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

odor discrimination and identification extra-seasonally, but they appear to demonstrate persistently depressed odor thresholds. 153,225,232 Suzuki et al 233 demonstrated that patients with seasonal AR for ≥ 10 years, in particular, experience extra-seasonal OD. Fewer studies have specifically investigated the effects of non-AR on olfaction. Some evidence suggests higher rates and more severe OD in patients with non-AR com pared with patients with AR, but this finding is inconsis tent among the published literature. 223,229,234,235 Two primary mechanisms have been proposed to explain the OD observed in patients with rhinitis. OD may be secondary to an obstructive phenomenon lead ing to reduced airflow through the OC. 236 However, the literature more strongly supports the notion that inflam matory cytokines detrimentally affect the function of the olfactory mucosa. 153,225,235–237 Murine models of AR have demonstrated OD secondary to infiltration of eosinophils, mast cells, plasma cells, macrophages, and neutrophils in the OE. 238–240 A study by Kim et al 239 demonstrated that mice with AR exhibited higher rates of olfactory stem cell apoptosis induced by TNF- α with a synergistic effect from IL-5. The literature strongly supports the association between rhinitis and OD with variable incidence and severity depending on the subtype of rhinitis and selection of the study population. OD is associated with rhinitis. Aggregate grade of evidence : C (Level 2: seven stud ies; Level 3: three studies; Level 4: nine studies). Non–COVID-19 related Although COVID-19 is the most well-known viral cause of olfactory loss to the general public, olfactory experts have been treating postviral OD (PVOD) for years before the pandemic. The pathophysiology of PVOD following an infectious illness has not been clearly delineated. 241 As noted above, olfaction is a complicated process that includes many cellular and signaling pathways. As a result, there is a difference in the pathophysiology between olfac tory loss in acute infectious processes and the more chronic PVOD. Nonetheless, studies have shown several key ele ments that may play a vital role in understanding how OD occurs following a viral infection. There are a multitude of viruses that have been shown to be present in the nasal respiratory epithelium of hyposmic/anosmic patients following a viral respiratory infection. These viruses include, but likely are not lim B Postviral Loss 1

ited to, parainfluenza, Epstein-Barr virus, coronavirus, rhinovirus, influenza virus, respiratory syncytial virus, adenovirus, coxsackievirus, enterovirus, poliovirus, and herpes virus. 241–244 One recent study has shown rhinovirus and coronavirus to be the most commonly identified viruses in PVOD. 245 Viruses have been shown to damage a variety of cells within the olfactory sys tem including OR neurons, which detect odorants and odorant-binding proteins. 242 Other studies have shown that the olfactory neuroepithelium undergoes cellular changes caused by viral insult. 241 These changes include the replacement of the neuroepithelium with respiratory like epithelium, a highly disorganized OE compared with patients without OD, and occasionally metaplastic squa mous epithelium. 201,246 Other studies show that there is an increase in neurogenesis in response to the viral insult. 247 This results in a larger proportion of immature neurons compared with mature neurons, which may impact overall olfactory ability. Additionally, dendrites in the epithelium of patients with postinfectious olfactory disorders have been shown to be truncated and not able to reach the surface layer as would be seen in healthy tissue. 201,246,247 This may result in the inability of the neuroepithelium to detect odorants. Recent translational studies have shown that viruses may also cause indirect damage to olfactory cell function. These studies demonstrate that olfactory cells may clear viral elements without destroying them, and that viral elements can persist in nerve tissue. 248,249 The immune response and persistence of viral elements do not fully explain the observed changes to olfactory neuroepithelium nor the presence of PVOD in some patients compared with others. These studies suggest that viral infections drive OD in varying ways depend ing on the host’s genetic makeup, immune response, and environment, so that there is not a clearly defined pathophysiological pathway at this time for all viral causes. In addition to the previously mentioned viral effects on OE in relation to PVOD, there is also the acute onset of nasal congestion that hinders OF and often accompanies a viral infection. 250 Nasal congestion limits the airflow among the OE, and without proper airflow, odorants are unable to be detected by the OE. This process is acute and short-lived, and the sense of smell would theoretically return once the inflammation subsides. Unfortunately for some patients, OD persists, likely because of neuroepithe lial injury after this acute stage. The exact percentage of patients with persistent OD is not well-defined because the total incidence of postviral olfactory loss (PVOL) is not known, although this group makes up ≈ 20% to 30% of most series accounting for the etiology of OD in patients presenting for treatment. 251 Nonetheless, 35% to 46% of patients with PVOD will gain clinically significant improvement. 252 For those who do not recover,