Multidisciplinary Decision-Making-ITAlian Consensus After Two Years of Real Practice on the Management of Severe Uncontrolled CRSwNP by Biologics (ITACA Study).

PURPOSE OF REVIEW: We aimed to reach an Italian multidisciplinary consensus on some crucial aspects of treatment decision making in CRSwNP, following 2 years of clinical experience in order to support specialists in the management of CRSwNP in clinical practice. We addressed issues relating to therapeutic decision-making and shared criteria for the treatment choice, as well as appropriate timing and criteria for evaluating treatment response, and highlighted the need for repeated multidisciplinary assessments. RECENT FINDINGS: A national survey has been conducted recently to understand how rhinology practice has changed in Italy with the advent of biologics and how this affects patients with uncontrolled, severe CRSwNP. Despite the many published consensus documents, practical recommendations, and protocols on the use of biologics in CRSwNP, heterogenous behaviors in practice are still observed mainly conditioned by the novelty of the topic. The consensus procedure followed a modified Delphi approach. The scientific board included 18 otorhinolaryngologists and 8 allergists, who selected the 4 main topics to be addressed and developed overall 20 statements. Consensus on these statements was sought by a larger group of 48 additional experts, through two rounds of voting, the first web-based, the second in presence with discussion and possible refinement of the statements. The statements reaching an average score ≥ 7 at the second voting round were approved. Five statements were proposed for each of the following topics: baseline evaluation of patients eligible for biologic therapy; choice between different therapeutic options; assessment of the response to biologic treatment; multidisciplinary management. At the first voting round, 19 out of the 20 statements reached a mean score ≥ 7. Following the discussion and a few consequent amendments, at the second round of voting all the 20 statements were approved.

Endoscopic approaches to the orbit: Transnasal and transorbital, a retrospective case series.

Introduction: Orbital pathologies requiring surgery are traditionally treated by open approach with different techniques depending on the lesion location. Recently, minimally invasive endoscopic approaches, such as the Endoscopic Endonasal Approach (EEA) and the Endoscopic Transorbital Approach (ETA) have been introduced in orbital surgery. Research question: The purpose of this study is to report the combined experience of the Neurosurgical and Ear-Nose-Throat (ENT) Units in the endoscopic approach of orbital pathologies. Material and methods: We retrospectively retrieved data on patients treated at our Institution between 2016 and 2021 with endoscopic approach for orbital pathologies. The Clavien-Dindo classification and the Scar Cosmesis Assessment and Rating (SCAR) Scale have been used to assess complications and cosmetic outcomes. Results: 39 patients met the inclusion criteria. EEA (15 patients) or ETA (20 patients) were chosen to approach the lesions. In three cases we used a combination of endoscopic and anterior orbitotomy and in one patient a combination of EEA + ETA. The type of procedure performed was orbital biopsy (9 cases), orbital decompression (6 cases), subtotal resection of the lesion (STR) (8 cases) and total resection of the lesion (GTR) (16 cases). The more frequent postoperative complications were diplopia (5.1%, with 1 case of permanent diplopia), trigeminal paraesthesia and dysesthesia (5.1%), palpebral edema (17.9%), periorbital ecchymosis (7.7%). Mean follow up time was 21 months (range 2-63 months). Discussion and conclusion: Endoscopic approaches to orbital compartments provide minimally invasive access to every orbital compartment with low complications rate and good cosmetic outcome.

