Kathleen M. Buchheit

Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene–Driven IL-33–Mediated Mast Cell Activation Pathway

Aspirin-exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2. The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared with polyps from aspirin-tolerant control subjects. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE2 synthase (ptges−/− mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of leukotriene C4 synthase, the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges−/− lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite–primed ptges−/− mice with lysine aspirin induce IL-33–dependent MC activation and bronchoconstriction. Thus, IL-33 is a component of a cysLT-driven innate type 2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.

Update on the Management of Aspirin-Exacerbated Respiratory Disease

Aspirin-exacerbated respiratory disease (AERD) is an adult-onset upper and lower airway disease consisting of eosinophilic nasal polyps, asthma, and respiratory reactions to cyclooxygenase 1 (COX-1) inhibitors. Management includes guideline-based treatment of asthma and sinus disease, avoidance of COX-1 inhibitors, and for some patients aspirin desensitization followed by high-dose aspirin therapy. Despite this, many patients have inadequately controlled symptoms and require multiple sinus surgeries. In this review, we discuss the current standard approaches to the management of AERD, and we introduce several therapeutics under development that may hold promise for the treatment of AERD.

Aspirin-Exacerbated Diseases: Advances in Asthma with Nasal Polyposis, Urticaria, Angioedema, and Anaphylaxis

Aspirin-exacerbated diseases are important examples of drug hypersensitivities and include aspirin-exacerbated respiratory disease (AERD), aspirin- or non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema, and aspirin- or NSAID-induced anaphylaxis. While each disease subtype may be distinguished by unique clinical features, the underlying mechanisms that contribute to these phenotypes are not fully understood. However, the inhibition of the cyclooxygenase-1 enzyme is thought to play a significant role. Additionally, eosinophils, mast cells, and their products, prostaglandins and leukotrienes, have been identified in the pathogenesis of AERD. Current diagnostic and treatment strategies for aspirin-exacerbated diseases remain limited, and continued research focusing on each of the unique hypersensitivity reactions to aspirin is essential. This will not only advance the understanding of these disease processes, but also lead to the subsequent development of novel therapeutics that patients who suffer from aspirin-induced reactions desperately need.

Progestogen Hypersensitivity: Heterogeneous Manifestations with a Common Trigger

Hypersensitivity to progestogen, previously known as autoimmune progesterone dermatitis, is an increasingly recognized clinical entity that presents specific diagnostic and treatment challenges. Clinical presentations are heterogeneous, but can consist of hypersensitivity symptoms associated with the progesterone surge during the luteal phase of the menstrual cycle or after exposure to exogenous progestins. With the increasing use of exogenous progesterone for contraception and fertility, more cases of hypersensitivity to exogenous progestins have been described. Here we will review proposed pathomechanisms for progestogen hypersensitivity (PH) as well as the clinical presentation of PH, testing strategies to aid in diagnosis, and treatment options for patients with hypersensitivity to progestogens.

COX-1 mediates IL-33–induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity

Background Classical Fc&egr;RI‐induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)–derived eicosanoids (leukotriene [LT] C4, prostaglandin [PG] D2, and thromboxane A2), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms. Objectives We sought to determine the regulation and significance of MC‐derived eicosanoids synthesized in response to IL‐33, a cytokine critical to innate type 2 immunity. Methods We used an ex vivo model of mouse bone marrow–derived mast cells and an IL‐33–dependent in vivo model of aspirin‐exacerbated respiratory disease (AERD). Results IL‐33 potently liberates AA and elicits LTC4, PGD2, and thromboxane A2 production by bone marrow–derived mast cells. Unexpectedly, the constitutive function of COX‐1 is required for IL‐33 to activate group IVa cytosolic phospholipase A2 with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX‐1 was dispensable for Fc&egr;RI‐driven CysLT production. Inhibition of COX‐1 prevented IL‐33–induced phosphorylation of extracellular signal‐related kinase, an upstream effector of cytosolic phospholipase A2, which was restored by exogenous PGH2, implying that the effects of COX‐1 required its catalytic function. Administration of a COX‐1–selective antagonist to mice completely prevented the generation of both PGD2 and LTC4 in a model of AERD in which MC activation is IL‐33 driven. Conclusions MC‐intrinsic COX‐1 amplifies IL‐33–induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD.

