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Kjell EJ Håkansson,1 Katrine Fjaellegaard,2,3 Andrea Browatzki,4 Melda Dönmez Sin,1 Charlotte Suppli Ulrik1,5 1Department of Respiratory Medicine, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark; 2Department of Respiratory Medicine, Zealand University Hospital Næstved, Næstved, Denmark; 3Institute of Regional Health Research, University Southern Denmark, Odense, Denmark; 4Department of Respiratory Medicine, North Zealand Hospital, Hillerød, Denmark; 5Institute of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Kjell EJ HåkanssonRespiratory Research Unit 237, Copenhagen University Hospital - Hvidovre, Kettegård Allé 30, 2650, Hvidovre, DenmarkEmail kjell@kjell.dkBackground and Objective: Prescribing inhaled corticosteroids (ICS) for bronchiectasis (BE) in the absence of obstructive lung disease is controversial. Studies investigating ICS therapy and impact on morbidity and mortality in BE are sparse.Methods: This study comprises all patients with BE managed at respiratory outpatient clinics at two university hospitals in the Capital Region of Denmark 2014– 2015. Baseline data were obtained from patient medical records, and patients were followed until April 2020.Results: Out of 264 patients, 122 (46%) were prescribed ICS with no demographic differences between users/non-users of ICS. Among patients prescribed ICS, 21% did not have a concomitant diagnosis of asthma or COPD. Patients prescribed ICS had lower lung function (median FEV1 65.2 vs 80.9%pred, p< 0.001) and a higher symptom burden in terms of cough (p 0.028), sputum production (p < 0.001) and dyspnea (p < 0.001). Pseudomonas-positive sputum cultures were more common in ICS-treated patients (6.5 vs 20%, p 0.010), as were previous severe exacerbations (41% vs 21%, p < 0.001). In terms of mortality, high-dose ICS use was associated with increased mortality in multivariable Cox regression adjusted for age, sex, FEV1 and concomitant asthma/COPD (HR 4.93 [95% CI 1.73– 14.0], p 0.003).Conclusion: In this cohort, close to one out of five patients with BE were prescribed ICS despite having no concomitant diagnosis of asthma or COPD. Overall, ICS treatment was associated with higher morbidity and mortality, though causation is difficult to establish.Keywords: follow-up cohort, descriptive study, all-cause mortality, ICS, non-cystic fibrosis bronchiectasis

Background: Social distancing measures introduced during the COVID-19 pandemic may have an effect on non-COVID-19 admissions for severe acute exacerbation of chronic obstructive pulmonary disease (s-AECOPD). Our aim was to determine the risk of s-AECOPD prior to and after the social distancing period was implemented in Denmark on March 12, 2020. Methods: A nationwide observational cohort study comparing data from all Danish inhabitants between calendar week 1 through 25 in 2019 and 2020, extracted from Danish health registries. A sub-study of s-AECOPD, all-cause mortality, and admissions to intensive care unit (ICU) in outpatients with specialist confirmed diagnosis of COPD was conducted for the same calendar periods. Results: A total of 3.0 million inhabitants aged 40+ years, corresponding to 3.0 million person-years, were followed for s-AECOPD. In the social distancing period in 2020, there were 6,212 incidents of s-AECOPD as compared to 11,260 incidents of s-AECOPD in the same time period in 2019, which corresponds to a relative risk reduction of 45%. In the COPD outpatient cohort (N=16,675), we observed a lower risk of s-AECOPD with the social distancing period (hazard ratio [HR] 0.34, 95%-confidence interval [CI] 0.33-0.36, p Conclusions: The social distancing period was associated with a risk reduction for hospital admittance with s-AECOPD of a larger magnitude than any other known intervention.

Background Systemic corticosteroid administration for severe acute exacerbations of COPD (AECOPD) reduces the duration of hospital stays. Corticosteroid-sparing regimens have showed non-inferiority to higher accumulated dose regimens regarding re-exacerbation risk in patients with AECOPD. However, it remains unclear whether 14-day or 2–5-day regimens would result in shorter admission durations and changes in mortality risk. We explored this by analysing the number of days alive and out of hospital based on two randomised controlled trials with different corticosteroid regimens. Methods We pooled individual patient data from the two available multicentre randomised trials on corticosteroid-sparing regimens for AECOPD: the REDUCE (n = 314) and CORTICO-COP (n = 318) trials. In the 14-day regimen group, patients were older, fewer patients received pre-treatment with antibiotics and more patients received pre-treatment with systemic corticosteroids. Patients randomly allocated to the 14-day and 2–5-day regimens were compared, with adjustment for baseline differences. Results The number of days alive and out of hospital within 14 days from recruitment was higher for the 2–5 day regimen group (mean 8.4 days; 95% confidence interval [CI] 8.0–8.8) than the 14-day regimen patient group (4.2 days; 95% CI3.4–4.9; p p p p = 0.15), new or aggravated hypertension (OR 1.5; 95% CI 0.9–2.7; p = 0.15), or mortality risk (HR 0.8; 95% CI 0.4–1.5; p = 0.45) during the 6-month follow-up period. Conclusion 14-day corticosteroid regimens were associated with longer hospital stays and fewer days alive and out of hospital within 14 days, with no apparent 6-month benefit regarding death or admission to ICU in COPD patients. Our results favour 2–5 day regimens for treating COPD exacerbations. However, prospective studies are needed to validate these findings.

