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Additional file 1: Figure S1. Relative proportions of allergic (subjects with either allergic rhinitis or allergic conjunctivitis or both) and non-allergic (subjects without allergic rhinitis or allergic conjunctivitis) cases of new asthma diagnoses in different age groups.

Additional file 1: Table S1. Bronchodilator response (BDR) in FEV1 grouped by age at asthma diagnosis in SAAS cohort after exclusion of ACO patients. Table S2. Bronchodilator response (BDR) in FEV1 grouped by age at asthma diagnosis in COREA cohort after exclusion of ACO patients.

Primary health care (PHC) providers are at the front line of asthma management. To evaluate how planned asthma follow-up occurred in PHC and whether lung function tests were used, 203 patients were followed for 12 years as part of a real-life asthma cohort Seinäjoki Adult Asthma Study (SAAS). A total of 152 patients had visits in PHC attending on average to four planned contacts during 12-year follow-up corresponding to one visit every third year. National guideline recommends annual visits. Patients with ≥4 contacts seemed to have more difficult asthma and better adherence to inhaled corticosteroid medication. Lung function tests were performed on average in 87.5% of annual planned follow-up contacts. Spirometry was performed in 70%, 71% and 97% of all contacts depending on whether it was a contact to GP, nurse or both. Overall, the frequency of follow-up contacts was insufficient but PHC adherence to lung function testing was excellent.

Low income rather than low education is associated with respiratory symptoms in northern Sweden

Difference in Dyspnea between Swedish and Finnish Speaking Persons in Western Finland : Association with Lifestyle

Background: Measurement of spirometry with bronchodilator response has been recommended to detect asthma. However, the diagnostic value of bronchodilator response in newly diagnosed steroid-naive adult patients with asthma remains unknown. Aims and Objectives: To evaluate the sensitivity of bronchodilator response in FEV1 as a diagnostic test for asthma in a real-life cohort of Seinajoki Adult Asthma Study (SAAS). Methods: In the diagnostic phase 369 spirometries with bronchodilation test were made for 219 steroid-naive patients. Fulfilments of three different thresholds of bronchodilator tests; ∆FEV1 ≥12% and ≥200mL, or ≥15% and ≥400mL of initial FEV1 and ∆FEV1 ≥9% of predicted FEV1 were measured. According to the NICE algorithm study patients were also separated to obstructive and non-obstructive groups according to the spirometry with the highest ∆FEV1%. Results: Of the total cohort, 35.6% fulfilled ∆FEV1 ≥12% and ≥200mL of initial FEV1, 18.3% fulfilled ∆FEV1 ≥15% and ≥400mL of initial FEV1 and 36.1% fulfilled ∆FEV1 ≥9% of predicted FEV1 at least on one occasion. One third (31%) of these steroid-naive patients were obstructive (pre FEV1/FVC Conclusions: In steroid-naive patients, the currently used thresholds of bronchodilator response have low sensitivity (18-36%) to diagnose asthma in adults. In obstructive patients, sensitivity is somewhat higher (27-56%) but far from optimal. If asthma suspicion exists after spirometry, further lung function tests need to be considered.

Background: To avoid over-diagnosing of asthma-COPD overlap (ACO), a higher cut-off of 400mL for bronchodilator response (BDR) in FEV1 has been proposed for patients with asthma diagnosed at age ≥40 years. However, it is not known how many asthmatics fulfill this criterion and whether BDR is related to age at diagnosis of adult-onset asthma. Aim: To assess if BDR in FEV1 is related to age at diagnosis of adult-onset asthma and how many subjects fulfill the 400 mL criterion of BDR. Methods: 1030 patients with adult-onset asthma (age of onset ≥15 years) were included; 245 from SAAS (Seinajoki Adult Asthma Study) and 785 from COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) cohorts, respectively. The BDR in FEV1 at the diagnosis of asthma was assessed. Patients were divided into groups based on age at asthma diagnosis: Results: BDR % in FEV1 did not differ between the groups with different age at asthma diagnosis. BDR % in FEV1 in age groups of Conclusion: BDR % in FEV1 at the diagnosis of adult-onset asthma does not vary according to age at diagnosis, and the limit of 400mL BDR in FEV1 is rarely reached. Our findings suggest that the cut-off for BDR of 400 mL has a low sensitivity to detect adult-onset asthma.

Health-related quality of life (HRQoL) is a well-established aspect of health that can be measured by both disease-specific and general instruments. The effect of uncontrolled asthma on generic HRQoL has not been shown in patients with clinically confirmed adult-onset asthma and with asthma control defined according to the Global Initiative for Asthma, so the aim of this study was to determine this. In the 12-year follow-up cohort of the Seinäjoki Adult Asthma Study (n = 203), patients with uncontrolled and partially controlled asthma had lower generic HRQoL as determined by 15D compared to the controlled group. On 10 out of 15 dimensions of 15D, the mean scores were significantly lower in patients with uncontrolled asthma compared with those with controlled asthma. The affected dimensions were mobility, breathing, sleeping, usual activities, mental function, discomfort and symptoms, depression, distress, vitality and sexual activity. In the Tobit regression analysis, a poorer 15D score was associated with uncontrolled asthma, lower postbronchodilator FEV1, female sex, depression, treated dyspepsia and poorer 15D score at diagnosis. Our results show that uncontrolled asthma affects everyday life in several aspects, including previously unknown components such as sexual activity and vitality.

