This transcript has been edited for clarity.
Welcome to influencer, Your Weekly Dose Commentary on a new medical study. i am dr F. Perry Wilson of the Yale School of Medicine.
SARS-CoV-2 is a strange virus, and not just because it’s so novel. The variability in clinical presentation and outcome is still confounding; The emergence of variants like Omicron with few connections to established lineages is strange; and then there is anosmia.
Looking back, it was perhaps our first clue that the virus that causes COVID-19 was an oddball – the high prevalence of olfactory loss. It’s an uncommon symptom, and even in early studies, it’s been shown to be a strong predictor that the upper respiratory syndrome a patient presented with was caused by COVID and not the flu or other cold virus.
It was initially speculated that the loss of smell was simply a symptom of blocked nasal passages, but this theory quickly evaporated as many patients reported persistent loss of smell long after the infection had cleared. SARS-CoV-2, it seemed, could affect the brain itself.
Anyone who has cared for COVID patients in the hospital will attest that in many cases the nervous system is not spared. COVID neuropathy and COVID delirium are not uncommon. But exactly how COVID affects nerve tissue and has been really difficult to unravel.
But this week, in JAMA network openwe have a decent effort to pull some of these strings thanks to the spinal tap data.
Researchers led by Arvid Edén of Sweden went straight to the source by examining the cerebrospinal fluid of patients hospitalized with COVID.
This is a multi-cohort study, which is broken down here. We have 21 patients with COVID and diseases of the nervous system – mainly encephalopathy; 23 patients with COVID and no nervous system problems; 41 hospitalized patients without COVID; and 10 healthy controls.
What immediately struck me was the fact that, overall, at baseline, the COVID patients with nervous system findings appeared to be less ill than those without. For example, they were less likely to receive betamethasone, a steroid. They had lower levels of C-reactive protein, a marker of inflammation, and were more likely to have moderate disease than severe disease, according to the WHO classification.
That raised my eyebrows a bit. If someone is critically ill with COVID, possibly intubated and sedated, how do you know if they have nervous system pathology at all? Unfortunately, the authors do not report on the use of sedation. But keep that in mind as we examine the properties in the spinal fluid of these patients.
OK. The big finding: None of these patients — zero — had COVID-RNA in their CSF. In other words, there is really no evidence of direct infection of brain cells by SARS-CoV-2 in this study.
But virtually all patients in both COVID groups had SARS-CoV-2 nucleocapsid antigen, a structural protein of the virus, in their CSF. And the amount in the CSF was directly proportional to the amount in the blood.
This means that parts of the virus can cross the blood-brain barrier, even if the whole virus itself cannot. Interestingly, only one patient with COVID had CSF spike protein, and this patient had no neurological symptoms.
However, the presence of nucleocapsid antigen did not differ between COVID patients with and without neurological symptoms. So what explains the symptoms?
Could it be the reaction to the antigen? The inflammation that the antigen triggers?
The authors examined a variety of inflammatory biomarkers in CSF. Compared to in-hospital controls—who had a spinal tap that ruled out infection—the levels of interleukins 6 and 10 and interferon gamma were significantly higher.
And while levels of all of these markers tended to be higher in those who were neurosymptomatic, the differences are not dramatic, with the exception of interferon gamma. Of course, keep in mind that people without neurological symptoms were more likely to receive betamethasone than those with neurological symptoms. It’s possible that inflammation was slightly lower in those without symptoms.
So is the case cracked? Have We Discovered How COVID Attacks the Brain? Does the COVID antigen slip through the blood-brain barrier and cause inflammation and all those neurological symptoms? It’s a nice story, but I don’t think this study backs it up anymore. A few things are clear. For one thing, the evidence for direct infection is minimal. It’s also clear that COVID causes inflammation, but inflammation doesn’t seem to correlate well with symptoms.
Of course, the same amount of inflammation can affect different people differently, depending on the brain’s underlying substrate. It may be that some people just “deal” with inflammation better than others. For example, it is not uncommon for people with mild dementia to become delirious in hospital due to entirely non-neurological processes.
Or, as is always the case in science, something else could be going on. This is what makes this type of research so fascinating, so important and so frustrating.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale. His work on science communication can be found in the Huffington Post, on NPR and here on Medscape. He tweets @fperrywilson and hosts an archive of his communications work at www.methodsman.com.
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