Publications by authors named "Charlotte Suppli Ulrik"

124 Publications

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

Chron Respir Dis 2021 Jan-Dec;18:1479973121994565

Department of Respiratory Medicine, Copenhagen University Hospital Hvidovre, Denmark.

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.
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http://dx.doi.org/10.1177/1479973121994565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894591PMC
February 2021

Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: protocol and statistical analysis plan.

Acta Anaesthesiol Scand 2021 Feb 14. Epub 2021 Feb 14.

Department of Intensive Care, Rigshospitalet, University of Copenhagen, Denmark.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear.

Methods: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol.

Discussion: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.
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http://dx.doi.org/10.1111/aas.13795DOI Listing
February 2021

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

Acta Anaesthesiol Scand 2021 Feb 14. Epub 2021 Feb 14.

Department of Intensive Care, Rigshospitalet, University of Copenhagen, Denmark.

Background: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia.

Methods: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors.

Discussion: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results.

Trial Registration: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.
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http://dx.doi.org/10.1111/aas.13793DOI Listing
February 2021

COPD patients prescribed inhaled corticosteroid in primary care: time for re-assessment based on exacerbation rate and blood eosinophils?

Respir Res 2021 Feb 12;22(1):54. Epub 2021 Feb 12.

Respiratory Research Unit Hvidovre, Department of Respiratory Medicine, Hvidovre Hospital, 2650, Hvidovre, Denmark.

Background And Objective: Inhaled corticosteroid (ICS) therapy for COPD should be guided by exacerbations and blood-eosinophils according to the GOLD 2020 strategy document. In the present study, we applied these recent recommendations in a large cohort of COPD patients recruited from general practice.

Methods: The participating general practitioners (n = 144) recruited patients with a diagnosis of COPD currently prescribed ICS and reported data on exacerbation history and blood-eosinophils. Clinical variables were compared using two-sample t-tests.

Results: The study cohort comprised 1,567 COPD patients (44% males and mean age 72 years). In the past 12 months, 849 (54%) of the COPD patients currently prescribed ICS had no exacerbation, whereas 383 (24%) and 328 (21%) patients, respectively, had a history of one exacerbation and two or more exacerbations. Compared to patients with one or no exacerbation, patients with ≥ 2 exacerbations (21%) per year reported more dyspnea (p < 0.001) and had higher degree of airflow obstruction (p < 0.001). Among patients with no and at least one exacerbation within the preceding 12 months, 30% and 26%, respectively, had a blood-eosinophil count ≥ 0.3 × 10/L. In patients with two or more exacerbations within the last 12 months, 77% had a blood-eosinophil count of ≥ 0.1 × 10/L. Furthermore, 166 patients (11%) had at least one hospital admission due to COPD exacerbation, and a blood-eosinophil count of ≥ 0.1 × 10/L.

Conclusion: This study of a large cohort of COPD patients currently prescribed inhaled corticosteroids suggests the need for re-evaluating the management strategy to increase benefit and reduce adverse effects of ICS treatment in COPD patients managed in primary care.
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http://dx.doi.org/10.1186/s12931-021-01651-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881579PMC
February 2021

Alcohol Consumption and the Risk of Acute Respiratory Distress Syndrome in COVID-19.

Ann Am Thorac Soc 2020 Dec 14. Epub 2020 Dec 14.

Gentofte University Hospital Department of Heart Diseases, 568366, Cardiology, Hellerup, Denmark;

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http://dx.doi.org/10.1513/AnnalsATS.202008-988RLDOI Listing
December 2020

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

J Allergy Clin Immunol Pract 2020 Nov 19. Epub 2020 Nov 19.

Department of Respiratory Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

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 × 10/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.
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http://dx.doi.org/10.1016/j.jaip.2020.11.013DOI Listing
November 2020

The Danish severe asthma register: an electronic platform for severe asthma management and research.

Eur Clin Respir J 2020 Nov 2;8(1):1842117. Epub 2020 Nov 2.

Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark.

The evaluation and management of severe asthma patients require collection of comprehensive information, which is often a challenge in a busy outpatient clinic. The Danish Severe Asthma Register (DSAR) was designed as an electronic patient record form that captures operational clinical data and provides a clinical overview of the severe asthma patient. DSAR is a nationwide register; all patients in Denmark who are treated with biologics for severe asthma are included, and data are as a minimum entered at start of biological treatment, after four and 12 months of treatment, and hereafter annually. Currently, there are data from 621 treatment courses with biologics included in DSAR, with 71% of patients treated with anti-IL-5 drugs and 29% with an anti-IgE drug. Patients enter Patient Reported Outcome Measures electronically on tablets when they arrive in the outpatient clinic and their answers are immediately available to the clinician during the consultation. Nurses and doctors enter clinical data into DSAR during the consultation. DSAR offers immediate access to well-presented longitudinal overview and automatically creates a journal output that can be copy-pasted into the hospital's existing health record form. DSAR is also currently expanding with an app, to be used for monitoring of home-treatment. In addition to serving as an electronic patient record form, DSAR will also provide opportunities to monitor the real-life efficacy of biological treatment for severe asthma in Denmark, and it will be a valuable research platform that will aid in answering important research questions on severe asthma in the future.
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http://dx.doi.org/10.1080/20018525.2020.1842117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646603PMC
November 2020

Treatment with the anti-IgE monoclonal antibody omalizumab in women with asthma undergoing fertility treatment: a proof-of-concept study-The PRO-ART study protocol.

BMJ Open 2020 11 12;10(11):e037041. Epub 2020 Nov 12.

Centre for Physical Activity Research, Rigshospitalet, Kobenhavn, Denmark.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-037041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662444PMC
November 2020

Echocardiographic abnormalities and predictors of mortality in hospitalized COVID-19 patients: the ECHOVID-19 study.

ESC Heart Fail 2020 10 22. Epub 2020 Oct 22.

Department of Cardiology, Herlev & Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Aims: The present study had two aims: (i) compare echocardiographic parameters in COVID-19 patients with matched controls and (2) assess the prognostic value of measures of left (LV) and right ventricular (RV) function in relation to COVID-19 related death.

