Does Eosinophil Heterogeneity Translate into Functional Diversity? A Review of the Evolving Paradigm of Eosinophil Heterogeneity in Asthma.

This review provides an overview of evidence supporting the existence of distinct homeostatic and inflammatory eosinophil subpopulations in health and disease. Particular emphasis is placed on describing the phenotypic and functional roles of these eosinophil subtypes in asthma, as well as the phenotypic changes induced by clinical therapy with the anti-IL-5 biologic agent, mepolizumab. Improved understanding of distinct eosinophil phenotypes may enable targeting of select subpopulations in the treatment of patients with type 2 inflammatory diseases such as asthma.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study.

Introduction: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR.

Activated sputum eosinophils associated with exacerbations in children on mepolizumab.

Background: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations.

Shared genetic architecture of blood eosinophil counts and asthma in UK Biobank.

Rationale: Asthma is a complex, heterogeneous disease strongly associated with type 2 inflammation, and blood eosinophil counts guide therapeutic interventions in moderate and severe asthma. Eosinophils are leukocytes involved in type 2 immune responses. Despite these critical associations between asthma and blood eosinophil counts, the shared genetic architecture of these two traits remains unknown.

iDESC: identifying differential expression in single-cell RNA sequencing data with multiple subjects.

Background: Single-cell RNA sequencing (scRNA-seq) technology has enabled assessment of transcriptome-wide changes at single-cell resolution. Due to the heterogeneity in environmental exposure and genetic background across subjects, subject effect contributes to the major source of variation in scRNA-seq data with multiple subjects, which severely confounds cell type specific differential expression (DE) analysis. Moreover, dropout events are prevalent in scRNA-seq data, leading to excessive number of zeroes in the data, which further aggravates the challenge in DE analysis.

Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.

Background: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19).

Objective: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease.

Methods: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021.

The new era of add-on asthma treatments: where do we stand?

Globally, a small proportion (5-12%) of asthma patients are estimated to have severe disease. However, severe asthma accounts for disproportionately high healthcare resource utilization. The Global Initiative for Asthma (GINA) management committee recommends treating patients with asthma with inhaled corticosteroids plus long-acting β-agonists and, when needed, adding a long-acting muscarinic receptor antagonist or biologic agent.

Inhibition of ABCC1 Decreases cAMP Egress and Promotes Human Airway Smooth Muscle Cell Relaxation.

In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gα (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface βAR (β-adrenoceptor), a G-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]).

Mapping geographic variability of severe uncontrolled asthma in the United States: Management implications.

Background: The US population-level data on asthma morbidity and mortality are available primarily through state-level surveys. We hypothesize that considerable county-level heterogeneity may be obscured by state-level data, thus impeding focused initiatives to improve asthma outcomes.

Objective: To assess heterogeneity in the prevalence of uncontrolled, severe, and severe uncontrolled asthma by evaluating state- and county-level morbidity reflected in large administrative claims data sets and identify relationships between pharmacotherapy-based morbidity and the Centers for Disease Control and Prevention's asthma mortality data.

Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma.

Introduction: Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria.

Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions.

Background: Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities.

Methods: This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA.

Single-cell characterization of a model of poly I:C-stimulated peripheral blood mononuclear cells in severe asthma.

Background: Asthma has been associated with impaired interferon response. Multiple cell types have been implicated in such response impairment and may be responsible for asthma immunopathology. However, existing models to study the immune response in asthma are limited by bulk profiling of cells.

Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial.

Background: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG mAb, selectively inhibits the IL-33 receptor, ST2.

Latent-space embedding of expression data identifies gene signatures from sputum samples of asthmatic patients.

Background: The pathogenesis of asthma is a complex process involving multiple genes and pathways. Identifying biomarkers from asthma datasets, especially those that include heterogeneous subpopulations, is challenging. Potentially, autoencoders provide ideal frameworks for such tasks as they can embed complex, noisy high-dimensional gene expression data into a low-dimensional latent space in an unsupervised fashion, enabling us to extract distinguishing features from expression data.

Profiling cellular heterogeneity in asthma with single cell multiparameter CyTOF.

Asthma is a chronic inflammatory disease of the airways that afflicts over 30 million individuals in the United States and over 300 million individuals worldwide. The inflammatory response in the airways is often characterized by the analysis of sputum, which contains multiple types of cells including neutrophils, macrophages, lymphocytes, and rare bronchial epithelial cells. Subtyping patients using microscopy of the sputum has identified both neutrophilic and eosinophilic infiltrates in airway inflammation.

Restoring Pulmonary and Sleep Services as the COVID-19 Pandemic Lessens. From an Association of Pulmonary, Critical Care, and Sleep Division Directors and American Thoracic Society-coordinated Task Force.

In March 2020, many elective medical services were canceled in response to the coronavirus disease 2019 (COVID-19) pandemic. The daily case rate is now declining in many states and there is a need for guidance about the resumption of elective clinical services for patients with lung disease or sleep conditions. Volunteers were solicited from the Association of Pulmonary, Critical Care, and Sleep Division Directors and American Thoracic Society.

Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.

Cystic fibrosis (CF) is a life-shortening, multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory responses that contribute to tissue injury. To define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.

Approaches for integrating heterogeneous RNA-seq data reveal cross-talk between microbes and genes in asthmatic patients.

Sputum induction is a non-invasive method to evaluate the airway environment, particularly for asthma. RNA sequencing (RNA-seq) of sputum samples can be challenging to interpret due to the complex and heterogeneous mixtures of human cells and exogenous (microbial) material. In this study, we develop a pipeline that integrates dimensionality reduction and statistical modeling to grapple with the heterogeneity.

A Network of Sputum MicroRNAs Is Associated with Neutrophilic Airway Inflammation in Asthma.

MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published.

New Therapies for Emerging Endotypes of Asthma.

The presentation, pathobiology, and prognosis of asthma are highly heterogeneous and challenging for clinicians to diagnose and treat. In addition to the adaptive immune response that underlies allergic inflammation, innate immune mechanisms are increasingly recognized to be critical mediators of the eosinophilic airway inflammation present in most patients with asthma. Efforts to classify patients by severity and immune response have identified a number of different clinical and immune phenotypes, indicating that the innate and adaptive immune responses are differentially active among patients with the disease.

Pulmonary artery pseudoaneurysm causing massive hemoptysis in hyperimmunoglobulin E syndrome: a case report.

Background: Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder defined by high serum immunoglobulin E titers that is associated with recurrent respiratory infections, formation of pneumoatoceles, recurrent skin abscesses, and characteristic dental and skeletal abnormalities.

Case Presentation: We report a case of a 56-year-old male with a history of HIES, cavitary mycetomas, and allergic bronchopulmonary aspergillosis who presented with recurrent massive hemoptysis. Bronchial artery angiography and bronchoscopy failed to identify active hemorrhage, and two embolizations of the bronchial artery did not resolve the bleeding.