NSAIDs)-exacerbated Respiratory Disease Research Articles

What is the contribution of IgE to nasal polyposis?

Taking a novel approach, this narrative review collates knowledge about nasal polyposis and the biological functions of IgE in several diseases (allergic rhinitis, allergic asthma, nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease, and chronic spontaneous urticaria) to consider which IgE-mediated mechanisms are relevant to nasal polyposis pathology. Atype 2 eosinophil-dominated inflammatory signature is typical in nasal polyp tissue of European patients with nasal polyposis, with a shift toward this endotype observed in Asian populations in recent years. Elevated polyclonal IgE is present in the nasal tissue of patients with and without allergy. It is derived from many different B-cell clones and, importantly, is functional (proinflammatory). Staphylococcus aureus enterotoxins are thought to act as superantigens, inducing production of polyclonal IgE via B-cell and T-cell activation, and triggering release of inflammatory mediators. In some patients, exposure to antigens/triggers leads to production of high levels of antigen-specific IgE, which mediates cross-linking of the high-affinity IgE receptor on various cells, causing release of inflammatory mediators. The efficacy of omalizumab confirms IgE as an important inflammatory mediator in nasal polyposis. By blocking IgE, omalizumab targets the T2 inflammation in nasal polyposis, reduces nasal polyp score and improves symptoms.

Burden of Disease in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease of the nasal mucosa and paranasal sinuses with an under-recognized clinical, humanistic, and economic burden. Patients with CRSwNP experience a high symptom burden, including nasal congestion, loss of smell, and rhinorrhea, which has a negative impact on physical and mental health-related quality of life, including sleep quality. Existing medical and surgical interventions, including local and systemic corticosteroids and endoscopic sinus surgery, may be associated with recurrence of nasal polyps and associated symptoms and with an increased risk of short- and long-term adverse effects, especially with repeated or long-term use. Because type 2 inflammation is implicated in the pathogenesis of several coexisting diseases, patients with CRSwNP often have comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. These patients, as well as those with high corticosteroid use and/or sinonasal surgical history, have more severe disease and associated symptom burden and represent a difficult-to-treat population under the existing management paradigm. This article reviews the clinical, humanistic, and economic burden of CRSwNP; it highlights the unmet need for effective and safe CRSwNP therapies that effectively control symptoms and minimize recurrence by targeting the underlying type 2 inflammatory disease pathophysiology.

Factors affecting upper airway control of NSAID-exacerbated respiratory disease: A real-world study of 167 patients.

BackgroundNonsteroidal anti‐inflammatory drug (NSAID) exacerbated respiratory disease (N‐ERD) is a triad with asthma, chronic rhinosinusitis with nasal polyps, and NSAID intolerance. Uncontrolled N‐ERD forms a major public health problem due to frequent and difficult‐to‐treat exacerbations and/or requiring putatively frequent endoscopic sinus surgeries (ESS). Our aim was to study factors affecting control of N‐ERD.MethodsRetrospective patient record data (patient characteristics, prior sinus surgeries, follow‐up data in 2020) from 167 N‐ERD patients undergoing consultation at three tertiary hospitals from 2001 to 2017 was used. Outcome measurements reflecting uncontrolled N‐ERD were revision ESS, corticosteroids/biological therapy, and antibiotic courses during 2016–2020. Associations were analyzed by using nonparametric tests, Cox's proportional hazard, and binary logistic regression models.ResultsNasal polyp eosinophilia increased the risk of revision surgery during the follow‐up (adjusted hazard ratio [aHR] 3.21, confidence interval 1.23–8.38). Also baseline oral corticosteroids (OCS; HR, 1.73, 1.04–2.89) and baseline surgery without total ethmoidectomy increased the risk of revision ESS (HR, 2.17, 1.07–4.42) in unadjusted models. In addition, both baseline OCS (adjusted odds ratio [aOR] 2.78, 1.23–6.26) and a history of ≥4 previous ESS (aOR, 2.15, 0.98–4.70) were associated with the use of OCS/biological therapy during the follow‐up, but not with high number of antibiotics.ConclusionsNasal polyp eosinophilia, baseline OCS, and a history of recurrent ESS predict uncontrolled N‐ERD. These factors might be clinically useful in risk‐estimation of uncontrolled disease and for organizing follow‐ups. Prospective cohort studies with larger sample size are needed to further study the factors affecting the upper airway control of N‐ERD.

Factors Affecting the Control of Chronic Rhinosinusitis With Nasal Polyps: A Comparison in Patients With or Without NERD

ObjectivesThe aim was to compare the control of chronic rhinosinusitis with nasal polyps (CRSwNP) after endoscopic sinus surgery (ESS), in patients with/without nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD).Study Desing: A retrospective hospital-based sample of CRSwNP patients with/without NERD with follow-up.SettingTertiary rhinology centers.MethodsElectronic patient record data from 116 CRSwNP patients (46 with NERD and 70 without NERD) undergoing ESS during 2001–17 were studied. Mean follow-up time was 9.9 years (range 1.1–15.3). Endpoints reflecting uncontrolled CRSwNP were revision ESS, and need for rescue/advanced therapy (e.g. antibiotics, oral corticosteroids and/or biological therapy) during follow-up. NERD was variable of interest and gender, age, asthma, allergic rhinitis (AR), smoking, Lund-Mackay (LM) score of sinus computed tomography scans previous ESS and baseline total ethmoidectomy were used as covariates.ResultsTwenty-one (49.7%) NERD patients and 18 (25.7%) non-NERD patients underwent revision ESS within a mean ± SD of 4.3 ± 2.8 and 3.7 ± 2.6 years, respectively (p = .013, by Logrank test). In Cox´s regression models, NERD, female gender, young age, asthma, AR, previous ESS, and lack of total ethmoidectomy were associated with revision-ESS. In adjusted model, only the total ethmoidectomy predicted revision-free survival. In adjusted logistic regression model, there was an insignificant trend that NERD and LM score were associated with the need for rescue/advanced therapy in the follow-up.ConclusionsPatients with NERD had higher risk of uncontrolled CRSwNP than patient group without NERD, as measured by revision ESS and/or need for rescue/advanced therapy in the follow-up. In addition, baseline total ethmoidectomy was associated with revision-free survival.

Management of Non-steroidal Anti-inflammatory Drug-exacerbated Respiratory Disease

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EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: Definitions and management

Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. Arational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed.

P505 DUPILUMAB EFFECT ON TYPE 2 INFLAMMATION BIOMARKERS IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS AND NSAID-ERD

Chronic rhinosinusitis with nasal polyps (CRSwNP) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) display type 2 inflammatory pathophysiology. Comorbid NSAID-ERD is associated with higher morbidity and polyp recurrence rates. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key and central drivers of type 2 inflammation. We report the effect of dupilumab on biomarkers of type 2 inflammation in patients with CRSwNP and comorbid NSAID-ERD in the SINUS-52 study (NCT02898454).

Non-steroidal anti-inflammatory drugs (NSAIDs) – exacerbated respiratory disease: epidemiology, pathogenesis, clinical findings and management

Non-steroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory disease (N-ERD) are characterized by non-allergic hypersensitivity (intolerance) to NSAIDs and aspirin in patients with asthma and/or eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP). Asthma in N-ERD patients is usually characterized by eosinophilic inflammation, tends to become severe and intractable, and needs chronic oral corticosteroid therapy. For some patients recurrent CSwNP is more significant problem due to nasal congestion, anosmia, and multiple repeated surgeries. Intolerance to aspirin and other NSAIDs limits the choice of pain relievers and antipyretics. Accidental use of these medications can lead to dangerous consequences, including anaphylaxis. This review presents the current understanding of the N-ERD pathogenesis and perspective trends in therapy.

Neutrophil infiltrates and eosinophil aggregates in chronic rhinosinusitis with nasal polyps and EGPA.