Methods And Results: In this prospective multicentre cohort study, 214 consecutive hospitalized COVID-19 patients underwent an echocardiographic examination (by pre-determined research protocol). All participants were successfully matched 1:1 with controls from the general population on age, sex, and hypertension. Mean age of the study sample was 69 years, and 55% were male participants. LV and RV systolic function was significantly reduced in COVID-19 cases as assessed by global longitudinal strain (GLS) (16.4% ± 4.3 vs. 18.5% ± 3.0, P < 0.001), tricuspid annular plane systolic excursion (TAPSE) (2.0 ± 0.4 vs. 2.6 ± 0.5, P < 0.001), and RV strain (19.8 ± 5.9 vs. 24.2 ± 6.5, P = 0.004). All parameters remained significantly reduced after adjusting for important cardiac risk factors. During follow-up (median: 40 days), 25 COVID-19 cases died. In multivariable Cox regression reduced TAPSE [hazard ratio (HR) = 1.18, 95% confidence interval (CI) [1.07-1.31], P = 0.002, per 1 mm decrease], RV strain (HR = 1.64, 95%CI[1.02;2.66], P = 0.043, per 1% decrease) and GLS (HR = 1.20, 95%CI[1.07-1.35], P = 0.002, per 1% decrease) were significantly associated with COVID-19-related death. TAPSE and GLS remained significantly associated with the outcome after restricting the analysis to patients without prevalent heart disease.

Conclusions: RV and LV function are significantly impaired in hospitalized COVID-19 patients compared with matched controls. Furthermore, reduced TAPSE and GLS are independently associated with COVID-19-related death.
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http://dx.doi.org/10.1002/ehf2.13044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755011PMC
October 2020

Proactive prophylaxis with azithromycin and hydroxychloroquine in hospitalized patients with COVID-19 (ProPAC-COVID): a statistical analysis plan.

Trials 2020 Oct 20;21(1):867. Epub 2020 Oct 20.

Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: There is an urgent need for treatments that can shorten hospitalization and lower the risk of secondary infection and death in patients with corona disease. The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease.

Methods: The ProPAC-COVID is a multi-center, randomized, placebo-controlled, double-blinded clinical trial. The primary outcome is number of days spent alive and out of hospital within 14 days from randomization. Randomization will be in blocks of unknown size, and the final allocation will be stratified for age, site of recruitment, and whether the patient has any chronic lung diseases. Data is analyzed using intention-to-treat (ITT) principles, and main analyses will also be subject to modified ITT analysis and per protocol analysis.

Discussion: This paper describes the detailed statistical analysis plan for the evaluation of primary and secondary endpoints of the ProPAC-COVID study. Enrolment of patients to the ProPAC-COVID study is still ongoing. The purpose of this paper is to provide primary publication of study results to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency.

Trial Registration: ClinicalTrials.gov NCT04322396 . Registered on 26 March 2020.
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http://dx.doi.org/10.1186/s13063-020-04795-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573513PMC
October 2020

Bone turnover biomarkers in COPD patients randomized to either a regular or shortened course of corticosteroids: a substudy of the randomized controlled CORTICO-COP trial.

Respir Res 2020 Oct 12;21(1):263. Epub 2020 Oct 12.

Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, Ground Floor, DK-2900, Hellerup, Denmark.

Background: Long-term treatment with corticosteroids causes loss of bone density, but the effects of using short-term high-dose systemic-corticosteroid therapy to treat acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are unclear. Our aim was to determine whether high-dose corticosteroid therapy affected bone turnover markers (BTMs) to a greater extent compared to low-dose corticosteroid therapy.

Methods: The CORTICO-COP trial (NCT02857842) showed that an eosinophil-guided corticosteroid intervention led to approximately 60% lower accumulated corticosteroid dose for hospitalized patients with AECOPD (low-dose group) compared with 5-day standard corticosteroid treatment (high-dose group). We compared the levels of BTMs C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 participants during AECOPD and at 1- and 3-month follow-up visits.

Results: CTX decreased and P1NP increased significantly over time in both treatment groups. There were no significant differences between the groups at 1- or 3-months follow-up for P1NP. A significant drop in CTX was seen at 3 months (down Δ24% from the baseline, p = 0.017) for the high dose group.

Conclusion: Short-term, high-dose systemic corticosteroid treatment caused a rapid suppression of biomarkers of bone resorption. Corticosteroids did not suppress biomarkers of bone formation, regardless of patients receiving low or high doses of corticosteroids. This therapy was, therefore, harmless in terms of bone safety, in our prospective series of COPD patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02857842 . Submitted August 2nd, 2016.
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http://dx.doi.org/10.1186/s12931-020-01531-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552546PMC
October 2020

TOB-STOP-COP (TOBacco STOP in COPd trial): study protocol-a randomized open-label, superiority, multicenter, two-arm intervention study of the effect of "high-intensity" vs. "low-intensity" smoking cessation intervention in active smokers with chronic obstructive pulmonary disease.

Trials 2020 Aug 21;21(1):730. Epub 2020 Aug 21.

Department of Internal Medicine C, Section of Respiratory Medicine, Herlev and Gentofte University Hospital, Hellerup, Denmark.

Background: Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and it contributes to the development of many other serious diseases. Smoking cessation in COPD patients is known to improve survival and reduce the number of hospitalization-requiring acute exacerbations of COPD. However, smoking cessation interventions in these patients have only been successful for approximately 15-20% for consistent smoking abstinence in 12 months. Thus, more effective interventions are needed for this patient group. The aim of this study is to determine whether a high-intensity intervention compared to a low-intensity intervention can increase the proportion of persistent (> 12 months) anamnestic and biochemical smoking cessation in active smokers with COPD.

Methods: This study is a randomized controlled trial. A total of 600 active smokers with COPD will be randomly assigned 1:1 to either a standard treatment (guideline-based municipal smoking cessation program, "low intensity" group) or an intervention ("high-intensity" group) group, which consists of group sessions, telephone consultations, behavior design, hotline, and "buddy-matching" (smoker matched with COPD patient who has ceased smoking). Both groups will receive pharmacological smoking cessation. The primary endpoint is anamnestic and biochemical (cotinine analysis in urine) validated smoking cessation after 12 months.

Discussion: The potential benefit of this project is to improve smoking cessation rates and thereby reduce smoking-related exacerbations of COPD. In addition, the project can potentially benefit from increasing the quality of life and longevity of COPD patients and reducing the risk of other smoking-related diseases.

