xRead - Olfactory Disorders (September 2023)

20426984, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/alr.22929, Wiley Online Library on [04/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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INTERNATIONAL CONSENSUS ON OLFACTION

nasal polyps (CRSwNP) has shown variation in airflow disruption based on polyp location that correlates to the degree of OD, with the greatest dysfunction in patients with OC polyps and the least dysfunction with polyps con fined to the middle meatus. 142,143 Similarly, OC opacifi cation on computed tomography (CT), reflective of OC patency, has been shown to correlate with OD differen tially by CRS type. 144,145 Removal of obstruction either through surgical 146–148 or anti-inflammatory 149,150 treat ment results in similar levels of improvement in olfaction. Additionally, chronic inflammation has been speculated to alter olfactory mucus composition, impeding conduction of odorants. 151 While airflow patency plays an important role, it does not fully correlate with the degree of olfactory loss in sinonasal inflammatory disease, 152–154 suggesting the con tribution of other mechanisms. In contrast to conductive loss, sensorineural OD involves disruption of OSN signal ing and processing. The pseudostratified OE is composed of multiple neuronal and non-neuronal cell types that may be affected by inflammation. Its location in the nasal air way makes it vulnerable both to direct injury from exoge nous inflammatory stimuli, as well as secondary injury from endogenous antimicrobial defenses of the adjacent respiratory mucosa. Although this damage disrupts OE integrity and function, the OE has a remarkable ability to regenerate, with mitotically active globose basal cells continuously replacing OSNs and maintaining the api cal non-neuronal barrier. 155–157 Horizontal basal cells pro vide a secondary, quiescent stem cell pool that is activated after severe injury. 100,90 The signaling pathways that guide regeneration are incompletely understood, but include p63 and Notch 158–160 in mice, and appear to be modulated by inflammatory mediators such as tumor necrosis fac tor (TNF) 161–167 and nuclear factor- κ B–mediated cross-talk between horizontal basal cells and immune cells. 168,169 In animal models, exposure of the OE to bacteria or allergens produces an influx of inflammatory cells associated with neuronal loss and decreased renewal of immature olfac tory neurons, 169–173 with similar findings noted in speci mens from anosmic patients. 174–177 Markers of inflamma tion, such as tissue eosinophilia 177,178 and the presence of type 2 cytokines in mucus obtained from the OC, 153,179–183 have been reported to correlate with olfactory loss in patients with CRSwNP. The OE is impacted by, and likely participates in, sinonasal inflammatory disease, with varying contribu tions of conductive and sensorineural mechanisms on OF and OE structure. Medical therapy that targets inflam mation likely improves olfaction both by increasing airflow and by reducing local inflammatory cells and mediators. 137,146,150,184 The expression of steroid receptors on OE cells 185,186 in animal models and the attenuation

of OE lesions after topical administration of steroids may suggest additional direct effects of corticosteroids on OE function. 187 Irreversible olfactory loss after longstanding sinonasal inflammatory disease may be a result of neu rogenic exhaustion or metaplastic changes to the OE. While reduction of sinonasal inflammation remains the primary treatment strategy, future therapies may target neuroprotective mechanisms or activation of progenitor cell–mediated regeneration. 188,189 Sinonasal inflammatory disease as a cause of olfactory dysfunction. Aggregate grade of evidence : B (Level 1: one study; Level 2: one study; Level 3: nine studies; Level 4: one study). Decreased odorant conduction as a mechanism of inflammation-associated OD. Aggregate grade of evidence : B (Level 1: one study; Level 2: three studies; Level 3: three studies; Level 4: five studies). Sensorineural mechanisms as an underlying cause of inflammation-associated OD. Aggregate grade of evidence : C (Level 3: three studies; Level 5: four studies). 2 Related to CRS a. In relation to phenotype (nasal polyps or no nasal polyps) The degree of OD commonly varies by CRS phenotype, with patients with CRSwNP usually demonstrating a higher prevalence and severity of olfactory impairment than patients with CRSsNP. 14,147,190–193 The factors con tributing to olfactory loss in patients with CRS are com plex and likely a consequence of multiple pathophysio logical mechanisms that may differ depending on phe notype. Mechanical obstruction of odorant transmission to the OC neuroepithelium can be a result of mucus, edema, and/or nasal polyps (NPs) and is usually more severe in patients with CRSwNP. 194,195 As noted in the prior section, in this mechanism, the polyps and edema characteristic of the CRSwNP phenotype block odorants from reaching the OC. Among patients with CRSwNP, OC opacification on CT scan correlates with the severity of OD. 196 Differences in orthonasal versus retronasal OF have been demonstrated, with retronasal OF better pre served compared with orthonasal function among patients with CRSwNP. 139,196 Patients with CRSsNP tend to have less OC opacification on CT scan, suggesting less disrup tion of odorant delivery as compared with CRSwNP. 196 Direct inflammation at the level of the neuroepithelium is another possible mechanism of CRS-related olfactory