In this case study, COVID-19-related OD was correlated with OB volume loss and abnormal MR spectroscopy findings, indicating neuronal destruction in the central nervous system (CNS) secondary to COVID-19 infection. Furthermore, rs-fMRI demonstrated olfactory FC impairments, thereby providing further insights into the underlying neuropathological process of COVID-19-related OD.
In the treatment for COVID-19-related OD, one patient was successfully challenged with oral VitA and ST, as demonstrated by (1) interval improvements in olfactory function; (2) structural restoration in OB volumes; as well as (3) olfactory network recovery and (4) enhanced cerebral perfusion. We hypothesis that VitA is an important metabolic substrate for robust neurogenesis at the olfactory apparatus and enhancement of olfactory functional neural connectivity. However, due to the limited scope of this report, the therapeutic efficacy of oral VitA and ST in the restoration of smell should be validated in large scale randomized–controlled trials.
The integrity of the mammalian OE is preserved by the mitotically active GBCs and dormant HBCs. The dormancy of HBCs is maintained by Notch1 signaling which is correlated with the expression of transcription factor protein 63 (ΔNp63α). During extensive OE injury, Notch1 signals and ΔNp63α expressions are downregulated, leading to HBCs activation and differentiation.8 Retinoic acid (RA), the active metabolite of VitA, has been shown to reduce ΔNp63α expression in HBCs, thereby promoting the differentiation of multipotent Sox2+ and Pax6+ progenitors via the canonical Wnt signaling pathway in the OE.6 Furthermore, the neurophysiological importance of RA signaling in the OE has been further demonstrated in the maintenance and survival of Ascl1+ GBCs.
Within the CNS, RA machineries have been identified in the murine and human brains, especially at the hippocampus and dentate gyrus. RA increases neurogenesis in the rodent subventricular zone (SVZ)–OB pathway, as demonstrated by increased bromodeoxyuridine-positive (BrdU+, proliferating cell marker) cells in SVZ neurospheres and altered cellular migration to the olfactory bulbs.9 In addition, depletion of doublecortin-positive (DCX+, immature neuronal marker) cells in the adult murine dentate gyrus was evident in the retinoid–deficient mouse model, indicating the crucial role of RA in the survival of neural progenitors.10
Olfactory stimulation via ST, as non-pharmaceutical intervention for post-infectious OD, was used to complement the therapeutic effects of oral VitA. MRI studies in ST-treated patients have demonstrated functional network improvements and structural increase of cortical thickness in the frontal cortex, where the olfactory apparatus is located. The exact therapeutic mechanism of ST is unknown; however, olfactory stimulations remain essential to the neuro-rehabilitation processes. Reversible and irreversible olfactory occlusion experiments in murine models have shown that olfactory stimuli are contributory to olfactory neurogenesis and glomeruli maturation. In this report, ST was delivered by the novel EPAR diffusers, which utilized ultrasonification to generate aerosolized essential oils for olfactory stimulation. The EPAR diffuser technology enhances the ST experience by facilitating the physiological penetration of aromatic molecules through the olfactory meatus to the OE at the roof of the nasal cavity, therefore providing potent olfactory stimulation and neurosensory rehabilitation.
In conclusion, structural and functional olfactory defects were identified in patients presenting with prolonged COVID-19-related OD. Preliminary evidence suggested that combination treatment by oral VitA and ST may induce robust neurogenesis at the olfactory apparatus, attain restoration of functional network connectivity, and achieve olfactory neurosensory rehabilitation. The therapeutic efficacy of oral VitA and ST for COVID-19-related OD should be validated in large scale randomized–controlled trials.