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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disease based on current evidence compared with the healthy population. Policy level : Use of a validated QOL survey is recom mended in individuals with OD related to CRS. Use of a validated QOL survey is an option in individuals with OD without sinonasal disease. Intervention : A validated olfactory QOL survey should be considered in individuals with CRS and in those who may have other diseases that impact olfaction. E Measurement of cytokine/mucin levels Olfaction requires odorant molecules to reach the OE, receptor binding, signal transduction and transmission, and interpretation in the CNS. Thus, any pathology in this process can result in loss of olfaction, leading to many potential causes for OD. Inflammatory sinonasal disease, such as CRS, is the most common cause of olfac tory loss, and it appears that many factors including local inflammation-mediated OE injury, nasal obstruction, and OC binding protein and mucous transport abnormali ties, among others, may be involved in OD in CRS. 175 Researchers have attempted to gain greater understand ing of the mechanisms involving inflammatory media tors such as cytokines, chemokines, and other proteins by assessment of the local microenvironment of the OE. Lane et al utilized a mouse model of reversible TNF α mediated inflammatory infiltration and found thinning of the OE with atrophy of axon bundles in the neural layer, and severely diminished electro-olfactogram (EOG) responses. 250 TNF- α may also affect OE regeneration, and downstream cytokines may play a role in inflammatory OD. 163,164,166,167 Other murine studies have implicated IL 4, IL-5, IL-13, IL-17c, chemokine (C-C motif) ligand (CCL) 28, and chemokine (C-C motif) receptor 5 in OD. 1261–1263,173 Six studies of human CRS-related dysosmia have corre lated psychophysical olfaction to OE biopsy or olfactory mucus samples. 177,179,180,183,216,1264 Olfaction in CRSsNP was inversely correlated with TNF- α , IL-5, and IL-10, and directly correlated with IL-7 and chemokine (C-X-C motif) ligand 5, while olfaction in CRSwNP was inversely corre lated with TNF- α , IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, CCL2, CCL5, and CCL11 and directly correlated with IL-6, IL 7, and vascular endothelial growth factor A. 179,180,183,1264 Two other studies utilizing hierarchical cluster analysis and OE tissue biopsies found associations between IL 2, IL-5, IL-13, and CCL11 and olfaction. 177,216 Only the inverse correlations of IL-5, IL-6, IL-10, IL-13, and CCL11 to olfaction in CRSwNP were found in multiple stud ies, with IL-6 also showing a direct correlation in one study. 179,180,183,1264

Four studies have evaluated inflammatory proteins in non–CRS-related OD. 181,1265–1267 Schubert et al 1266 found no associations between baseline systemic C reactive protein, IL-6, and TNF- α to subsequent devel opment of OD over 10 years and Darnell et al 1265 found a systemic cytokine profile associated with frailty (high IL-1 receptor antagonist, low IL-4, low IL-13) had significantly higher odds of worse olfaction. Henkin et al 181 found that IL-6 levels were significantly higher in the plasma, saliva, and nasal mucus of hypos mic patients compared with normosmic patients. Yoo et al 1267 evaluated OC mucus concentrations of 18 pro teins in non-CRS patients and found inverse correlations between psychophysical olfaction and cyclin-dependent kinase inhibitor 2A (CDKN2A/P16INK4a), basic fibroblast growth factor, CCL2, CCL20, and granulocyte-macrophage colony-stimulating factor, and a direct correlation with stem cell factor. Notably, the results from non-CRS studies were largely dissimilar to the findings from the CRS stud ies, pointing to the likelihood that OD in CRS-related and non-CRS–related causes occur via distinct mechanisms. It must be noted that these human studies described are all observational and thus can only establish associations and are not designed to determine causality. However, these studies do show that the measurement of inflam matory mucus proteins is a viable avenue of investigation. In summary, numerous nasal mucus proteins have been associated with OF, but only a few cytokines (IL-5, IL 6, IL-10, IL-13, and CCL11) have shown reproducibility of the associations among multiple studies. This variability is likely attributable to the heterogeneity of etiology of OD. Although promising as a way to identify potential ther apeutic targets and/or strategies, further investigation is required to transform this potential into a clinical tool. Multiple nasal mucus proteins have been associated with OF, with a few cytokines showing reproducibility of association with OF among multiple human and murine studies (IL-5, IL-6, IL-10, IL-13, and CCL11). Some of the inconsistency in findings are likely related to the heterogeneity of causes of OD and further study into these associations is required. Aggregate grade of evidence : C (majority of observa tional studies with variable results, Level 3: two studies; Level 4: eight studies). F Electro-olfactogram The EOG is an electrophysiological equivalent of olfac tory activation at the level of the olfactory mucosa. It rep resents the summated generator potentials of OSNs in response to an olfactory stimulus. While this measurement