Distinguishing Molecular Features of Allergic Fungal Rhinosinusitis

Abstract

Objective Allergic fungal rhinosinusitis (AFRS) is a clinical subtype of chronic rhinosinusitis with nasal polyps (CRSwNP), characterized by eosinophilic mucin, evidence of fungal elements within the mucin, fungal-specific type I hypersensitivity, and characteristic computed tomography findings. It remains controversial whether AFRS represents a disease with a unique pathophysiology from chronic rhinosinusitis or is merely a severe form of CRSwNP. The goal of this study was to identify molecular features unique to AFRS. Study Design Cross-sectional case-control. Setting Single academic tertiary referral institution. Subjects and Methods Subjects included 86 patients undergoing endoscopic sinus surgery: CRSwNP (n = 34), AFRS (n = 37), and healthy controls (n = 15). Pathway and correlation analyses were performed with whole-genome microarray data for study patients undergoing surgery for recalcitrant chronic rhinosinusitis. Our findings were confirmed with quantitative polymerase chain reaction and immunohistochemical studies. Results AFRS was uniquely characterized by a pronounced association with adaptive T helper 2-associated immune gene expression. AFRS exhibited altered expression of proteins associated with secretory salivary peptides-namely, histatin, a peptide with known antifungal activity in the oral cavity. Furthermore, the expression of histatins correlated negatively with that of type 2 inflammatory mediators. We confirm the decreased expression of histatins in AFRS when compared with CRSwNP by quantitative polymerase chain reaction and localized its expression to a submucosal cell population. Conclusion There exist clear molecular profiles that distinguish AFRS from CRSwNP. This divergence translates into an altered ability to control fungal growth and may in part explain some of the phenotypical differences between CRSwNP and AFRS.

Aspergillus fumigatus induction of IL‐33 expression in chronic rhinosinusitis is PAR2‐dependent

“…Because the induction of intracellular calcium signaling in primary SNECs by A. fumigatus has not been explored, it remains to be determined if A. fumigatus also upregulates IL‐33 expression by using PAR2 to activate CRACs. The upregulation of several calcium‐related signaling pathways and receptors in CRSwNP was recently reported; this signaling modality will be the subject of future investigations. Calcium‐related signaling pathways in response to fungal protease interactions represent potential novel therapeutic targets for the treatment of CRSwNP.…”

Understanding and clinical relevance of chronic rhinosinusitis endotypes

“…In less prevalent cases, endotypes of CRS may be related to well‐defined mechanisms of disease that can be delineated using clinical knowledge. For example, AFRS may represent a distinct endotype of CRS that is defined as rhinosinusitis produced through a chronic allergic reaction to ambient fungal elements that may reach or colonise the paranasal sinus cavities . CRS in the setting of eosinophilic granulomatosis with polyangiitis (EGPA) may also be considered a distinct CRS endotype defined by sinus disease caused by the underlying vasculitis.…”

Current understanding of allergic fungal rhinosinusitis

“…The authors also reveal that the expression of histatins negatively correlates with the expression of several type 2 inflammatory mediators, including IL-13RA1, IL-4R, and periostin. 15 Taken together, disruptions in innate immune signaling and epithelial barrier function appear to go hand-in-hand with the pronounced type 2 inflammation observed in AFRS. Future studies will elucidate the mechanisms surrounding decreased barrier protein expression in AFRS, whether this is the result of specific cytokine-mediated suppression, an inciting factor in Th2 inflammation, defect in activation of antifungal pathways, or a combination of mechanisms.…”

“…Several works from the group of the senior author have demonstrated the incidence of comorbid asthma to be nearly half of that of CRSwNP. 10 , 13 , 14 , 15 For instance, in a prospective study of 410 patients, Promsopa et al 14 recently used pulmonary function testing (PFT) to evaluate the prevalence of asthma CRS subtypes. This study found 23.6% of AFRS patients as compared to 48.3% of CRSwNP patients with PFT-confirmed asthma.…”

“…The study was limited by small sample size (7 patients total) and the rationale for evaluating the target genes under study was not clear. Tyler et al 15 recently sought to describe the gene expression variations in AFRS that make it unique when compared to CRSwNP. The study included a total of 86 patients (37 AFRS, 34 CRSwNP, 15 healthy control).…”