Upper Airway Comorbidities of Asthma.

Asthma, characterized as a chronic heterogeneous airway disease, often presents with common comorbid conditions. The concept of 'one-airway-one-disease' was coined, emphasizing the connection between asthma and upper airway comorbidities (UACs) such as allergic or non-allergic rhinitis, chronic rhinosinusitis with or without nasal polyps, and aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease more than 20 years ago. Since then, numerous studies demonstrate that UACs are closely related and affect asthma phenotypes. Recognizing and managing these UACs are crucial aspects of comprehensive asthma care. Addressing these conditions as part of asthma treatment can lead to better control of symptoms, improved lung function and the quality of life. Moreover, it is important to explore the field of respiratory biologics that represent the latest advancements in medical treatment options for asthma patients with UACs.

Nasal polyp antibody-secreting cells display proliferation signature in aspirin-exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.

IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.

Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD. OBJECTIVE: Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. METHODS: A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production. RESULTS: Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis. CONCLUSION: Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.

Updates on immune mechanisms in aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally develops in previously healthy young adults and is unremitting and challenging to treat. The classical triad of asthma, nasal polyposis, and pathognomonic respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors is accompanied by high levels of mast cell activation, cysteinyl leukotriene production, platelet activation, and severe type 2 respiratory inflammation. The "unbraking" of mast cell activation and further cysteinyl leukotriene generation induced by cyclooxygenase-1 inhibition reflect an idiosyncratic dependency on cyclooxygenase-1-derived products, likely prostaglandin E2, to maintain a tenuous homeostasis. Although cysteinyl leukotrienes are clear disease effectors, little else was known about their cellular sources and targets, and the contributions from other mediators and type 2 respiratory inflammation effector cells to disease pathophysiology were unknown until recently. The applications of targeted biological therapies, single-cell genomics, and transgenic animal approaches have substantially advanced our understanding of aspirin-exacerbated respiratory disease pathogenesis and treatment and have also revealed disease heterogeneity. This review covers novel insights into the immunopathogenesis of aspirin-exacerbated respiratory disease from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

Radiopathologic predictors of 1- and 2-year frontal sinusotomy outcomes in a southeast Asian chronic rhinosinusitis population.

BACKGROUND: The frontal sinus and its drainage pathway are difficult spaces to navigate surgically. The complexity of the frontal recess anatomy as well as inflammatory factors may influence outcomes of endoscopic frontal sinusotomy. It is not clear which factors are more important in determining post-operative frontal ostium patency. OBJECTIVE: The objective is to investigate whether the distribution of fronto-ethmoidal cells, frontal recess dimensions and sinonasal inflammation predict frontal ostium patency at 1- and 2-years after endoscopic frontal sinusotomy. METHODS: A retrospective review of 94 chronic rhinosinusitis patients (185 sides) who had undergone endoscopic frontal sinusotomies between 2015 and 2019 was conducted. Computed tomography was used to evaluate the type of fronto-ethmoidal cells present and determine the dimensions of the frontal recess. The International Classification of the Radiological Complexity of frontal recess and frontal sinus was used to grade the complexity of frontal recess anatomy. Mucosal inflammation was graded according to a structured histopathology report. Frontal ostium patency at 1- and 2-years post-operatively was recorded. RESULTS: The frontal ostium patency rates were 80.9% and 73.4% at 1- and 2-years respectively. Eosinophilic predominance (adjusted OR 3.5, 95% CI 1.6-8.0, p = 0.003) and mucosal ulceration on histology (adjusted OR 4.5, 95% CI 1.1-17.9, p = 0.033) predicted ostial stenosis at 1 year. Smoking (adjusted OR 7.6, 95% CI 2.4-24.7, p = 0.001), aspirin exacerbated respiratory disease (AERD) (adjusted OR 7.6, 95% CI 1.9-30.1, p = 0.004) and histological findings of severe inflammation (adjusted OR 8.9, 95% CI 1.9-41.2, p = 0.005) were independent predictors of ostial stenosis at 2 years. Frontal cell patterns, frontal recess dimensions and frontal recess complexity did not predict frontal ostium stenosis at both 1- and 2-years post-operatively. CONCLUSION: Post-operative control of sinonasal inflammation is important in maintaining frontal ostium patency, regardless of frontal cell patterns or frontal recess dimensions.

