes in the prevalence of asthma and respiratory symptoms in western Sweden between 2008 and 2016.

BACKGROUND: Asthma is a common chronic inflammatory disease of the airways, with a noticeable increase in prevalence during the second half of the 20th century. Recent studies assessing the prevalence trends among adults have been inconsistent. We investigated the changes in the prevalence of asthma, respiratory symptoms, and risk factors between 2008 and 2016 in western Sweden. METHODS: The West Sweden Asthma Study (WSAS) is a population-based study which started in 2008 (WSAS I) and then repeated in 2016 (WSAS II) in western Sweden. Randomly selected individuals aged 16-75 years (N = 18 087 in 2008 and N = 24 534 in 2016) completed a questionnaire regarding obstructive lung diseases, respiratory symptoms, potential risk factors, and also questions from the GA2 LEN survey. RESULTS: The prevalence of reported ever asthma, physician-diagnosed asthma, use of asthma medication, and current asthma increased significantly from 9.6% to 11%, 8.3% to 10%, 8.6% to 9.8%, and 8.1% to 9.1%, respectively, between 2008 and 2016. There were also increases in the prevalence of respiratory symptoms during the same period. The greatest increase occurred in young adults aged 16-25 years. Female gender, allergic rhinitis, obesity, and family history of asthma remained the strongest risk factors for asthma in 2016 as it was in 2008. CONCLUSION: There were moderate increases in asthma and respiratory symptoms in adults in western Sweden between 2008 and 2016, the greatest increase occurring in younger adults. The potential risk factors for asthma remained the same during the study period.

High prevalence of severe asthma in a large random population study.

BACKGROUND: The prevalence of asthma severity is not well described at a population level. OBJECTIVE: We sought to determine the prevalence of phenotypic signs of asthma severity among asthmatic patients in a general population and to describe risk factors for asthma severity. METHODS: We performed an epidemiologic study conducted between 2008 and 2012 (West Sweden Asthma Study). A postal questionnaire was sent to a random population (n = 30,000) in west Sweden, with 18,087 responses. A total of 2,006 subjects were carefully phenotyped. Only subjects with "active asthma" (symptoms or medication in the last year, n = 744) were analyzed in this study to determine the degree of severity of the disease within an asthma cohort. Phenotypes of severity were calculated based on (1) multiple symptoms during the day despite ongoing use of asthma medications, (2) FEV1 of less than 70% of predicted value, (3) daily or almost daily use of rescue medications, (4) nighttime symptoms once a week or more, and (5) oral corticosteroid use/emergency department visits. Asthmatic patients were grouped as having nonsevere disease, 1 sign of severity, or 2 or more signs of severity. RESULTS: A total of 36.2% of asthmatic patients expressed at least 1 sign of asthma severity, and 13.2% had 2 or more signs. The group with 2 or more signs was older in age and had higher body mass index, a higher rate of tobacco smoking, and lower lung function. Bronchial hyperreactivity, airway inflammation, and sensitization were significantly different among the 3 groups. At a population level, the prevalence of asthma severity was 3.1% for 1 sign and 1.3% for at least 2 signs. CONCLUSION: More than 1 in 3 asthmatic patients show at least 1 sign of asthma severity. The phenotypes of asthma severity are highly diverse, which is important to consider when implementing personalized medicine in asthmatic patients.

Pattern of Cardiovascular Comorbidity in COPD in a Country with Low-smoking Prevalence: Results from Two-population-based Cohorts from Sweden.

