Dupilumab's impact on nasal citology: Real life experience after 1 year of treatment.

BACKGROUND: Biologic agents are considered a new revolutionized therapy for severe and recurrent forms of CRSwNP which disease burden is not sufficiently controlled by conservative and/or surgical treatments. Recent Research has focused on evaluating their real-life efficacy in CRSwNP, as only limited reports on real-life data are available. However, in most studies, the response to treatment is evaluated in terms of improvement in Nasal Polyp Score (NPS) or in Sino-Nasal Outcome test (SNOT-22) scores. However, both criteria do not consider nasal immunophlogosis, which can be easily assessed by nasal cytology. The aim of our study was to evaluate changings in the nasal inflammatory infiltrate of CRSwNP patients treated with Dupilumab for 12 months. METHODS: 27 patients suffering from severe CRSwNP treated with Dupilumab were recruited. Nasal cytology findings, NPS, SNOT-22, ACT scores and blood eosinophil count at T0 (before treatment) and at T1 (after 1 year of treatment) were compared. RESULTS: After 1 year of biological therapy with Dupilumab, NPS, SNOT-22 and, among the 17 asthmatic patients, ACT scores improved significantly. At T1, a statistically significant percentage of patients showed negative citology. Moreover, a significant reduction in the mast cell-eosinophilic pattern and an increase of neutrophils and bacteria was reported. CONCLUSIONS: The response to treatment can be considered both in the case of negative nasal cytology and in the case of the appearance of neutrophils and bacteria. In this context, eosinophils, the specific target of biological therapies, play a crucial role in regulating tissue homeostasis and, consequently, the nasal immunophlogosis.

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.

Diagnostic therapeutic assistance pathway (PDTA) of type 2 chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a complex and heterogeneous disorder whose etiopathogenetic picture is not yet completely known and is classically divided into CRS with (CRSwNP) and without nasal polyps (CRSsNP). But today the distinction is made with type 2 and nontype 2 variants. A rational and defined pathway for the diagnosis of chronic rhinosinusitis is an indispensable means to be able to arrive at a correct identification of the patient. This typing is essential to be able to arrive at the correct course of treatment, which turns out to be different for different types of patients. For this reason, the realization of a diagnostic therapeutic pathway represents a fundamental way for the otolaryngologist specialist but not only, since today diagnostics has a multidisciplinary framework. In the present work, precise indications have been developed to arrive at a correct diagnosis. The various diagnostic pathways and processes to arrive at a correct therapeutic framing have been highlighted. Therapy ranging from medical therapy to surgical therapy without neglecting the new biological therapies. It does not represent a guideline but a diagnostic method that can be adapted to all the various territorial realities.

Proposal for a new diagnostic-therapeutic algorithm in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the nose and the paranasal sinuses characterized by the presence of nasal polyps and persistent symptoms of nasal obstruction, anterior or posterior rhinorrhea, facial pain or pressure, and reduction or loss of smell, lasting longer than 12 weeks. Several therapeutic strategies are nowadays available to treat CRSwNP as a function of disease severity. However, a standardized therapeutic algorithm has not yet been proposed. Since CRSwNP severity can be assessed by the Clinical-Cytological Grading (CCG) and the consequent reduction in patients' Quality of Life can be defined with the Sino Nasal Outcome Test-22 (SNOT-22), we aimed to propose a new diagnostic-therapeutic algorithm, that takes into consideration both the characteristics of the patients, including the CCG, nasal obstruction, and SNOT-22, and all the therapies available today.

Eosinophil-mast cell pattern of intraepithelial infiltration as a marker of severity in CRSwNP.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is defined as a Type 2 eosinophilic disease, while CRSsNP is considered a Type 1 neutrophilic disease. Since neutrophils are also activated in eosinophilic CRSwNP, the eosinophil-neutrophil dualism has been revaluated. Among the inflammatory cells infiltrating sinus-nasal tissues, the role of mast cells (MCs) is not already recognized, although Clinical-Cytological Grading, which defines the severity of CRSwNP, attributes to mixed eosinophil-MC forms of CRSwNP a greater risk of recurrence. We aimed to examine nasal polyps from both a cytological and histopathological point of view, to evaluate the presence and localization of MCs. Cytological and histological examination of 39 samples of nasal polyps were performed. Immunohistochemistry was used to evaluate the presence of Tryptase + CD117 + MCs, which were counted both in the epithelial layer and in the lamina propria. A statistically significant correlation was found between intraepithelial MCs and CRSwNP severity (p < 0.001) and between the total eosinophil count and the total mast cell count (p < 0.001). Cytological examination and immunohistochemistry were comparable in detecting the presence of intraepithelial MCs (p = 0.002). The histological cut-off of 6 intraepithelial MCs was identified to detect severe CRSwNP (p < 0.001). MCs have been shown to be located in the lamina propria of almost all eosinophilic nasal polyps without significantly affecting their severity. Intraepithelial MCs are associated with greater severity of CRSwNP. Histopathological criteria of the eosinophil-MC form of CRSwNP in addition to the eosinophilic one, should be defined to guarantee patients effective and tailored treatments.

