Introduction: Multiple reports propose using eosinophils (EOS) in blood to identify patients with chronic obstructive pulmonary disease (COPD) at increased risk for exacerbations. Others, including biologic therapy trials, report dissimilar results, possibly due to enrichment for those with a history of exacerbations. In a previous cross-sectional analysis (Lancet Res Med, PMID:29146301) of the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort, we found significant associations of greater retrospective exacerbation frequency with high sputum EOS, but not high blood EOS. Here, we examined whether elevated baseline blood or sputum EOS predicted future exacerbations. Methods: We stratified SPIROMICS participants having COPD by GOLD criteria (N=740) based on baseline high blood (≥300/microL) or sputum (≥2%) EOS. We evaluated EOS associations with prospective exacerbations (up to 10.54 years for visit 5) using zero-inflated negative binomial models with age, sex, race, smoking pack years, current smoker, asthma diagnosis, prior total exacerbations, and raw slope of post-bronchodilator FEV1 as covariates. Results: Neither blood nor sputum EOS were significantly associated with greater longitudinal exacerbations rates, nor was either associated with exacerbation counts in adjusted multivariate models. Conclusions: Neither higher blood or sputum EOS are predictive of increased future exacerbations in the SPIROMICS cohort. Although not population-based, SPIROMICS is a multi-center cohort of heavy smokers without enrichment for previous exacerbations; hence, it may more closely represent general populations, in which this question should be further studied.

Rationale: Nebulizers are an alternative to handheld devices for providing inhaled therapy. We identified factors and trends associated with nebulizer use in SPIROMICS. Methods: SPIROMICS is a prospective cohort study with 2,981 enrolled participants across four strata, both never-smokers and smokers with and without COPD. We use stratified logistic and linear mixed models to analyze nebulizer use among tobacco-exposed subjects with preserved spirometry (TEPPS) and those with COPD at enrollment visit 1 (V1) and after 4-7 years of follow-up at visit 5 (V5). Results: Of COPD participants, regular nebulizer use is reported in 9.5% to 21.5% at V1 and V5, respectively. A majority of participants in GOLD stage 4 (53.9%) and GOLD group D (50.7%) use nebulizers regularly. When adjusted for comorbidities and previous exacerbations, baseline nebulizer use is not associated with decreased FEV1, CAT, or SGRQ scores but is correlated with increased prospective exacerbations. Among those who did not use nebulizers at V1, initiation during subsequent visits is correlated with higher rates of future exacerbations. At V5, 32.9% report daily nebulizer use, of which only 0.9% are long-acting bronchodilators. Among TEPPS, 3.6% and 7.7% report nebulizer use at V1 and V5, respectively; of regular users, only 6.4% use long-acting medications at V5. In multivariate analysis, nebulizer use among TEPPS at V5 is not associated with age, history of asthma, smoking exposure, or FEV1 but is with increased symptoms and exacerbations during follow-up. Conclusion: Nebulizer use occurs among most participants with advanced COPD, and less so among TEPPS, yet long-acting drugs are underutilized. Nebulizer use is correlated with exacerbations.

Background: Asthma exacerbations (AEs) impact quality of life, productivity, and healthcare costs, and can even be life-threatening. Therefore, identifying potential biomarkers to prevent AEs is a priority in asthma research. Aim: To identify susceptibility loci associated with AEs in individuals from multiple ancestral backgrounds. Methods: AEs were defined based on the presence of asthma-related hospitalizations, acute emergency care, school absences, or oral corticosteroids use in the last 6 to 24 months. A meta-analysis of genome-wide association studies (GWAS), analysing 9.6 million genetic variants, was conducted in 9,392 patients with asthma (4,989 of European-descent, 2,181 Hispanic/Latinos, 1,250 Singaporean Chinese, and 972 African Americans). A total of 36,477 European and 1,078 non-European subjects with asthma were included in the replication stage. Functional effects of genetic variation were investigated in silico and with DNA methylation data from 595 individuals. Results: From the 126 independent variants suggestively associated in the discovery phase (p≤5×10-5), two loci at the vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 region (VCAM1/EXTL2, rs12091010) and the pantothenate kinase 1 gene (PANK1, rs943126) were consistently replicated: p=5.35x10-3 and p=1.30x10-2, respectively. These were associated with DNA methylation levels and gene expression of nearby genes in whole blood. Conclusions: The largest multi-ancestry meta-analysis of GWAS of AEs identified two regulatory loci at genes involved in host defence and inflammation. Supported by MCIN/AEI/10.13039/501100011033 (SAF2017-83417R & PID2020-116274RB-I00) & fellowship PRE2018-083837 MINECO/AEI/FEDER, UE.

