Comparative real-world outcomes of dupilumab versus endoscopic sinus surgery in the treatment of severe CRSwNP patients.

INTRODUCTION: Management of severe chronic rhinosinusitis with nasal polyps (CRSwNP) has changed significantly in recent years, with different treatments now available including biologics and endoscopic sinus surgery (ESS), although there are still few comparative studies. We aimed to compare 1-year outcomes of patients with severe CRSwNP treated with dupilumab or ESS plus intranasal corticosteroids (INCS). METHODS: In this retrospective, real-life, observational, cohort study, we enrolled 101 patients with severe CRSwNP who were treated with INCS and either ESS (n = 49) or dupilumab (n = 52). The following outcomes were considered: nasal polyp score (NPS), Sino Nasal Outcome Test-22 (SNOT-22), visual analogue scale (VAS) for specific symptoms, Sniffin' Sticks identification test (SSIT), need for oral corticosteroids (OCS) and local eosinophilia detected by nasal cytology. RESULTS: ΔNPS was significantly higher in the surgery group up to 12 months when the difference with dupilumab group was no longer significant (ΔNPS: 4 vs. 4.1). ΔVAS rhinorrhoea, ΔVAS smell and ΔSNOT-22 were significantly higher in the dupilumab group at 12 months (p < .05). SSIT scores were significantly better in the dupilumab group starting from the first month of follow-up (p < .05). In the dupilumab group, only 6.1% of patients had detectable local eosinophilia compared to 57% in the surgery group alongside with a lower need for OCS (16.3% vs. 61%). CONCLUSIONS: Both dupilumab and ESS were effective in improving outcomes in patients with severe CRSwNP over 12 months. Nevertheless, patients treated with dupilumab had greater improvement in terms of SNOT-22, VAS rhinorrhoea, VAS smell and SSIT scores, with better control of local inflammation and less need for OCS.

Switching of biological therapy to dupilumab in comorbid patients with severe asthma and CRSwNP.

PURPOSE: Nowadays, several efficacious biologic drugs are used for severe asthma with or without chronic rhinosinusitis with nasal polyps (CRSwNP). However, it has been observed that not all comorbid patients (asthma/CRSwNP) receiving biologic treatment for asthma experience satisfactory control of both conditions equally. METHODS: We selected 20 patients who had both severe asthma and comorbid CRSwNP under biological treatment with benralizumab, omalizumab or mepolizumab with adequate control of asthma but inadequate control of nasal symptoms. Patients were switched to dupilumab and outcomes were evaluated at baseline (T0), at 3 months (T1), at 6 months (T2), at 12 months (T3) and finally at 18 months (T4). Data were collected at each time point including blood tests measuring eosinophil levels and total IgE, SNOT22, ACT, NPS score, rhinomanometry, olfactory testing, and nasal cytology. RESULTS: The results showed an overall improvement in all the outcomes. Peripheral eosinophilia was observed consistently with existing literature. All patients registered an improvement in sinonasal outcomes, while only one patient had a worsening of asthma. Three patients interrupted the therapy due to various causes: poor asthma control, onset of psoriasis and thrombocytopenia. CONCLUSIONS: The response to a biologic treatment for CRSwNP control may be heterogenous and it seems that patients may benefit from switching improving control in equal measure in the upper and lower airway. Further studies to explore the endotype/phenotype which best fits with each biologic are mandatory to personalize the therapy.

Temporal trends of blood eosinophilia in severe uncontrolled CRSwNP treated with dupilumab: a real-life study.

PURPOSE: Induced eosinophilia is commonly related to dupilumab treatment. We analysed the temporal trends of blood eosinophilia in patients with severe uncontrolled CRSwNP during the first year of treatment with dupilumab in real-life setting to evaluate its correlation with outcomes of response and adverse events (AEs). METHODS: Seventy-four patients with severe uncontrolled CRSwNP treated with dupilumab at our institution were enrolled. At each visit, we evaluated AEC, outcomes of response to treatment and AEs. RESULTS: A significant increase in AEC was observed since the first month with a peak at 3 months; at 12 months, the values returned comparable to those at baseline. A ≥ 50% increase of the baseline AEC with a value greater than 500 cells/mm3 was documented in 38/74 patients (Group A) regardless of the time of observation, whereas in 36/74 patients (Group B), no changes were observed. Analysing the blood eosinophilia trend over time in group A, we observed a temporary eosinophilia with early onset (within 6 months), persistent eosinophilia with early onset, and eosinophilia with late onset. No differences in terms of outcomes of response to treatment or AEs were found between Group A and Group B, or between patients who developed an AEC ≥ 1500 cells/mm3 or not. CONCLUSION: In our series, we observed that an increase in AEC with different temporal trends may be observed in CRSwNP patients during the first year of treatment with dupilumab. In our series, eosinophilia is not correlated with a negative outcome of response to treatment or a risk of AEs.

