Pathogenesis of Olfactory Disorders in COVID-19

Abstract

Since the outbreak of the SARS-CoV-2 pandemic, olfactory disorders have been reported as a frequent symptom of COVID-19; however, its pathogenesis is still debated. The aim of this review is to summarize the current understanding of the pathogenesis of smell impairment in the course of COVID-19 and to highlight potential avenues for future research on this issue. Several theories have been proposed to explain the pathogenesis of COVID-19-related anosmia, including nasal obstruction and rhinorrhea, oedema of the olfactory cleft mucosa, olfactory epithelial damage either within the olfactory receptor cells or the supporting non-neural cells (either direct or immune-mediated), damage to the olfactory bulb, and impairment of the central olfactory pathways. Although the pathogenesis of COVID-19-related anosmia is still not fully elucidated, it appears to be mainly due to sensorineural damage, with infection of the olfactory epithelium support cells via the ACE1 receptor and disruption of the OE caused by immense inflammatory reaction, and possibly with direct olfactory sensory neurons infection mediated by the NRP-1 receptor. Involvement of the higher olfactory pathways and a conductive component of olfactory disorders, as well as genetic factors, may also be considered.

The Retrospective Pilot Study of the Prevalence of Olfactory Dysfunction or Loss of Smell, Loss of Taste and Oral Manifestations among COVID-19 Positive Health Workers in Muscat, Oman

“…The reason of the increased prevalence of loss of smell or olfactory dysfunction (OD) in our study is agreeable, because it is an established fact, that the smell impairment is one of the frequent symptoms of COVID-19 infection [21]. Although the pathogenesis of the OD is not still clear but it is suggested that the COVID-19 virus prefers the ACE2 receptors that are expressed in epithelial cells of oral mucosa and nasal mucosa [22]. A multicentric study in patients from China, France and Germany reported the loss of smell or the loss or taste in 19% before the other symptoms [14].…”

Oral SARS-CoV-2 Inoculation Causes Nasal Viral Infection Leading to Olfactory Bulb Infection: An Experimental Study

“…ACE2, a receptor for SARS-CoV-2, is mainly expressed in the supporting cells and basal cells of the OE, while the mature ORNs rarely express ACE2 ( Brann et al., 2020 ; Ueha et al., 2021 ). However, considering that NRP1, the other SARS-CoV-2 receptor is found in almost all cell types of the OE ( Cantuti-Castelvetri et al., 2020 ; Ziuzia-Januszewska and Januszewski, 2022 ), it is unsurprising that almost the entire OE is impaired by SARS-CoV-2 infection. In the present validation, the numbers of all ORN-related cells, including ORN progenitors, immature ORNs, and mature ORNs, were reduced in each area of the OE compared to the control group, although differences were observed in each area of the OE.…”

Evidence for the spread of SARS-CoV-2 and olfactory cell lineage impairment in close-contact infection Syrian hamster models

“…ACE2 is also expressed in the basal olfactory progenitor cells (Brann et al, 2020;Butowt and von Bartheld, 2021), and the low number of SOX2-positive cells on day 3 post infection suggests that SARS-CoV-2 infection may have directly impaired the olfactory progenitor cells. In addition, as the other receptor of SARS-CoV-2, neuropilin-1 is expressed in almost all cells of the OE (Cantuti-Castelvetri et al, 2020;Ziuzia-Januszewska and Januszewski, 2022), it is not surprising that all ORN lineage cells could be affected by SARS-CoV-2. Thereafter, by day 14, the olfactory progenitors and immature ORNs had developed, and epithelial regeneration had become active, but mature ORNs had not sufficiently regenerated, suggesting that overall recovery from SARS-CoV-2 infectioninduced OE damage may require longer than 14 days (Figure 6).…”