Chronic Rhinosinusitis with Nasal Polyps: A Survey on Routine Management and Evaluation of Disease Control in Practice.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease with a significant impact on quality of life. The overall goal of CRSwNP management, as with other chronic conditions, is to achieve "disease control", and for that reason, a definition of control of disease is pivotal in deciding the best treatment strategy. Although many staging systems have already been developed to evaluate the disease, disease control is not yet to be standardized, and a specific tool that is consistently applied and accepted by all practitioners is still missing in daily clinical practice. To gain an overview of the implementation and limitations of existing guidelines and to shed light on real-life definitions of control and disease severity, we conducted a nationwide survey of otorhinolaryngologists routinely treating CRSwNP to identify unmet clinical needs in Italy. The results showed homogeneous responses regarding the knowledge contained in international guidelines while highlighting the difficulty of their implementation in day-to-day practice. Respondents called attention to the importance of clinical symptoms, giving more weight to the patient's perspective. Among the symptoms to be considered, respondents emphasized nasal obstruction, followed by loss of sense of smell and rhinorrhea. Others also believe that the physician's perspective should be considered, and the inclusion of endoscopy as a measure of control was warranted by many. The need for a specific tool that is able to unequivocally ascertain disease control is increasingly pivotal in this new era of biologics for treating CRSwNP.

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.

Silicone septal splint for recurrent epistaxis in HHT patients: experience of a national referral centre.

Objective: To report our experience in the use of silicone septal splint for recurrent severe epistaxis in hereditary haemorrhagic telangiectasia patients (HHT). Methods: This is a descriptive analysis carried out at the Otorhinolaryngology Department of Fondazione IRCCS Policlinico San Matteo in Pavia, a reference centre for the treatment and diagnosis of HHT. We retrospectively evaluated HHT patients who underwent silicone septal splint positioning after the endoscopic surgical treatment of epistaxis from 2000 to 2022. Results: Of the 506 patients surgically treated in the period of analysis, 74 patients underwent silicone septal splint positioning and 37 were post-operatively interviewed. With a mean of 2.4 previous surgical treatments and a mean epistaxis severity of 7.38, the majority of patients presented with septal perforation (71.6%). On average, patients maintained the splint in place for 54.5 months, with a good tolerability and a significant reduction in epistaxis severity, need for blood transfusion and improvement of haemoglobin levels. Conclusions: In HHT patients with recurrent severe epistaxis and with septal perforation, the placement of septal splints offers a useful additional strategy in the management of nosebleeds.

The role of the osteoplastic flap in the endoscopic era: a retrospective multicentre experience on revision surgery.

Objective: To retrospectively review the experience of five tertiary-care university hospitals on frontal sinus revision surgery with osteoplastic flap (OPF). Methods: Descriptive analysis of patients who underwent frontal sinus surgery with OPF after one or more endoscopic procedures for benign and inflammatory pathologies from 2000 to 2022. Clinical charts were reviewed for demographics, indications, clinical presentation, previous frontal procedures, OPF technique and outcomes. Results: Of the 124 patients who underwent an OPF procedure, 33 met inclusion criteria. With a mean of 2.1 previous endoscopic surgeries, Draf III was the most common former procedure. In 30 (91%) cases OPF was part of a combined procedure. The most common indications were inverted papilloma (61%), mucocele (9%) and chronic rhinosinusitis (6%). Frontal outflow stenosis (36%) and mucocele (9%) were the most frequent complications observed. Improvement of overall symptoms and patient satisfaction after the OPF procedure were recorded. Conclusions: Even in the endoscopic era, OPF still represents a paramount procedure that should be included in the rhino-surgeon's armamentarium, in particular in patients with challenging pathologies and anatomy when previous endoscopic endonasal attempts have failed.

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.

Impact of SARS-CoV-2 infection in patients with hereditary hemorrhagic telangiectasia: epidemiological and clinical data from the comprehensive Italian retrospective multicenter study.

