NSAID-exacerbated Respiratory Disease Research Articles

The Burden of Nonsteroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease: Interplay Between Quality of Life and Economic Implications

NSAID-Exacerbated Respiratory Disease (NSAID-ERD) presents a significant challenge in clinical management, owing to recalcitrant disease with accompanying profound impacts on patient quality of life. Though asthma represents a significant component of this disease, quality of life disruptions are driven primarily by recalcitrant sinonasal complaints, olfactory dysfunction, and the associated psychosocial and dietary implications. This review delves into specific quality of life metrics used to assess NSAID-ERD and the associated healthcare burden and financial implications of this disease, offering insights into the comparative challenges in chronic rhinosinusitis with nasal polyps (CRSwNP) where available. The article reviews the associated costs and cost-effectiveness of NSAID-ERD-directed therapies, including endoscopic sinus surgery, aspirin desensitization, and biologic therapy. While some of these emerging treatment approaches show promise, they also present numerous unanswered questions, reflecting the dynamic nature of this field. As the landscape of NSAID-ERD management continues to evolve, this review provides insights into the challenges faced by clinicians and underscores the need for further research to optimize patient care and quality of life outcomes.

Being born in autumn or winter is associated with asthma and allergic rhinitis in Finland.

Our population-based study has previously shown that being born in winter or spring was associated with adult-onset asthma. The aim was to study if season of birth (SOB) is associated with airway allergy and related diseases: NSAID exacerbated respiratory disease (N-ERD), asthma, allergic rhinitis (AR), nonallergic rhinitis (NAR), chronic rhinosinusitis with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) in Finland. A randomly sampled retrospective registry-based follow-up data (n=74,868) of patients visiting Hospital District of Helsinki and Uusimaa (HUS) in Finland was used. The birth date, sex, visit date and comorbidities were collected from electronic health record data during visits from 2005 to 2019. The mean (SD, range) age of the sample was 34.53 (25.47, 0-102) years, with 48.7 % being men. We divided the whole population in four groups based on the season they were born (SOB-groups). When observing these four SOB-groups, the proportion of those having asthma was 43.1%, 42.1%, 41.1%, 42.7%, in winter, spring, summer, and autumn SOB-groups, respectively. The proportion of those having AR was 12.6%, 12.0%, 10.7%, 12.1%, respectively. When having summer as a reference, being born in any other time of year was significantly associated with AR and, being born in autumn or winter was associated with asthma. No significant association was observed in CRS or N-ERD or NAR groups in adjusted models. The study suggests that early life immunological events may have a role a role in pathogenesis of asthma and AR. As no association was observed between SOB and CRSsNP, CRSwNP, N-ERD or NAR, further studies on this are warranted.

Aspirin Desensitization in Treatment of Chronic Rhinosinusitis with Nasal Polyposis: Current Protocols and Evidence

Abstract Purpose of Review Aspirin-exacerbated respiratory disease (AERD), or NSAID-exacerbated respiratory disease (NERD), is a heterogeneous inflammatory syndrome characterized by Samter’s clinical triad of chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and nonallergic hypersensitivity to all cyclooxygenase-1 (COX-1) inhibiting NSAIDs. This review focuses on randomized controlled trials and meta-analyses published on the clinical efficacy of aspirin therapy in AERD/NERD, as well as recent works published to explore the current outpatient ASA desensitization protocols in the US. Recent Findings Many AERD/NERD patients fail first-line therapies for treatment of asthma and CRSwNP and often need repeated sinus surgeries and frequent courses of oral corticosteroids to control symptoms. While COX-1 inhibiting NSAIDs are known to cause exacerbations in AERD/NERD, aspirin desensitization followed by maintenance oral high-dose aspirin therapy is proven to modulate the inflammatory cascade and has become a well-established treatment for most AERD/NERD patients. However, biologics are an emerging treatment option for pediatric patients and patients who are not candidates for aspirin desensitization. Summary Aspirin therapy after desensitization is beneficial for the majority of patients; however, the benefits, adverse effects, patient comorbidities, patient preferences, and all available treatment options must be considered in selecting an individualized treatment plan to address AERD/NERD.

An update on nonsteroidal anti-inflammatory drug-induced urticaria.

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management. The study is a narrative review conducted by collecting the most relevant and up-to-date data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles. Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDs-exacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDs-induced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed. HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced.

Beyond T2-asthma biomarkers: risk stratification for NSAID-Exacerbated Respiratory Disease

Type 2 (T2)-asthma is often associated with chronic rhinosinusitis with nasal polyposis (CRSwNP). Additionally, non-steroidal anti-inflammatory drug intolerance leads to NSAID-exacerbated respiratory disease (N-ERD). Previous transcriptomic data in non-CRSwNP T2-asthma patients showed differentially expressed genes (DEGs). Of them, we focused onALOX15,CLC,CYSLTR2,HRH4, andSMPD3to investigate their role in T2-asthma patients. The study included 100 healthy controls (HCs) and 103T2-asthma patients, divided into asthmatics (54), asthmatics with CRSwNP (30), and N-ERD (19). Quantitative PCR analysis was performed on blood-derived RNA samples first to validate the five DEGs. The data were further analyzed to find potential associations and biomarkers. Patients, regardless of stratification, exhibited significantly higher gene expressions than HCs. The patterns of association revealed thatALOX15was exclusively present in the non-comorbidity group,SMPD3andCLCin the comorbidity groups, andHRH4in all patient groups.ALOX15, CYSLTR2, andSMPD3expression showed potential as biomarkers to confirm the diagnosis of T2-asthma using peripheral blood eosinophils (PBE) as the initial criterion. PBE combined with gene expressions, especiallySMPD3, may improve the diagnosis.CLCandCYSLTR2expressions play a specific role in discriminating N-ERD. We validated the transcriptomic data of five DEGs in T2-asthma. Different patterns of association were identified in patient stratification, suggesting different molecular mechanisms underlying the spectrum of T2-asthma. Potential biomarkers were also found and used to design an algorithm with practical diagnostic utility for T2-asthma, including risk stratification for N-ERD.

Importance of aspirin challenges in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by asevere course of chronic rhinosinusitis with nasal polyps (CRSwNP), comorbid asthma, and NSAID hypersensitivity. The gold standard for N-ERD diagnosis is challenge with acetylsalicylic acid (ASA). In expert recommendations, the diagnosis of N-ERD is established based on aplausible positive history of NSAID hypersensitivity and CRSwNP with asthma. The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which apositive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed. ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is ahigh concordance between apositive history of NSAID hypersensitivity obtained by rhinologists and the measured data of ASA challenge in patients with CRSwNP and comorbid asthma. Therefore, ASA challenge is primarily indicated in patients with an unclear history of NSAID hypersensitivity.

Extracellular vesicle miRNAs drive aberrant macrophage responses in NSAID-exacerbated respiratory disease.

Extracellular vesicles (EVs) have been implicated in the pathogenesis of asthma, however, how EVs contribute to immune dysfunction and type 2 airway inflammation remains incompletely understood. We aimed to elucidate roles of airway EVs and their miRNA cargo in the pathogenesis of NSAID-exacerbated respiratory disease (N-ERD), a severe type 2 inflammatory condition. EVs were isolated from induced sputum or supernatants of cultured nasal polyp or turbinate tissues of N-ERD patients or healthy controls by size-exclusion chromatography and characterized by particle tracking, electron microscopy and miRNA sequencing. Functional effects of EV miRNAs on gene expression and mediator release by human macrophages or normal human bronchial epithelial cells (NHBEs) were studied by RNA sequencing, LC-MS/MS and multiplex cytokine assays. EVs were highly abundant in secretions from the upper and lower airways of N-ERD patients. N-ERD airway EVs displayed profoundly altered immunostimulatory capacities and miRNA profiles compared to airway EVs of healthy individuals. Airway EVs of N-ERD patients, but not of healthy individuals induced inflammatory cytokine (GM-CSF and IL-8) production by NHBEs. In macrophages, N-ERD airway EVs exhibited an impaired potential to induce cytokine and prostanoid production, while enhancing M2 macrophage activation. Let-7 family miRNAs were highly enriched in sputum EVs from N-ERD patients and mimicked suppressive effects of N-ERD EVs on macrophage activation. Aberrant airway EV miRNA profiles may contribute to immune dysfunction and chronic type 2 inflammation in N-ERD. Let-7 family miRNAs represent targets for correcting aberrant macrophage activation and mediator responses in N-ERD.