How to manage recurrences after surgery in CRSwNP patients in the biologic era: a narrative review.

Objective: This narrative review analyses factors affecting recurrence of Chronic rhinosinusitis with nasal polyps (CRSwNP) after surgery, such as type, extension and completeness of endoscopic sinus surgery (ESS). We also described new implications in the management of recurrences after the advent of biologics. Methods: We identified four topics: definition of disease state; factors linked to recurrence of polyps; evaluation and management of recurrence in clinical practice. Results: We analysed the differences between exacerbation and recurrence, as well as the concept of "controlled disease". We focused on potential predictors of recurrence after ESS, such as type 2 inflammation, asthma, aspirin-exacerbated respiratory disease, incomplete initial surgery and lack of adherence to long-term post-operative local corticosteroids. We discussed the new aspects of diagnosis and treatment of recurrences after surgery, summarising our suggestions in a detailed algorithm for practical management of patients with recurrent disease. Conclusions: The results emphasised the importance of accurate evaluation of patients with CRSwNP recurrence, focusing on the reasons of failure and risk of disease progression, in order to guide personalised interventions. It is crucial to define the concept of appropriate surgery, which affects the choice between starting a biologic or repeating surgery.

Evaluation of switching or simultaneous use of biologic treatment in patients with severe chronic rhinosinusitis with nasal polyps and severe asthma. Considerations in clinical decision making.

INTRODUCTION: Type 2 targeting biologics have reached the market first for asthma and since 2019 also for CRSwNP. As clear guidelines and predictors for optimal biological choice are missing, patients are sometimes required to switch biologic therapy in order to find the optimal treatment result. In this paper, we evaluate reasons for switching biologics and the treatment effects after each sequential switch. MATERIALS AND METHODS: Ninety-four patients who switched from one biologic to another for their treatment of CRSwNP and asthma were evaluated. RESULTS: Twenty patients experienced satisfactory control of CRSwNP, but insufficient control of severe asthma. Fifty-one patients experienced satisfactory control of severe asthma, but insufficient control of CRSwNP/EOM. Twenty-eight patients experienced insufficient control of both upper and lower airways. Thirteen patients had to switch because of side effects. Furthermore, two cases are described to clarify clinical decision-making. DISCUSSION: For abovementioned patients, a multidisciplinary approach is mandatory to find the best suitable biologic. It seems ineffective to switch to a second anti-IL5 treatment if the first one is not successful. Most patients that failed omalizumab and/or an anti-IL-5 treatment are well controlled on dupilumab. Therefore, we suggest to use dupilumab as first choice when switching biologic agents.

Dupilumab in the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP): A multicentric observational Phase IV real-life study (DUPIREAL).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with significant morbidity and reduced health-related quality of life. Findings from clinical trials have demonstrated the effectiveness of dupilumab in CRSwNP, although real-world evidence is still limited. METHODS: This Phase IV real-life, observational, multicenter study assessed the effectiveness and safety of dupilumab in patients with severe uncontrolled CRSwNP (n = 648) over the first year of treatment. We collected data at baseline and after 1, 3, 6, 9, and 12 months of follow-up. We focused on nasal polyps score (NPS), symptoms, and olfactory function. We stratified outcomes by comorbidities, previous surgery, and adherence to intranasal corticosteroids, and examined the success rates based on current guidelines, as well as potential predictors of response at each timepoint. RESULTS: We observed a significant decrease in NPS from a median value of 6 (IQR 5-6) at baseline to 1.0 (IQR 0.0-2.0) at 12 months (p < .001), and a significant decrease in Sino-Nasal Outcomes Test-22 (SNOT-22) from a median score of 58 (IQR 49-70) at baseline to 11 (IQR 6-21; p < .001) at 12 months. Sniffin' Sticks scores showed a significant increase over 12 months (p < .001) compared to baseline. The results were unaffected by concomitant diseases, number of previous surgeries, and adherence to topical steroids, except for minor differences in rapidity of action. An excellent-moderate response was observed in 96.9% of patients at 12 months based on EPOS 2020 criteria. CONCLUSIONS: Our findings from this large-scale real-life study support the effectiveness of dupilumab as an add-on therapy in patients with severe uncontrolled CRSwNP in reducing polyp size and improving the quality of life, severity of symptoms, nasal congestion, and smell.

