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BackgroundInhaled corticosteroids (ICS) are commonly used to treat COPD and are associated with increased risk of pneumonia. The aim of this study was to assess if accumulated use of ICS is associated with a dose-dependent risk of a positive airway culture with Pseudomonas aeruginosa in patients with COPD.MethodsWe conducted a multiregional epidemiological cohort study including Danish COPD patients followed in outpatient clinics during 2010–2017. ICS use was categorised based on accumulated prescriptions redeemed 365 days prior to cohort entry. Cox proportional hazard regression model was used to estimate the risk of acquiring P. aeruginosa. Propensity score matched models were used as sensitivity analyses.ResultsA total of 21 408 patients were included in the study, of which 763 (3.6%) acquired P. aeruginosa during follow-up. ICS use was associated with a dose-dependent risk of P. aeruginosa (low ICS dose: HR 1.38, 95% CI 1.03 to 1.84, p=0.03; moderate ICS dose: HR 2.16, 95% CI 1.63 to 2.85, pConclusionUse of ICS in patients with COPD followed in Danish outpatient clinics was associated with a substantially increased and dose-dependent risk of acquiring P. aeruginosa. Caution should be taken when administering high doses of ICS in severely ill patients with COPD. These results should be confirmed in comparable cohorts and other settings.

Social distancing measures introduced on March 12, 2020, in Denmark during the COVID-19 pandemic may affect non–COVID-19 admissions for severe acute exacerbation of chronic obstructive pulmonary disease (s-AECOPD). We compared rates of s-AECOPD in a nationwide, observational, semi-experimental cohort study using data from all Danish inhabitants between calendar week 1 through 25 in 2019 and 2020. In a sub-cohort of patients with chronic obstructive pulmonary disease, we examined incidence of s-AECOPD, admissions to an intensive care unit, and all-cause mortality. 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, compared with 11,260 incidents in 2019, resulting in a 45% relative risk reduction. In the cohort with chronic obstructive pulmonary disease (n = 16,675), we observed a lower risk of s-AECOPD in the social distancing period (subdistribution hazard ratio (HR) = 0.34, 95% confidence interval (CI): 0.33, 0.36; absolute risk: 25.4% in 2020 and 42.8% in 2019). The risk of admissions to an intensive care unit was reduced (subdistribution HR = 0.64, 95% CI: 0.47, 0.87), as was all-cause mortality (HR = 0.83, 95% CI: 0.76, 0.90). Overall, the social distancing period was associated with a significant risk reduction for hospital admittance with s-AECOPD.

Aim: To determine the risk of type 2 diabetes onset associated with accumulated inhaled corticosteroids (ICS) dose during the previous year in patients with chronic obstructive pulmonary disease (COPD). Materials and methods: We conducted a nationwide observational cohort study based on data from patients with COPD between 1 January 2010 and 31 December 2017 extracted from Danish health databases. Patients were followed for 7 years, until death or a type 2 diabetes event. A propensity-matched Cox model and an adjusted Cox proportional hazards model (stratified on body mass index [BMI]) were used to estimate the hazard ratio (HR) for new-onset type 2 diabetes. Results: A total of 50 148 patients with COPD were included, 3566 (7.1%) of whom had a type 2 diabetes event. During the previous year before study entry, 35 368 patients (70.5%) used ICS. The propensity-matched Cox model (N = 33 466) showed an increased risk of type 2 diabetes, which progressed with increasing accumulated ICS dose (low-ICS: HR 1.076, confidence interval [CI] 1.075-1.077, P 2. Conclusions: In patients with COPD, ICS use was associated with a moderate dose-dependent increase in the occurrence of type 2 diabetes.