Rare Disease patients manifested high concern regarding the possible increased risk of severe outcomes and worsening of disease-specific clinical manifestation due to the impact of COVID-19. Our aim was to assess the prevalence, outcomes, and impact of COVID-19 in patients with a rare disease such as Hereditary Hemorrhagic Telangiectasia (HHT) in Italian population. A nationwide, multicentric, cross-sectional observational study was conducted on patients with HHT from five Italian HHT centers by online survey. The association between COVID-19-related signs and symptoms and nosebleeds worsening, the impact of personal protective equipment on nosebleeds pattern, and the relationship between the presence of visceral AVMs and severe outcomes were analyzed. Out of 605 total survey responses and eligible for analysis, 107 cases of COVID-19 were reported. A mild-course COVID-19 disease, not requiring hospitalization, was observed in 90.7% of patients, while the remaining eight cases needed hospitalization, two of them requiring intensive-care access. No fatal outcome was recorded and 79.3% of patients reported a complete recovery. No difference in infection risk and outcome between HHT patients and general population was evidenced. No significative interference of COVID-19 on HHT-related bleeding was found. The majority of patients received COVID-19 vaccination, with relevant impact on symptoms and need for hospitalization in case of infection. COVID-19 in HHT patients had an infection profile similar to the general population. COVID-19 course and outcome were independent from any specific HHT-related clinical features. Moreover, COVID-19 and anti-SARS-CoV-2 measures did not seem to affect significantly HHT-related bleeding profile.

Practical recommendations for managing severe chronic rhinosinusitis with nasal polyps in the era of biologics.

Objective: We conducted a national survey to understand how rhinology practice has changed with the advent of biologics and how this affected patients with uncontrolled, severe chronic rhinosinusitis with nasal polyps (CRSwNP). We aimed to analyse the results of the survey and infer practical recommendations for clinical practice. Methods: A group of ear, nose, and throat specialists (ENTs) experienced in the management of CRSwNP developed a 74-question survey. ENTs from rhinology centres authorised to prescribe biologics in the context of the national health system were invited to answer it between 01/05/2022 and 31/07/2022. The responses underwent descriptive analyses, and the authors discussed the results and derived practical recommendations for clinical practice. Results: ENTs working in rhinology centres changed their practices coinciding with the advent of biologics. CRSwNP evaluations have become more complex because they involve diagnostic confirmation, determining the patients' immunologic profile, and other factors. We observed heterogenous behaviours in practice that may be conditioned by the novelty of the topic. The results of the survey were used to develop practical recommendations for ENTs and are summarised herein. Conclusions: Clinical practice in rhinology outpatient clinics has changed profoundly in the era of biologics. Our practical recommendations for clinicians working in rhinology centres are expected to help standardise practice and improve care.

Hereditary hemorrhagic telangiectasia: First demonstration of a founder effect in Italy; the ACVRL1 c.289_294del variant originated in the country of Bergamo 200 years ago.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, affecting 1:5000 individuals worldwide. All the genes associated to the disease (ENG, ACVRL1, SMAD4, GDF2) belong to the TGF-ß/BMPs signaling pathway. We found 19 HHT unrelated families, coming from a Northern Italy region and sharing the ACVRL1 in-frame deletion c.289_294del (p.H97_N98). METHODS: To test the hypothesis of a founder effect, we analyzed 88 subjects from 19 families (66 variant carriers, showing clinical signs of HHT, and 22 non-carriers, unaffected) using eight microsatellite markers within 3.7 Mb around the ACVRL1 locus. After the haplotype reconstruction, age estimation of the variant was carried out. RESULTS: We observed a common disease haplotype in 16/19 families, while three families showed evidence of recombination around the ACVRL1 locus. The subsequent age estimation analyses suggested that the mutation occurred about 8 generations ago, corresponding to about 200 years ago. We also present novel in silico and modeling data supporting the variant pathogenicity: the deletion alters the protein stability and removes the unique extracellular glycosylation site. CONCLUSION: We have demonstrated, for the first time, a "founder effect" for a HHT pathogenic variant in Italy.

