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

  1. Vijay K. Jidigam
  2. Rupesh Singh
  3. Julia C. Batoki
  4. Caroline Milliner
  5. Onkar B. Sawant
  6. Vera L. Bonilha
  7. Sujata Rao

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Abstract

Purpose

The purpose of this study is to assess for histopathological changes within the retina and the choroid and determine the long-term sequelae of the SARS-CoV-2 infection.

Methods

Eyes from seven COVID-19-positive and six similar age-matched control donors with a negative test for SARS-CoV-2 were assessed. Globes were evaluated ex vivo with macroscopic, SLO and OCT imaging. Macula and peripheral regions were processed for Epon embedding and immunocytochemistry.

Results

Fundus analysis shows hemorrhagic spots and increased vitreous debris in several of the COVID-19 eyes compared to the controls. 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

In situ analysis of the retinal tissue suggests 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.

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  1. Version published to 10.1007/s00417-021-05460-1
  2. Rapid Reviews Infectious Diseases

    Manuel Landecho

    Review 2: "Histopathological assessments reveal retinal vascular changes, inflammation, and gliosis in patients with lethal COVID-19"

    This preprint provides an in situ analysis of retinal tissue and suggests that there are severe subclinical abnormalities that could be detected in the eyes of covid-19 positive patients. The relevance of these findings in in-vivo evaluation among COVID-19 patients is needed.

  3. Rapid Reviews Infectious Diseases

    Alessandro Invernizzi

    Review 1: "Histopathological assessments reveal retinal vascular changes, inflammation, and gliosis in patients with lethal COVID-19"

    This preprint provides an in situ analysis of retinal tissue and suggests that there are severe subclinical abnormalities that could be detected in the eyes of covid-19 positive patients. The relevance of these findings in in-vivo evaluation among COVID-19 patients is needed.

  5. ScreenIT

    SciScore for 10.1101/2021.02.25.21251531: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Pathology analysis was performed with the approval of the Cleveland Clinic Institutional Review Board (IRB #20-755) and Institutional Biosafety Committee (IBC# 2018).
    IACUC: Pathology analysis was performed with the approval of the Cleveland Clinic Institutional Review Board (IRB #20-755) and Institutional Biosafety Committee (IBC# 2018).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Choroids were stained with UEA Lectin and Iba-1 antibody.
    Iba-1
    suggested: None
    Software and Algorithms
    SentencesResources
    Briefly, fundus macrophotography (FM) images were collected using a Zeiss AxioCam MRC5 camera equipped with a macro zoom lens and AxioVision AC Software (Zeiss)
    AxioVision
    suggested: (AxioVision Imaging System, RRID:SCR_002677)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This study has some limitations, including the small sample size and the broad inclusion criteria. The severity of the viral infection is unknown, and the duration of hospitalization could severely impact the histopathological findings, thus limiting the generalization of the findings. Owing to the small numbers of available control eyes available, the cause of death for these control cohorts will notably have a huge impact on all the assessments reported. All care was taken to ensure that the investigated cohorts were closely matched in terms of age as well as the duration that these patients were maintained on ventilators. These limitations do not appear to change the results as many of the reported findings could only be observed in the deceased patients with COVID-19. Further evaluation with a much larger sample size is needed to determine the effects of SAR-CoV-2 infection on retinal morphology, vasculature, inflammation and gliosis. In conclusion, we observed several ocular anomalies the COVID-19 cohorts compared to the control cohorts. Surprisingly, despite the small sample size, there were some consistent differences detected between the patient cohorts and the COVID-19 negative patients. Of note are the subclinical microvasculature features that we observed. As some of these observations have not been noted previously these histopathological analyses of the post-mortem eyes from the COVID-19 patients suggest that as more individuals recover from the COVID-19 infectio...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  6. Version published to 10.1101/2021.02.25.21251531v1 on medRxiv