Background: Inhaled corticosteroids (ICS) are widely used in chronic obstructive pulmonary disease (COPD), despite the known risk of severe adverse effects including pulmonary infections. Research Question: Our study investigates the risk of acquiring a positive Haemophilus influenzae airway culture with use of ICS in outpatients with COPD. Study Design and Methods: We conducted an epidemiological cohort study using data from 1 January 2010 to 19 February 2018, including 21,218 outpatients with COPD in Denmark. ICS use 365 days prior to cohort entry was categorised into low, moderate, and high, based on cumulated ICS dose extracted from a national registry on reimbursed prescriptions. A Cox proportional hazards regression model was used to assess the future risk of acquiring H. Influenzae within 365 days from cohort entry, and sensitivity analyses were performed using propensity score matched models. Results: In total, 801 (3.8%) patients acquired H. Influenzae during follow-up. Use of ICS was associated with a dose-dependent increased risk of acquiring H. Influenzae with hazard ratio (HR) 1.2 (95% confidence interval (CI) 0.9–1.5, p value = 0.1) for low-dose ICS; HR 1.7 (95% CI 1.3–2.1, p value < 0.0001) for moderate dose; and HR 1.9 (95% CI 1.5–2.4, p value < 0.0001) for high-dose ICS compared to no ICS use. Results were confirmed in the propensity-matched model using the same categories. Conclusions: ICS use in outpatients with COPD was associated with a dose-dependent increase in risk of isolating H. Influenzae. This observation supports that high dose ICS should be used with caution.

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified COPD, age ≥40 years, and no previous cancer. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder were assessed by Cox proportional hazards models. We observed a dose-dependent increase in the risk of antidepressant-use with ICS cumulated dose (HR 1.05, 95% CI 1.03–1.07, p = 0.0472 with low ICS exposure, HR 1.10, 95% CI 1.08–1.12, p &lt, 0.0001 with medium exposure, HR 1.15, 95% CI 1.11–1.15, p &lt, 0.0001 with high exposure) as compared to no ICS exposure. We found a discrete increased risk of admission to psychiatric hospitals in the medium and high dose group (HR 1.00, 95% CI 0.98–1.03, p = 0.77 with low ICS exposure, HR 1.07, 95% CI 1.05–1.10, p &lt, 0.0001 with medium exposure, HR 1.13, 95% CI 1.10–1.15, p &lt, 0.0001 with high exposure). The association persisted when stratifying for prior antidepressant use. Thus, exposure to ICS was associated with a small to moderate increase in antidepressant-use and psychiatric admissions.

Background Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. Methods This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20–365 from study allocation and (ii) days alive and without exacerbation within days 20–365 from the study allocation. Discussion This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. Trial registration ClinicalTrials.gov NCT03262142. Registered on August 25, 2017.

Background: Due to repeated exacerbations a large group of patients with chronic obstructive pulmonary disease (COPD) are often exposed to oral corticosteroids (OCS). Corticosteroids may be thrombogenic. We evaluated the risk of venous thromboembolia and death in patients with acute exacerbation of COPD (AECOPD) according to two different dosing regimens.Method: This was a nationwide observational cohort study of outpatients with COPD with a 6 month follow up time. It was based on a linked administrative registry data between January 1st 2010 and 28th February 2018. In total 30.473 patients treated with either short course (250mg) of OCS for AECOPD were included in the study. Cox proportional hazard regression was used to estimate the risk of VTE hospitalization or all-cause mortality.Results: The incidence of VTE was low. However, long course of OCS was associated with an increased risk of VTE compared to short course, (HR 1.73, CI 1.08 to 2.79; p < 0.0001). Furthermore, we found a higher risk of all-cause mortality in the long course group, HR 1.62 (CI 1.57 to 1.62; p

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.

