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Key points Racial disparities influence the completion of aspirin (ASA) desensitization and ASA‐exacerbated respiratory disease (AERD) diagnosis age. Public insurance correlates with an official AERD diagnosis after age 50. Social factors, including race and insurance status, impact AERD diagnosis and adherence to ASA desensitization. [ABSTRACT FROM AUTHOR]

Aspirin-exacerbated respiratory disease (AERD) is a recurrent condition that poses significant management challenges. Currently, the primary treatment options for AERD include avoidance of aspirin and other nonsteroidal anti-inflammatory drugs, standard medical and surgical treatment. Several targeted biologics also provide new ways for managing respiratory symptoms. Aspirin desensitization is the only etiological treatment available for AERD. Ongoing aspirin therapy post-desensitization is crucial for maintaining therapeutic efficacy. This article reviews the application and advancements in aspirin desensitization as well as subsequent aspirin therapy in patients with AERD. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis is divided into two groups, which are Chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). The rate of post-surgical recurrence in the CRSwNP is high, and predicting factors are unknown. This study aims to identify and evaluate risk factors associated with treatment-resistant and recurrent CRSwNP. This cross-sectional study evaluates demographic data and atopic risk factors in patients with CRSwNP, including a high IgE level (≥100 U/mL), skin prick test (SPT) for aeroallergens, aspirinexacerbated respiratory disease (AERD), and asthma prevalence. An oral aspirin challenge was performed to diagnose AERD. 191 patients with CRSwNP were enrolled, with 73 patients in the recurrent, and 118 patients in the non-recurrent group. The mean age of the patients in the recurrent group was 45.08±12.05. The mean age of the patients in the non-recurrent group was 42.89±11.73. 49. Asthma prevalence in recurrent- CRSwNP is significantly higher than non-recurrent CRSwNP Asthma severity in recurrent CRSwNP and AERD patients was significantly higher than in nonrecurrent CRSwNP and non-AERD patients. The level of IgE in the recurrent- CRSwNP is higher than non-recurrent CRSwNP. Positive SPT results for tree, weed, and mite allergens were higher in the non-recurrent- CRSwNP group compared to the recurrent CRSwNPgroup. Asthma had a significantly higher difference in AERD compared to non-AERD. The level of IgE in AERD is higher than non-AERD. Recurrent CRSwNP patients and AERD patients had Higher IgE levels. Asthma is more prevalent and more severe in both AERD and recurrent CRSwNP. However, a positive SPT result has been seen higher in non-recurrent CRSwNP. [ABSTRACT FROM AUTHOR]

Cavernous sinus thrombosis (CST) is a rare but life-threatening condition most commonly arising from trauma and paranasal sinus infections. The diagnosis of CST remains a formidable challenge despite advancements in medicine. Early identification and therapeutic intervention require an increased level of clinical awareness and a profound understanding of the pathophysiology of the disorder. This report presents a case of CST in a 58-year-old female with a long history of nasal and paranasal sinus polyposis and aspirin-induced asthma.

Chronic rhinosinusitis with nasal polyposis is a common inflammatory condition, with subtypes like aspirin-exacerbated respiratory disease, allergic fungal rhinosinusitis, and central compartment atopic disease sharing a common type 2 inflammatory pathway. Respiratory biologic therapies have been developed that target type 2 inflammation. In this article, we discuss the use of respiratory biologic therapies for nasal polyposis in general, as well as within the various subtypes of nasal polyps. Further, we discuss future roles of novel biologic therapies targeting type 2 inflammation in nasal polyposis. [ABSTRACT FROM AUTHOR]

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Introduction. We present a case of type 1 Kounis syndrome in a patient with recurrent myocardial infarction with non-obstructive coronary arteries (MINOCA) due to allergic coronary vasospasm. Awareness of doctors about this pathology will allow identifying the MINOCA causes and prescribing pathogenetic treatment.Brief description. A 51-year-old woman with aspirin-exacerbated respiratory disease (asthma, rhinosinusitis with nasal polyposis, aspirin hypersensitivity, eosinophilia) without cardiovascular risk factors developed three recurrent myocardial infarctions against the background of vasospastic angina over a 6-month period. Despite the typical clinical performance, stable ST segment elevation, unchanged coronary arteries on coronary angiography, the vasospastic MI was not immediately established. The patient received long-term treatment for type 1 MI, including beta-blockers. Recurrent MI occurred against the background of an asthma attack. During the second and third hospitalization for MI, coronary angiography revealed a spasm of the right coronary artery, which completely resolved with the nitroglycerin administration. Intracoronary ultrasound made it possible to rule out atherosclerotic involvement of the infarct-related artery. Subsequently, microvascular angina developed, which was confirmed by positron emission tomography. Vasospastic angina in combination with microvascular angina, MIBOCA with asthma attacks, were regarded as type 1 Kounis syndrome. Over the next 2 years, the patient received pathogenetic treatment, and no recurrent cardiovascular events were observed.Discussion. Lack of awareness about Kounis syndrome led to incomplete examination of the patient with MIBOCA and the prescription of pathogenetically unreasonable tehrapy, which could contribute to recurrent MI within 6 months.

Background: Previous studies have determined that up to 6% of patients with aspirin-exacerbated respiratory disease (AERD) have family history of AERD, indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking. Objectives: We sought to examine whether WES can identify pathogenic variants associated with AERD. Methods: Diagnoses of AERD were confirmed in patients with nasal polyps and asthma. WES was performed using an Illumina sequencing platform. Human Phenotype Ontology terms were used to define the patients’ phenotypes. Exomiser was used to annotate, filter, and prioritize possible disease-causing genetic variants. Results: Of 39 patients with AERD, 41% reported a family history of asthma and 5% reported a family history of AERD. Pathogenic exome variants in the filaggrin gene (FLG) were found in 2 patients (5%). Other variants not known to be pathogenic were detected in an additional 16 patients (41%) in genes related to epithelial integrity and cellular interactions, including genes encoding desmoglein 3 (DSG3), dynein axonemal heavy chain 9 (DNAH9), collagen type VII alpha 1 chain (COL7A1), collagen type XVII alpha 1 chain (COL17A1), chromodomain helicase DNA binding protein-7 (CHD7), TSC complex subunit 2/tuberous sclerosis-2 protein (TSC2), P-selectin (SELP), and platelet-derived growth factor receptor-alpha (PDGFRA). Conclusion: WES identified a monogenic susceptibility to AERD in 5% of patients with FLG pathogenic variants. Other variants not previously identified as pathogenic were found in genes relevant to epithelial integrity and cellular interactions and may further reveal genetic factors that contribute to this condition.

Background: Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity. Methods: CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund–Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation. Results: Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores. Conclusions: Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement.

Objective: Previous in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling. Study Design: Functional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling. Setting: Academic medical center. Methods: Effects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre‐and posttreatment during a placebo‐controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways. Results: Administration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle. Conclusion: Restoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell‐cycle pathways. The maximal effect in patients with high levels of type 1‐enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery‐unresponsive CRS patients. [ABSTRACT FROM AUTHOR]

Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti-IL-5/IL-5 receptor, anti-IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D2 antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials.

Background: Current aspirin desensitization protocols for aspirin-exacerbated respiratory disease (AERD) require from 1 to 3 days to complete. Objective: Our aim was to assess the implementation of a 1-day versus 2-day aspirin desensitization protocol in patients with aspirin-exacerbated respiratory disease. Methods: We used a preintervention-postintervention quality improvement design to compare the completion rates, reaction rates, and estimated costs of a 2-day versus 1-day aspirin desensitization. The cost for each desensitization was estimated on the basis of 2017-2020 US Medicare standards. We included the predesensitization variables for FEV1 value, urinary leukotriene E4 level, absolute eosinophil count (AEC), and total IgE level for each group. Results: A total of 15 patients underwent a 2-day aspirin desensitization in the 4-year (2017-2020) preintervention period and were compared with 8 patients who underwent a 1-day aspirin desensitization in the 1-year (2021) postintervention period. The desensitization completion rate (93% vs 100% [P = 1]) and the mean number of reactions requiring intervention during the desensitization protocols (0.26 vs 0.8 [P = .14]) were similar between groups. The average time frame between last polypectomy and desensitization was longer in the 2-day group (1946 vs 39.2 days [P = .03]). The mean values for FEV1 level, urinary leukotriene E4 level, absolute eosinophil count, and total IgE level were 76% vs 83% (P = .6), 1084 vs 385 pg/mg (P = .2), 686 vs 306 cells/μL (P = .74), and 735 vs 278 kU/L (P = .5), respectively. The estimated direct cost reduction was $762 per aspirin desensitization for using 1-day vs 2-day aspirin desensitization. Conclusion: Compared with a 2-day protocol, the implementation of a 1-day aspirin desensitization was characterized by similar completion and reaction rates as well as lower costs.

Aspirin therapy after desensitization, aspirin-exacerbated respiratory disease, aspirin desensitization, asthma, dupilumab, chronic rhinosinusitis, nasal polyps, NSAID-exacerbated respiratory disease Keywords: aspirin desensitization; aspirin therapy after desensitization; aspirin-exacerbated respiratory disease; asthma; chronic rhinosinusitis; dupilumab; nasal polyps; NSAID-exacerbated respiratory disease EN aspirin desensitization aspirin therapy after desensitization aspirin-exacerbated respiratory disease asthma chronic rhinosinusitis dupilumab nasal polyps NSAID-exacerbated respiratory disease 974 977 4 09/05/23 20230901 NES 230901 Key messages We evaluated nasal eosinophil markers in 22 adults with NSAID-exacerbated respiratory disease treated with dupilumab Nasal fluid eosinophilic cationic protein decreased during dupilumab treatment in participants co-treated with aspirin therapy. For patients on ATAD and dupilumab, there was no significant change in the peripheral blood eosinophil levels, which may have occurred because patients on ATAD and dupilumab had higher pre-dupilumab peripheral blood eosinophil levels. [Extracted from the article]

Background: Aspirin‐exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin‐tolerant asthma (ATA). Objectives: This study aimed to investigate the long‐term clinical outcomes between AERD and ATA. Methods: AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real‐world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD. Results: Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p <.05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p <.01) than those with ATA. In a 10‐year follow‐up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group. Conclusion and Clinical Relevance: We demonstrated that AERD patients presented poorer long‐term clinical outcomes than ATA patients in real‐world data analyses. [ABSTRACT FROM AUTHOR]

Objective: To determine whether an electronic health record (EHR) system can be used to identify cases of aspirin‐exacerbated respiratory disease (AERD) in an area outside of a regional referral center with low rates of aspirin desensitization therapy. Study Design: Retrospective chart review single academic tertiary care hospital. Setting: Single‐site academic tertiary care hospital. Methods: Using Epic's SlicerDicer function, an algorithm was created and applied to all patient charts from 2013 to 2021. The algorithm was as follows: "Allergy/Contraindication to NSAIDs OR aspirin" AND "Diagnosis of Nasal polyp AND "Diagnosis of Asthma." Clinical data including demographics, NSAID reaction, and specialist involvement was collected. Results: A total of 54 potential cases of AERD were identified. Thirty‐two were determined to have AERD after chart review, yet 12 of these patients (37.5%) had no mention of AERD within the chart. The 54 patients were stratified into 2 cohorts based on reaction to NSAIDs: respiratory (n = 29) or unspecified (n = 25). Of the patients in the respiratory reaction group, 26 were found to have clinical AERD, demonstrating a positive predictive values (PPV) of 89.7%. The overall PPV was 59.3%. Those with a respiratory reaction to NSAIDS listed in the EHR were more likely to have clinical AERD (odds ratio 27.44; confidence interval 6.08‐123.85; p < 0.0001). Only 2 patients (6.3%) underwent aspirin desensitization. Conclusion: AERD remains under‐diagnosed in the study population. The informatics algorithm presented here has a high positive predictive value for identifying clinical AERD patients in a geographical area with low rates of aspirin desensitization and may aid in identifying candidates for expanded treatment options. [ABSTRACT FROM AUTHOR]

Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity. CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund–Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation. Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores. Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Previous studies have suggested that patients with aspirin‐exacerbated respiratory disease (AERD) have a high likelihood of alcohol intolerance. The purpose of this systematic review is to identify if there is sufficient evidence to confirm this correlation and the impact of medical therapy on subsequent alcohol tolerance. Data Sources: PubMed, EMBASE, SCOPUS, EBSCO, Google Scholar, Cochrane Library, and Grey literature. We also performed snowballing on the identified observational studies (OS) for additional data. Review Methods: A systematic review was conducted from 1968 to 2022 to identify those studies describing AERD symptomatology triggered by alcohol intake. The primary outcome was to analyze the current literature for the association between alcohol intolerance and AERD symptoms. The secondary outcome looked for improvement in alcohol tolerance after aspirin desensitization or biological therapy. Results: A total of 775 studies were identified and 40 abstracts were evaluated. From these, 5 studies met the inclusion criteria. Of the 5 manuscripts, there was 1 case‐control, 2 cohort, and 2 cross‐sectional studies. A total of 522 participants with AERD and a history of alcohol consumption were included, with 52.8% reporting at least 1 sinopulmonary exacerbation after alcohol intake. One of 3 studies noted improvement in alcohol tolerance after medical therapy with aspirin desensitization. Conclusion: The current literature suggests that patients with AERD have a high risk of alcohol intolerance. Additionally, aspirin desensitization may improve alcohol tolerance in this patient population. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease phenotypically classified by the absence (CRSsNP) or presence of nasal polyps (CRSwNP). The latter may also be associated with asthma and hypersensitivity towards nonsteroidal anti-inflammatory drugs (NSAID) as a triad termed NSAID-exacerbated respiratory disease (N-ERD). The role of the microbiome in these different disease entities with regard to the underlying inflammatory process and disease burden is yet not fully understood. To address this question, we measured clinical parameters and collected nasal samples (nasal mucosal fluids, microbiome swabs from middle meatus and anterior naris) of patients suffering from CRSsNP (n=20), CRSwNP (n=20) or N-ERD (n=20) as well as from patients without CRS (=disease controls, n=20). Importantly, all subjects refrained from taking local or systemic corticosteroids or immunosuppressants for at least two weeks prior to sampling. The nasal microbiome was analyzed using 16S rRNA gene amplicon sequencing, and levels of 33 inflammatory cytokines were determined in nasal mucosal fluids using the MSD platform. Patients suffering from N-ERD and CRSwNP showed significantly worse smell perception and significantly higher levels of type 2 associated cytokines IL-5, IL-9, Eotaxin and CCL17. Across all 4 patient groups, Corynebacteria and Staphylococci showed the highest relative abundances. Although no significant difference in alpha and beta diversity was observed between the control and the CRS groups, pairwise testing revealed a higher relative abundance of Staphylococci in the middle meatus in N-ERD patients as compared to CRSwNP (p<0.001), CRSsNP (p<0.01) and disease controls (p<0.05) and of Lawsonella in patients suffering from CRSwNP in middle meatus and anterior naris in comparison to CRSsNP (p<0.0001 for both locations) and disease controls (p<0.01 and p<0.0001). Furthermore, we observed a positive correlation of Staphylococci with IL-5 (Pearson r=0.548) and a negative correlation for Corynebacteria and Eotaxin-3 (r=-0.540). Thus, in patients refraining from oral and nasal corticosteroid therapy for at least two weeks known to alter microbiome composition, we did not observe differences in microbiome alpha or beta diversity between various CRS entities and disease controls. However, our data suggest a close association between increased bacterial colonization with Staphylococci and decreased colonization by Corynebacteria as well as increased type 2 inflammation. [ABSTRACT FROM AUTHOR]

Coronary vasospasm is a relatively well-documented cause for ischemia and myocardial infarction in patients with nonobstructive coronary artery disease. Patients with coexisting eosinophilia present with severe manifestations and are often refractory to traditional therapies. There are few reported cases in the literature. We describe 3 cases occurring within 10 months. (Level of Difficulty: Intermediate.)

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease phenotypically classified by the absence (CRSsNP) or presence of nasal polyps (CRSwNP). The latter may also be associated with asthma and hypersensitivity towards non-steroidal anti-inflammatory drugs (NSAID) as a triad termed NSAID-exacerbated respiratory disease (N-ERD). The role of the microbiome in these different disease entities with regard to the underlying inflammatory process and disease burden is yet not fully understood. To address this question, we measured clinical parameters and collected nasal samples (nasal mucosal fluids, microbiome swabs from middle meatus and anterior naris) of patients suffering from CRSsNP (n=20), CRSwNP (n=20) or N-ERD (n=20) as well as from patients without CRS (=disease controls, n=20). Importantly, all subjects refrained from taking local or systemic corticosteroids or immunosuppressants for at least two weeks prior to sampling. The nasal microbiome was analyzed using 16S rRNA gene amplicon sequencing, and levels of 33 inflammatory cytokines were determined in nasal mucosal fluids using the MSD platform. Patients suffering from N-ERD and CRSwNP showed significantly worse smell perception and significantly higher levels of type 2 associated cytokines IL-5, IL-9, Eotaxin and CCL17. Across all 4 patient groups, Corynebacteria and Staphylococci showed the highest relative abundances. Although no significant difference in alpha and beta diversity was observed between the control and the CRS groups, pairwise testing revealed a higher relative abundance of Staphylococci in the middle meatus in N-ERD patients as compared to CRSwNP (p

