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Abstract “Epidemiology of comorbidities and their association with asthma control” (Tomisa, G., Horváth, A., Sánta, B. et al. Epidemiology of comorbidities and their association with asthma control. Allergy Asthma Clin Immunol 17, 95 (2021). https://doi.org/10.1186/s13223-021-00598-3 ) is an interesting paper reflecting data collection from more than 12,000 asthmatic patients in Hungary regarding their condition and associated comorbidities. We found it valuable that the paper provides an overview of asthma comorbidities not usually considered in similar reports. Nevertheless, we believe that chronic rhinosinusitis (CRS) with or without nasal polyps (CRSwNP or CRSsNP) should have been listed due to its high incidence and prevalence, its association with asthma which is also endorsed in both GINA and EPOS, as well as in several peer-reviewed scientific papers, and to reflect the role of this comorbidity in poor control and a most severe presentation of asthma for the patient. Consequently, several targeted therapies (especially monoclonal antibodies) used for several years in severe forms of asthma are now indicated also for the effective treatment of nasal polyps.

Abstract Background Asthma is a common disease in childhood and adolescence with lifelong consequences particularly among those at risk of severe disease, poor control and/or frequent exacerbations. Specialist care is recommended for at-risk children and adolescents, yet access to specialist management in free-to-access healthcare settings remains poorly understood. Methods A Danish nationwide cohort of children and adolescents aged 2–17 years with persistent asthma, defined as repeated redemption of inhaled corticosteroids (ICS) during 2015, were followed for two years, to identify at-risk children and adolescents comprising those with severe asthma (classified according to GINA 2020 guidelines), poor control (defined as use of 400/600 (ages 2–11/12 +) annual doses of short-acting bronchodilators), or frequent exacerbations (defined as use of oral steroids or hospitalization), and access to specialist care. The population is chosen due to detailed medical records in the setting of universal health care. Results The cohort comprised of 29,851 children and adolescents (59% boys), with a median age of 9 years. While 17% of children were on high dose ICS, 22% were on daily ICS below GINA low dose cut-off. Prevalence of severe asthma (3.0–6.5%) was lower than poor asthma control (6.4–25%); both declined from childhood to adolescence. Exacerbations occurred in 7.1–9.0% of children, with median number of exacerbations being 1 (IQR 1–1). Despite being classified as having mild-to-moderate asthma, 15% had poor asthma control and 3.8% experienced exacerbation(s), respectively. While 61% of children with severe asthma and 58% with exacerbation-prone disease were in specialist care, only 24% with uncontrolled disease were receiving specialist care. Of children and adolescents using high-dose ICS, 71% were managed in primary care, while the use of additional controllers was more common in specialist care. Conclusions Throughout childhood and adolescence, there was a high prevalence of severe asthma and poor control, although their prevalence declined with age. We demonstrate a large unmet need for specialist care among children with at-risk asthma, particularly among those with poorly controlled asthma, even in a system with free-to-access, tax-funded healthcare.

Introduction As a common chronic disease seen across all ages, asthma has the potential to incur high societal and individual costs from both direct healthcare costs and loss of productivity. Most previous studies use smaller, selected populations to assess the cost of asthma, possibly reducing generalisability. We, therefore, aimed to assess the total, nationwide economic burden of asthma by severity from both an individual and a societal perspective.Methods The annual cost of asthma was assessed in a Danish nationwide cohort of patients aged 18–45 during 2014–2016 as excess healthcare costs, loss of income and welfare expenditure compared with controls (matched 1:4) using national registries. Asthma severity was defined as mild-to-moderate (steps 1–3 or step 4 without exacerbations) or severe (step 4 with exacerbations or step 5).Results Across 63 130 patients (mean age 33, 55% female), the annual excess cost of asthma compared with controls was predicted to €4095 (95% CI €3856 to €4334) per patient. Beyond direct costs related to treatment and hospitalisations (€1555 (95% CI €1517 to €1593)), excess indirect costs related to loss of income (€1060 (95% CI €946 to €1171)) and welfare expenditure (eg, sick pay and disability pensions) (€1480 (95% CI €1392 to €1570)) were seen. Crude pooling of excess costs resulted in an annual societal cost of €263 million for all included patients.Severe asthma (4.5%) incurred 4.4 times higher net costs (€15 749 (95% CI 13 928 to €17 638)) compared with mild-to-moderate disease (€3586 (95% CI €3349 to €3824)). Furthermore, patients with severe asthma experienced an annual loss of income of €3695 (95% CI €4106 to €3225) compared with controls.Conclusion In young adults with asthma, a significant societal and individual financial burden of disease was seen across severities. Expenditure was mainly driven by loss of income and welfare utilisation, rather than direct healthcare costs.

Abstract Background Chronic cough, more than 8 weeks, can either be without co-morbidity called unexplained chronic cough (UCC) or with co-morbidity called refractory chronic cough (RCC). Using datasets from the Danish National Prescription Registry (Prescription Registry) and Danish National Patient Registry (Patient Registry) we wanted to investigate the prevalence and factors of importance of cough in a Nationwide registry. Material and methods Inclusion criteria were patients 18–90 years with at least one final cough diagnosis (ICD-10 DR05/DR059) in Patient registry or patients who have redeemed ≥2 prescriptions for relevant cough-medication within a 90-day harvest in the Prescription registry from 2008 to 2017. To validate this study’s chosen proxy on chronic cough an analysis of the Patient registry sub-population with a contact of ≥8 weeks and then final diagnosis code DR05/DR059 was also performed. The population was divided into UCC and RCC. Results Of the 104,216 patients from the Prescription registry, 52,727 were classified as having UCC and 51,489 were classified with RCC. From the Patient registry 34,260 were included, of whom 12,278 had UCC and 21,982 had RCC. Cough were frequently found among females (p

Background Real-life evidence on prevalence and management of severe asthma is limited. Nationwide population registries across the Nordic countries provide unique opportunities to describe prevalence and management patterns of severe asthma at population level. In nationwide register data from Sweden, Norway and Finland, we examined the prevalence of severe asthma and the proportion of severe asthma patients being managed in specialist care. Methods This is a cross-sectional study based on the Nordic Dataset for Asthma Research (NORDSTAR) research collaboration platform. We identified patients with severe asthma in adults (aged ≥18 years) and in children (aged 6–17 years) in 2018 according to the European Respiratory Society/American Thoracic Society definition. Patients managed in specialist care were those with an asthma-related specialist outpatient contact (only available in Sweden and Finland). Results Overall, we identified 598 242 patients with current asthma in Sweden, Norway and Finland in 2018. Among those, the prevalence of severe asthma was 3.5%, 5.4% and 5.2% in adults and 0.4%, 1.0%, and 0.3% in children in Sweden, Norway and Finland, respectively. In Sweden and Finland, 37% and 40% of adult patients with severe asthma and two or more exacerbations, respectively, were managed in specialist care; in children the numbers were 56% and 41%, respectively. Conclusion In three Nordic countries, population-based nationwide data demonstrated similar prevalence of severe asthma. In children, severe asthma was a rare condition. Notably, a large proportion of patients with severe asthma were not managed by a respiratory specialist, suggesting the need for increased recognition of severe asthma in primary care.

