Difficult-To-Treat and Severe Asthma: Can Real-World Studies On Effectiveness of Biological Treatments Change the Lives of Patients?

Many different phenotypes that characterize severe asthma are supported by intricate pathomechanisms called endotypes. The latter are driven by molecular interactions, mediated by intercellular networks. With regard to the biological treatments of either allergic or non-allergic eosinophilic type 2 asthma, real-world studies have confirmed the positive effects of currently available antibodies directed against immunoglobulins E (IgE), interleukin-5 (IL-5) and its receptor, as well as the receptors of interleukins-4 (IL-4) and 13 (IL-13). The best way to treat severe asthma should be chosen based on the peculiar phenotypic and endotypic traits of each patient. This will lead to relevant improvements in both clinical and functional outcomes. In particular, biological therapies can change the lives of asthma patients with a strong impact on quality of life. Unfortunately, patients with severe non-type-2 asthma, who continue to have pertinent unmet needs, are not receiving satisfactory advances within the context of biological treatments. It is also hopeful that in the next future new therapeutic strategies will be specifically implemented for these people, perhaps offering them the opportunity to improve their current, mostly inadequate asthma management.

Targeting IL-4 and IL-13 Receptors on Eosinophils in CRSwNP Patients: The Clinical Efficacy of Dupilumab.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease linked to type 2 inflammation. Several biologics have demonstrated therapeutic potential for the treatment of this pathology in which IL-4, IL-5 and IL-13 represent the major cytokines involved in the control of eosinophilic respiratory inflammation. 25% of CRSwNP patients relapse after the use of oral glucocorticoids or after surgery and often require several surgeries during their lifetime. In our study we enrolled 14 patients, 11 male and 3 female. The inclusion criteria were: age ≥ 18 years; confirmed diagnosis of chronic rhinosinusitis with severe nasal polyposis; disease severity with NPS Nasal Polyposis Endoscopic Score total score ≥ 5 and/or SNOT-22 ≥ 50; previous treatment failure due to lack of efficacy or discontinuation of systemic corticosteroid therapy and/or non-response or recurrence following surgery. The results presented in this study showed the ability of Dupilumab to improve all the parameters analysed. In particular, statistically significant data were obtained for NPS, SNOT-22, NRS, and IgE in patients exposed to Dupilumab treatment for 24 weeks, highlighting the ability of Dupilumab to produce clinical benefit in CRWwNP patients. In light of these data, the administration of dupilumab every two weeks represents a valid clinical strategy that ENT specialists can adopt for the treatment of adults with inadequately controlled CRSwNP.

Real-Life Effects of Omalizumab on Chronic Rhinosinusitis with Nasal Polyposis.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease of the nasal and sinus mucosa. This inflammatory process is supported by a multitude of cytokines, including IL-4, IL-5, and IL-13 produced by Th2 cells, as well as by IgE produced by B lymphocytes in response to a stimulus. Omalizumab is an anti-IgE monoclonal antibody with well-recognized roles in allergic asthma and chronic spontaneous urticaria. The aim of this study was to evaluate the clinical efficacy of omalizumab in a cohort of 13 patients suffering from chronic rhinosinusitis with CRSwNP. The inclusion criteria considered were as follows: 18 years of age, with a diagnosis of chronic rhinosinusitis with severe nasal polyposis expressed by an NPS greater than or equal to 5 and/or a SNOT-22 greater than or equal to 50. In addition, in the enrolled patients, the classic treatment with corticosteroids had to have been suspended due to recurrence after surgery or lack of response. Our results highlighted that omalizumab treatment for 16 weeks improved the parameters analyzed: SNOT-22, NPS, NRS, and NCS. The clinical efficacy of omalizumab was further strengthened by a significant improvement in respiratory function as well as reductions in the nasal polyps' size and in the associated symptoms.

Cellular and Biochemical Characterization of Mesenchymal Stem Cells from Killian Nasal Polyp.