The effect of systemic inflammation and comorbidities on treatment and outcome of adult-onset asthma remains unknown and is the objective of this study.As part of the Seinäjoki Adult Asthma Study (SAAS) with a 12-year follow-up, serum interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP) and lung function were measured and clinical information on comorbidities and medication collected from 170 patients with adult-onset asthma without chronic obstructive pulmonary disease.At follow-up visit, 54% of the patients had systemic inflammation as indicated by elevated IL-6 or hsCRP, 58% had at least one comorbidity and 30% at least two comorbidities (other than asthma related). Patients with systemic inflammation were treated with higher dose of inhaled corticosteroid (ICS) and they had lower lung function and higher blood neutrophils compared with patients without. Patients having ≥2 comorbidities had lower Asthma Control Test score and this association remained significant in adjusted analysis. Patients with both systemic inflammation and comorbidities showed poorest outcome of asthma. In multivariate regression analysis, high ICS dose was predicted by elevated IL-6, elevated blood neutrophils and eosinophils and poorer lung function at baseline and follow-up.Altogether, in patients with adult-onset asthma, elevated IL-6 was associated with use of high-dose ICS while multi-morbidity was linked to worse symptoms of asthma.

Background: Asthma is currently divided into different phenotypes, with age at onset as a relevant differentiating factor. In addition, asthma with onset in adulthood seems to have a poorer prognosis, but studies investigating age-specific incidence of asthma with a wide age span are scarce. Objective: To evaluate incidence of asthma diagnosis at different ages and differences between child- and adult-diagnosed asthma in a large population-based study, with gender-specific analyzes included. Methods: In 2016, a respiratory questionnaire was sent to 8000 randomly selected subjects aged 20-69 years in western Finland. After two reminders, 4173 (52.3%) subjects responded. Incidence rate of asthma was retrospectively estimated based on the reported age of asthma onset. Adult-diagnosed asthma was defined as a physician-diagnosis of asthma made at >= 18 years of age. Results: Among those with physician-diagnosed asthma, altogether, 63.7% of subjects, 58.4% of men and 67.8% of women, reported adult-diagnosed asthma. Incidence of asthma diagnosis was calculated in 10-year age groups and it peaked in young boys (0-9 years) and middle-aged women (40-49 years) and the average incidence rate during the examined period between 1946 and 2015 was 2.2/1000/year. Adult-diagnosed asthma became the dominant phenotype among those with physician-diagnosed asthma by age of 50 years and 38 years in men and women, respectively. Conclusions: Asthma is mainly diagnosed during adulthood and the incidence of asthma diagnosis peaks in middle-aged women. Asthma diagnosed in adulthood should be considered more in clinical practice and management guidelines.

Background Antibodies against the IL-5 pathway have been developed for the treatment of late-onset eosinophilic corticosteroid-resistant asthma. However, the prevalence of severe asthma and the proportion of patients who could benefit from such treatment among the general population of asthmatics remain unknown. Objective To evaluate the prevalence and characteristics of patients eligible to anti-IL-5 treatment and severe asthma in an unselected cohort of adult-onset asthma. Methods Seinajoki Adult Asthma Study is a 12-year follow-up study of patients with new-onset adult asthma (n = 203). Prevalence was estimated based on information collected at 12-year follow-up visit. Health care use was collected from the whole 12-year follow-up period. Results The prevalence of anti-IL-5-treatable patients was 2%, when the following criteria were used: daily use of medium-to-high inhaled corticosteroid (ICS) dose and long-acting β2-agonist, ≥2 exacerbations/previous year and blood eosinophil count ≥300 cells/μL or fraction of exhaled nitric oxide ≥ 50 ppb. The prevalence of severe asthma, as defined according to European Respiratory Society/American Thoracic Society, was 5.9%, and only 1 patient met criteria for both groups. When compared with anti-IL-5 eligible patients, severe asthmatics were more often current smokers at diagnosis, obese, used higher ICS dose, and had higher blood neutrophils 12 years after diagnosis. Both groups differed from nonsevere asthma by a higher number of all and unplanned respiratory-related visits to health care. Severe asthmatics showed the highest number of hospitalizations. Conclusions In a cohort of unselected consecutive patients with adult-onset asthma, 5.9% fulfilled criteria for severe asthma and 2% qualified for anti-IL-5 treatment. Both groups represent a high burden to health care and specifically targeted treatment could lead to lower use of health care at long term.

Background: Therapeutic mAbs targeting the IL-5 or IL-5Rα have been developed for treatment of severe eosinophilic asthma. However, prevalence of severe asthma and proportion of asthmatics who might benefit from such treatments remain unknown. Aims and Objectives: To evaluate the prevalence and characteristics of patients (pts) eligible for anti-IL-5/Rα treatment in an unselected cohort of adult-onset asthma. Methods: Seinajoki Adult Asthma Study (SAAS) is a 12-year follow-up study of pts with new-onset adult asthma (n=203). Prevalence was estimated based on information collected at the 12-year follow-up visit. Details of health care use were collected from the entire follow-up period. Pts eligible for anti‒IL-5/Rα treatment were defined as: daily use of medium-to-high ICS dosages/LABA, ≥2 exacerbations/previous year, and blood eosinophil count ≥300 cells/µl (or FeNO ≥50 ppb). Results: Prevalence of anti-IL-5/Rα-treatable pts was 2%, while prevalence of severe asthma (ERS/ATS criteria), was 5.9%. Only one patient met criteria for both groups. Compared with pts eligible for anti‒IL-5/Rα therapy, severe asthmatics were more often current smokers at diagnosis and obese, used higher ICS dose and had higher blood neutrophils 12 years after diagnosis. Both groups differed from non-severe asthma by higher numbers of all planned and unplanned respiratory-related visits to healthcare. Severe asthmatics had the highest number of hospitalizations. Conclusions: Of pts with adult-onset asthma, 5.9% had severe asthma and 2% might have benefitted from anti-IL-5/anti-IL-5Rα treatment. Both groups represent a high burden to society, and targeted treatment could lead to lower long-term health care utilization.