Social distancing measures introduced during the coronavirus disease 2019 pandemic have reduced admission rates for various infectious and noninfectious respiratory diseases. We hypothesized that rates of asthma exacerbations would decline following the national lockdown in Denmark.To determine weekly rates of in- and out-of-hospital asthma exacerbations before and during the social distancing intervention implemented on March 12, 2020.All individuals older than 18 years with at least 1 outpatient hospital contact with asthma as the main diagnosis from January 1, 2013, to December 31, 2017, were included. Weekly asthma exacerbation rates from January 1, 2018, to May 22, 2020, were calculated. An interrupted time-series model with the lockdown on March 12, 2020, as the point of interruption was used.A total of 38,225 patients with asthma were identified. The interrupted time-series model showed no immediate fall in exacerbation rates during the first week after March 12, 2020. However, there was a significant decline in weekly exacerbation rates in the following 10 weeks (change in trend for exacerbations requiring hospitalization: -0.75 [95% CI, -1.39 to -0.12]; P.02 and in all asthma exacerbations: -12.2 [95% CI, -19.1 to -5.4; P.001), amounting to a reduction of approximately 1 and 16.5 exacerbations per year per 100 patients in the cohort, respectively.The introduction of the social distancing measures in Denmark did not lead to an immediate reduction in asthma exacerbation rates; however, a gradual decline in exacerbation rates during the following 10-week period was observed.

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated with long and short OCS regimens. In this nationwide cohort study of 30,473 COPD outpatients treated for AECOPD, we compared the risk of VTE hospitalisation and all-cause mortality within 6 months in OCS dose of &gt, 250 mg vs. ≤ 250 mg. A multivariable Cox proportional hazard regression was used to estimate the risk. The incidence of VTE hospitalisations was 0.23%. A long OCS treatment course was associated with an increased risk of VTE compared to a short course (hazard ratio (HR) 1.69, [95% confidence interval (CI) 1.05 to 2.72], p &lt, 0.031). A higher risk of all-cause mortality was seen in the group of COPD patients treated with a long OCS course (HR 1.71, [95% CI 1.63 to 1.79], p &lt, 0.0001). The risk of reported VTE hospitalisation was higher among AECOPD patients treated with long courses of OCS, but the absolute risk was low, suggesting under-reporting of the condition.

Background Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). Methods In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs. Results The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, –1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively. Conclusions In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Inhaled corticosteroids (ICS) are commonly used to treat COPD and are associated with increased risk of pneumonia. The aim of this study was to assess if accumulated use of ICS is associated with a dose-dependent risk of a positive airway culture withWe conducted a multiregional epidemiological cohort study including Danish COPD patients followed in outpatient clinics during 2010-2017. ICS use was categorised based on accumulated prescriptions redeemed 365 days prior to cohort entry. Cox proportional hazard regression model was used to estimate the risk of acquiringA total of 21 408 patients were included in the study, of which 763 (3.6%) acquiredUse of ICS in patients with COPD followed in Danish outpatient clinics was associated with a substantially increased and dose-dependent risk of acquiring

Background: Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids (GC), and thus may affect the therapeutic effects of GCs. We investigated the prevalence of adrenal suppression after treatment with GCs and evaluated whether GR SNPs were associated with the risk of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). Methods: In an observational prospective cohort study, we recruited 77 patients with severe COPD receiving five days GC treatment for an exacerbation of COPD. 49% of patients also received regular inhaled corticosteroids. Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK and 9β SNPs. Results: The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 1 month after GC treatment was 4/77 (5%). There was no correlation between high-sensitivity (p-value 0.79) or low-sensitivity (p-value 0.26) GR haplotypes and stimulated cortisol levels for COPD patients treated with GCs. There was no difference between adrenal suppression and metabolic disorders in COPD patients stratified for high vs. low GC-sensitivity GR haplotypes plus wild type (p-value > 0.05). Corticotropin stimulated P-cortisol did not differ between carriers and non-carriers for Bcl1, 9β, ER22/23K and N363S. For carriers of the high sensitivity GR gene haplotype, the association between inhaled corticosteroid dose and stimulated P-cortisol concentrations was more inverse (slope –0.25 vs. -0.10) than in patients with the low sensitivity haplotype. Conclusions: Five percent of patients had an insufficient adrenal function. The Bcl1 and N363S polymorphisms do not seem to increase the risk of adrenal suppression or metabolic disorders in adults treated with corticosteroids for COPD exacerbations.Trial Registration: The trial was registered at clinicaltrials.gov (NCT03140761) at May 4, 2017 with URL https://clinicaltrials.gov/ct2/show/NCT03140761.