I. Executive Summary: Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document.Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary.Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided.Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is closely associated with tissue remodeling. Epithelial-to-mesenchymal transition (EMT), a process of tissue remodeling, can be a therapeutic target of CRSwNP. Glucocorticoids are a type of steroid hormone that is used primarily in medical therapy for patients with CRSwNP; however, their effects on EMT in the airway epithelium remain unknown. To investigate the effects of dexamethasone and fluticasone propionate, a class of glucocorticoids, on transforming growth factor-β1 (TGF-β1) -induced EMT, we used A549 cells, human primary nasal epithelial cells (hPNECs) and ex vivo organ culture of the inferior turbinate. TGF-β1 induced changes in cell morphology, suppressed the expression of E-cadherin and enhanced the expression of a-smooth muscle actin, vimentin and fibronectin in A549 cells. However, glucocorticoids inhibited EMT, migration and invasion enhancement by TGF-β1. We found that the induction of phosphorylated ERK, p38 and the activity of Snail and Slug transcription factors by TGF-β1 were suppressed by glucocorticoids. Glucocorticoids also had a similar effect in hPNECs and ex vivo organ cultures of the inferior turbinate. These findings suggest that glucocorticoids might be a useful therapy for preventing tissue remodeling by blocking the EMT initiated by TGF-β1-induced MAPK and Snail/Slug signaling pathways in CRSwNP.

Chronic rhinosinusitis is involved in tissue remodeling of nasal mucosa such as nasal myofibroblast differentiation and extracellular matrix production. Apigenin (4’,5,7-trihydroxyflavone) is a bioflavonoid compound and has anti-tissue remodeling characteristics. The aims of this study were to evaluate the effect of apigenin on TGF-β1-induced myofibroblast differentiation and extracellular matrix accumulation and to determine the underlying mechanism. Nasal fibroblasts and ex vivo nasal inferior turbinate tissues were stimulated with TGF-β1 with or without apigenin. The expression levels of α-SMA, fibronectin and collagen type I were determined by real-time PCR, western blot and immunocytochemical staining. Mitogen-activated protein kinase (MAPK) phosphorylation induced by TGF-β1 were determined by western blot analysis. The transcriptional activity of NF-κB was measured by luciferase assay. Migration effects of fibroblasts were evaluated by wound scratch and transwell migration assay. Contractile activity was determined by collagen gel contraction assay. The expression levels of α-SMA, fibronectin, and collagen type I significantly increased in TGF-β1-stimulated nasal fibroblasts. In TGF-β1-stimulated nasal fibroblasts, apigenin inhibited the expressions of α-SMA, fibronectin, and collagen type I. Inhibitors of MAPK (p-38, JNK) and NF-κB blocked the expression of α-SMA, fibronectin and collagen type I. Apigenin suppressed the activation of MAPK (p-38, JNK) and NF-κB induced by TGF-β1 treatment. Apigenin also inhibited the functional activity of fibroblasts by reducing the migration and collagen contractile activities. These results suggests the possible use of apigenin as a chronic rhinosinusitis therapeutic agent which can suppress tissue remodeling in nasal mucosa.

In airway epithelium, thymus and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) are induced by defective epithelial barriers such as E-cadherin and attract the effector cells of Th2 immunity. However, the association between the epithelial barrier and CCL17 expression has not been studied in chronic rhinosinusitis with nasal polyp (CRSwNP). Thus, we aimed to evaluate the expression of CCL17 and its regulation by Th cytokines in nasal polyp (NP) epithelial cells. The expression and distribution of CCL17, CCL22, E-cadherin and/or epidermal growth factor receptor (EGFR) were measured using real-time PCR, western blot, and immunohistochemistry and compared between normal ethmoid sinus epithelium and NP epithelium. In addition, the expression level of CCL17 was determined in cultured epithelial cells treated with IL-4, IL-5, IL-13, TNF-α, and IFN-γ. The expression of CCL17 was decreased in the NP epithelium compared to the epithelium of normal ethmoid sinus, whereas the expression of CCL22 was not decreased. E-cadherin was differentially distributed between the epithelium of normal ethmoid sinus and NP epithelium. EGFR was also decreased in NPs. Interestingly, the stimulation of cultured epithelial cells with Th2 cytokines, IL-4 and IL-5, resulted in an upregulation of CCL17 expression only in NP epithelial cells whereas the expression of CCL17 was increased in both normal epithelial cells and NP epithelial cells by Th1 cytokines. Our results suggest that the decreased expression of CCL17 in defective NP epithelium may be closely connected to NP pathogenesis and can be differentially regulated by cytokines in the NP epithelium of patients with CRSwNP.

BackgroundChronic rhinosinusitis (CRS) is inflammatory disease of sinonasal mucosa. Thymic stromal lymphopoietin (TSLP) is associated with Th-2 response and induced by pathogen, allergen, Toll-like receptor (TLR) ligands, and cytokines. Fibroblasts have known to modulators of wound healing, from inflammation to tissue remodeling. We examined effect of lipopolysaccharide (LPS) on TSLP production and underlying mechanisms. We aimed to determine whether effects of commonly used medications in CRS, corticosteroids and macrolides, are related to LPS-induced TSLP in nasal fibroblasts.ResultsFibroblasts were isolated from inferior turbinate tissues of CRS patients. TSLP and TLR4 expression was determined by RT-PCR, western blot, ELISA, and immunofluorescence staining. MAPK, Akt, and NF-κB phosphorylation was determined by western blot and/or luciferase assay. LPS increased TSLP expression in a dose- and time-dependent manner. LPS antagonist and corticosteroids inhibited TLR4 expression in LPS-stimulated fibroblasts. LPS-RS, macrolides, corticosteroids, and specific inhibitors suppressed LPS-induced alterations. Ex vivo culture showed similar results.ConclusionsLPS induces TSLP production via TLR4, MAPK, Akt, and NF-κB pathways. Effects of corticosteroids and macrolides are related to LPS-induced TSLP expression. We would explore new treatment modalities targeting LPS-induced TSLP production that could replace current usage of corticosteroid and macrolides in treatment of CRS.