Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update.

INTRODUCTION: Biologics targeting type 2 inflammation have revolutionized the way we treat patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). Particularly in severe and difficult-to-control cases, these drugs have provided a new reality for these patients, allowing for the effective and safe treatment of extensive diseases that were not completely managed with the typical strategy of surgery and topical medications. OBJECTIVES: The experience achieved with the approval of these medications by ANVISA for use in CRSwNP and the knowledge obtained regarding outcomes, adverse effects, and the ideal patient profile prompted the update of the previously published guideline, with a detailed review of the most recent scientific literature, the personal experiences of experts, and the adaptation to the reality of the Brazilian healthcare system, both public and private. RESULTS: We proposed a new eligibility criterion for biologics in patients with CRSwNP based on four pillars of indication: the impact of the disease on the patient's life, whether in the presence of specific symptoms or in overall quality of life; the extent of sinonasal disease; the presence of type 2 comorbidities, considering other associated diseases that may also benefit from anti-T2 biologics, and the presence of biomarkers to define type 2 inflammation, especially those associated with worse disease prognoses. CONCLUSIONS: This innovative and pioneering method has two major advantages. First, it ensures a comprehensive evaluation of patients; second, it is flexible, as advancements in our understanding of the disease and changes in cost-effectiveness can be addressed by simply adjusting the required score for indication, without the need to modify the entire evaluation scheme.

Global expert views on the diagnosis, classification and pharmacotherapy of allergic rhinitis in clinical practice using a modified Delphi panel technique.

Background: Diagnosis, classification, and treatment of allergic rhinitis (AR) varies considerably despite the availability of treatment guidelines. Objectives: We aimed to carry out a two-part modified Delphi panel study to elucidate global expert management of AR in real life. Methods: The modified Delphi panel study was composed of two ten-minute online questionnaires sent to global AR experts, aiming to identify areas of consensus (defined as >75% respondent agreement) on aspects of their real-world daily practice related to AR diagnosis, classification, and pharmacotherapy. A workshop discussion with respondents held after the first-round questionnaire informed the development of the second-round questionnaire. Results: Eighteen experts (from 7 countries across 3 continents) completed both questionnaires in September-October 2021 and January 2022, respectively. The majority of respondents agreed that diagnosis of AR is best confirmed using a mixture of observation and testing (n = 15) and collaborating with colleagues across other specialties (n = 14). Experts agreed that severity (n = 18), upper/lower respiratory tract involvement (n = 15) and symptom frequency (n = 14) are important factors when classifying AR, however consensus was not reached on which classification tool should be used. Although there were mixed opinions on the preferred pharmacotherapy treatment in the presented case studies, respondents largely agreed on which treatments require less monitoring (intranasal corticosteroid therapies [INCS]) and when treatments should be stepped down (≤3 months). Although opinions varied across respondents, some respondents considered as-needed INCS treatment and surgery to be viable treatment options. Conclusion: We identified clear differences between real-world practice and treatment guidelines related to the management of AR. Furthermore, we recognized differences among physicians concerning their clinical practice in the pharmacological treatment of AR. These findings highlight the need for greater research into the management of AR and further indicate there is still a major gap between treatment guidelines and daily practice, even among specialists, suggesting a need for local guideline adaptation and implementation plans.

Guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps (CRSwNP) in Brazil / Diretriz para o uso dos imunobiológicos em rinossinusite crônica com pólipo nasal (RSCcPN) no Brasil

Abstract Introduction Severe uncontrolled chronic rhinosinusitis with nasal polyps has a negative impact on an individual's quality of life. Therefore, new biologics have emerged for use in specific phenotypes of chronic rhinosinusitis, changing the paradigms of its treatment. Objective To review the current status of biologic treatment indications in chronic rhinosinusitis. Methods The Brazilian Academy of Rhinology brought together different specialists to suggest a course of action, considering its particularities and aspects related to the national reality. Results Of particular interest for decision making will be the identification of subgroups of patients refractory to pre-existing treatment options and the construction of a strategy that improves their quality of life, with the best cost-benefit ratio. Conclusion The use of biologics is a valid option for treatment in more severe cases. This strategy must be better understood and improved in the future, with more studies and greater clinical experience.

