Eugene R. Bleecker

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV₁). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV₁, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.

Background: Some patients with asthma are also labeled with COPD. A real-world cross-sectional analysis of pharmacy claims is a novel approach to identify factors associated with these complex phenotypes. Aim: Examine the morbidity of asthma vs asthma and COPD over the lifespan. Methods: Age-related prevalence and systemic corticosteroid (SCS) and short-acting beta2-agonist (SABA) use were retrospectively analyzed via IQVIA Longitudinal Access and Adjudication Data. 5.6 M US patients with an asthma diagnosis (dx) in 2015–2018 and a 2016 medication claim were included. Exacerbations were defined by SCS use and symptom burden by SABA fills within 1 year of first asthma claim. Results: 4.47 M had an asthma dx (mean[SD] 31[23], median 26 yrs) and 1.15 M had an asthma and COPD dx (52[21], 57 yrs), of which 251,723 were <40 yrs. At all ages, incidence of asthma alone was greater (Fig.). Patterns of age-related exacerbations and symptom burden rose and fell similarly; however, asthma and COPD patients had more exacerbations and symptom burden over the lifespan. For both groups the proportion of patients with ≥2 SCS or ≥3 SABA fills was lowest at age 12-17 and peaked at age 35-49. Conclusion: Some asthmatics are labeled as also having COPD. These patients show greater disease burden than those with asthma alone. The early onset and age-related patterns of morbidity imply factors outside of tobacco contribute to a dual asthma and COPD label.

Systemic corticosteroid use to manage uncontrolled asthma and its associated healthcare burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE and Embase databases to identify English-language articles published in 2010–2017, using search terms for asthma with keywords for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use in children (>5 yr old), adolescents (12–17 yr old), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroids were commonly used for asthma management and were more frequently used in patients with severe asthma than in those with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with an increased risk of acute and chronic adverse events, even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and healthcare resource use. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated adverse events for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and the risks of acute and chronic complications increase with the cumulative oral corticosteroid dosage.

Background: Severe asthma is heterogeneous, with different phenotypes and endotypes. Aims and Objectives: We identified subsets of benralizumab-treated patients (pts) with severe asthma by assignment to Severe Asthma Research Program (SARP) clinical clusters. Methods: Pts (N=2,281) from SIROCCO (Lancet 2016:2115; n=1,082) and CALIMA (Lancet 2016:2128; n=1,199) were assigned to clusters via a discriminant function based on 11 predictors. Drug responses were compared with the Kruskal-Wallis test (nominal p-values). Results: Pts met criteria for 4 of 5 SARP clusters. Cluster 2 pts (n=393) were 81% atopic with early onset moderate asthma (mean age 15 yrs). Cluster 4 pts (n=386) were 82% atopic with early onset severe asthma (mean age 11 yrs). Cluster 3 pts (n=641) were 50% atopic with late-onset severe asthma (mean age 47 yrs). Cluster 5 pts (n=861) were 55% atopic with late-onset asthma (mean age 33 yrs) and persistent airflow obstruction. All clusters had annual exacerbation rate reductions for combined benralizumab arms vs. placebo, which were greater in late-onset asthma clusters (Cluster 3, −48%; 5, −50%; pp=0.08; 3, −57%, pp=0.28; 5, −53%, p1 improved between benralizumab and placebo in Clusters 3 (+130 mL; p=0.0005) and 5 (+160 mL; p1 increased 410 mL vs. baseline (p<0.0001). Conclusions: Benralizumab improved lung function and reduced exacerbations in all clusters, with greater effects in late-onset asthma Clusters 3 and 5 vs. early onset Clusters 2 and 4. This supports the importance of understanding asthma heterogeneity and responsiveness to targeted therapies.

Although type-2–induced (T2-induced) epithelial dysfunction is likely to profoundly alter epithelial differentiation and repair in asthma, the mechanisms for these effects are poorly understood. A role for specific mucins, heavily N-glycosylated epithelial glycoproteins, in orchestrating epithelial cell fate in response to T2 stimuli has not previously been investigated. Levels of a sialylated MUC4β isoform were found to be increased in airway specimens from asthmatic patients in association with T2 inflammation. We hypothesized that IL-13 would increase sialylation of MUC4β, thereby altering its function and that the β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) would regulate the sialylation. Using human biologic specimens and cultured primary human airway epithelial cells (HAECs),we demonstrated that IL-13 increases ST6GAL1-mediated sialylation of MUC4β and that both were increased in asthma, particularly in sputum supernatant and/or fresh isolated HAECs with elevated T2 biomarkers. ST6GAL1-induced sialylation of MUC4β altered its lectin binding and secretion. Both ST6GAL1 and MUC4β inhibited epithelial cell proliferation while promoting goblet cell differentiation. These in vivo and in vitro data provide strong evidence for a critical role for ST6GAL1-induced sialylation of MUC4β in epithelial dysfunction associated with T2-high asthma, thereby identifying specific sialylation pathways as potential targets in asthma.

BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar “molecular phenotypes” may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype. METHODS. We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids. RESULTS. The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation. CONCLUSION. These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT01969344. FUNDING. Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C.

The identification of smoking-related lung disease in current and former smokers with normal FEV1 is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV1/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group. We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV1 and FEV1/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV1/FVC criteria thresholds. The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV1 and FEF25–75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV1/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality. Ever-smokers with normal FEV1 and FEV1/FVC < 0.70 but > LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone.