Neurologic Long COVID Patients Show Immune Dysregulation

Broad immune dysregulation was seen in the cerebrospinal fluid (CSF) of a small cohort of people with long COVID neurologic symptoms, a deep phenotype analysis showed.

People with persistent neurologic symptoms after SARS-CoV-2 infection had lower levels of CD4+ and CD8+ T cells compared with healthy controls, reported Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH in Bethesda, Maryland, and co-authors.

In addition, B cells and other types of immune cells were increased in people with lasting neurologic symptoms, suggesting immune dysregulation may play a role in mediating long COVID, the researchers wrote in Neurology: Neuroimmunology and Neuroinflammation. Autonomic testing also showed dysfunction.

The findings call for further investigations to confirm these changes and to evaluate the role of immunomodulatory agents in clinical trials, Nath and co-authors said.

The results also may guide researchers in further characterizing neurologic long COVID -- also known as neurologic post-acute sequelae of COVID-19 or neuro-PASC -- as its natural history and subtypes are not yet defined, they added.

Nath and colleagues conducted an observational study of 12 people with persistent neurological symptoms after SARS-CoV-2 infection at the NIH Clinical Center. They compared CSF and autonomic function results with data collected before the COVID pandemic from healthy volunteers in other NIH studies.

Evaluations occurred a median of 9 months after acute SARS-CoV-2 infection, and COVID was diagnosed between March and December 2020. Nearly all participants -- 11 of 12 -- had mild infection; one had moderate disease.

All participants were white, mean age was 45, and 83% of participants were women. Only one participant had received a SARS-CoV-2 vaccine before being evaluated.

More than half of participants (58%) had a history of depression or anxiety before COVID-19. A third (4 participants) had a prior history of resolved long-term disability after an infectious disease.

Most participants (83%) had a Karnofsky Performance Status score of 80 or less, indicating disabling disease. Neurologic exams showed signs consistent with mild peripheral neuropathy in 3 participants (25%).

Cognitive testing showed evidence for mild cognitive impairment. Half of participants had a Montreal Cognitive Assessment score less than 26. Short-term memory was the domain most commonly affected.

Varying degrees of microsmia were seen on the University of Pennsylvania Smell Identification Test in eight participants (66%), but no one had anosmia. Brain MRI scans largely were normal, with no structural abnormalities in brainstem and olfactory pathways that could be correlated with long COVID.

CSF analysis showed no evidence for pleocytosis in any participants. Unique intrathecal oligoclonal bands were seen in 3 cases (25%).

Compared with healthy controls, long COVID participants had lower frequencies of effector memory phenotype both for CD4 + T cells (P<0.0001) and for CD8 + T cells (P=0.002). They also had an increased frequency of antibody-secreting B cells (P=0.009) and some increase in immune checkpoint molecules.

"The persistence of these immune abnormalities several months after a mild infection suggests the possibility of either a persistent infection or an aberrant immune response to the infection," Nath and co-authors observed.

Autonomic testing showed abnormalities, including decreased baroreflex-cardiovagal gain (P=0.009) and increased peripheral resistance during tilt-table tests (P<0.0001) in long COVID participants compared with controls. CSF levels of catechols did not differ between the long COVID and control groups.

Limitations included the study's small sample size and its lack of a fully matched control group, Nath and co-authors acknowledged.

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