Background The 2022 Global Initiative for Asthma guidelines emphasise the inhaled long-acting β2-agonist formoterol as part of the first treatment step, and therefore formoterol use among athletes will probably increase. However, prolonged supratherapeutic use of inhaled β2-agonists impairs training outcomes in moderately trained men. We investigated whether inhaled formoterol, at therapeutic doses, imposes detrimental effects in endurance-trained individuals of both sexes. Methods 51 endurance-trained participants (31 male, 20 female; mean±sd maximal oxygen consumption (V̇O2max) 62±6 mL·min−1·kg bw−1 and 52±5 mL·min−1·kg bw−1, respectively) inhaled formoterol (24 µg; n=26) or placebo (n=25) twice daily for 6 weeks. At baseline and follow-up, we assessed V̇O2max and incremental exercise performance during a bike-ergometer ramp-test; body composition by dual-energy X-ray absorptiometry; muscle oxidative capacity by high-resolution mitochondrial respirometry, enzymatic activity assays and immunoblotting; intravascular volumes by carbon monoxide rebreathing; and cardiac left ventricle mass and function by echocardiography. Results Compared to placebo, formoterol increased lean body mass by 0.7 kg (95% CI 0.2–1.2 kg; treatment×trial p=0.022), but decreased V̇O2max by 5% (treatment×trial p=0.013) and incremental exercise performance by 3% (treatment×trial p

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) and asthma frequently co-exist and share pathologic features. Taking a “global” treatment approach benefits diagnosis and treatment of both, but care is often siloed by specialty: joined-up clinics are uncommon. Our objectives were to explore expert opinion to give practical suggestions to identify adults needing global airways care; enhance cross-specialty working; and widen knowledge to support diagnosis and management, integrate with existing care pathways, and supplement existing guidelines.MethodsSixteen practicing physicians from northern Europe were invited for their national and/or international standing in treating asthma and/or chronic rhinosinusitis. Appreciative Inquiry techniques were used to guide their discussions.ResultsKey themes arising were screening and referral, collaboration on management, awareness and education, and research. Provided are screening criteria and suggestions for specialist referrals, and pointers for physicians to optimize their knowledge of global airways disease. Collaborative working is underscored, and practical suggestions are given for multidisciplinary teamworking within global airways clinics. Research gaps are identified.ConclusionThis initiative provides practical suggestions for optimizing the care of adults with CRSwNP and asthma. Discussion of the role of allergy and drug exacerbations on these conditions, and care for patients with other global airways diseases were beyond scope; however, we expect some principles of our discussion will likely benefit patients with related conditions. The suggestions bridge asthma and CRSwNP management guidelines, envisioning interdisciplinary, global airway clinics relevant to various clinical settings. They highlight the value of joint screening for early recognition and referral of patients.

ABSTRACTObjective To evaluate if high-intensity interval training three times weekly for 12 weeks improves asthma control in overweight, postmenopausal women with uncontrolled, late-onset asthma.Methods The reported study is a randomized clinical pilot study (www.clinicaltrials.gov; NCT03747211) that compared 12 weeks of high-intensity interval training (spinning) with usual care. The five-question Asthma Control Questionnaire (ACQ-5) was used as primary outcome. Secondary measures included systemic inflammation and inflammation of the airways, body composition, and cardiac function during exercise.Results We included 12 women with asthma (mean age 65 years (SD 6); mean body mass index 30 kg/m2 (SD 2)) from whom eight were randomized to exercise and four to control. Baseline ACQ-5 was 1.95 (SD 0.53) in the control group and 2.03 (0.54) in the exercise group. Patients had a mean blood eosinophil level of 0.16 × 109cells/L (SD 0.07) and a mean fraction of exhaled nitric oxide of 23 ppb (SD 25). Mixed models showed that participants in the exercise group reduced their ACQ-5 by 0.55 points (95%CI −1.10 to −0.00; P = 0.08) compared with the control group. The exercise group significantly reduced their mean body fat percentage (−2.7%; 95%CI −4.5 to −0.8; P = 0.02), fat mass (−2.8 kg; 95%CI −5.1 to −0.4; P = 0.044) and android fat mass (−0.33 kg; 95%CI −0.60- −0.06; P = 0.038). In analyses of cardiac measures, we saw no significant effects on right ventricular function (fractional area change), diastolic function or left ventricular function.Conclusions Although changes in ACQ-5 were slightly insignificant, these preliminary findings indicate that aerobic exercise training can be used as a means to improve asthma control in overweight, postmenopausal women with asthma.

ABSTRACTPurpose When first-line chronic rhinosinusitis (CRS) treatment fails, patients can either be treated with oral or injected systemic corticosteroids. Although the EPOS and international guidelines for CRS do not mention injected corticosteroids, it is commonly used by ear, nose, and throat specialists. While the risks of systemic corticosteroids, in general, are known, the pros and cons of injected and oral corticosteroids (OCS) in CRS treatment are unclear.Methods A systematic review of studies that report the effects and/or side effects of injected and oral corticosteroids in the treatment of CRS was made according to the PRISMA guidelines.Results Altogether, 48 studies were included, only five studies reported on injected corticosteroids, and five attended with side effects. Three studies found beneficial effects of OCS perioperatively on sinus surgery, while four articles found no effect. Nineteen articles reported that OCS resulted in an improvement in symptoms. Two articles presented a longer-lasting effect of injected corticosteroids than OCS. Three studies reported adverse side effects of systemic corticosteroids, while two studies showed no adverse side effects. One study showed less adrenal suppression after injected corticosteroids compared to OCS. The evidence is not strong but shows a positive effect of systemic corticosteroids that lasts longer with injections.Conclusion Although systemic corticosteroids are widely used to treat CRS, there is a lack of studies comparing the OCS and injected corticosteroids. The evidence is sparse, however, injected steroids show longer effects with fewer side effects. An RCT study is needed to compare OCS and injected corticosteroids.

[This corrects the article DOI: 10.1371/journal.pone.0277767.].