Resumo Introdução A rinossinusite crônica com pólipos nasais grave não controlada impacta negativamente na qualidade de vida do indivíduo. Para esses casos, novos imunobiológicos têm surgido, para uso em fenótipos específicos da rinossinusite crônica, e mudaram os paradigmas de seu tratamento. Objetivo Revisar o estado atual das indicações de imunobiológicos em rinossinusite crônica. Método A Academia Brasileira de Rinologia reuniu diferentes especialistas para sugerir uma conduta que considerasse suas particularidades e seus aspectos relacionados à realidade nacional. Resultados De particular interesse para a tomada de decisão serão a identificação dos subgrupos de pacientes refratários às opções de tratamento pré-existentes e a construção de uma estratégia que realmente melhore a qualidade de vida deles, dentro da melhor relação custo-benefício. Conclusão O uso de imunobiológicos é uma opção válida para tratamento em casos mais graves. Essa estratégia deve ser mais bem compreendida e aprimorada no futuro, com mais estudos e maior experiência clínica.

Guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps (CRSwNP) in Brazil.

INTRODUCTION: Severe uncontrolled chronic rhinosinusitis with nasal polyps has a negative impact on an individual's quality of life. Therefore, new biologics have emerged for use in specific phenotypes of chronic rhinosinusitis, changing the paradigms of its treatment. OBJECTIVE: To review the current status of biologic treatment indications in chronic rhinosinusitis. METHODS: The Brazilian Academy of Rhinology brought together different specialists to suggest a course of action, considering its particularities and aspects related to the national reality. RESULTS: Of particular interest for decision making will be the identification of subgroups of patients refractory to pre-existing treatment options and the construction of a strategy that improves their quality of life, with the best cost-benefit ratio. CONCLUSION: The use of biologics is a valid option for treatment in more severe cases. This strategy must be better understood and improved in the future, with more studies and greater clinical experience.

Expanding the limits of endoscopic intraorbital tumor resection using 3-dimensional reconstruction / Expandindo os limites da ressecção endoscópica de tumor intraorbital utilizando reconstrução tridimensional

Abstract Introduction: Endoscopic orbital surgery is a nascent field and new tools are required to assist with surgical planning and to ascertain the limits of the tumor resectability. Objective: We purpose to utilize three-dimensional radiographic reconstruction to define the theoretical lateral limit of endoscopic resectability of primary orbital tumors and to apply these boundary conditions to surgical cases. Methods: A three-dimensional orbital model was rendered in 4 representative patients presenting with primary orbital tumors using OsiriX open source imaging software. A 2-Dimensional plane was propagated between the contralateral nare and a line tangential to the long axis of the optic nerve reflecting the trajectory of a trans-septal approach. Any tumor volume falling medial to the optic nerve and/or within the space inferior to this plane of resectability was considered theoretically resectable regardless of how far it extended lateral to the optic nerve as nerve retraction would be unnecessary. Actual tumor volumes were then superimposed over this plan and correlated with surgical outcomes. Results: Among the 4 lesions analyzed, two were fully medial to the optic nerve, one extended lateral to the optic nerve but remained inferior to the plane of resectability, and one extended both lateral to the optic nerve and superior to the plane of resectability. As predicted by the three-dimensional modeling, a complete resection was achieved in all lesions except one that transgressed the plane of resectability. No new diplopia or vision loss was observed in any patient. Conclusion: Three-dimensional reconstruction enhances preoperative planning for endoscopic orbital surgery. Tumors that extend lateral to the optic nerve may still be candidates for a purely endoscopic resection as long as they do not extend above the plane of resectability described herein.

Resumo Introdução: A cirurgia orbital endoscópica é um campo emergente e são necessárias novas ferramentas para auxiliar no planejamento cirúrgico e determinar os limites da ressecabilidade tumoral. Objetivo: Usar a reconstrução radiográfica tridimensional para definir o limite lateral teórico de ressecabilidade endoscópica de tumores orbitais primários e aplicar essas condições de limites a casos cirúrgicos. Método: Um modelo orbital tridimensional foi aplicado a quatro pacientes representativos com tumores orbitais primários utilizando o software de imagem de fonte aberta OsiriX. Um plano bidimensional foi propagado entre a narina contralateral e uma linha tangencial ao eixo longo do nervo óptico que reflete a trajetória de uma abordagem transeptal. Qualquer volume de tumor situado medialmente ao nervo óptico e/ou dentro do espaço inferior a esse plano de ressecabilidade foi teoricamente considerado ressecável, independentemente de quão longe ele se estendia até o nervo óptico, pois a retração do nervo seria desnecessária. Os volumes reais do tumor foram então sobrepostos sobre esse plano e correlacionados com os resultados cirúrgicos. Resultados: Entre as quatro lesões analisadas, duas eram totalmente mediais ao nervo óptico, uma se estendia lateralmente ao nervo óptico, mas permaneceu inferior ao plano de ressecabilidade, e uma se estendia lateralmente ao nervo óptico e superior ao plano de ressecabilidade. Conforme previsto pelo modelo tridimensional, uma ressecção completa foi obtida em todas as lesões, exceto uma, que transgrediu o plano de ressecabilidade. Nenhuma nova diplopia ou perda de visão foi observada em qualquer paciente. Conclusão: A reconstrução tridimensional melhora o planejamento pré-operatório para a cirurgia orbital endoscópica. Os tumores que se estendem lateralmente ao nervo óptico podem ainda ser candidatos à ressecção puramente endoscópica, desde que não se estendam além do plano de ressecabilidade aqui descrito.

