An adjoint-based approach for the surgical correction of nasal septal deviations.

Deviations of the septal wall are widespread anatomic anomalies of the human nose; they vary significantly in shape and location, and often cause the obstruction of the nasal airways. When severe, septal deviations need to be surgically corrected by ear-nose-throat (ENT) specialists. Septoplasty, however, has a low success rate, owing to the lack of suitable standardized clinical tools for assessing type and severity of obstructions, and for surgery planning. Moreover, the restoration of a perfectly straight septal wall is often impossible and possibly unnecessary. This paper introduces a procedure, based on advanced patient-specific Computational Fluid Dynamics (CFD) simulations, to support ENT surgeons in septoplasty planning. The method hinges upon the theory of adjoint-based optimization, and minimizes a cost function that indirectly accounts for viscous losses. A sensitivity map is computed on the mucosal wall to provide the surgeon with a simple quantification of how much tissue removal at each location would contribute to easing the obstruction. The optimization procedure is applied to three representative nasal anatomies, reconstructed from CT scans of patients affected by complex septal deviations. The computed sensitivity consistently identifies all the anomalies correctly. Virtual surgery, i.e. morphing of the anatomies according to the computed sensitivity, confirms that the characteristics of the nasal airflow improve significantly after small anatomy changes derived from adjoint-based optimization.

Multidimensional Impact of Dupilumab on Chronic Rhinosinusitis with Nasal Polyps: A Complete Health Technology Assessment of Clinical, Economic, and Non-Clinical Domains.

Chronic RhinoSinusitis with Nasal Polyps (CRSwNP) represents a condition mainly caused by the type 2 inflammation presence and marked by the existence of polyps within the nasal and paranasal sinuses. The standard of care includes intranasal steroids, additional burst of systemic steroids, if needed, and surgery. However, recurrence is common, especially among patients with comorbid type 2 inflammatory diseases. Recently, biological drugs, addressing the underlying cause of the disease, have been approved in Italy (dupilumab, omalizumab, and mepolizumab). A Health Technology Assessment was conducted to define multidimensional impact, assuming Italian NHS perspective and a 12-month time horizon. The EUnetHTA Core Model was deployed, using the following methods to analyze the domains: (i) literature evidence; (ii) administration of semi-structured questionnaires to 17 healthcare professionals; (iii) health economics tools to define the economic sustainability for the system. Evidence from NMA and ITC showed a more favorable safety profile and better efficacy for dupilumab compared with alternative biologics. All the analyses, synthesizing cost and efficacy measures, showed that dupilumab is the preferable alternative. Specifically, the cost per responder analysis for dupilumab, exhibiting a 67.0% response rate at Week 52, is notably economical at 14,209EUR per responder. This presents a more economical profile compared with the cost per responder for omalizumab (36.2% response rate) at 24,999EUR and mepolizumab (28.5% response rate) at 31,863EUR. These results underscore dupilumab's potential, not merely in terms of clinical outcomes, but also in terms of economic rationality, thereby solidifying its status as a valid and preferrable alternative in the management of CRSwNP, in the context of the Italian NHS.

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.

Oncocytic papillary cystadenoma of the larynx: a case report.

BACKGROUND: Cystadenoma of the salivary glands is a rare benign clinical condition affecting both major and minor salivary glands equally. It constitutes approximately 2% of total neoplasms and 4.2-4.7% of benign formations in minor salivary glands. Typically presenting as a slow-growing, painless neoplasm, it can be distinguished from Cystadenolymphoma (Whartin's Tumor) by the absence of lymphoid elements in histological examination. While mostly located in the oral cavity and oropharynx, it can also be found in sinonasal mucosa, and rare cases have been identified in the larynx. CASE PRESENTATION: A 75-year-old Caucasian woman presented to the ear, nose, and throat department with complaints of dysphonia and headaches persisting for several months. Dysphonia had developed months after an unspecified vocal cord surgery elsewhere. Flexible laryngoscopy identified a left-sided cystic swelling affecting the supraglottic space, leading to respiratory obstruction and dysphonia. Head and neck computed tomography confirmed a 1.9 × 1.7 cm bilobed cystic mass originating from the left Morgagni ventricle. Microlaryngoscopy with CO2 laser excision and biopsy revealed a histopathological diagnosis of oncocytic papillary cystadenoma. Post-surgery, the patient fully recovered from dysphonia, with no significant complications noted. Long-term clinical surveillance was advised to detect potential recurrences promptly. CONCLUSION: Ectopic minor salivary gland tumors, both benign and malignant, should be taken into consideration as potential differential diagnosis for any swelling arising within the upper digestive tract mucosa. Ears, nose, and throat clinical examination completed by videolaryngoscopy can easily point out the location of the mass. Imaging is mandatory for differential diagnosis and for surgical planning. Surgical excision can provide both diagnosis and definitive cure.