Characterization of epidemiological distribution and outcome of COVID-19 in patients with hereditary hemorrhagic telangiectasia: a nationwide retrospective multi-centre study during first wave in Italy.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) continues to have a devastating impact across the world. A number of pre-existing common clinical conditions were reported to represent risk factors for more severe COVID-19 outcomes. Hereditary Hemorrhagic Telangiectasia (HHT) is a rare vascular heritable disorders, characterized by complications secondary to visceral Arterio-Venous Malformations. The impact of HHT, as well as for many Rare Diseases (RDs) on infection susceptibility profile and clinical adverse outcome risk is an unresolved issue. OBJECTIVES: The main objectives were: to assess the clinical features and outcomes of HHT patients infected with COVID-19; to compare the relative infection risk in these patients with the Italian general population throughout the first pandemic wave; to investigate the factors potentially associated with severe COVID-19 outcome in HHT patients, and the possible impact of COVID-19 infection on HHT-related symptoms/complications. Finally, we aimed to estimate how the lockdown-associated wearing of personal protective equipment/individual protection devices could affect HHT-related telangiectasia bleeding frequency. METHODS: The study is a nation-wide questionnaire-based survey, with a multi-Center retrospective cross-sectional design, addressed to the whole Italian HHT population. COVID-19 cases, occurring throughout the first pandemic wave, were collected by a questionnaire-based semi-structured interview. Only the cases ascertained by laboratory confirmation (molecular/serological) were included for epidemiological estimates. Information concerning eventual SarS-Cov-2 infection, as well as regarding HHT-related manifestations and HHT-unrelated co-morbidities were collected by the questionnaire. Prevalence data were compared to Italian general population in the same period. RESULTS: The survey disclosed 9/296 (3.04%) COVID-19 cases, 8/9 of them being resident in Lombardy, the main epidemic epicenter. Pneumonia was reported by 4/9 patients, which prompted hospital admission and intensive care management in 2 cases. No fatal outcome was recorded. After careful refinement of epidemiological analysis, the survey evidenced overlapping infection risk in HHT compared to general population. CONCLUSIONS: COVID-19 infection profile parallels geographical distribution of epidemic foci. COVID-19 in HHT patients can lead to highly variable clinical profile, likely overlapping with that of general population. The HHT disease does not seem to involve a different approach in terms of hospital admission and access to intensive care with respect to general population.

Bilateral Choanal Atresia and Endoscopic Surgery: A Chance for CHARGE Patients.

Bilateral choanal atresia (CA) is a rare congenital malformation frequently associated with other anomalies. CHARGE association is closely linked to bilateral CA. The aim of this study was to describe the outcomes of the endoscopic repair in bilateral CA, and to assess the role of postoperative nasal stenting in two cohorts of CHARGE-associated and non-syndromic CA. Thirty-nine children were retrospectively analyzed (16 patients had CHARGE-associated CA). The rate of postoperative neochoanal restenosis was 31.3% in the CHARGE population, and 47.8% in the non-syndromic CA cohort. Data on postoperative synechiae and granulation tissue formation, need for endonasal toilette and dilation procedures, and number of procedures per patient were presented. Stent positioning led to a higher number of postoperative dilation procedures per patient in the non-syndromic cohort (p = 0.018), and to a higher rate of restenosis both in the CHARGE-associated, and non-syndromic CA populations. Children with CHARGE-associated and non-syndromic bilateral CA benefitted from endonasal endoscopic CA correction. The postoperative application of an endonasal stent should be carefully evaluated.

Nasal Endoscopy in the Clinical Diagnosis of Hereditary Hemorrhagic Telangiectasia.

OBJECTIVES: To evaluate the role of nasal endoscopy for early clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) in children and to investigate the characteristics of epistaxis and mucocutaneous telangiectases in our pediatric population. STUDY DESIGN: From May 2016 to December 2019, a cross-sectional observational study was conducted, recruiting children aged 2-18 years with a parent affected by HHT. To identify the Curaçao criteria, all children underwent collection of clinical history, mucocutaneous examination, and nasal endoscopy. The clinical data were then compared with the genetic data acquired subsequently. RESULTS: Seventy children (median age, 10.8 years) were included. All underwent nasal endoscopy without complications. Forty-six children were positive by genetic testing; of these, 26 % had skin and oral telangiectases and 91 % had nasal telangiectases. The diagnostic sensitivity of the Curaçao criteria increased from 28 % (95 % CI, 16%-43 %) to 85 % (95 % CI, 71%-94 %; P < .0001) when the nasal telangiectases were included. CONCLUSIONS: The magnified and complete endoscopic view of the nasal cavities proved useful in increasing the diagnostic sensitivity of the Curaçao criteria. Such an examination turned out to be feasible and safe. For this reason, we believe that nasal endoscopy should be included in the diagnostic assessment of pediatric patients with suspected HHT.