Background Prescribed inhaled corticosteroid (ICS) doses in asthma have been studied in cross-sectional settings whereas long-term follow-up studies have not been carried out. Objective To evaluate prescribed medication longitudinally by calculating cumulative ICS doses and dose changes in a cohort of new-onset adult asthma during 12 years and in different groups of asthma control. Methods A total of 203 patients were followed for 12 years as part of Seinajoki Adult Asthma Study (SAAS). All asthma-related visits and prescribed medication over the study period were collected from medical records. Results Total cumulative ICS dose for the 12-year follow-up period was 3.4g (±SEM 0.1) per patient. Both respiratory specialists and GPs prescribed step-ups and step-downs in ICS treatment and in total 649 dose changes were noted during the follow-up (median 3(1–5) per patient). Patients with uncontrolled asthma received higher ICS doses throughout the follow-up period, and therefore, cumulative 12-year ICS dose (3.8g ± SEM 0.2) in this group was higher than that in those with partially controlled (3.4g ± SEM 0.2) or controlled disease (2.9g ± SEM 0.2) (p = 0.0001). Patients with uncontrolled asthma were also prescribed a higher number of ICS dose changes than patients with controlled disease. Conclusion Despite frequent dose changes and high ICS doses during the 12-year follow-up, the level of asthma control remained poor in patients with uncontrolled asthma. This suggests that high ICS doses may not be effective enough for management of disease in patients with uncontrolled adult-onset asthma and novel targeted treatments are required.

Background: Asthma phenotypes can be differentiated by age of disease onset, but studies investigating age-specific incidence of asthma with a wide age span are scarce. Objectives: To evaluate incidence of asthma diagnosis at different ages and dominance between child- and adult-diagnosed asthma in a population-based study, by gender. Methods: In February 2016, a respiratory questionnaire was sent to 8000 randomly selected subjects aged 20-69 years in western Finland. After two reminders, 4173 (52.3%) subjects responded. Adult-diagnosed asthma was defined as physician-diagnosis of asthma made at ≥ 18 years of age. Results: Prevalence of physician-diagnosed asthma was 11.2%. Among those with asthma, altogether, 63.7% (95% CI 59.0-68.1%) of subjects, 58.4% (51.2-65.2%) of men and 67.8% (61.6-73.3%) of women (p=0.046), reported adult-diagnosed asthma. Incidence of asthma diagnosis was calculated in 10-year age groups and it peaked in young boys (0-9 years) and middle-aged women (40-49 years) (Figure 1). The average incidence rate during the examined period 1946-2015 was 2.2/1000/year. Adult-diagnosed asthma became the dominant phenotype among asthmatics by age of 50 years and 38 years in men and women, respectively. Conclusion: Asthma is mainly diagnosed in adulthood and the incidence of asthma diagnosis peaks in middle-aged women.

Background: Onset of allergic asthma has a strong association with childhood. Much less is known about adult onset asthma and its association with allergy.Objectives: To assess the proportion of al ...

Background: Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known to mediate nociception and neurogenic inflammation, and to be activated by reactive oxygen and nitrogen species (ROS and RNS) produced at the sites of inflammation. Because neurogenic inflammation as well as the release of ROS and RNS are typical features of early stages of allergic responses, we hypothesized that TRPA1 may be involved in triggering and/or amplifying allergic inflammation. Objective: This study aims at exploring the role of TRPA1 ion channel in acute ovalbumin-induced allergic inflammation in applicable murine models. Methods: The effects of pharmacological blockade and genetic deletion of TRPA1 in ovalbumin-induced allergic conjunctivitis and acute paw inflammation were studied in mice sensitized to ovalbumin. Results: Ovalbumin-induced allergic conjunctivitis was milder in TRPA1-deficient mice and alleviated in wild-type mice treated with the TRPA1 antagonist TCS 5861528. Subcutaneous challenge with ovalbumin caused a significant paw edema and interleukin (IL)-4 production in sensitized mice; these responses were attenuated in animals treated with the TRPA1 antagonist and in TRPA1-deficient mice. Interestingly, blockade of the major secondary effector of TRPA1, substance P, also resulted in attenuated ovalbumin-induced paw edema and IL-4 production. However, the splenocytes’ responses to ovalbumin were similar in cells from wild-type and TRPA1-deficient mice sensitized to ovalbumin. Conclusion: These results introduce a novel concept that TRPA1 mediates early events in allergic inflammation, but does not seem to affect allergic sensitization, and could therefore be a novel drug target to treat conditions associated with allergic inflammation.

Asthma is characterised by variable and reversible expiratory airflow limitations. Thus, it is logical to use the change in forced expiratory volume in 1 s (FEV

Background: There is a lack of knowledge on the association between daily physical activity and lung function in patients with asthma. Objective: This study aims to examine the association between daily physical activity and asthma control, lung function, and lung function decline in patients with adult-onset asthma. Design: This study is part of Seinäjoki Adult Asthma Study (SAAS), where 201 patients were followed for 12 years after asthma diagnosis. Daily physical activity was assessed at follow-up by a structured questionnaire and used to classify the population into subgroups of low (≤240 min) or high (>240 min) physical activity. Three spirometry evaluation points were used: 1. diagnosis, 2. the maximum lung function during the first 2.5 years after diagnosis (Max0–2.5), 3. follow-up at 12 years. Results: High physical activity group had slower annual FEV1 (p

Background: Differences between obstructive asthma and asthma-COPD overlap syndrome (ACOS) are poorly known. Aims: To evaluate these differences in Seinajoki Adult-onset Asthma Study (SAAS) cohort. Methods: 257 patients were diagnosed with new-onset adult asthma during 1999-2002. After 12 years (2012-2013) patients (n=203) were re-evaluated, and 2 groups of patients were chosen for analysis: 1) non-smoking asthmatic patients with fixed obstruction ( 1 /FVC 1 /FVC Results: ACOS patients had lower pulmonary diffusing capacity and higher number of comorbidities as compared to asthmatics with fixed obstruction. Levels of blood neutrophils and interleukin-6 (IL-6) were higher in the ACOS-group. Levels of blood eosinophils, IgE, high sensitivity CRP (hsCRP) or FeNO did not differ between the groups (Table 1). Conclusion: ACOS differs from non-smoking asthmatics with fixed obstruction most significantly by lower diffusing capacity, higher levels of blood neutrophils and IL-6, and by higher number of comorbidities. Shown are median (IQ range) or mean ± SD

Eosinophils are abundantly present in most phenotypes of asthma and they contribute to the maintenance and exacerbations of the disease. Regulators of eosinophil longevity play critical roles in determining whether eosinophils accumulate into the airways of asthmatics. Several cytokines enhance eosinophil survival promoting eosinophilic airway inflammation while for example glucocorticoids, the most important anti-inflammatory drugs used to treat asthma, promote the intrinsic pathway of eosinophil apoptosis and by this mechanism contribute to the resolution of eosinophilic airway inflammation. Mitochondria seem to play central roles in both intrinsic mitochondrion-centered and extrinsic receptor-mediated pathways of apoptosis in eosinophils. Mitochondria may also be important for survival signalling. In addition to glucocorticoids, another important agent that regulates human eosinophil longevity via mitochondrial route is nitric oxide, which is present in increased amounts in the airways of asthmatics. Nitric oxide seems to be able to trigger both survival and apoptosis in eosinophils. This review discusses the current evidence of the mechanisms of induced eosinophil apoptosis and survival focusing on the role of mitochondria and clinically relevant stimulants, such as glucocorticoids and nitric oxide.

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Disease burden and multimorbidity in adult-onset asthma increase dose dependently with smoked pack-yearshttp://bit.ly/311627j

Asthma is a chronic inflammatory disease of the airways manifesting in many different phenotypes. Allergic asthma, comprising approximately half of patients with asthma, is characterized by the accumulation of eosinophils into the lungs. Eosinophils release factors that damage the surrounding cells and participate in the maintenance and exacerbation of inflammation. In the absence of any inflammatory survival-prolonging factors, eosinophils die by apoptosis in few days but in inflamed airways, eosinophil survival is thought to be prolonged due to the surrounding pro-inflammatory factors such as IL-5, IL-3 and GM-CSF. Resolution of eosinophilic inflammation is an important goal in the treatment of allergic asthma. Apoptosis is a physiological and non-inflammatory way to eliminate these harmful cells, and development of drugs targeting eosinophil apoptosis is one possible strategy for the therapy of allergic asthma. Importance of this strategy is supported by the fact that promotion of eosinophil apoptosis is a property of many anti-asthmatic agents such as glucocorticoids, the current main anti-inflammatory therapy of asthma, theophylline and leukotriene modifiers. β2 agonists have been shown to modulate eosinophil longevity by increasing survival. Also, anti-IL-5 antibody mesolizumab has shown efficacy in reducing asthma exacerbations in patients with severe eosinophilic asthma. Many potential future anti-asthmatic agents, such as Siglec-8 activating antibody and novel humanized anti-IL-5 antibody MEDI-563, have the property of inducing eosinophil apoptosis. This MiniReview aims to present eosinophil apoptosis as a therapeutic target in the treatment of allergic asthma. We summarize the effects and mechanisms of current and potential future anti-asthmatic drugs on eosinophil apoptosis and additionally, discuss the potential factors that promote eosinophil longevity in the lungs.

