Low-dose, long-term macrolide therapy in asthma: An overview

Macrolides, a class of antimicrobials isolated from Streptomycetes more than 50 years ago, are used extensively to treat sinopulmonary infections in humans. In addition, a growing body of experimental and clinical evidence indicates that long-term (years), low (sub-antimicrobial)-dose 14- and 15-membered ring macrolide antibiotics, such as erythromycin, clarithromycin, roxithromycin and azithromycin, express immunomodulatory and tissue reparative effects that are distinct from their anti-infective properties. These salutary effects are operative in various lung disorders, including diffuse panbronchiolitis, cystic fibrosis, persistent chronic rhinosinusitis, nasal polyposis, bronchiectasis, asthma and cryptogenic organizing pneumonia. The purpose of this overview is to outline the immunomodulatory effects of macrolide antibiotics in patients with asthma

SARS-CoV-2 Infection in the COPD Population is Associated with Increased Healthcare Utilization: An Analysis of Cleveland Clinic\u27s COVID-19 Registry

Background: We sought to determine whether COPD conferred a higher risk for healthcare utilization in terms of hospitalization and clinical outcomes due to COVID-19. Methods: A cohort study with covariate adjustment using multivariate logistic regression was conducted at the Cleveland Clinic Health System in Ohio and Florida. Symptomatic patients aged 35 years and older who were tested for SARS-CoV-2 between March 8 and May 13, 2020 were included. Findings: 15,586 individuals tested for COVID-19 at the Cleveland Clinic between March 8, 2020 and May 13, 2020 met our inclusion criteria. 12.4% of COPD patients (164/1319) tested positive for COVID-19 compared to 16.6% (2363/14,267) of the non-COPD population. 48.2% (79/164) of COVID-19 positive COPD patients required hospitalization and 45.6% (36/79) required ICU admission. After adjustment for covariates, rates of COVID-19 infection were not significantly different than the non-COPD population (adj OR 0.97; CI: 0.89-1.05), but COPD patients had increased healthcare utilization as demonstrated by risk for hospitalization (adj OR 1.36; CI: 1.15-1.60), ICU admission (OR 1.20; CI: 1.02-1.40), and need for invasive mechanical ventilation (adj OR 1.49; CI: 1.28-1.73). Unadjusted risk for in-hospital mortality was higher in the COPD population (OR 1.51; CI: 1.14-1.96). After adjusting for covariates however, the risk for in-hospital mortality was not significantly different than the non-COPD population (adj OR 1.08: CI: 0.81-1.42). Interpretation: Our analysis demonstrated that COPD patients with COVID-19 had a higher risk for healthcare utilization, although adjusted in-hospital mortality risk was not different than the non-COPD patients with COVID-19

Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive patients with COPD: An analysis of Cleveland Clinic's COVID-19 registry.

Inhaled Corticosteroids (ICS) are commonly prescribed to patients with severe COPD and recurrent exacerbations. It is not known what impact ICS cause in terms of COVID-19 positivity or disease severity in COPD. This study examined 27,810 patients with COPD from the Cleveland Clinic COVID-19 registry between March 8th and September 16th, 2020. Electronic health records were used to determine diagnosis of COPD, ICS use, and clinical outcomes. Multivariate logistic regression was used to adjust for demographics, month of COVID-19 testing, and comorbidities known to be associated with increased risk for severe COVID-19 disease. Amongst the COPD patients who were tested for COVID-19, 44.1% of those taking an ICS-containing inhaler tested positive for COVID-19 versus 47.2% who tested negative for COVID-19 (p = 0.033). Of those who tested positive for COVID-19 (n = 1288), 371 (28.8%) required hospitalization. In-hospital outcomes were not significantly different when comparing ICS versus no ICS in terms of ICU admission (36.8% [74/201] vs 31.2% [53/170], p = 0.30), endotracheal intubation (21.9% [44/201] vs 16.5% [28/170], p = 0.24), or mortality (18.4% [37/201] vs 20.0% [34/170], p = 0.80). Multivariate logistic regression demonstrated no significant differences in hospitalization (adj OR 1.12, CI: 0.90-1.38), ICU admission (adj OR: 1.31, CI: 0.82-2.10), need for mechanical ventilation (adj OR 1.65, CI: 0.69-4.02), or mortality (OR: 0.80, CI: 0.43-1.49). In conclusion, ICS therapy did not increase COVID-19 related healthcare utilization or mortality outcome in patients with COPD followed at the Cleveland Clinic health system. These findings should encourage clinicians to continue ICS therapy for COPD patients during the COVID-19 pandemic

