Different immunological types of CRSwNP in the context of the new European EAACI nomenclature : Part3: Hypersensitivity reactions of typeVI

Chronic rhinosinusitis (CRS) has aprevalence of up to 11% in Europe and the United States, making it one of the most common chronic diseases. Classification according to immunological endotypes is increasingly being incorporated into disease definitions, particularly for chronic rhinosinusitis with nasal polyps (CRSwNP). Genetic and epigenetic alterations within the mucosal immune system play an important role in this context. Identification of endotypes may help to elucidate disease heterogeneity and guide development of personalized therapeutic approaches. In part1 of this publication series, we presented the immunological classification of typeIV hypersensitivity reactions (T1, T2, and T3 endotypes). The European Academy of Allergy and Clinical Immunology (EAACI) recently published aposition paper introducing the updated nomenclature for immunological hypersensitivity reactions based on nine distinct immunological reaction types. The antibody-mediated reactions originally classified by Coombs and Gell as typeI, typeII, and typeIII have been expanded and described in greater detail. Epithelial barrier defects are defined as typeV hypersensitivity reactions and are the focus of part2 of this publication series. TypeV hypersensitivity is characterized by impairment of epithelial barrier function, resulting in aberrant and persistent activation of the mucosal immune system and, consequently, chronic inflammation. In addition to barrier dysfunction, microbial dysbiosis and dysregulation of immune responses play amajor role, including broad activation of Th1, Th2, and Th17 pathways, accompanied by aloss of regulatory T andBcells (Treg, Breg). Further mechanisms involve the production of serum (s)IgE against inhalant or food allergens; activation of macrophages (Mφ); and release of proinflammatory cytokines, chemokines, and inflammatory mediators such as histamine and leukotrienes. Loss of epithelial barrier integrity may result from defects in several key components, including structural elements; tight junction proteins; protective antiproteases; expression of antimicrobial proteins; and altered transport of ions, protons, water, or antimicrobial substances. Disruption of the epithelial barrier is also associated with activation of sensory nerve fibers within the mucosa, thereby contributing to the development of inflammatory symptoms. In patients with CRSwNP, immunological hyperreactivity reactions of various types-particularly typeIV, typeV, and typeVI hypersensitivity-may occur in either isolation or combination. While typeIV and typeVI reactions primarily contribute to the cellular inflammatory response and chronic persistence, typeV reactions, characterized by dysregulated receptor signaling, are increasingly recognized as clinically relevant in the context of epithelial barrier defects and impaired mucosal regeneration. The aim of this second part of the review is to elucidate the mechanisms underlying typeV hypersensitivity reactions and to discuss their implications for extended diagnostic and therapeutic approaches in CRSwNP.

Multidisciplinary consensus on a stepwise treatment algorithm for management of chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis (CRS) affects up to 11% of the population in Europe and the USA, making it one of the most common chronic diseases. The classification of immunological endotypes, particularly the T2 endotype, is gaining increasing importance. This classification is based on the Coombs and Gell hypersensitivity model, which categorizes cell-mediated typeIV reactions into T1, T2, and T3 endotypes. In chronic rhinosinusitis with nasal polyps (CRSwNP), genetic and epigenetic alterations in the mucosal immune system play akey role. Identifying specific endotypes helps to better understand the heterogeneity of the disease and develop tailored treatment approaches. This paper aims to systematize the underlying immunological mechanisms and highlight their relevance for diagnosis and therapy. The European Academy of Allergy and Clinical Immunology (EAACI) recently published an updated nomenclature for immunological hypersensitivity reactions. The original Coombs and Gell classification of antibody-mediated reactions (typeI-III) has been expanded. Cell-mediated reactions now include: typeIVa (T1) → Th1-dominated reactions; typeIVb (T2) → Th2-dominated reactions; typeIVc (T3) → Th17-dominated reactions. These new insights into T1, T2, and T3 signaling pathways form the basis of this study. Additional mechanisms such as epithelial barrier defects (typeV), chemical reactions (typeVI), and metabolism-related immune dysregulations (typeVII) are addressed separately. Endotyping reveals distinct regional differences: The T2 (Th2-high) endotype, predominant in Europe, North and South America, and Australia, is characterized by elevated Th2 cytokines (IL‑4, IL‑5, IL-13) and eosinophilic inflammation. The T1 (Th1-high) endotype shows dominant interferon-gamma activity and non-eosinophilic, mainly neutrophilic inflammation. The T3 (Th17-high) endotype is defined by increased IL-17 presence and can occur in both eosinophilic and non-eosinophilic CRSwNP. In CRSwNP patients, all three hyperreactivity endotypes (T1, T2, T3) can occur individually or in combination. The T2 endotype is the most common in Europe. Targeted endotyping enables differentiated treatment approaches and novel therapeutic options.