Introduction This exploratory real-world study in the US compared exacerbation reduction and systemic corticosteroids (SCS) prescriptions in asthma patients on dupilumab, versus omalizumab, benralizumab, and mepolizumab. Methods Electronic medical record (EMR) data from TriNetX Dataworks was used to identify patients with asthma diagnosis (≥12 years of age) who initiated (index) dupilumab, omalizumab, benralizumab, or mepolizumab between November 2018 and September 2020 (with 12 months pre- and post-index [unless patient died] information). Dupilumab, benralizumab, and mepolizumab were compared in patients with ≥2 pre-index exacerbations. Inverse probability treatment weighting was applied to each of the comparison cohorts. Post-index asthma exacerbations and SCS prescription orders were analyzed using negative binomial regression models. Pairwise comparisons were performed between dupilumab and omalizumab, benralizumab, or mepolizumab. The model included baseline exacerbation rates and pre-index variables with ≥10% standardized differences between index biologics for doubly robust estimations. Results Overall, 2138 dupilumab-initiators, 1313 omalizumab-initiators, 918 benralizumab-initiators, and 992 mepolizumab-initiators fulfilled inclusion criteria. Of which, 825 dupilumab, 461 benralizumab, and 451 mepolizumab patients had ≥2 exacerbations during pre-index. In the post-index period, dupilumab significantly (p<0.0001) reduced exacerbations by 44% versus omalizumab, 24% versus benralizumab, and 28% versus mepolizumab. (Figure 1). Likewise, dupilumab treatment significantly (p<0.05) reduced SCS prescriptions by 28% versus omalizumab, 16% versus benralizumab, and 25% versus mepolizumab in the post-index period. Conclusion This exploratory EMR study, demonstrated a significantly greater reduction in asthma exacerbations and SCS prescriptions in patients prescribed with dupilumab versus those on omalizumab, benralizumab, or mepolizumab. Results should be interpreted within the limitations of EMR data.

Biologics for severe asthma can significantly impact on the burden of disease and also have the potential to reduce asthma mortality. By reviewing the literature and contacting the pharmaceutical companies, the present paper aims at providing a worldwide snapshot of biologic drugs availability, related with the trend of asthma mortality rate, as a marker of the burden of the disease.A decline in the global rate of annual asthma mortality was observed until the 1980s, but overall no further reduction occurred, and the current mortality estimation is 0.19 deaths per 100.000 people. A higher mortality rate has been registered in low and middle-income countries (LMICs), where poor socioeconomic conditions and lack of access to the medical resources are more relevant. The availability of monoclonal antibodies is mainly limited to the developed and high-income countries. Furthermore the overall “asthma management system” in LMICs suffers from a number of restrictions that hamper the widespread availability of biologics besides their costs. The availability of generic drugs in the field of biologics for severe asthma could contribute to facilitate their widespread accessibility. But before that, awareness and expertise regarding severe asthma, and proper tools to assess and manage it, deserve to be shared worldwide. Collaboration projects involving physicians from all the countries through the scientific Academies network and with the support of the Companies active in the field may provide an initial concrete opportunity.

Telomeres shorten in replicating somatic cells and with age; in human leukocytes, telomere length (TL) is associated with a host of aging-related diseases1,2. To date, 16 genome-wide association studies (GWAS) have identified twenty-three loci associated with leukocyte TL3–18, but prior studies were primarily in individuals of European and Asian ancestry and relied on laboratory assays including Southern Blot and qPCR to quantify TL. Here, we estimated TL bioinformatically, leveraging whole genome sequencing (WGS) of whole blood from n=75,176 subjects in the Trans-Omics for Precision Medicine (TOPMed) Program. We performed the largest multi-ethnic and only WGS-based genome-wide association analysis of TL to date. We identified 22 associated loci (p-value <5×10−8), including 10 novel loci. Three of the novel loci map to genes involved in telomere maintenance and/or DNA damage repair: TERF2, RFWD3, and SAMHD1. Many of the 99 pathways identified in gene set enrichment analysis for the 22 loci (multiple-testing corrected false discovery rate (FDR) <0.05) pertain to telomere biology, including the top five (FDR<1×10−9). Importantly, several loci, including the recently identified TINF2 and ATM6 loci, showed strong ancestry-specific associations.

BACKGROUND. In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA).

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Introduction Studies have shown that a prior asthma exacerbation is the strongest predictor of a future exacerbation. Using long-term observational data, we examined whether this association persists using 10-year follow-up data. Methods TENOR II was a multicenter, observational study with a cross-sectional single follow-up assessment of patients with severe/difficult-to-treat asthma more than 10 years after enrollment in the TENOR I study. Multivariable logistic regression assessed predictors of an ATS severe exacerbation at TENOR II using TENOR II variables, with the exception of a severe exacerbation from TENOR I, defined as 1 or more corticosteroid bursts within the 3 months before enrollment. Results A total of 288 patients were included. Mean age was 58.4 (16.0) years, 66.7% were female. Nearly half (46.9%) were obese and a quarter (25.0%) had ever smoked. Geometric mean of total IgE level was 68.9 IU/mL and mean eosinophil level was 197.6 (144.9) µL. Mean % predicted pre- and post-bronchodilator FEV1 was 72.9% and 78.3%, respectively. 71.2% of patients used combined ICS/LABA medication. Statistically significant predictors of a severe exacerbation were combined ICS/LABA use (odds ratio (OR) 3.5, 95% CI: 1.5, 8.0; p=0.004), a severe exacerbation at TENOR I (OR 2.5, 95% CI: 1.3, 4.8; p=0.007), and % predicted post-bronchodilator FEV1 (OR 1.2, 95% CI: 1.0, 1.4; p=0.046). Conclusions A prior severe exacerbation remains a predictor of a future exacerbation in patients with severe/difficult-to-treat asthma after more than a decade. Combined ICS/LABA use, and low post-bronchodilator lung function also increased the odds of a future exacerbation.