The histopathological study of inflammatory cells and their tendency to form aggregates in chronic rhinosinusitis with nasal polyps (CRSwNP) has shown promising results in determining the pathogenesis and predicting clinical outcome. Bilateral nasal polyps also occur in over 70% of patients with eosinophilic granulomatosis with polyangiitis (EGPA). The study aim was to investigate neutrophil infiltrates and eosinophil aggregates in CRSwNP and EGPA tissues of Caucasian patients. A histopathological study was performed on surgical specimens of nasal polyps from 144 adults (15 with allergic fungal rhinosinusitis; 19 with nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (NERD); 16 with intrinsic asthma; 21 with extrinsic asthma; 21 with allergy; 22 with eosinophil CRSwNP (ECRSwNP); 17 with non-ECRSwNP; 13 with EGPA). Focusing on the presence of tissue eosinophil aggregates, NERD and ECRSwNP were the sub-cohorts with the highest rate. Neutrophil infiltrate rate was significantly higher in EGPA sub-cohort than in all CRSwNP sub-cohorts apart from non-ECRSwNP. Structured histopathology is increasingly identifying the different histotypes of CRSwNP. This analysis can be used to better understand CRSwNP endotypes and develop targeted therapies. The response to therapy and therefore control of CRSwNP relapses definitely depends on our ability to act on the underlying inflammatory pattern. Key points • Systematic analysis of how neutrophil infiltrates and eosinophilic aggregates are distributed in the different phenotypes of CRSwNP and EGPA. • Neutrophil infiltrates and eosinophil aggregates are strong risk factors for nasal polyps' refractoriness. • NERD and ECRSwNP are the sub-cohorts of CRSwNP with the highest rate of tissue eosinophil aggregates. • Neutrophil infiltrates are significantly higher in EGPA.

Heterogeneity of lower airway inflammation in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) asthma is characterized by chronic rhinosinusitis and intolerance of aspirin and other COX1 inhibitors. Clinical data point to a heterogeneity within the N-ERD phenotype. Our aim was to investigate immune mediator profiles in the lower airways of patients with N-ERD. Levels of cytokines (determined by using Luminex assay) and eicosanoids (determined by using mass spectrometry) were measured in bronchoalveolar lavage fluid (BALF) from patients with N-ERD (n= 22), patients with NSAID-tolerant asthma (n= 21), and control subjects (n= 11). mRNA expression in BALF cells was quantified by using TaqMan low-density arrays. Lower airway eosinophilia was more frequent in N-ERD (54.5%) than in NSAID-tolerant asthma (9.5% [P= .009]). The type-2 (T2) immune signature of BALF cells was more pronounced in the eosinophilic subphenotype of N-ERD. Similarly, BALF concentrations of periostin and CCL26 were significantly increased in eosinophilic N-ERD and correlated with T2 signature in BALF cells. Multiparameter analysis of BALF mediators of all patients with asthma revealed the presence of 2 immune endotypes: T2-like (with an elevated level of periostin in BALF) and non-T2/proinflammatory (with higher levels of matrix metalloproteinases and inflammatory cytokines). Patients with N-ERD were classified mostly as having the T2 endotype (68%). Changes in eicosanoid profile (eg, increased leukotriene E4 level) were limited to patients with N-ERD with airway eosinophilia. Blood eosinophilia appeared to be a useful predictor of airway T2 signature (area under the curve [AUC]= 0.83); however, surrogate biomarkers had moderate performance in distinguishing eosinophilic N-ERD (for blood eosinophils, AUC= 0.72; for periostin, AUC= 0.75). Lower airway immune profiles show considerable heterogeneity of N-ERD, with skewing toward T2 response and eosinophilic inflammation. Increased production of leukotriene E4 was restricted to a subgroup of patients with eosinophilia in the lower airway.

High Discontinuation Rates of Peroral ASA Treatment for CRSwNP: A Real-World Multicenter Study of 171 N-ERD Patients

Nonsteroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease (N-ERD) consists of chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and NSAID intolerance. Acetylsalicylic acid treatment after desensitization (ATAD) is a treatment option for uncontrolled N-ERD. To evaluate peroral ATAD's long-term effectiveness on CRSwNP disease control. The retrospective data (patient characteristics, sinus surgeries before ATAD, ATAD, follow-up data [2019]) were collected from patient records of 171 patients with N-ERD (102 ATAD patients, 69 controls with CRSwNP+N-ERD without ATAD) who underwent tertiary hospital consultation from 2001 to 2017. Outcome measurements were ATAD discontinuation, revision sinus surgery, and corticosteroid and antibiotic courses for airway infections during 2016-2019. Associations were analyzed by survival and nonparametric methods. The ATAD group had more tissue eosinophilia, symptoms, and sinus surgeries before ATAD than others. The ATAD discontinuation rate was 63%, independent of ATAD dose or duration, usually due to side effects. Compared with the N-ERD group without ATAD, ATAD (mean duration, 2.9 years) did not affect the revision endoscopic sinus surgery rate (P=.21, by the log-rank test) or the number of peroral corticosteroid courses per year (P > .05, by the Mann-Whitney U-test) during the follow-up (mean, 7.6 years) despite the dose or duration of ATAD. The discontinuation rate of ATAD was high (63%), and ATAD did not affect revision sinus surgery rate nor the need of peroral corticosteroids during follow-up. However, the remaining 37% of the ATAD group did continue the treatment, indicating that they may have benefited from ATAD.

Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n= 15) and healthy individuals (n= 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.

Symptom Control of Patients With Chronic Rhinosinusitis With Nasal Polyps Under Maintenance Therapy With Daily Acetylsalicylic Acid.

Nonsteroidal anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (NERD) is defined by intolerance to cyclooxygenase 1 inhibitors, chronic rhinosinusitis with recurrent nasal polyps, and/or intrinsic bronchial asthma. Long-term administration of acetylsalicylic acid (ASA) after desensitization has been used to mitigate these sequelae, but the optimal dose and balancing symptom relief and side effects remain unsettled. Retrospective data analysis of 85 patients with NERD receiving maintenance therapy of 300 mg ASA was followed by questionnaires (our own, not validated and the Sino-Nasal Outcome Test-20). We received responses from 55 patients and examined 30 of them clinically. Patients with no ASA-associated side effects were 56.4% (56 of 85 patients) of the cohort. In this study, 60% (33 of 55 patients) continued prophylaxis of 300 mg ASA daily for an average of 34.7 months. Elective surgery was the most frequent cause of discontinuation of ASA (21.8%; 12 of 55 patients). Rhinomanometry values were significantly improved with ASA (P < .05; Wilcoxon), but there was no significant reduction in nasal polyposis or improvement in olfaction at the time of follow-up examination. Minor clinical improvements were identified. Side effects were well tolerated by most patients, and no serious sequelae occurred. The indications for long-term ASA therapy in NERD patients remain unsettled.

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

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

Artificial neural network identifies nonsteroidal anti-inflammatory drugs exacerbated respiratory disease (N-ERD) cohort.

BackgroundTo date, there has been no reliable in vitro test to either diagnose or differentiate nonsteroidal anti‐inflammatory drug (NSAID)–exacerbated respiratory disease (N‐ERD). The aim of the present study was to develop and validate an artificial neural network (ANN) for the prediction of N‐ERD in patients with asthma.MethodsThis study used a prospective database of patients with N‐ERD (n = 121) and aspirin‐tolerant (n = 82) who underwent aspirin challenge from May 2014 to May 2018. Eighteen parameters, including clinical characteristics, inflammatory phenotypes based on sputum cells, as well as eicosanoid levels in induced sputum supernatant (ISS) and urine were extracted for the ANN.ResultsThe validation sensitivity of ANN was 94.12% (80.32%‐99.28%), specificity was 73.08% (52.21%‐88.43%), and accuracy was 85.00% (77.43%‐92.90%) for the prediction of N‐ERD. The area under the receiver operating curve was 0.83 (0.71‐0.90).ConclusionsThe designed ANN model seems to have powerful prediction capabilities to provide diagnosis of N‐ERD. Although it cannot replace the gold‐standard aspirin challenge test, the implementation of the ANN might provide an added value for identification of patients with N‐ERD. External validation in a large cohort is needed to confirm our results.

The Burden of Non-steroidal anti-inflammatory exacerbated respiratory disease from the patient's perspective - a qualitative analysis of posts from the Samter's Society.

