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.