Study suggests cortical hemorrhage in fetal brain may be linked to COVID-19

In a recent study published in brainresearchers evaluated the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on fetal brain health.

Background

Previous studies have shown that maternal SARS-CoV-2 infection and immune responses increase the risk of alterations in fetal brain development, fetal death, growth restriction, and serious medical conditions such as intraventricular hemorrhage and pneumonia. has been reported. It has been reported that SARS-CoV-2 can infect developing human neurons within brain organoids. However, a contrasting finding of higher SARS-CoV-2 presence in the choroid plexus of organoids has also been reported.

About research

In the current study, researchers evaluated the effects of coronavirus disease 2019 (COVID-19) on fetal brain tissue.

This study was conducted in the United Kingdom (UK) between July 2020 and mid-April 2022, and human fetal tissue between 9.0 and 21.0 pcw (post-conception weeks) was obtained from HDBR (Human Developmental Biology Resource) . In addition, lung specimens were obtained from SARS-CoV-2 positive individuals. Immunofluorescence and immunohistochemical analyzes were performed and immunostained sections were analyzed using confocal microscopy.

Furthermore, ISH (on site hybridization) analysis was performed using SARS-CoV-2 ribonucleic acid (RNA). Bleeding was quantified based on the number and size of erythrocyte clusters within the tissue. The team counted the number of hemorrhagic specimens associated with SARS-CoV-2 infection cases as https://coronavirus.data.gov.uk/ website.

To assess the chronicity of bleeding, we examined the presence of ferric deposits after RBC lysis by Prussian blue staining. The team then examined the number of cleaved caspase-3+ cells to determine whether old or recent bleeding was associated with increased cell death within cortical tissue. -2 Spike (S) protein expression was investigated in placental, amniotic, and umbilical cord cells.

result

A total of 661 specimens were obtained at 21.0 months, mostly due to elective termination with no documented abnormalities. There were 62 chromosomal trisomy specimens (44 each of trisomy 21, trisomy 18, trisomy 16, trisomy 13, triploid, 12 specimens, 1 specimen, 1 specimen, and 3 specimens). ).

Of the 661 fetal brain specimens, cortical hemorrhages were observed in 26 specimens. Among 300 randomly selected specimens from 4,917 specimens procured from the Human Developmental Biology resource between September 1999 and December 2019, only two similar cases with cortical hemorrhages were found. Observed. Therefore, the number of fetal specimens with cortical hemorrhages observed in our study was unusual.

Of the 26 hemorrhagic specimens tested, 25 normal specimens were obtained from elective abortions and 1 specimen was trisomy 21. The presence of SARS-CoV-2 was detected in early and late fetal brains associated with cortical hemorrhages. SARS-CoV-2 spike (S) expression was sparse in cortical microtubule-associated protein 2 (MAP2)-positive and HuC/D-positive neurons and nestin- and Hopx (a homeodomain-only protein)-positive radial glia. Sox2 (sex-determining region Y-box 2)-positive ventricular and subventricular zone progenitors.

On the contrary, SARS-CoV-2 S was abundant within the choroid plexus in cortical hemorrhagic specimens. Furthermore, SARS-CoV-2 was sparsely present in placenta, umbilical cord and amniotic tissues, indicating the presence of SARS-CoV-2 in maternal and fetal tissues. Cortical hemorrhages were associated with decreased vascular integrity and increased immune cell infiltration in the fetal brain.

The average surface area of ​​RBC clusters was 0.02 mm² 0.05mm² The surface area of ​​the largest cluster is 1.3 mm, among non-hemorrhagic and hemorrhagic specimens, respectively.²In cortical regions of hemorrhagic specimens, vessels located proximal to erythrocyte clusters showed significantly lower expression of claudin-5 compared to vessels located far from erythrocyte clusters.

Hemorrhagic specimens were collected during the highest number of COVID-19 cases. The gestational stage of haemorrhagic specimens varied between 8.0 and 22 pcw, with most specimens (58%) obtained between 12.0 and 14.0 pcw. Hemorrhagic specimens containing more red blood cell clusters and no cells stained with Prussian blue staining (indicating recent bleeding) had the fewest number of stained areas (indicating old bleeding), indicating that the specimen was bleeding. indicates that it may indicate a different point in time than the appearance of . .

Recent bleeding was commonly observed in younger specimens (12.0–14.0 pcw) compared to older specimens (19.0–21.0 pcw). There was no statistically significant increase in caspase-3+ cells or cortical wall thickness among specimens with recent or old hemorrhage compared with non-hemorrhagic specimens.

Elevated angiotensin-converting enzyme 2 (ACE2) expression was observed in the choroid plexus epithelium, and significant SARS-CoV-2 S and nucleocapsid (N) protein expression was observed in all five hemorrhagic specimens comprising the choroid plexus. (2.5 times above background). immunostaining), compared to non-bleeding specimens in aquaporin 1-positive cells. Low SARS-CoV-2 S expression was observed in one non-hemorrhagic specimen of the choroid plexus.

Overall, the study results showed that SARS-CoV-2 infection can affect the fetal brain in early pregnancy. Compared to non-hemorrhagic specimens, those with cortical hemorrhages contained a significantly larger surface area of ​​erythrocyte clusters, significantly more erythrocyte clusters per square millimeter of fetal tissue, and the surface area of ​​cortical tissue containing erythrocyte clusters. significantly increased. Further studies need to be conducted to assess the neurodevelopmental sequelae of COVID-19.