Cardiovascular diseases are the most common comorbidities in COPD, due to common risk factors such as smoking. The prevalence of current smokers in Sweden has decreased over four decades to around 10%. The aim of the present study was to investigate the prevalence, distribution and associations of cardiovascular comorbidities in COPD by disease severity in two large areas of Sweden, both with low-smoking prevalence. Data from clinical examinations in 2009-2012, including spirometry and structured interview, from two large-scale population studies, the West Sweden Asthma Study (WSAS) and the OLIN Studies in Northern Sweden, were pooled. COPD was defined using post-bronchodilator spirometry according to the fixed ratio FEV1/FVC <0.70 and the lower limit of normal (LLN5th percentile) of the ratio of FEV1/FVC. Of the 1839 subjects included, 8.7% and 5.7% had COPD according to the fixed ratio and the LLN criterion. Medication for heart disease or hypertension among those with moderate-to-severe COPD was more common than among those without COPD (fixed ratio definition of COPD: 51% vs. 23%, p < 0.001; LLN definition: 42% vs. 24%, p = 0.002). After adjusting for known risk factors for COPD, including smoking, age, socio-economic status, and occupational exposure for gas, dust and fumes, only heart failure remained significantly, and independently, associated with COPD, irrespective of the definitions of COPD. Though a major decrease in smoking prevalence, the pattern of cardiovascular comorbidities in COPD still remains similar with previously performed studies in Sweden and in other Westernized countries as well.

Survivin controls biogenesis of microRNA in smokers: A link to pathogenesis of rheumatoid arthritis.

MicroRNAs (miRs) represent a part of epigenetic control of autoimmunity gaining increasing attention in rheumatoid arthritis (RA). Since cigarette smoking plays important role in RA pathogenesis and reprograms transcriptional profile of miRNAs, we ask if the onco-protein survivin, a novel biomarker of RA, may provide a link between smoking and miRNA. Studying survivin expression in leukocytes of 144 female RA patients we observed that smoking patients had higher survivin transcription and a remarkable spreading of survivin isoforms. This was associated with restricted pattern and low production of miRs. Additionally, miRNA processing enzymes Dicer and DGRC8 were decreased in the patients with survivin isoform spreading. The direct contribution of survivin in miRs biogenesis was confirmed by a massive increase of miRs production following inhibition of survivin in leukocyte cultures. Dicer is shown to mediate these effects of survivin. Chromatin immunoprecipitation analysis demonstrated binding of survivin to the Dicer promoter region. Dicer expression increased 5-folds following survivin inhibition. Taken together, this study presents experimental evidence of a novel cellular function of survivin, control of miRs biogenesis. Up-regulation of survivin in smokers suggests its role as effector of the adverse epigenetic control in RA.

Increased prevalence of allergic asthma from 1996 to 2006 and further to 2016-results from three population surveys.

BACKGROUND: During the latter half of the 20th century, the prevalence of asthma and many other allergic diseases has increased. Information on asthma prevalence trends among adults after 2010, especially regarding studies separating allergic asthma from non-allergic asthma, is lacking. OBJECTIVE: The aim was to estimate prevalence trends of current asthma among adults, both allergic and non-allergic, from 1996 to 2016. METHODS: Three cross-sectional samples from the same area of Sweden, 20-69 years, participated in surveys with the same questionnaire in 1996 (n=7104 participants, 85% response rate), 2006 (n=6165, 77%) and 2016 (n=5466, 53%), respectively. Allergic rhino-conjunctivitis (ARC) was used as a marker for allergic sensitization to define allergic asthma. RESULTS: The prevalence of current asthma increased from 8.4% (95% CI: 7.8-9.0) in 1996 to 9.9% (95% CI: 9.2-10.6) in 2006 and 10.9% (95% CI: 10.1-11.7) in 2016 (P<.001). Allergic asthma increased from 5.0% (95% CI: 4.5-5.5) in 1996 to 6.0% (95% CI: 5.4-6.6) in 2006 and further to 7.3% (95% CI: 6.6-8.0) in 2016 (P<.001), while the prevalence of non-allergic asthma remained stable around 3.4%-3.8%. The increase in current asthma was most pronounced among women and among the middle-aged. Physician-diagnosed asthma, asthma medication use and ARC also increased significantly, while the prevalence of symptoms common in asthma such as wheeze and attacks of shortness of breath decreased slightly or was stable. The prevalence of current smoking decreased from 27.4% in 1996 to 12.3% in 2016. CONCLUSIONS AND CLINICAL RELEVANCE: The prevalence of allergic asthma increased from 1996 to 2006 and further to 2016, while the prevalence of non-allergic asthma remained on a stable prevalence level. The prevalence of symptoms common in asthma decreased slightly or was stable despite a substantial decrease in the prevalence of current smoking. Clinicians should be aware that the previously observed increase in prevalence of allergic asthma is still ongoing.

Smoking activates cytotoxic CD8+ T cells and causes survivin release in rheumatoid arthritis.

CD8+ T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8+ T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8+ T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8+ T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8+ T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1-IL-7R+ CD8+ T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+ T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+ T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA.

Lung Function Abnormalities in Smokers with Ischemic Heart Disease.

RATIONALE: The aim of the ALICE (Airflow Limitation in Cardiac Diseases in Europe) study was to investigate the prevalence of airflow limitation in patients with ischemic heart disease and the effects on quality of life, healthcare use, and future health risk. OBJECTIVES: To examine prebronchodilator and post-bronchodilator spirometry in outpatients aged greater than or equal to 40 years with clinically documented ischemic heart disease who were current or former smokers. METHODS: This multicenter, cross-sectional study was conducted in 15 cardiovascular outpatient clinics in nine European countries. Airflow limitation was defined as post-bronchodilator FEV1/FVC less than 0.70. MEASUREMENTS AND MAIN RESULTS: Among the 3,103 patients with ischemic heart disease who were recruited, lung function was defined for 2,730 patients. Airflow limitation was observed in 30.5% of patients with ischemic heart disease: 11.3% had mild airflow limitation, 15.8% moderate airflow limitation, 3.3% severe airflow limitation, and 0.1% very severe airflow limitation. Most patients with airflow limitation (70.6%) had no previous spirometry testing or diagnosed pulmonary disease. Airflow limitation was associated with greater respiratory symptomatology, impaired health status, and more frequent emergency room visits (P < 0.05). CONCLUSIONS: Airflow limitation compatible with chronic obstructive pulmonary disease affects almost one-third of patients with ischemic heart disease. Although airflow limitation is associated with additional morbidity and societal burden, it is largely undiagnosed and untreated. Clinical trial registered with www.clinicaltrials.gov (NCT 01485159).

Relevance of specific IgE antibody titer to the prevalence, severity, and persistence of asthma among 19-year-olds in northern Sweden.

BACKGROUND: Although sensitization to indoor allergens is strongly associated with asthma, there are questions as to how this relates to asthma symptoms. OBJECTIVE: We sought to study the relevance of IgE antibodies to cat and dog allergens in an area in which (1) the climate discourages cockroach, fungal, and mite growth and (2) dander allergens are known to be present in schools and houses without animals. METHODS: IgE to 8 allergens was tested in 963 sera from a population-based study on 19-year-olds, and associations with asthma symptoms, diagnosis, and treatment were examined. In positive sera IgE to specific cat and dog allergens was also assayed. RESULTS: IgE specific for animal dander had the highest prevalence and strongest relationship to asthma diagnosis. Furthermore, asthma severity, as judged by the frequency of symptoms and use of treatment, was directly associated with the titer of IgE antibodies to animal dander. Among the 103 subjects who had current asthma at age 19 years, 50 had asthma before age 12 years. Among those 50, the odds ratios for asthma related to any IgE antibodies to animal dander or high-titer IgE antibodies (≥17.5 IU/mL) were 9.2 (95% CI, 4.9-17) and 13 (95% CI, 6.9-25), respectively. In multivariable analysis IgE antibodies to Fel d 1 and Can f 5 were each associated with current asthma. CONCLUSION: High-titer IgE antibodies to cat and dog allergens were strongly associated with the diagnosis, severity, and persistence of asthma; however, a large proportion of patients with current asthma did not live in a house with a cat or dog.