Background: The long‐term goals of asthma treatment are to achieve well control of symptoms and to minimize the future risk of asthma exacerbation. Identifying biomarkers for uncontrolled asthma is important for improving the asthma outcome. This study aimed to investigate the association of the levels of eosinophil‐derived neurotoxin (EDN) with asthma control status in specific asthma phenotype, aspirin‐exacerbated respiratory disease (AERD), and aspirin‐tolerant asthma (ATA). Methods: A total of 136 adult asthmatics, including 47 asthmatics with AERD and 89 asthmatics with ATA, were enrolled. Plasma, sputum, and urine were collected at enrollment and the levels of EDN were measured by the K‐EDN ELISA kit. Urinary leukotriene E4 (LTE4) level was measured using liquid chromatography–mass spectrometry (LC‐MS)/MS methods. Asthma control status was evaluated according to the GINA guideline, asthma control test and asthma control questionnaire scores. Results: In the total study subjects, sputum levels of EDN as well as of urine and plasma EDN showed significantly higher levels in patients with uncontrolled asthma than in those with well‐controlled or partly‐controlled asthma (ANOVA, p < 0.001); in patients with AERD, the sputum EDN levels showed significant correlations with ACT, ACQ, and AQLQ scores (p = 0.010, r = −0.536, p = 0.001, r = 0.665, and p < 0.001, r = −0.691, respectively), while no differences were noted in patients with ATA. Sputum EDN level was the only significant factor for ACT, ACQ, and AQLQ scores in patients with AERD (p = 0.001, p < 0.001, and p < 0.001, respectively) in the multivariate analysis adjusting for age, sex, peripheral eosinophil count, and urine LTE4. The ROC curve analysis demonstrated that sputum EDN can predict uncontrolled asthma with 80% sensitivity and 88.2% specificity for ACT ≤ 19 (area under the ROC curve [AUC] = 0.824, p = 0.019); 71.4% sensitivity and 86.7% specificity for ACQ ≥ 1.5 (AUC = 0.752, p = 0.049) only in AERD patients. Conclusion: The level of sputum EDN may be a potential biomarker for identifying the asthma control status in patients with AERD. [ABSTRACT FROM AUTHOR]

AERD subjects demonstrated increased sensitivity to DB ( I p i < 0.01) and sucrose ( I p i < 0.01) compared with CRSsNP, while CRSsNP subjects demonstrated a reduced sensitivity to DB ( I p i < 0.05) and sucrose ( I p i < 0.05) compared with controls (Figure 1). It was anticipated that in AERD, unique genetic polymorphisms in DB-responsive T2Rs may result in upregulation of the receptors and resulting type-2 inflammation. Keywords: aspirin-exacerbated respiratory disease; bitter; chronic rhinosinusitis; gene; open array; sensory; taste EN aspirin-exacerbated respiratory disease bitter chronic rhinosinusitis gene open array sensory taste 269 272 4 02/21/23 20230301 NES 230301 INTRODUCTION Chronic rhinosinusitis (CRS), a disease of long-standing sinonasal inflammation, is divided into two phenotypes: CRS with and without nasal polyposis (CRSwNP, CRSsNP). [Extracted from the article]

Background: Aspirin-exacerbated respiratory disease (AERD) is a chronic condition characterized by the presence of asthma, chronic rhinosinusitis with nasal polyposis, and sensitivity to aspirin and other non-steroidal anti-inflammatory drugs. Diagnosis is based on careful clinical history and physical examination, characteristic laboratory and radiographic findings, and, in unclear cases, aspirin challenge. Established treatment is founded on comprehensive endoscopic sinus surgery followed by topical steroids and aspirin desensitization. T2 biologics are now available for refractory cases. Objective: To summarize the historic literature on AERD, its diagnosis and treatment options, as well as to review the most current publications on the topic and explore areas for future research. Methods: A literature review utilizing the PubMed database was performed. Results: Seminal journal articles regarding the diagnosis and treatment of AERD were reviewed with close attention to evidence-based protocols and knowledge gaps in the field as areas for future research. Conclusion: AERD is a complex disease which requires careful diagnostic work-up and coordinated care between the allergist and rhinologist to facilitate optimal treatment outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Biologics are used in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of this retrospective study was to evaluate the effects of biologics initiated for asthma on coexistent CRS and the influence of comorbid factors, including aspirin-exacerbated respiratory disease (AERD) and secretory otitis media (SOM). Methods: A review of electronic health records (2009–2020) at a Finnish tertiary center was conducted to identify CRS patients treated with biologics for their asthma. We identified the type of biologic and treatment response, by comparing nasal polyp score (NPS), sinonasal outcome test (SNOT)-22, need for oral corticosteroids (OCS) and antibiotics, frequency of visits, and endoscopic sinus surgeries (ESS) pretreatment and during treatment. Results: 55 patients were treated with anti-immunoglobulin E (IgE) (n = 18) or anti-interleukin-5/5-receptor (IL-5/5R) (n = 37) biologics. Treatment lasted for an average of 4.1 years. Seventy-five percent (n = 41) had CRSwNP and 25% (n = 14) had CRSsNP. Of all patients, 24% (n = 13) had comorbid AERD and 22% (n = 12) had SOM. Biologic therapy reduced the need for OCS courses (anti-IgE, n = 17, p = 0.03; anti-IL-5/5R, n = 35, p = 0.01) and for daily OCS in anti-IL-5/5R (n = 35, p = 0.001) but not in anti-IgE patients (n = 16, p = 0.07). Biologics also improved NPS by 0.5 point (n = 32, p = 0.009) and SNOT-22 by 14 points (n = 7, p = 0.02) in CRSwNP patients. The overall discontinuation rate was 37.7% (n = 20) and was independent of type of biologic. Conclusion: Treatment with anti-IgE and/or anti-IL-5/5R biologics reduced the overall need for OCS medication in individuals with asthma and concomitant CRS, but despite this, the discontinuation rate was high. [ABSTRACT FROM AUTHOR]