Trial Registration: ClinicalTrials.gov NCT04088942 . Registered on 13 September 2019.
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http://dx.doi.org/10.1186/s13063-020-04653-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441548PMC
August 2020

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

Acta Anaesthesiol Scand 2020 10 30;64(9):1365-1375. Epub 2020 Jul 30.

Department of Intensive Care, Copenhagen University Hospital, Copenhagen, Denmark.

Introduction: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.
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http://dx.doi.org/10.1111/aas.13673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404666PMC
October 2020

ARIA-EAACI statement on asthma and COVID-19 (June 2, 2020).

Authors:
Jean Bousquet Marek Jutel Cezmi A Akdis Ludger Klimek Oliver Pfaar Kari C Nadeau Thomas Eiwegger Anna Bedbrook Ignacio J Ansotegui Josep M Anto Claus Bachert Eric D Bateman Kazi S Bennoor Elena Camelia Berghea Karl-Christian Bergmann Hubert Blain Mateo Bonini Sinthia Bosnic-Anticevich Louis-Philippe Boulet Luisa Brussino Roland Buhl Paulo Camargos Giorgio Walter Canonica Victoria Cardona Thomas Casale Sharon Chinthrajah Mübeccel Akdis Tomas Chivato George Christoff Alvaro A Cruz Wienczyslawa Czarlewski Stefano Del Giacco Hui Du Yehia El-Gamal Wytske J Fokkens Joao A Fonseca Yadong Gao Mina Gaga Bilun Gemicioglu Maia Gotua Tari Haahtela David Halpin Eckard Hamelmann Karin Hoffmann-Sommergruber Marc Humbert Nataliya Ilina Juan-Carlos Ivancevich Guy Joos Musa Khaitov Bruce Kirenga Edward F Knol Fanny W Ko Seppo Koskinen Marek L Kowalski Helga Kraxner Dmitry Kudlay Piotr Kuna Maciej Kupczyk Violeta Kvedariene Amir H Abdul Latiff Lan T Le Michael Levin Desiree Larenas-Linnemann Renaud Louis Mohammad R Masjedi Erik Melén Florin Mihaltan Branislava Milenkovic Yousser Mohammad Mario Morais-Almeida Joaquim Mullol Leyla Namazova Hugo Neffen Elisabete Nunes Paul O'Byrne Robyn O'Hehir Liam O'Mahony Ken Ohta Yoshitaka Okamoto Gabrielle L Onorato Petr Panzner Nikos G Papadopoulos Gianni Passalacqua Vincenzo Patella Ruby Pawankar Nhân Pham-Thi Bernard Pigearias Todor A Popov Francesca Puggioni Frederico S Regateiro Giovanni Rolla Menachem Rottem Boleslaw Samolinski Joaquin Sastre Jurgen Schwarze Aziz Sheikh Nicola Scichilone Manuel Soto-Quiros Manuel Soto-Martinez Milan Sova Stefania Nicola Rafael Stelmach Charlotte Suppli-Ulrik Luis Taborda-Barata Teresa To Peter-Valentin Tomazic Sanna Toppila-Salmi Ioanna Tsiligianni Omar Usmani Arunas Valiulis Maria Teresa Ventura Giovanni Viegi Theodor Vontetsianos De Yun Wang Sian Williams Gary W K Wong Arzu Yorgancioglu Mario Zernotti Mihaela Zidarn Torsten Zuberbier Ioana Agache

Allergy 2020 Jun 26. Epub 2020 Jun 26.

Transylvania University Brasov, Brasov, Romania.

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http://dx.doi.org/10.1111/all.14471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361514PMC
June 2020

Asthma-like symptoms in young children increase the risk of COPD.

J Allergy Clin Immunol 2021 Feb 12;147(2):569-576.e9. Epub 2020 Jun 12.

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Chronic obstructive pulmonary disease (COPD) may originate in early life and share disease mechanisms with asthma-like symptoms in early childhood. This possibility remains unexplored on account of the lack of long-term prospective studies from infancy to the onset of COPD.

Objective: We aimed to investigate the relationship between asthma-like symptoms in young children and development of COPD.

Methods: In a population-based cohort of women who gave birth at the central hospital in Copenhagen during period from 1959 to 1961, we investigated data from 3290 mother-child pairs who attended examinations during pregnancy and when the children were aged 1, 3, and 6 years. COPD was assessed from the Danish national registries on hospitalizations and prescription medication since 1994. A subgroup of 930 individuals underwent spirometry testing at age 50 years.

Results: Of the 3290 children, 1 in 4 had a history of asthma-like symptoms in early childhood. The adjusted hazard ratio for hospitalization for COPD was 1.88 (95% CI = 1.32-2.68), and the odds ratio for prescription of long-acting muscarinic antagonists was 2.27 (95% CI = 1.38-3.70). Asthma-like symptoms in early childhood were also associated with a reduced FEV percent predicted and an FEV-to-forced vital capacity ratio at age 50 years (-3.36% [95% CI = -5.47 to -1.24] and -1.28 [95% CI = -2.17 to -0.38], respectively) and with COPD defined according to Global Initiative for Chronic Obstructive Lung Disease stage higher than 1 (odds ratio = 1.96 [95% CI = 1.13-3.34]).

Conclusion: This 60-year prospective follow-up of a mother-child cohort demonstrated a doubled risk for COPD from childhood asthma-like symptoms.
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http://dx.doi.org/10.1016/j.jaci.2020.05.043DOI Listing
February 2021

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.

Trials 2020 Jun 10;21(1):513. Epub 2020 Jun 10.

Section of Respiratory Medicine, Department of Medicine, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, Denmark.

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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http://dx.doi.org/10.1186/s13063-020-04409-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284668PMC
June 2020

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice.

