INTRODUCTION:Metformin and physical activity have been suggested as beneficial for chronic lung disease; however, there are no prior randomized trials. METHODS:The Diabetes Prevention Program (DPP) was a 3-year trial that randomized 3234 individuals at risk for diabetes to metformin, lifestyle intervention or placebo. After the DPP, 88% of participants enrolled in the DPP Outcomes Study that offered lifestyle intervention to all and open-label continuation of metformin. Spirometry was performed at approximately 19 and 22 years post-randomization. Lung function measures were compared in an intention-to-treat (ITT) analysis by original randomization group. Models were unadjusted and adjusted for demographics, body size, smoking and sitting/standing at spirometry. Additional analyses tested prevalence of obstruction (FEV1/FVC <70%), restrictive pattern (FVC < LLN and FEV1/FVC ≥70%), preserved ratio impaired spirometry (PRISm: FEV1 <80% predicted, FEV1/FVC ≥70%) and symptoms (COPD Assessment Test [CAT] score ≥10). RESULTS:The 1888 participants with spirometry were a mean (±SD) age of 68.2 ± 9.3 years, 70% female and 6% currently smoked and 33% had previously smoked cigarettes. Mean follow-up time was 19.0 ± 0.8 years. The mean FEV1 was 2.14 ± 0.60 L, FVC 2.74 ± 0.74 L, FEV1/FVC 78.4 ± 6.4%, mean BMI was 32.4 ± 6.7 kg/m2 and 58% had diabetes. In both unadjusted and adjusted ITT analyses, randomization group was not associated with FEV1, FVC or FEV1/FVC. Likewise, rates of obstruction, restrictive pattern, PRISm or symptoms did not differ by randomization group. CONCLUSIONS:In this long-term follow-up after a randomized trial, we found no significant associations between randomization to metformin or lifestyle intervention and lung function or respiratory symptoms.

Obesity is a significant health issue, as it is related to human diseases such as asthma and respiratory viral infections. Asthma patients with obesity have more severe diseases, which can be presented with type 1 (e.g., IFN-γ) high inflammation. The interactions of obesity or saturated fatty acids (e.g., palmitic acid, PA) with IFN-γ in airway viral infections have not been clear. In this study, we determined the role of obesity risk factors high-fat diet (HFD) and PA in rhinovirus infection in the context of IFN-γ stimulation in mice and cultured human tracheobronchial epithelial cells. We further examined the therapeutic effect of a glycolytic inhibitor on metabolic reprogramming and viral infection in our experimental models. In mice, HFD in combination with IFN-γ significantly increased lung rhinovirus levels as well as neutrophilic inflammation. Similarly, PA and IFN-γ combination increased viral infection in mice, but HFD or PA alone had a minimal effect on viral infection. Mouse model data were confirmed in cultured primary healthy human airway epithelial cells where PA and IFN-γ together increased viral load. Mechanistically, HFD or PA in combination with IFN-γ up-regulated the glycolytic pathway and generated metabolites favoring viral replication. Inhibition of glycolysis by 2-DG effectively reduced viral infection in human airway epithelial cells. Our data suggest that hosts with obesity along with type 1 high inflammation may be at an increased risk of respiratory viral infections. Intervention of the glycolytic pathway or its metabolites may reduce the severity of viral infection.

Asthma morbidity significantly affects children of all racial backgrounds; however, African American children experience a greater disease burden than children from other racial groups. Despite the known influence of air pollution on asthma outcomes, its role in the efficacy of asthma treatments remains underexplored. To examine how exposure to particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) influenced treatment outcomes in the NIH AsthmaNet Best African American Response to Asthma Drugs (BARD) trial. The BARD trial randomized 224 African American children to four asthma treatments consisting of inhaled corticosteroids (ICS) and long-acting beta antagonists (LABA) administered in a randomized crossover fashion. Treatment efficacy was assessed by the frequency of asthma exacerbations, percent predicted FEV1 (%PFEV1), and annualized asthma control days. Residential exposures to PM2.5, NO2, and O3 were estimated using a validated spatiotemporal model. Mixed effects models were used to evaluate the interaction between pollution exposure and treatment efficacy, adjusting for age, household triggers and trial site. PM2.5, NO2, and O3 exposures ranged substantially across participants: from 2.28 - 15.3 μg/m3, 2.34 - 63.7 ppm, and 2.57 - 23.7 ppb, respectively. NO2 and PM2.5 exposures were not associated with increased exacerbations post-treatment (p for interaction = 0.15 and 0.08, respectively). However, NO2 exposure significantly modified the effect of high-dose ICS+LABA therapy on lung function. Children with below median NO2 exposures while on ICS + LABA had a reduction of 5.86 (1.16, 10.56) in %PFEV1 compared to those with above-median NO2 exposures. Residential high NO2 exposure may significantly attenuate the efficacy of ICS+LABA therapy on lung function in African American children. These findings suggest the need to consider environmental factors in clinical trials and asthma management strategies.