Profiling the immunological characteristics of exacerbation of chronic rhinosinusitis with nasal polyps.

Objective To investigate the impact of steroid-eluting implants after endoscopic sinus surgery (ESS) on health care resource use (HCRU) in chronic rhinosinusitis patients with (CRSwNP) and without (CRSsNP) nasal polyps. Methods This retrospective, observational cohort study using real-world evidence data included adult patients with CRS who underwent ESS in 2015–2019 with at least 24 months of data before and after ESS. Patients who received implants were matched to patients who did not based on a propensity score developed using baseline characteristics and NP status. HCRU was compared between cohorts within each CRSwNP and CRSsNP subgroup using chi-square tests (binary variables). Results The implant cohort in the CRSwNP subgroup had fewer all-cause outpatient (90.0% vs. 93.9%, p < .001) and all-cause otolaryngology (64.3% vs. 76.4%, p < .001) visits as well as fewer endoscopy (40.5% vs. 47.4%, p = .005) and debridement (48.8% vs. 55.6%, p = .007) procedures than the non-implant cohort. The implant cohort in the CRSsNP subgroup had fewer all-cause outpatient (88.9% vs. 94.2%, p < .001) and all-cause otolaryngology (53.5% vs. 74.4%, p < .001) visits as well as fewer endoscopy (31.8% vs. 41.7%, p < .001) and debridement (36.7% vs. 53.4%, p <.001) procedures than the non-implant cohort. Revision sinus surgery was reduced in the implant cohort in both subgroups, and reached statistical significance in the CRSwNP subgroup (3.8% vs. 6.0%, p = .039) but not in the CRSsNP subgroup (3.6% vs. 4.2%, p = .539). Conclusions Overall, patients receiving implants had lower HCRU for 24 months after sinus surgery independent of nasal polyp status, and revision surgery was reduced in CRSwNP patients. These findings provide additional evidence that long-term reductions in HCRU may be achieved with steroid-eluting implant use during sinus surgery. What is known on this topic Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have a disproportionately higher burden of disease and consume greater healthcare resources than chronic rhinosinusitis patients without nasal polyps (CRSsNP). CRSwNP patients represent approximately 30% of CRS patients who undergo surgery, but their clinical course is disproportionally complicated by disease recurrence and revision surgery. Steroid-eluting sinus implants have been shown in clinical trials to improve short-term postoperative outcomes after endoscopic sinus surgery (ESS) in CRS patients in general. A recent real-world evidence study reported that steroid-eluting sinus implants following ESS were associated with a reduction in HCRU in CRS patients followed for 18 months, but the impact of implants on HCRU in CRSwNP and CRSsNP patients separately remains unknown. What this study adds In this observational study, reduced HCRU was observed in CRSwNP and CRSsNP patients who receive steroid-eluting sinus implants. Use of implants in CRSwNP and CRSsNP patients was associated with a significant reduction in healthcare visits (all-cause outpatient, all-cause otolaryngology), and sinus procedures (endoscopy, debridement). Revision surgery was significantly reduced in the implant cohort of CRSwNP patients and trended lower in the implant cohort of CRSsNP patients. Use of implants had no significant impact on all-cause ER/urgent care visits or sinus-related imaging.

Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity

Chronic rhinosinusitis (CRS) is an inflammatory condition of the nasal airway and paranasal sinuses that can broadly be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). The relationship between CRS and atopy to inhalant allergens remains unclear. We sought to examine the presence of atopy in patients failing medical therapy for both types of CRS. The objective of this research was to analyze the frequency and distribution of allergen sensitivity in patients failing medical therapy for CRSwNP and CRSsNP in comparison to rhinitis patients without CRS and the general population. A prospectively collected database of 334 consecutive CRS patients who had surgery after failing maximal medical therapy was queried to identify those who met inclusion criteria: a sinus computed tomography (CT), an endoscopy consistent with CRS, and skin-prick testing with 24 common inhalant allergens in 8 classes at our institution (n = 125). Additionally, data from these CRS patients were compared to a group of 50 patients diagnosed with rhinitis who had similar symptoms but radiologically normal CT scans, as well as published normative population skin-prick testing data obtained from the National Health and Nutrition Examination Study III (NHANES III). The relationship between atopy, as assessed by the frequency of skin test positivity, and radiological disease severity, was assessed for several allergen classes in CRSwNP, CRSsNP and rhinitis patients. One or more positive skin results were observed in 103 of 125 (82.4%) CRS patients who underwent surgery--a prevalence significantly higher than that found in the NHANES III study (p < 0.05) but not different from the rhinitis control group (36/50, 72.0%). The most prevalent positive skin test results were to dust mites and ragweed in CRSwNP, CRSsNP, and rhinitis patients. Comparing these 3 patient groups, there were no significant differences in the rates of positive skin-test results to any single allergen. However, the median number of skin test–positive results was higher in CRSwNP patients compared to CRSsNP and rhinitis patients. Consistent with other studies, we found that CRSwNP patients were more likely to be male and have concurrent asthma. In our series of patients failing medical therapy for CRS, we found higher rates of atopy compared with the general population but not compared with rhinitis patients. CRSwNP patients with medically refractory sinusitis were more likely to have multiple positive skin tests and asthma as compared to the general population or patients with either CRSsNP or rhinitis. Host barrier dysfunction may play a role in enabling multisensitization.

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have deficiencies in circulating and sinonasal levels of the inactive form of vitamin D3, 25-hydroxycholecalciferol (25VD3). Moreover, CRSwNP patients have reduced epithelial cell-specific expression of 1α-hydroxylase; the enzyme responsible for the conversion of 25VD3 to its metabolically active form, 1α,25-dihydroxyvitamin D3 (1,25VD3). The objective of this work was to determine the impact of sinonasal 1α-hydroxylase levels combined from all cellular sources on subjective disease severity and to identify variables influencing its expression. Blood and sinus tissue explants were collected at the time of surgery from control, chronic rhinosinusitis without nasal polyps (CRSsNP), CRSwNP, and allergic fungal rhinosinusitis (AFRS) patients. 1α-Hydroxylase was measured by immunostaining with flow cytometric analysis. Subjective disease severity was measured by the 22-item Sino-Nasal Outcomes Test (SNOT-22). 1,25VD3 and 25VD3 were measured by enzyme-linked immunosorbent assay (ELISA). Patients with CRSwNP or AFRS have reduced 1α-hydroxylase and 1,25VD3 compared to controls or CRSsNP. Circulating 1,25VD3 levels were the same among all groups. No differences in sinonasal 1α-hydroxylase or 1,25VD3 were found between CRSwNP and AFRS. Gender, age, race, atopy, and systemic 25VD3 had no impact on sinonasal 1α-hydroxylase levels in any group. However, CRSwNP patients with asthma had higher 1α-hydroxylase than those without asthma. Total 1α-hydroxylase levels inversely correlated with SNOT-22 in CRSwNP, but not CRSsNP. Patients with CRSwNP and AFRS both have reduced sinonasal 1α-hydroxylase and 1,25VD3 compared to controls or CRSsNP. Reductions in intracellular 1α-hydroxylase combined from all sinonasal cell types were associated with more severe subjective disease severity in CRSwNP.

Circulating BAFF as novel biomarker in distinguishing chronic rhinosinusitis with nasal polyps endotypes and predicting postoperative recurrence

BackgroundA disintegrin and metalloproteinase 8 (ADAM8) has been implicated in eosinophilic inflammation; however, its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains to be elucidated. This study aimed to investigate the predictive significance of ADAM8 levels in nasal secretions for the endotypes and disease control status of CRSwNP.MethodsA cohort comprising 120 CRSwNP patients and 45 healthy controls (HCs) was assembled, delineating 53 non-eosinophilic CRSwNP (neCRSwNP) and 67 eosinophilic CRSwNP (eCRSwNP) patients. Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were utilized to measure ADAM8 levels in nasal mucosal tissues and secretions from all participants. The receiver operating characteristic (ROC) curves and Pearson correlation analysis were employed to assess the predictive capability of ADAM8 levels in predictiving CRSwNP endotypes and disease control status.ResultsADAM8 levels in nasal secretions were elevated in CRSwNP patients compared to HCs, with a more pronounced increase observed in eCRSwNP patients. Elevated ADAM8 concentrations in nasal secretions were positively correlated with peripheral blood eosinophil counts and percentages, tissue eosinophil counts, serum total IgE, Lund–Mackay scores, and Lund-Kennedy scores. Ultimately, 103 CRSwNP patients completed the follow-up protocol, with 72 classified as the controlled group and 31 as the uncontrolled group. Uncontrolled CRSwNP patients exhibited significantly higher ADAM8 levels in nasal secretions compared to the controlled group. The ROC curves indicated that ADAM8 in nasal secretions exhibits robust discriminatory capacity for eCRSwNP and postoperative disease control status.ConclusionADAM8 in nasal secretions emerges as a potential novel biomarker for the prognostication of CRSwNP endotypes and the postoperative disease control status.

IntroductionSevere eosinophilic asthma (SEA) often co-occurs with chronic rhinosinusitis with nasal polyps (CRSwNP), worsening asthma symptoms. Earlier studies have shown that benralizumab improves asthma outcomes with greater efficacy if patients present CRSwNP.MethodsThis post hoc analysis of the ANANKE study (NCT04272463) reports data on the long-term effectiveness of benralizumab between SEA patients with and without CRSwNP (N = 86 and N = 75, respectively) treated for up to 96 weeks.ResultsBefore benralizumab initiation, CRSwNP patients displayed longer SEA duration, greater oral corticosteroid (OCS) use and blood eosinophil count. After 96 weeks of treatment, the annual exacerbation rate (AER) decreased in both groups, with CRSwNP patients achieving considerable reductions than No-CRSwNP patients (severe AER dropped by 100% and 95.6%, respectively). While lung function improvement was comparable at week 96, CRSwNP patients showed a faster response to benralizumab, with a rise of forced expiratory volume in 1 s (FEV1) at 16 weeks that was maintained throughout the study. Median OCS daily dose decreased to 0.0 mg in both groups at 96 weeks, but benralizumab OCS-sparing effect was faster in CRSwNP patients (median OCS dose was 0.0 mg and 2.5 mg in CRSwNP and No-CRSwNP patients respectively, at 48 weeks). Although asthma control test (ACT) median scores were comparable, greater proportions of CRSwNP patients displayed well-controlled asthma (ACT ≥ 20) than No-CRSwNP patients at all time points.DiscussionThese findings show benralizumab long-term effectiveness in SEA patients with and without CRSwNP, highlighting its superior and faster-acting benefits on asthma outcomes in presence of CRSwNP.

Fevipiprant in CRSwNP and comorbid asthma: Wrong target population or wrong PGD2 receptor?

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Thymic stromal lymphopoietin (TSLP) plays an important role in mediating the type-2-inflammatory response. This study examined how TSLP and interleukin (IL)-4 levels in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) correlated with clinical and postoperative outcomes. Solid-phase sandwich ELISA was used to analyze TSLP and IL-4 levels in mucus (n = 47), plasma (n = 17), polyp (n = 30), inferior (n = 25), and middle (n = 26) turbinate tissue collected during functional endoscopic sinus surgery (FESS) in CRSwNP patients (n = 76) and controls (n = 11). Inclusion criteria includes patients with medical treatment refractory CRSwNP confirmed by endoscopy or maxillofacial CT. Exclusion criteria include history of immunodeficiency, coagulation disorders, fungal sinusitis, or cystic fibrosis. Levels of TSLP and IL-4 were correlated with SNOT-22, UPSIT, and fractional exhaled nitric oxide (FeNO) using MannWhitney U two-tailed test and linear regression with Spearman correlation coefficient test. TSLP is elevated in the inferior turbinates (effect size = 2.695, p = 0.0007) of CRSwNP patients compared to controls. IL-4 is expressed at elevated levels in the inferior (effect size = 3.092, p < 0.0001) and middle turbinates (effect size = 2.041, p = 0.019) compared to controls. Mucus TSLP (r = 0.4013, p = 0.0153) and IL-4 (r = 0.6138, p < 0.0001) positively correlate with preoperative FeNO levels. Lower TSLP in the inferior (r = -0.5179, p = 0.0231) and middle turbinates (r = -0.5075, p = 0.0224) and lower IL-4 in the inferior turbinates (r = -0.5205, p = 0.0223) correlate with a greater improvement in SNOT-22 post-FESS. TSLP and IL-4 are elevated in patients with CRSwNP and correlated with increased preoperative FeNO levels and decreased sinonasal quality of life benefit after FESS. Expression of TSLP and IL-4 may play a role in guiding postoperative expectations in patients with treatment refractory CRSwNP.

Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma