Impact of family socioeconomic position on childhood asthma outcomes, severity, and specialist referral - a Danish nationwide study.

BACKGROUND: Asthma is the most common chronic illness in children, carrying a major burden. Socioeconomic position (SEP) affects adult asthma outcomes, but its impact on childhood asthma, particularly in primary versus specialist care, has not been studied thoroughly. METHODS: In a Danish cohort consisting of all children aged 2-17 years redeeming inhaled corticosteroids in 2015, parental SEP impact on asthma outcomes was investigated. Workforce attachment, income, education, and metropolitan residence were chosen as covariates in logistic regression. Outcomes were uncontrolled (excessive use of short-acting beta2-agonists), exacerbating (oral corticosteroid use or hospitalization), and severe asthma (according to GINA 2020). RESULTS: The cohort comprised 29,851 children (median age 8.0, 59% boys). 16% had uncontrolled asthma, 8% had ≥1 exacerbation. Lower income and metropolitan residence correlated with higher odds of poor control, exacerbations, and severe asthma. Lower education correlated with worse asthma outcomes. Education and income were protective factors in primary care, but not in specialist care. Metropolitan residence was the sole factor linked to specialist care referral for severe asthma. CONCLUSION: Low parental SEP and metropolitan residence associated with poor asthma outcomes. However, specialist care often mitigated these effects, though such care was less likely for at-risk children in non-metropolitan areas.

Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies.

BACKGROUND: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal. RESEARCH QUESTION: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? STUDY DESIGN AND METHODS: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment. RESULTS: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy. INTERPRETATION: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy.

Childhood Asthma and Parental Antidepressant Use in a Nationwide Danish Cohort.

Background: Paediatric asthma is associated with caregiver depression, which in turn is associated with poor asthma control. Although sociodemographic risk factors are associated with parental depression among children with asthma, the contribution of these factors to caregiver depression in free-to-access universal healthcare settings is unknown. Methods: The association between childhood asthma and parental antidepressant use was investigated in a Danish nationwide cohort of children aged 2-17 years that redeemed inhaled corticosteroids in 2015. The odds of antidepressant use were estimated in comparison to control families that were matched 1:1 on the number of siblings, residence, income, and education. Results: Among the families of 28,595 children with actively treated asthma, 12% of mothers and 6.2% of fathers were on antidepressant therapy, compared to 9.3% and 5.3% in controls (p<0.001). Paediatric asthma was associated with increased odds of parental antidepressant use (OR 1.29 (1.23-1.35)), even after adjusting for parental asthma. Poor asthma control, but not higher asthma severity, was associated with higher odds of antidepressant use (1.43 (1.31-1.56)). Compared with the controls, families with two or more children with asthma had higher OR (1.42 (1.29-1.56)) than those with a single child (OR 1.27 (1.21-1.34)). Low socioeconomic status was associated with parental antidepressant use. Conclusion: Caregiver depression in a Danish cohort is more prevalent among mothers than among fathers and is associated with poor asthma control in children. Antidepressant use among caregivers was associated with total family asthma burden and was independent of socioeconomic status.

Burden and unmet need for specialist care in poorly controlled and severe childhood asthma in a Danish nationwide cohort.

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.

Beyond direct costs: individual and societal financial burden of asthma in young adults in a Danish nationwide study.

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.

Adherence to inhaled corticosteroids in relation to quality of life and symptoms of anxiety and depression in asthma.