Authors:
Jean Bousquet Josep M Anto Claus Bachert Tari Haahtela Torsten Zuberbier Wienczyslawa Czarlewski Anna Bedbrook Sinthia Bosnic-Anticevich G Walter Canonica Victoria Cardona Elisio Costa Alvaro A Cruz Marina Erhola Wytske J Fokkens Joao A Fonseca Maddalena Illario Juan-Carlos Ivancevich Marek Jutel Ludger Klimek Piotr Kuna Violeta Kvedariene Ltt Le Désirée E Larenas-Linnemann Daniel Laune Olga M Lourenço Erik Melén Joaquim Mullol Marek Niedoszytko Mikaëla Odemyr Yoshitaka Okamoto Nikos G Papadopoulos Vincenzo Patella Oliver Pfaar Nhân Pham-Thi Christine Rolland Boleslaw Samolinski Aziz Sheikh Mikhail Sofiev Charlotte Suppli Ulrik Ana Todo-Bom Peter-Valentin Tomazic Sanna Toppila-Salmi Ioanna Tsiligianni Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Samantha Walker Sian Williams Arzu Yorgancioglu Ioana Agache Cezmi A Akdis Rute Almeida Ignacio J Ansotegui Isabella Annesi-Maesano Sylvie Arnavielhe Xavier Basagaña Eric D Bateman Annabelle Bédard Martin Bedolla-Barajas Sven Becker Kazi S Bennoor Samuel Benveniste Karl C Bergmann Michael Bewick Slawomir Bialek Nils E Billo Carsten Bindslev-Jensen Leif Bjermer Hubert Blain Matteo Bonini Philippe Bonniaud Isabelle Bosse Jacques Bouchard Louis-Philippe Boulet Rodolphe Bourret Koen Boussery Fluvio Braido Vitalis Briedis Andrew Briggs Christopher E Brightling Jan Brozek Guy Brusselle Luisa Brussino Roland Buhl Roland Buonaiuto Moises A Calderon Paulo Camargos Thierry Camuzat Luis Caraballo Ana-Maria Carriazo Warner Carr Christine Cartier Thomas Casale Lorenzo Cecchi Alfonso M Cepeda Sarabia Niels H Chavannes Ekaterine Chkhartishvili Derek K Chu Cemal Cingi Jaime Correia de Sousa David J Costa Anne-Lise Courbis Adnan Custovic Biljana Cvetkosvki Gennaro D'Amato Jane da Silva Carina Dantas Dejan Dokic Yves Dauvilliers Giulia De Feo Govert De Vries Philippe Devillier Stefania Di Capua Gerard Dray Ruta Dubakiene Stephen R Durham Mark Dykewicz Motohiro Ebisawa Mina Gaga Yehia El-Gamal Enrico Heffler Regina Emuzyte John Farrell Jean-Luc Fauquert Alessandro Fiocchi Antje Fink-Wagner Jean-François Fontaine José M Fuentes Perez Bilun Gemicioğlu Amiran Gamkrelidze Judith Garcia-Aymerich Philippe Gevaert René Maximiliano Gomez Sandra González Diaz Maia Gotua Nick A Guldemond Maria-Antonieta Guzmán Jawad Hajjam Yunuen R Huerta Villalobos Marc Humbert Guido Iaccarino Despo Ierodiakonou Tomohisa Iinuma Ewa Jassem Guy Joos Ki-Suck Jung Igor Kaidashev Omer Kalayci Przemyslaw Kardas Thomas Keil Musa Khaitov Nikolai Khaltaev Jorg Kleine-Tebbe Rostislav Kouznetsov Marek L Kowalski Vicky Kritikos Inger Kull Stefania La Grutta Lisa Leonardini Henrik Ljungberg Philip Lieberman Brian Lipworth Karin C Lodrup Carlsen Catarina Lopes-Pereira Claudia C Loureiro Renaud Louis Alpana Mair Bassam Mahboub Michaël Makris Joao Malva Patrick Manning Gailen D Marshall Mohamed R Masjedi Jorge F Maspero Pedro Carreiro-Martins Mika Makela Eve Mathieu-Dupas Marcus Maurer Esteban De Manuel Keenoy Elisabete Melo-Gomes Eli O Meltzer Enrica Menditto Jacques Mercier Yann Micheli Neven Miculinic Florin Mihaltan Branislava Milenkovic Dimitirios I Mitsias Giuliana Moda Maria-Dolores Mogica-Martinez Yousser Mohammad Steve Montefort Ricardo Monti Mario Morais-Almeida Ralph Mösges Lars Münter Antonella Muraro Ruth Murray Robert Naclerio Luigi Napoli Leyla Namazova-Baranova Hugo Neffen Kristoff Nekam Angelo Neou Björn Nordlund Ettore Novellino Dieudonné Nyembue Robyn O'Hehir Ken Ohta Kimi Okubo Gabrielle L Onorato Valentina Orlando Solange Ouedraogo Julia Palamarchuk Isabella Pali-Schöll Peter Panzner Hae-Sim Park Gianni Passalacqua Jean-Louis Pépin Ema Paulino Ruby Pawankar Jim Phillips Robert Picard Hilary Pinnock Davor Plavec Todor A Popov Fabienne Portejoie David Price Emmanuel P Prokopakis Fotis Psarros Benoit Pugin Francesca Puggioni Pablo Quinones-Delgado Filip Raciborski Rojin Rajabian-Söderlund Frederico S Regateiro Sietze Reitsma Daniela Rivero-Yeverino Graham Roberts Nicolas Roche Erendira Rodriguez-Zagal Christine Rolland Regina E Roller-Wirnsberger Nelson Rosario Antonino Romano Menachem Rottem Dermot Ryan Johanna Salimäki Mario M Sanchez-Borges Joaquin Sastre Glenis K Scadding Sophie Scheire Peter Schmid-Grendelmeier Holger J Schünemann Faradiba Sarquis Serpa Mohamed Shamji Juan-Carlos Sisul Mikhail Sofiev Dirceu Solé David Somekh Talant Sooronbaev Milan Sova François Spertini Otto Spranger Cristiana Stellato Rafael Stelmach Michel Thibaudon Teresa To Mondher Toumi Omar Usmani Antonio A Valero Rudolph Valenta Marylin Valentin-Rostan Marilyn Urrutia Pereira Rianne van der Kleij Michiel Van Eerd Olivier Vandenplas Tuula Vasankari Antonio Vaz Carneiro Giorgio Vezzani Frédéric Viart Giovanni Viegi Dana Wallace Martin Wagenmann De Yun Wang Susan Waserman Magnus Wickman Dennis M Williams Gary Wong Piotr Wroczynski Panayiotis K Yiallouros Osman M Yusuf Heather J Zar Stéphane Zeng Mario E Zernotti Luo Zhang Nan Shan Zhong Mihaela Zidarn

Allergy 2021 01 23;76(1):168-190. Epub 2020 Oct 23.

