Josefin Eklöf

Background: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition where many patients are given antibiotics like amoxicillin and macrolides (clarithromycin, azithromycin, roxithromycin) for bacterial infections. Recent concerns about clarithromycin’s potential link to cardiovascular events have arisen, despite its effectiveness against respiratory pathogens. This study aims to compare the cardiovascular risk of macrolide antibiotics versus amoxicillin in suspected COPD patients. Method: We used the Danish National Health Service Prescription Database (DNHSP) to identify COPD patients and their use of antibiotics. The included COPD patients were divided into four groups: amoxicillin users, roxithromycin users, clarithromycin users and azithromycin users. Data from multiple registries were merged to track hospitalizations, causes of death, and major adverse cardiovascular events (MACEs) as the primary endpoint. Patients were followed for a 3-year period. We applied adjusted Cox regression and sensitivity analyses with IPTW and IPCW to address confounders and censoring. Results: Our study involved 45,869 patients who were prescribed a long-acting muscarinic antagonist, over the age of 40 years old and who received one of the following antibiotics: amoxicillin, azithromycin, clarithromycin, or roxithromycin. No increased risk of MACEs was observed in macrolide-treated patients compared to those treated with amoxicillin (azithromycin: HR 0.97: 95% CI 0.83–1.13 p = 0.69, clarithromycin: HR 1.06 95% CI 0.87–1.28 p = 0.57, roxithromycin: HR 1.04 95% CI 0.91–1.18 p = 0.60), as confirmed by the sensitivity analysis (azithromycin: HR 0.95 95% CI 0.82–1.11 p = 0.52, clarithromycin: HR 1.05 95% CI 0.87–1.27 p = 0.60, roxithromycin: HR 1.05 95% CI 0.92–1.19 p = 0.48). Similarly, hazard ratios for all-cause mortality and cardiovascular death among the antibiotic groups showed no significant statistical differences. Conclusions: These findings suggest that there is no difference in the risk of MACEs, all-cause mortality, or cardiovascular death between the amoxicillin group and the macrolide group in a large and unselected population of COPD patients.

Background/Objectives: Inhaled corticosteroids (ICS) increase the risk of pneumonia caused by various pathogens in patients with chronic obstructive pulmonary disease (COPD). Treatment may also increase the risk of infection with non-tuberculous mycobacteria (NTM), although evidence remains limited. The aim of this study was to assess the association between ICS treatment and the risk of NTM isolation among patients with COPD. Methods: This retrospective register-based cohort study included patients with a specialist-verified COPD diagnosis between 2008 and 2021. ICS exposure was based on redeemed prescriptions during the year preceding the index date. Exposure was calculated as the mean daily budesonide-equivalent dose and categorized as none, low, medium, or high. A cause-specific Cox proportional hazards regression model with death as a competing risk was applied, adjusted for potential confounders. Sensitivity analyses included, among others, an inverse probability of treatment weighted model, and a time-dependent Cox regression model. Results: A total of 120,006 patients were included, with a median follow-up time of 4.9 years. During follow-up, 378 (0.32%) patients reached the primary endpoint. Medium- and high-dose ICS were associated with an increased hazard of NTM isolation, with hazard ratios of 1.39 (95% CI 1.06–1.88, p = 0.020) and 1.52 (95% CI 1.14–2.04, p = 0.005), respectively. This association remained significant for high-dose ICS across all sensitivity analyses. Conclusions: In patients with COPD, ICS treatment was associated with an increased and dose-dependent hazard of NTM isolation, particularly at high doses. High-dose ICS should, therefore, be prescribed with caution.

Respiratory disease contributes to the excess mortality seen in rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD) is frequently encountered. The aim of this study was to investigate the risk of severe acute exacerbation, pneumonia, and death among patients with RA and COPD compared with patients with COPD alone. The study population was patients with hospital-based, outpatient follow-up for COPD identified from the Danish COPD registry. Diagnoses of RA, information about hospitalizations for acute exacerbations of COPD (AECOPD), pneumonia, and vital status were obtained from National Health Registries. Follow-up was 12 months after first outpatient contact for COPD. Hospitalizations for AECOPD and pneumonia, and risk of death in COPD with or without RA, were compared using Cox proportional hazards regression analysis. Covariates were balanced using inverse probability of treatment (IPT) weighting. The study included 58 655 patients with hospital-based follow-up for COPD, 2033 (3.5%) of whom had RA. More than 25% of the cohort experienced hospitalization with AECOPD and/or pneumonia in the first year after first outpatient COPD hospital contact. IPT-weighted unadjusted Cox regression analysis showed similar risk of hospitalization with AECOPD among patients with RA and COPD [hazard ratio (HR) 1.004, 95% confidence interval (CI) 0.89-1.13] and death (HR 1.13, 95% CI 0.98-1.30), but increased risk of hospitalization for pneumonia (HR 1.26, 95% CI 1.11-1.42). The increased risk of pneumonia associated with RA may be attributed to immunosuppression. The findings should lead to increased focus on optimizing COPD therapies and preventive measures.

