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

Abstract

IMPORTANCELoss 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 PARTICIPANTSThis 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 in controls (P < .001), whereas axon density was 2.973 (0.963) × 10 4 /mm 2 in patients with COVID-19 and 3.867 (0.670) × 10 4 /mm 2 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.

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

“…This is important for two reasons. First, the severity of microvascular endotheliopathy seen in olfactory tissue in acute COVID-19 correlates with the extent of olfactory axonal damage ( 104 ). Second, even if non-neuronal cells are the main targets of the virus in the olfactory mucosa ( 105 ), these cells could be a source of persistent viral RNA in PASC.…”

SARS-CoV-2 causes brain inflammation via impaired neuro-immune interactions

“…Since it was reported that surgically-induced disruption of olfactory bulb function through olfactory bulbectomy (OBX) resulted in a decrease in ChAT positive cells in the MS 43 , the decrease in ChAT positive cells and disruption of the CAP in the S1 mouse could be due to olfactory bulb dysfunction. Thus, severe damage to the olfactory bulb due to SARS-CoV-2 infecting the olfactory system 44,45 could be the main cause of CAP disruption in COVID-19. However, the olfactory bulb damage in the S1 mouse was thought to be due to the calcium elevating activity of S1 protein.…”

Revealing the mystery of persistent smell loss in long COVID patients

“…SARS-CoV-2 infection of the OE results in an inflammatory environment. A recent report by Ho et al provided evidence for the degeneration of olfactory axon injury microvasculopathy in the post-mortem samples, and this indicates a local inflammation in the micro-vessels [92]. It is accompanied by the infiltration of the innate immune cells, as evidenced by co-staining for IBA, a myeloid marker, and the N protein of SARS-CoV-2 [66].…”