Measuring Nasal Patency and the Sense of Smell in CRSwNP Patients Treated with Dupilumab.

Chronic rhinosinusitis with nasal polyps (CRSwNP) in the most severe forms is associated with a poor quality of life. Dupilumab has been suggested as an add-on treatment option for severe CRSwNP. Severe CRSwNP patients treated with dupilumab in different rhinological units were followed up at 1, 3, 6 and 12 months from the first administration and were considered for this study. At baseline (T0) and at each follow-up, patients underwent nasal endoscopy and completed the sinonasal outcome test (SNOT)-22, a visual analogue scale (VAS) for smell/nasal obstruction, peak nasal inspiratory flow (PNIF) and the Sniffin' Sticks identification test (SSIT). The aim of the present study was to evaluate the effects of dupilumab in patients with severe uncontrolled CRSwNP on recovering nasal obstruction and smell impairment. Moreover, the method between PNIF and SSIT with the highest correlation with patients' response to dupilumab was evaluated. One hundred forty-seven patients were included. All parameters improved during treatment (p < 0.001). At T0, no correlations were found between PNIF and nasal symptoms. Nevertheless, during the following evaluations significant correlations between PNIF changes and both nasal symptoms and NPS were observed (p < 0.05). At T0, SSIT did not correlate with SNOT-22. Similarly to PNIF, during the follow-up SSIT changes significantly correlated with nasal symptom and NPS (p < 0.05). Comparing PNIF and SSIT correlations with SNOT-22 and NPS, PNIF showed a higher correlation with both. Dupilumab improves nasal obstruction and the sense of smell. PNIF and SSIT are effective tools in monitoring patients' response to dupilumab.

Is There Any Reliable Predictor of Functional Recovery Following Post-thyroidectomy Vocal Fold Paralysis?

BACKGROUND: Predicting definitive outcomes of post-thyroidectomy vocal fold paralysis (VFP) is challenging. We aimed to identify reliable predictors based on intraoperative neuromonitoring (IONM) and flexible fiberoptic laryngostroboscopy (FFL) findings. METHODS: Among 1172 thyroid operations performed from April to December 2021, all patients who exhibited vocal fold paralysis (VFP) at post-operative laryngoscopy were included. IONM data, including type of loss of signal (LOS), were collected. Patients underwent FFL, with arytenoid motility assessment, at 15, 45 and 120 days post-operatively. Patients were divided into two groups: those who recovered vocal fold motility (VFM) by the 120th post-operative day (recovery group) and those who did not (non-recovery group). RESULTS: Fifty-nine VFP cases (5.0% of total patients) met the inclusion criteria. Eight patients were lost at follow-up and were excluded. Overall, 9 patients were included in the non-recovery group (0.8% of total patients) and 42 in the recovery group. Among various predictive factors, only arytenoid fixation (AF) at the 15th post-operative day and Type I LOS were significant predictors for no VFM recovery (p = 0.007, RR = 9.739, CI:1.3-72.3 and p = 0.001, RR = 9.25, CI:2.2-39.3 for AF and Type I injury, respectively). The combination of type of LOS and arytenoid motility at the 15th post-op day yielded satisfactory predictive values for the progression of transient VFP to permanent. CONCLUSIONS: Arytenoid motility at the 15th post-op day and type II LOS are associated with recovery of VFM. Type of LOS and FFL could be included in the follow-up protocols of patients with VFP to reliably predict clinical outcomes.

Real-Life Experience in the Management of Sinonasal Complications of Dental Disease or Treatments.