Novel therapeutic approaches targeting endotypes of severe airway disease.

Introduction: Severe asthma and chronic rhinosinusitis (CRS), with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP), are heterogeneous diseases characterized by different mechanistic pathways (endotypes) and variable clinical presentations (phenotypes).Areas covered: This review provides the clinician with an overview of the prevalence and clinical impact of severe chronic upper and lower airways disease and suggests a novel therapeutic approach with biological agents with possible biomarkers. To select relevant literature for inclusion in this review, we conducted a literature search using the PubMed database, using terms 'severe airways disease' AND 'endotype' AND 'treatment.' The literature review was performed for publication years 2010-2020, restricting the articles to humans and English language publications.Expert opinion: The coronavirus disease (COVID-19) pandemic has brought forth many challenges for patients with severe airway disease and healthcare practitioners involved in care. These patients could have an increased risk of developing severe SARS-CoV-2 disease, although treatment with biologics is not associated with a worse prognosis. Eosinopenia on hospital admission plays a key role as a diagnostic and prognostic biomarker.

Fluorophores Use in Pituitary Surgery: A Pharmacokinetics and Pharmacodynamics Appraisal.

(1) Background: Despite many surgical and technological advances, pituitary adenoma surgery is still burdened by non-negligible rates of incomplete tumor resection, mainly due to difficulties in differentiating pathology from normal pituitary tissue. Some fluorescent agents have been recently investigated as intraoperative contrast agents in pituitary surgery. The aim of this study is to evaluate the actual knowledge about the usefulness of such fluorophores with a particular focus on both the pharmacokinetics and pharmacodynamics issues of the pituitary gland. (2) Methods: We reviewed the current literature about fluorophores use in pituitary surgery and reported the first fully endoscopic experience with fluorescein. (3) Results: The studies investigating 5-ALA use reported contrasting results. ICG showed encouraging results, although with some specificity issues in identifying pathological tissue. Low-dose fluorescein showed promising results in differentiating pathology from normal pituitary tissue. Apart from the dose and timing of administration, both the fluorophores' volume of distribution and the histological variability of the interstitial space and vascular density played a crucial role in optimizing intraoperative contrast enhancement. (4) Conclusions: Both pharmacokinetics and pharmacodynamics issues determine the potential usefulness of fluorophores in pituitary surgery. ICG and fluorescein showed the most promising results, although further studies are needed.

Endoscopic surgical treatment of epistaxis in hereditary haemorrhagic telangiectasia: our experience.

OBJECTIVES: Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterised by epistaxis. Surgical procedures for epistaxis vary from diathermocoagulation to nasal closure. The aim of this paper is to report our experience in endoscopic surgical management of epistaxis in HHT patients. METHODS: This is a descriptive, longitudinal study carried out at the Otorhinolaryngology Department of IRCCS Policlinico San Matteo in Pavia, a reference centre for the treatment and diagnosis of HHT. We retrospectively evaluated HHT patients who underwent surgery for epistaxis from 1996 to 2015, including only those treated with endoscopic surgery. RESULTS: Among the 591 patients hospitalised and screened for HHT, 323 (54.7%) underwent endoscopic surgery for epistaxis, for a total of 679 procedures. General anaesthesia was used in 77.2% of procedures; argon plasma coagulation was the instrument of choice in the majority of patients, followed by lasers and quantum molecular resonance technology. CONCLUSIONS: We report one of the largest cohorts undergoing endoscopic treatment of epistaxis in HHT patients. This mini-invasive surgical treatment allowed us to control epistaxis without major complications and nasal packaging and can be repeated over time. For these reasons, we recommend it as first choice in case of epistaxis in HHT patients.