University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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http://dx.doi.org/10.1111/all.14422DOI Listing
January 2021

Bringing asthma care into the twenty-first century.

NPJ Prim Care Respir Med 2020 06 5;30(1):25. Epub 2020 Jun 5.

Respiratory Research Unit Hvidovre, Department of Respiratory Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Despite access to diagnostic tests and effective therapies, asthma often remains misdiagnosed and/or poorly controlled or uncontrolled. In this review, we address the key issues of asthma diagnosis and management, recent evidence for levels of asthma control, the consequences of poor control and, in line with that, explore the potential reasons for poor asthma control and acute exacerbations. Based on recent evidence and current guidelines, we also aim to provide practical answers to the key questions of how to improve asthma management, with the best possible prevention of exacerbations, addressing the basics-adherence, inhaler misuse, obesity and smoking-and how to facilitate a new era of asthma care in the twenty-first century. We hope this review will be useful to busy primary care clinicians in their future interactions with their patients with both suspected and proven asthma.
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http://dx.doi.org/10.1038/s41533-020-0182-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275071PMC
June 2020

Characteristics of patients with COVID-19 pneumonia at Hvidovre Hospital, March-April 2020.

Dan Med J 2020 May 15;67(6). Epub 2020 May 15.

Introduction: The first case of coronavirus disease 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus-2 occurred in Denmark on 27 February 2020. On 10 March, the first case of COVID-19 pneumonia was admitted to Hvidovre Hospital.

Methods: Retrospective case review of individuals 18 years or older who were admitted consecutively to Hvidovre Hospital from 10 March through 23 April 2020.

Results: A total of 175 individuals were admitted with COVID-19 pneumonia. The median age was 71 years, 48.6% were male and 71% had at least one co-morbidity. The most commonly presenting symptoms were dyspnoea, dry cough, and fever. The majority of patients had lymphopenia, elevated liver function tests and C-reactive protein. Nearly two in three presented with multilobar infiltration by chest X-ray. Respiratory failure leading to invasive mechanical ventilation developed in 27 patients (15.4%). By 20 April, 23 of 175 (13.1%) patients remained hospitalised, 43 (24.6%) had died and 109 (62.3%) had been discharged.

Conclusions: The manifestations of COVID-19 at presentation were similar to those seen in other reports. Our population was older, slightly overrepresented by women and had a high level of co-morbidity. COVID-19 admittance was associated with frequent need of intensive care and mechanical ventilation that was associated with a very high mortality.

Funding: none.

Trial Registration: not relevant.
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May 2020

Fertility Treatment Resulting in Live Births in Women with Asthma - Associated with Perennial Allergy?

J Asthma Allergy 2020 24;13:145-152. Epub 2020 Apr 24.

Department of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.

Background: Asthma has been linked with prolonged time to pregnancy compared to healthy controls, also asthma has been linked to a higher need for fertility treatment. However, knowledge of the possible association between allergy and need for fertility treatment is limited. Our aim was to explore a possible difference in having had fertility treatment in women with asthma and live births in those with perennial allergy (animals, fungi and dust mites) compared to no allergy/seasonal allergy. The primary outcome of interest was fertility treatment.

Patients and methods: Women enrolled in the Management of Asthma during Pregnancy (MAP) program at Hvidovre Hospital, DK, were included in the present analysis provided they fulfilled the following criteria: 1) diagnosed with asthma and current anti-asthma therapy and 2) first visit to the respiratory outpatient clinic within the first 18 weeks of pregnancy. Participants were divided into two groups: asthma with perennial allergy (cases) and asthma with seasonal/no allergy (controls). Logistic regression analysis was applied, and findings expressed as odds ratios (OR).

Results: Among women with asthma and perennial allergy (n=544 cases), 13.8% (n=75) had fertility treatment, compared to only 10.1% (n=39) among women with asthma and seasonal/no allergy (n=388, controls) (OR 1.43, 95% CI 0.95-2.16, p=0.087). This association remained statistically insignificant after adjusting for confounders, including BMI (OR 1.19, 95% CI 0.77-1.84, p=0.433). In women ≥35 years of age, 28% (n=44) and 20% (n=19), respectively, among cases and controls had fertility treatment (OR 1.60, 95% CI 0.87-2.94, p=0.132), and likewise, statistically insignificant after adjusting for confounders (OR 1.41, 95% CI 0.74-2.69, p<0.293).

Conclusion: In women with asthma and live births, our study revealed a trend towards an association between perennial allergy and a higher need for fertility treatment compared to seasonal/no allergy.
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http://dx.doi.org/10.2147/JAA.S246873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187931PMC
April 2020

Comparison of Characteristics Between ICS-Treated COPD Patients and ICS-Treated COPD Patients with Concomitant Asthma: A Study in Primary Care.

Int J Chron Obstruct Pulmon Dis 2020 28;15:931-937. Epub 2020 Apr 28.

Department of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.

Background And Objective: Inhaled corticosteroids (ICS) for COPD has been much debated. Our aim was to identify characteristics associated with prescribing ICS for patients with COPD alone compared to those with concomitant asthma in general practice.

Patients and methods: Participating general practitioners (GPs) (n=144) recruited patients with COPD (ICPC 2nd ed. code R95) currently prescribed ICS (ACT code R03AK and R03BA). Data, if available, on demographics, smoking habits, spirometry, COPD medication, dyspnea score, and exacerbation history were retrieved from the medical records. Logistic regression analysis was used to identify possible differences in characteristics between patients with COPD alone compared to those having a concomitant diagnosis of asthma.

Results: A total of 2.289 (45% males) COPD patients on ICS were recruited. Compared to patients with COPD alone (n=1.749), those with COPD and concomitant asthma (n=540) were younger (p<0.001), had higher BMI, higher FEV/FVC ratio, higher blood eosinophil count and less life-time tobacco exposure (36 and 26 pack-years, respectively). Compared to COPD alone, logistic regression analysis showed that COPD with concomitant asthma was significantly associated to age (OR 0.94; CI 0.92 to 0.97; p<0.001), pack-years of smoking (OR 0.98; CI 0.97 to 0.99; p<0.001), %pred (OR 1.02; CI 1.00 to 1.03; p=0.005), and doctor-diagnosed depression (OR 2.59; CI 1.20 to 5.58; p=0.015).