Diagnosis and management of sinonasal complications of dental diseases or treatment (SCDDT) may be challenging. We aimed to report our real-life experience in patients treated with endoscopic endonasal approach describing data about symptoms, etiology, extension of the disease and success rate. We evaluated retrospectively data about 262 patients diagnosed as SCDDT and managed from August 2015 to May 2022. In 44.65% cases, maxillary sinus complications were determined by a dental disorder; the remaining 55.34% of cases were iatrogenic. Patients were managed according to our multidisciplinary protocol including ENT, dental, and radiological evaluation. Treatments were planned with a personalized approach, based on the patient's clinical characteristics; all patients were treated with an endonasal endoscopic mini-invasive conservative approach. Combined dental treatment was performed simultaneously in 152/262 (58%) of patients; in the remaining cases, it was postponed after surgery. The overall treatment success rate (symptom resolution and endoscopically observed maxillary sinus healing) was 96.5%. At 15 days after surgery, we observed a significant improvement in the quality of life. The mean post-operative Sinonasal outcome test-22 (SNOT-22) score was significantly lower compared to baseline (6 versus 43.4; p < 0.05). Our study showed that endoscopic sinus surgery can be a successful procedure for treatment of SCDDT, leading to fast resolution of sinonasal symptoms and improving the quality of life. Furthermore, the technique allows removal of migrated dental material or dental implants even in challenging cases.

Proposal for a Structured Outpatient Clinic for Dupilumab Treatment in Chronic Rhinosinusitis with Nasal Polyps in the First Year of Treatment.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common disease of the nose and paranasal sinuses with important economic and sanitary burdens, as well as having a great impact on patients' quality of life. In this field, a new therapeutic approach for those patients who have been described as affected by severe uncontrolled CRSwNP, resistant to medical and best surgical treatment, is represented by subcutaneous human monoclonal antibodies (including dupilumab) that block specific targets involved in the type 2 inflammatory pathway which most commonly drives CRSwNP pathophysiology. This paper aims to report our experience in the management of severe uncontrolled CRSwNP and, in particular, describe our diagnostic workup including baseline evaluation and follow-up visits in the first year of treatment. We also describe into detail our multidisciplinary approach to the disease. We finally report the outcomes of treatment in a real-life setting. In this outpatient real-life setting, our results confirmed the effectiveness of dupilumab in reducing the volume of nasal polyps and restoring nasal obstruction and sense of smell, as well as improving patients' quality of life. The adherence to the dupilumab treatment was very high. The dose of administration was never modified in patients in the first year of treatment. All the patients respected the plan of the visits at proposed time points. We believe that the structural organization of our outpatient clinic appears to be functional: it allows us to study patients thoroughly before starting treatment and to make a proper follow-up after it starts. We believe that sharing both our strict clinical flowchart and growing experience with dupilumab with the medical community can lead to more standardized and effective pathways of care for CRSwNP patients.

Sinonasal Biomarkers Defining Type 2-High and Type 2-Low Inflammation in Chronic Rhinosinusitis with Nasal Polyps.

The complex pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) generates a spectrum of phenotypes with a wide variety of inflammatory states. We enrolled 44 very-likely-to-be type 2 CRSwNP patients in order to evaluate the load of inflammation and to analyze human interleukins in nasal secretion. Clinical data were collected to evaluate the severity of the disease. High levels of IL-5, IL-4, IL-6, and IL-33 were detected in all type 2 CRSwNP patients. By analyzing type 2 cytokine profiles and local eosinophil count, we identified two coherent clusters: the first was characterized by high levels of IL-4, IL-5, IL-6, and a high-grade eosinophil count (type 2-high); the second had lower levels of cytokines and poor or absent eosinophilic inflammation (type-2 low). IL-5 levels were significantly higher within the type 2 cytokine and it was the most reliable biomarker for differentiating the two clusters. In type 2-high inflammatory profile clinical scores, the mean number of previous surgeries and need for systemic corticosteroids were significantly higher compared to type 2-low. Our research demonstrated the potential role of type 2 biomarkers, and in particular, of IL-5 in identifying patients with a more severe phenotype based on a high inflammatory load.

Mepolizumab Improves Outcomes of Chronic Rhinosinusitis with Nasal Polyps in Severe Asthmatic Patients: A Multicentric Real-Life Study.

