Reduced olfactory bulb volume accompanies olfactory dysfunction after mild SARS-CoV-2 infection

Abstract

Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis. Data of non-vaccinated COVID-19 convalescents recruited within the framework of the prospective Hamburg City Health Study COVID Program between March and December 2020 were analyzed. At baseline, 233 participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022, olfactory function was assessed at follow-up including quantitative olfactometric testing with Sniffin' Sticks. This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of self-reported olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute self-reported olfactory dysfunction had a significantly lower olfactory bulb volume at baseline than normally smelling individuals. Olfactory bulb volume at baseline predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume. Our work demonstrates an association of long-term self-reported smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19.

Figure 1

Study timeline. E1 examination at baseline, E2 examination at follow-up; PCR +   positive polymerase chain reaction test for SARS-CoV-2.

Figure 2

Exemplary 3D visualization of olfactory bulb segmentation results. Volumetric visualization of the left and right olfactory bulb (highlighted) and surrounding brain areas. (a) coronal, anterior–posterior; (b) axial, inferior-superior; (c) sagittal, right-left.

Figure 3

Association of olfactory bulb volume and olfactory function. (a) Trajectory of olfactory function along timepoints. Blue dots indicate proportion of individuals with self-reported olfactory dysfunction. Gray dots show the average impairment as operationalized by the visual analogue scale. (b) Group differences of olfactory bulb volume at baseline between participants with and without self-reported olfactory dysfunction with respect to different timepoints. Olfactory bulb volume at baseline was significantly lower in individuals that exhibited self-reported olfactory dysfunction during both examination timepoints but not during the acute infection. (c) Association of the time interval from positive PCR to examination and olfactory bulb volume. A smaller interval was significantly associated with lower olfactory bulb volume. Non-hospitalized participants are represented by blue dots, hospitalized participants by white dots. (d) Linear associations between olfactory bulb volume and olfactometry scores. A low olfactory bulb volume at baseline was significantly associated with a lower olfactometry score at follow-up. Dot colors indicate hospitalization status as in c. (e) Group differences of olfactory bulb volume between participants with sustained self-reported olfactory dysfunction at follow-up and those with recovered olfaction to that point. Olfactory bulb volume was significantly lower in participants with sustained self-reported olfactory dysfunction. Abbreviations: ${\mathit{eta}}_p^2$ = partial eta squared indicating the effect size as provided by the analysis of covariance, p p-value, $r_{\mathit{sp}}$ Spearman correlation coefficient, PCR polymerase chain reaction, E1 examination at baseline, E2 examination at follow-up.