ABSTRACTObjective We investigate symptoms of anxiety and depression among women with asthma prior to fertility treatment.Methods This is a cross-sectional study of women screened for eligibility to the PRO-ART study (RCT of omalizumab versus placebo in asthmatic women undergoing fertility treatment (NCT03727971)). All participants were scheduled for in vitro fertilization (IVF) treatment at four public fertility clinics in Denmark. Data on demographics and asthma control (ACQ-5) were obtained. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS-A and D, respectively) and defined as being present on both subscales if a score >7 was obtained. Spirometry, diagnostic asthma test, and measurement of fractional exhaled nitric oxide (FeNO) were conducted.Results A total of 109 women with asthma were included (mean age 31.8 ± 4.6 and BMI 25.5 ± 4.6). Most women had male factor infertility (36.4%) or unexplained infertility (35.5%). Twenty-two percent of the patients reported uncontrolled asthma (ACQ-5 score > 1.5). The mean HADS-A and HADS-D scores were 6.0 ± 3.8 (95% CI 5.3–6.7) and 2.5 ± 2.2 (95% CI 2.1–3.0), respectively. Thirty (28.0%) women reported anxiety symptoms, and four (3.7%) had concomitant depressive symptoms. Uncontrolled asthma was significantly associated with both depressive (p = 0.04) and anxiety symptoms (p = 0.03).Conclusions More than 25% of women with asthma prior to fertility treatment had self-reported symptoms of anxiety, and just below 5% had self-reported depressive symptoms, possibly related to uncontrolled asthma.

ABSTRACTBackground: Treatment guidelines for asthma management are derived almost exclusively from the results of controlled clinical trials undertaken in carefully selected patient populations; meaning that their outcomes may not reflect the true performance of treatments when used in general daily medical practice. The aim of this meta-analysis was to combine the results of observational studies investigating the fluticasone propionate/formoterol (FP/FORM) fixed-dose combination in real-world asthma patients. Methods: A systemic literature review was completed in March 2019 using the PubMed database. We identified 394 studies. Five studies, which included a total of 4756 patients treated with FP/FORM, were judged eligible and included in the meta-analysis. Results: The estimated severe asthma exacerbation rate was 11.47% (95% CI, 5.8 to 18.72%), calculated from the random effect model. A sensitivity analysis excluding 2 studies (one was an outlier, and the exacerbation rate for the studied treatment alone could not be determined in the other) showed a 7.04% rate of severe asthma exacerbations. The estimated relative risk of the incidence of severe asthma exacerbations was 0.323 (95% CI, 0.159 to 0.658). The estimated asthma control rate was 60.6% (95% CI, 55.7% to 65.6%). The odds of achieving asthma control significantly increased by FP/FORM compared with pre-study conditions (estimated odds ratio: 2.214 [95% CI, 1.292 to 3.795]; p

Since 1993, regular population health surveys in Greenland have supported and monitored the public health strategy of Greenland and have monitored cardiometabolic and lung diseases. The most recent of these surveys included 2539 persons aged 15+ from 20 communities spread over the whole country. The survey instruments included personal interviews, self-administered questionnaires, blood sampling, anthropometric measurements, blood pressure, ECG, oral glucose test, pulmonary function, hand grip strength and chair stand test. Blood samples were analysed for glucose, glycated haemoglobin (HbA1c), insulin, incretin hormones, cholesterol, kidney function, fatty acids in erythrocyte membranes and mercury, urine for albumin-creatinine ratio, and aliquots were stored at −80°C for future use. Data were furthermore collected for studies of the gut microbiome and diabetes complications. Survey participants were followed up with register data. The potential of the study is to contribute to the continued monitoring of risk factors and health conditions as part of Greenland’s public health strategy and to study the epidemiology of cardiometabolic diseases and other chronic diseases and behavioural risk factors. The next population health survey is planned for 2024. The emphasis of the article is on the methods of the study and results will be presented in other publications.

BACKGROUND: Although exercise and daily physical activity (PA) have long been known to benefit patients with chronic disorders, knowledge is limited regarding asthma.OBJECTIVE: In a Danish setting, our aim was to measure physical activity, sedentary behavior, and physical capacity among patients with asthma. We hypothesized that people with severe asthma would be less active and more sedentary than their mild-moderate counterparts.METHODS: Adults with asthma were recruited through respiratory outpatient clinics and subsequently examined twice, 4 weeks apart. At each visit, participants underwent a series of lung function tests, questionnaires, and maximum oxygen uptake testing (VO2max). Between the visits, participants wore an accelerometer continuously for 4 weeks, measuring sedentary time and daily steps. Sixty patients, 27 with mild-moderate asthma (GINA 1–3) and 33 with severe asthma (GINA 4–5), completed both visits and had valid accelerometer measurements.RESULTS: No significant differences between the two groups were found in sedentary time, number of steps or VO2max. VO2max was significantly correlated with FeNO (r = −0.30, p

Asthma and exercise-induced bronchoconstriction are highly prevalent in elite athletes compared with the general population. Some athletes have classic asthma with allergic sensitization; however, it seems that a proportion of athletes develop asthma as a result of several years of intensive training. It leads us to believe that asthma in athletes consists of at least two distinct endotypes – classic early-onset, Type 2 mediated asthma, and asthma with later onset caused by exercise which might be classified as non-Type 2 asthma. The purpose of this review is to evaluate the current literature on asthma in athletes focusing on inflammation and examine if asthma in athletes could be characterized as either Type 2- or non-Type 2 asthma.

Objectives To evaluate the efficacy of intensive smoking cessation interventions (ISCIs) directly compared with shorter interventions (SIs), measured as successful quitting. Method Medline, Embase, the Cochrane Library and CINAHL were searched on 15 October 2021. Peer-reviewed randomised controlled trials (RCTs) of adult, daily smokers undergoing an ISCI were included. No setting, time or language restrictions were imposed. Risk of bias and quality of evidence was assessed using the Cochrane tool and Grading of Recommendations, Assessment, Development and Evaluation, respectively. Meta-analyses were conducted using a random-effects model. Results 17 550 unique articles were identified and 17 RCTs evaluating 9812 smokers were included. 14 studies were conducted in Europe or the USA. The quality of the evidence was assessed as low or moderate. Continuous abstinence was significantly higher in ISCIs in the long term (risk ratio 2.60, 95% CI 1.71–3.97). Direction and magnitude were similar in the short term; however, they were not statistically significant (risk ratio 2.49, 95% CI: 0.94–6.56). When measured as point prevalence, successful quitting was still statistically significant in favour of ISCIs, but lower (long term: 1.64, 1.08–2.47; short term: 1.68, 1.10–2.56). Sensitivity analysis confirmed the robustness of the results. Conclusion ISCIs are highly effective compared to SIs. This important knowledge should be used to avoid additional morbidity and mortality caused by smoking.

