Histopathological assessments reveal retinal vascular changes, inflammation and gliosis in patients with lethal COVID-19

Abstract

Importance: We are in the midst of the human coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), which is of historic proportions, the likes of which we have not seen in 102 years. Despite being primarily a respiratory virus, COVID-19 can also present with non-respiratory signs, including ocular symptoms as conjunctival hyperemia, chemosis, epiphora, increased secretions, ocular pain, photophobia and dry eye. The virus has also been detected within the anterior chamber and in the ocular fluids suggesting that ocular tissue maybe affected due to Sars-CoV-2 infection. Objective: To assess for histopathological changes within the retina and the choroid and determine the long-term sequelae of the viral infection. Design, Setting, and Participants: 12 donor eyes from COVID-19 positive individuals and similar age matched donor eyes from patients with negative test for SARS-CoV-2 were assessed. Eyes were fixed in 4% paraformaldehyde and 0.5% glutaraldehyde in PBS within 6 hours postmortem. Main Outcomes and Measures: Globes were evaluated with macroscopic, SLO and OCT imaging. Macula and peripheral regions were processed for epon-embedding and immunocytochemistry with markers for SARS-CoV-2 infection, gliosis, inflammation and vasculature. Results: Fundus analysis shows hemorrhagic spots and increased vitreous debris in several of the COVID-19 eyes compared to the control. OCT based measurements indicated an increased trend in retinal thickness in the COVID-19 eyes, however the difference was not statistically significant. Histology of the retina showed presence of hemorrhages and central cystoid degeneration in several of the donors. Whole mount analysis of the retina labeled with markers showed changes in retinal microvasculature, increased inflammation, and gliosis in the COVID-19 eyes compared to the controls. The choroidal vasculature displayed localized changes in density and signs of increased inflammation in the COVID-19 samples. Conclusions and Relevance: In situ analysis of the retinal tissue suggested that there are severe subclinical abnormalities that could be detected in the COVID-19 eyes. This study provides a rationale for evaluating the ocular physiology of patients that have recovered from COVID-19 infections to further understand the long-term effects caused by this virus.

Retinal vessels modifications in acute and post-COVID-19

“…Our study does not allow to clearly establish a correlation between the changes we identified in retinal vasculature and the increased risk for thrombotic events known to characterize COVID-19 patients. However, the acute and long lasting modifications to retinal vessels that we were able to observe in COVID-19 could easily be caused or accompanied by an endothelial damage 29 and facilitate blood stasis 19 , two of the three factors of the Virchow’s triad, favoring cloths formation 33 . Further studies are needed to investigate the actual correlation between retinal alterations and thrombotic risk in COVID-19 patients.…”

“…In fact, the endothelial activation in COVID-19 correlates with diseases severity 29 and chronic vessels alterations have been documented in patients with severe COVID-19 30 . To further support this theory, recent pathology study on post-mortem eyes from patients who died from COVID-19 reported the presence of retinal vessels walls remodelling 19 .…”

“…There is increasing evidence of a damage induced by COVID-19 to the vascular system 17 , 18 , including the vessel supporting the ocular district 19 . Coagulation disorders are also common in COVID-19 patients, and both hospitalized and non-hospitalized subjects are at high risk for venous thromboembolism 20 .…”

“…Recently, we analyzed the retinal vessels of patients with acute COVID-19 and, besides non-specific signs of retinal microcirculation impairment like intraretinal hemorrhages and cotton wool spots, we found that both retinal arteries and veins were significantly dilated compared to those of subjects unexposed to the virus 6 . These findings had two possible explanations: a direct structural damage to the vessels walls caused by the virus 19 or a transient modification induced by the cytokine storm 26 typical of COVID-19 2 , 27 . In the current study we found that most of the retinal and vascular alterations of the acute phase regressed with time.…”

COVID-19-Related Retinal Micro-vasculopathy – A Review of Current Evidence

“…50 In keeping with the reduction in vessel density in in vivo studies, severely reduced microvascular density has also been reported in retina flat mount from donor eyes from COVID subjects compared to controls, which has led some investigators to propose direct effect of virus infection on endothelial cell damage. 51,52 However, the detection of virus within the retina in post-mortem studies has been inconsistent. In addition to direct effects, hypercoagulation and vasculopathy may also lead to the observed retinal findings.…”