Immunopathogenesis of Neurological Manifestations in Long Covid:  Persistent Neuroinflammation, Autoimmunity, and Emerging Therapeutic  Strategies: A Narrative Review

Bethasiwi Purbasari; Rahmad   Rahmad

doi:10.36418/syntax-literate.v11i7.65030

Bethasiwi Purbasari Universitas Brawijaya
Rahmad Rahmad Universitas Brawijaya

DOI: https://doi.org/10.36418/syntax-literate.v11i7.65030

Keywords: Long COVID, PASC, neuroinflammation, neuroimmunology, microglial activation

Abstract

Long COVID (post-acute sequelae of SARS-CoV-2 infection [PASC]) affects an estimated 1030% of SARS-CoV-2 survivors, with neurological and neuropsychiatric symptoms persisting well beyond the acute phase. The immune mechanisms underlying persistent central nervous system (CNS) dysfunction remain incompletely understood, and no approved treatment is currently available. This review aimed to synthesize published evidence on the neuroimmune mechanisms underlying Long COVID and to link mechanistic findings with clinical manifestations and potential pharmacological targets. Peer-reviewed studies and preprints from MEDLINE and PubMed were reviewed, covering postmortem neuropathology, advanced neuroimaging, cerebrospinal fluid (CSF) proteomics, peripheral blood immunophenotyping, and clinical pharmacology data published between 2020 and 2025. Five pathological axes were identified: (1) viral neuroinvasion and bloodbrain barrier disruption through ACE2-dependent and ACE2-independent pathways; (2) persistent microglial activation, T-cell exhaustion, and cytokine dysregulation; (3) autoantibodies targeting G protein-coupled receptors (GPCRs) and synaptic proteins, contributing to dysautonomia and cognitive impairment; (4) endothelial dysfunction, fibrin microclot formation, and complement-mediated thromboinflammation; and (5) clinical phenotypes potentially amenable to mechanism-guided therapies, including Janus kinase (JAK) inhibitors, low-dose naltrexone, intravenous immunoglobulin (IVIg), and antihistamines. Neurological manifestations of Long COVID reflect a self-reinforcing, multi-axis immunopathological process. Effective management requires endotype-based patient stratification and combination therapeutic approaches supported by mechanistic evidence.

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