Asthma and infertility are the most common disorders among women of reproductive age. Time to pregnancy is prolonged in women with asthma, and importantly, age seems to be a more important risk factor regarding fertility in women with asthma compared to women without asthma. Some data have shown a higher frequency of miscarriages in women with asthma, although the data are conflicting on this issue as studies have observed no association between asthma and pregnancy loss. Furthermore, studies have shown no negative effect of asthma on the total number of offspring. Pregnancy may, thus, have a significant impact on women with asthma, as well as on their offspring. The age of the women has an important impact on ability to conceive, but also for the pregnancy itself, with higher risk of uncontrolled asthma as well as asthma exacerbations with increasing age. Well-controlled asthma decreases the risk of maternal and fetal complications, while poorly controlled and undertreated asthma is associated with a range of risks for both mother and fetus. Asthma treatment should follow the general guidelines for asthma therapy, irrespective of pregnancy status, including treatment with inhaled corticosteroids, β2-agonists and muscarinic antagonists. Targeted treatment with biologics for severe asthma seems to be without important adverse effects. The use of systemic corticosteroids may be associated with adverse events during the first trimester; however, an exacerbation with the associated risk of hypoxaemia is worse for the fetus. Best possible asthma control may be achieved using repeated measurements of fractional exhaled nitric oxide (FENO), as the use of FENO compared with symptoms registration only has been shown to reduce exacerbation rate. In conclusion, women with asthma should be encouraged to conceive at an early age, might experience miscarriages, but the number of offspring are the same as in women without asthma. Well treated asthma is important for the well-being of both the mother and the unborn fetus.

BackgroundType 2 inflammation underlies the chronicity of disease in subgroups of patients with asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and atopic dermatitis (AD), that often co-exist. Although several studies have investigated the unmet needs of asthma, AD and CRSwNP as such, little is known about the similarities and differences in experiences and perspectives of the current management of patients with comorbid Type 2 inflammatory diseases.AimsTo improve insight into the common and organ-specific needs of patients with Type 2 inflammation and comorbidities, allowing the formulation of recommendations to better address these needs in the future.MethodologyThis qualitative study was conducted between July 2021 and December 2021 using semi-structured face-to-face or telephone interviews with patients suffering from year-long severe chronic Type 2 inflammation and at least one co-morbid inflammatory condition. Seven participating academic centers in Europe interviewed asthma (Copenhagen and Leuven), CRSwNP (London, Amsterdam and Crete) and/or AD (Oldenburg and Zurich) patients on patient characteristics, disease severity, shortcomings of current care pathways and suggestions for improvement of care. Transcripts were analyzed using an inductive thematic analysis approach.ResultsEighty-one patients with severe Type 2 inflammation and comorbidities were interviewed. Similar needs were recognized by patients with Type 2 inflammation, with both a lack of coordination in care and a lack of a real cure reported as being most frustrating. However, several needs are specific to asthma, CRSwNP and AD. Suggestions for improvement of care were generic across diseases, such as the implementation of a multidisciplinary approach, the improved facilitation of access to better treatments, the increase of general awareness on disease burden, and better educational programs for healthcare providers and patients. Of note, patients with CRSwNP also stated the need for alternatives to sinus surgery, whereas patients with asthma requested better medical care to prevent exacerbations and patients with AD would warmly welcome the reimbursement of emollients.ConclusionPatients with asthma, CRSwNP and AD have shared unmet needs that need to be addressed by physicians, the academic community and health policy makers. This survey provides unique recommendations made by patients for the implementation of better care.

Research question Does menopausal hormone therapy (HT) with exogenous oestrogens and progestogens change the use of inhaled anti-asthma medications in women with asthma? Methods In a population-based matched cohort study using the Danish registries, we included women with asthma aged 45–65 years from 1 June 1995 to 30 June 2018. We investigated whether HT with oestrogen and/or progestogens was associated with changes in use of inhaled anti-asthma therapies in the 12 months following initiation. We used exposure density matching to match exposed subjects with unexposed subjects on age, household income and level of education. An exposed subject was defined as receiving HT. We calculated mean dose of medications and odds ratios of increases in the 12 months following HT initiation. Results We included 139 483 women with asthma, of whom 116 014 (83.2%) were unexposed subjects and 23 469 (16.8%) exposed subjects. Mean±sd age was 53.0±5.2 years. Initiation of HT was not consistently associated with increased mean doses of inhaled corticosteroids (ICS), or long- and short-acting β2-agonists. Women receiving systemic oestrogens had increased odds ratios of large increases (>100 µg) in ICS at 6 months (OR 1.09; 95% CI 1.04–1.13; p

Abstract Background Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. Methods ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR’s collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. Conclusions ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001-2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder.

Lung diseases can complicate pregnancy, but little is known about the experiences of pregnancy among women living with such diseases. This survey aimed to understand the experiences of women with a lung condition before and during pregnancy, in childbirth and post-partum. The survey was translated into nine languages and hosted online between March and May 2018. This paper reports on 327 women who had asthma, cystic fibrosis (CF), lymphangioleiomyomatosis (LAM) and sarcoidosis as a sole or primary lung condition. Women with CF and LAM were most likely to report that their condition influenced their decision to have children. Those with CF and LAM who did become pregnant reported greater satisfaction with their healthcare during pregnancy and gave more consideration to factors such as location and type of birth; they were also more concerned about the impact of the pregnancy on their health than women with other diseases. Women with sarcoidosis reported receiving conflicting advice as to both the impact of their condition on pregnancy and how becoming pregnant might impact their health. Women with asthma reported not always being able to access the information they needed from healthcare professionals. The results suggest that healthcare providers should be having dialogues with affected women early on, from before conception, throughout the pregnancy and after giving birth, and training should be provided to healthcare staff to equip them with the information they need to do this.

Background There is growing evidence that upper airway symptoms coexist with lower airway symptoms in COPD. Still, the prevalence and impact of upper airway disease on the nature and course of COPD remain unclear. We aimed to describe this in a cross-sectional study. Methods We examined a cohort of COPD patients with pulmonary function tests, induced sputum, blood eosinophils, atopy tests and computed tomography (CT) of the paranasal sinuses. Lower airway symptoms were assessed using the COPD Assessment Test (CAT), and upper airway symptoms were assessed using the nasal subdomain of the 22-item Sino Nasal Outcome Test (SNOT22nasal). We recruited patients from five sites in Denmark and Sweden. We excluded patients with a history of asthma. Findings In total, 180 patients (female 55%, age 67±8 years, forced expiratory volume in 1 s (FEV1 %) 52.4±16.6, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage: A: 18%, B: 54%, C: 3%, D: 25%) were included in the study. Seventy-four patients (41%) reported high upper airway symptoms (UAS, defined as SNOT22nasal≥6) with a median score of 10 (IQR 8–13). Patients with high UAS reported higher CAT scores (17.4±7.5 versus 14.9±6.6, p