Killian's (antrochoanal) polyp is a unilateral nasal polypoid lesion of the maxillary sinus especially affecting children and young adults with unilateral nasal obstruction, pus discharge, and headache. Although its etiology is unclear, chronic inflammation, autoreactivity, allergies, and viral infections are implicated in its formation and development, causing nasal tissue remodeling. In this context, we isolated and cultured mesenchymal stem cells from surgical biopsies of three patients with Killian nasal polyp (KNP-MSCs) while healthy nasal tissue (HNT-MSCs) was used as control. Our results demonstrated that KNP-MSCs exhibited reduced cell proliferation compared to HNT-MSCs, and migrated less than the control, showing a partial epithelial phenotype with low mRNA levels of I-CAM and a significant increase of E-cad. Subsequently, both MSCs were induced to osteoblastic or adipocyte differentiation for up to 20 days. KNP-MSCs underwent to differentiate into osteoblasts but exhibited reduced ALP activity and calcium deposits and low mRNA levels of osteogenesis-associated genes compared to osteogenic induced-HNT-MSCs. Conversely, KNP-MSCs and HNT-MSCs have shown the same adipogenic differentiation potential, with a similar lipid droplet amount, adipocyte gene expression, and triacylglycerols content. Taken together, these results first demonstrated the cellular and molecular characterization of MSCs derived from the Killian nasal polyp.

Deficit in Adipose Differentiation in Mesenchymal Stem Cells Derived from Chronic Rhinosinusitis Nasal Polyps Compared to Nasal Mucosal Tissue.

Chronic rhinosinusitis of the nasal mucosa is an inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia, and in some cases, it can result in the development of nasal polyposis. Nasal polyps are benign lobular-shaped growths that project in the nasal cavities; they originate from inflammation in the paranasal mucous membrane and are associated with a high expression of interleukins (IL)-4, IL-5, IL-13, and IgE. Polyps derive from the epithelial-mesenchymal transition of the nasal epithelium resulting in a nasal tissue remodeling. Nasal polyps from three patients with chronic rhinosinusitis as well as control non-polyp nasal mucosa were used to isolate and cultivate mesenchymal stem cells characterized as CD73+, CD90+, CD105+/CD14-, CD34-, and CD45-. Mesenchymal stem cells (MSCs) cultures were induced to differentiate toward adipocytes, where lipid droplets and adipocyte genes PPARγ2, ADIPO-Q, and FABP4 were observed in control non-polyp nasal mucosa-derived mesenchymal cells but were scarcely present in the cultures derived from the nasal polyps, where apoptosis was evident. The modulation of the response to adipogenic stimulus in polyps represents a change in the molecular response that controls the cascade required for differentiation as well as possible means to specifically target these cells, sparing the normal mucosa of the nasal sinuses.

Maxillary sinus mucocele with orbital complications.

INTRODUCTION: Maxillary sinus mucocele is an unusual clinic entity (incidence of 3-10%), represented by mucous secretion lined by respiratory stratified pavemented epithelium and its origin is mainly secondary to infections, inflammations, surgery, trauma or neoplasia. CASE REPORT: We present a case of maxillary sinus mucocele. Subject of the study is a 74 aged patient referring positive anamnesis for nasal cavity surgery. His symptoms appeared six months ago and he complainted vertical ocular diplopia and ocular tension sensation, without rhinologic complaints. Oculistic examination confirmed an isolated left inferior rectus palsy, and CT showed mucous secretion occupying left maxillary sinus, with bone erosion to the orbital floor until orbital muscles. MRI is the gold standard for differential diagnosis with neoplastic lesions but the patient refused to perform this radio-diagnostic exam. He underwent to Endoscopic sinus surgery, consisting in middle meatal antrostomy and removal of the mucocele. Four months later the endoscopic follow-up showed regular maxillary cavity and regular ocular motility. CONCLUSION: In our opinion the rebuilding of the eroded bone is not mandatory if the integrity of the maxillary upper wall mucosa is respected, and antrostomy with drainage allows to recover ocular and paranasal sinus function. KEY WORDS:, Diplopia, Endoscopic sinus surgery.