Objective: The upcoming introduction of mepolizumab represents a promising treatment for chronic rhinosinusitis with nasal polyps (CRSwNP). The present study aimed to evaluate the effectiveness of mepolizumab on sinonasal outcomes of comorbid CRSwNP and severe asthma in a real-life setting. The primary endpoint was to evaluate changes in the SinoNasal Outcome Test (SNOT)-22 score, Nasal Polyp (NP) score, and blood eosinophil count during a 12-month treatment with mepolizumab. Secondary endpoints were to quantify mepolizumab's effects on the mentioned parameters, identify clinical variables influencing the degree of response to treatment, and portray responder and nonresponder patients. Methods: A multicentric retrospective no-profit observational study on severe asthmatic patients, treated with mepolizumab, and comorbid CRSwNP was conducted. All patients were followed for at least 12 months. SNOT-22 score, NP score, and blood eosinophil count (and other CRS-specific variables) were collected at baseline and after 12 months. Results: Forty-three patients were included. A statistically significant reduction was observed for SNOT-22 score (mean t0 SNOT-22 54.8 ± 25.9; mean t12 SNOT-22 31.5 ± 21.3, p < 0.0001), NP score (median t0 NPS 3 (IQR 3); median t12 NPS 2 (IQR 4), p < 0.0001), and blood eosinophil count (mean t0 blood eosinophils 804.7 ± 461.5 cell/µL; mean t12 blood eosinophils 107.5 ± 104.6 cell/µL, p < 0.0001) after 12 months of treatment. Twenty patients (47%) gained improvement both in clinical and endoscopic outcome. Mepolizumab responder patients presented a t0 SNOT-22 significantly higher than nonresponders (p = 0.0011). Conclusions: Mepolizumab improved CRSwNP outcomes in a population of severe asthmatic patients. No clinical feature emerged to outline the profile of a "typical" responder patient, except for baseline SNOT-22 score, which seemed to affect the response to treatment. Further studies would be necessary to supplement these preliminary evaluations.

Effectiveness of Dupilumab in the Treatment of Patients with Severe Uncontrolled CRSwNP: A "Real-Life" Observational Study in the First Year of Treatment.

The aim of this study was to evaluate the efficacy of dupilumab in the treatment of severe uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), with or without asthma as add-on therapy with intra-nasal corticosteroids in a real-life setting over the first year of treatment. Our data demonstrated that subcutaneous 300 mg dupilumab administered at home via a pre-filled auto-injector every two weeks, based on indications set by the Italian Medicines Agency, was rapidly effective in reducing the size of polyps, decreasing symptoms of disease, improving quality of life, and recovering olfaction. Significant improvement was observed after only 15 days of treatment, and it progressively increased at 6 and 12 months. Dupilumab was also effective in reducing the local nasal eosinophilic infiltrate, in decreasing the need for surgery and/or oral corticosteroids, and in improving control of associated comorbidities such as chronic eosinophilic otitis media and bronchial asthma. After 12 months of treatment, 96.5% of patients had a moderate/excellent response. From our data, it was evident that there was a group of patients that showed a very early response within one month of therapy, another group with early response within six months from baseline, and a last group that improved later within 12 months. The results of this study support the use of dupilumab as an effective option in the current standard of care for patients affected by severe uncontrolled CRSwNP.

Efficacy of Biologics on Refractory Eosinophilic Otitis Media Associated with Bronchial Asthma or Severe Uncontrolled CRSwNP.

Eosinophilic otitis media (EOM) is a difficult-to-treat otitis media characterized by eosinophilic accumulation in the middle ear mucosa and effusion. It is resistant to conventional treatments and strongly associated with asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of our study is to evaluate the effectiveness of biologics drugs in the control of EOM. This is a retrospective no-profit real-life observational study, involving patients affected by refractory EOM and in treatment with different biologics for concomitant severe eosinophilic asthma or severe uncontrolled CRSwNP (Dupilumab: n = 5; Omalizumab: n = 1; Mepolizumab: n = 1; Benralizumab: n = 1). We analyzed data at baseline and at the 6-month follow-up, including specific nasal and otological parameters. We observed an improvement of all nasal outcomes, including NPS, SNOT-22, VAS, and smell function. Regarding specific otological parameters, we observed a significant reduction in the mean value of COMOT-15 score and of Otitis Severity Score at 6-month follow-up compared to baseline (p < 0.05). Finally, we observed an improvement in terms of air conduction hearing levels during the treatment. Our results demonstrated that anti type-2 inflammatory pathway biologics can be effective in improving symptoms control and in reducing the severity of eosinophilic otitis media when treating coexisting type-2 diseases, such as asthma and or CRSwNP.