Background Exercise-induced laryngeal obstruction (EILO) is a common cause of exertional breathlessness and wheeze yet is frequently misdiagnosed as asthma. Insight regarding the demographic characteristics, laryngeal abnormalities and impact of EILO is currently limited, with data only available from individual centre reports. The aim of this work was to provide a broader perspective from a collaboration between multiple international expert centres. Methods Five geographically distinct clinical paediatric and adult centres (3 Denmark, 1 UK, 1 USA) with an expertise in assessing unexplained exertional breathlessness completed database entry of key characteristic features for all cases referred with suspected EILO over a 5-year period. All included cases completed clinical asthma workup and continuous laryngoscopy during exercise (CLE) testing for EILO. Results Data were available for 1007 individuals (n=713 female (71%)) with a median (range) age of 24 (8–76) years, and of these 586 (58%) were diagnosed with EILO. In all centres, EILO was frequently misdiagnosed as asthma; on average there was a 2-year delay to diagnosis of EILO, and current asthma medication was discontinued in 20%. Collapse at the supraglottic level was seen in 60%, whereas vocal cord dysfunction (VCD) was only detected/visualised in 18%. Nearly half (45%) of individuals with EILO were active participants in recreational-level sports, suggesting that EILO is not simply confined to competitive/elite athletes. Conclusion Our findings indicate that key clinical characteristics and the impact of EILO/VCD are similar in globally distinct regions, facilitating improved awareness of this condition to enhance recognition and avoid erroneous asthma treatment.

Background: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed. Methods: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1–4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined. Findings: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration. Interpretation: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials. Funding: The study was funded by Innovationsfonden Denmark and UNION therapeutics.

Introduction Late-onset asthma in postmenopausal women is characterised by poor disease control with daily symptoms and reduced quality of life despite treatment with inhaled antiasthma therapies. These patients represent a phenotype that is characterised by low eosinophilic airway inflammation, severe symptoms, moderate obesity and poor response to inhaled antiasthma therapies, which highlights the need of identification of alternative treatment strategies. Thus, this study aims to evaluate if regular high-intensity aerobic exercise improves symptom control in postmenopausal women with asthma.Methods and analysis This is an ongoing randomised controlled trial planning to enrol 40 postmenopausal women with late-onset asthma. Participants are randomised 1:1 either to supervised exercise training (spinning) three times per week for 12 weeks or to usual care. The primary outcome is change from baseline to follow-up in the Asthma Control Questionnaire. Secondary outcomes are changes in markers of systemic inflammation, airway inflammation, body composition and right ventricular function of the heart.Ethics and dissemination The study is approved by the Ethics Committee in the Capital Region of Denmark nr. H-18028966 and the Danish Data Protection Agency nr. VD-2019–59. The methods used in the study are well known and have a low risk with a chance of substantial improvement in disease control in this patient group. Results are planned to be published in an international peer-reviewed medical journal regardless of outcome.Trial registration number NCT03747211.

Introduction Patients with obstructive lung diseases are possibly at risk of developing severe outcomes of coronavirus disease 2019 (COVID-19). Therefore, the aim of this study was to determine the risk of severe outcomes of COVID-19 among patients with asthma and COPD. Methods We performed a nationwide cohort study of patients with COVID-19 from 1 February to 10 July 2020. All patients with COVID-19 registered in the Danish registers were included. Using International Classification of Diseases (ICD) codes and medication history, patients were divided into asthma, COPD or no asthma or COPD. Primary outcome was a combined outcome of severe COVID-19, intensive care or death. Results Out of 5104 patients with COVID-19 (median age 54.8 years (25–75th percentile 40.5 to 72.3); women, 53.0%), 354 had asthma and 432 COPD. The standardised absolute risk of the combined end-point was 21.2% (95% CI 18.8–23.6) in patients with COPD, 18.5% (95% CI 14.3–22.7) in patients with asthma and 17.2% (95% CI 16.1–18.3) in patients with no asthma or COPD. Patients with COPD had a slightly increased risk of the combined end-point compared with patients without asthma or COPD (risk difference 4.0%; 95% CI 1.3–6.6; p=0.003). In age standardised analyses, there were no differences between the disease groups. Low blood eosinophil counts (

Introduction Asthma is associated with prolonged time to pregnancy and a higher need for fertility treatment. However, the mechanism underlying this association remains incompletely understood. Previous research points to asthma-driven systemic inflammation also affecting the reproductive organs and thereby fertility. The aim of this study was to determine if treatment with omalizumab prior to fertility treatment will increase pregnancy rate among women with asthma by decreasing the systemic asthma-related inflammation and, by that, to provide insight into the underlying mechanisms.Methods and analysis This is an ongoing prospective multicentre randomised controlled trial planned to enrol 180 women with asthma recruited from fertility clinics in Denmark. The patients are randomised 1:1 to either omalizumab or placebo. The primary endpoint is the difference in pregnancy rate confirmed with ultrasound at gestational week 7 of pregnancy. The secondary endpoints are change in sputum and blood eosinophil cell count, change in biomarkers, change in microbiota, together with rate of pregnancy loss, frequency of malformations, pre-eclampsia, preterm birth, birth weight, small for gestational age and perinatal death between groups.Ethics and dissemination The methods used in this study are of low risk, but if successful, our findings will have a large impact on a large group of patients as infertility and asthma are the most common chronic diseases among the young population. The study has been approved by the Ethics Committee–Danish national research ethics committee (H-18016605) and the Danish Medicines Agency (EudraCT no: 2018-001137-41) and the Danish Data Protection Agency (journal number: VD-2018486 and I-Suite number 6745). The test results will be published regardless of whether they are positive, negative or inconclusive. Publication in international peer-reviewed scientific journals is planned.Trial registration number NCT03727971.

Processing of induced sputum is time consuming and requires trained personnel, and consequently the use of induced sputum is limited to few sites globally. The six-gene signature (6GS) is an mRNA-based gene signature that was developed to provide a clinically feasible method for inflammatory phenotyping. In this study, we assessed whether the 6GS would perform similarly in induced sputum sampled using a simplified method, by which induced sputum can be sampled and stored directly for later qPCR analyses, to the conventional method of manual plug selection. Two separate sputum samples were collected from 27 patients with asthma; one processed as a whole sample in an Oragene-RNA RE 100 vial and one processed using manual plug selection. Expression of 6GS was measured in both samples, of which 20 pairs (74%) had enough samples and results of sufficient quality of gene expression for further analyses. We found a significantly higher median RNA concentration in whole sampled sputum and consistently stronger gene expression compared to the plug method. Further, we found the two methods to agree, as 97% of observations were within the limits of agreement, as well as having a good-to-excellent reliability using intraclass correlation. Finally, we found 6GS in the whole sampled sputum to perform equal to or better than the manually selected plugs for discriminating inflammatory phenotypes defined by sputum differential count. In conclusion, whole sampling of induced sputum provides a clinically feasible method for inflammatory phenotyping.

