Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms

Abstract

Importance: Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population.

Objective: To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction.

Design, setting, and participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test.

Main outcomes and measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies.

Results: Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated.

Conclusions and relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.

Figure 1.. Anti–SARS-CoV-2 and Autoantibody Profiling

A, Coronal 3-dimensional cube T2-weighted fluid-attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) of patient 1. A linear hyperintense lesion in the right frontal centrum semiovale is noted (arrowhead). B, Cerebrospinal fluid (CSF) and sera from patients and controls were screened for anti–SARS-CoV-2 antibodies on a Luminex platform encoding whole-spike and nucleocapsid proteins, the spike receptor-binding domain (RBD), and spike, nucleocapsid, and ORF3a peptide antigens. The heatmap values represent the fold change of the median fluorescence intensity of averaged technical replicates for each biospecimen relative to negative controls. C, Select anatomic regions immunostained by patient 1’s CSF and CSF from patient 2’s first and second lumbar punctures (LPs) at a 1:4 dilution. White arrowheads in the olfactory bulb, cortex, and cerebellum indicate immunostained mitral cells, cortical neurons, and Purkinje cells, respectively. Yellow arrowheads indicate neuronal processes. Scale bars are 10 μM. IgG indicates immunoglobulin G.

Figure 2.. Anti–SARS-CoV-2 and Autoantibody Profiling

A, Heatmap of human phage display immunoprecipitation sequencing data for patient 1’s cerebrospinal fluid (CSF) and serum. TCF4 and KIF21A are highlighted in green and orange, respectively. Values represent log₁₀(fold change) relative to the mean reads per 100 000 for bead controls. The black and white barcode on the left indicates rows of individual peptides that correspond to a given protein. B, Dot plot of patient 1’s CSF TCF4 and KIF21A peptide human phage display immunoprecipitation sequencing read counts compared with CSF from 66 pediatric patients with other neurologic diseases (POND). C, HEK 293 cell overexpression cell-based assay. Untransfected cells or cells transfected with FLAG-tagged TCF4 were immunostained with CSF (1:10) and a rabbit anti-FLAG antibody. Cells were then counterstained with anti–human IgG 488 (green) and anti–rabbit IgG 594 (red). Arrowheads indicate an example of a TCF4-overexpressing cell that was immunostained by CSF IgG. Scale bars are 10 μM. R1 and R2 indicate technical replicates 1 and 2, respectively.