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Severe asthma trajectories in adults: findings from the NORDSTAR cohort.
von Bülow, A, Hansen, S, Sandin, P, Ernstsson, O, Janson, C, Lehtimäki, L, Kankaanranta, H, Ulrik, C, Aarli, BB, Geale, K, et al
The European respiratory journal. 2023;(3)
Abstract
BACKGROUND There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma. METHODS We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018. RESULTS Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma. CONCLUSIONS Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma.
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Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes.
Hvidtfeldt, M, Sverrild, A, Pulga, A, Frøssing, L, Silberbrandt, A, Hostrup, M, Thomassen, M, Sanden, C, Clausson, CM, Siddhuraj, P, et al
The Journal of allergy and clinical immunology. 2023;(1):107-116.e4
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Abstract
BACKGROUND Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation. OBJECTIVE We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment. METHODS In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (Feno) with a cutoff of 25 parts per billion. RESULTS Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with Feno-high and Feno-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with Feno-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, -0.42; P = .04), and in those with Feno-low asthma, it correlated with the density in the airway smooth muscle (ρ, -0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33. CONCLUSIONS Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with Feno-high asthma and with airway smooth muscle mast cells in patients with Feno-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
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Eosinophilic airway diseases: basic science, clinical manifestations and future challenges.
Janson, C, Bjermer, L, Lehtimäki, L, Kankaanranta, H, Karjalainen, J, Altraja, A, Yasinska, V, Aarli, B, Rådinger, M, Hellgren, J, et al
European clinical respiratory journal. 2022;(1):2040707
Abstract
Eosinophils have a broad range of functions, both homeostatic and pathological, mediated through an array of cell surface receptors and specific secretory granules that promote interactions with their microenvironment. Eosinophil development, differentiation, activation, survival and recruitment are closely regulated by a number of type 2 cytokines, including interleukin (IL)-5, the key driver of eosinophilopoiesis. Evidence shows that type 2 inflammation, driven mainly by interleukin (IL)-4, IL-5 and IL-13, plays an important role in the pathophysiology of eosinophilic airway diseases, including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Several biologic therapies have been developed to suppress type 2 inflammation, namely mepolizumab, reslizumab, benralizumab, dupilumab, omalizumab and tezepelumab. While these therapies have been associated with clinical benefits in a range of eosinophilic diseases, their development has highlighted several challenges and directions for future research. These include the need for further information on disease progression and identification of treatable traits, including clinical characteristics or biomarkers that will improve the prediction of treatment response. The Nordic countries have a long tradition of collaboration using patient registries and Nordic asthma registries provide unique opportunities to address these research questions. One example of such a registry is the NORdic Dataset for aSThmA Research (NORDSTAR), a longitudinal population-based dataset containing all 3.3 million individuals with asthma from four Nordic countries (Denmark, Finland, Norway and Sweden). Large-scale, real-world registry data such as those from Nordic countries may provide important information regarding the progression of eosinophilic asthma, in addition to clinical characteristics or biomarkers that could allow targeted treatment and ensure optimal patient outcomes.
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Impact of Socioeconomic Status on Adult Patients with Asthma: A Population-Based Cohort Study from UK Primary Care.
Busby, J, Price, D, Al-Lehebi, R, Bosnic-Anticevich, S, van Boven, JFM, Emmanuel, B, FitzGerald, JM, Gaga, M, Hansen, S, Hew, M, et al
Journal of asthma and allergy. 2021;:1375-1388
Abstract
INTRODUCTION Asthma morbidity and health-care utilization are known to exhibit a steep socioeconomic gradient. Further investigation into the modulators of this effect is required to identify potentially modifiable factors. METHODS We identified a cohort of patients with asthma from the Optimum Patient Care Research Database (OPCRD). We compared demographics, clinical variables, and health-care utilization by quintile of the UK 2011 Indices of Multiple Deprivation based on the location of the patients' general practice. Multivariable analyses were conducted using generalized linear models adjusting for year, age, and sex. We conducted subgroup analyses and interaction tests to investigate the impact of deprivation by age, sex, ethnicity, and treatment step. RESULTS Our analysis included 127,040 patients with asthma. Patients from the most deprived socio-economic status (SES) quintile were more likely to report uncontrolled disease (OR: 1.54, 95% CI: 1.16, 2.05) and to have an exacerbation during follow-up (OR: 1.27, 95% CI: 1.13, 1.42) than the least deprived quintile. They had higher blood eosinophils (ratio: 1.03; 95% CI: 1.00, 1.06) and decreased peak flow (ratio: 0.95, 95% CI: 0.94, 0.97) when compared to those in the least deprived quintile. The effect of deprivation on asthma control was greater among those aged over 75 years (OR = 1.81, 95% CI: 1.20, 2.73) compared to those aged less than 35 years (OR: 1.22, 95% CI: 0.85, 1.74; pinteraction=0.019). Similarly, socioeconomic disparities in exacerbations were larger among those from ethnic minority groups (OR: 1.94, 95% CI: 1.40, 2.68) than white patients (OR: 1.24, 95% CI: 1.10, 1.39; pinteraction=0.012). CONCLUSION We found worse disease control and increased exacerbation rates among patients with asthma from more deprived areas. There was evidence that the magnitude of socioeconomic disparities was elevated among older patients and those from ethnic minority groups. The drivers of these differences require further exploration.
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Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Sivapalan, P, Ulrik, CS, Bojesen, RD, Lapperre, TS, Eklöf, JV, Håkansson, KEJ, Browatzki, A, Tidemansen, C, Wilcke, JT, Janner, J, et al
Trials. 2020;(1):513
Abstract
OBJECTIVES The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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Bronchoscopic mucosal cryobiopsies as a method for studying airway disease.
Hvidtfeldt, M, Pulga, A, Hostrup, M, Sanden, C, Mori, M, Bornesund, D, Larsen, KR, Erjefält, JS, Porsbjerg, C
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(1):27-34
Abstract
BACKGROUND Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. OBJECTIVE To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. METHODS Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. RESULTS A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. CONCLUSION AND CLINICAL RELEVANCE By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments.
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Effects of Exercise and Diet in Nonobese Asthma Patients-A Randomized Controlled Trial.
Toennesen, LL, Meteran, H, Hostrup, M, Wium Geiker, NR, Jensen, CB, Porsbjerg, C, Astrup, A, Bangsbo, J, Parker, D, Backer, V
The journal of allergy and clinical immunology. In practice. 2018;(3):803-811
Abstract
BACKGROUND Behavioral interventions focusing on exercise and healthy diet improve asthma control in obese patients with asthma, but whether these interventions can lead to improvements in nonobese patients remains unclear. OBJECTIVES In a randomized, controlled parallel-group design, we studied the effects of an 8-week intervention of either exercise (high-intensity interval training), diet (high protein/low glycemic index), or a combination of the 2, on asthma control and clinical outcomes in nonobese patients with asthma. METHODS Nonobese adult patients with asthma (n = 149) were randomized to 1 of 4 groups: an exercise group, a diet group, an exercise + diet group, or a control group. Outcomes included Asthma Control Questionnaire (ACQ) score, asthma-related quality-of-life (Asthma-Related Quality-of-Life Questionnaire [AQLQ]) score, inflammatory cell counts in induced sputum, FEV1, fractional exhaled nitric oxide, and airway hyperresponsiveness (AHR). RESULTS A total of 125 patients completed the study and were included in the data analysis. Patients in the exercise + diet group improved the ACQ score from 1.9 ± 0.7 to 1.0 ± 0.7 and the AQLQ score from 5.2 ± 0.8 to 6.2 ± 0.7, which was statistically significant when compared with changes in the control group (P < .05 and <.01, respectively). The exercise group and the diet group did not improve either the ACQ score or the AQLQ score significantly compared with the control group and there were no significant changes in sputum cell counts, FEV1, fractional exhaled nitric oxide, or AHR within any groups following the intervention period. CONCLUSIONS The combination of exercise and diet improves asthma control in nonobese patients, but does not affect AHR or airway inflammation.
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Feasibility of high-intensity training in asthma.