Background: Poor asthma control, often caused by non-adherence with controller medication, is a well-known risk factor for impaired quality of life (QoL) and major mood disorders (MMD). Previous studies have shown a relationship between non-adherence, lower QoL, and MMD across chronic diseases, but the relationship remains uncertain in asthma. Methods: All asthma patients followed at the respiratory outpatient clinic at Copenhagen University Hospital - Hvidovre were invited to fill-in the Hospital Anxiety and Depression Scale (HADS) and the Mini Asthma Quality of Life Questionnaire (miniAQLQ). Medication Possession Ratio (MPR) was calculated using pharmacy redemption data. Relationships between questionnaire scores, inhaled corticosteroid MPR and use of rescue medication were investigated using Pearson correlation and multivariable linear regression adjusted for age, sex, FEV1, and GINA Step. Data from scheduled visits were collected from patients' medical records. Results: A total of 308 patients (73% females, median age 51 years (interquartile range (IQR) 37, 62)) completed the questionnaires and had 1-year medication data available. Median adherence to inhaled corticosteroids (ICS) was 57% (35%, 75%) with 18% of patients having adherence above 80%. Of the participating patients, 14% and 27% reported depressive and anxiety-related symptoms, respectively, and 72% reported impaired QoL. In correlation analyses, ICS adherence was not significantly associated with either prevalence of MMD symptoms or impaired QoL in asthma patients. However, a strong correlation was found between ACQ-6 and both MMD symptoms and impaired QoL, as well as between rescue medication use and impaired QoL. In adjusted analysis, however, the latter correlation was no longer statistically significant. Conclusion: Our results suggest that ICS adherence is not directly correlated with either impaired quality of life or major mood disorder symptoms in asthma patients. Self-reported asthma control, on the other hand, is strongly correlated with both QoL and MMD.

Complete response to anti-interleukin-5 biologics in a real-life setting: results from the nationwide Danish Severe Asthma Register.

Background: Phase III regulatory trials show that anti-interleukin (IL)-5 biologics efficiently reduce exacerbations and the use of maintenance oral corticosteroids (mOCS) in patients with severe eosinophilic asthma. However, patients eligible for these trials differ significantly compared with real-life severe asthma populations. Therefore, our aim was to explore efficacy in a real-life setting. The Danish Severe Asthma Register (DSAR) is a complete, nationwide register that comprises all Danish patients on biological therapy for severe asthma. Methods: This prospective study identified patients in the DSAR who were complete responders to anti-IL-5 biologics after 1 year of treatment. A complete response was defined as resolution of the parameter setting the indication, i.e. recurrent exacerbations and/or use of mOCS. Results: A total of 289 out of 502 (58%) patients were complete responders to anti-IL-5 biologics after 12 months. Complete responders had greater improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire (ACQ) score compared with noncomplete responders (Δ 210 versus 30 mL; p<0.0001 and Δ -1.04 versus -0.68; p=0.016, respectively). A complete response was predicted by age at onset, less severe disease at baseline (i.e. no mOCS and lower ACQ score) and higher blood eosinophils. Conclusions: More than half of Danish patients treated with anti-IL-5 biologics for severe asthma achieve a complete response to treatment, thereby becoming free from asthma exacerbations and the need for mOCS. Complete responders also achieved superior effects on lung function and symptoms compared with noncomplete responders.

Socioeconomic status is associated with healthcare seeking behaviour and disease burden in young adults with asthma - A nationwide cohort study.

INTRODUCTION: Specialist management of asthma has been shown to associate with socioeconomic status (SES). However, little is known about the influence of SES on care burden in universal healthcare settings. METHODS: Patients aged 18-45 years using inhaled corticosteroids (ICS) were followed in national databases. Impact of asthma was investigated using negative binomial regression adjusted for age, sex, comorbidity, and GINA 2020 Step. Uncontrolled asthma was defined as >600 annual SABA puffs, ≥2 prednisolone courses and/or ≥1 hospitalization. RESULTS: A total of 60,534 (55% female, median age 33 (IQR 25-39)) patients were followed for 10.1 years (IQR 5.2-14.3)). Uncontrolled asthma resulted in 6.5 and 0.51 additional annual contacts to primary care and pulmonologists, respectively.Unscheduled and primary care burden was dependent on SES, increasing with rural residence, lower education, income and receiving welfare. Differences in planned respiratory care were slight, only seen among divorced, low income- or welfare recipients. Lower SES was consistently associated with an increased utilization of SABA and prednisolone. No dose-response relationship between ICS use and SES could be identified. CONCLUSION: Lower SES in asthma is a risk factor for a predominance of unscheduled care and adverse outcomes, warranting further attention to patients' background when assessing asthma care.

