Effects of COVID-19 on the human central olfactory system: a natural pre-post experiment

Reduced olfactory function is the symptom with the highest prevalence in COVID-19 with nearly 70% of individuals with COVID-19 experiencing partial or total loss of their sense of smell at some point during the disease. The exact cause is not known but beyond peripheral damage, studies have demonstrated insults to both the olfactory bulb and central olfactory brain areas. However, these studies often lack both baseline pre-COVID-19 assessments and a control group and could therefore simply reflect preexisting risk factors. Right before the COVID-19 outbreak, we completed an olfactory focused study including structural MR brain images and a full clinical olfactory test. Opportunistically, we invited participants back one year later, including 9 participants who had experienced mild to medium COVID-19 (C19+) and 12 that had not (C19-), thereby creating a pre-post controlled natural experiment with a control group. Despite C19+ participants reporting subjective olfactory dysfunction, few showed signs of objectively altered function one year later. Critically, all but one individual in the C19+ group had reduced olfactory bulb volume with an average volume reduction of 14.3%, but this did not amount to a significant between group difference compared to the control group (2.3% reduction) using inference statistics. No morphological differences in cerebral olfactory areas were found but we found stronger functional connectivity between olfactory brain areas in the C19+ croup at the post measure. Taken together, these data suggest that COVID-19 might cause a long-term reduction in olfactory bulb volume but with no discernible differences in cerebral olfactory regions.