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.

Early increase in eosinophil count may predict long-term hypereosinophilia during dupilumab treatment: a 2-year observational study.

KEY POINTS: In a limited subset of patients, dupilumab-induced hypereosinophilia is persistent. Two-month follow-up eosinophil count may predict long-lasting hypereosinophilia.

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.

Use of a Fiberoptic-Laser Approach During Endoscopic Sinus Surgery: A Cadaver Feasibility Study.

Aims: The aim of the present study is to evaluate the clinical applicability of laser energy during an oro-nasal endoscopic approach (ONEA) in the management of the anterior maxillary sinus wall. Methods: An experiment on three adult human cadavers was performed to study the nasal cavities with angled rigid scopes and using the ONEA technique. In order to evaluate the effectiveness of laser energy on the bone, the drilling effect was compared to laser energy (1470 nm diode laser, continuous wave, power 8, 9 and 10 W). Results: Compared to a rigid angled scope, the ONEA technique allowed complete visualization of the anterior wall of the maxillary sinus. Microscopic analysis of frontal bone revealed similar bone Exeresis with high-speed drilling (270.28 µm) and laser approaches (285.73-456.6 µm). Conclusions: The laser ONEA technique is an innovative, mini-invasive, and safe approach to the anterior wall of the maxillary sinus. Additional study is warranted to further develop this technique.

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.

Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines.

Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

The impact of near-infrared autofluorescence on postoperative hypoparathyroidism during total thyroidectomy: a case-control study.

PURPOSE: Near-infrared autofluorescence is a new technology in thyroid surgery to better localize and preserve parathyroid glands. The purpose of this study is to assess if the adoption of NIR-AF can improve in short-, medium-, and long-term post-operative calcium and PTH levels compared to conventional "naked eye" surgery in patients undergoing TT for benign or malignant conditions. METHODS: 134 patients undergone total thyroidectomy between January 2020 and June 2022; 67 were treated with conventional thyroidectomy, the other 67 underwent surgery adopting an autofluorescence detecting device. RESULTS: Significant differences were found between the two groups in percentage of patients with short-term hypocalcemia (p = 0.04) and short-term hypoparathyroidism (p = 0.011). Median short-term (p = 0.01) and medium-term (p = 0.03) PTH levels were significantly higher in autofluorescence group, while, short- (p = 0.001), medium- (p < 0.001) and long-term (p = 0.019) percentage variation of PTH levels from baseline were significantly higher in the standard-care group. Finally, the prescription of oral calcium (p < 0.01) after surgery were significantly lower in the autofluorescence group. CONCLUSION: The adoption of near-infrared autofluorescence during total thyroidectomy is related to lower short-term hypocalcemia and hypoparathyroidism rates, decreased variation of post-operative PTH levels in short- and medium- and long-term, reducing the necessity of supplementation therapy with oral calcium compared to conventional surgery.

Endoscopic and external dacryocystorhinostomy: A therapeutic proposal for distal acquired lacrimal obstructions.

Endoscopic (END-DCR) and external dacryocystorhinostomies (EXT-DCR) are nowadays considered the gold standard techniques for non-oncologic distal acquired lacrimal disorders (DALO). However, no unanimous consensus has been achieved on which of these surgeries is the most suitable to the individual patient. Herein, we review the available literature of the last 30 years with the aim of defining a simple and reproduceable treatment algorithm to treat DALO. A search of PubMed, EMBASE, Scopus and Cochrane databases was last performed in December 2021 to examine evidence regarding the role of END-DCR and EXT-DCR in primary and revision surgeries. If considered primary surgeries, END-DCR should be preferred in case of intranasal comorbidities, given the possibility to directly visualize and treat potential intranasal pathologies. Conversely, EXT-DCR should be chosen in case of need/preference for local anesthesia, given the major historical experience and wider surgical field that helps to resolve intra-operatory complications (e.g., bleeding) in an uncollaborative patient. In the absence of the abovementioned conditions, the decision of one or other approach should be discussed with the patient. In recurrent cases, END-DCR should be considered the treatment of choice given the major likelihood to visualize the causes of primary failure and directly resolve it. In conclusion, END-DCR should be considered the treatment of choice in revision cases or in primary ones associated with intranasal pathologies, whereas EXT-DCR should be chosen if local anesthesia is needed. In the absence of these scenarios, it is still open to debate which of these two approaches should be used.