Disease Control, Not Severity, Drives Job Absenteeism in Young Adults with Asthma - A Nationwide Cohort Study.

Introduction: The impact of asthma and disease control on job absenteeism in young adults is sparsely investigated and conflicting evidence exist. Based on a nationwide cohort, the present study aims to describe the overall job absenteeism across asthma severities and describe the possible influence of asthma control. Methods: REASSESS is a nationwide cohort of Danish asthma patients aged 18-45 using controller medication between 2014 and 2018, followed retrospectively for up to 15 years using national databases. Impact of asthma was investigated using negative binomial regression adjusted for age, sex, Charlson score and level of education and presented as adjusted incidence rate ratios with 95% confidence intervals. Results: A total of 60,534 patients with asthma (median age 33 (25, 39), 55% female, 19% uncontrolled disease and 5.7% possible severe asthma) were followed for 12.7 (6.5-14.8) years. The prevalence of any absenteeism was more common in both mild-to-moderate and possible severe asthma compared to the background population (67%, 80% and 62%, respectively; p < 0.0001). Compared to the background population, mild-to-moderate and possible severe asthma were more likely to have temporary sick leave (1.37 (1.33-1.42); 1.78 (1.62-1.96)), unemployment (1.11 (1.07-1.14); 1.26 (1.15-1.38)) and obtain disability benefits (1.67 (1.66-1.67); 2.64 (2.63-2.65)). Uncontrolled asthma had increased temporary sick leave (1.42 (1.34-1.50)), unemployment (1.40 (1.32-1.48)) and disability (1.26 (1.26-1.27)) when compared to controlled disease. Significant increases in absenteeism could be measured already at ≥100 annual doses of rescue medication (1.09 (1.04-0.1.14)), patients' first moderate or severe exacerbation (1.31 (1.15-1.49) and 1.31 (1.24-1.39), respectively). Further increases in absenteeism were observed with increasing rescue medication use and severe exacerbations. Conclusion: Across severities, job absenteeism is increased among patients with asthma compared to the background population. Increases in absenteeism was seen already at ≥100 annual doses of rescue medication, representing a substantial, and probably preventable, reduction in productivity among young adults.

High Use of Antidepressant Medication in Both Mild-to-Modelate and Possible Severe Asthma - A Nationwide Cohort Study.

PURPOSE: In asthma, increased severity has been linked to depression assessed as assessed by patient-reported outcomes. However, little is known about predictors of antidepressant use in asthma compared to the background population. METHODS: The study consists of 60,534 asthma patients aged 18-45 and a 1:1 age- and sex-matched control group. Using national registries and prescription data, the prevalence of and risk factors for antidepressant use were investigated by logistic regression adjusted for age, sex, workforce and civil status, income- and education-level and comorbidity. Results presented as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: A total of 16% and 22%, respectively, among patients with mild-to-moderate and possible severe asthma redeemed antidepressant drugs, compared to 10% of controls. Antidepressant use was more prevalent amongst patients with high rescue medication use (>600 annual doses) and those with a history of moderate or severe exacerbation(s). Both mild-to-moderate and possible severe asthma were independent risk factors for antidepressant use (OR 1.40 (95% CI 1.35, 1.46) and OR 1.55 (95% CI 1.41, 1.70), respectively). Female sex, age, being divorced or never married, having only primary education or currently being under education, as well as being on welfare/transfer income increased odds of antidepressant use. Completing higher education and having high income were associated with lower odds. CONCLUSION: In asthma, antidepressant use is significantly higher than in the background population. Even after adjusting for known risk factors, asthma remains a predictor of antidepressant use, signalling a psychologic burden related to living with asthma.

Determining Persistence with an Inhaled Corticosteroid in Asthma: Assessment Using an Objective Measurement vs the Self-Reported Foster Score.