Nearly 8% of the U.S. population is diagnosed with asthma, leading to more than 5 million office visits and 1 million emergency department visits annually. Both outpatient and inpatient internal medicine clinicians treat asthma frequently, but nuances in diagnosis and management have emerged. This article highlights many of these developments.

BACKGROUND:Severe asthma affects 5% to 10% of patients with asthma but constitutes close to one-half of the medical costs related to asthma due to higher morbidity and health care utilization. Biologic agents have become a standard of care in those unresponsive to standard treatments yet the choice of biologic agent is complex due to the varying mechanisms of action, efficacies, and lack of head-to-head comparisons. Therefore, clinicians need further clinical guidance to optimize their use. STUDY DESIGN AND METHODS:Panelists developed key clinical questions utilizing the population, intervention, comparator, and outcome (PICO) format to address choice of a biologic agent in severe asthma for adult patients aged ≥ 18 years. A comprehensive systematic search was performed using MEDLINE (via OVID), EMBASE, Web of Science, and CINAHL to identify relevant articles, which were then screened for inclusion using document evaluation tools. Each included article underwent quality assessment, data extraction, and pooled analysis to support grade level recommendation for each of the PICO questions. RESULTS:Our systematic review and critical analysis of the literature on the 7 PICO questions related to choice of biologic agent in severe asthma patients resulted in 7 evidence-based recommendations. INTERPRETATION:Characteristics such as quality of life impairment, baseline lung function, frequency of exacerbation, baseline oral corticosteroid use, asthma endotype, biomarkers, and comorbid conditions can impact the biologic choice. Evidence for selecting biologic agents in severe asthma is limited by the absence of comparative effectiveness trials. Additional high-quality evidence is needed to inform choice of biologic agents in these patients.

Mucus hypersecretion is an important pathological problem in respiratory diseases. Mucus accumulates in the airways of people with asthma and contributes to airflow limitation by forming plugs that occlude airways. Current treatments have minimal effects on mucus or its chief components, the polymeric mucin glycoproteins MUC5AC and MUC5B. This treatment gap reflects a poor molecular understanding of mucins that could be used to determine how they contribute to airway obstruction. Because of the prominence of glycosylation as a defining characteristic of mucins, we investigated characteristics of mucin glycans in asthma and in a mouse model of allergic asthma. Mucin fucosylation was observed in asthma, and in healthy mice it was induced as part of a mucous metaplastic response to allergic inflammation. In allergically inflamed mouse airways, mucin fucosylation was dependent on the enzyme fucosyltransferase 2. Fut2 gene-deficient mice were protected from asthma-like airway hyperreactivity and mucus plugging. These findings provide mechanistic and translational links between observations in human asthma and a mouse model that may help improve therapeutic targeting of airway mucus.

Mucus is a crucial component of airway host defense. For optimal protection, its chief components-the mucins MUC5AC and MUC5B-need to be tightly regulated. Their expression localizes to specific secretory epithelial cell types capable of producing and secreting massive glycopolymers. In asthma, abnormal mucus is an important clinical problem that is effectively treated with therapies that directly target mucins. This review summarizes what is known about how mucin gene regulation, protein synthesis, and secretion are regulated in healthy and asthmatic lungs. Ultimately, a better understanding of these processes could help identify novel ways of preventing or reversing airway mucus dysfunction.

