xRead - Nasal Obstruction (September 2024) Full Articles

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International consensus statement on rhinosinusitis

epithelial cells (SNECs) produce antifungal peptides and proinflammatory cytokines that recruit other immune cells ie, tissue-resident macrophages and neutrophils and, at the later stage eosinophils, that directly contribute to fungal clearance. Production of cathelicidins and defensins, 2 key antimicrobial peptides associated with mucosal innate immunity were upregulated in CRS patients but notably not in CRS patients with eosinophilic mucin such as AFRS. 623 In addition, CRS with eosinophilic mucin was also noted for deficient pulmonary surfactant protein (SP-D). 624 A microarray analysis comparing sinonasal mucosal tissue from CRSwNP vs AFRS patients noted that the most differentially downregulated gene in AFRS was histatin 1, an antimicrobial peptide with antifungal activity. 625 Defects in the innate immune response to fungi would hinder clearance of inhaled spores allowing the spores to germinate and contribute to the pathogenesis of some CRSwNP such as AFRS. Since the ICAR-RS-2016 review, several studies have been published describing molecular mechanisms by which fungi can lead to the Type 2 immune response. As noted above, fungal spores can germinate into a hyphal form within the sinuses generating several components capable of inciting an immune response including pro teases and parts of the cell wall such as b-glucans. IL-33 is a key epithelial cell derived cytokine and driver of the Type 2 immune response. Sinonasal epithelial cells increase IL-33 expression and production when challenged with fungi. 626,627 This increase in IL-33 is in part associated with a fungal serine protease activated receptor 2 (PAR2). 628 In AFRS, PAR2 expression is increased on SNECs. 628,629 In addition, fungi can also drive an increased intracellu lar uptake of calcium via P2X 7 receptor activation that also leads to increase in IL-33 secretion. 627 These 2 path ways describe how fungi can initiate the Type 2 immune response of CRSwNP via IL-33. Activation of PAR2 by fungal protease can also suppress the antiviral Type 1 immune response by SNECs, skew ing toward a Type 2 immune response. 630 Homma et al. describe in vitro studies in which SNECs pre-incubated with A. fumigatus extract suppressed the Type 1 response typically incited by human rhinovirus serotype 16 expo sure. This pathway was PAR2 dependent. Exposed to fungi, SNECs may become more vulnerable to viral infections and skew these cells to a Type 2 immune response through activation of PAR2. 630 In addition, fungi have been linked to the pathogenesis of allergic asthma. 630 Similar to CRSwNP, asthma is char acterized by a Type 2 immune response associated with ele vated eosinophils and cytokines such as IL-4, IL-5, and IL 13. Millien et al. describe fungal protease cleaving locally present fibrinogen into fibrinogen cleavage products (FCPs) that can activate Toll-like receptor 4 (TLR4). Acti

vation of TLR4 in SNECs leads to increased IL-13 receptor expression, increased MUC5AC (a protein found in mucus) and increased production of antimicrobial peptides. This pathway also leads to elevated T helper 2 response to fungi with increased IgE production and ultimately pulmonary hyperreactivity (asthma). Given the high comorbidity of allergic asthma with CRSwNP and the FCP activated-TLR4 pathway in SNECs leading to increased mucus production and Type 2 immune response, it seems likely that this fungi activated pathway contributes to the pathophysiology of some subtypes of CRSwNP. These new studies highlight pathways by which fungi can incite the Type 2 immune response characteristic of CRSwNP. However, direct causal studies linking fungi to the etiopathology of CRS are lacking. An animal model of CRS would be needed to perform these causal studies. Although mouse models for CRS have yet to be widely used, several models have been proposed initiated by either challenge with a fungal allergen or a Staphylococcal enterotoxin sug gesting an etiologic role of these agents in CRS. To date though, these models utilized non-physiologic routes of challenge such as intraperitoneal injections or required an adjuvant in addition to the allergen. As such, fungi as the etiologic agent of CRS still remains inconclusive. Future studies differentiating AFRS from CRS therefore remain a priority for rhinologic research.

Fungus as a Contributing Factor for CRS Aggregate Grade of Evidence: C (Level 4: 14 stud ies; Table IX-5).

IX.C.4 Contributing Factors for CRS: Neo-osteogenesis Because of limited data, CRSsNP and CRSwNP are com bined in this analysis. Bone involvement in CRS is identified in 36% and 66% of patients and may play a role in CRS pathogen esis and the recalcitrant disease process. 265,637–646 The first experimentally-induced RS in animal studies initially reported presence of bone involvement and inflammation in the 1990s. 647,648 Kennedy et al. 638 followed this with descriptions of ethmoid bone remodeling in human sub jects. Another study by Giacchi et al. 649 identified higher rates of periosteal reaction, increased bone turnover, and the formation of immature woven bone in CRS patients when compared to controls. Similarly, histological samples