Chiarella, Sergio E.

Interleukin 33 (IL-33) is a cytokine of the IL-1 family that acts as an alarmin in both innate and adaptive immunity. IL-33 is constitutively nuclear in epithelial and endothelial cells, where its activity is limited by nuclear retention. Release of IL-33 in response to cellular stress or injury can mediate type 2 immune responses or tissue repair, depending on the local tissue environment. IL-33 activity is regulated at multiple levels, including nuclear retention, oxidation, proteolytic processing, and metabolic regulation. Following its release, oxidation rapidly suppresses IL-33 activity, while mast cell and neutrophil proteases can generate smaller active fragments that target cells expressing the IL-33 ST2 receptor. Simultaneously, tissue metabolic status influences cellular responsiveness through the mTORC1 and AMPK pathways, which link metabolic capacity to effector function. These conditions may explain why IL-33 can mediate an inflammatory response, but in other circumstances, it contributes to tissue repair. Such pleiotropic properties may also underline the variability in clinical responses to IL-33/ST2-targeted therapies across various diseases. The appreciation of IL-33 as a cytokine whose activity is conditioned by its structural, redox, and metabolic environment is critical to optimizing its therapeutic potential as a target.

Objective To evaluate the effects of mepolizumab therapy on the blood transcriptome in patients with severe eosinophilic asthma (SEA) and to determine whether changes in gene expression predict responsiveness to mepolizumab treatment. Methods Fourteen consecutive patients diagnosed with SEA were prospectively enrolled. Each patient had sequential blood samples obtained pre-initiation and at 4, 8, and 12 weeks post-initiation of mepolizumab. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples for bulk RNA sequencing. Paired differential expression (DE) gene analysis was performed comparing baseline gene expression versus all timepoints. Changes in gene expression were also compared between responders versus nonresponders to mepolizumab treatment. Finally, gene set enrichment analysis was evaluated across timepoints and its interaction with the response to mepolizumab treatment. Results Principal component analysis of all genes demonstrated a homogeneous distribution, which did not separate into distinct groups based on either timepoint or therapeutic response. At week 12, 149 genes had significant DE (FDR < 0.05) compared to baseline. When performing all-way timepoint comparisons, 74 genes (63 protein-coding) were found to be downregulated at weeks 4, 8 and 12 compared to baseline, but no differences were observed between post baseline timepoints. Twenty-eight genes (16 protein-coding) did change with progression of time and were associated with response to therapy, and 56 protein-coding genes distinguished responders and nonresponders. At week 12, nonresponders had a high enrichment of genes involved with signaling pathways, including cytokines, growth factors, cell differentiation markers, and protein kinases. Conclusion In this exploratory study, mepolizumab use was associated with limited global transcriptomic separation with some preliminary differential-expression and enrichment findings. No definitive mechanistic or predictive response signatures were identified due to the study limitations. Future studies, including larger cohorts followed for longer durations with interrogation of specific immune subsets, may offer additional insight into the pathophysiology of severe eosinophilic asthma and into predicting response to mepolizumab treatment.

Background Respiratory allergic diseases are experiencing changes influenced by genetic factors, environmental shifts, and social and demographic elements. These evolving patterns, together with rapid advances in diagnosis and treatment, require a thorough review of emerging trends. Objective To examine future directions in managing respiratory allergic diseases, focusing on changing disease patterns, environmental factors, diagnostic innovations, and therapeutic advances toward precision medicine. A literature search was conducted in PubMed and Scopus databases covering 2015–2025. Studies addressing human populations with allergic rhinitis or asthma were included, emphasizing emerging patterns, environmental factors, diagnostic technologies, and therapeutic innovations, while reviews, conference proceedings, case reports, and studies without clinical relevance were excluded. Initial screening identified 52 studies, and 21 additional studies were identified through complementary searches, resulting in 73 studies in the final analysis. Summary of findings Climate change is a key factor affecting disease patterns, with pollen seasons starting 10–40 days earlier and yearly emissions increasing by up to 200%. Regarding pathogenesis, early-life rhinovirus C infections with IgE sensitization significantly increase asthma risk (HR = 4.06), while severe asthma shows 40–84% eosinophilic patterns, depending on the assessment approach. On the diagnostic front, advances include multiplex platforms, proteomic biomarkers, and microRNAs. Therapeutically, innovations encompass biologics combined with allergen immunotherapy, nanobody-based therapeutics, and microbiota interventions. Conclusions These developments point toward personalized management of respiratory allergic diseases. However, challenges remain in research with underrepresented populations and accessibility. Moving forward, the key priority is integrating this diverse knowledge into practical strategies that advance precision medicine in respiratory allergic diseases.

