Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19

Abstract

Loss of smell is an early and common presentation of COVID-19 infection. Although it has been speculated that viral infection of olfactory neurons may be the culprit, it is unclear whether viral infection causes injuries in the olfactory bulb region. To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study. This multicenter postmortem cohort study was conducted from April 7, 2020, to September 11, 2021. Deceased patients with COVID-19 and control individuals were included in the cohort. One infant with congenital anomalies was excluded. Olfactory bulb and tract tissue was collected from deceased patients with COVID-19 and appropriate controls. Histopathology, electron microscopy, droplet digital polymerase chain reaction, and immunofluorescence/immunohistochemistry studies were performed. Data analysis was conducted from February 7 to October 19, 2021. (1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue. Olfactory tissue from 23 deceased patients with COVID-19 (median [IQR] age, 62 [49-69] years; 14 men [60.9%]) and 14 control individuals (median [IQR] age, 53.5 [33.25-65] years; 7 men [50%]) was included in the analysis. The mean (SD) axon pathology score (range, 1-3) was 1.921 (0.569) in patients with COVID-19 and 1.198 (0.208) in controls (P < .001), whereas axon density was 2.973 (0.963) × 104/mm2 in patients with COVID-19 and 3.867 (0.670) × 104/mm2 in controls (P = .002). Concomitant endothelial injury of the microvasculature was also noted in olfactory tissue. The mean (SD) microvasculopathy score (range, 1-3) was 1.907 (0.490) in patients with COVID-19 and 1.405 (0.233) in control individuals (P < .001). Both the axon and microvascular pathology was worse in patients with COVID-19 with smell alterations than those with intact smell (mean [SD] axon pathology score, 2.260 [0.457] vs 1.63 [0.426]; P = .002; mean [SD] microvasculopathy score, 2.154 [0.528] vs 1.694 [0.329]; P = .02) but was not associated with clinical severity, timing of infection, or presence of virus. This study found that COVID-19 infection is associated with axon injuries and microvasculopathy in olfactory tissue. The striking axonal pathology in some cases indicates that olfactory dysfunction in COVID-19 infection may be severe and permanent.