INTRODUCTION: Adherence with controller medication is a major challenge in asthma management. Thus, a reliable method of measurement is mandatory to assess adherence. AIM: To examine the test-retest reliability on adherence with inhaled corticosteroids in adults with asthma using, a self-reported adherence score (Foster score). METHODS: Patients with asthma and >1 routine follow-up appointment at a university hospital outpatient clinic reported Foster scores. The objective Medication Possession Ratio (MPR) was calculated based on pharmacy redemption data and physician-prescribed doses of inhaled corticosteroids. The difference between Foster score and MPR at the first and second visit was assessed using a Bland-Altman plot, outcomes reported as limits of agreements and bias. Foster scores from both visits were used to calculate an intraclass correlation coefficient (ICC). RESULTS: Self-reported adherence with asthma controller medication measured by Foster score was significantly higher than the objective MPR (p < 0.0001). The Bland-Altman plot for MPR and Foster score at the first and second visit showed upper and lower limits of agreement of 83.5 - (-1.6) and 80.9 - (-6.9) and bias was 41.0 and 37.0, respectively. Of the included patients, 93.1% reported identical Foster scores between visits, resulting in an excellent ICC of 0.92. Absolute median difference between Foster scores and MPR at first and second visit was 8.7 percentage points (p = 0.049). CONCLUSION: Foster score shows an excellent ICC; however, its poor agreement with objective measures of adherence suggests that clinicians should not rely on Foster scores alone to assess adherence with inhaled corticosteroids in patients with asthma.

Adherence with controller medication in adults with asthma - impact of hospital admission for acute exacerbation.

OBJECTIVE: Uncontrolled asthma is associated with higher risk of hospital admissions and death. Low adherence to inhaled corticosteroid (ICS), the cornerstone of asthma therapy, is well-documented. Our aim was to investigate if hospital admission with an acute exacerbation of asthma changes ICS adherence. METHODS: This retrospective cohort study comprises 241 patients hospitalized with an asthma exacerbation over 12 months (May 2019-April 2020). The primary outcome was proportion of ICS adherent patients, defined as Medication Possession Ratio (MPR) ≥80%, in the six-month period before and after admission. RESULTS: The pre- to post-admission proportion of ICS adherent patients increased from 10% to 13% (p = 0.25) and the mean ICS MPR increased from 34% to 42% (p < 0.001). Different patterns of post-discharge adherence were observed, as adherent patients remained adherent, while patients with poor pre-admission adherence increased their adherence during two months after discharge followed by a decline in MPR. Co-variates such as sex, age, body mass index (BMI), GINA 2020-treatment step did not predict improvement in adherence after discharge. CONCLUSIONS: Admission with an asthma exacerbation did not increase the proportion of patients adherent with controller medication, primarily ICS. Although an improvement in adherence was initially seen primarily in previously poorly adherent patients, this increase was transient as it decreased over time post-discharge.

Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial.

BACKGROUND: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). RESULTS: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14 versus 9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group versus two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group versus six patients receiving placebo (p=0.57). CONCLUSIONS: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.

Socioeconomic biases in asthma control and specialist referral of possible severe asthma.

BACKGROUND: Although socioeconomic impact on asthma control has been investigated, little is known about its relationship to specialist referral of patients with possible severe asthma, especially in a public healthcare setting. The present study aims to identify socioeconomic patterns in disease control and referral of patients with asthma in a nationwide cohort of adult patients treated with inhaled corticosteroids (ICS). METHODS: Asthma patients fulfilling the following criteria were included: aged 18-45 years and redeeming two or more prescriptions of ICS during 2014-2018 based on data from Danish national registers. Possible severe asthma was defined as Global Initiative for Asthma 2020 step 4 (with either two or more courses of systemic steroids or at least one hospitalisation) or step 5 treatment. Findings presented as odds ratios (95% confidence intervals). RESULTS: Out of 60 534 patients (median age 34 years, 55% female), 3275 (5.7%) were deemed as having possible severe asthma, of whom 61% were managed in primary care alone. Odds of specialist management for possible severe asthma decreased with age (OR 0.66, 95% CI 0.51-0.85; 36-45 versus 18-25 years), male sex (OR 0.75, 95% CI 0.64-0.87), residence outside the Capital Region (OR 0.70, 95% CI 0.59-0.82) and with receiving unemployment or disability benefits (OR 0.75, 95% CI 0.59-0.95). Completion of higher education increased odds of specialist referral (OR 1.28, 95% CI 1.03-1.59), when compared to patients with basic education. CONCLUSION: Even in settings with nationally available free access to specialist care, the majority of patients with possible severe asthma are managed in primary care. Referral of at-risk asthma patients differs across socioeconomic parameters, calling for initiatives to identify and actively refer these patients.