Biologic therapy in patients with severe NSAID-exacerbated respiratory disease and previous aspirin desensitization : Results of a multicentric study

Chronic rhinosinusitis with nasal polyps (CRSwNP) is atype‑2 inflammatory disease of the upper airways, with severe impairment of quality of life. Persons affected by NSAID-exacerbated respiratory disease (NERD) usually present with highly dynamic recurrence of polyps and disease despite prior treatment with sinus surgeries, oral corticosteroids, and aspirin desensitization (ATAD). Biologic therapy has fundamentally changed the choice of therapeutic concept; however, limited data exist on subgroups such as NERD patients. The aim of the current article is to report on amulticenter retrospective study on add-on therapy with dupilumab, omalizumab, and mepolizumab in patients with NERD. This is aretrospective cohort study of patients (NERD+, status after ATAD) in three reference centers in Germany (Munich, Mainz, Berlin). Subjective and objective parameters were collected at 4, 8, and 12months after biologic therapy initiation in accordance with current EPOS/EUFOREA (European Position Paper on Rhinosinusitis and Nasal Polyps/European Forum for Research and Education in Allergy and Airway Diseases) guidelines. Biologic agents were chosen depending on availability and patient characteristics. Treatment was commenced in 122patients meeting the criteria for CRSwNP and NERD. The endoscopic polyp score, SNOT-22 questionnaire score, visual analogue scoring of total symptoms/severity of disease, and sense of smell (psychophysical testing with Sniffin'Sticks/Brief Smell Identification Test, B‑SIT; Sensonics, Inc., Haddon Heights, NJ, USA) improved significantly after 4 and 12months of add-on therapy (p < 0.0001). All three biologic agents significantly improved one or more disease parameter. Adverse events were not life threatening but led to change of biologic agent in 4cases. Patients rated biologic therapy significantly better than ATAD, with improved long-term disease control. Add-on biologic therapy is effective, safe, and widely accepted among CRSwNP + NERD patients. Future studies might allow for personalized algorithms with sequential surgery, ATAD, and/or biologic therapy.

Deep immune profiling of chronic rhinosinusitis in allergic and non-allergic cohorts using mass cytometry

Chronic rhinosinusitis (CRS) is a persistent nasal and paranasal sinus mucosa inflammation comprising two phenotypes, namely CRS with nasal polyps (CRSwNP) and without (CRSsNP). CRSwNP can be associated with asthma and hypersensitivity to non-steroidal anti-inflammatory drug (NSAID) in a syndrome known as NSAID-exacerbated respiratory disease (N-ERD). Furthermore, CRS frequently intertwines with respiratory allergies. This study investigated levels of 33 different nasal and serum cytokines and phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) within cohorts of CRS patients (n = 24), additionally examining the influence of comorbid respiratory allergies by mass cytometry. N-ERD patients showed heightened type 2 nasal cytokine levels. Mass cytometry revealed increased activated naive B cell levels in CRSwNP and N-ERD, while resting naive B cells were higher in CRSsNP. Th2a cell levels were significantly elevated in allergic subjects, but not in CRS groups. In conclusion, there are distinct immunological features in PBMCs of CRS phenotypes and allergy.

Does aspirin therapy after desensitization still have a role in treatment of chronic rhinosinusitis with nasal polyposis in the era of biologics?

