Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Neuroimmune interplay during type 2 inflammation: Symptoms, mechanisms, and therapeutic targets in atopic diseases.

Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation.

Mast Cells in Aspirin-Exacerbated Respiratory Disease.

PURPOSE OF REVIEW: Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. RECENT FINDINGS: Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.

Real-Life Response to Biologics in Severe Asthma with Nasal Polyposis: Insights from the Belgian Severe Asthma Registry.

BACKGROUND: Nasal polyposis (NP) is a comorbidity of type 2 severe asthma (SA) which could influence response to SA biologics. METHODS: We evaluated (super-) response in SA patients with (NP +) and without NP (NP-) enrolled in the Belgian Severe Asthma Registry (BSAR). RESULTS: 914 patients, of whom 31% NP + , were included. At enrollment, NP + patients had higher annual exacerbation rates, higher number of emergency room visits and more elevated type 2 biomarkers. In the longitudinal subanalysis of 104 patients, both groups had significant and similar asthma responses to asthma biologics, except for a greater increase in FEV1 in the NP + group. Super-response was achieved in 33 patients (32%), irrespective of NP status or type of biologic. CONCLUSION: In conclusion, both NP + and NP - patients had positive treatment responses, with some able to achieve super-response. In SA patients with NP, a greater FEV1 improvement as compared to SA patients without NP was observed.

Dupilumab improves sleep quality in chronic rhinosinusitis with nasal polyps.

PURPOSE: Chronic rhinosinusitis with nasal polyps (CRSwNP) often alters sleep quality. Dupilumab emerged as an innovative and effective therapy for refractory/recurrent severe CRSwNP. The aim of this observational retrospective study was to evaluate the sleep quality in patients with CRSwNP who underwent treatment with dupilumab. MATERIALS AND METHODS: Forty-five patients treated with dupilumab for CRSwNP were enrolled. Clinical parameters (age, sex, comorbidities, Nasal Polyp Score - NPS, Asthma Control Test - ACT), nasal cytology, quality of life (Sino Nasal Outcome Test 22 - SNOT-22), sleep quality (Pittsburgh Sleep Quality Index - PSQI, Epworth Sleepiness Scale - ESS), and risk of sleep apnea (STOP-BANG) were recorded before treatment (T0), and after 3 (T1), 6 (T2), and 12 months (T3). RESULTS: NPS, ACT and SNOT-22 total score improved during treatment (p < 0.05). Meanwhile, all sleep parameters evaluated with SNOT-22, ESS and PSQI improved over time (p < 0.001), expect for PSQI Use of sleeping medications. Indeed, sleep drugs are rarely used before and during the treatment. The global sleep quality was classified as poor in 88.9 % of cases at T0 and decreased to 5.7 % at T3. A high risk of sleep apnea was revealed by the STOP-BANG in 68.9 % of cases at T0 and 2.8 % of patient at T3 (p < 0.001). CONCLUSIONS: Dupilumab improves the sleep quality and reduce the risk of sleep apnea in patients with severe CRSwNP. Its favorable effect occurs within 3 months and is maintained during the treatment.

Occurrence of mucosa-affecting diseases of the upper airways in middle ear cholesteatoma patients: a nationwide case-control study.

PURPOSE: Exploring a possible link between upper airway inflammation and the development of cholesteatoma by studying the association between mucosa-affecting diseases of the upper airways and cholesteatoma surgery. METHODS: This is a nationwide case-control study of 10,618 patients who underwent surgery for cholesteatoma in Sweden between 1987 and 2018. The cases were identified in the National Patient Register and 21,235 controls matched by age, sex and place of residency were included from national population registers. Odds ratios (OR) and corresponding 95% confidence intervals were used to assess the association between six types of mucosa-affecting diseases of the upper airways and cholesteatoma surgery. RESULTS: Chronic rhinitis, chronic sinusitis and nasal polyposis were more common in cholesteatoma patients than in controls (OR 1.5 to 2.5) as were both adenoid and tonsil surgery (OR > 4) where the strongest association was seen for adenoid surgery. No association was seen between allergic rhinitis and cholesteatoma. CONCLUSION: This study supports an association between mucosa-affecting diseases of the upper airways and cholesteatoma. Future studies should aim to investigate the mechanisms connecting mucosa-affecting diseases of the upper airways and cholesteatoma formation regarding genetic, anatomical, inflammatory and mucosa properties.

Patterns of recurrence in patients with CRSwNP who underwent complete FESS.

PURPOSE: To analyze recurrence patterns of chronic sinusitis with nasal polyposis (CRSwNP) in patients who underwent complete FESS and identify predisposing factors for different patterns of recurrence. METHODS: Retrospective analysis of patients with CRSwNP who underwent complete FESS at our tertiary medical center. Recurrence patterns were classified into edema, polyp and normal endoscopy, as well as into early (within 6 months) and late recurrence. Statistical analysis to identify risk factors for recurrence included univariate, multivariate logistic regression and cox regression models. RESULTS: 114 patients were included with an average follow-up of 27 months. 91% were categorized as type-2 inflammation. Recurrence was observed in 65.8% of patients within a mean of 12.9 months. 46.7% had polyp recurrence while 53.3% had edema recurrence. Early recurrence was observed in 41%. Serum eosinophilia > 500 cells/uL was found to be significantly associated with recurrence (RR = 1.62, p-value = 0.046), and particularly with polyp recurrence (RR = 3.9, p-value = 0.001). No predictive factors for early recurrence were identified. Edema recurrence was managed with intranasal corticosteroids while polyp recurrence required systemic therapy including biologic therapy. CONCLUSIONS: In this study, two thirds of patients experienced post operative recurrence, either mucosal edema or nasal polyps, with similar frequency during an average follow up of over 2 years. Early recurrence was noted in 41% of recurrent cases. Serum eosinophils > 500 cells/uL was the only risk factor for recurrence on multivariate analysis, more accurate markers are needed for improved treatment allocation to CRSwNP patients.

Efficacy of dupilumab in real-life settings: a STROBE study.

BACKGROUND: Dupilumab, a monoclonal antibody targeting IL-4 and IL-13, has demonstrated its efficacy in several clinical trials. However, to date, real-life data remains limited. OBJECTIVE: The aim of our study was to assess the real-life impact of dupilumab on patients with severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) quality of life. MATERIALS AND METHODS: This was a retrospective, monocentric, observational, real-life study, conducted in accordance with the STROBE guidelines. The following parameters were collected before treatment and at 1, 4, and 12 months: Sino-Nasal Outcome Test-22 (SNOT-22), nasal polyp score (NPS), Sniffin' Sticks-16 (SST-16), visual analog scale (VAS) for loss of smell, nasal congestion score (NCS), gustatory VAS, asthma control, oral corticosteroid usage, surgery rates, and occurrence of side effects. RESULTS: The study included 47 patients. SNOT-22 scores decreased from 52.4 ± 24.3 to 12.7 ± 10.5 at 12 months (p < 0.001). NPS decreased from 6.15 ± 1.71 to 1.57 ± 1.40 at 12 months (p < 0.001). SST-16 scores increased from 1.6 ± 2.83 to 9.1 ± 5.4 at 12 months (p < 0.001). NCS decreased from 2.45 ± 0.72 to 0.38 ± 0.63 at 12 months (p < 0.001). Prior to treatment, 72.3% were using oral corticosteroids, compared to 17.0% at 12 months (p < 0.01). Two patients required additional surgery, and 17% reported completely uncontrolled asthma, compared to 0% at 12 months (p < 0.01). CONCLUSION: Our real-life results confirm the efficacy of Dupilumab in the treatment of severe and uncontrolled CRSwNP.

Chronic rhinosinusitis with nasal polyposis and biological agents: the ARIA-ITALY Survey.

Summary: Background. Chronic rhinosinusitis (CRS) is an inflammatory disease that affects the nasal mucosa and the paranasal sinuses. CRS can be associated by nasal polyposis (CRSwNP phenotype) in up to 30% of patients and it is frequently associated with bronchial asthma. CRSwNP shows predominantly an underlying activation of type 2 inflammatory pathways with the involvement of eosinophils, IgE, interleukin (IL)-4, IL-5 and IL-13. Biological drugs that target these inflammatory cytokines are currently a therapeutic option recognized by guidelines for the treatment of uncontrolled form of the disease. Methods. As part of the activity of the "ARIA-Italy" working group, a panel of 255 Italian Ear, Nose and Throat (ENT) specialists, pneumologists and immuno-allergologists actively participated in this national survey and answered a series of questions geared toward understanding the main criteria for patient characterization and therapeutic decision, highlighting multidisciplinarity, and the implementation of the management of CRSwNP patients, as a part of the precision medicine concept and the appropriate use of the biologicals. Results. Two hundred and fifty-five experts and specialists participated in the survey. Conclusions. The results of this survey obtained from an extensive number of active specialists throughout Italy allow some important concluding remarks to be drawn. The main points of agreement were that multidisciplinary care teams provide many benefits but that, once the team is established, meetings and communication between members must be coordinated. Finally, the dissemination of national disease registries and the continuous updating of guidelines and position papers related to CRSwNP and comorbidities should be encouraged.

The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis.

These evidence-based guidelines support patients, clinicians, and other stakeholders in decisions about the use of intranasal corticosteroids (INCS), biologics, and aspirin therapy after desensitization (ATAD) for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). It is important to note that the current evidence on surgery for CRSwNP was not assessed for this guideline nor were management options other than INCS, biologics, and ATAD. The Allergy-Immunology Joint Task Force on Practice Parameters formed a multidisciplinary guideline panel balanced to include the views of multiple stakeholders and to minimize potential biases. Systematic reviews for each management option informed the guideline. The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation approach to inform and develop recommendations. The guideline panel reached consensus on the following statements: (1) In people with CRSwNP, the guideline panel suggests INCS rather than no INCS (conditional recommendation, low certainty of evidence). (2) In people with CRSwNP, the guideline panel suggests biologics rather than no biologics (conditional recommendation, moderate certainty of evidence). (3) In people with aspirin (nonsteroidal anti-inflammatory drug)-exacerbated respiratory disease, the guideline panel suggests ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). The conditions for each recommendation are discussed in the guideline.

IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis.

BACKGROUND: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described. OBJECTIVE: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS. METHODS: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls. RESULTS: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures. CONCLUSIONS: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Type 2 inflammation drives an airway basal stem cell program through insulin receptor substrate signaling.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. OBJECTIVE: We sought to determine the role of T2 cytokines in regulating airway BCs. METHODS: Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. RESULTS: Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP. CONCLUSIONS: These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.

The Effectiveness of Biological Agents on Chronic Rhinosinusitis with Nasal Polyposis in Patients with Comorbid Asthma: A Multicenter Real-Life Study from Türkiye.

Background and Objectives: Real-life data on the efficacy of biologic agents (BAs) on asthma-comorbid CRSwNP are needed. Our primary goal is to investigate the effects of BAs on CRSwNP symptoms, as well as endoscopic and tomography scores. Our secondary goal is to show a reduction in the frequency of acute sinusitis exacerbations and the need for surgery. Materials and Methods: We conducted a multicenter, retrospective, real-life study. We screened the patients with asthma-comorbid CRSwNP treated with omalizumab or mepolizumab. A total of 69 patients (40 F/29 M; omalizumab n = 55, mepolizumab n = 14) were enrolled. We compared the visual analog scale (VAS), sinonasal outcome test-22 (SNOT-22), nasal congestion score (NCS), Lund-Mackay computed tomography score (LMS), and total endoscopic polyp scores (TPS) before and after BAs. We evaluated the endoscopic sinus surgery (ESS) and acute exacerbations of chronic rhinosinusitis (AECRS) frequencies separately, according to the BAs. Results: The overall median (min-max) age was 43 (21-69) years. The median (min-max) of biologic therapy duration was 35 (4-113) months for omalizumab and 13.5 (6-32) for mepolizumab. Significant improvements were seen in VAS, SNOT-22, and NCS with omalizumab and mepolizumab. A significant decrease was observed in TPS with omalizumab [95% CI: 0-4] (p < 0.001), but not with mepolizumab [95% CI: -0.5-2] (p = 0.335). The frequency of ESS and AECRS were significantly reduced with omalizumab [95% CI: 2-3] (p < 0.001) and [95% CI: 2-5] (p < 0.001); and mepolizumab [95% CI: 0-2] (p = 0.002) and [95% CI: 2-8.5] (p < 0.001), respectively. There was no significant difference in LMS with either of the BAs. Conclusions: Omalizumab and mepolizumab can provide a significant improvement in the sinonasal symptom scores. BAs are promising agents for CRSwNP patients with frequent exacerbations and multiple surgeries.

Heterogeneity of asthma with nasal polyposis phenotypes: A cluster analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) affects a significant number of asthmatic patients and is notably associated with a more difficult-to-control asthma and marked inflammation. We need more studies on this specific asthma phenotype and its possible subphenotypes, in order to better individualize treatments. AIM: The aim of this study is to identify and characterize subphenotypes of asthma patients with CRSwNP using clinical, physiological and inflammatory variables. METHODS: K-means cluster analysis was performed on 17 clinical, physiological, and inflammatory variables from 1263 patients of all asthma severity and on a subpopulation of patients with asthma and CRSwNP. Study was registered on ClinicalTrials.gov (NCT03694847). RESULTS: On the overall population, three groups were identified. Cluster T1 (n = 708) are young, have a short asthma duration and a low prevalence of CRSwNP. Cluster T2 (n = 263) have the longest asthma duration and Cluster T3 (n = 292) are older with the shortest asthma duration. Patients in Clusters T2 and T3 have similar prevalences of CRSwNP. On the subpopulation of asthma with CRSwNP, three clusters were also identified. Cluster S1 (n = 83) have mild-to-moderate asthma with normal lung function. Clusters S2 (N = 53) and S3 (N = 42) include patients with severe asthma and decreased lung function, but those in Cluster S2 have a longer asthma duration, whereas those Cluster S3 have late-onset asthma. CONCLUSIONS: Despite coexistence of asthma and CRSwNP, not all patients have the same evolution of their asthma. Different phenotypes of asthma with CRSwNP can be identified and exploration of the characteristics of these subgroups could lead to a better individualized, targeted management.

Implications of CD45RA and CD45RO T cell subsets in patients of chronic rhinosinusitis with nasal polyposis infected with Aspergillus flavus.

T cell subsets (CD4 and CD8) play a prominent role in the development of chronic rhinosinusitis with nasal polyposis (CRSwNP). Colonization with Aspergillus flavus is recognized as a trigger for the growth of nasal polyps. The fungal proteins initiate the recruitment of T cells into the nasal mucosa, which contributes to the progression of nasal polyps. The study included 50 cases of CRSwNP and 50 healthy controls. Biopsies were subjected to KOH and culture for mycological investigation. We examined the changes in T helper (CD4+) and T cytotoxic (CD8+) in total T cells (CD3+) and expression of naive (CD45RA) and memory (CD45RO) cell markers in T cell subsets in peripheral blood mononuclear cells (PBMCs) challenged by A. flavus antigens in cases before and after treatment and in healthy controls by flow cytometry. Predominantly, A. flavus (86%) identified in nasal polyp biopsies of patients. An increased percentage of CD3+CD4+ T cells observed after A. flavus stimulation in patients when compared with healthy controls. The expression of CD4+CD45RA+ cells was significantly (P < .05) reduced in patients and increased CD4+CD45RO+ was observed upon stimulation with A. flavus in patients when compared with healthy control. Continuous exposure to inhaled fungal spores may induce aberrant immune responses to A. flavus spores, causing an allergic immunological reaction with high CD4+T cell responses, resulting in an unfavourable outcome. Elevated CD4+CD45RO+ T cells may transform the pathogenic response and highlight the chances of A. flavus reactive T cells involvement in prompting inflammation in CRSwNP.

European Academy of Allergy and Clinical Immunology position paper on endoscopic scoring of nasal polyposis.

Nasal endoscopy is not only used for the diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP), but also for monitoring the response to therapy playing an important role in both daily practice and research. In contrast to patient-reported outcomes, endoscopic nasal polyp scoring by independent blinded readers is an objective measurement, not influenced by the placebo effect. It is safer and cheaper compared with computed tomography imaging and therefore, better suited for regular assessments of the extent of the disease. Since the early 90s, a variety of endoscopic staging methods have been proposed and used in clinical research, making it hard to compare results from different studies. This paper resulted from a task force with experts in the field of CRSwNP, originated by the Ear, Nose and Throat section of the European Academy of Allergy and Clinical Immunology and aims to provide a unified endoscopic NP scoring system that can serve as a reference standard for researchers, but also as a useful tool for practitioners involved in the management of CRSwNP.

Different aspects of severe asthma in real life: Role of Staphylococcus aureus enterotoxins and correlation to comorbidities and disease severity.