Machiko Matsumoto-Sasaki,1 Kaoruko Simizu,1 Masanobu Suzuki,2 Masaru Suzuki,1 Hirokazu Kimura,1 Yuji Nakamaru,2 Yoichi M Ito,3 Akihiro Honma,2 Satoshi Konno1 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 3Data Science Center, Promotion Unit, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, JapanCorrespondence: Kaoruko Simizu, Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Japan, Tel +81-11-706-5911, Fax +81-11-706-7899, Email okaoru@med.hokudai.ac.jpPurpose: Biologics have been used increasingly for the treatment of severe asthma. However, established guidelines for the selection, switching, or discontinuation of biologics do not exist. We aimed to identify the clinical characteristics of patients with asthma who required switching biologics and the factors associated with switching biologics.Patients and Methods: This was a retrospective study of 42 patients with severe asthma treated with biologics at the Hokkaido University Hospital between 23rd June 2016 and 30th April 2021, when two biologics were available in Japan. We compared the characteristics of subjects who continued and switched biologics. The time to switch the biologics was assessed by type 2 inflammatory biomarkers, pulmonary function indices, and the presence of comorbidities, including the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score and aspirin exacerbated respiratory diseases (AERD), using the Kaplan–Meier method and a multivariate Cox proportional hazards model.Results: Eight and five patients were treated by mepolizumab and benralizumab at baseline, respectively among the 31% (13/42) who switched the biologics. Subjects who required switching biologics were characterized by high blood eosinophil counts, younger age, JESREC scores of 11 points or higher, and AERD. The time taken to switch biologics was significantly shorter in the subgroups with high JESREC scores (≥ 11) or AERD, compared with their counterparts with low JESREC scores or without AERD (both, P < 0.05). JESREC scores of ≥ 11, but not the presence of AERD, were associated with time to switch biologics.Conclusion: The presence of eosinophilic chronic rhinosinusitis based on JESREC scores of ≥ 11 and younger age were factors associated with switching biologics in asthma.Keywords: aspirin-exacerbated respiratory disease, asthma, biologics, comorbidities, eosinophilic chronic rhinosinusitis

Abstract Background The long‐term goals of asthma treatment are to achieve well control of symptoms and to minimize the future risk of asthma exacerbation. Identifying biomarkers for uncontrolled asthma is important for improving the asthma outcome. This study aimed to investigate the association of the levels of eosinophil‐derived neurotoxin (EDN) with asthma control status in specific asthma phenotype, aspirin‐exacerbated respiratory disease (AERD), and aspirin‐tolerant asthma (ATA). Methods A total of 136 adult asthmatics, including 47 asthmatics with AERD and 89 asthmatics with ATA, were enrolled. Plasma, sputum, and urine were collected at enrollment and the levels of EDN were measured by the K‐EDN ELISA kit. Urinary leukotriene E4 (LTE4) level was measured using liquid chromatography–mass spectrometry (LC‐MS)/MS methods. Asthma control status was evaluated according to the GINA guideline, asthma control test and asthma control questionnaire scores. Results In the total study subjects, sputum levels of EDN as well as of urine and plasma EDN showed significantly higher levels in patients with uncontrolled asthma than in those with well‐controlled or partly‐controlled asthma (ANOVA, p

Background: The impact of anosmia on quality‐of‐life (QoL) for patients with aspirin‐exacerbated respiratory disease (AERD) is poorly understood. We aimed to investigate how the severity of smell loss and olfactory dysfunction (OD) in patients with AERD affects their QoL, mental health and physical well‐being. Methods: Five validated QoL questionnaires (Sinonasal Outcome Test‐22, Asthma Control Test, Healthy Days Core Module‐4, Short Form‐36 and Patient Health Questionnaire‐4) and two newly developed questionnaires assessing severity and consequences of OD were electronically sent to all 2913 patients in the Brigham and Women's Hospital AERD registry. Responses were received from 853 participants for analysis. Results: Overall, 85% of participants reported a present diminished sense of smell and/or taste, and 30% categorized their OD severity was, "as bad as it can be." There were significant relationships between the severity of self‐reported OD and both psychological distress and general health scores, even after adjusting for asthma control. Additionally, incidence rates for physically and mentally unhealthy days in the prior month were higher for patients with moderate or severe OD than for normosmic patients. Patients with diminished smell responded that they could not identify spoiled food (86%), did not enjoy food (71%), felt unsafe (63%) and had encountered dangerous situations (51%) as consequences of their OD. Conclusions: Anosmia and hyposmia severely impact the physical, emotional and mental health of AERD patients, and lead to safety concerns in their daily lives. The importance of olfaction and the relevance of OD to patients' QoL should be acknowledged and evaluated by clinicians caring for these patients. [ABSTRACT FROM AUTHOR]