Background Previous cluster analyses on asthma are based on cross-sectional data. Objective To identify phenotypes of adult-onset asthma by using data from baseline (diagnostic) and 12-year follow-up visits. Methods The Seinajoki Adult Asthma Study is a 12-year follow-up study of patients with new-onset adult asthma. K-means cluster analysis was performed by using variables from baseline and follow-up visits on 171 patients to identify phenotypes. Results Five clusters were identified. Patients in cluster 1 (n = 38) were predominantly nonatopic males with moderate smoking history at baseline. At follow-up, 40% of these patients had developed persistent obstruction but the number of patients with uncontrolled asthma (5%) and rhinitis (10%) was the lowest. Cluster 2 (n = 19) was characterized by older men with heavy smoking history, poor lung function, and persistent obstruction at baseline. At follow-up, these patients were mostly uncontrolled (84%) despite daily use of inhaled corticosteroid (ICS) with add-on therapy. Cluster 3 (n = 50) consisted mostly of nonsmoking females with good lung function at diagnosis/follow-up and well-controlled/partially controlled asthma at follow-up. Cluster 4 (n = 25) had obese and symptomatic patients at baseline/follow-up. At follow-up, these patients had several comorbidities (40% psychiatric disease) and were treated daily with ICS and add-on therapy. Patients in cluster 5 (n = 39) were mostly atopic and had the earliest onset of asthma, the highest blood eosinophils, and FEV 1 reversibility at diagnosis. At follow-up, these patients used the lowest ICS dose but 56% were well controlled. Conclusions Results can be used to predict outcomes of patients with adult-onset asthma and to aid in development of personalized therapy (NCT02733016 at ClinicalTrials.gov).

Background: Predictors of long-term lung function decline in adult-onset asthma are not known. Aims: To evaluate the determinants for accelerated loss of lung function in a 12-year follow-up as a part of Seinajoki Adult-onset Asthma Study (SAAS). Methods: 257 adults were diagnosed with new-onset asthma during 1999-2002. After 12 years patients (n=203) were re-evaluated. Spirometry measurement points were:1.) baseline (i.e. time of diagnosis), 2.) the maximum lung function (Max 0-2.5 ) during the first 2.5 years after diagnosis (i.e. after start of therapy) and 3.) after 12 years of follow-up. The predictors of annual FEV 1 decline between Max 0-2.5 and follow-up were assessed by multiple linear regression analysis. Results: The predictors of lung function decline are presented in Table1. Conclusion: Smoked pack-years >10, increased age, weight gain and ongoing inflammation predict accelerated loss of lung function in adult-onset asthma. Interestingly, good initial response to anti-inflammatory therapy may indicate also accelerated decline in FEV 1 later on.

Rationale Long-term prognosis of adult-onset asthma is poorly known. Objective To evaluate 12-year prognosis of adult-onset asthma and the factors associated with disease prognosis. Methods Seinajoki Adult-onset Asthma Study (SAAS) is a 12-year real-life single-center follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialized care. Remission was defined by no symptoms and no asthma medication use for 6 months. Asthma control was evaluated according to Global Initiative for Asthma 2010. Factors associated with current asthma control were analyzed by multinomial multivariate logistic regression. Main results A total of 203 patients (79% of the baseline population) were followed for 12 years. Remission occurred in 6 (3%) patients. In 34% asthma was controlled, in 36% it was partially controlled and in 30% uncontrolled. Uncontrolled asthma was predicted by elevated body-mass index at baseline, smoking (pack-years) and current allergic or persistent rhinitis. Elevated blood eosinophils and good lung function (FEV 1 ) at baseline protected from uncontrolled asthma. In contrast, gender, age at the onset or baseline symptoms (Airways Questionnaire 20) were not significant predictors of uncontrolled disease. Conclusions During a 12-year follow-up, remission of adult-onset asthma was rare occurring in only 3% of patients. The majority of patients (66%) presented either with uncontrolled or partially controlled asthma. This study is registered at ClinicalTrials.gov with identifier number NCT02733016.

The aim of this study was to evaluate the effect of smoking on lung function decline in adult-onset asthma in a clinical, 12-year follow-up study.In the Seinäjoki Adult Asthma Study, 203 patients were followed for 12 years (1999–2013) after diagnosis of new-onset adult asthma. Patients were divided into two groups based on smoking history: 0–2.5) and 3) after 12 years of follow-up.Between Max0–2.5 and follow-up, the median annual decline in absolute forced expiratory volume in 1 s (FEV1) was 36 mL in the group of patients with 1 % pred (p=0.006), forced vital capacity (FVC) (p=0.035) and FEV1/FVC (p=0.045) were also accelerated in the group of patients with ≥10 pack-years smoked. In multivariate regression analysis, smoking history ≥10 pack-years became a significant predictor of accelerated decline in FEV1.Among patients with clinically defined adult-onset asthma, smoking history ≥10 pack-years is associated with accelerated loss of lung function.

Eosinophils play a major role in asthma. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). β(2)-Adrenoceptor agonists have been shown to prolong survival and delay apoptosis of eosinophils. The aim of the present study was to evaluate the mechanisms, especially the role of cAMP pathway, in the prolongation of human eosinophil survival by a selective β(2)-agonist salbutamol. Isolated human peripheral blood eosinophils were cultured in the absence or presence of a β(2)-agonist salbutamol and the indicated antagonists/inhibitors under sterile conditions. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding. Salbutamol prolonged survival of human eosinophils and it was inhibited by a β-receptor antagonist propranolol and mimicked by cell-permeant cAMP analogues dibutyryl- and 8-bromo-cAMP. Pharmacological inhibitors of adenylyl cyclase (SQ-22,536) and protein kinase A (Rp-8-CPT-cAMPS) antagonized the effects of salbutamol. The survival-prolonging action of salbutamol was potentiated by a phosphodiesterase inhibitor rolipram (EC(50) for the salbutamol effect was 13.6 ± 4.0 and 8.1 ± 3.1 nM in the absence and presence of rolipram, respectively; p=0.0142, n=10). In contrast, inhibition of Ca(2+)-activated K(+)-channels by apamin, charybdotoxin, iberiotoxin or paxilline did not affect the ability of salbutamol to prolong eosinophil survival. Taken together, the present results suggest that salbutamol at clinically relevant concentrations decreases apoptosis in human eosinophils by activating the cannonical β(2)-receptor-adenylyl cyclase-cAMP-protein kinase A pathway.