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count.

BACKGROUND: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. OBJECTIVE: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). METHODS: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. RESULTS: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/µL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (<150 cells/µL: 55.0% vs 31.3%; ≥150 cells/µL: 49.5% vs 28.1%; <300 cells/µL: 50.7% vs 29.0%; ≥300 cells/µL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. CONCLUSIONS: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.

Advances in mast cell biology.

Mast cells (MCs) contribute prominently to all allergic diseases, yet are still poorly understood owing to their exclusive residence in tissues. Recently, the use of RNA-sequencing, proteomics, and other technological advances have accelerated the acquisition of new knowledge. This includes an expanded definition of MC heterogeneity and developmental origins, previously unrecognized functions for MCs, discoveries of genetic causes of MC-related disorders, the introduction of new therapies for clonal MC disease, and the identification of new potential target for treatments. This issue of Advances addresses key studies from 2020 to 2021.

Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease.

BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.

Long-term role of zileuton in the treatment of chronic rhinosinusitis in aspirin exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis (CRS) in the setting of Aspirin Exacerbated Respiratory Disease (AERD) have high rate of treatment failure and disease recurrence. OBJECTIVE: Evaluate the long-term effect of zileuton on sinonasal outcomes in patients with AERD. METHODS: AERD patients were reviewed and divided into two cohorts, depending if they were treated with zileuton during their clinical course. Demographic data, 22-item sinonasal outcome test (SNOT-22), Lund-Kennedy (LK) endoscopy score, duration of treatment, and number of sinus surgeries performed were collected. RESULTS: 40 AERD patients were included, with follow-up duration up to 10 years (avg of 5.2 years). All patients were treated with topical saline and budesonide irrigations, intranasal steroid spray, and montelukast. 19 patients had uncontrolled sinus disease requiring multiple steroid tapers and were switched from montelukast to zileuton (cohort 1, 47.5%) at some point in their treatment. 21 patients (cohort 2, 52.5%) never needed zileuton. The average duration of treatment with zileuton was 6 years. Patients who required zileuton had a worse SNOT-22 (32.1 vs 19, p = 0.117), worse LK score (8.1 vs 7.5, p = 0.504), and higher average number of surgeries (1.9 vs 1.6, p = 0.343). The outcomes in the zileuton cohort trended toward improvement, however these did not reach statistical significance with an improved SNOT-22 from 32.1 to 27.4 (p = 0.617) and LK score from 7.9 to 6.2 (p = 0.092); The addition of zileuton significantly lowered the number of surgeries needed to an average of 0.5 (p < 0.0001). CONCLUSION: Zileuton may help decrease the number of sinus surgeries needed in AERD.

Leukotriene D4 paradoxically limits LTC4-driven platelet activation and lung immunopathology.

BACKGROUND: The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C4 (LTC4), LTD4, and LTE4, have different biologic half-lives, cellular targets, and receptor specificities. CysLT2R binds LTC4 and LTD4in vitro with similar affinities, but it displays a marked selectivity for LTC4in vivo. LTC4, but not LTD4, strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLT2R-mediated, platelet- and IL-33-dependent pathway. OBJECTIVE: We sought to determine whether LTD4 functionally antagonizes LTC4 signaling at CysLT2R. METHODS: We used 2 different in vivo models of CysLT2R-dependent immunopathology, as well as ex vivo activation of mouse and human platelets. RESULTS: LTC4-induced CD62P expression; HMGB1 release; and secretions of thromboxane A2, CXCL7, and IL-33 by mouse platelets were all were blocked by a selective CysLT2R antagonist and inhibited by LTD4. These effects did not depend on CysLT1R. Inhaled LTD4 blocked LTC4-mediated potentiation of ovalbumin-induced eosinophilic inflammation; recruitment of platelet-adherent eosinophils; and increases in IL-33, IL-4, IL-5, and IL-13 levels in lung tissue. In contrast, the effect of administration of LTE4, the preferred ligand for CysLT3R, was additive with LTC4. The administration of LTD4 to Ptges-/- mice, which display enhanced LTC4 synthesis similar to that in aspirin-exacerbated respiratory disease, completely blocked the physiologic response to subsequent lysine-aspirin inhalation challenges, as well as increases in levels of IL-33, type 2 cytokines, and biochemical markers of mast cell and platelet activation. CONCLUSION: The conversion of LTC4 to LTD4 may limit the duration and extent of potentially deleterious signaling through CysLT2R, and it may contribute to the therapeutic properties of desensitization to aspirin in aspirin-exacerbated respiratory disease.