The use of near-infrared autofluorescence during total laryngectomy with hemi- or total thyroidectomy.

PURPOSE: The aim of this study is to describe the use of near-infrared autofluorescence (NIR-AF) to identify and preserve parathyroid glands (PGs) in a group of patients with advanced hypopharyngeal/laryngeal cancer undergone total (pharyngo)laryngectomy with hemi- or total thyroidectomy. METHODS: At San Raffaele Hospital, Milan (Italy), from January 2021 to May 2021, 7 patients affected by cT4a laryngeal squamous cell carcinoma (SCC) underwent surgery using an autofluorescence detection system (Fluobeam-Fluoptics®). For proper surgical planning, the demolition phase envisaged extension of the intervention to 4 hemithyroidectomies and 3 total thyroidectomies associated, respectively, with homolateral or bilateral CCND. Serum calcium, ionized calcium, and parathyroid hormone (PTH) levels at post-operative day (POD) 1 and 2 and at 2 weeks after surgery were monitored. Finally, we compared the data obtained with a cohort of patients who underwent surgery without the adoption of NIR-AF. RESULTS: With the use of NIR-AF, 18/20 PGs were identified, of which 7/18 were preserved exclusively thanks to the use of autoflorescence. The technique also made it possible to identify and isolate three PGs from the surgical specimen, which were subsequently transplanted only after intraoperative histological confirmation. On POD-1, 3/7 patients (42.8%) were hypocalcemic; on POD-2 and after 2 weeks only 1/7 patient (14.2%) was hypocalcemic. Comparing the two groups, we highlighted that the utilization of NIR-AF was related to a significant decrease of median serum (p = 0.026) and ionized calcium levels (p = 0.017) 2 weeks after surgery. Using this new technology, in no case did definitive histological examination reveal the presence of PGs in the surgical specimen, reaching an accuracy of 100%. CONCLUSIONS: In our cohort of patients who underwent total (pharyngo)laryngectomy with hemi- or total thyroidectomy, the use of near-infrared autofluorescence improved medium term postoperative hypocalcemia rates. This new technology helps to achieve a better calcemic outcome compared to the standard naked eye approach, since it helps the surgeon to identify and preserve parathyroid glandular tissue with a lower incidence of post-operative hypocalcemia.

Comparison of guidelines for prescription and follow-up of biologics for chronic rhinosinusitis with nasal polyps.

PURPOSE: To compare international and regional guidelines for prescription and monitoring of response to biologics in chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: A literature review was performed to identify publications reporting indications for biologic therapy in CRSwNP. A full-text reading identified specific issues for comparison: prior surgery, evidence of type 2 inflammation (T2I), smell function, comorbidities, use of systemic corticosteroids, impact on quality of life, and endoscopic and CT findings were compared for the prescription, while the monitoring of the treatment was described in relation to timing, classification of response and criteria for withdrawal. RESULTS: Ten publications were found. Prior surgery was strictly necessary in five guidelines, while in all the remaining it was variably recommended. A confirmation of T2I was considered necessary in one publication, unnecessary in two, and recommended or constituted only one of the factors to consider in seven. All the other issues analyzed were variably considered. Reevaluation was suggested at 4-6 months and 1 year, mostly assessing improvement in the same criteria used for prescription. CONCLUSIONS: A combination of subjective and objective findings is used for the identification of patients with CRSwNP who are indicated for biologic therapy. Major debate has developed on the need for previous surgery, which is generally recommended, or strictly necessary for some authors. Confirmation of T2I is generally suggested, but compulsory only in a minority of guidelines. Smell function, use of systemic corticosteroids, and the impact on quality of life are the other factors most frequently considered.

Determination of costs for the CSRwNP pathway. A time-driven activity-based costing experiment.

Objectives: The study aims to define the economic resources needed to manage chronic rhinosinusitis with nasal polyposis (CRSwNP), assuming the hospital perspective, based on different patient characteristics, within a 24-month time horizon. Methods: Real-world data were collected in 3 Italian hospitals. A time-driven activity-based costing approach was implemented to map and assess the pathways for CRSwNP. The following drivers were considered: diagnostic services, drugs, consumables, human resources, equipment and overhead costs based on the length of stay. Costs related to management of comorbidities and adverse events were evaluated. Three main groups of patients were identified: ineligible for surgery; having 1 intervention; having more than 1 intervention. The economic absorption of patients who continued corticosteroid treatment was analysed. Results: Patients experiencing 1 intervention had a cost of 3,453.31 € that increased to 4,705.03 € for those who required additional surgery. The cost of intranasal corticosteroids was 649.20 €, whereas the cost of oral corticosteroids was 37.60 € per patient. Conclusions: The results demonstrate the strategic relevance of analytical cost definitions of the clinical pathway for CRSwNP, which can help to support decision makers in the review of internal procedures and in the definition of proper reimbursement tariffs.

Mast Cell Cytokines in Acute and Chronic Gingival Tissue Inflammation: Role of IL-33 and IL-37.

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory-immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.

Radiographic protrusion of dental implants in the maxillary sinus and nasal fossae: A multidisciplinary consensus utilising the modified Delphi method.

The aim of the present study was to generate an international and multidisciplinary consensus on the clinical management of implant protrusion into the maxillary sinuses and nasal fossae. A total of 31 experts participated, 23 of whom were experts in implantology (periodontologists, maxillofacial surgeons and implantologists), 6 were otolaryngologists and 2 were radiologists. All the participants were informed of the current scientific knowledge on the topic based on a systematic search of the literature. A list of statements was created and divided into three surveys: one for all participants, one for implant providers and radiologists and one for otolaryngologists and radiologists. A consensus was reached on 15 out of 17 statements. According to the participants, osseointegrated implants protruding radiographically into the maxillary sinus or nasal fossae require as much monitoring and maintenance as implants fully covered by bone. In the event of symptoms of sinusitis, collaboration between implant providers and otolaryngologists is required. Implant removal should be considered only after pharmacological and surgical management of sinusitis have failed.

Survey on Use of Local and Systemic Corticosteroids in the Management of Chronic Rhinosinusitis with Nasal Polyps: Identification of Unmet Clinical Needs.

Background: Local and systemic corticosteroids have long been the workhorse in management of chronic rhinosinusitis with nasal polyps (CRSwNP), although there is no universally accepted modality of prescription. We carried out a survey in Italy to capture current trends in the use of topical and systemic corticosteroids in patients with CRSwNP. Methods: A survey was set up on Survey Monkey®. Each author distributed the link to the survey in an ad hoc manner and a total of 437 participants filled out the survey. Results: Mometasone furoate (79.3%) was the most frequently prescribed, administered daily by 61.9% of participants; the remaining preferred to discontinue treatment for brief periods to reduce side effects or to modulate the therapy in mild cases. The majority believe that a short cycle of systemic steroids should be prescribed for re-exacerbation of symptoms and that the number of cycles in the previous year should be evaluated to define control of the disease even if international guidelines do not provide clear indications on this topic. A certain degree of divergence emerged from responses regarding how long and the maximal dose of systemic steroids which place patients at high risk for adverse events. Finally, systemic corticosteroids seem to offer only temporary benefit on recovery of smell without guaranteeing long-term control even if the patient is adherent to topical corticosteroids. Conclusions: Our results highlight the need for clear guidelines on oral steroids, which could help supporting the use of a precision medicine approach, including indications for new biological agents.

Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

Hypereosinophilia management in patients with type 2 chronic rhinosinusitis treated with dupilumab: preliminary results.

PURPOSE: Biological therapies are gaining relevance in the management of CRSwNP with few adverse events reported. Among these, dupilumab, an anti-IL4-Ra monoclonal antibody, is frequently associated with hypereosinophilia (HE) which usually remains silent and progressively resolves, although some cases of systemic involvement occurs. The aim of this paper is to describe our experience and propose a management flowchart for HE during therapy with dupilumab. METHODS: Patients with CRSwNP who satisfied EPOS2020 criteria for biological therapies were included in this prospective study. Each case was discussed in a multidisciplinary meeting with subsequent prescription of dupilumab; all patients were candidates to follow-up bi-monthly for 6 months, while additional blood tests were scheduled in the event of HE. RESULTS: A total of 21 patients with a mean age of 48.4 years were enrolled. Of these, 15 of 21 presented an asthma comorbidity and 9 of 21 ASA sensitivity. Four patients (19%) developed HE with AEC > 1.5 × 109/L, whereas it occurred in 9.5% (two patients) if considered AEC > 3 × 109/L. No cases of hypereosinophilic syndrome were recorded. Following our decision-making flowchart, two patients received short-term corticosteroid therapy, whereas the other two were only eligible for closer follow-up. CONCLUSIONS: During dupilumab therapy, HE may occur and should be considered benign when < 3 × 109/L in the absence of organ involvement. Conversely, in case of HE ≥ 3 × 109/L, an empirical approach with short-term corticosteroid therapy should be considered to debulk the blood from eosinophils and prevent potential organ involvement.