New Study Identifies Immune Dysregulation and Neurocirculatory Abnormalities in Long COVID

Article

Taken together, the findings added to the growing evidence that widespread immunological and autonomic nervous system changes may contribute to long COVID.

Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke

Avindra Nath, MD

Findings from a small-scale, National Institutes of Health (NIH)-operated study assessing long-term outcomes of patients with SARS-CoV-2 infection found differences in immune cell profiles and autonomic dysfunction, including lower levels of CD4+ and CD8+ T cells.

Although the study included 12 patients, the findings add to the growing evidence that widespread immunological and autonomic nervous system changes may contribute to long COVID. Conducted between October 2020 and April 2021, the cohort was comprised of mostly those with a history of mild infection (92%; n = 11) and females (83%). Led by Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke (NINDS), patients had a median time of evaluation of 9 months (range, 3-12) following infection.

Patients were intensely followed and underwent clinical examination, questionnaires and brain imaging, extensive analyses of blood and cerebrospinal fluid (CSF) samples, and autonomic testing. Although most presented with mild infection, the cohort included only those whose neurologic symptoms persisted. Of note, only 1 participant had already received a SARS-CoV-2 vaccine before being evaluated.

In comparison with healthy volunteers, immunophenotyping of cerebrospinal fluid (CSF) of patients with neuro-post acute sequelae (PASC) had lower frequencies of effector memory phenotype both for CD4+ T cells (P <.0001) and for CD8+ T cells (P = .002), as well as increased frequency of antibody-secreting B cells (P = .009), and increased frequency of cells expressing immune checkpoint molecules. There was also an increase in cells expressing with T cell immunoglobulin (IgG) and ITIM domains on CD8+ T cells (67.3 [±10] vs 53.7 [±12]; P = .006) and of programmed death ligand 1 on monocytes (CD3- CD14+: 35.9 [±21] vs 15.6 [±9]; P = .02).

Using the Montreal Cognitive Assessment (MoCA), half (n = 6) of the patients showed evidence of mild cognitive impairment, with short-term memory impairment, found to some degree in all participants, as the most commonly affected domain. Four individuals demonstrated evidence for severe dysfunction. As assessed through Karnofsky Performance Status (KPS), 4 participants (33%) had a score of 70, indicating inability to carry on normal activity. On PROMIS questionnaires, the most prominent findings were high T-scores for reported fatigue (65 [+9]; range, 44-72) and low T scores for reported cognitive function abilities (35 [+9]; range, 26-59).

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All brain MRI scans were normal, except for 1 patient who reported small caliber of the olfactory bulbs consistent with bilateral olfactory bulb hypoplasia. The individual, a 34-year-old woman, reported phantom burning smells as part of her neuro-post acute sequelae (PASC) and had moderate microsimia per UPSIT. "This finding was considered to be congenital in view of bilaterally shallow olfactory fossae and small olfactory sulci," the study investigators wrote.

Additional incidental findings included mild chronic small vessel ischemic changes in a 58-year-old woman, a pituitary hyperintense lesion in a 51-year-old woman, and an enlarged perivascular space in the basal ganglia with adjacent gliosis in a 48-year-old woman. Three cases (25%) had unique intrathecal oligoclonal bands (OCBs), of which 1 case—the previously mentioned 51-year-old woman with new onset seizures—also had a high CSF-serum immunoglobulin index. These 3 cases did not have any previous history of disabling systemic infection.

During head-up tilt-table testing, the neuro-PASC group had higher mean values for systolic and diastolic blood pressure, MAP, and heart rate than healthy volunteers. Two of the 11 participants with PASC and 7 of the 22 healthy volunteers developed tilt-evoked sudden hypotension, resulting in cessation of the tilt testing for safety reasons. Removal of data from these participants did not affect obtained group differences in the physiologic measures.

In comparison with healthy volunteers, CSF levels of catechols did not differ between the groups. The neuro-PASC group had lower mean plasma levels of 3, 4-dihydroxyphenylglyol (DHPG) and 3, 4-dihydroxyphenylacetic acid, whereas levels of other catechols did not differ. DHPG was still decreased (P = .03) after excluding data from participants with neuro-PASC who were on a drug known to interfere with neuronal uptake of catecholamines (tricyclic antidepressant, duloxetine).

REFERENCE
1. Mina Y, Enose-Akahata Y, Hammoud DA, et al. Deep phenotyping of neurologic postacute sequelae of SARS-CoV-2 infection. 2023;10(4). doi:10.1212/NXI.00000000000200097
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