Obesity is one of the factors associated with the severity of asthma. Obesity is associated with aggravation of the pathophysiology of asthma, including exacerbations, airway inflammation, decreased pulmonary function, and airway hyperresponsiveness. The present review addresses the characteristics of asthma with obesity, focusing especially on the heterogeneity caused by the degree of type 2 inflammation, sex differences, the onset of asthma, and race differences. To understand the severity mechanisms in asthma and obesity, such as corticosteroid resistance, fatty acids, gut microbiome, and cytokines, several basic research studies are evaluated. Finally, possible future therapies, including weight reduction, microbiome-targeted therapies, and other molecular targeted therapies are addressed. We believe that the present review will contribute to better understanding of the severity mechanisms and the establishment of novel treatments for severe asthma patients with obesity. 

Impact of obesity in asthma: Possible future therapies.

Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low "ILC9" phenotype and produce prodigious amounts of IL-9. A combination of large-scale proteomic analyses, lung intravital microscopy, and adoptive transfer of ILC9 cells revealed that high IL-9 expression distinguishes a multicytokine-producing state-of-activated ILC2s with an increased capacity to initiate IL-5-dependent allergic airway inflammation. Similar to IL-33 and TSLP, TL1A is expressed in airway basal cells in healthy and asthmatic human lungs. Together, these results indicate that TL1A is an epithelium-derived cytokine and an important cofactor of IL-33 in the airways.

TL1A is an epithelial alarmin that cooperates with IL-33 for initiation of allergic airway inflammation.

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease. 

Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification.

In this instalment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With 6 biologics now approved for use in this area comprising 4 different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data. We use 4 variations of a case of severe uncontrolled asthma to develop concepts and considerations introduced in the previous installment ("Workup of Severe Asthma") and discuss pregnancy-related, biomarker-related, comorbidity-related, and corticosteroid dependency-related considerations when choosing a biologic. The related questions of deciding when, why, and how to switch from one biologic to another also are discussed. Overall, we consider that the choice of biologics should be based on the available clinical trial data for the desired efficacy outcomes, the biomarker profile of the patient, safety profiles (eg, when pregnancy is considered), and opportunities to target 2 comorbidities with 1 biologic. Using systemic and airway biomarkers (blood eosinophils and exhaled nitric oxide) and other phenotypic characteristics, we suggest a framework to facilitate therapeutic decision-making. Post hoc studies and new comparative studies are needed urgently to test this framework and to determine whether it allows us to make other clinically useful predictions. 

How I do it. Choosing the right biologic for the right patient with severe asthma

The hallmark of most patients with severe asthma is type 2 inflammation, driven by innate and adaptive immune responses leading to either allergic or non-allergic eosinophilic infiltration of airways. The cellular and molecular pathways underlying severe type 2 asthma can be successfully targeted by specific monoclonal antibodies. 

Type 2 severe asthma: pathophysiology and treatment with biologics

The field of asthma has undergone a dramatic change in recent years. Advances in our understanding of type 2 airway inflammation have driven the discovery of monoclonal antibodies targeting specific aspects of the immune pathway. In landmark trials, these drugs have shown efficacy in reducing asthma attacks and exposure to oral corticosteroids, important causes of morbidity in people with asthma. Our review explores the key features of type 2 inflammation in asthma and summarizes the clinical trial evidence of the novel monoclonal antibody treatments and future avenues for treatment.

/pdf/type-2-inflammation-and-biological-therapies-in-asthma-301ejcon.pdf

Type 2 inflammation and biological therapies in asthma: Targeted medicine taking flight.

In this Review, we discuss the key features of type 2 inflammation in asthma, summarize the clinical trial evidence of monoclonal antibody asthma treatments, and explore future avenues for targeted asthma treatment.

/pdf/type-2-inflammation-and-biological-therapies-in-asthma-34qvonim.pdf

Type 2 inflammation and biological therapies in asthma: Targeted medicine taking flight

Biologics for chronic severe asthma: a network meta-analysis

RCT Abstract - Treating eosinophilic exacerbations of asthma and COPD with benralizumab: a double-blind, double-dummy, active-placebo randomised controlled trial (ABRA)

Background: Mepolizumab is an anti-interleukin-5 monoclonal antibody for severe eosinophilic asthma (SEA). The effects of mepolizumab, or the addition of oral corticosteroids (OCS) to mepolizumab, on molecular mechanisms in the airway epithelium are poorly understood. Aim: Determine the transcriptional effects of mepolizumab followed by prednisolone or placebo on the nasal epithelium in patients with SEA. Methods: MAPLE was a randomized, double-blind, placebo-controlled crossover trial of prednisolone at stable state in adults with SEA after mepolizumab (Yang F, JACI Pract 2022;10:2925-34.e12). OCS had a minor effect on FEV1 but not on symptoms. Nasal scrape samples were taken before mepolizumab, and after OCS and placebo. RNA was extracted using Qiagen kits and sequenced on good quality samples using Illumina Novaseq. Results: 5 paired samples comparing pre- to post- mepolizumab on placebo revealed 377 differentially expressed genes (DEG) for gene ontology analysis (adj p &lt;0.1, abs log2fold &gt;0.5). Genes down-regulated by mepolizumab related to the structure and function of cilia. Genes up-regulated by mepolizumab related to extracellular matrix structure and keratinisation. 6 paired samples comparing OCS to placebo on mepolizumab revealed 30 DEGs. Genes down-regulated by OCS included leukocyte chemotaxis, mast cell tryptase, and the 15-lipoxygenase pathway. Conclusions: Mepolizumab affects transcription of genes related to nasal epithelial cell structure, but it is unclear how this relates to epithelial function. Prednisolone in addition to mepolizumab suppresses additional biology unaffected by IL-5 inhibition. The relationship of these additional effects to clinical outcome is unresolved. Funder GSK

Additional effects of oral prednisolone following mepolizumab on the nasal transcriptome

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