Long COVID Immune Profiles Appear Largely Normal

— Brain inflammation may not be a cause of long COVID cognitive problems

A computer rendered cross section of the spine.

Spinal fluid immune profiles were largely normal in people with neurologic long COVID symptoms in a case-control study, suggesting brain inflammation was not a cause of long COVID cognitive symptoms.

In 37 people with post-COVID neuropsychiatric conditions -- most commonly, brain fog -- there was no evidence of abnormal cytokines in cerebrospinal fluid (CSF) or blood-brain barrier dysfunction, reported Shelli Farhadian, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut, and co-authors in a research letter published in .

"Our results indicate that neuroinflammation and blood-brain barrier dysfunction are unlikely to be drivers of neuropsychiatric symptoms after COVID-19, and that interventions aimed at quieting brain inflammation likely won't help people with post-COVID conditions," Farhadian told app.

"We've previously found, through our studies of chronic HIV infection and other diseases, that many CSF cytokines are abnormally high in people with infections affecting the brain, and others have shown that they are also abnormally high during other neuroinflammatory diseases," she noted.

"After 3 years, we still don't understand why some people experience symptoms after having COVID," Farhadian said.

Neuroinflammation, coagulopathy, neuronal injury, and possible viral infection in the central nervous system have been suggested as possible mechanisms behind long COVID neurologic and psychiatric symptoms.

The work by Farhadian's group "is an important study that shows the difficulty in investigating the pathophysiology of PASC [post-acute sequelae of SARS-CoV-2 infection]," observed Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, who wasn't involved with the research.

"There do not appear to be any major immune abnormalities on routine investigation of the CSF, including a cytokine panel," Nath told app. "This may represent heterogeneity within this population or that more sophisticated research tools, such as multi-omic approaches, will be necessary to decipher the underlying mechanisms."

Farhadian and colleagues studied CSF and blood samples from 37 participants in the with new or worsened neuropsychiatric symptoms at least 3 months after laboratory-confirmed COVID-19. Most long COVID participants (78%) had acute illness when the Alpha variant was the dominant circulating strain.

The control group included 22 asymptomatic participants recruited before the COVID-19 pandemic. Long COVID participants had a median age of 48, 73% were women, and 11% were Black. Controls had a median age of 51.5, 32% were women, and 46% were Black.

Brain fog and cognitive impairment (84%) and excessive fatigue (84%) were the most frequent long COVID symptoms.

The long COVID group did not have elevated CSF white blood cell count and protein levels compared with controls. The CSF-to-blood albumin ratio, a marker of blood-brain barrier integrity, did not vary significantly between groups. The CSF immunoglobulin G (IgG) index and a comparison of oligoclonal bands in CSF and blood did not show evidence of intrathecal immunoglobulin production.

Tumor necrosis factor-alpha levels were higher and monocyte chemoattractant protein-1 and interleukin (IL)-6 levels were lower in the long COVID group, but these differences were not significant after accounting for multiple comparisons. Levels of neopterin, a marker of microglial cell activation, were not elevated in long COVID participants.

"There were no significant differences in any of the other cytokines or chemokines tested in the CSF or in the plasma," the researchers wrote.

The results echoed those of a small Swedish study that showed people with neurocognitive long COVID of CSF abnormalities.

"These findings are important and reassuring, as they confirm our recently published research, indicating that neuro post-COVID condition is not due to ongoing neuroinflammation," Nelly Kanberg, MD, of Sahlgrenska University Hospital in Sweden, told app.

The Yale study had several limitations, Farhadian and co-authors acknowledged. The sample size was small and the long COVID and control groups were not balanced by sex and race. In addition, the control group had higher rates of smoking and alcohol use and lower rates of antidepressant use, which may have influenced CSF biomarker results.

  • Judy George covers neurology and neuroscience news for app, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more.


This research was supported by grants from the NIH and the Merck Investigator Studies Program.

A co-author reported receiving grants from the National Institute of Mental Health during the conduct of the study. No other disclosures were reported.

Primary Source

JAMA Network Open

Farhadian SF, et al "Self-reported neuropsychiatric post-COVID-19 condition and CSF markers of neuroinflammation" JAMA Netw Open 2023; DOI: 10.1001/jamanetworkopen.2023.42741.