Conclusion: In COPD patients currently prescribed ICS, the presence of concomitant asthma was associated with being younger, having less tobacco exposure, more preserved lung function and a higher likelihood of doctor-diagnosed depression compared to COPD alone.
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http://dx.doi.org/10.2147/COPD.S241561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196437PMC
April 2020

Assessment of fitness for recreational scuba diving in candidates with asthma: a pilot study.

BMJ Open Sport Exerc Med 2020 15;6(1):e000624. Epub 2020 Jan 15.

Respiratory Research Unit, Hvidovre Hospital, Hvidovre, Denmark.

Background: Asthma may be regarded as a contraindication to scuba diving.

Purpose: A clinical algorithm to assess fitness to dive among individuals with asthma was developed and tested prospectively in clinical practice.

Study Design: Cohort study.

Methods: All patients with possible asthma referred to Hvidovre Hospital, Denmark, for assessment of fitness to dive over a 5-year period (2013-2017) were included. Fitness to dive was assessed by case history, spirometry and mannitol challenge test. All patients with ≥10% decline in forced expiratory volume in 1 s (FEV) (at any point during the challenge test) were offered step-up asthma therapy and rechallenge after at least 3 months. Patients with <10% decline in FEV after administration of a maximum dose of mannitol at the latest challenge were classified as having no medical contraindications to scuba diving.

Results: The study cohort comprised 41 patients (24 men; mean age 33 years), of whom 71% and 63% of men and women, respectively, were treated with rescue bronchodilator and inhaled corticosteroid. After the first mannitol challenge test, 21 patients were classified as having no medical contraindications to scuba diving, of whom 16 were currently prescribed asthma medication. After step-up asthma therapy and rechallenge test, an additional seven patients were classified as having no medical contraindications to scuba diving. Overall, using this clinical algorithm, 28 (68%) of the referred patients were finally assessed as having no medical contraindications to scuba diving.

Conclusion: Using a clinical algorithm with mannitol challenge to assess fitness to dive among patients with possible asthma and allowing a rechallenge test after step-up asthma therapy increased the proportion of individuals classified as having no medical contraindications to scuba diving. However, as this algorithm has so far not been evaluated against actual scuba diving safety, further studies are clearly needed before it can be implemented with confidence for use in clinical practice.

Clinical Relevance: An algorithm to assess fitness for scuba diving among individuals with possible asthma using bronchial challenge test, with the option of step-up asthma therapy and rechallenge for reassessment, has been developed for clinical use.
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http://dx.doi.org/10.1136/bmjsem-2019-000624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010986PMC
January 2020

Protocol for a multicentre randomised controlled trial to investigate the effect on asthma-related quality of life from breathing retraining in patients with incomplete asthma control attending specialist care in Denmark.

BMJ Open 2019 12 31;9(12):e032984. Epub 2019 Dec 31.

Department for Regional Health Research, Naestved Hospital, University of Southern Denmark, Naestved, Denmark.

Introduction And Aim: Uncontrolled asthma is a global health challenge with substantial impact on quality of life (QoL) and overall healthcare costs. Unrecognised and/or unmanaged comorbidities often contribute to presence of uncontrolled asthma. Abnormalities in breathing pattern are termed dysfunctional breathing and are not only common in asthma but also lead to asthma-like symptoms and reduced QoL, and, in keeping with this, improvement with breathing normalisation. Evidence-based guidelines recommend breathing retraining interventions as an adjuvant treatment in uncontrolled asthma. Physiotherapy-based breathing pattern modification interventions incorporating relaxation have been shown to improve asthma-related QoL in primary care patients with impaired asthma control. Despite anecdotal reports, effectiveness of breathing retraining in patients referred to secondary care with incomplete asthma control has not been formally assessed in a randomised controlled trial (RCT). We aim to investigate the effect of breathing exercises on asthma-related QoL in patients with incomplete asthma control despite specialist care.

Methods And Analysis: This two-armed assessor-blinded multicentre RCT will investigate the effect of physiotherapist-delivered breathing retraining on asthma QoL questionnaire (MiniAQLQ) in addition to usual specialist care, recruiting from seven outpatient departments and one specialised clinic representing all regions of Denmark during 2017-2019. We will include 190 consenting adults with incomplete asthma control, defined as Asthma Control Questionnaire 6-item score ≥0.8. Participants will randomly be allocated to either breathing exercise programme in addition to usual care (BrEX +UC) or UC alone. BrEX compiles three physiotherapy sessions and encouragement to perform home exercise daily. Both groups continue usual secondary care management. Primary outcome is between-group difference in MiniAQLQ at 6 months. Secondary outcomes include patient-reported outcome measures, spirometry and accelerometer.

Ethics And Dissemination: Ethics Committee, Region Zealand (SJ-552) and Danish Data Protection Agency (REG-55-2016) approved the trial. Results will be reported in peer-reviewed scientific journals.

Trial Registration Number: NCT03127059; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-032984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955530PMC
December 2019

The biomarkers suPAR and blood eosinophils are associated with hospital readmissions and mortality in asthma - a retrospective cohort study.

Respir Res 2019 Nov 15;20(1):258. Epub 2019 Nov 15.

Department of Respiratory Medicine, Copenhagen University Hospital Amager and Hvidovre, Kettegård Allé 30, 2650, Hvidovre, Denmark.

Introduction: Prognostic biomarkers in asthma are needed. The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with asthma control and with prognosis in acutely admitted medical patients. We investigated if suPAR and blood eosinophil counts at the time of admission for asthma are associated with readmission and mortality.

Methods: Our cohort comprised 1341 patients (median age 45.3, IQR 30.1-63.1) acutely admitted with a diagnosis of asthma to Hvidovre Hospital, Denmark (November 2013 to March 2017). Patients had suPAR and blood eosinophils measured at admission. Outcomes were 365-day readmission and all-cause mortality. Logistic regression analysis adjusted for age, sex, C-reactive protein, and Charlson comorbidity score was used to assess the association of the two biomarkers with readmission and all-cause mortality.