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease. It is defined by asthma, chronic rhinosinusitis with nasal polyposis, and a hypersensitivity reaction to aspirin or nonsteroidal anti-inflammatory drugs. Aspirin desensitization (AD) has been confirmed as an effective treatment to control AERD inflammation through the modulation of immune responses. We aimed to review AERD with an overview of the epidemiology, pathophysiology, and treatment. We also discussed the effect of AD on immunological markers involved in AERD pathogenesis. A search of electronic databases on AERD was performed. We included five randomized clinical trials (RCTs) on AD. We also searched databases for recent studies that investigated the effect of AD on the immunological mechanisms of AERD. RCTs have demonstrated the therapeutic effectiveness of AD on the patients' quality of life, asthma symptom score, inhaled and oral steroid use, forced expiratory volume in 1 sec (FEV1), and inflammatory mediators. The clinical benefits of AD can occur though the regulation of innate and adaptive immune responses that are involved in the pathogenesis of AERD. In addition to the valuable effects of AD in RCTs, some side effects such as gastrointestinal bleeding, asthma exacerbation, or rash have been reported that should be considered for reaching an optimal protocol for AD. [ABSTRACT FROM AUTHOR]

Background: Patients with aspirin-exacerbated respiratory disease (AERD) have difficult-to-treat asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and often require treatment with biologic therapy for asthma or CRSwNP. Healthcare utilization in patients with AERD has not been well described since the advent of respiratory biologics., Objective: To determine real-world healthcare utilization and quality of life among patients with AERD and to understand the impact of dupilumab, a monoclonal antibody targeting the interleukin 4 receptor, on patient-reported health outcomes and healthcare utilization., Methods: We conducted a longitudinal survey study of 98 patients with AERD recruited from the Brigham and Women's Hospital AERD registry. Patients completed online questionnaires describing their medication history, healthcare utilization, and quality of life every 3 months for 2 years., Results: At the end of 24 months, participants who were on dupilumab at the start of the study and those who started dupilumab had a significant reduction in the number of reported poor health days in the preceding month compared to patients not on dupilumab ( P < .001 and P < .01, respectively). Participants on dupilumab and those who started dupilumab also had significantly lower overall sinonasal outcome test-22 and asthma control test scores compared to those not on dupilumab over 24 months ( P < .05 for both groups)., Conclusion: Dupilumab therapy significantly improves health-related quality of life in patients with AERD, specifically as it pertains to patient assessment of days of overall poor health and quality of life related to sinonasal and asthma symptoms., Competing Interests: Declaration of Conflicting InterestsK.B. has served on scientific advisory boards for AstraZeneca, Sanofi, Regeneron, and GlaxoSmithKline and has received consulting fees from Genentech. T.L. has served on scientific advisory boards for AstraZeneca, Eli Lilly, Regeneron, Sanofi, and GlaxoSmithKline. J.B. has served on scientific advisory boards for GlaxoSmithKline. The other authors declare no conflicts of interest.

Biologic medications have dramatically altered the landscape for treatment of allergic conditions including aspirin-exacerbated respiratory disease (AERD) and allergic bronchopulmonary aspergillosis (ABPA). Biologics should be considered for patients who are refractory to first line therapies for ABPA. Biologics should be discussed with patients with AERD. Variable responses to different biologics indicate that there may be various endotypes of AERD and ABPA, similar to asthma. Alternative biologics may be considered in patients who fail to respond to initial treatment., Competing Interests: Disclosure J. Huang: nothing to disclose. A.A. White: Speaker Bureau for Regeneron/Sanofi, Optinose, AstraZeneca, Amgen, GSK, Blueprint; Advisory Board: Blueprint, Cogent, GSK, Regeneron; Research Support: Regeneron, United States, AstraZeneca, United Kingdom., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD), the clinical triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and respiratory reactions to cyclooxygenase 1 inhibitors, is often challenging to manage, with many patients failing first-line therapies for CRSwNP and asthma. There are now 6 biologic medications approved for asthma and/or severe CRSwNP: omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab. With the availability of respiratory biologic treatment for both asthma and CRSwNP, clinicians now have a multitude of additional management options for patients with NSAID-ERD. Herein, we review the currently available clinical trial and real-world evidence for biologic efficacy and safety in patients with NSAID-ERD, discuss the mechanisms of biologic therapy specific to NSAID-ERD, and review evidence regarding the use of biologic therapy versus endoscopic sinus surgery for CRSwNP in patients with NSAID-ERD. We propose a management approach for choosing biologic therapy or endoscopic sinus surgery paired with aspirin therapy after desensitization for patients with NSAID-ERD., (Copyright © 2024. Published by Elsevier Inc.)