Toennesen, LL, Soerensen, ED, Hostrup, M, Porsbjerg, C, Bangsbo, J, Backer, V
European clinical respiratory journal. 2018;(1):1468714
Abstract
Background: High-intensity interval training is an effective and popular training regime but its feasibility in untrained adults with asthma is insufficiently described. Objective: The randomized controlled trial 'EFFORT Asthma' explored the effects of behavioural interventions including high-intensity interval training on clinical outcomes in nonobese sedentary adults with asthma. In this article we present a sub analysis of data aiming to evaluate if patients' pre-intervention levels of asthma control, FEV1, airway inflammation and airway hyperresponsiveness (AHR) predicted their training response to the high-intensity interval training program, measured as increase in maximal oxygen consumption (VO2max). Design: We used data from the EFFORT Asthma Study. Of the 36 patients randomized to the 8-week exercise intervention consisting of high-intensity training three times per week, 29 patients (45% females) completed the study and were included in this data analysis. Pre-intervention assessment included the asthma control questionnaire (ACQ), spirometry, fractional exhaled nitric oxide (FeNO) and AHR to mannitol. VO2 max was measured during an incremental cycle test. Results: The majority of included patients had partly or uncontrolled asthma reflected by a mean (SD) ACQ at 1.7 (0.6). Median (IQR) FeNO was 28.5 (23.8) ppb and 75% had a positive mannitol test indicating AHR. The association between patients' training response measured as increase in VO2max and pre-intervention ACQ scores was not statistically significant (p = 0.49). Likewise, the association between patients' increase in VO2max and FeNO as well as AHR was not statistically significant (p = 0.80 and p = 0.58). Conclusions: Included asthma patients could adhere to the high-intensity interval protocol and improve their VO2max regardless of pre-intervention levels of asthma control, airway inflammation and AHR.
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Two-week inhalation of budesonide increases muscle Na,K ATPase content but not endurance in response to terbutaline in men.
Hostrup, M, Jessen, S, Onslev, J, Clausen, T, Porsbjerg, C
Scandinavian journal of medicine & science in sports. 2017;(7):684-691
Abstract
While chronic systemic administration of glucocorticoids increases muscle Na+ ,K+ ATPase content, such effect is unexplored after therapeutic inhalation. We investigated the effect of therapeutic inhalation of the glucocorticoid budesonide on Na+ ,K+ ATPase content of skeletal muscle in men. Ten healthy trained subjects, aged 23 ± 4 years (mean ± 95% CI), participated in the study. Before and after 2 weeks of daily inhalation of budesonide (1.6 mg/day), a biopsy was taken from the vastus lateralis muscle for measurement of Na+ ,K+ ATPase content and blood samples were drawn for determination of plasma budesonide, cortisol, and K+ . Subjects' performance during cycling to fatigue at 90% of incremental peak power output (iPPO) was measured in response to 4 mg inhaled terbutaline to maximally stimulate Na+ ,K+ ATPase activity. Plasma concentrations of budesonide rose to 5.0 ± 1.6 nM with the intervention, whereas no changes were observed in plasma cortisol. Muscle Na+ ,K+ ATPase content increased (P ≤ 0.01) by 46 ± 34 pmol/(g wet wt) (17% increase) with the intervention. Cycling performance at 90% of iPPO did not change (P = 0.21) with the intervention (203 vs 214 s) in response to terbutaline. The present observations show that therapeutic inhalation of glucocorticoids increases muscle Na+ ,K+ ATPase content, but does not enhance high-intensity cycling endurance in response to terbutaline.
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Treatment of exercise-induced bronchoconstriction.
Backer, V, Sverrild, A, Porsbjerg, C
Immunology and allergy clinics of North America. 2013;(3):347-62, viii
Abstract
Exercise-induced bronchoconstriction (EIB) describes the transient narrowing of the airways during, and particularly after exercise and occurs commonly in asthmatic individuals. Limitation of exercise capacity is a frequent complaint in all age groups, and severity of EIB ranges from mild impairment of performance to severe bronchospasm and a large reduction in FEV1. Treatment of EIB varies from daily to less frequent therapy, depending on the level of activity. In this article, the authors evaluate the treatment possibilities before, during, and after exercise. They also review medications currently used to treat EIB.