Reduced Effectiveness of Anti-IgE Treatment Among Adults with Severe Asthma with Older Age of Asthma Onset: Results from the CHRONICLE Study.

Purpose: Younger age of asthma onset (AAO) has been associated with an allergic phenotype, whereas eosinophilic phenotypes have been associated with older AAO. In randomized trials, biologic efficacy among adults with severe asthma (SA) has varied by age at asthma onset. To determine whether these associations observed in trials apply to real-world outcomes, this study examined biologic effectiveness by AAO and biologic class in a large, real-world cohort.

Patient and clinician preferences for biologic treatments for severe uncontrolled asthma: a discrete choice experiment (DCE).

Objectives: To estimate the preferences of patients with asthma and asthma-treating clinicians for attributes of biologic treatments, to compare patients' and clinicians' preferences, and to better understand the reasons for their preferences.

Methods: Adults with moderate-to-severe asthma and clinicians who treat asthma in the US completed a cross-sectional, online survey including a discrete choice experiment (DCE) that consisted of seven attributes spanning treatment efficacy, risk and convenience. Marginal utilities were estimated using a mixed logit model, and relative attribute importance scores calculated.

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.

KMT2D regulates activation, localization, and integrin expression by T-cells.

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function.

Gaps in Care Among Uncontrolled Severe Asthma Patients in the United States.

Background: Understanding the implementation of key guideline recommendations is critical for managing severe asthma (SA) in the treatment of uncontrolled disease.

Objective: To assess specialist visits and medication escalation in US patients with SA after events indicating uncontrolled disease (EUD) and associations with health outcomes and social disparity indicators.

Methods: Patients with SA appearing in administrative claims data spanning 2015 to 2020 were indexed hierarchically on asthma-related EUD, including hospitalizations, emergency department visits with systemic corticosteroid treatment, or outpatient visits with systemic corticosteroid treatment.

Geographic variation in disease burden among patients with severe persistent asthma in the United States.

Background: In the United States, a few studies have evaluated geographic variation of severe asthma at the subnational level.

Objective: To assess state-level geographic variation in the prevalence and characteristics of severe persistent asthma in the United States.

Methods: Patients aged above or equal to 12 years with severe persistent asthma were identified using nationally representative data from IQVIA open-source Medical/Pharmacy Claims and PharMetrics Plus databases (January 2019-December 2020).

At-home asthma mortality unchanged despite declining mortality in other settings: US death certificate data (2000-2019).

Background: Asthma mortality rates in the United States have declined since 1999; however, asthma mortality by place of death has not been comprehensively evaluated.

Objective: To evaluate temporal trends in asthma mortality rates and place of death in the United States.

Methods: We conducted a population-based analysis using data from the Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research platform to evaluate deaths with asthma as the underlying cause (2000-2019) among US residents of all ages.

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR).

Background: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma.

Incremental cost burden among patients with severe uncontrolled asthma in the United States.

The economic burden of severe asthma and severe uncontrolled asthma (SUA) is significant. Updated assessments of health care resource utilization (HCRU) and cost are needed given the increase in treatment options and updates to guidelines in recent years. To describe all-cause and asthma-related HCRU and costs among patients with SUA vs patients with nonsevere asthma in the United States using real-world data.

Eosinophil responses during COVID-19 infections and coronavirus vaccination.

Eosinophils are circulating and tissue-resident leukocytes that have potent proinflammatory effects in a number of diseases. Recently, eosinophils have been shown to have various other functions, including immunoregulation and antiviral activity. Eosinophil levels vary dramatically in a number of clinical settings, especially following eosinophil-targeted therapy, which is now available to selectively deplete these cells.

KMT2C/D COMPASS complex-associated diseases [KCOM-ADs]: an emerging class of congenital regulopathies.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations.

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome.

Background: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified.

Objective: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses).

Prenatal and perinatal history in Kabuki Syndrome.

Kabuki syndrome (KS) is a disorder of epigenetic dysregulation due to heterozygous mutations in KMT2D or KDM6A, genes encoding a lysine-specific methyltransferase or demethylase, respectively. The phenotype is highly variable, including congenital cardiac and renal anomalies, developmental delay, hypotonia, failure to thrive, short stature, and immune dysfunction. All affected individuals have characteristic facial features.

Central Diabetes Insipidus in a Patient With NFKB2 Mutation: Expanding the Endocrine Phenotype in DAVID Syndrome.

Context: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a recently described, rare disorder characterized by anterior pituitary hormone deficiencies and common variable immunodeficiency associated with NFKB2 mutations. Posterior pituitary hormone deficiencies have not been reported in patients with DAVID syndrome.

Case Description: We report a pediatric patient who initially presented with hypogammaglobulinemia and alopecia totalis, who was identified to have a de novo NFKB2 mutation at one year of age.

Kabuki syndrome: international consensus diagnostic criteria.

Background: Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in or . Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal.

Intratracheal myriocin enhances allergen-induced Th2 inflammation and airway hyper-responsiveness.

Introduction: Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis.

Methods: Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo.

Lipid Mediators of Allergic Disease: Pathways, Treatments, and Emerging Therapeutic Targets.

Bioactive lipids are critical regulators of inflammation. Over the last 75 years, these diverse compounds have emerged as clinically-relevant mediators of allergic disease pathophysiology. Animal and human studies have demonstrated the importance of lipid mediators in the development of asthma, allergic rhinitis, urticaria, anaphylaxis, atopic dermatitis, and food allergy.

Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.

Background: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported.

Objective: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations.

Combined immune deficiency in a patient with a novel NFKB2 mutation.

NFKB2 encodes the p100/p52 protein, a critical mediator of the canonical and noncanonical NFkB signaling pathways. Here we report the comprehensive immune evaluation of a child with a novel NFKB2 mutation and provide evidence that aberrant NFKB2 signaling not only causes humoral immune deficiency, but also interferes with the TCR-mediated proliferation of T cells. These observations expand the known phenotype associated with NFKB2 mutations.