Expanding the limits of endoscopic intraorbital tumor resection using 3-dimensional reconstruction.

INTRODUCTION: Endoscopic orbital surgery is a nascent field and new tools are required to assist with surgical planning and to ascertain the limits of the tumor resectability. OBJECTIVE: We purpose to utilize three-dimensional radiographic reconstruction to define the theoretical lateral limit of endoscopic resectability of primary orbital tumors and to apply these boundary conditions to surgical cases. METHODS: A three-dimensional orbital model was rendered in 4 representative patients presenting with primary orbital tumors using OsiriX open source imaging software. A 2-Dimensional plane was propagated between the contralateral nare and a line tangential to the long axis of the optic nerve reflecting the trajectory of a trans-septal approach. Any tumor volume falling medial to the optic nerve and/or within the space inferior to this plane of resectability was considered theoretically resectable regardless of how far it extended lateral to the optic nerve as nerve retraction would be unnecessary. Actual tumor volumes were then superimposed over this plan and correlated with surgical outcomes. RESULTS: Among the 4 lesions analyzed, two were fully medial to the optic nerve, one extended lateral to the optic nerve but remained inferior to the plane of resectability, and one extended both lateral to the optic nerve and superior to the plane of resectability. As predicted by the three-dimensional modeling, a complete resection was achieved in all lesions except one that transgressed the plane of resectability. No new diplopia or vision loss was observed in any patient. CONCLUSION: Three-dimensional reconstruction enhances preoperative planning for endoscopic orbital surgery. Tumors that extend lateral to the optic nerve may still be candidates for a purely endoscopic resection as long as they do not extend above the plane of resectability described herein.

P-glycoprotein and chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a heterogeneous definition that includes different disease states that usually are associated with abnormal inflammatory responses. Besides being prevalent, the mechanisms involved in its pathogenesis are not clear and there are few therapeutic options with tolerable side effects. P-glycoprotein (P-gp) is an efflux pump responsible of extruding xenobiotics and cellular metabolites from multiple cell types. It has been widely studied in the cancer field, due to its ability to confer resistance to chemotherapy. It also promotes Type 2 helper T-cell polarizing cytokine secretion in CRS and may represent a potential target to differentiate subtypes of CRS and personalize treatment. This state-of-the-art review explores current knowledge on the participation of P-gp in the pathogenesis of CRS, the P-gp inhibition as a novel targeted therapeutic strategy and the exosomal P-gp test, a non-invasive biomarker that can represent an important advance in the field of rhinology.

Compartmental Endoscopic Surgical Anatomy of the Inferior Intraconal Orbital Space.

Objectives This study aims to define the endoscopic anatomy of inferior intraconal space, in terms of its neurovascular structures and relationship to fixed anatomic landmarks. Design A cadaveric anatomical study was conducted. Setting This study was conducted at an academic cranial base center. Participants Cadaveric subjects have been investigated. Main Outcome Measures After dissection of the inferior intraconal space, the number and position of ophthalmic artery (OA) and oculomotor nerve (OMN) branches to the inferior rectus muscle (IRM) were quantified relative to the fixed landmark of the posterior maxillary wall. The point where the OMN branch to the inferior oblique muscle (IOM) crossed the lateral IRM margin was quantified. Results A total of 18 OA branches were identified with a mean ± standard deviation of 2.6 ± 0.53 branches. The mean distance of the OA branch insertion from the posterior maxillary wall was 7.11 ± 5.65 mm. The average number of OMN branches to the IRM was 1.63 ± 0.74 with a mean insertion distance of 1.88 ± 1.89 mm. The OMN branch to the IOM crossed the lateral IRM margin 5.38 ± 5.42 mm from the posterior maxillary wall. Conclusions This cadaveric study quantifies the variability of two critical neurovascular structures salient to endoscopic approaches to the inferior intraconal space, the OMN, and OA contributions to the IRM. Knowledge of the interrelationship between these structures is essential in safe technique for dissection.