A causal relationship between rheumatoid arthritis and bronchiectasis? A systematic review and meta-analysis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease primarily affecting joints but often also associated with lung involvement such as bronchiectasis (BE). The aim of the present systematic review and meta-analysis is to provide an update on the current evidence regarding the prevalence and association between RA and BE. This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines with literature search using the terms 'Bronchiectasis AND Rheumatoid Arthritis' without a date limitation on PubMed during May 2020. A total of 28 studies fulfilled the predefined criteria and were included in the present review, with 19 being cross-sectional studies. Twenty-three studies were included in the meta-analysis. The pooled prevalence estimate was 2.69% (95% CI 1.63-4.42) in clinically defined BE, and 24.9% (95% CI 19.21-31.67) in radiologic disease. Many inconsistencies exist regarding potential risk factors for BE in RA patients such as gender, RA duration and severity, as both negative and positive associations have been reported. Although very little is known about possible causative mechanisms between RA and BE, potential pathways might be antigenic stimulation from pulmonary mucus and/or systemic inflammation from joint disease affecting the lungs. At present, the available evidence of bronchiectasis in patients with RA is insufficient to identify RA-associated risk factors for the development of BE, possibly apart from duration of RA, and, consequently, also to fully explore a possible causal relationship between the two disease. However, the increased prevalence of BE in RA patients warrants further studies to explore the association between RA and BE.

Remission and Changes in Severity Over 30 Years in an Adult Asthma Cohort.

BACKGROUND: Long-term follow-up studies of adults with well-characterized asthma are sparse. OBJECTIVE: We aimed to examine long-term remission and change in disease severity over 30 years in adults with asthma. METHODS: A total of 125 individuals diagnosed with asthma between 1974 and 1990 at a Danish respiratory and allergy clinic, based on history and objective assessments, were included. At follow-up (2017-2019), participants completed questionnaires and had spirometry, bronchodilator reversibility, airway responsiveness, and blood biomarkers measured. Based on these assessments, participants were classified as having either active asthma, clinical remission (no symptoms or prescribed asthma medication within the last year), or complete remission (fractional exhaled nitric oxide <50 parts per billion, no bronchodilator reversibility, no airway hyperresponsiveness, and no airflow limitation). Changes in severity were determined according to Global Initiative for Asthma guidelines based on symptom control and currently prescribed medication. RESULTS: At follow-up, 25% (n = 31) and 15% (n = 19), respectively, had clinical and complete remission. Our analyses showed that a longer duration of symptoms before the initial assessment (odds ratio, 0.86; 95% confidence interval, 0.75-0.98) was associated with a lower chance of asthma remission. At follow-up, 30% had well-controlled asthma compared with none at baseline. Female sex, previous severe exacerbation(s), and older age at baseline were associated with uncontrolled asthma at follow-up. Blood-eosinophil count (≥0.3 × 109/L) and prescribed inhaled corticosteroid (ICS) at baseline were associated with being prescribed medium/high-dose ICS at follow-up. CONCLUSION: Despite 30 years of follow-up, asthma rarely remits in adults, especially in individuals with longer duration and presumably more severe disease. Initial signs of pronounced disease activity were associated with uncontrolled asthma at follow-up.

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.

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).