The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.

Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. OBJECTIVE: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. METHODS: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. RESULTS: The mean number of basophils (CD45+CD203c+FcεRI+CD117-) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = -0.56; P = .004). CONCLUSIONS: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.

Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. RESULTS: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. CONCLUSIONS: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.

Aspirin challenge and desensitization in patients with suspected AERD in Qatar.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a chronic disease characterized by chronic rhinosinusitis, nasal polyposis, asthma, and intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin challenge is considered the gold standard for diagnosing AERD. Many patients with AERD have reported clinical benefits when desensitized to aspirin and maintained on daily aspirin therapy. In this study, we have summarized aspirin challenges and aspirin desensitization in our division during the past ten years. METHODS: We reviewed aspirin challenges and desensitization procedures performed in the Allergy and Immunology Division at the Hamad Medical Corporation, Doha, Qatar, between 2010 and 2020 from our procedures log registry and reported the results of the procedures. RESULTS: The procedures were performed for patients with chronic rhinosinusitis, nasal polyposis, and bronchial asthma with a historical reaction to NSAIDs or those never exposed to NSAIDs. The challenge and desensitization procedure protocol is outlined in table.1. Of the 45 procedures performed, 36 (80%) patients reacted during aspirin desensitization; and their characteristics, historical reaction to NSAIDs, provoking dose, length of desensitization, and types of reactions were reviewed. Of the reactors, 32 (88%) patients completed aspirin desensitization successfully. The mean ( ± SD) age of patients was 46 ( ± 11.6) years, and 51% were women. The historical symptoms were asthma symptoms (56%) and naso-ocular (21%). The common (71%) reaction during the procedure was asthma symptoms, and 29% had naso-ocular symptoms. The provoking dose was 50-75 mg in most patients. The desensitization procedure was carried out over 2 days in most patients; however, 29% of the patients needed more than 2 days to complete the desensitization. None of the reactors needed emergency epinephrine use or hospital admission. CONCLUSION: In our review, desensitization was successful in all the patients who reacted to aspirin, and it was the only therapeutic choice for patients with AERD before the era of biologics. The procedure was well tolerated in most patients. Aspirin challenge was positive in 80% of our patients with suspected AERD, and this has an important diagnostic value that may help in choosing the proper biologic, such as dupilumab, for these patients.

Pre-intervention SNOT-22 scores predict outcomes in aspirin exacerbated respiratory disease.

PURPOSE: This study evaluated whether stratified preoperative, pre- aspirin desensitization (AD) sinonasal symptom scores predict postoperative, post-AD outcomes in Aspirin exacerbated respiratory disease (AERD). MATERIALS AND METHODS: Retrospective chart review of patients with aspirin challenge-proven AERD who underwent endoscopic sinus surgery followed by AD was performed. Preoperative, postoperative/pre-AD, and postoperative/post-AD sinonasal symptom scores were collected (22-item Sino-Nasal Outcomes Test, SNOT-22). A longitudinal linear mixed-effects model was used for data analysis. RESULTS: Forty-seven patients (59.6% female) aged 48.0 ± 13.2 were included. Average time from surgery to AD was 70.0 ± 52.8 days. Preoperative SNOT-22 scores (n = 47) were divided into tertiles (cutoffs of 36 and 54 indicating mild [22.5 ± 13.7], moderate [44.3 ± 12.2], and severe [72.9 ± 19.7] disease). This corresponded to 12 (25.5%), 18 (38.3%), and 17 (36.2%) subjects being categorized into mild, moderate, and severe tertiles, respectively. Postoperative, pre-AD SNOT-22 in all disease groups decreased and were not significantly different (12.3 ± 13.7, 11.1 ± 12.2, 22.7 ± 19.7; p = 0.074). At short-term post-AD, only the severe group worsened (35.0 ± 20.3, p < 0.001), whereas other groups demonstrated negligible change (9.3 ± 14.3 and 14.4 ± 12.2). At long-term post-AD, all groups redemonstrated convergence in symptom scores (23.7 ± 20.9, 19.4 ± 15.4, and 31.0 ± 27.6, p = 0.304). CONCLUSION: Preoperative SNOT-22 scores may be used as a predictor of postoperative, post-AD patient-reported outcomes in AERD. Patients with mild and moderate disease may derive benefit from surgery and AD alone, while those with severe disease may require additional interventions (e.g., biologics).