Asthma is characterised by variable and reversible expiratory airflow limitations. Thus, it is logical to use the change in forced expiratory volume in 1 s (FEV1) in response to a bronchodilator (ΔFEV1BDR) as a diagnostic tool; increases of ≥12% and ≥200 mL from the baseline FEV1 are commonly used values. We aimed to evaluate the historical development of diagnostic cut-off levels for the ΔFEV1BDR for adults and the evidence behind these recommendations.We searched for studies from the reference lists of all the main statements, reports and guidelines concerning the interpretation of spirometry and diagnostics for asthma and conducted a literature search.A limited amount of evidence regarding the ΔFEV1BDR in healthy populations was found, and even fewer patient studies were found. In healthy persons, the upper 95th percentile for the absolute ΔFEV1BDR ranges between 240 mL and 320 mL, the relative ΔFEV1BDR calculated from the initial FEV1 ranges from 5.9% to 13.3% and the ΔFEV1BDR calculated from the predicted FEV1 ranges from 8.7% to 11.6%. However, the absolute and percentage ΔFEV1BDR values calculated from the initial FEV1 are dependent on age, sex, height and the degree of airway obstruction. Thus, the use of the ΔFEV1BDR calculated from the predicted FEV1 might be more appropriate.Not enough data exist to assess the sensitivity of any of the cut-off levels for the ΔFEV1BDR to differentiate asthma patients from healthy subjects. Further studies in newly diagnosed asthma patients are needed.

Asthma is characterized by accumulation of eosinophils in the lungs and delayed apoptosis may be one mechanism leading to eosinophilia. Nitric oxide (NO), present in inflamed lungs, has been shown to possess both anti- and proeosinophilic properties. We previously showed that NO induces apoptosis in the presence of survival prolonging cytokine IL-5 in human eosinophils. In the present study, we examined the intracellular mechanisms of NO-induced apoptosis in granulocyte macrophage-colony stimulating factor (GM-CSF)-treated eosinophils concentrating on the role of caspases and calpains. Eosinophils were isolated from human blood and apoptosis was determined by relative DNA fragmentation assay, morphological analysis and/or Annexin-V FITC assay. We showed that NO-donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) induced apoptosis in GM-CSF-treated eosinophils. SNAP-induced DNA fragmentation was totally prevented by an inhibitor of caspase-6 (Z-VEID-FMK). Decreased levels of caspase-6 proenzyme and increased amounts of cleaved lamin A/C in SNAP-treated cells indicated activation of caspase-6. Furthermore, SNAP-induced lamin A/C and B fragmentation was totally abolished by an inhibitor of caspase-6. According to our results, caspase-6 mediates lamin and DNA fragmentation also in spontaneously dying eosinophils. Inhibitor of calpains prevented most of DNA fragmentation related to spontaneous apoptosis but had no effect in eosinophils undergoing NO-induced apoptosis. In the present study we showed that caspase-6 is essential for the executive phase involving lamin and DNA fragmentation in both NO-induced and spontaneous eosinophil apoptosis. However, differences in the involvement of calpains suggest that the intracellular signalling in NO-induced apoptosis has specific features at the level of proteases. This study demonstrates new mechanisms for NO-induced and spontaneous apoptosis in human eosinophils.

Oligodeoxynucleotide (ODN) sequences containing unmethylated cytidine phosphate guanosine (CpG) motifs prevalent in bacterial DNA attenuate allergic lung inflammation in experimental models of asthma but failed to inhibit eosinophilia and improve lung function in patients with asthma. Bacterial respiratory tract infections exacerbate asthma in humans. Increased eosinophil survival is a critical factor leading to persistent eosinophilic airway inflammation. Apoptosis is regarded as a key mechanism in the resolution of eosinophilic inflammation. The aim of this study was to investigate the effects of bacterial DNA and CpG ODNs on human eosinophil apoptosis in vitro and to elucidate the signalling pathway. Eosinophils were isolated from human peripheral blood by CD16- or CD16-, CD19- and CD304-negative selection. Apoptosis was determined by flow cytometric analysis of relative DNA content, Annexin-V staining and/or morphological analysis. Toll-like receptor 9 (TLR9) expression was studied by using western blotting and intracellular flow cytometry. Bacterial DNA and phosphorothioate-modified CpG ODNs, but not vertebrate DNA, were found to delay spontaneous eosinophil apoptosis. The effect of CpG ODNs was dependent on endosomal acidification and reversed by inhibitory ODN, which suggests involvement of TLR9 pathway. Furthermore, we demonstrated TLR9 expression in eosinophils derived from both atopic and healthy donors. Non-CpG ODNs had occasionally parallel but less profound effect on eosinophil apoptosis, which was not dependent on endosomal acidification. The anti-apoptotic effect of CpG ODNs was dependent on phosphatidylinositol 3-kinase (PI3K) and nuclear factor-kappaB (NF-kappaB) but not mitogen-activated protein kinases (MAPKs) as determined by inhibitor studies. Although our results suggest CpG-dependent involvement of TLR9 in the action of phosphorothioate-modified ODNs, we interestingly found that the anti-apoptotic action of native bacterial DNA in eosinophils is not dependent on unmethylated CpG motifs. This suggests that bacterial DNA contains a currently unknown recognition structure lacking from vertebrate DNA. Bacterial DNA-mediated suppression of eosinophil apoptosis is a novel mechanism for exacerbation of eosinophilic lung inflammation associated with bacterial respiratory tract infection.

Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Most studies with asthma have been performed in patients being otherwise healthy. However, in real life, comorbid diseases are very common in adult patients. We review here the emerging comorbid conditions to asthma such as obesity, metabolic syndrome, diabetes mellitus type 2 (DM2), and cardiac and psychiatric diseases. Their role as risk factors for incident asthma and whether they affect clinical asthma are evaluated. Obesity, independently or as a part of metabolic syndrome, DM2, and depression are risk factors for incident asthma. In contrast, the effects of comorbidities on clinical asthma are less well-known and mostly studies are lacking. Cross-sectional studies in obese asthmatics suggest that they may have less well controlled asthma and worse lung function. However, no long-term clinical follow-up studies with these comorbidities and asthma were identified. These emerging comorbidities often occur in the same multimorbid adult patient and may have in common metabolic pathways and inflammatory or other alterations such as early life exposures, systemic inflammation, inflammasome, adipokines, hyperglycemia, hyperinsulinemia, lung mechanics, mitochondrial dysfunction, disturbed nitric oxide metabolism, and leukotrienes.

Background: Systemic inflammation, characterized by elevated IL-6, has been associated with chronic respiratory diseases and cardiovascular, psychiatric and rheumatic disorders. However, its role in patients with adult-onset asthma with and without comorbidities is unclear. Aims and Objectives: To compare lung function and levels of IL-6 in patients with adult-onset asthma with and without comorbidities. Methods: Seinajoki Adult Asthma Study (SAAS) is a 12-year follow-up of patients (n=203) with new-onset asthma diagnosed at adult age . Clinical information on comorbidities and medication were collected from all participants . Lung function was measured at baseline and follow-up. Serum levels of IL-6 were determined by ELISA. Results: In this material, 110 (54 %) suffered from at least one of the following comorbidities: diabetes, hypertonia, coronary heart disease, hypercholesterolemia, psychiatric disorder, COPD or systemic rheumatic disease (selected comorbid group). Thirty six patients (18 %) suffering from other comorbid condition(s) such as non-specific musculoskeletal disorders were excluded. Fifty seven patients (28 %) showed no other disease in addition to asthma/asthma-related conditions. In comparison to patients with no comorbidities, patients with selected comorbidities showed elevated levels of IL-6, lower lung function, higher AQ20 score and higher proportion of uncontrolled asthma despite higher daily dose of ICS. IL-6 level was positively associated with the number of selected comorbidities and showed a negative correlation to post-bronchodilator FEV1 (R=-0,338, p Conclusions: Comorbidities and elevated IL-6 levels may play a role in poor outcome of patients with adult-onset asthma.

Background: The long-term prognosis of adult-onset asthma is not known. Objective: To evaluate the 12-year prognosis of adult-onset asthma with regards to remission and control of asthma and to evaluate the factors associated with the prognosis. Methods: Seinajoki Adult-onset Asthma Study (SAAS) is a 12-year real-life single-center follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialized care. Remission was defined by no symptoms and no asthma medication usage for 6 months. Asthma control was evaluated according to GINA 2010. Factors associated with current asthma control were analyzed by multinomial multivariate logistic regression. Results: A total of 203 patients were followed for 12 years. Remission occurred in 6 (3%) patients. In 34 % asthma was controlled, in 36% it was partly controlled and in 30% uncontrolled. Uncontrolled asthma was predicted by elevated body-mass index at baseline, smoking (pack-years) and current allergic or persistent rhinitis. Elevated blood eosinophils and good lung function (FEV1) at baseline protected from uncontrolled asthma. In contrast, gender, age at the onset of the disease or symptoms (AQ-20) at baseline were not significant predictors of uncontrolled asthma. Conclusions: During a follow-up for 12-years, remission of adult-onset asthma was rare occurring in only 3 % of patients. The majority of patients (66 %) showed either uncontrolled or partially controlled asthma.

Background: The long-term prognosis of adult-onset asthma is not known. Aims and objectives: To explore the diagnostics and prognosis of adult-onset asthma and the organization of long-term asthma care. Methods: Seinajoki Adult Asthma Study (SAAS) was initiated as a single-center 12-year real-life follow-up study of patients presenting with a new-onset asthma at adult age (≥15 years) and treated in primary and specialized care. Inclusion criteria: symptoms of asthma, a diagnosis of new-onset asthma by a respiratory specialist and confirmed by lung function measurements. Exclusion criterion: inability to provide signed informed consent. In 2000-2002 patients (n=257) were included in the study from their diagnostic visit. Results: Twelve years later 203 patients (79%) returned to a control visit. The mean age of the patients (n=203) at the diagnostic visit was 46.0 years (range 15-86), 118 of them (58.1%) were women and 103 (50.7%) were current or ex-smokers. Only 16 (8 %) had FEV1/FVC ratio < 0.70 in post-bd spirometry with a smoking history of ≥ 10 pack-years. The main demographic and clinical characteristics at baseline and control visit are shown in Table. | | Baselinea | Follow-upa | P-valueb | || | Age (y) | 46.0 (13.7) | 58.2 (13.6) | | | BMI (kg/m2) | 27.1 (24.1-29.7) | 28.1 (24.4-31.4) | 0.000 | | IgE (kU/l) | 84 (35-174) | 61 (24-163) | 0.046 | | B-eos (109/l) | 0.28 (0.15-0.42) | 0.17 (0.10-0.27) | 0.000 | | pre-bd FEV1 (% pred) | 82.8 (71.0-92.2) | 86.0 (76.0-96.0) | 0.000 | | AQ-20 | 7 (4-10) | 4 (2-7) | 0.000 | * aMean (SD) or median (25th-75th percentile). bRelated samples Wilcoxon signed rank test or t-test. Conclusions: SAAS is a long-term follow-up study, that offers an excellent opportunity to evaluate the diagnostics, prognosis and organization of care in patients with adult-onset asthma.