Budget impact analysis of a digital monitoring platform for COPD

Abstract Background Chronic obstructive pulmonary disease (COPD) is a progressive debilitating condition with frequent exacerbations that have a high burden for patients and society. Digital tools may help to reduce the economic burden for patients and payers by improving outcomes. The Propeller platform is a digital self-management tool that facilitates passive monitoring of inhaler medication utilization, potentially assisting the healthcare team to identify patients at risk of a COPD exacerbation who may require further intervention. This study estimated the budget impact of Propeller from commercial payer and Medicare fee-for-service payer perspectives. Methods An Excel-based model was used to estimate the budget impact of Propeller for COPD patients in commercial and Medicare population sizes of 5 million members. Data on prevalence, baseline healthcare resource utilization (HCRU), and baseline use of rescue and controller inhaler medications with unit costs (adjusted to 2020 US dollars) were obtained from peer-reviewed literature. Data on reductions in HCRU during Propeller usage were based on direct evidence. Estimates for costs of remote monitoring were obtained from publicly available information. All patients were assumed to have insurance claims related to ongoing remote monitoring. Results The estimated number of annual eligible COPD patients for commercial and Medicare was 212,200 and 606,600, respectively. Propeller decreased costs by an estimated $2,475 (commercial) and$915 (Medicare) per enrolled patient. The greatest increase in expenditure was for remote monitoring related expenses. After accounting for estimated reductions in hospitalizations, emergency department visits and short-acting beta-agonist use, total net savings were approximately $1.60 and$1.70 per-member per-month for commercial and Medicare payers, respectively. Conclusion Propeller is projected to be cost saving from both the commercial and Medicare payer perspectives

Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank

Abstract Background Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with systemic consequences that can cause a muscle loss phenotype (MLP), which is characterized by the loss of muscle mass, muscle strength, or loss of both muscle and fat mass. There are limited data comparing the individual traits of MLP with clinical outcomes in a large unbiased cohort of COPD patients. Our aim was to determine the proportion of patients who met criteria for MLP in an unbiased sample of COPD patients at the population-level. We also determined if specific MLP features were associated with all-cause and COPD-related mortality. Methods A retrospective population-based cohort analysis of the UK Biobank was performed. COPD was defined by a FEV1/FVC ratio < 0.7, physician established diagnosis of COPD, or those with a COPD-related hospitalization before baseline assessment. MLP included one or more of the following: 1) Low fat-free mass index (FFMI) on bioelectric impedance analysis (BIA) or 2) Appendicular skeletal muscle index (ASMI) on BIA, 3) Low muscle strength defined by handgrip strength (HGS), or 4) Low muscle and fat mass based on body mass index (BMI). Cox regression was used to determine the association between MLP and all-cause or COPD-related mortality. All models were adjusted for sex, age at assessment, ethnicity, BMI, alcohol use, smoking status, prior cancer diagnosis and FEV1/FVC ratio. Results There were 55,782 subjects (56% male) with COPD followed for a median of 70.1 months with a mean(± SD) age at assessment of 59 ± 7.5 years, and FEV1% of 79.2 ± 18.5. Most subjects had mild (50.4%) or moderate (42.8%) COPD. Many patients had evidence of a MLP, which was present in 53.4% of COPD patients (34% by ASMI, 26% by HGS). Of the 5,608 deaths in patients diagnosed with COPD, 907 were COPD-related. After multivariate adjustment, COPD subjects with MLP had a 30% higher hazard-ratio for all-cause death and 70% higher hazard-ratio for COPD-related death. Conclusions Evidence of MLP is common in a large population-based cohort of COPD and is associated with higher risk for all-cause and COPD-related mortality

Additional file 1 of Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank

Supplementary Material 1

Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease

Abstract Background Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age‐related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. Methods To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome‐wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non‐Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity‐associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n = 3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. Results Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non‐coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A > T in the FTO gene (β = 0.151, SE = 0.021, P = 1.40 × 10−12 for UK Biobank |β= 0.220, SE = 0.041, P = 9.99 × 10−8 for COPDGene) and chr 18 SNP rs11664369C > T nearest to the AC090771.2 gene (β = 0.129, SE = 0.024, P = 4.64 × 10−8 for UK Biobank |β = 0.203, SE = 0.045, P = 6.38 × 10−6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence‐associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. Conclusions Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD