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

common cause of short-term olfactory impairment asso ciated with the “common cold” caused by endemic coronaviruses. 259,260 However, although nasal congestion is sometimes reported by patients with COVID-19, it is less frequently reported than with other coronavirus associated upper respiratory infections (URIs), 262 suggest ing that an alternative or additional mechanism may be responsible. Nevertheless, localized obstruction caused by edema within the OC has been proposed as one potential mecha nism, and one study has shown a high prevalence of com plete obstruction of the OC in MRI scans performed within 15 days of onset of COVID-19 OD, 262 which had resolved in more than half of cases at 1-month follow-up, accompanied by improvement in OF. In contrast, other radiological stud ies of patients with more persistent loss have found this to be an uncommon persistent finding. 263 Whether obstruc tion of the OC contributes to the severity of early OD by preventing access of odorants to the OSNs or reflects a con sequence of epithelial injury is unclear at this time. Injury to the OE Olfactory epithelial injury has been demonstrated in prior cases of postviral loss and could account for the tran sient edema noted in the OC discussed above. Histologi cal studies in prior non–COVID-19 cases of postviral loss have demonstrated damage to the OE including OSNs and consequent scarring and atrophy, with correlation found between the severity of epithelial destruction and OD. 264 A postmortem study of two patients with COVID-19 reporting anosmia showed focal atrophy of the OE, leuko cytic infiltration of the lamina propria, and evidence of axonal damage in the olfactory nerve fibers. 265 Similarly, animal models of SARS-CoV-2 266 have demonstrated mas sive destruction of the OE after nasal inoculation and loss of cilia, with evidence of recovery observed as early as day 4 after exposure, although incomplete by day 14. Angiotensin-converting enzyme 2 (ACE2), a receptor on the cell surface required for SARS-CoV-2 viral entry, has been shown to be expressed by the sustentacular support ing cells and basal cells of the OE, but not on the OSNs themselves. 267,268 Staining from a preclinical study showed that SARS-CoV-2 infected the sustentacular cells but not OSNs, and the virus was not found in the OB or central nervous system (CNS). 269 The sustentacular cells support olfactory receptor neuron function in a number of ways, including endocytosing odorant-binding proteins, remov ing toxic volatiles, and supplying glucose to the cilia of the olfactory receptor neuron. Therefore, damage to these cells may precipitate reduced sensitivity and the loss of cilia from the OSNs, resulting in OD even though the

OSNs do not themselves express ACE2 or become directly infected. Injury to the supporting cells as the predominant mechanism causing OD seems consistent with the rapid pattern of recovery reported in the majority of patients, with many reporting resolution within the first 7 to 14 days, 270–272 faster than would be expected for immediate OSN replacement and maturation but in keeping with the faster recovery of sustentacular cells. 273 In more severe cases, loss of the supporting cells could lead to an even tual secondary loss of the OSNs, as their role in support ing the normal inherent regenerative turnover of OSNs is consistent with the presentation of many of these patients with initial recovery from their COVID-19–related loss who then present 3 to 4 months later with a secondary hypos mia, often accompanied by parosmia. In addition, the immune response may play a role in COVID-19–related OD. Large increases in macrophages are found in the OE and lamina propria of animal mod els after SARS-CoV-2 infection. 267 Persistence of inflam mation may prevent recovery of the OE and restoration of the OSNs. Induction of inflammation in a murine model of CRS-associated anosmia demonstrated inhibition of basal cell differentiation and neuronal depletion. 169 Results of olfactory epithelial biopsies from 3 deceased COVID-19 patients showed significantly higher levels of the proin flammatory cytokine TNF- α than biopsies taken from non infected living controls, 274 although postmortem artifact cannot be excluded. Some of the most recent studies, cur rently only available in preprint and therefore to be inter preted with caution, propose an inflammatory-mediated loss of odorant receptor expression on otherwise intact OSNs; this is supported by animal models 275 and olfactory epithelial biopsies harvested from patients with COVID-19 postmortem. 276 Clinical studies have found that the severity of OD is inversely correlated with recovery rates, 270,271 and may also reflect the severity of epithelial injury. Results of an in vivo biopsy of a patient with anosmia persisting 3 months after diagnosis showed extensive destruction of the OE consis tent with mucosal biopsies harvested early in the course of infection in animal models. 277 OB infection and propagation to the CNS Propagation of viruses by retrograde axonal transport to the OB and beyond to the CNS is well described 278 and has been shown to be associated with anos mia in herpetic encephalitis 279 in murine models. Animal models of OC43 coronavirus infection have demonstrated viral particles within the OB 3 days after inoculation 280 and through the cortex by day 7. ACE2 transgenic mice inoculated with SARS-CoV-1 similarly