The prevalence of analgesic intolerance syndrome (AIS), internationally known as NSAID-exacerbated respiratory disease (NERD), is reported to be 0.5-5.7% in the general population. The disease often begins with nasal symptoms, which are later joined by chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and respiratory hypersensitivity reactions following use of nonsteroidal anti-inflammatory drugs (NSAIDs). In the setting of chronic respiratory disease, the type2 inflammatory endotype is predominant in approximately 80% of patients with CRSwNP, rendering biologics directed against interleukin (IL)-4, IL‑5, IL-13, and IgE of high clinical interest, particularly in patients with severe CRSwNP and NERD. NERD is often associated with CRSwNP and asthma. Patients with CRSwNP and NERD have been treated, among other therapies, with aspirin therapy after desensitization (ATAD). With the approval of monoclonal antibodies for CRSwNP and asthma, the question arises as to what extent ATAD, which is associated with undesirable side effects, is still useful in the treatment of CRSwNP. In this manuscript, the use of ATAD in CRSwNP patients is discussed from different medical and socioeconomic points of view, both alternatively to or in combination with monoclonal antibodies. Accordingly, both ATAD and biologics continue to play asupporting role in modern treatment of CRSwNP in NERD patients, and should be used judiciously to complement each other.

Quality of Life in NSAIDs-Exacerbated Respiratory Disease on or off Intranasal Lysine Aspirin Therapy

Quality of Life in NSAIDs-Exacerbated Respiratory Disease on or off Intranasal Lysine Aspirin Therapy

Upregulation of Platelet-Activating Factor Receptor Expression and Lyso-Platelet-Activating Factor Isoforms in Human Nasal Polyp Tissues

Background: The Platelet-Activating Factor (PAF)/receptor (PAFR) system is involved in asthma and allergic rhinitis; however, its role in chronic rhinosinusitis (CRS) is still unclear. This study aimed to assess the expression of PAFR and the concentration of Lyso-PAF isoforms in the nasal polyps (NP) of patients suffering from CRS with/without comorbidities such as asthma and NSAID-exacerbated respiratory disease (N-ERD) compared to healthy nasal mucosa (NM) from control subjects. Methods: NM (n = 8) and NP tissues were obtained from patients undergoing surgery for septal deviation/turbinate hypertrophy or endoscopic sinus surgery, respectively. Three phenotypes were studied: CRSwNP with no asthma (n = 6), CRSwNP with non-steroidal anti-inflammatory drug (NSAID)-tolerant asthma (n = 6), and CRSwNP with NSAID-exacerbated respiratory disease (n = 6). PAFR protein and mRNA were assessed via immunochemistry, immunofluorescence, Western blot, and real-time quantitative PCR. Lyso-PAF isoforms (C16, C18, and C18:1) were quantified via mass spectrometry. Results: PAFR protein was expressed in the NM and NP, concretely in epithelial cells and submucosal glands. Compared to NM, PAFR mRNA expression was higher in all NP phenotypes (p &lt; 0.05) while all Lyso-PAF isoform concentrations were higher in the NP from asthmatic patients (p &lt; 0.05). Lyso-PAF C16 and C18 concentrations were higher in the NP from asthmatic patients than in the NP from patients without asthma. Conclusions: The PAF/PAFR system could play a pathophysiological role in CRSwNP pathogenesis.

Does NSAID exacerbated respiratory disease (N-ERD) accompanying severe asthma affect biological treatment response? Efficacy of omalizumab and mepolizumab in N-ERD

IntroductionNon-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) accompanies severe asthma in about 15% of the patients and may adversely affect the prognosis. Omalizumab and mepolizumab are biologics used in patients with severe asthma. The objective of this study is to assess the respiratory improvements, after these biologics in severe asthmatic patients stratifed by the presence of concomitant Non-erosive reflux disease (N-ERD) and the effect of omalizumab and mepolizumab in severe asthmatics with N-ERD. Material & methodThe population of this three-center, retrospective, cross-sectional, observational study comprised patients using omalizumab or mepolizumab for severe asthma. Patients administered these biologics for severe asthma were comparatively analyzed for the presence of N-ERD; asthma control test (ACT) scores, number of attacks, and the changes in forced expiratory volume in 1 s (FEV1) were assessed. Subsequently, patients who were found to have N-ERD were analyzed using visual analog scale (VAS) in terms of the changes in their nasal parameters (ie, nasal obstruction, facial pain, anterior-posterior rhinitis, and hyposmia), according to whether they use omalizumab or mepolizumab. ResultsThe use of biologics resulted in a significant improvement in ACT and FEV1 and reduction in attacks in 28 severe asthmatics with N-ERD and 125 without N-ERD. Although both biologics resulted in a significant improvement in the respiratory parameters, omalizumab treatment resulted in a significant improvement in nasal parameters except hyposmia, mepolizumab treatment resulted in a significant improvement only in posterior rhinitis, and nasal obstruction among the nasal parameters. ConclusionThis study is the first to address both omalizumab and mepolizumab treatments in severe asthmatics with N-ERD. The improvement in nasal parameters was more pronounced in patients who were administered omalizumab. Large-scale randomized controlled studies are needed to corroborate the findings of this study.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. The aim of this study is to characterize disease progression in N-ERD. Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. Patients (N= 240) were mostly female (68%) and self-identified as non-White (77%). Half (N= 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR]= 1.3, 95% confidence interval [CI]: 1.06-1.7, P= .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR= 3.3, 95% CI: 1.5-7.4, P= .004) and pollution exposure (OR= 4.4, 95% CI: 1.6-11.9, P= .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P= .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Risk factors of NSAID-exacerbated respiratory disease: Apopulation-based study.

