Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)?

Arianna Di Stadio, Evanthia Bernitsas, Ignazio La Mantia, Michael J Brenner, Massimo Ralli, Luigi Angelo Vaira, Andrea Colizza, Carlo Cavaliere, Matteo Laudani, Teresa C Frohman, Marco De Vincentiis, Elliot M Frohman, Marta Altieri, Arianna Di Stadio, Evanthia Bernitsas, Ignazio La Mantia, Michael J Brenner, Massimo Ralli, Luigi Angelo Vaira, Andrea Colizza, Carlo Cavaliere, Matteo Laudani, Teresa C Frohman, Marco De Vincentiis, Elliot M Frohman, Marta Altieri

Abstract

Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin' Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.

Keywords: COVID-19; PASC; SARS-CoV-2; TDM; anosmia; disease-modifying therapy; hyposmia; interferon; long COVID; long-haul COVID; multiple sclerosis; neuroinflammation; olfaction; olfactory; olfactory training; post-acute sequelae of SARS-CoV-2 infection; smell; smell disorders; threshold detection identification.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The graph shows the difference in composite olfactory threshold, discrimination, and identification (TDI) scores for patients with multiple sclerosis (MS) at T0 and T1. No statistically significant variances were observed between T0 and T1 in these patients, as shown in the estimation plot (right side of the image).
Figure 2
Figure 2
The graph shows the differences in composite olfactory threshold, discrimination, and identification (TDI) scores of patients with COVID-19 (MS) at T0 and T1. Statistically significant variances were observed between T0 and T1 in these patients. as shown in the estimation plot (right side of the image).
Figure 3
Figure 3
The figure shows the details of the recovery of the smell function in patients with COVID-19 after being treated with PEA-LUT and olfactory rehabilitation for 3 months.
Figure 4
Figure 4
The graph shows the detailed differences in threshold, detection, and identification (TDI Sniffin’ Score) between patients with MS at T1 and patients with COVID-19 after treatment.

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