Background: The BREATHE study is a cross-sectional study of real-life patients with asthma and/or COPD in Denmark and Sweden aiming to increase the knowledge across severities and combinations of obstructive airway disease. Design: Patients with suspicion of asthma and/or COPD and healthy controls were invited to participate in the study and had a standard evaluation performed consisting of questionnaires, physical examination, FeNO and lung function, mannitol provocation test, allergy test, and collection of sputum and blood samples. A subgroup of patients and healthy controls had a bronchoscopy performed with a collection of airway samples. Results: The study population consisted of 1403 patients with obstructive airway disease (859 with asthma, 271 with COPD, 126 with concurrent asthma and COPD, 147 with other), and 89 healthy controls (smokers and non-smokers). Of patients with asthma, 54% had moderate-to-severe disease and 46% had mild disease. In patients with COPD, 82% had groups A and B, whereas 18% had groups C and D classified disease. Patients with asthma more frequently had childhood asthma, atopic dermatitis, and allergic rhinitis, compared to patients with COPD, asthma + COPD and Other, whereas FeNO levels were higher in patients with asthma and asthma + COPD compared to COPD and Other (18 ppb and 16 ppb vs 12.5 ppb and 14 ppb, p

Abstract Background Lung function is an important predictor of morbidity and mortality, with accelerated lung function decline reported to have immense consequences for the world’s healthcare systems. The lung function decline across individual’s lifetime is a consequence of age-related changes in lung anatomical structure and combination of various environmental factors; however, the exact molecular mechanisms contributing to this decline are not fully understood. DNA methylation is an epigenetic modification that changes across individual’s lifetime, as well as allows for interplay between environmental and genetic factors. DNA methylation plays a crucial role in regulation of gene expression, with increasing evidence linking aberrant DNA methylation levels with a number of common human diseases. In this study, we investigated possible associations between genome-wide DNA methylation levels and lung function in 169 pairs of middle-aged monozygotic twins (86 male pairs: mean age (min-max) = 66 years (57–79); 83 female pairs: mean age (min-max) = 66 years (56–78)). The twins were collected from the Danish Twin Registry and were examined at baseline (1998–1999) and follow-up (2008–2011) visits. Using the twin design, we correlated intra-pair differences in cross-sectional and longitudinal lung function with intra-pair blood DNA methylation differences at follow-up by linear regression analyses adjusted for sex, age, BMI, smoking, and blood cell composition measured for each individual with the use of flow cytometry. Results We identified several differentially methylated CpG sites associated with forced expiratory volume the first second (FEV1) and forced vital capacity (FVC). Three probes identified for level of FVC were located in GLIPR1L2 gene (lowest p value = 7.14 × 10−8), involved in innate immunity and tumour-suppressor/pro-oncogenic mechanisms. Change in FEV1 during the 11-year follow-up period was associated with blood DNA methylation level in TRIM27 gene (p value = 1.55 × 10−6), a negative regulator of CD4 T cells, and also involved in cancer development. Several enriched pathways were identified, especially for FEV1, with one being “TGFBR” (Benjamini-Hochbergadj p value = 0.045), the receptor for TGFβ, a growth factor involved in normal lung tissue repair through pro-fibrotic effects. Conclusions Our findings suggest that epigenetic regulation of immunological- and cancer-related genes, as well as TGF-β-receptor-related genes, may be involved in the cross-sectional level and longitudinal change in lung function in middle-aged monozygotic twins.

Abstract The prevalence of asthma and allergic diseases is disproportionately distributed among different populations, with an increasing trend observed in Western countries. Here we investigated how the environment affected genotype-phenotype association in a genetically homogeneous, but geographically separated population. We evaluated 18 single nucleotide polymorphisms (SNPs) corresponding to 8 genes (ADAM33, ALOX5, LT-α, LTC4S, NOS1, ORMDL3, TBXA2R and TNF-α), the lung function and five respiratory/allergic conditions (ever asthma, bronchitis, rhinitis, dermatitis and atopy) in two populations of Inuit residing either in the westernized environment of Denmark or in the rural area of Greenland. Our results showed that lung function was associated with genetic variants in ORMDL3, with polymorphisms having a significant interaction with place of residence. LT-α SNP rs909253 and rs1041981 were significantly associated with bronchitis risk. LT-α SNP rs2844484 was related to dermatitis susceptibility and was significantly influenced by the place of residence. The observed gene-phenotype relationships were exclusively present in one population and absent in the other population. We conclude that the genotype-phenotype associations relating to bronchitis and allergy susceptibility are dependent on the environment and that environmental factors/lifestyles modify genetic predisposition and change the genetic effects on diseases.

Background Recent registry studies have demonstrated a higher prevalence of asthma among women with polycystic ovary syndrome (PCOS). We aimed to assess the association and heritability of PCOS and asthma in a Danish twin cohort. Methods Data for 32 382 female twins from the Danish Twin Registry were included. Twins with PCOS were identified by searching the Danish National Patient Registry for International Classification of Diseases-10 code E28.2. Asthma was diagnosed by questionnaires. Results 103 (0.3%) women had a PCOS diagnosis. The risk of asthma was increased among women with PCOS compared with women without (18% versus 9%, respectively; OR 2.11 (95% CI 1.13–3.96); p=0.02). After adjustment for age, body mass index, alcohol consumption and smoking status, the risk of asthma was still increased, but was no longer statistically significant (OR 1.54 (95% CI 0.75–3.17); p=0.24). Variance components analysis showed that shared environmental factors explained 49% (95% CI 24–68%) and unique environmental factors explained 51% (95% CI 32–76%) of the susceptibility to PCOS. For asthma, 44% (95% CI 28–61%) of the variance was explained by genetic factors, whereas 25% (95% CI 11–38%) was ascribable to shared environmental factors and 31% (95% CI 26–36%) to unique environmental factors. Conclusion The risk of asthma is twice as high among female twins with PCOS. The individual susceptibility to PCOS is mainly due to environmental factors and not genetics.