Asthma with NSAID-exacerbated respiratory disease (NERD) is associated with uncontrolled or severe asthma. NERD patients are more prone to severe allergic reactions and their asthma exacerbations lead to hospitalisations twice as often compared to patients with non-NERD-asthma. NERD patients are prone to recurrent nasal polyposis requiring frequent endoscopic sinus surgeries. However, the early risk factors of NERD are not fully understood. The aim was to identify risk factors of NERD among patients with adult-onset asthma. We used data from 1350 population-based adult asthmatics with adult-onset asthma from Finnish national registers. NERD was defined as self-reported wheeze or other typical respiratory symptoms after ingestion of NSAIDs. Thirty-six covariates covering several domains (personal characteristics, life-style, early life factors, asthma characteristics and multimorbidities) were selected based on literature and were studied in association with NERD using logistic regressions. The study population included 153 (11.3%) asthmatics with NERD. Thirty-six covariates were entered in univariate logistic regression analysis, in which 23 were associated with NERD (p<0.05). These variables were entered in a multivariable logistic regression model in which allergic respiratory symptoms, female sex, osteoarthritis, difficult asthma, nasal polyps, second-hand smoke exposure at home, having 3 or more older siblings and being overweight were significantly associated with asthma with NERD (p<0.05). Overweight decreased the risk of NERD, other factors increased it. According to our study, risk factors of NERD in part are associated with female sex, BMI, exposure to tobacco smoke, allergy, orthopaedic disorders and infection history, and their early recognition might thus be important to manage the burden of NERD.

The nasal microbiome in patients suffering from non-steroidal anti-inflammatory drugs-exacerbated respiratory disease in absence of corticosteroids.

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<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.

Monoclonal antibody or aspirin desensitization in NSAID-exacerbated respiratory disease (N-ERD)?

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a clinical syndrome characterized by nasal polyposis, asthma, and intolerance to aspirin/NSAID. It affects approximately 15% cases of severe asthma, 10% of nasal polyps and 9% of rhinosinusitis. N-ERD results in associated asthma exacerbations, oral corticosteroids bursts, corticosteroid-dependent disease, and multiple endoscopic sinus surgeries. Unknown influences cause polyp epithelium to release alarmins, such as IL-33 and TSLP. These cytokines activate lymphoid cells, both Th2 and ILC2, to release cytokines such as IL5, IL4 and IL13, resulting in complex type 2 inflammation involving mast cells, eosinophils and platelets. Arachidonic acid released from such cells is metabolized into mediators. N-ERD is characterized by an imbalance in eicosanoid levels, especially CysLTs, PDG and PGE2. Patients with N-ERD present nasal symptoms (congestion, hyposmia/anosmia, nasal discharge) and lower airways symptoms (cough, sneezing, shortness of breath, chest tightness), anosmia, severe hyposmia as well as severe asthma which impacts the quality of life in this disease and leads to safety concerns in patients daily lives. Despite the variety of treatment strategies, the likelihood of recurrence of symptoms is high in patients with N-ERD. The most important strategies for treating N-ERD are listed as following: drug therapies, aspirin desensitization, monoclonal antibodies and other therapies associated. N-ERD treatment remains a major challenge in the current situation. Selecting the appropriate patient for aspirin desensitization, monoclonal antibodies or both is essential. This review provides an overview on aspirin desensitization and biologics in N-ERD and might help in decision making from both the perspective of the physician and patient. Patient characteristics, safety, efficacy, health care costs, but also patient preferences are all factors to take into account when it comes to a choice between biologics or aspirin desensitization.