Asthma is a heterogeneous chronic respiratory disease driven by diverse inflammatory pathways that vary across patients. The recognition of distinct molecular endotypes has led to the development of targeted biologic therapies that have transformed the management of moderate-to-severe asthma. However, selecting the most appropriate biologic therapy for each patient remains challenging. Health providers often rely on trial-and-error approaches that may delay disease control, increase costs, and expose patients to unnecessary side effects. Biomarkers are key to precision asthma care, as they provide objective measures of underlying disease mechanisms. Established biomarkers such as blood eosinophil count, fractional exhaled nitric oxide, and serum total immunoglobulin E are important for identifying type 2-high asthma. Sputum biomarkers offer direct insight into airway inflammation, but their use is limited by technical complexity and availability across centers. Emerging biomarkers, including proteomic, transcriptomic, metabolomic, and genomic biomarkers, show promise in further refining biologic therapy selection. In addition, digital biomarkers derived from electronic health records, wearable devices, and artificial intelligence-based algorithms offer new opportunities to capture real-world changes in disease and treatment response. Non-medical drivers of health, particularly socioeconomic factors, are increasingly recognized as modifiers of biologic effectiveness and may also be helpful in selecting biologic therapies. This review summarizes the existing evidence on established and emerging biomarkers used to guide biologic therapy selection in asthma. Integrating multiple biomarkers will be essential to improve biological selection, monitor response, and ultimately achieve the goal of remission in asthma.

This JAMA Insights explores the management of severe refractory asthma, including medications, access to specialists, and managing environmental triggers.

Abstract RATIONALE: 4G4G/4G5G SERPINE1 genotypes produce high concentrations of plasminogen activator inhibitor-1 and are associated with worse asthma outcomes. A secondary analysis of the American Lung Association (ALA) SOYA trial showed that soy isoflavones significantly reduced asthma exacerbations versus placebo among patients with 4G4G/4G5G SERPINE1 genotypes. We hypothesized that baseline characteristics predict optimal responders to soy isoflavones among this subgroup. METHODS: ALA-SOYA was a randomized controlled trial that tested the efficacy of soy isoflavones vs. placebo for reducing asthma exacerbations among adolescents and adults with symptomatic asthma. In this responder analysis among participants with 4G4G/4G5G SERPINE1 genotypes, baseline demographic and clinical characteristics were tested for effect modification of the treatment assignment (soy/placebo) on the primary outcome of annualized number of asthma exacerbations using interaction terms in negative binomial regression models, with a significance threshold of p-interaction=0.15. RESULTS: Data were available for n=168 participants. Soy reduced the annualized number of asthma exacerbations relative to placebo among patients with 4G4G/4G5G SERPINE1 genotypes (incident rate ratio (IRR)=0.37, 95% confidence interval (CI): 0.15-0.90, p=0.028). Self-reported adherence to baseline controller therapy was the only significant effect modifier of this association (interaction p=0.115), with those using inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) controller therapy at least twice weekly experiencing reductions in asthma exacerbations with soy versus placebo (IRR = 0.25, 95% CI: 0.09-0.69; p= 0.007) but not among those using ICS/LABA controller therapy less frequently (IRR = 1.33, 95% CI: 0.22-8.02; p= 0.757). CONCLUSION: Soy isoflavones reduce asthma exacerbations among patients with the 4G4G/4G5G SERPINE1 genotypes and are most effective in those with greater adherence to asthma controller therapy regimens.

In this review, we discuss the risks and adverse effects reported for the current Food and Drug Association (FDA)-approved biologics used in the management of asthma, including omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab, and tezepelumab. Our review focuses on the risk of hypersensitivity reactions, infection, and malignancy. Where relevant, we have included information regarding the risk of cardiovascular disease and eosinophilia, and we have included specific information regarding vaccine use among patients receiving the above biologics. We also review currently available data regarding the use of biologics in the context of pregnancy. Our goal is to provide a comprehensive resource for providers utilizing these agents, so that they may adequately counsel patients about the risks of therapy and identify adverse events if they occur.

Introduction: Nitrogen dioxide (NO 2 ) is known to be a trigger for asthma exacerbation. However, little is known about the role of seasonal variation in indoor and outdoor NO 2 levels in childhood asthma in a mixed rural-urban setting of North America. Methods: This prospective cohort study, as a feasibility study, included 62 families with children (5-17 years) that had diagnosed persistent asthma residing in Olmsted County, Minnesota. Indoor and outdoor NO 2 concentrations were measured using passive air samples over 2 weeks in winter and 2 weeks in summer. We assessed seasonal variation in NO 2 levels in urban and rural residential areas and the association with asthma control status collected from participants’ asthma diaries during the study period. Results: Outdoor NO 2 levels were lower (median: 2.4 parts per billion (ppb) in summer, 3.9 ppb in winter) than the Environmental Protection Agency (EPA) annual standard (53 ppb). In winter, a higher level of outdoor NO 2 was significantly associated with urban residential living area ( P = .014) and lower socioeconomic status (SES) ( P = .027). For both seasons, indoor NO 2 was significantly higher ( P < .05) in rural versus urban areas and in homes with gas versus electric stoves ( P < .05). Asthma control status was not associated with level of indoor or outdoor NO 2 in this cohort. Conclusions: NO 2 levels were low in this mixed rural-urban community and not associated with asthma control status in this small feasibility study. Further research with a larger sample size is warranted for defining a lower threshold of NO 2 concentration with health effect on asthma in mixed rural-urban settings.