Perspectives of Italian Physicians and Patients in the Treatment of Otitis Externa: A Real-Life Study.

(1) Background: Otitis externa (OE) is a common inflammatory disease of the external ear canal. Given the numerous manifestations of OE, the high rate of recurrence of the disease, as well as the emergence of resistance to antibiotics, therapeutic strategies are numerous and still not well standardized. The aim of this study was to investigate the patient journey of Italian patients suffering from OE, paying greater attention to new therapeutic options. (2) Methods: We conducted a national survey to evaluate the characteristics of patients affected by OE and to analyze the most-prescribed treatments. (3) Results: OE is a common, often relapsing disease that has several clinical manifestations. Prior to observation, the combination of corticosteroids and topical antibiotics was the most common therapeutic strategy. At the time of observation, new liposomal ozone-based preparations were the most-prescribed treatment. (4) Conclusions: This multi-center study investigated key aspects of the OE patient journey, highlighting the growing problem of antibiotic resistance. Restoring a correct ear microbiome is the therapeutic goal. In this context, new liposomal ozone-based drugs represent a promising therapeutic strategy.

Nasal cytology and histology in CRSwNP: Two sides of the same coin.

Knowledge of chronic rhinosinusitis with nasal polyps (CRSwNP) has increased rapidly over the past decade. However, the study of the histological features of nasal polyps has not gone hand in hand with the study of the inflammatory mechanisms underlying CRSwNP. Indeed, precisely because they are benign neoformations, nasal polyps have not attracted the attention of pathologists over the years. Nasal cytology has shown that CRSwNP, generally defined as a Type-2 disease, is characterized not only by eosinophilic but also mast cell inflammation and, in particular, the most severe forms of CRSwNP are precisely characterized by a mixed eosinophilic-mast cell inflammation. Interestingly, mast cells cannot be visualized by histology due to limitations in staining and magnification, and therefore are not commonly described in histological reports of nasal polyps. However, immunohistochemistry can highlight these latter cells and specifically this technique has recently demonstrated that mast cells are located in the lamina propria of almost all types of polyps and in the epithelial level of the most severe forms. Unfortunately, the latter technique is not commonly carried out in clinical practice by virtue of the high cost and time burden. On the other hand, nasal cytology is an easy-to-apply and economic diagnostic tool, commonly practiced in rhinological setting, which can effectively fill the gap between histology and immunohistochemistry, allowing to non-invasively establish the endotype of nasal polyps and to highlight all cytotypes, including mast cells, that cannot be visualized by the other two techniques. The recent demonstration of the close correlation between mast cell intraepithelial infiltrate and CRSwNP severity paves the way for new therapeutic possibilities aimed at reducing not only eosinophilic infiltration but also mast cell infiltration.

Local Allergic Rhinitis: Lights and Shadows of a Mysterious Entity.

Local allergic rhinitis (LAR) is, to date, a debated and complex entity, still orphan of global consideration and a multicentric approach. LAR does not seem to find a proper positioning in the classic classifications and phenotypes of chronic rhinitis, and its pathophysiology relies specifically on the presence of local IgE. These patients in fact have a suggestive clinical history of allergic rhinitis in the presence of negative skin prick tests and serum IgE tests for the suspect allergen. Nasal allergen challenge, assessment of local IgE, basophil activation test (BAT), and nasal cytology are, at the moment, the most used tests in the diagnostic approach to the disease, despite their limitations. Considering that the correct interpretation of diagnostic tests and their clinical relevance is fundamental in the assessment of the right diagnosis and the subsequent therapy, we propose a new diagnostic approach that encompasses all of these methodologies and suggest that several pragmatic randomized control trials as well as prospective, multicentric studies directed at the long-term follow-up of LAR be carried out to further investigate this debated entity.