Bronchial epithelial cell transcriptome shows endotype heterogeneity of asthma in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) is currently classified as a type-2 (T2) immune-mediated disease characterized by asthma, chronic rhinosinusitis, and hypersensitivity to cyclooxygenase-1 inhibitors. The aim of this study was to characterize immunological endotypes of N-ERD based on the gene expression profile in the bronchial epithelium. mRNA transcriptome (mRNA-sequencing) was analyzed in bronchial brushings from patients with N-ERD (n=22), those with nonsteroidal anti-inflammatory drug-tolerant asthma (NTA, n= 21), and control subjects (n=11). Additionally, lipid and protein mediators were measured in bronchoalveolar lavage fluid (BALF). Initial analysis of the entire asthma group revealed 2 distinct gene expression signatures: "T2-high" with increased expression of T2-related genes (eg, CLCA1, CST1), and "proinflammatory" characterized by the expression of innate immunity (eg, FOSB, EGR3) and IL-17A response genes. These endotypes showed similar prevalence in N-ERD and NTA (eg, T2-high: 33% and 32%, respectively). T2-high asthma was characterized by increased expression of mast cell and eosinophil markers, goblet cell hyperplasia, and elevated LTE4 and PGD2 in BALF. Patients with a proinflammatory endotype showed mainly neutrophilic inflammation and increased innate immunity mediators in BALF. Furthermore, the proinflammatory signature was associated with a more severe course of asthma and marked airway obstruction. These signatures could be recreated invitro by exposure of bronchial epithelial cells to IL-13 (T2-high) and IL-17A (proinflammatory). T2-high signature was found only in one-third of patients with N-ERD, which was similar to what was found in patients with NTA. The proinflammatory endotype, which also occurred in N-ERD, suggests a novel mechanism of severe disease developing on a non-T2 background.

Computed tomography findings of paranasal sinuses in patients with eosinophilic granulomatosis with polyangiitis: Comparison with other eosinophilic sinus diseases and clinical relevance of their severity

BackgroundAlthough 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. MethodsCT 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. ResultsTotal 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. ConclusionsAlthough 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.

Comparison of the clinical outcomes of patients with NSAID-exacerbated respiratory disease receiving aspirin or biologicals

Objective NSAID-exacerbated respiratory disease (NERD) is characterized by exacerbation of respiratory symptoms after NSAID intake. While research for specific treatment options continues in patients who cannot tolerate or are unresponsive to aspirin treatment after aspirin desensitization (ATAD), biologicals have emerged as a new therapeutic option in NERD patients. The aim of this study was to compare the quality of life, and the sinonasal and respiratory outcomes of NERD patients treated with ATAD or biologicals. Methods Patients who have been followed up at a tertiary care allergy center and who have been receiving at least one of ATAD, mepolizumab or omalizumab for at least six months were included. Evaluations were made using sinonasal outcome test (SNOT-22), asthma control test (ACT), short form-36 (SF-36), blood eosinophil counts, need for recurrent functional endoscopic sinus surgeries (FESS), and asthma or rhinitis exacerbations requiring oral corticosteroids (OCS). Results A total of 59 patients comprised of 35 (59%) females and 24 (41%) males with a mean age of 46.1 (min-max, 20–70) years were included. The baseline blood eosinophil count was higher, and a significant decrease in blood eosinophil counts was observed in the mepolizumab group compared to ATAD group (p = 0.001, p < 0.001, respectively). At follow-up, the rate of recurrent FESS was lower in the group that received mepolizumab (p = 0.02). Conclusions In NERD patients, mepolizumab significantly decreased blood eosinophil counts and recurrent FESS. There was no significant difference between the patients receiving ATAD or mepolizumab regarding other clinical parameters.