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Multicenter Study
. 2022 Jun 1;79(6):544-553.
doi: 10.1001/jamaneurol.2022.0154.

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

Cheng-Ying Ho  1   2 , Mohammad Salimian  3 , Julia Hegert  3 , Jennifer O'Brien  2 , Sun Gyeong Choi  2 , Heather Ames  2 , Meaghan Morris  1 , John C Papadimitriou  2 , Joseph Mininni  2 , Peter Niehaus  1   2 , Allen Burke  2 , Leyla Canbeldek  2 , Jonathan Jacobs  2 , Autumn LaRocque  2 , Kavi Patel  2 , Kathryn Rice  2 , Ling Li  4 , Robert Johnson  5   6 , Alexandra LeFevre  5   6 , Thomas Blanchard  5   6 , Ciara M Shaver  7 , Ann Moyer  8 , Cinthia Drachenberg  2
Affiliations
Multicenter Study

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

Cheng-Ying Ho et al. JAMA Neurol. .

Abstract

Importance: 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.

Objective: To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study.

Design, setting, and participants: 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.

Main outcomes and measures: (1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shaver reported grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Electron Micrographs Demonstrate a Spectrum of Olfactory Axonal Injuries in Patients With COVID-19
A spectrum of axonal degeneration including organelle aggregation, myelin sheath disintegration, myelin sheath vacuolization, and myelin debris can be seen in COVID-19 cases. Scale bars represent 2 μm. The arrowhead indicates myelin debris.
Figure 2.
Figure 2.. Axon Losses Ranging From Mild to Severe Are Observed in Toluidine Blue-Stained Semithin Sections of the Lateral Olfactory Tract From Patients With COVID-19
Scale bars represent 10 μm.
Figure 3.
Figure 3.. Olfactory Axon Pathology, Axon Losses, and Microvasculopathy Are Significantly Worse in Patients With COVID-19 Than Control Individuals
A, C, and E, Comparisons between individuals with COVID-19 and control individuals (t test). Individuals with COVID-19 are further divided into smell normal (NL) and smell abnormal (ABN) groups for the comparisons in B, D, and F (1-way analysis of variance).
Figure 4.
Figure 4.. Electron Micrographs of Olfactory Microvasculature From Patients With COVID-19 Demonstrate a Spectrum of Endothelial Injuries
A spectrum of microvascular endothelial injury including cytoplasmic swelling, cytoplasmic vacuolization, ultrastructural abnormalities in mitochondria, and lysosome accumulation can be seen in patients with COVID-19. Note the occlusion of the capillary lumen by the swollen cytoplasm of the endothelial cells in the severe case (D). Scale bars represent 2 μm. The asterisk indicates a cytoplasmic vacuole. Ly indicates lysosome; R, red blood cell.
See this image and copyright information in PMC

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