Long-term impact of endoscopic orbital decompression on sinonasal-specific quality of life.

OBJECTIVE: Endoscopic orbital decompression (EOD) is the workhorse surgical intervention for severe thyroid eye disease in Graves disease. Although EOD is a safe and effective procedure, the objective of this study is to determine the impact of orbital decompression on long-term sinonasal-pecific quality of life. METHODS: Retrospective study of 27 patients who underwent EOD by a single surgeon. The primary endpoint was change in preoperative 22-item Sinonasal Outcomes Test (SNOT-22) score at a minimum of 1 year. The secondary endpoint was to determine whether the performance of septoplasty for surgical access in patients without nasal obstruction impacted domain 1 (i.e., rhinologic domain) and total SNOT-22 scores. RESULTS: The mean follow-up was 25.7 ± 11.4 months. Domain 1 scores significantly increased at the first postoperative visit (P ≤ 0.01) and returned to baseline values between 1 and 3 months. At 1 year, significant improvements in both total score and domain 4 and 5 (psychological and sleep dysfunction, respectively) scores were seen (P < 0.01 for all scores). Septoplasty was not associated with a significant change in SNOT-22 score at 1 year (P = 0.48). CONCLUSION: Endoscopic orbital decompression is associated at 1 year with a significant improvement in sinonasal-specific quality of life, which is driven by the psychological and sleep dysfunction domains. Adjunctive septoplasty has no significant impact on SNOT-22 scores. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:785-788, 2018.

Exosomes mediate interepithelial transfer of functional P-glycoprotein in chronic rhinosinusitis with nasal polyps.

OBJECTIVE: P-glycoprotein (P-gp) drives type-2 helper T-cell inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) through unknown posttranslational mechanisms of overexpression. A recent randomized clinical trial demonstrated that inhibition of P-gp was as effective as oral steroids and biologics in treating CRSwNP. Exosomes are 30- to 150-nm vesicles capable of intercellular membrane protein transfer. The aims of this study were 1) to determine whether CRSwNP mucus exosomes are enriched with P-gp, and 2) whether exosomal P-gp can be functionally transferred to autologous epithelial cells as a putative mechanism for the proinflammatory overexpression of P-gp in CRSwNP. STUDY DESIGN: Institutional review board-approved study in CRSwNP and control patients (n = 10 per group). METHODS: P-gp content of purified mucus exosomes was characterized by transmission electron microscopy and enzyme-linked immunosorbent assay. Epithelial transfer of exosomal P-gp was determined by time-lapse fluorescent microscopy and calcein acetoxymethylester functional P-gp assay. RESULTS: CD63+/P-gp+ exosomes were detected in both groups. P-gp was significantly enriched in CRSwNP exosomes relative to control (median 198.5; interquartile range 123.6-270.5 vs. 74.4; 41.3-95.0 pcg P-gp/109 exosomes, P = 0.002). Exosomes were absorbed by epithelial cells within 10 minutes, resulting in a significant increase in P-gp activity in CRSwNP patients relative to control (P = 0.006). CONCLUSION: Here we demonstrate the presence and P-gp enrichment of mucus-derived exosomes, or rhinosomes, in CRSwNP. These rhinosomes are capable of rapid intercellular transfer of P-gp, leading to increased P-gp function within recipient cells. This represents a novel mechanism for maintaining P-gp overexpression in CRSwNP, and more generally for interepithelial transfer of other proteins between mucosal epithelial cells. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:E295-E300, 2017.

Secreted P-glycoprotein is a noninvasive biomarker of chronic rhinosinusitis.