Results: Compared to event-free patients, patients who were either readmitted (n = 452, 42.3%) or died (n = 57, 5.3%) had significantly higher suPAR concentrations (p < 0.0001) and lower eosinophil counts (p = 0.0031) at admission. The highest odds of readmission or mortality were observed for patients in either the 4th suPAR quartile (p < 0.0001) or with eosinophil counts < 150 cells/μL at admission. Increasing levels of suPAR were associated with 365-day readmission (OR 1.3 [1.0-1.6]; p = 0.05) and mortality (OR 2.9 [1.7-5.1]; p = 0.0002). Eosinophil count > 300 cells/μL was significantly associated with lower odds of readmission (OR 0.64 [0.5-0.9]; p = 0.005) and lower mortality (OR 0.7 [0.6-0.9]; p = 0.0007).

Conclusions: In patients acutely admitted with asthma, elevated suPAR concentrations together with blood eosinophil count < 150 cells/μL at the time of hospital admission were associated with both 365-day all-cause readmission and mortality.
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http://dx.doi.org/10.1186/s12931-019-1234-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858677PMC
November 2019

Precision medicine and treatable traits in chronic airway diseases - where do we stand?

Curr Opin Pulm Med 2020 01;26(1):33-39

Hvidovre Hospital, Respiratory Research Unit Hvidovre, Hvidovre Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Department of Respiratory Medicine Department of Paediatric Pulmonology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands Airways Clinical Research Center, Section of Pulmonary and Care Medicine, Baylor College of Medicine, Houston, Texas, USA Department of Respiratory Medicine and Allergology, Skåne University Hospital, Institute for Clinical Science, Lund University, Lund, Sweden Department of Respiratory Medicine, Thomayer Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic Department Clin Pharm and Pharmacol, University Medical Center Groningen and QPS-NL, University Groningen, Groningen, The Netherlands.

Purpose Of Review: To provide an update on the implementation of precision medicine, based on treatable traits and mechanisms, in the daily clinical management of chronic airways diseases.

Recent Findings: Recent insights into the complex and heterogeneous nature of chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma identified several clinical and inflammatory phenotypes. This shifted the management focus of these diseases away from the prototypic disease labels and paved the way for developing novel targeted therapies.The concept of precision medicine aims to link the right patient to the right treatment, while minimizing the risk of adverse effects. Several treatable features ('treatable traits') have now been identified for these chronic airway diseases, including pulmonary, extra-pulmonary, and psychological/lifestyle/environmental traits. As the next step, innovative detection techniques should clarify underlying mechanisms and molecular pathways of these treatable traits and novel reliable point-of-care (composite) biomarkers to help predict responders to targeted therapies must be developed.

Summary: Precision medicine links the right patient to the right treatment. Identification of treatable traits in asthma and COPD will help optimize the treatment approach in these heterogeneous diseases. Furthermore, in-depth identification of underlying molecular pathways and reliable biomarkers in chronic airways diseases to guide targeted treatment in individual patients is in progress.
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http://dx.doi.org/10.1097/MCP.0000000000000639DOI Listing
January 2020

Efficacy of bronchial thermoplasty in patients with severe asthma.

J Asthma 2021 Feb 18;58(2):216-222. Epub 2019 Oct 18.

Respiratory Research Unit, Dept. of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark.

To investigate the efficacy and safety of bronchial thermoplasty (BT) in clinical practice in adults with severe, refractory asthma. Prospective, single-center, open, observational study comprising patients with uncontrolled asthma (asthma control questionnaire (ACQ) >1.5) and/or frequent exacerbations despite treatment with at least high dose inhaled corticosteroids plus a second controller. Efficacy outcomes was change from baseline 4, 8, 12 and 24 months in FEV, FVC and FEV/FVC ratio, asthma control questionnaire (ACQ) score and asthma quality of life score (mini-AQLQ). Results are presented as median with interquartile ranges (IQR). The following were recorded as adverse events: Un-scheduled health care contacts, rescue courses of oral corticosteroid (OCS) and/or antibiotics for exacerbation for exacerbations/respiratory tract infections (RTI). Six-teen patients were enrolled (nine males, median age 50 years; 14 followed for 24 months). Compared to baseline, an improvement in FEV, FVC, FEV/FVC ratio, mini-AQLQ and ACQ was observed, i.e.FEV (IQR) 1.98 L (1.65-2.45) vs. 2.45 L (2.09-2.93) ( = 0.006), FVC (IQR) 3.23 L (2.76-4.05) vs. 3.75 L (3.22-4.36) ( = 0.041), FEV/FVC 0.60 (IQR: 0.55-0.70) vs. 0.66 (IQR: 0.63-0.71) ( = 0.016), mini-AQLQ 4.0 (IQR: 3.2-4.9) vs. 5.6 (IQR 4.5-6.5) ( = 0.008, and ACQ 2.9 (IQR: 2.1-3.7) versus 1.5 (IQR 1.0-2.4) ( = 0.004). On the other hand, an increase was observed in unscheduled visits ( = 0.005), as well as use of OCS and antibiotics ( = 0.009 and  = 0.003, respectively). BT in adults with severe asthma improved ACQ, mini-AQLQ and lung function, but resulted in an increased frequency of unscheduled doctor-visits and rescue courses of OCS and antibiotics.
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http://dx.doi.org/10.1080/02770903.2019.1678636DOI Listing
February 2021

Next-generation ARIA care pathways for rhinitis and asthma: a model for multimorbid chronic diseases.

