Cerebrospinal fluid cytokine, chemokine, and SARS-CoV-2 antibody profiles in children with neuropsychiatric symptoms associated with COVID-19

Abstract

Background: Neuropsychiatric symptoms and CSF cytokine, chemokine, and SARS-COV-2 antibody profiles are unknown in pediatric patients with COVID-19 or multisystem inflammatory syndrome (MIS-C), (NP-COVID-19). Methods: Children at a single pediatric institution quaternary referral center with laboratory-confirmed COVID-19 or MIS-C and neuropsychiatric symptoms were included in this retrospective case series. Clinical symptoms, ancillary testing data, treatments and outcomes are described. Multiplexed electrochemiluminescence assays for cytokines, chemokines and SARS-CoV-2 antibodies were tested in the CSF NP-COVID-19 patients compared to five controls and were analyzed using the Student's t-test. Results: Three of five NP-COVID-19 patients had psychiatric symptoms, and two patients had encephalopathy and seizures. All patients had full or near resolution of neuropsychiatric symptoms by discharge. One patient received intravenous steroids for treatment for psychiatric symptoms; 3/5 other patients received immunotherapy for MIS-C, including IVIG, high-dose steroids, anakinra, and tocilizumab. Pro-inflammatory chemokines, including MIG, MPC, MIP-1β, and TARC were significantly elevated in NP-COVID-19 patients compared to controls. Two of five patients had elevated CSF neurofilament light chain. CSF SARS-CoV-2 antibody titers to the full-length spike, receptor binding domain and N-terminal domain were significantly elevated. SARS-CoV-2 antibody titers strongly correlated with pro-inflammatory chemokines/cytokines, including IL-1β, IL-2, IL-8, TNF-α, and IFN-γ (P≤0.05 for all). Conclusions: A spectrum of neuropsychiatric clinical manifestations can occur in children with SARS-CoV-2 infection. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV-2 mediated NP-COVID-19. Additional study is required to understand the pathophysiologic mechanisms of neuroinflammation in children with COVID-19 and MIS-C.

Neurological Complications in Children Hospitalized With Seizures and Respiratory Infections: A Comparison Between SARS-CoV-2 and Other Respiratory Infections

“…The pathophysiological mechanisms for neurological manifestations have been reported to include inflammatory cytokines, endothelial complications, and direct viral invasion 7 , 8 . Systemic pro-inflammatory cytokines are elicited by influenza and SARS-CoV-2 infections, 9 and children with neuropsychiatric symptoms in SARS-CoV-2 have increased CSF cytokines 10 . CNS specific antibody-mediated inflammation is uncommon.…”

Suicidality and COVID‑19: Suicidal ideation, suicidal behaviors and completed suicides amidst the COVID‑19 pandemic (Review)

“…Accordingly, several mechanisms may be implicated in infection-associated brain damage as follows: The direct neurotropic effects of SARS-CoV-2 mediated by the retrograde axonal transport of the virus from the respiratory mucosa, hypoxic brain injury, peripheral inflammation and monocyte-macrophage system activation that precipitate neuronal dysfunction, and the disruption of the blood-brain barrier that induces a prolonged state of neuroinflammation and possibly neurodegeneration ( 60-64 ). The SARS-CoV-2-induced cytokine ‘storm’ has been shown to play a major role in the propagation of neuropsychiatric symptoms associated with COVID-19, while aberrations in inflammatory cytokines have been proposed as pathophysiological correlates of suicidality ( 22 , 63 , 65 , 66 ). In addition, neurotransmitter imbalances, including GABAergic, glutamatergic and serotoninergic pathways, as well as widespread neuronal network dysfunction, have been suggested to provide neurobiological links to COVID-19 suicidality.…”

Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

“…A cardinal feature of SARS-CoV2 infection is the presence of a systemic inflammatory milieu called cytokine storm, including IL1, IL6, IL12, IL18, CCL2, CCL5, GM-CSF, TNF a , and IFNγ, storm ( Arunachalam et al, 2020 , Garcia-Beltran et al, 2021 , Hadjadj et al, 2020 , Lucas et al, 2020 ). Since ACE2, the cellular entry receptor of SARS-CoV2, is widely expressed in various tissues, including the brain, direct infection of vulnerable parenchymal cell subsets by SARS-CoV2 could result in dysregulated peripheral tissue inflammation as well as neurological complications in COVID-19 patients ( Bridges et al, 2021 , Chen et al, 2020 , Hensley et al, 2021 , Ngo et al, 2021 , Ziegler et al, 2020 ). While the hyperinflammatory syndrome in SARS-CoV2 infection is contributed by various effector cell types, emerging evidence has pointed to a critical participation of major innate immune cell subsets of both peripheral and CNS origins in this pathology.…”