Reduced cellular diversity and an altered basal progenitor cell state inform epithelial barrier dysfunction in human type 2 immunity

Tissue barrier dysfunction is a poorly defined feature hypothesized to drive chronic human inflammatory disease1,2. The epithelium of the upper respiratory tract represents one such barrier, responsible for separating inhaled agents, such as pathogens and allergens, from the underlying submucosa. Specialized epithelial subsets—including secretory, glandular, and ciliated cells—differentiate from basal progenitors to collectively realize this role3-5. Allergic inflammation in the upper airway barrier can develop from persistent activation of Type 2 immunity (T2I), resulting in the disease spectrum known as chronic rhinosinusitis (CRS), ranging from rhinitis to severe nasal polyps6-8. Whether recently identified epithelial progenitor subsets, and their differentiation trajectory, contribute to the clinical presentation and barrier dysfunction in T2I-mediated disease in humans remains unexplored3,9,10. Profiling twelve primary human samples spanning the range of clinical severity with the Seq-Well platform11 for massively-parallel single-cell RNA-sequencing (scRNA-seq), we report the first single-cell transcriptomes for human respiratory epithelial cell subsets, immune cells, and parenchymal cells (18,036 total cells) from a T2I inflammatory disease, and map key mediators. We find striking differences between non-polyp and polyp tissues within the epithelial compartments of human T2I cellular ecosystems. More specifically, across 10,383 epithelial cells, we identify a global reduction in epithelial diversity in polyps characterized by basal cell hyperplasia, a concomitant decrease in glandular and ciliated cells, and phenotypic shifts in secretory cell function. We validate these findings through flow cytometry, histology, and bulk tissue RNA-seq of an independent cohort. Furthermore, we detect an aberrant basal progenitor differentiation trajectory in polyps, and uncover cell-intrinsic and extrinsic factors that may lock polyp basal cells into an uncommitted state. Overall, our data define severe T2I barrier dysfunction as a reduction in epithelial diversity, characterized by profound functional shifts stemming from basal cell defects, and nominate a cellular mechanism for the persistence and chronicity of severe human respiratory disease.

Progestogen Hypersensitivity: An Evidence-Based Approach to Diagnosis and Management in Clinical Practice

Heterogeneous presentations of disease pose particular diagnostic and management challenges to the clinician. Progestogen hypersensitivity (PH) classically consists of hypersensitivity symptoms to endogenous progesterone during the luteal phase of the menstrual cycle. However, with the rise of assisted fertility and the exponential growth in the use of exogenous progestins for contraception, PHs prevalence and symptom heterogeneity have increased. In this article, we focus on the clinical approach to PH diagnosis with an emphasis on key elements of the history, physical, and testing modalities. We also review the current evidence for successful management and treatment across a broad range of patients.

Aspirin Desensitization and High-Dose Aspirin Therapy in Aspirin-Exacerbated Respiratory Disease

The management of chronic rhinosinusitis with nasal polyps associated with aspirin-exacerbated respiratory disease (AERD) has historically been variable, and the symptoms are usually refractory to common therapies. Aspirin desensitization followed by high-dose aspirin therapy has been shown to improve asthma and sinus symptoms scores, decrease corticosteroid use, and reduce rates of revision sinus surgery with 70–80 % of patients with AERD reporting benefit. Aspirin desensitization is safely performed in the outpatient setting by specialists trained in asthma and allergic diseases with experience in performing aspirin desensitization and the capability to treat anaphylaxis. Both the procedure of desensitization and the high-dose aspirin therapy have low rates of adverse events and have been shown to be cost-effective. The mechanism by which high-dose aspirin provides clinical benefits remains unknown, and clinicians currently are not able to predict which patients will respond to the therapy. High-dose aspirin therapy is indicated for patients who are refractory to standard medical therapy, require frequent bursts of oral steroids, or have recurrent nasal polyps, an indication which captures the majority of patients with AERD. Thus, as a safe and effective treatment option for patients with AERD, aspirin desensitization is now considered part of the mainstay in management of patients with AERD.