OBJECTIVE: The discovery of noninvasive biomarkers of chronic rhinosinusitis (CRS) is critical to enable our ability to provide prognostic information and targeted medical therapy. Epithelial P-glycoprotein (P-gp) is overexpressed in CRS and exists in an extracellular, secreted form. The objective of this study was to determine whether secreted P-gp concentrations are elevated in CRS and can be used to predict disease severity. METHODS: Institutional review board-approved study examining mucus concentrations of P-gp in 36 patients (10 control, 16 CRS without nasal polyps [CRSsNP], and 10 CRS with nasal polyps [CRSwNP]). P-gp concentrations were determined by enzyme-linked immunosorbent assay and normalized to total protein (TP). Clinical indices of disease severity, including the Sino-Nasal Outcomes Test (SNOT-22) and Lund-Mackay score, were collected for all patients. RESULTS: Secreted P-gp concentration was significantly higher in CRS versus control patients (mean ± standard deviation; 247.8 ± 224.8 vs. 102.4 ± 81.7 pcg P-gp/µg TP, P = 0.022). A threshold value of 250 pcg/µg TP was used to differentiate low versus high secretors. High P-gp secretors with CRS (sNP and wNP, n = 9) demonstrated significantly higher SNOT-22 and Lund-Mackay scores (57.1 ± 7.9 and 13.9 ± 7.3) versus low secretors (38.3 ± 23.9 and 6.8 ± 7.3; P = 0.030 and P = 0.013, respectively) and had a significantly higher proportion of CRSwNP (66.7%) versus the low secretors (23.5%, n = 17, P = 0.046). CONCLUSION: P-gp secretion levels are significantly elevated in patients with CRS. High P-gp secretion is associated with a higher incidence of CRSwNP and confers worse subjective and objective measures of disease severity. The presence of elevated P-gp secretion may therefore represent a novel noninvasive biomarker of CRS and could be used to predict patients who may benefit from P-gp inhibitory therapeutic strategies. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E1-E4, 2017.

Impact of endoscopic dacryocystorhinostomy on sinonasal quality of life.

BACKGROUND: Dacryocystorhinostomy (DCR) is the criterion standard of surgical treatment for complete nasolacrimal obstruction and dacryocystitis. There has been an expansion in the indication of the endonasal DCR (eDCR), but the impact of surgical manipulating an otherwise healthy nasal mucosa on postoperative sinonasal quality of life remains unknown. The purpose of this study was to determine whether patients who underwent eDCR experienced any decrement in sinonasal quality of life. METHODS: A retrospective chart review of 44 patients who underwent eDCR between June 2012 and May 2015. The primary outcome was the total and nasal-specific domain 1 scores of the disease specific validated Sino-Nasal Outcomes Test 22. Preoperative scores were compared with the postoperative scores on days 0-30, 30-90, and 90-180 visits. A subgroup analysis of patients without nasal symptoms who underwent concomitant nasal surgical procedures was also performed. RESULTS: A statistically significant increase was observed between the preoperative score and the first postoperative score (days 0-30) in both total (7.5 [0-44] to 24 [0-51], median [interquartile range]) and domain 1 (2.5 [0-11] to 9 [0-18]) scores (p = 0.0066 and p = 0.0001, respectively). In contrast, there was no statistically significant difference between the pre- and postoperative scores on days 30-90 or 90-180. Similar results were observed in the subgroup analysis. CONCLUSION: Analysis of our findings indicated that, in general, eDCR was well tolerated by patients and nasal symptom scores returned to baseline values within 30-90 days of surgery. The concomitant performance of septoplasty in the setting of asymptomatic septal deviation did not confer any long-term improvement in symptoms of nasal obstruction.

Bypassing the blood-brian barrier using established skull base reconstruction techniques.

BACKGROUND: Neurological disorders represent a profound healthcare problem accounting for 6.3% of the global disease burden. Alzheimer's disease alone is expected to impact over 115 million people worldwide by 2050 with a cost of over $1 trillion per year to the U.S. economy. Despite considerable advances in our understanding of the pathogenesis and natural history of neurological disorders, the development of disease modifying therapies have failed to keep pace. This lack of effective treatments is directly attributable to the presence of the blood-brain and blood-cerebrospinal fluid barriers (BBB and BCSFB) which prevent up to 98% of all potential neuropharmaceutical agents from reaching the central nervous system (CNS). These obstacles have thereby severely limited research and development into novel therapeutic strategies for neurological disease. Current experimental methods to bypass the BBB, including pharmacologic modification and direct transcranial catheter implantation, are expensive, are associated with significant complications, and cannot be feasibly scaled up to meet the chronic needs of a large, aging patient population. TRANSMUCOSAL DRUG DELIVERY: An innovative method of direct CNS drug delivery using heterotopic mucosal grafts was described. This method is based on established endoscopic skull base nasoseptal flap reconstruction techniques. The model has successfully demonstrated CNS delivery of chromophore-tagged molecules 1000 times larger than those typically permitted by the BBB. CONCLUSIONS: This innovative technique represents the first described method of permanently bypassing the blood-brain barrier using purely autologous tissues. This has the potential to dramatically improve the current treatment of neurological disease by providing a safe and chronic transnasaldelivery pathway for high molecular weight neuropharmaceuticals.