Background In the EFFORT (Effects of Exercise and Diet in Nonobese Asthma Patients – A Randomized Controlled Trial) study, maximum exercise capacity (V′O2max) increased significantly within a 2-month high-intensity spinning period. Furthermore, the study concluded that only the combined exercise and diet intervention improved asthma control, significantly. This study examined whether original improvements in V′O2max and asthma control were present 1 year after intervention completion. Method In the original trial, 149 patients were randomised into four study groups. Participants were assessed with an incremental cycle ergometer test and the Asthma Control Questionnaire (ACQ). Of the 149 patients, 66 accepted the follow-up invitation. Participants were distributed in their original groups: exercise group (n=18), diet group (n=117), combined diet and exercise group (n=115) and the control group (n=110). Patients were assessed with original procedures. Though, upon measuring V′O2max, the original four study groups were merged into one spinning group (n=127) and one nonspinning group (n=133). Results Comparing the spinning and nonspinning group, there was no significant between-group difference in V′O2max, at 1-year follow-up (p=0.3). In addition, there was no significant between-group difference in ACQ score (p=0.6). Hence, in the combined group, the initial improvement in the ACQ score had regressed to pre-intervention values within 1 year from study completion. Conclusion There were no measurable long-lasting effects on V′O2max 1 year after the intervention was completed. Furthermore, there was no long-lasting effect of the combined intervention on asthma control.

Background: Listening to music as a means of relieving anxiety before and during endoscopy has been examined in several studies but results so far are contradictory and inconclusive. Aims: We aimed to determine whether listening to music could reduce anxiety prior to and during bronchoscopy, and whether it is influenced by the patient’s preference in music. Methods: 300 patients undergoing bronchoscopy for suspected lung cancer were randomly assigned to: self-selected music, specially-designed music (MusiCureTM), or control (no sound). Spielberger’s State-Trait Anxiety Inventory (STAI) was administered three times: at admission, after 20 min with or without music (preceding bronchoscopy), and shortly before discharge. The primary outcome was STAI state score after 20 min, with or without exposure to music prior to bronchoscopy. Results: On average, music reduced the STAI score by 2.5 points (95% CI, 1.1 to 4.0; p

Background: The use of music to relieve anxiety has been examined in various studies, but the results are inconclusive. Methods: From April to October 2015, 160 patients undergoing examination of pulmonary nodules were randomly assigned to MusiCure or no music. MusiCure was administered through earplugs to ensure blinding of the staff and was played from admission to the operating theatre to the end of the bronchoscopy. Spielberger's State-Trait Anxiety Inventory (STAI) was administered on admission, immediately before bronchoscopy, and on discharge. Secondary outcomes were p-cortisol, physiological variables, dosage of sedatives, movements measured by Actigraph, bronchoscopy duration, number of re-examinations, and overall perception of the sounds in the operating theatre measured by Visual analogue scale. Results: The STAI scores were similar on admission, but after a 10-min wait in the operating theatre, scores varied significantly between patients with and without music, with lower scores in the music group [median (interquartile range, IQR) 35 (18) vs. 43 (25); p=0.03]. Post hoc multiple regression revealed treatment group as insignificant when adjusting for sex and baseline anxiety. However, there was a significantly more positive perception of the sounds in the operating theatre in the music group (median (IQR) 8.2 (1.8) vs. 5.4 (6.8); p

Asthma is one of the most common chronic diseases worldwide affecting more than 300 million people. Symptoms are often non-specific and include coughing, wheezing, chest tightness, and shortness of breath. Asthma may be highly variable within the same individual over time. Although asthma results in death only in extreme cases, the disease is associated with significant morbidity, reduced quality of life, increased absenteeism, and large costs for society. Asthma can be diagnosed based on report of characteristic symptoms and/or the use of several different diagnostic tests. However, there is currently no gold standard for making a diagnosis, and some degree of misclassification and inter-observer variation can be expected. This may lead to local and regional differences in the treatment, monitoring, and follow-up of the patients. The Danish National Database for Asthma (DNDA) is slated to be established with the overall aim of collecting data on all patients treated for asthma in Denmark and systematically monitoring the treatment quality and disease management in both primary and secondary care facilities across the country. The DNDA links information from population-based disease registers in Denmark, including the National Patient Register, the National Prescription Registry, and the National Health Insurance Services register, and potentially includes all asthma patients in Denmark. The following quality indicators have been selected to monitor trends: first, conduction of annual asthma control visits, appropriate pharmacological treatment, measurement of lung function, and asthma challenge testing; second, tools used for diagnosis in new cases; and third, annual assessment of smoking status, height, and weight measurements, and the proportion of patients with acute hospital treatment. The DNDA will be launched in 2016 and will initially include patients treated in secondary care facilities in Denmark. In the nearby future, the database aims to include asthma diagnosis codes and clinical data registered by general practitioners and specialised practitioners as well.

Background: Several studies have shown that the use of pulmonary medication is widespread and often initiated without initial spirometry. Early detection of chronic obstructive pulmonary disease (COPD) by spirometry in General Practice is essential for an early and correct implementation of medical treatment. Aim: The aim of the present study was to evaluate the use of regular therapy following diagnostic spirometry for COPD in General Practice from February 2008 to February 2009. Method: Spirometry data and results were linked through Statistics Denmark with information from the Register of Medicinal Product Statistics using the unique personal identification code. Data were analysed to evaluate the impact of screening on use of regular COPD therapy. Primary outcome was initiation of regular therapy following COPD diagnosis with spirometry. Results: In a population of 3,376 individuals at risk, 1,458 underwent spirometric assessment with 631 being diagnosed with COPD; 110 of those received regular therapy before assessment with this figure increasing to 161 after spirometry. Of 827 participants not receiving a COPD diagnosis, 36 received regular therapy prior to assessment and 42 received regular therapy after spirometry despite no established COPD diagnosis. Conclusion: There is a significant chance of receiving regular therapy after being diagnosed with COPD. However, a large proportion of subjects diagnosed with COPD did not receive regular therapy following diagnosis. Efforts should be made to ensure correct diagnosis and correct medical treatment according to guidelines in individuals with COPD.

Background: low vitamin D status in pregnancy can influence the offspring’s lung function and contribute to childhood asthma development. The objective of this study was to examine the influence of neonatal vitamin D status on the development of asthma among children age 3−9 years in a large population sample. Method: in a case-cohort study utilizing a Danish biobank and register data we examined the association between neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentrations and incidence of asthma among children aged 3−9 years. Cases of asthma (n = 911) were randomly selected among all cases of asthma in the Danish National Patient Register from children born between 1992 and 2002. The sub-cohort (n = 1423) was randomly selected among all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first asthma diagnoses by quintiles of 25(OH)D3. Results: the median 25(OH)D3 (interquartile range) for asthma cases was 23 nmol/L (14−35) and the sub-cohort 25 nmol/L (14−40). The hazard ratio for developing asthma between ages 3 and 9 years was lower for children in the fifth quintile of neonatal 25(OH)D3 compared to children in the first quintile, both in the unadjusted (0.61 95% CI: 0.46−0.80) and adjusted (0.55 95% CI: 0.39−0.77) analyses. Conclusion: the results from our study suggest that higher neonatal vitamin D concentration may reduce the risk of developing childhood asthma at ages 3−9 years, indicating that neonatal vitamin D status as a proxy of vitamin D status during the prenatal period is important for normal immune- and lung development.