Exacerbations of chronic obstructive pulmonary disease (COPD) often require treatment with oral corticosteroids (OCS). While OCS can improve forced expiratory volume in first second (FEV1) in the short term, there are still concerns about their potential cardiovascular adverse effects. Evidence on whether short-term OCS use increases the risk of major adverse cardiovascular events (MACE) remains lacking. We hypothesized that short-term OCS use in patients with COPD would be associated with an increased one-year risk of MACE compared with antibiotic treatment alone. We conducted a registry-based, nationwide cohort study in outpatients diagnosed with COPD in the Danish Register of COPD (DrCOPD) between 2010 and 2022. Exposure was defined as prescription of OCS and antibiotics for respiratory infections in the year before baseline (defined as DrCOPD entry). Exposed patients were propensity score matched on clinical parameters to patients prescribed antibiotics for respiratory infections but no OCS. The primary outcome was all MACE, as a composite outcome, within 365 days following baseline. A total of 4,666 patients were included. Short-term OCS exposure was not associated with increased risk of MACE during one-year follow-up compared to use of antibiotics for respiratory infections (hazard ratio = 0.84, 95% CI 0.66 – 1.07, p = 0.17). The findings were consistent in a sensitivity analysis using an adjusted Cox model in the unmatched population. Secondary analyses of individual MACE components showed no significant differences in risk. An additional sensitivity analysis stratified by cumulative OCS dose revealed no dose-response relationship for the primary outcome (all MACE). Short-term OCS use was not associated with an increased risk of MACE within 365 days among outpatients with COPD.

Background: Non-cystic fibrosis bronchiectasis (BE) is a chronic lung condition characterized by irreversible bronchial dilation and presented with persistent respiratory symptoms, recurrent respiratory infections, and decreased quality of life. Inhaled corticosteroids (ICSs) are frequently prescribed in patients with bronchiectasis, despite limited evidence supporting their clinical efficacy. Inhaled corticosteroids have been associated with increased risk of respiratory infection with Haemophilus influenzae (H. influenzae) in other groups of lung diseases. We aimed to evaluate the association between ICS use and the risk of isolating H. influenzae from lower respiratory tract samples in patients with bronchiectasis. Methods: A retrospective cohort study was conducted using data from 2010 to 2018, encompassing all patients diagnosed with bronchiectasis in outpatient clinics in Eastern Denmark. ICS use was standardized in budesonide equivalent doses and categorized in tertiles: low (H. influenzae from lower respiratory tract samples post-cohort entry. Cox proportional hazards models, adjusted for relevant confounders, estimated hazard ratios (HRs), and inverse probability-of-treatment weighting (IPTW) was used in sensitivity analyses. Results: Among 3663 patients (mean age 66 years; 61% female), 2175 (59.4%) did not use ICS, while 484 (13.2%), 508 (13.9%), and 496 (13.5%) were in the low-, moderate-, and high-dose ICS groups, respectively. Furthermore, 594 (16.22%) patients had a lower respiratory tract culture positive for H. influenzae during follow-up. High-dose ICS use was associated with an increased risk of H. influenzae; HR 1.63 (95% Cl, 1.19 to 2.12, p < 0.005) compared with no ICS use. No association for low or moderate ICS use was found: low-dose ICS HR 0.75 (95% Cl, 0.52 to 1.07, p = 0.11) and moderate-dose ICS HR 1.27 (95% Cl, 0.93 to 1.72, p = 0.12). IPTW analysis confirmed the main finding. Conclusions: High-dose ICS use in patients with bronchiectasis was associated with an increased risk of acquiring H. influenzae in the lower respiratory tract. Hence, patients with bronchiectasis should be cautiously prescribed high-dose ICS.

Background: Elevated pulmonary pressures can lead to right ventricular dysfunction, worsen respiratory status and increase overall morbidity in COPD patients. Yet, little is known about the impact of right-sided pressure changes during acute exacerbation in COPD (AECOPD) on patient outcomes. Our aim was to determine whether pulmonary pressures are elevated during AECOPD compared with the stable phase and to investigate the association between tricuspid regurgitation (TR) gradient during AECOPD and days alive and out of hospital (DAOH). Methods: This was a multicentre, prospective study of pulmonary pressures changes in patients with AECOPD and stable-phase COPD. Inclusion criteria were diagnosis of COPD and admission with AECOPD. Transthoracic echocardiography (TTE), including TR gradient, tricuspid annular plane systolic excursion (TAPSE), right ventricular diameter and right atrial parameters, was performed during AECOPD and the stable phase. Results: Of 250 patients, 232 underwent TTE during AECOPD and 107 completed stable-phase follow-up. Reasons for incomplete follow-up included death (n=46), withdrawal (n=23), poor TTE quality (n=21) and unmeasurable TR gradients (n=35). TR gradient increased significantly during AECOPD, with a mean difference of 6.0 (95% CI 2.5–9.6) mmHg, while TAPSE, right ventricular diameter and right atrial size showed no significant changes. Higher TR gradients during AECOPD correlated with lower DAOH. Conclusion: TR gradients were significantly elevated during AECOPD, suggesting that transient right-sided pressure spikes are associated with COPD exacerbations. However, the direction of this association remains unclear and further research is needed to determine whether right-sided pressure changes contribute to exacerbations or whether exacerbations themselves drive these pressure spikes.