Biofilm in sino-nasal infectious diseases: the role nasal cytology in the diagnostic work up and therapeutic implications.

BACKGROUD: Biofilm formation has been recently recognised as one of the most important etiopathological mechanisms underlying chronic rhinosinusitis (CRS) and its recalcitrance. In this context, nasal cytology (NC) has become an integral part of diagnostic work up of patients suffering from sino-nasal diseases, since it is an easy-to-apply, reproducible and non-invasive diagnostic tool that allows to assess both the nasal inflammatory infiltrate and the presence of biofilms on nasal mucosal surface, further orienting the therapeutic choices in case of infectious diseases for eradicating infections and biofilms. Nevertheless, biofilms are typically resistant to common antibiotic treatments and may trigger or maintain chronic inflammation. Hence, the importance of correctly detecting the presence of biofilm and identifying new effective treatments. PURPOSE: The aim of this brief review is to better clarify the role of biofilm in the pathogenesis and recurrence of sino-nasal disorders and to highlight the role of nasal cytology (NC) in the rhino-allergologic diagnostic path and in the evaluation of the effectiveness of new treatments.

Nasal Cytology: A Easy Diagnostic Tool in Precision Medicine for Inflammation in Epithelial Barrier Damage in the Nose. A Perspective Mini Review.

Nasal cytology is a diagnostic tool that can be used in precision rhinology medicine. Particularly in non-allergic rhinitis and chronic rhinosinusitis forms it can be useful to evaluate biomarkers of both surgical or biological therapy and especially in the follow-up it must be used to predict the prognostic index of recurrence of nasal polyposis. All inflammatory cytokines are also linked to the presence of cells such as eosinophils and mastcells and nasal cytology is a non-invasive and repeatable method to assess the situation in real life.

Turbinate surgery: which rhinitis are most at risk.

BACKGROUND AND AIM: Allergic rhinitis (AR) and non-allergic rhinitis (NAR) belong to field of vasomotor rhinitis, characterized by nasal hyper-reactivity. Since AR and NAR are two separate nosological entities, these rhinopaties can coexist in the same patient in up to 15-20% of cases. Overlapped rhinitis (ORs) are associated with intense and persistent symptoms and are often misdiagnosed. Typically, when medical treatment fails, patients undergo turbinate surgery. We evaluated which rhinopaties are most at risk of undergoing turbinate surgery and established the percentage of ORs.  Methods: The study included 120 patients undergoing turbinate surgery for turbinate hypertrophy. Anterior rhinoscopy, nasal endoscopy, nasal cytology, skin prick tests (SPT) and/or specific IgE serum assays (CAP-RAST) were performed preoperative on all patients. RESULTS: Among patients with indication for turbinate surgery, 75% suffered from AR, whereas 25% of them had NAR. On closer analysis, only 7 (8%) of allergic patients presented a "pure" allergy.  NAR with eosinophils and mast cells (NARESMA) represented the most common type of superimposed rhinitis (62.5%), while NAR with mast cells (NARMA) and with eosinophils (NARES) represented 25% and 12.5% of the superimposed forms, respectively. CONCLUSION: Most of the patients undergoing turbinate surgery actually have complex forms of rhinitis. The non-allergic component of ORs often causes therapeutic failure. NARESMAs overlapping ARs are at most risk of undergoing turbinate surgery. Correctly framing a rhino-allergological patient is essential in order to guarantee the most adequate treatment. Hence the importance of introducing in clinical practice investigations, including allergy tests and nasal cytology.

Amanita Section Phalloideae Species in the Mediterranean Basin: Destroying Angels Reviewed.

In Europe, amatoxin-containing mushrooms are responsible for most of the deadly poisonings caused by macrofungi. The present work presents a multidisciplinary revision of the European species of Amanita sect. Phalloideae based on morphology, phylogeny, epidemiology, and biochemistry of amatoxins and phallotoxins. Five distinct species of this section have been identified in Europe to date: A. phalloides, A. virosa, A. verna, the recently introduced North American species A. amerivirosa, and A. vidua sp. nov., which is a new name proposed for the KOH-negative Mediterranean species previously described as A. verna or A. decipiens by various authors. Epitypes or neotypes are selected for species lacking suitable reference collections, namely A. verna and A. virosa. Three additional taxa, Amanita decipiens, A. porrinensis, and A. virosa var. levipes are here considered later heterotypic synonyms of A. verna, A. phalloides, and A. amerivirosa, respectively.

