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

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Key Points

Question  What are the neuropathologic changes of COVID-19 in the olfactory region?

Findings  In this cohort study of 23 deceased patients with COVID-19 and 14 matched controls, more severe axon pathology, axon losses, and microvascular pathology were noted in olfactory tissue from patients with COVID-19 than that from the control individuals. The olfactory pathology was particularly severe in patients with reported smell alterations but were not associated with the clinical severity, timing of infection, or the presence of SARS-CoV-2 in the olfactory tissue.

Meaning  In the region of olfactory bulb and olfactory tract, COVID-19 infection was associated with axon pathology and microvasculopathy, particularly in patients with smell alterations; the olfactory pathology did not result from direct viral injury and may be associated with local inflammation.


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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Article Information

Accepted for Publication: January 13, 2022.

Published Online: April 11, 2022. doi:10.1001/jamaneurol.2022.0154

Corresponding Author: Cheng-Ying Ho, MD, PhD, Department of Pathology, Johns Hopkins University School of Medicine, 1800 Orleans St, Zayed M2101, Baltimore, MD 21287 (

Author Contributions: Dr Ho had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ho, Papadimitriou, Mininni, Li.

Acquisition, analysis, or interpretation of data: Ho, Salimian, Hegert, O'Brien, Choi, Ames, Morris, Papadimitriou, Mininni, Niehaus, burke, Canbeldek, Jacobs, LaRocque, Patel, Rice, Johnson, LeFevre, Blanchard, Shaver, Moyer, Drachenberg.

Drafting of the manuscript: Ho, Hegert, Canbeldek.

Critical revision of the manuscript for important intellectual content: Ho, Salimian, O'Brien, Choi, Ames, Morris, Papadimitriou, Mininni, Niehaus, burke, Jacobs, LaRocque, Patel, Rice, Li, Johnson, LeFevre, Blanchard, Shaver, Moyer, Drachenberg.

Statistical analysis: Ho, Papadimitriou, Niehaus, Drachenberg.

Obtained funding: Ho.

Administrative, technical, or material support: Ho, Salimian, O'Brien, Ames, Papadimitriou, Mininni, burke, Jacobs, Rice, Li, Johnson, LeFevre, Blanchard, Shaver, Drachenberg.

Supervision: Ho, Shaver.

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.

Funding/Support: This study was supported by the National Institutes of Health (grant K08NS102468 to Dr Ho and grant 75N95019C00048-P00006-9999-1 to Dr Blanchard).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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