xRead - Olfactory Disorders (September 2023)

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INTERNATIONAL CONSENSUS ON OLFACTION

and IgE, among others. Although these inflammatory pro teins are most commonly seen in patients with CRSwNP, they may also be elevated in patients with CRSsNP, sug gesting that phentoypes are not always reflective of under lying endotype. 197 OC neuroepithelium remodeling rep resents another potential mechanism for CRS olfactory loss. 201 Biopsy of the OC in patients with chronic inflam mation has shown changes to the neuroepithelium, with resulting squamous metaplasia, fibrosis, or replacement of the OE with respiratory epithelium. 177,202,203 Several stud ies have also found associations between olfaction and OB remodeling. 177,204 When examining objective disease burden among patients with CRSsNP, higher severity of sinonasal inflammation has been associated with smaller OB volumes (OBVs) and decreased retronasal OF. 204 Inflammatory-related changes in the olfactory neuroep ithelium, as previously described, are postulated to result in decreased sensory input to the OB resulting in a decrease in OBV. Additionally, among patients with CRSwNP, changes in OBVs have been examined in response to med ical and surgical treatment with a correlation observed between improvement in OF and increase in OBV. 205 b. In relation to endotype CRS has been traditionally classified based on clini cally observed phenotype, 208 eg, the presence (CRSwNP) or absence (CRSsNP) of NPs, the presence of aspirin sensitivity (aspirin-related respiratory disease [AERD]), or the presence of fungal elements in allergic fungal sinusitis. 209–212 The CRSwNP and AERD phenotypes have significantly higher prevalence of OD, as previously dis cussed. However, in recent years, there has been a research push toward classifying CRS into endotypes unified by common pathobiological or molecular mechanism rather than clinically observed characteristics. These efforts are motivated, in part, by the new availability of precision bio logic drugs that target specific mechanisms of inflamma tion in CRS. Additionally, there is evidence that certain phenotypes such as CRSwNP may have significant endo typic heterogeneity in different parts of the world. 213–215 Of particular interest to olfactory outcomes in CRS has been the ability of monoclonal antibodies against type 2 inflammation (previously known as Th2 inflammation) to improve OF in CRSwNP. Clinical trials studying these medications allow insight into mechanisms driving CRS associated olfactory loss. This section will summarize endotyping studies in CRS that have specifically evaluated olfaction with mention of randomized controlled studies of precision biologics that report olfactory outcomes. A number of studies have examined tissue and mucus biomarkers from the OC of patients with CRS, mostly in a cross-sectional fashion (Table VII-3). In terms of endo typing, several studies have reported measurement of indi

vidual cytokines, chemokines, and or cellular products and their relationship to olfaction, 177,179,180,183 whereas one study utilized supervised or unsupervised mechanisms to dimensionally reduce inflammatory mediators and clas sify patients into clusters organized by commonalities in their inflammatory profile. 216 The latter method of anal ysis, while commonly thought of as endotyping, does not always produce pathogenically unifying clusters, as a sin gle cluster can be identified by multiple mechanisms. From these studies, type 2 cytokines such as IL-5 and IL-13, as well as markers of eosinophilia, measured in olfactory tis sue or in secretions in the OC appear consistently related with OD as measured using both the UPSIT R andSSmea surements. In the studies that have utilized larger panels of inflammatory mediators, IL-6 and IL-10 cytokines in olfac tory mucus, which are not traditionally considered type 2 cytokines, have also been associated with OD in more than one independent study. 179,183 While these studies do elucidate inflammatory media tors present in the OC among patients with OD, they do not provide a mechanistic understanding of how type 2 inflam mation causes olfactory loss. Evidence does suggest that at least some of the olfactory loss is conductive in nature, with the identified inflammatory factors also correlated with edema in the narrow OC, as measured by radiographic opacification. 183 Interestingly, in the studies that have sep arated analyses out by CRSsNP and CRSwNP phenotypes, the associations between endotype and OF appear signifi cant primarily among patients with CRSwNP, suggesting that the effects of type 2 inflammation explain a greater portion of the variance in OF among these patients. 183 Currently, there are no studies that have utilized endotyp ing approaches to predict olfactory outcomes after surgery; however, a recent study found that eosinophilic inflamma tion in the superior turbinate was predictive of olfactory deficit after 3 months of sinus surgery. 217 The two biologic medications specifically targeting aspects of type 2 inflammation in CRSwNP included objec tively measured olfaction as an end point. 218–220 These will not be discussed in detail here, but the improvements observed relative to placebo nonetheless provide defini tive evidence that type 2 inflammation is mechanistically important to olfactory deficit. Dupilumab, which targets the common receptor of IL-4 and IL-13, is known to inhibit lymphocyte differentiation and lineage commitment and plays a role in Th0 to Th2 differentiation, B-cell isotype switching to IgE, and antibody secretion and differenti ation of epithelial cells into mucus-secreting cells. 221,222 Omalizumab, in contrast, targets soluble and cell-bound IgE. Evidence that both of these precision biological med ications improved olfactory outcomes in patients with CRSwNP relative to placebo provides evidence that these inflammatory effects directly or indirectly cause olfac-