Exosomes in the nose induce immune cell trafficking and harbour an altered protein cargo in chronic airway inflammation.

BACKGROUND: Exosomes are nano-sized extracellular vesicles participating in cell-to-cell communication both in health and disease. However, the knowledge about the functions and molecular composition of exosomes in the upper airways is limited. The aim of the current study was therefore to determine whether nasal exosomes can influence inflammatory cells and to establish the proteome of nasal lavage fluid-derived exosomes in healthy subjects, as well as its alterations in individuals with chronic airway inflammatory diseases [asthma and chronic rhinosinusitis (CRS)]. METHODS: Nasal lavage fluid was collected from 14 healthy subjects, 15 subjects with asthma and 13 subjects with asthma/CRS. Exosomes were isolated with differential centrifugation and the proteome was analysed by LC-MS/MS with the application of two exclusion lists as well as using quantitative proteomics. Ingenuity Pathways Analysis and GO Term finder was used to predict the functions associated with the exosomal proteome and a migration assay was used to analyse the effect on immune cells by nasal exosomes. RESULTS: Firstly, we demonstrate that nasal exosomes can induce migration of several immune cells, such as monocytes, neutrophils and NK cells in vitro. Secondly, a mass spectrometry approach, with the application of exclusion lists, was utilised to generate a comprehensive protein inventory of the exosomes from healthy subjects. The use of exclusion lists resulted in the identification of ~15 % additional proteins, and increased the confidence in ~20 % of identified proteins. In total, 604 proteins were identified in nasal exosomes and the nasal exosomal proteome showed strong associations with immune-related functions, such as immune cell trafficking. Thirdly, a quantitative proteomics approach was used to determine alterations in the exosome proteome as a result of airway inflammatory disease. Serum-associated proteins and mucins were more abundant in the exosomes from subjects with respiratory diseases compared to healthy controls while proteins with antimicrobial functions and barrier-related proteins had decreased expression. CONCLUSIONS: Nasal exosomes were shown to induce the migration of innate immune cells, which may be important as the airway epithelium is the first line of defence against pathogens and allergens. The decreased expression in barrier and antimicrobial exosomal proteins in subjects with airway diseases, could possibly contribute to an increased susceptibility to infections, which have important clinical implications in disease progression.

Occupational exposure to chemicals drives the increased risk of asthma and rhinitis observed for exposure to vapours, gas, dust and fumes: a cross-sectional population-based study.

OBJECTIVES: Occupational exposure to the composite measure vapours, gases, dusts and fumes (VGDF), contribute to the burden of asthma and rhinitis. The objective was to evaluate occupational exposure to VGDF, which is further divided into the components chemicals, organic and inorganic dust in relation to asthma and rhinitis. METHODS: Previously examined participants from three population-based cohorts in the Obstructive Lung disease In Northern Sweden (OLIN) studies were re-examined during 2002-2004. In total, 4036 participated in a structured interview and answered a questionnaire on occupational exposures. RESULTS: Occupational exposure to VGDF increased the risk of asthma, and concomitant asthma and rhinitis. Exposure to chemicals, but not dust, showed a similar pattern. Exposure to chemicals increased the risks (OR, 95% CI) of rhinitis without asthma (1.29, 1.10 to 1.52), asthma without rhinitis (1.42, 1.15 to 1.77) and concomitant asthma and rhinitis (1.60, 1.31 to 1.96) when adjusted for confounders such as age, smoking habits, body mass index and sex. The association between exposure to chemicals and asthma and rhinitis remained independent of exposure to dust and was also so when excluding exposure to isocyanates and welding fumes. The results were similar for women and men, as well as for never-smokers and participants without a history of allergy. CONCLUSIONS: In this cross-sectional population-based study, occupational exposure to chemicals contributed substantially to the increased risk of asthma and rhinitis observed for occupational exposure to VGDF.