Viral Antigen Seen in Cerebrospinal Fluid of COVID Patients

Viral antigen was detectable in cerebrospinal fluid (CSF) of COVID-19 patients and was tied to immune activation in the central nervous system, a small hospital-based study in Sweden showed.

Among 44 hospitalized COVID-19 patients, CSF nucleocapsid antigen was detectable in 89% of those with available data and correlated with the immune activation markers neopterin and interferon γ, reported Arvid Edén, MD, PhD, of Sahlgrenska Academy at the University of Gothenburg, and co-authors.

Neurosymptomatic patients had a more pronounced inflammatory CSF profile than neuroasymptomatic patients. The variance could not be attributed to differences in COVID-19 severity, the researchers reported in JAMA Network Open.

“The presence of viral antigen has not been known previously and provides additional information regarding what may cause immune responses within the central nervous system in patients with COVID-19,” Edén told MedPage Today.

“It should be noted that we found viral antigen in CSF but not actual virus, at least when we measured viral RNA,” Edén pointed out.

“Our interpretation is that the virus itself does not cross into CSF in any significant way,” he said. “Rather, the effects we see in biomarker studies are likely a consequence of a general response to the infection throughout the body.”

The researchers looked at CSF samples of adult patients admitted to Sahlgrenska University Hospital from March 2020 through June 2021. They assessed 44 COVID patients — 26 moderate cases and 18 severe cases — and included 10 healthy controls and 41 COVID-negative patient controls. Median age of COVID patients was 57, and 68% were men.

CSF samples were collected during the acute phase of COVID, a median of 12 days from symptom onset. Of the 44 COVID patients, 21 were neuroasymptomatic and 23 were neurosymptomatic; 21 of the 23 neurosymptomatic patients had encephalopathy, one had encephalitis, and one had Guillain-Barré syndrome.

All CSF samples tested negative for SARS-CoV-2 RNA. Nucleocapsid antigen was detected in 31 of 35 patients and was significantly correlated with CSF neopterin (r=0.38, P=0.03) and interferon γ (r=0.42, P=0.01).

No differences in CSF nucleocapsid antigen concentrations were seen in patient groups. COVID patients had markedly increased CSF neopterin, β2-microglobulin, interleukin (IL)-2, IL-6, IL-10, and tumor necrosis factor α compared with controls.

Neurosymptomatic patients had significantly higher median CSF interferon γ (86 vs 21 fg/mL; P=0.03). Principal component analysis showed that neurosymptomatic patients had a significantly higher inflammatory biomarker profile compared with neuroasymptomatic patients.

Median CSF concentrations of neurofilament light (NfL), a marker of axonal injury, were higher in COVID patients compared with controls (960 vs 618 ng/L, P=0.002), after adjusting for age. The researchers found no significant differences in any of the CSF biomarkers in patients with moderate compared with severe COVID.

The findings suggest viral components can contribute to central nervous system immune responses without direct viral invasion, Edén and colleagues observed.

“Although CSF nucleocapsid antigen concentrations were not significantly different between patient groups, patients with COVID-19 had higher concentrations of CSF NfL compared with controls, and neurosymptomatic patients had a more marked immune activation biomarker profile, suggesting that the magnitude of the central nervous system immune response, possibly triggered by viral components, contributes to the neuropathogenesis of COVID-19,” they wrote.

The study had several limitations, the researchers acknowledged. The sample size was small and most neurosymptomatic patients had encephalopathy. Residual confounding variables may have influenced results. In addition, the researchers did not assess CSF samples for patients with mild COVID-19 who were not hospitalized.