A subset of patients with chronic rhinosinusitis with nasal polyps and asthma have non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD). Typically, these patients often have more difficult to treat symptoms of both chronic rhinosinusitis and asthma. They also have higher rates of revision after endoscopic sinus surgery. In this paper we aim to include the patient's perspective of living with N-ERD. In this qualitative study, three months of posts from the Samter's Society Support Group on social media were screened and analysed. Thematic analysis revealed eight main themes with subthemes in relation to patient interpretations when living with NERD. Main themes included symptom severity, quality of life, biological treatment options, diet, surgery, medical treatment, lack of awareness of N-ERD, conflicts between medical professionals and the importance of the support group. This study adds to the growing body of evidence that many patients with N-ERD are living with uncontrolled disease which has significant impact on their quality of life. In addition, it has identified important themes that are relevant to know for doctors treating these patients. The results are also important for future research purposes. Finally, it has highlighted the importance of patient advocacy groups in providing support to patients living with chronic disease.

IL10 rs1800872 Is Associated with Non-Steroidal Anti-Inflammatory Drugs Exacerbated Respiratory Disease in Mexican-Mestizo Patients.

Non-steroidal anti-inflammatory drugs (NSAID) exacerbated respiratory disease (N-ERD) is a disease integrated by asthma, nasal polyps, and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAID). Genetic association studies have explored single nucleotide polymorphisms (SNPs) in genes involved in theoretical pathophysiological mechanisms, but most of these lack replication of findings in second populations. Our objective was to evaluate the association of SNPs in candidate genomic regions described in Asian and European subjects with N-ERD in Mexican-mestizo patients. We designed a replicative study in two stages. We included 381 SNPs selected by fine mapping of associated genes in a microarray, which were tested in three groups: N-ERD (N), asthma (A), and control group (CG); by means of GoldenGate array, positive results by genetic models were validated in the second stage in another population through qPCR with the same methodology. In the allelic model, we identified 11 SNPs in N vs. CG comparison, and five in N vs. A and A vs. CG, respectively. By genetics models, all SNPs in PPARG, rs13239058 in TBXAS1, and rs1554286 and rs1800872 in IL10 were associated in both models. In the second stage, only rs1800872CC showed an association in the dominant model comparing N vs. GC, p = 0.004, OR = 0.44. In conclusion, rs1800872 in IL10 was the only associated with N-ERD in Mexican-mestizo patients.

Can nasal acetylsalicylic acid challenge predict the severity of non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD)? .

Background: Non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD) complicates the clinical course of chronic rhinosinusitis with nasal polyps (CRSwNP) and severe asthma. We aimed to determine the detection rate of NERD in patients with CRSwNP, asthma, and history of NSAID intolerance using nasal challenge with acetylsalicylic acid (ASA) and the relationship between the severities of response to ASA challenges and the grade of N-ERD. Materials and methods: Three groups of patients were included: CRSwNP with asthma and clinical history of analgesics intolerance (CRSwNP-AAI n = 18), CRSwNP with asthma but without a clinical history of analgesics intolerance (CRSwNP-A n = 20), and CRSwNP without asthma or analgesics intolerance (n = 18). All subjects were challenged nasally with 16 mg ASA and monitored with active anterior rhinomanometry. Rhinological (nasal polyp score), pulmonary (spirometry, Asthma Control Test (ACT), and asthma treatment), and psychometric questionnaire scores were recorded and correlated with rhinomanometric data following nasal challenges (flow depressions and symptom scores). Results: Nasal ASA challenge detected N-ERD in 96.7% of CRSwNP-AAI patients and 45% of CRSwNP-A patients. No N-ERD was seen in the CRSwNP group. The control grade of asthma measured with ACT scores was significantly lower in the groups CRSwNP-AAI (MV 18.22) and CRSwNP-A (MV 19.75) when compared to the CRSwNP group (MV 24.39) (p = 0.000). In the CRSwNP-AAI group, 11 patients had uncontrolled asthma (61%), and in the CRSwNP-A group, 9 patients had uncontrolled asthma (45%). No correlation was found between rhinology and pulmonary parameters, nasal symptoms, and the severity of nasal ASA challenges. Specific reactions were detectable under the therapy of prednisolone and omalizumab. Conclusion: N-ERD might not always be detected by screening a patient’s medical history. Nasal ASA challenges are recommended in patients with CRSwNP and asthma. The nasal challenge with ASA positively confirms the N-ERD diagnosis. Moreover, N-ERD is a differential diagnosis in patients with severe asthma with the need for prednisolone or omalizumab therapy. The severity of the reaction to the ASA challenge in controlled and uncontrolled asthma patients is independent of the grade of N-ERD.