Recent research suggests that women with polycystic ovary syndrome (PCOS) have a higher risk of asthma. However, the severity of asthma, use of antiasthma medication and effect on fertility have yet to be investigated. In a case–control cross-sectional registry study using the Danish National Patient Register and other Danish registries, asthma prevalence, asthma severity, antiasthma medication use and fertility outcome were investigated among two groups of women with PCOS (n=1358 and n=17 123) and a healthy control group (n=5340). Both asthma prevalence (OR 1.45, 95% CI 1.24–1.70) and mean daily inhaled corticosteroid dose were higher among women with PCOS compared with healthy controls, whereas asthma severity was the same in women with and without PCOS. Women with PCOS and asthma had more in vitro fertilisation treatments than women in the control group with asthma, but the numbers of children per woman and spontaneous abortions were the same. Women with PCOS have a higher prevalence of asthma and a higher use of inhaled corticosteroids, whereas asthma severity is the same in women with and without PCOS. Asthma is associated with more in vitro fertilisation treatments in women with PCOS.

Asthma is characterised by inflammation and respiratory symptoms. Current asthma treatment is based on severity of asthma symptoms only. Exhaled nitric oxide fraction (FeNO) is not recommended by the Global Initiative for Asthma guidelines. The aim was to compare the usefulness of a FeNO guided versus symptom-based treatment in achieving improved asthma control assessed by airway hyperresponsiveness (AHR). 80 asthmatic patients were included in a double-blinded, parallel, randomised controlled trial with follow-up visits after 8, 24 and 36 weeks. Treatment was tailored using either a FeNO or Asthma Control Questionnaire (ACQ) based algorithm. Inclusion criteria were asthma symptoms and a provocative dose causing a 15% fall in forced expiratory volume in 1 s 0.05). When using FeNO as a treatment management tool, lowering of airway responsiveness occurred earlier than using ACQ. However, airway responsiveness and asthma control after 9 months were similar.

Introduction: In recognition of the value of long-term real-world data, a postauthorization safety study of the inhaled corticosteroid (ICS) fluticasone propionate and long-acting β 2 -agonist (LABA) formoterol fumarate (fluticasone/formoterol; Flutiform ® ) was conducted. Methods: This was a 12-month observational study of outpatients with asthma aged ⩾ 12 years in eight European countries. Patients were prescribed fluticasone/formoterol according to the licensed indication, and independently of their subsequent enrolment in the study. They were then treated according to local standard practice. The study objectives were to evaluate the safety and effectiveness of fluticasone/formoterol under real-world conditions. Results: The safety population for this study comprised 2539 patients (mean age 47.7 years; 94.3% aged ⩾ 18 years; 63.4% female). Most patients (1538/2539, 60.6%) had switched to fluticasone/formoterol from another ICS/LABA, primarily due to lack of efficacy (1150/2539, 45.3%). Three quarters (77.4%) of patients were treated for 12 months, and 80.6% continued fluticasone/formoterol treatment after the study. Adverse events (AEs) occurred in 60.0% patients, and 10.2% had AEs considered possibly related to fluticasone/formoterol [most commonly asthma exacerbation (2.0% patients), dysphonia (1.8%) and cough (1.1%)]. Thirty-six severe AEs, but no serious AEs, were considered possibly related to fluticasone/formoterol. The proportion of patients with controlled asthma (based on Asthma Control Test score ⩾ 20) increased from 29.4% at baseline to 67.4% at study end (last observation carried forward). The proportion of patients experiencing at least one severe exacerbation decreased from 35.8% in the year prior to enrolment to 9.8% during the study. Improvements from baseline to study end were also observed in Asthma Quality of Life scores and physician/patient reports of satisfaction with treatment. Conclusion: In this real-world postauthorization safety study, fluticasone/formoterol demonstrated a safety profile consistent with that seen in controlled clinical trials, with effectiveness in improving asthma control.

Although a minority of asthma patients suffer from severe asthma, they represent a major clinical challenge in terms of poor symptom control despite high-dose treatment, risk of exacerbations, and side effects. Novel biological treatments may benefit patients with severe asthma, but are expensive, and are only effective in appropriately targeted patients. In some patients, symptoms are driven by other factors than asthma, and all patients with suspected severe asthma (‘difficult asthma’) should undergo systematic assessment, in order to differentiate between true severe asthma, and ‘difficult-to-treat’ patients, in whom poor control is related to factors such as poor adherence or co-morbidities. The Nordic Consensus Statement on severe asthma was developed by the Nordic Severe Asthma Network, consisting of members from Norway, Sweden, Finland, Denmark, Iceland and Estonia, including representatives from the respective national respiratory scientific societies with the aim to provide an overview and recommendations regarding the diagnosis, systematic assessment and management of severe asthma. Furthermore, the Consensus Statement proposes recommendations for the organization of severe asthma management in primary, secondary, and tertiary care.

The fixed ratio criterion of forced expiratory volume in 1 s/forced vital capacity

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. Objectives: The purpose of the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study was to correlate clinical features and biomarkers with molecular characteristics in a well-profiled COPD cohort. Methods: A total of 67 COPD subjects (forced expiratory volume in the first second of expiration [FEV 1 ]: 45%-80% predicted) and 63 healthy smoking and nonsmoking controls underwent multiple assessments including patient questionnaires, lung function, and clinical biomarkers including fractional exhaled nitric oxide (FENO), induced sputum, and blood. Measurements and main results: The impact of inhaled corticosteroids (ICSs), and to a lesser extent current smoking, was more associated with symptom control, exacerbation rates, and clinical biomarkers, than severity by FEV 1 . The ICS-treated smoking subjects were most symptomatic, with significantly elevated scores on patient-reported outcomes and more annual exacerbations ( P

The current gold-standard method for diagnosing exercise-induced laryngeal obstruction (EILO) is continuous laryngoscopy during exercise (CLE), with severity classified by a visual grade scoring system. We evaluated the precision of this approach, by evaluating test–retest reliability of CLE and both inter- and intra-rater variability. In this prospective case–control study, subjects completed four consecutive treadmill CLE tests under identical conditions. Laryngoscopic video recordings were anonymised and graded by three expert raters. 2 months following initial scoring, videos were re-randomised and rating repeated to assess intra-rater agreement. 20 subjects (16 cases and four controls) completed four CLE tests. The time to exhaustion increased by 30 s (95% CI 0.02–57.8, p

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.