BACKGROUND: Asthma, with several phenotypes and endotypes, is considered particularly suited for precision medicine. The identification of different non-invasive biomarkers may facilitate diagnosis and treatment. Recently, Staphylococcus aureus and its enterotoxins (SE) have been found to have a role in inducing persistent type 2 airway inflammation in severe asthma, but also in such comorbidities as chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: The aim of this retrospective study was to evaluate the prevalence of SE-IgE sensitization in a multicentric Italian cohort of severe asthmatic patients and correlate it with demographic and clinical characteristics. RESULTS: A total of 249 patients were included in the analysis, out of which 25.3% were staphylococcal enterotoxin B (SEB)-IgE positive. We found a meaningful association between SEB-IgE and female gender, a positive association was also measured between CRS and CRSwNP. No significant association was found between SEB-IgE sensitization and atopy, the occurrence of exacerbations and corticosteroid dosages. In the SEB-IgE-positive patient, blood eosinophil count does not appear to be correlated with the severity of the disease. Patients with SEB-IgE sensitization are, on average, younger and with an earlier disease onset, thus confirming the possibility to consider SEB-IgE sensitization as an independent risk factor for developing asthma. CONCLUSIONS: Our data confirm that the search for SE in the initial screening phase of these patients is helpful to better phenotype them, may predict the evolution of comorbidities and lead to a targeted therapeutic choice; in this point of view this represents a goal of precision medicine.

Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis.

BACKGROUND: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. OBJECTIVES: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. METHODS: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. RESULTS: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p < .01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. CONCLUSION: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

The importance of follow-up examinations in chronic rhinosinusitis with nasal polyposis.

PURPOSE: Clinical examinations following functional endoscopic sinus surgery (FESS) for chronic rhinosinusitis with nasal polyps (CRSwNP) are critical for physicians to assess results of the intervention and to early identify recurrences. However, no clear consensus on the frequency and timing of clinical examinations following surgery exists. The aim of this study was to analyze CRSwNP recurrences after FESS with a specific focus on the adherence to follow-up examinations. MATERIALS AND METHODS: Sixty patients who underwent FESS for CRSwNP were enrolled. Clinical parameters were recorded. Adherence to follow-up examinations with nasal fiber optic endoscopy and regular administration of nasal steroids were analyzed. RESULTS: Adherence to periodic clinical examinations and regular treatment with nasal steroids was 25 %. CRSwNP recurrence was observed in 56.7 % of cases at the last follow-up examination. No statistically significant difference concerning nasal symptoms was observed between patients with and without current recurrence (p > 0.05). Subjects who underwent regular examinations and prompt treatment of small recurrences had a lower probability of relapse at their last examination (7.7 % versus 38.2 %, respectively; p < 0.001). Polyp grade > 2 in patients with or without adherence were seen in 15.4 % and 42.9 % of cases, respectively (p < 0.05). CONCLUSIONS: Adherence to follow-up examinations with nasal optic fiber endoscopy is crucial to early identify recurrence after surgery and promptly treat it with medical therapy.

The role of intranasal corticosteroids in chronic rhinosinusitis with nasal polyposis treated with dupilumab.

PURPOSE: Dupilumab represents an innovative and effective therapy for refractory/recurrent severe chronic rhinosinusitis with nasal polyps (CRSwNP). Intranasal corticosteroids should be used during treatment with biological agents. However, adherence to nasal therapy may not be complete. The aim of this study was to evaluate the role of intranasal corticosteroids in patients with CRSwNP who underwent treatment with dupilumab. MATERIALS AND METHODS: Fifty-two patients treated with dupilumab for CRSwNP were enrolled. Clinical parameters (age, sex, comorbidities, blood eosinophils, Nasal Polyp Score - NPS, Visual Analogue Scale - VAS - for smell loss, Asthma Control Test - ACT), quality of life (Sino Nasal Outcome Test 22 - SNOT-22 questionnaire), nasal cytology, and adherence to regular administration of intranasal corticosteroids were recorded before treatment (T0), and after 3 (T1), 6 (T2), and 12 months (T3). RESULTS: NPS, VAS for smell, ACT and SNOT-22 total score and subscores improved during treatment (p < 0.05). Blood eosinophils reached a peak at T1-T2 and then decreased toward baseline at T3. Adherence to regular treatment with intranasal steroids was 61.5 %. No statistically significant differences in all the clinical outcomes were observed between patients who regularly used intranasal steroids and other subjects (p > 0.05). Nasal cytology showed a decrease of eosinophils and an increase of neutrophils during treatment. CONCLUSIONS: Dupilumab is still effective in patients who are using topical nasal steroids with variable adherence (real world settings).