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) is a distinct clinical syndrome characterized by nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, asthma, and nasal polyposis. Its diagnosis is challenging owing to variable presentations and a lack of simple tests, leading to diagnostic delays. Recent research has revealed its genetic predispositions, environmental triggers, and associations with atopy and second-hand tobacco smoke exposure or smoking cessation. Despite its severity, diagnostic awareness remains low, leading to the delay in effective management. Therapeutically, NSAID-ERD necessitates multidisciplinary approaches, often combining surgical interventions with medical management, including aspirin desensitization and biologic agents. However, predictive biomarkers for treatment response remain elusive. Understanding the underlying mechanisms driving NSAID-ERD pathogenesis and identifying reliable biomarkers are crucial for enhancing diagnostic accuracy and refining targeted therapeutic strategies for this debilitating condition. This review aims to provide a thorough understanding of NSAID-ERD, covering its history, clinical features, epidemiology, diagnosis, systemic and molecular biomarkers, available treatment options, and avenues for future research., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Ga-Young Ban,1,2 Seung-Hyun Kim,3 Hae-Sim Park4 1Department of Pulmonary, Allergy and Critical Care Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea; 2Allergy and Clinical Immunology Research Center, Hallym University College of Medicine, Chuncheon, Korea; 3Translational Research Laboratory for Inflammatory Disease, Clinical Trial Center, Ajou University Medical Center, Suwon, 16499, Korea; 4Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, KoreaCorrespondence: Hae-Sim ParkDepartment of Allergy and Clinical Immunology, Ajou University School of Medicine, Worldcup-ro 164, Youngtong-gu, Suwon-si, Suwon, 443-380, KoreaTel +82-31-219-5150Fax +82-31-219-5154Email hspark@ajou.ac.krBackground: Cysteinyl leukotrienes (CysLTs) are key mediators for bronchoconstriction, eosinophil recruitment and mucus production in the airways of asthmatic patients. To better understand the role of CysLTs in different asthma phenotypes, we compared the levels of arachidonic acid metabolites in relation to asthma control status and phenotypes in adult asthmatics on regular anti-asthma medications.Methods: A total of 137 adult asthmatics (47 with aspirin-exacerbated respiratory disease [AERD] and 90 asthmatics with aspirin-tolerant asthma [ATA]) and 20 healthy controls were enrolled. Arachidonic acid metabolites in serum and urine were analyzed using LC-MS/MS methods, and clinical data, including asthma control status, exhaled NO (FeNO) and lung function tests, were collected.Results: Urine LTE4 levels were significantly higher in AERD patients on inhaled corticosteroid-long-acting β2- agonist plus leukotriene receptor antagonist (LTRA) treatment than in ATA patients (P=0.001). No differences were found in the serum or urine levels of 15-HETE, TXB2, or PGF2α. High serum LTE4 levels were associated with lower FEV1% and uncontrolled status in AERD patients (P=0.006 and P=0.002, respectively), but not in ATA patients. Multivariate analysis demonstrated that blood eosinophil counts, FeNO levels and aspirin hypersensitivity were significant factors affecting urine LTE4 levels.Conclusion: Despite LTRA treatment in AERD, the LTE4 levels remained high and showed close associations with blood eosinophilia, high FeNO levels and impaired disease control. Our real-world evidence indicates that control of asthma is not fully achieved by blocking the CysLT pathway with LTRA. Thus, introduction of treatment modalities targeting eosinophilia could be a better option for patients with high CysLTs.Keywords: asthma, leukotrienes, asthma control, aspirin-exacerbated respiratory disease, eosinophil

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease. It is defined by asthma, chronic rhinosinusitis with nasal polyposis, and a hypersensitivity reaction to aspirin or nonsteroidal anti-inflammatory drugs. Aspirin desensitization (AD) has been confirmed as an effective treatment to control AERD inflammation through the modulation of immune responses. We aimed to review AERD with an overview of the epidemiology, pathophysiology, and treatment. We also discussed the effect of AD on immunological markers involved in AERD pathogenesis. A search of electronic databases on AERD was performed. We included five randomized clinical trials (RCTs) on AD. We also searched databases for recent studies that investigated the effect of AD on the immunological mechanisms of AERD. RCTs have demonstrated the therapeutic effectiveness of AD on the patients’ quality of life, asthma symptom score, inhaled and oral steroid use, forced expiratory volume in 1 sec (FEV1), and inflammatory mediators. The clinical benefits of AD can occur though the regulation of innate and adaptive immune responses that are involved in the pathogenesis of AERD. In addition to the valuable effects of AD in RCTs, some side effects such as gastrointestinal bleeding, asthma exacerbation, or rash have been reported that should be considered for reaching an optimal protocol for AD.

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. Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. 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. 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 E 2 levels. Dupilumab increased nasal prostaglandin E 2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E 4 , 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. 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 E 2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells. [ABSTRACT FROM AUTHOR]

BackgroundAspirin-exacerbated respiratory disease (AERD) is characterized by tissue eosinophilia and mast cell activation, including abundant production of prostaglandin D2 (PGD2). Group 2 innate lymphoid cells (ILC2s), which promote tissue eosinophilia and mast cell responses, undergo chemotaxis and cytokine production in response to PGD2, but it is unknown whether ILC2s are active in patients with AERD.ObjectiveWe sought to determine whether ILC2 numbers change in peripheral blood and the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD.MethodsBlood and nasal scrapings were collected at baseline, during reactions, and after completion of ketorolac/aspirin challenge/desensitization in 12 patients with AERD. ILC2s and eosinophils were quantitated by means of flow cytometry. Urine was also collected, and quantification of PGD2 metabolite and leukotriene E4 levels was done by using ELISA. Baseline and nonsteroidal anti-inflammatory drug reaction clinical data were correlated with cell changes.ResultsILC2 numbers significantly increased in nasal mucosal samples and decreased in blood at the time of COX-1 inhibitor reactions in 12 patients with AERD. These changes were not observed in 2 patients without AERD. Furthermore, eosinophil numbers decreased in blood concurrently with significant increases in urinary PGD2 metabolite and leukotriene E4 levels. The magnitude of increases in nasal mucosal ILC2 numbers positively correlated with maximum symptom scores during challenges. Furthermore, blood ILC2 numbers during the reaction correlated with time for the reaction to resolve, possibly reflecting reaction severity.ConclusionsILC2s are recruited to the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD, correlating with enhanced production of prostaglandins and leukotrienes.

Samter's triad, also known as aspirin-exacerbated respiratory disease, is characterized by nasal polyposis, bronchial asthma, and aspirin intolerance. Here, we present a case of a 36-year-old woman with a history of Samter's triad and recurrent dacryocystitis. After combined dacryocystorhinostomy and endoscopic sinus surgery, pathological specimens of the lacrimal sac showed respiratory fibrosis with chronic inflammation and eosinophilic infiltration. Our case demonstrates that Samter's triad is a potential etiology for inflammatory nasolacrimal duct obstruction.