Objectives: Non-cystic fibrosis bronchiectasis (BE) is a chronic airway disease with increasing prevalence, reduced quality of life, and increased mortality. Inhaled corticosteroids (ICS) are used in BE despite limited evidence of effect on lung function parameters. ICS may increase the risk of Staphylococcus aureus (S. aureus) infections in patients with BE, but this is unexplored. We examined the association between ICS use prior to BE diagnosis at different doses and the risk of S. aureus isolation in patients with BE. Methods: We conducted a national register-based cohort study including Danish patients with a BE diagnosis code between 2001 and 2018 with a 1-year follow-up time from the date of diagnosis. ICS exposure was categorized based on accumulated prescriptions redeemed 365 days before BE diagnosis and divided into none, low, moderate, or high use based on clinically relevant doses. A cause-specific Cox proportional hazards regression model was used to estimate the risk of S. aureus isolation. A sensitivity analysis, an inverse probability of treatment weighted model (IPTW), was performed. Results: A total of 5093 patients were included in this study. S. aureus was isolated in 156 patients (3.1%). High-dose ICS was associated with an increased risk of S. aureus isolation, HR 3.81 (95% CI 2.51; 5.79). No association for low or moderate use was found, low-dose HR 1.22 (95% CI 0.77; 1.93), and moderate-dose HR 1.24 (95% CI 0.72; 2.16). IPTW analysis yielded similar results. Conclusions: High-dose ICS use in patients with BE was associated with an increased risk of S. aureus isolation. ICS should be used cautiously in patients with BE.

Background: Vitamin K is a cofactor necessary for the biological activity of proteins like Matrix Gla Protein (MGP), which reduce calcification and help preserve lung function. This study aims to determine, first, whether low vitamin K status is associated with chronic obstructive pulmonary disease (COPD), and secondary, whether the level of vitamin K is associated with COPD severity, smoking exposure, or mortality. Methods: The plasma concentration of dephosphorylated uncarboxylated (dp-uc) MGP was used as an inverse biomarker for vitamin K in 98 COPD patients from the CODEX-P COPD study and 986 controls from the DanFunD study. Low vitamin K status was defined as the upper quartile of dp-ucMGP (>589 pmol/L). Using a logistic regression model, we examined whether low vs. high/moderate vitamin K status increased the odds ratio (OR) of having COPD. Secondary analyses, in the COPD cohort only, examined the association between low vitamin K status and COPD severity, smoking exposure in packyears and all-cause mortality, using a Welch’s t-test and log-rank test, respectively. Results: Low vitamin K status was associated with increased odds of having COPD, OR 9.7 (95% CI [5.5 to 17.5], p < 0.001). We found no associations between low vitamin K and COPD severity (est. −0.03, p = 0.7; 95% CI [−0.2 to 0.1]), smoking exposure (p = 0.7), or all-cause mortality (p = 0.5). Conclusions: Low vitamin K status was associated with substantially higher odds of having COPD compared to high/moderate vitamin K status. No association was found between low vitamin K status and COPD severity, smoking exposure, or all-cause mortality. Further studies are needed to determine if vitamin K plays a role in the pathophysiology of COPD and whether supplement therapy is indicated.

Background: Current knowledge on psychiatric illness following periods of social distancing during the COVID-19 pandemic is mostly limited to smaller studies in selected populations. This nationwide study of all 4.6 million Danish adults examined if periods of social distancing were associated with changes in surrogate measures of mental health. Methods: All Danish adults (≥18 years) were included and rates of collection of antidepressant prescriptions, psychiatric hospital admissions, and suicide or suicide attempts for the periods March 12, 2020–May 20, 2020 (lockdown period 1), and December 21, 2020–March 1, 2021 (lockdown period 2), were compared to corresponding periods 1 year prior. Individuals were censored due to death or SARS-CoV-2 infection. Results: Antidepressant consumption increased for both period 1 and period 2, with an incidence rate ratio (IRR) of 1.02 (95% CI: 1.01–1.02, p < 0.001) and IRR 1.08 (95% CI: 1.08–1.09, p < 0.001) respectively, compared to the control periods. Psychiatric hospitalization rates decreased significantly, with an IRR of 0.65 (95% CI: 0.63–0.66, p < 0.001) for period 1, and IRR 0.86 (95% CI: 0.84–0.88, p < 0.001) for period 2. The risk of suicide did not increase in period 1, IRR 0.96 (95% CI: 0.82–1.13, p = 0.64), but seemed increased during period 2, IRR 1.19 (95% CI: 1.02–1.38, p = 0.03). Conclusion: Periods of social distancing during the COVID-19 pandemic were associated with an increase of antidepressant consumption, but decreased rates of psychiatric hospitalization. Suicide risk seemed increased during the second lockdown period.

Background: The effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes. Methods: Multicenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365. Results: The trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27–0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6–1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3–4.5) in the control group, p = 0.037. Conclusions: Use of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial. Trial Registration: ClinicalTrials.gov, NCT03262142, registration date 2017–08-25.