A classification of chronic rhinosinusitis with nasal polyps based on structured histopathology.

In chronic rhinosinusitis with nasal polyps (CRSwNP), tools based on objective evidence, such as histopathology, are needed to assist clinical decision-making. The main aim of this exploratory investigation was to determine whether structured histopathology could be used to classify CRSwNP in homogeneous histological clusters. A cohort of 135 CRSwNP patients was assessed, on the basis of clinicopathological features: allergic fungal rhinosinusitis (17 patients); non-steroidal anti-inflammatory drug-exacerbated respiratory disease (19 patients); intrinsic asthma (18 patients); extrinsic asthma (21 patients); allergy (21 patients); histologically eosinophilic (22 patients); and histologically non-eosinophilic (17 patients). For structured histopathology, we considered: the degree of inflammation; eosinophil count; eosinophil aggregates; neutrophil infiltration; goblet cell hyperplasia; basement membrane thickening; fibrosis; hyperplastic/papillary changes; squamous metaplasia; mucosal ulceration; and subepithelial oedema. Cluster analysis identified four distinct sets of cases. On discriminant analysis, the global error rate was 1.48%, and the stratified error rates were 4.34%, 0%, 0%, and 0% for clusters 1, 2, 3 and 4, respectively. Cluster 1 was characterised by infrequent fibrosis (<4.5% of cases). Cluster 2 mainly featured neutrophil infiltration in 100% of cases, hyperplastic/papillary changes in 70% of cases, and fibrosis in 65% of cases. Cluster 3 showed fibrosis in 100% of cases. Cluster 4 showed hyperplastic/papillary changes in 100% of cases, and fibrosis in 92% of cases. This study shows that cluster analysis can identify different histotypes among CRSwNP patients. The next step will be to investigate, in a larger series, the clinical (e.g. prognostic) implications of identifying such homogeneous clusters of patients with CRSwNP on the basis of their structured histopathology.

Emerging Contribution of Histopathology to Our Understanding of Chronic Rhinosinusitis Endotypes: Tissue Eosinophil Count and Aggregates.

Background Rhinologists are currently trying to find evidence useful for classifying chronic rhinosinusitis with nasal polyps (CRSwNP) in terms of pathophysiology-based endotypes. This would help us to tailor targeted therapies and follow-up protocols to each patient, improving treatment efficacy and reducing relapse risk. The histopathological study of inflammatory cells in tissue and their tendency to form aggregates has shown promise in determining the pathogenesis and predicting the clinical outcome. Objective The main purpose of this study was to assess tissue eosinophil count, eosinophil aggregation, and their relationship to different CRSwNP phenotypes. Methods A consecutive series of 96 patients who underwent endoscopic sinus surgery for CRSwNP was retrospectively assessed. Our structured histopathological approach considered eosinophil count and eosinophil aggregates. Results Patients’ clinical features included allergic fungal rhinosinusitis (AFRS) in 17 cases, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD) in 19 cases, intrinsic asthma in 18 cases, extrinsic asthma in 21 cases, and allergy in 21 cases. Statistical analysis revealed more eosinophil aggregates in patients with NERD than in those with AFRS ( P = .020), intrinsic asthma ( P = .019), or extrinsic asthma ( P = .029). NERD patients had a significantly higher tissue eosinophil count than the other groups considered, apart from the AFRS ones. AFRS patients had a higher tissue eosinophil count than patients with intrinsic asthma. Conclusion Our results showed in particular that the NERD patient group’s rhinosinusitis was sustained by a significantly more severe eosinophilic reaction than in the other groups. Structured histopathology can provide useful information for classifying CRSwNP on pathophysiological grounds.