Asthma is a heterogeneous condition that is often comorbid with obesity and influenced by diverse risk factors. Elucidating the association of gut microbial characteristics with asthma could improve our understanding of the pathophysiology. Here, we investigate relationships of host genetics and stool microbiota characteristics with asthma among US Hispanic/Latino adults, while considering the influence of obesity status, using host whole genome sequencing and stool shotgun metagenomic microbiota data from participants of the Hispanic Community Health Study/Study of Latinos. We evaluate cross-sectional associations of microbiota characteristics with asthma and analyse whether they are modified by obesity status (body mass index≥30 kg/m2). We assess differences in alpha diversity, beta diversity, and taxonomic abundance with asthma, independent of obesity, and interactions between asthma and obesity using covariate-adjusted regression-based methods. We generate an asthma polygenic risk score (PRS) and compare the classification accuracy of genetic and microbial factors for asthma status. We report that asthma is associated with differences in overall taxonomic composition (beta diversity; p = 0.001), which is not dependent on obesity status (p = 0.31). Asthma is not associated with alpha diversity metrics (p > 0.17), though obesity is associated with lower alpha diversity (p < 0.01). We identify multiple taxa that are associated with asthma, including decreased abundance of Lactobacillus and Enterococcus species, and some taxonomic associations vary by obesity status. Compared to models including baseline risk factors and an asthma PRS, microbial information improves classification accuracy of asthma (p = 0.04). Our results support that there are microbiota characteristics associated with asthma in Hispanic/Latino adults independent of obesity.

Background: Prior studies have identified predictors of asthma exacerbations; however, most lack integration of type 2 (T2) inflammatory markers. Research Question: In a large electronic health record database, what are predictors of asthma exacerbation rates and is there interaction by T2 inflammation, female sex, and obesity? Study Design and Methods: This is a retrospective cohort study using electronic health record data of patients with asthma followed for at least 1 year in the UCHealth system. The primary outcome was asthma exacerbation rate, defined by the prescription of an oral corticosteroid burst. Predictors of interest included T2 high inflammation, defined as absolute eosinophil count (AEC) ≥ 300 cells/μL, BMI, and sex. Predictors of the numbers of exacerbation and prespecified interactions were identified with negative binomial models. A natural cubic spline was used to model the dose response between AEC and exacerbation rate. Results: The cohort included 70,939 patients with asthma; 52% had T2 high inflammation and 62% were female, with 70% of patients being overweight or obese. Individuals with T2 high inflammation had higher adjusted rates of exacerbation (adjusted incidence rate ratio, 1.13; 95% CI, 1.10-1.16). AEC predicted exacerbation frequency in a dose-dependent manner. There was significant effect modification by sex, with female participants with T2 high inflammation having increased exacerbation rates compared with male participants with T2 high inflammation. Interpretation: This study finds an increase in exacerbation rate among patients with T2 high inflammation with asthma and shows a dose-dependent response to AEC. To our knowledge, this is the first study to find effect modification by sex and T2 status, identifying a group of patients who could potentially benefit from T2-targeted biologic therapy to decrease their exacerbation rate.

Purpose of reviewThis review provides a comprehensive overview of the non-T asthma phenotypes. Asthma is an umbrella term that defines a complex group of heterogenous airway disorders, which are broadly categorized into predominantly T2 or non-T2 phenotypes depending on the presence and levels of airway and systemic biomarkers associated with a T2 inflammatory response. Individuals with predominant T2 asthma have greater numbers of peripheral blood eosinophils, exhaled nitric oxide and IgE. These patients have more atopy and earlier onset asthma. In contrast, the absence or low levels of these biomarkers define non-T2 asthma. This is a heterogenous group with a later onset of asthma that is also more commonly associated with obesity and with females.Recent findingsThis article summarizes new information regarding the plasticity that exists between T2 and non-T2 mechanisms, including their role in exacerbation-prone and nonexacerbating asthma, and many of the risk factors associated with the non-T2 phenotype, such as viral infections, ambient air pollution exposure, smoking, genetic and metabolic factors. It also provides new information on the immunological and metabolic mechanisms associated with non-T2 asthma. We also discuss how to manage this asthma phenotype and how treatment responses differ for these patients.SummaryNon-T2 asthma defines a heterogenous group of asthma phenotypes. However, acknowledging that the absence of T2 biomarkers is influenced by several factors is important and can longitudinally change in relation to exacerbations, particularly in children.