Background: The effect of smoking on the long-term decline in lung function in adult-onset asthma is not known. Aims and Objectives: To evaluate the effect of smoked pack-years on lung function decline in a 12-year follow-up as a part of Seinajoki Adult-onset Asthma Study (SAAS). Methods: Patients (n=257) were diagnosed to have new-onset adult asthma during 2000-2002. At the time of diagnosis smoking history was assessed. After 12 years (2012-2013) patients (n=203) were evaluated for lung function and smoking status. Patients were divided into two groups based on smoked pack-years: ≤ 10 and >10. The changes in pre-bronchodilator spirometry values were evaluated. Measurement points were: baseline (i.e. time of diagnosis), the maximum lung function (Max 0-2.5 ) during first 2.5 years after diagnosis (i.e. start of therapy), and after 12 years of follow-up. Differences between groups were compared with student9s t-test or Mann-Whitney U-test. Results: History of smoked pack-years did not significantly affect the change in lung function between baseline and Max 0-2.5 after diagnosis. In contrast, the annual decline in lung function between Max 0-2.5 and 12 years was more rapid among patients with >10 pack-years (table 1). Conclusion: In patients with adult-onset asthma the decline in lung function is more rapid if smoking history exceeds 10 pack-years.

Seinajoki Adult Asthma Study (SAAS): a protocol for a 12-year real-life follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialised care

Differences between asthma–COPD overlap syndrome (ACOS) and adult-onset asthma are poorly understood. This study aimed to evaluate these differences in a clinical cohort of patients with adult-onset asthma, as a part of the Seinäjoki Adult Asthma Study (SAAS).188 patients were diagnosed with adult-onset asthma and re-evaluated 12 years after diagnosis. They were divided into three groups based on smoking history and post bronchodilator spirometry values: 1) never- and ex-smokers with 1)/forced vital capacity (FVC) ≥0.7) patients with ≥10 pack-years; and 3) ACOS patients with ≥10 pack-years and FEV1/FVC ACOS patients had lower diffusing capacity (DLCO/VA 86% predicted versus 98 or 96% predicted; pversus 3.60 or 3.85×109 L−1; p=0.008), and higher IL-6 levels (2.88 versus 1.52 or 2.10 pg·mL−1, pThis study shows distinct differences in diffusing capacity, blood neutrophil and IL-6 levels, bronchial reversibility, lung function and comorbidities between ACOS and adult-onset asthma. The present findings should be considered in the comprehensive assessment of adult asthma patients.

Asthma is a common chronic disease, which can affect patients at any age. Recently, cluster analyses have suggested that patients with asthma can be divided into different phenotypes and that the age at the onset of the disease is a critical defining factor. The prognosis of allergic childhood-onset asthma is relatively well known, whereas the prognosis of adult-onset asthma remains unclear.We undertook a systematic review to identify studies that evaluated the long-term prognosis of new-onset asthma diagnosed at adult age. Criteria used (set 1) were: 1. adult-onset asthma, 2. physician diagnosed asthma (including objective lung-functions) 1 year before the first visit, 3. follow-up time of at least 5 years, 4. objective lung function measurements used at follow-up and 5. not a comparative trial. Another set of studies (set 2) with less strict criteria were gathered.The main result of this systematic review is that the amount of evidence on the prognosis of new-onset asthma diagnosed at adult age is very limited. Only one study (n = 250) fulfilled the criteria (set 1) and it suggests that the five-year prognosis of new-onset asthma diagnosed at adult age may not be favorable, the proportion of patients being in remission was less than 5%. Furthermore, six additional follow-up studies (n = 964) were identified including mainly patients with adult-onset asthma (set 2). These studies had variable endpoints and the results could not be combined.Further follow-up studies that recruit patients with new-onset adult asthma are needed to understand the prognostic factors in adult-onset asthma.

Eosinophil apoptosis is considered critical for the resolution of eosinophilic inflammation in the airways of asthmatics. Apoptosis can be mediated by an extrinsic receptor-activated pathway or alternatively by an intrinsic pathway via distortion of mitochondrial function. Both of these pathways lead to activation of the caspase cascade resulting in degradation of cellular components. We describe here two methods to explore intracellular mechanisms mediating eosinophil apoptosis. Eosinophil staining by fluorescent probe JC-1 followed by flow cytometric analysis is a reliable method for determination of the state of mitochondrial membrane potential (∆Ψm). Lost ∆Ψm indicates distorted mitochondrial function and apoptosis. We also describe a method to explore the activation of effector caspase-6 by assessing degradation of its substrate lamin A/C by immunoblotting.

Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.