[Display omitted] 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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Respiratory allergies affect humans worldwide, causing extensive morbidity and mortality. They include allergic rhinitis (AR), asthma, pollen food allergy syndrome (PFAS), aspirin-exacerbated respiratory disease (AERD), and nasal polyps (NPs). The study of respiratory allergic diseases requires new technologies for early and accurate diagnosis and treatment. Omics technologies provide the tools required to investigate DNA, RNA, proteins, and other molecular determinants. These technologies include genomics, transcriptomics, proteomics, and metabolomics. However, proteomics is one of the main approaches to studying allergic disorders' pathophysiology. Proteins are used to indicate normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. In this field, the principal goal of proteomics has been to discover new proteins and use them in precision medicine. Multiple technologies have been applied to proteomics, but that most used for identifying, quantifying, and profiling proteins is mass spectrometry (MS). Over the last few years, proteomics has enabled the establishment of several proteins for diagnosing and treating respiratory allergic diseases. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis with nasal polyps is affecting up to 3% of Western populations. About 10% of patients with nasal polyps also suffer from asthma and intolerance to aspirin, a syndrome called aspirin-exacerbated respiratory disease. Although eosinophilic inflammation is predominant in polyps of both diseases, phenotypic differences in the tissue-derived microenvironment, elucidating disease-specific characteristics, have not yet been identified. We sought to obtain detailed information about phenotypic and transcriptional differences in epithelial and immune cells in polyps of aspirin-tolerant and intolerant patients. Cytokine profiles in nasal secretions and serum of patients suffering from aspirin-exacerbated respiratory disease (n = 10) or chronic rhinosinusitis with nasal polyps (n = 9) were assessed using a multiplex mesoscale discovery assay. After enrichment for immune cell subsets by flow cytometry, we performed transcriptomic profiling by employing single-cell RNA sequencing. Aspirin-intolerant patients displayed significantly elevated IL-5 and CCL17 levels in nasal secretions corresponding to a more pronounced eosinophilic type 2 inflammation. Transcriptomic profiling revealed that epithelial and mast cells not only complement one another in terms of gene expression associated with the 15-lipoxygenase pathway but also show a clear type 2-associated inflammatory phenotype as identified by the upregulation of POSTN , CCL26 , and IL13 in patients with aspirin-exacerbated respiratory disease. Interestingly, we also observed cellular stress responses indicated by an increase of MTRNR2L12 , MTRNR2L8 , and NEAT1 across all immune cell subsets in this disease entity. In conclusion, our findings support the hypothesis that epithelial and mast cells act in concert as potential drivers of the pathogenesis of the aspirin-exacerbated respiratory disease. [ABSTRACT FROM AUTHOR]

Objective: To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma. Data Sources: Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Review Methods: A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy. Conclusions: uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity. Implications for Practice: Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents. [ABSTRACT FROM AUTHOR]

Objective: To review and evaluate outcomes of patients with aspirin-exacerbated respiratory disease (AERD) following endoscopic sinus surgery and subsequent aspirin desensitization. Methods: Electronic searches of OVID MEDLINE (1948 to September 10, 2019), EMBASE (1980 to September 10, 2019), and PubMed were performed on September 10, 2019. A systematic review of the literature was performed using the 2009 PRISMA guidelines. Studies with both preoperative and postoperative data for patients with AERD who underwent sinus surgery and aspirin desensitization were considered appropriate for inclusion. Publications were written in English and included patients aged 18 years or older. Results: Six studies met inclusion criteria for this systematic review. The primary outcome measure was change in symptom profile measured by patient-reported quality of life scores. The results demonstrate statistically significant improvement in symptoms following endoscopic sinus surgery, with sustained improvement following aspirin desensitization. Revision surgery rates were significantly lower in patients maintained on aspirin therapy. Conclusion: This review suggests that surgery followed by aspirin desensitization results in improvement in both subjective and objective outcome measures. The adjunctive use of aspirin desensitization allows for long-term stability in symptom scores. Recurrence of polyps and worsening symptoms requiring revision surgery occurs when aspirin maintenance therapy is interrupted.

Aspirin-exacerbated respiratory disease (AERD) is frequently diagnosed in patients with severe type 2 airway inflammation presenting with nasal polyps and severe asthma. It has been associated with a recalcitrant course with high medical and surgical requirements. The advent of recent biological and other targeted treatments show promise in the medical management of patient with AERD. The goal of complete disease control where patients no longer require recurrent surgical procedures, systemic corticosteroid exposure and may live with a stable and relatively normal quality of life is now within reach. Further work is necessary to identify biomarkers predictive of treatment response.

Merin E Kuruvilla,1 Kristine Vanijcharoenkarn,1 Joshua M Levy2 1Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University School of Medicine, Atlanta, GA, USA; 2Department of Otolaryngology – Head & Neck Surgery, Emory University School of Medicine, Atlanta, GA, USACorrespondence: Joshua M LevyEmory University School of Medicine, 550 Peachtree St NE, 11th Floor, Atlanta, GA 30308, USAEmail Joshua.Levy2@emory.eduAbstract: Mast cells (MC) have recently been demonstrated to play an integral role in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). When activated, MCs release pre-formed granules of many pro-inflammatory mediators, including histamine, serotonin, and various chemokines and cytokines including tumor necrosis factor (TNF)-α, interferon ɣ (IFN ɣ), macrophage inhibitory factor, transforming growth factor, interleukin (IL) 1, 3– 6, 9, 10, 13 and 16. These mediators promote inflammation in AERD by recruiting or activating a network of cells involved in acute and chronic inflammatory pathways, such as endothelial, epithelial, stromal, and other immune cells. Several studies have implicated multifactorial pathways for MC activation in AERD beyond classical IgE mediated mechanisms. The elucidation of these complex networks therefore represents important targets for innovative patient therapeutics. This review summarizes classic and alternative pathways of MC activation in AERD with a special focus in relation to new and emerging treatment strategies.Keywords: mast cells, aspirin-exacerbated respiratory disease, asthma, drug sensitivity, humanized monoclonal antibody