Asthma and metabolic disorders (obesity, diabetes, metabolic syndrome) are comorbid, but the underlying mechanisms of this association are poorly understood. We previously found that insulin pathway genes are downregulated in asthmatic airway epithelium. Moreover, epidemiological studies have shown that insulin resistance associates with asthma independently of obesity. We hypothesized that insulin dysregulation contributes to asthma pathogenesis by promoting epithelial barrier dysfunction and inflammation. We evaluated this by assessing gene, protein, and metabolic profiles of normal and asthmatic human bronchial epithelium (NHBE; AHBE) at baseline and in insulin-manipulated conditions. We found: (1) AHBE had lower baseline levels of phospho-Akt (Ser473). With insulin restimulation, phospho-Akt (Ser473) and phospho-GSK-3β (Ser9) were decreased in AHBE, confirming AHBE insulin resistance; (2) NHBE barrier dysfunction in insulin-deficient air-liquid interface cultures closely resembled the AHBE phenotype; (3) AHBE had higher levels of GLUT1 glucose transporter and increased anabolic vs. energetic glucose utilization, indicating altered glucose metabolism; and (4) AHBE had a distinct metabolic signature from NHBE, featuring an increase in amino acid metabolism. Our study provides a needed mechanistic framework for understanding the connection between AHBE dysfunction and insulin resistance and provides novel paths for managing comorbid allergic and metabolic disorders. Supported by NIH/NIAID and the Bazley Research Foundation Immune Mechanisms of Human Disease (HUM)

BACKGROUND:Asthma morbidity significantly affects children of all racial backgrounds; however, Black children experience a greater disease burden than children from other racial groups. Despite the known influence of air pollution on asthma outcomes, its role in the efficacy of asthma treatments remains underexplored. OBJECTIVE:We sought to examine how exposure to particulate matter <2.5 μm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) influenced treatment outcomes in the National Institutes of Health AsthmaNet Best African American Response to Asthma Drugs trial. METHODS:The trial randomized 224 Black children to 4 asthma treatments consisting of an inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) administered in a randomized crossover fashion. Treatment efficacy was assessed by the frequency of asthma exacerbations, percent predicted FEV1, and annualized asthma control days. Residential exposures to PM2.5, NO2, and O3 were estimated using a validated spatiotemporal model. Mixed-effects models were used to evaluate the interaction between pollution exposure and treatment efficacy, adjusting for age, household triggers, and trial site. RESULTS:PM2.5, NO2, and O3 exposures ranged substantially across participants from 2.28 to 15.3 μg/m3, 2.34 to 63.7 ppm, and 2.57 to 23.7 ppb, respectively. NO2 and PM2.5 exposures were not associated with increased exacerbations post-treatment (P for interaction = .15 and .08, respectively). However, NO2 exposure significantly modified the effect of high-dose ICS+LABA therapy on lung function. Children with below median NO2 exposures while receiving ICS+LABA therapy had a reduction of 5.86 (95% CI 1.16, 10.56) in percent predicted FEV1 compared with children with above median NO2 exposures. CONCLUSION:Residential high NO2 exposure may significantly attenuate the efficacy of ICS+LABA therapy on lung function in Black children. These findings suggest the need to consider environmental factors in clinical trials and asthma management strategies.

BACKGROUND:While randomized controlled trials (RCTs) in asthma management are designed to balance known and unknown variables across treatment groups, including social and environmental co-exposures, it remains important to consider how these co-exposures influence disease progression and treatment outcomes. The importance of considering socio-environmental co-exposures in the context of asthma is twofold: 1) asthma disproportionately affects low-income urban communities, where air pollution and chronic stress are pervasive; and 2) despite the wide range of asthma treatments, inadequate disease control persists. METHODS:In the present ancillary study of the Step-Up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations (STICS) RCT, we investigated how socio-environmental factors, such as air pollution exposure and healthcare access, modify the effect of inhaled corticosteroid (ICS) therapy in children with asthma. The original STICS RCT evaluated the efficacy and safety of increasing the dose of inhaled glucocorticoids from a baseline daily low dose to five times the daily dose for 7 days in school-age children with mild -to-moderate persistent asthma who began to have short-term loss of asthma control (Jackson et al., 2018 Mar 8) [1]. Our study adds onto those findings by incorporating residential level particulate matter 2.5 μg/m3 (PM2.5) and geographic health provider shortage areas (HPSA) as potential modifiers. RESULTS:Consistent with the main trial results, we did not find a difference in the number of exacerbations between treatment arms. However, we found the effect of receiving 5xICS, as compared with 1xICS on the time to prednisone was significantly different for children living in areas a shortage of health professionals (HR: 2.09; 95 % CI: 0.74, 5.95) than for children living in no shortage areas (HR: 0.40; 95 % CI: 0.21, 0.77). CONCLUSION:This finding underscores the importance of considering environmental and social factors in asthma treatment. TRIAL REGISTRATION:ClinicalTrials.gov ID NCT02066129 https://clinicaltrials.gov/study/NCT02066129.