Personalized Management of Patients with Chronic Rhinosinusitis with Nasal Polyps in Clinical Practice: A Multidisciplinary Consensus Statement.

Chronic rhinosinusitis (CRS) is a sino-nasal chronic inflammatory disease, occurring in 5-15% of the general population. CRS with nasal polyps (CRSwNP) is present in up to 30% of the CRS population. One-third of CRSwNP patients suffer from disease that is uncontrolled by current standards of care. Biologics are an emerging treatment option for patients with severe uncontrolled CRSwNP, but their positioning in the treatment algorithm is under discussion. Effective endotyping of CRSwNP patients who could benefit from biologics treatment is required, as suggested by international guidelines. Other issues affecting management include comorbidities, such as allergy, non-steroidal anti-inflammatory drug-exacerbated respiratory disease, and asthma. Therefore, the choice of treatment in CRSwNP patients depends on many factors. A multidisciplinary approach may improve CRSwNP management in patients with comorbidities, but currently there is no shared management model. We summarize the outcomes of a Delphi process involving a multidisciplinary panel of otolaryngologists, pulmonologists, and allergist-immunologists involved in the management of CRSwNP, who attempted to reach consensus on key statements relating to the diagnosis, endotyping, classification and management (including the place of biologics) of CRSwNP patients.

Update of endoscopic classification system of adenoid hypertrophy based on clinical experience on 7621 children.

Introduction: Nasal endoscopy is likely to be the method of choice to evaluate nasal obstruction and adenoid hypertrophy (AH) in children given its excellent diagnostic accuracy and low risk for the patient. The aim of this study was to update the previous classification of AH to guide physicians in choosing the best therapeutic option. Materials and methods: This is a retrospective observational study including 7621 children (3565 females; mean age 5.92; range: 3-14 years) who were managed for adenoid hypertrophy at our institution between 2003 and 2018. All patients were initially treated with medical therapy and then with surgery if not adequately controlled. We performed a specific analysis based on the presence or absence of comorbidities. Results: In 1845 (24.21%) patients, adenoid obstruction was classified as Grade I when the fiberoptic endoscopy showed adenoid tissue occupying < 25% of choanal space. In 2829 of 7621 (37.12%) patients, the adenoid tissue was scored as Grade II since it was confined to the upper half of nasopharynx, with sufficiently pervious choana and visualisation of tube ostium. In 1611 of 7621 (21.14%) cases, adenoid vegetation occupied about 75% of the nasopharynx with partial involvement of tube ostium and considerable obstruction of choanal openings, and was classified as Grade III. Finally, 1336 of 7621 (17.53%) patients were scored as Grade IV due to complete obstruction with adenoid tissue reaching the lower choanal border without allowing the visualisation of the tube ostium. Based on resolution of symptoms in Grade III obstruction after medical therapy (that was mostly seen in patients without comorbidities), we divided patients in two subclasses: Grade IIIA was not associated with comorbidities, while Grade IIIB was correlated with important comorbidities. Conclusions: These results can be useful to guide medical or surgical therapeutic intervention. In patients with class IIIB AH, surgical treatment offered adequate control not only of nasal symptoms but also of associated comorbidities.

Chronic rhinosinusitis with nasal polyps: how to identify eligible patients for biologics in clinical practice.

Objective: This study compared three severity measures for chronic rhinosinusitis with nasal polyps (CRSwNP). The outcome was to identify patients who are eligible for biological therapy. Methods: 330 adult patients with CRSwNP were examined. Nasal polyp score (NPS), sinonasal outcome test (SNOT-22) and clinical-cytological grading (CCG) were compared. Clinical history, past surgery and asthma control test were also considered. Results: Only 45 (13.6%) patients had a contextual positivity to the three severity measures. The concordance among tests was slight/fair. Patients with severe disease (all tests positive) had more impaired parameters. The mixed cytotype (OR = 4.07), nasal obstruction (OR = 10.06), post-nasal drip (OR = 1.98), embarrassment (OR = 2.53) and difficulty falling asleep (OR = 1.92) were significantly associated with severe CRSwNP. Conclusions: To identify candidates for biological therapy, the contextual use of NPS, SNOT-22 and CCG is preferable. In this way, global assessment of CRSwNP, including morphology, inflammation, comorbidity, symptoms and quality of life is possible.