Beta-Blockers in High-Risk Outpatients with Chronic Obstructive Pulmonary Disease are Associated with All-Cause Mortality - The STATUETTE Cohort Study.

Background: Beta-blockers have been proposed to improve COPD-related outcomes, yet studies report conflicting results. We aimed to investigate the effect of beta blockers on time-to-first exacerbation and all-cause mortality in high-risk COPD outpatients. Methods: All COPD outpatients managed at the Department of Respiratory Medicine, Copenhagen University Hospital - Hvidovre, Denmark in 2016 were followed for 3.5 years in this retrospective, registry-based cohort study. Outcomes were time-to-first acute exacerbation of COPD (AECOPD) or death. The association was estimated using time-varying crude and multivariable Cox proportional hazard regression adjusted for age, sex, BMI, use of COPD medication, smoking status, cardiovascular disease and COPD severity. Results: The cohort comprised 950 COPD outpatients, mean age 71 (SD 11) years, and FEV1 44% predicted (IQR 33%; 57%). The annual exacerbation rate was 0.88 (SD 1.68) and 211 patients (22%) had a history of hospitalization requiring AECOPD within 12 months. Of the enrolled patients, 247 (26%) were prescribed beta blockers. Beta-blocker use was associated, although with borderline significance, with increased all-cause mortality (HR 1.37 (95% CI, 0.99 to 1.89, p = 0.059)). On the other hand, beta blocker use did not reduce the risk of AECOPD (HR = 0.89 (95% CI 0.71 to 1.10; p = 0.270)), which remained non-significant after stratifying for severity of exacerbations. Conclusion: We found an association between beta blocker use and all-cause mortality in high-risk COPD outpatients. No association was found between beta blocker use and risk of AECOPD.

Inhaled Corticosteroid Therapy in Bronchiectasis is Associated with All-Cause Mortality: A Prospective Cohort Study.

Background 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.

Self-reported vs. objectively assessed adherence to inhaled corticosteroids in asthma.

BACKGROUND: Adherence to inhaled corticosteroids (ICS) in asthma is vital for disease control. However, obtaining reliable and clinically useful measures of adherence remains a major challenge. We investigated the association between patient-reported adherence and objectively measured adherence based on filled prescriptions with inhaled corticosteroids in adults with asthma. METHODS: In total, 178 patients with asthma were asked to self-assess adherence during routine visits at a respiratory outpatient clinic. Self-assessment was performed using Foster score ("How many days in a 7-day week do you take your medication as prescribed?", with the answer divided by 7). Objective adherence was calculated as medication possession ratio (MPR). Bivariate and multivariable linear regression, adjusted for age, sex, FEV1, GINA treatment step, excessive use of SABA, and history of exacerbations were used for analyses. RESULTS: Of the included patients, 87.6% reported a Foster score of 100%, while the mean ICS MPR was 54.0% (SD 25%). Complex regimens such as twice-daily dosing or dual inhaler-use were associated with lower adherence (p = 0.015 and p < 0.001, respectively). Foster score was predictive of ICS MPR, with an absolute 32% increase in MPR between patients reporting Foster scores of 0 and 100% (95% CI 13-50%, p < 0.001). Female sex predicted higher ICS MPR (p = 0.019). Previous asthma-related hospitalization(s) predicted lower ICS MPR (p = 0.039). CONCLUSION: Although a weak association was found between Foster score and ICS MPR, findings do not support the use of Foster score, and by that self-reported adherence, as a reliable marker of controller adherence in asthma due to significant mismatch between patient-reported adherence and MPR. Future studies should address the complex interplay between patient-reported and objectively assessed adherence to controller medication in asthma.

Hydroxychloroquine as a primary prophylactic agent against SARS-CoV-2 infection: A cohort study.

OBJECTIVE: Hydroxychloroquine has been proposed as a primary prophylactic agent against coronavirus disease 2019 (COVID-19). This study aimed to investigate if patients treated with hydroxychloroquine for a non-COVID-19 indication had a lower risk of verified infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared with matched controls. METHODS: A cohort comprising all persons in Denmark collecting hydroxychloroquine prescriptions in 2020 and 2019 (i.e., both during and before SARS-CoV-2 was confirmed in Denmark), matched by age and sex with controls, was studied. Data were collected using the Danish national registries, which contain complete information on patient health data, prescriptions and microbiological test results. The main outcome was microbiologically verified SARS-CoV-2 infection. RESULTS: In total, 5488 hydroxychloroquine users were matched with 54,486 non-users. At baseline, the groups differed in terms of diagnoses of pulmonary disease, cardiovascular disease, renal disease, gastrointestinal/metabolic disease and dementia, as well as treatment with antirheumatic drugs. The final model was adjusted for these potential confounders. Use of hydroxychloroquine for non-COVID-19 indications was not associated with any change in confirmed SARS-CoV-2 (hazard ratio 0.90, 95% confidence interval 0.76-1.07). This result was robust in the propensity-score-matched sensitivity analysis. CONCLUSION: This study, which is the largest to date to investigate the primary prophylactic effect of hydroxychloroquine against SARS-CoV-2, does not support any prophylactic benefit of hydroxychloroquine in the prevention of infection with SARS-CoV-2.

[Statins and COPD: relationship with inflammation, exacerbations and mortality].

The role of statins on the disease course of COPD is controversial. Observational studies have shown a reduction in mortality and exacerbations, but results of randomised clinical trials (RCTs) of statin treatment and its effect on adverse outcomes are conflicting. Recent meta-analyses suggest the need for further RCTs including COPD patients both with and without concurrent cardiovascular disease (CVD). As there are no known detrimental effects of statins in COPD patients, we conclude in this review, that statins should be prescribed more frequently in these patients due to the common co-morbidity with CVD.

High suPAR and Low Blood Eosinophil Count are Risk Factors for Hospital Readmission and Mortality in Patients with COPD.

Introduction: The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with increased mortality in chronic obstructive pulmonary disease (COPD), while elevated blood eosinophils have been associated with better survival. We hypothesized that suPAR and blood eosinophil count are independent risk factors for readmission and mortality after an acute admission in patients with COPD. Methods: This retrospective cohort study comprised 4022 patients with prevalent COPD acutely admitted to Hvidovre Hospital, Denmark. Irrespective of cause of admission, suPAR and blood eosinophils were measured, and patients were followed up to 365 days. Associations with 365-day respiratory readmission, all-cause readmission and all-cause mortality were investigated by Cox regression analyses adjusted for age, sex, Charlson score and C-reactive protein. Results: suPAR was significantly elevated in patients who later experienced readmission or died. At 365 days, hazard ratios (HRs) for all-cause readmission and mortality reached 1.61 (95% CI 1.40-1.85; p<0.0001) and 3.40 (95% CI 2.64-4.39; p<0.0001), respectively, for COPD patients in the fourth suPAR quartile compared to patients in the first suPAR quartile. High blood eosinophils (>300 cells/µL) were associated with lower risk of mortality (HR 0.49, 95% CI 0.39-0.62; p<0.0001) compared with patients with <150 cells/µL. When stratifying patients by suPAR quartiles and blood eosinophil counts, the highest relative mortality rate was found in patients belonging to both the fourth suPAR quartile and the low blood eosinophil (<150 cells/µL) group. Conclusion: In this cohort of COPD patients acutely admitted to a hospital, elevated suPAR concentrations were associated with both higher risk of all-cause readmission and mortality, whereas higher blood eosinophil count was associated with lower risk of mortality.

Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease.

AIMS: We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease. METHODS AND RESULTS: We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice. CONCLUSION: 14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise.

Circulating microRNAs have proven to be reliable biomarkers, due to their high stability, both in vivo in the circulation, and ex vivo during sample preparation and storage. Small nucleolar RNAs (snoRNAs) are a different type of small non-coding RNAs that can also be reliably measured in plasma, but have only been studied sporadically. In this study, we aimed to identify RNA-biomarkers that can distinguish between different exercise regimes and that entail clues about muscle repair and recovery after prolonged exhaustive endurance exercise. We compared plasma microRNA profiles between two cohorts of elite cyclists, subjected to two different types of exercise regimes, as well as a cohort of patients with peripheral artery disease (PAD) that were scheduled to undergo lower limb amputation, due to critical limb ischemia. In elite athletes, muscle tissue recovers quickly even after exhaustive exercise, whereas in PAD patients, recovery is completely impaired. Furthermore, we measured levels of a specific group of snoRNAs in the plasma of both elite cyclists and PAD patients. Using a multiplex qPCR screening, we detected a total of 179 microRNAs overall, of which, on average, 161 microRNAs were detected per sample. However, only 30 microRNAs were consistently expressed in all samples. Of these, two microRNAs, miR-29a-3p and miR193a-5p, that responded differently two different types of exercise, namely exhaustive exercise and non-exhaustive endurance exercise. Using individual rt/qPCR, we also identified a snoRNA, SNORD114.1, which was significantly upregulated in plasma in response to endurance exercise. Furthermore, two microRNAs, miR-29a-3p and miR-495-3p, were significantly differentially expressed in athletes compared to PAD patients, but only following exercise. We suggest that these two microRNAs could function as markers of impaired muscle repair and recovery. In conclusion, microRNAs miR-29a-3p and miR-193a-5p may help us distinguish between repeated exhaustive and non-exhaustive endurance exercise. MicroRNA miR-29a-3p, as well as miR-495-3p, may further mark impaired muscle recovery in patients with severe critical limb ischemia. Furthermore, we showed for the first time that a circulating snoRNA, SNORD114.1, is regulated in response to exercise and may be used as biomarker.