Autopsy Study Reveals Immune Cell Infiltration into CNS

I had previously written about an autopsy study that found SARS-CoV-2 RNA existed in the brain, providing evidence for direct viral infiltration into the CNS (Puelles et al., 2020) – however, this virus is likely causing neurological symptoms in ways beyond direct infiltration. Writing in The Lancet Microbe, Schurink et al. provide evidence that the inflammatory response during COVID-19 leads to immune cell infiltration into many organs, including the brain. The breadth of tissue they analyzed was extensive, so I will only summarize their findings on the brain.

The authors sampled organs from 21 patients in the Netherlands that were confirmed to have COVID-19 by qRT-PCR (Schurink et al., 2020). Next-of-kin gave consent for brain autopsy for 9 of these patients. The organs they sampled included “lungs, upper respiratory tract, submandibular gland, heart, gastrointestinal tract, kidneys, adipose tissue, and brain.” The samples were stained with hematoxylin and eosin, as well as antibodies against SARS-CoV-2 nucleocapsid proteins and other immune cell markers. Immunohistochemistry for SARS-CoV-2 was negative in the brain of all patients sampled. The results of histological analysis of brain autopsy samples were as follows:

“Brain hypoxic changes, manifesting as hypereosinophilia or nuclear and cytoplasmatic condensation of neurons in the cerebrum and cerebellum on HE staining, were observed in all patients, of whom five were mechanically ventilated. All patients showed an extensive inflammatory response, affecting both white and grey matter, irrespective of disease course (median 11 days [range 5–31]). The response was present in all regions examined […] and most severe in the cranial medulla oblongata and olfactory bulb, characterised in all nine patients by activation and clustering of microglia (HLA-DR-positive), astrogliosis (GFAP-positive), and perivascular cuffing of T cells (CD3-positive). Sparse T cells (CD3-positive, and CD4-positive, or CD8-positive) were also noted in the parenchyma in all patients. Neutrophilic plugs were identified in three (33%) patients, with a disease course of 8, 22, and 25 days […]. No loss of myelin or haemorrhages were seen […].”

To my knowledge, this is one of the first studies that utilized specific stains to describe the immune response in the brain (and other organs) of lethal COVID-19 cases. In contrast to this study, other studies have found viral RNA in brain samples, a discrepancy that the authors hypothesize is due to swift viral clearance due to the large inflammatory response. In this study, the authors found that the brain regions with the most severe inflammatory response were the olfactory bulbs, which corresponds well with symptoms of anosmia seen in COVID-19, and the medulla oblongata, which controls respiratory rhythm generation among other functions. Previously, there has been ample debate on whether COVID-19 causes respiratory failure exclusively through pulmonary dysfunction or through a combination of pulmonary dysfunction and medullary respiratory center dysfunction (see blog post from 5/4/2020). This case provides some evidence that the latter may be true. 

I highly recommend my readers take a look at this paper, as it effectively demonstrates that COVID-19 is a truly systemic disease that affects every major organ system in the body.