Authors:
J Jean Bousquet Holger J Schünemann Alkis Togias Marina Erhola Peter W Hellings Torsten Zuberbier Ioana Agache Ignacio J Ansotegui Josep M Anto Claus Bachert Sven Becker Martin Bedolla-Barajas Michael Bewick Sinthia Bosnic-Anticevich Isabelle Bosse Louis P Boulet Jean Marc Bourrez Guy Brusselle Niels Chavannes Elisio Costa Alvaro A Cruz Wienczyslawa Czarlewski Wytske J Fokkens Joao A Fonseca Mina Gaga Tari Haahtela Maddalena Illario Ludger Klimek Piotr Kuna Violeta Kvedariene L T T Le Desiree Larenas-Linnemann Daniel Laune Olga M Lourenço Enrica Menditto Joaquin Mullol Yashitaka Okamoto Nikos Papadopoulos Nhân Pham-Thi Robert Picard Hilary Pinnock Nicolas Roche Regina E Roller-Wirnsberger Christine Rolland Boleslaw Samolinski Aziz Sheikh Sanna Toppila-Salmi Ioanna Tsiligianni Arunas Valiulis Erkka Valovirta Tuula Vasankari Maria-Teresa Ventura Samantha Walker Sian Williams Cezmi A Akdis Isabella Annesi-Maesano Sylvie Arnavielhe Xavier Basagana Eric Bateman Anna Bedbrook K S Bennoor Samuel Benveniste Karl C Bergmann Slawomir Bialek Nils Billo Carsten Bindslev-Jensen Leif Bjermer Hubert Blain Mateo Bonini Philippe Bonniaud Jacques Bouchard Vitalis Briedis Christofer E Brightling Jan Brozek Roland Buhl Roland Buonaiuto Giorgo W Canonica Victoria Cardona Ana M Carriazo Warner Carr Christine Cartier Thomas Casale Lorenzo Cecchi Alfonso M Cepeda Sarabia Eka Chkhartishvili Derek K Chu Cemal Cingi Elaine Colgan Jaime Correia de Sousa Anne Lise Courbis Adnan Custovic Biljana Cvetkosvki Gennaro D'Amato Jane da Silva Carina Dantas Dejand Dokic Yves Dauvilliers Antoni Dedeu Giulia De Feo Philippe Devillier Stefania Di Capua Marc Dykewickz Ruta Dubakiene Motohiro Ebisawa Yaya El-Gamal Esben Eller Regina Emuzyte John Farrell Antjie Fink-Wagner Alessandro Fiocchi Jean F Fontaine Bilun Gemicioğlu Peter Schmid-Grendelmeir Amiran Gamkrelidze Judith Garcia-Aymerich Maximiliano Gomez Sandra González Diaz Maia Gotua Nick A Guldemond Maria-Antonieta Guzmán Jawad Hajjam John O'B Hourihane Marc Humbert Guido Iaccarino Despo Ierodiakonou Maddalena Illario Juan C Ivancevich Guy Joos Ki-Suck Jung Marek Jutel Igor Kaidashev Omer Kalayci Przemyslaw Kardas Thomas Keil Mussa Khaitov Nikolai Khaltaev Jorg Kleine-Tebbe Marek L Kowalski Vicky Kritikos Inger Kull Lisa Leonardini Philip Lieberman Brian Lipworth Karin C Lodrup Carlsen Claudia C Loureiro Renaud Louis Alpana Mair Gert Marien Bassam Mahboub Joao Malva Patrick Manning Esteban De Manuel Keenoy Gailen D Marshall Mohamed R Masjedi Jorge F Maspero Eve Mathieu-Dupas Poalo M Matricardi Eric Melén Elisabete Melo-Gomes Eli O Meltzer Enrica Menditto Jacques Mercier Neven Miculinic Florin Mihaltan Branislava Milenkovic Giuliana Moda Maria-Dolores Mogica-Martinez Yousser Mohammad Steve Montefort Ricardo Monti Mario Morais-Almeida Ralf Mösges Lars Münter Antonella Muraro Ruth Murray Robert Naclerio Luigi Napoli Leila Namazova-Baranova Hugo Neffen Kristoff Nekam Angelo Neou Enrico Novellino Dieudonné Nyembue Robin O'Hehir Ken Ohta Kimi Okubo Gabrielle Onorato Solange Ouedraogo Isabella Pali-Schöll Susanna Palkonen Peter Panzner Hae-Sim Park Jean-Louis Pépin Ana-Maria Pereira Oliver Pfaar Ema Paulino Jim Phillips Robert Picard Davor Plavec Ted A Popov Fabienne Portejoie David Price Emmanuel P Prokopakis Benoit Pugin Filip Raciborski Rojin Rajabian-Söderlund Sietze Reitsma Xavier Rodo Antonino Romano Nelson Rosario Menahenm Rottem Dermot Ryan Johanna Salimäki Mario M Sanchez-Borges Juan-Carlos Sisul Dirceu Solé David Somekh Talant Sooronbaev Milan Sova Otto Spranger Cristina Stellato Rafael Stelmach Charlotte Suppli Ulrik Michel Thibaudon Teresa To Ana Todo-Bom Peter V Tomazic Antonio A Valero Rudolph Valenta Marylin Valentin-Rostan Rianne van der Kleij Olivier Vandenplas Giorgio Vezzani Frédéric Viart Giovanni Viegi Dana Wallace Martin Wagenmann De Y Wang Susan Waserman Magnus Wickman Dennis M Williams Gary Wong Piotr Wroczynski Panayiotis K Yiallouros Arzu Yorgancioglu Osman M Yusuf Heahter J Zar Stéphane Zeng Mario Zernotti Luo Zhang Nan S Zhong Mihaela Zidarn

Clin Transl Allergy 2019 9;9:44. Epub 2019 Sep 9.

260University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy.

Main Body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care.

Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
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http://dx.doi.org/10.1186/s13601-019-0279-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734297PMC
September 2019

Female asthma and atopy - impact on fertility: a systematic review.

J Asthma Allergy 2019 24;12:205-211. Epub 2019 Jul 24.

Department of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.

Background And Objective: Asthma is one of the most common chronic diseases among women of reproductive age, and previous studies have suggested a link between female asthma and infertility. The aim of the present review is to provide an update on current knowledge of the association between female asthma and/or atopy and a reduction in fertility, ie, number of offspring, time to pregnancy (TTP) and need for fertility treatment.

Methods: Systematic review performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guidelines.

Results: A total of 14 studies fulfilled the predefined criteria for inclusion in the present review. Six studies investigated the association between female asthma and/or atopy and number of offspring, of which one reported a positive, two a negative, and three no association. Three studies addressed the association between asthma and TTP and found that TTP was significantly prolonged in asthmatic women compared to non-asthmatic women. Five studies investigated subfertility and the need for fertility treatments of which two studies found a higher prevalence of infertility among women prescribed anti-asthma medication. One study found no difference in the number of fertility treatments of asthmatic women compared to non-asthmatic women, whereas three studies reported that female asthma was associated with significantly more fertility treatment compared to non-asthmatic women.

Conclusion: Although the available evidence is conflicting, there is a clear trend toward an association between female asthma and a reduction in fertility, and by that a larger proportion requiring fertility treatment, even though female asthma might not negatively affect total number of offspring.
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http://dx.doi.org/10.2147/JAA.S203576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664855PMC
July 2019