Background: Pulmonary P. aeruginosa infections increase morbidity in COPD patients. While low resolution molecular typing has shown that the same clonal lineage can persist and adapt in the lungs, the prevalence of chronic infections in consistently sampled COPD cohorts remains unknown. Objective: The study aim was to determine the prevalence and genetic adaptation of persistent P. aeruginosa infections in patients with COPD. Methods: Whole-genome sequencing study of P. aeruginosa strains sampled longitudinally from sputum cultures in 23 patients enrolled in an ongoing randomized controlled trial in Denmark (clinicaltrials.gov: NCT03262142). Results: A total of 153 P. aeruginosa isolates were sequenced in 23 patients during 365 days of follow-up. Genome sequencing showed that 18 patients were infected with clonal lineages that persisted for at least 30 days (Figure 1). We identified 37 P. aeruginosa genes that were independently mutated in two or more lineages, suggesting a positive selection for adaptive mutations. Mutation in the same genes have previously been shown to be important for persistent infections in patients with genetically defined mucociliary clearance defects. Conclusion:P. aeruginosa persists and genetically adapts in patients with COPD. Thus, our results indicate parallelism to P. aeruginosa infections in patients with genetically defined mucociliary clearance defects.

Background: The impact of P. aeruginosa on long-term prognosis in COPD remains unknown. Objective: To determine whether P. aeruginosa is associated with increased risk of exacerbation or death in patients with COPD. Methods: Observational cohort study on 22.053 COPD outpatients (Fig.1). Time-dependent Cox proportional hazard regression model was used to estimate a) hospitalisation for exacerbation or all-cause mortality and b) all-cause mortality after 2 years. Results:P. aeruginosa was found in 4.1% of the patients. Hospital admissions (80% and 48%,p Conclusions:P. aeruginosa is associated with substantially worsened long-term prognosis in COPD. A randomized controlled trial is needed to conclude whether targeted antibiotic interventions can improve the prognosis in this highly vulnerable group of patients.

To provide an update on efficacy and safety of antibiotic treatments for stable non-cystic fibrosis (CF) bronchiectasis (BE). Systematic review based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was done. Twenty-six studies (1.898 patients) fulfilled the inclusion criteria. Studies of inhaled tobramycin have revealed conflicting results regarding quality of life (QoL), exacerbations and admissions, but may result in sputum cultures negative for Pseudomonas aeruginosa, whereas studies investigating the effect of inhaled gentamycin have shown positive effects on sputum bacterial density, decrease in sputum cultures positive for P. aeruginosa, QoL and exacerbation rate, but no improvement in forced expiratory volume in first second (FEV1). Oral azithromycin can reduce exacerbations, together with minor improvements in QoL and FEV1. Furthermore, oral erythromycin reduces exacerbations, but has no effect on lung function, symptoms or QoL. Inhaled ciprofloxacin may reduce P. aeruginosa in sputum cultures, but without changes in lung function, exacerbations or QoL. Although with limited evidence, inhaled colistin may have effects on P. aeruginosa density, exacerbations and QoL, whereas studies on aztreonam revealed no significant clinical improvements in the outcomes of interest, including exacerbation rate. Adverse events, including bronchospasm, have been reported in association with tobramycin and aztreonam. Several antibiotic treatment regimens have been shown to improve QoL and exacerbation rate, whereas findings regarding sputum production, lung function and admissions have been conflicting. Evidence-based treatment algorithms for antibiotic treatment of stable non-CF BE will have to await large-scale, long-term controlled studies.

Background: The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome. Methods: This is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 × 109 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV1, and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage. Discussion: This will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD. Trial registration: Clinicaltrials.gov, NCT02857842 , 02-august-2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016.

Aim: Update on efficacy and safety of non-antibiotic therapy for stable non-cystic fibrosis (CF) bronchiectasis. Methods: Systematic review based on the PRISMA-guidelines. Results: Fifteen studies (1278 patients) fulfilled the inclusion criteria. Studies (n = 3) suggest that inhaled hypertonic saline may be beneficial in patients with non-CF BE, although possibly not superior to isotonic saline. The effect of hypertonic saline on QoL, lung function, and exacerbation rate has, at best, been inconsistent. Inhaled mannitol (n = 6) affects sputum characteristics, but with no significant effect on exacerbation rate, lung function, or sputum, although it may have an effect on QoL and time to first exacerbation. High-dose inhaled corticosteroids (ICS) (n = 4) reduce sputum volume and eosinophils, possibly due to concomitant asthma, but with no effect on sputum purulence and bacteriology, lung function and exacerbation rate, although it seems to have positive impact on QoL and respiratory symptoms. One study investigating add-on long-acting beta2-agonist to ICS (n = 40) reported an effect on QoL, but no effect on lung function or exacerbation rate. Conclusion: Airway clearing techniques, including hypertonic saline and mannitol, and asthma controller medication may have beneficial effects in patients with non-CF BE, but only limited evidence suggests an effect on lung function and exacerbation rate.