Differences in men and women suffering from CRSwNP and AERD in quality of life.

PURPOSE: While the overall impact of chronic rhinosinusitis (CRS) on patients' health is diverse, many affected individuals have a substantially impaired quality of life (QoL). The aim of this study was to evaluate the impact of sex-associated differences specifically in the subgroups of CRS with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) by assessing QoL parameters in women and men separately. METHODS: In a retrospective single-center study, 59 patients with CRSwNP (39 males and 20 females) and 46 patients with AERD (18 males and 28 females) were included. Patient-reported outcome measures (PROM) evaluating QoL via the Sino-Nasal Outcome Test-20 German Adapted Version (SNOT-20 GAV) as well as the total polyp score (TPS) were analysed. RESULTS: There was no significant difference in TPS (p = 0.5550) and total SNOT-20 GAV scores (p = 0.0726) between male or female patients with CRSwNP or AERD. Furthermore, no significant sex differences were found within disease groups regarding the subcategories of the SNOT-20 GAV items. CONCLUSION: Thus, quality of life is severely impaired in patients suffering from various forms of CRS regardless of their sex.

NSAID-ERD Syndrome: the New Hope from Prevention, Early Diagnosis, and New Therapeutic Targets.

PURPOSE OF REVIEW: This review summarizes the latest information on the appropriate identification, evaluation, and treatment of patients with nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD), also known as aspirin-exacerbated respiratory disease (AERD). Within the framework of our understanding of the underlying pathophysiology of NSAID-ERD, we also provide an update regarding new surgical techniques and newly available or upcoming medical therapies that may benefit these patients. RECENT FINDINGS: There have been considerable developments regarding recommendations for both the extent and timing of sinus surgery for NSAID-ERD. The last few years have also given us several new biologic medications that warrant consideration in the treatment of patients with recalcitrant NSAID-ERD. Further clinical trials are underway to investigate additional medications that may decrease the type 2 inflammation that dominates this disease. Despite the severe lower respiratory inflammation and recurrent nature of the nasal polyps in patients with NSAID-ERD, significant recent advances now afford much-improved quality of life for these patients. Careful collaboration between Allergy/Immunology and Rhinology specialists is imperative to ensure proper treatment of patients with NSAID-ERD.

Statement of the Spanish Society of Allergology and Clinical Immunology on Provocation Tests With Aspirin/Nonsteroidal Anti-inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used throughout the world. They are frequently involved in hypersensitivity reactions, which range from local or mild reactions to systemic and severe reactions. Consequently, it is necessary to perform an exhaustive study of patients in order to make an accurate diagnosis, search for safe procedures in the case of severe reactions, and identify alternative treatment options. Various guidelines and protocols address the management of hypersensitivity to NSAIDs, although these vary widely from country to country. The Committees of Asthma, Rhinoconjunctivitis, and Drug Allergy of the Spanish Society of Allergy and Clinical Immunology (SEAIC) propose the present position statement on available options for provocation testing with aspirin/NSAIDs. This document is the fruit of an exhaustive review of current evidence and is based on recent publications addressing the diagnosis of patients with hypersensitivity to NSAIDs and on a consensus-oriented discussion among a group of experts from the SEAIC. The main objective was to draft an easy-toread, practical guideline for health care professionals in specialist areas who assess and manage patients with suspected hypersensitivity to NSAIDs. Furthermore, indications, contraindications, and procedures for oral, bronchial, and nasal provocation tests with aspirin/NSAIDs have been updated.