UNLABELLED: Post-COVID-19 syndrome (PCS), also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), represents a heterogeneous set of persistent clinical manifestations developing after acute infection. These conditions are associated with immune dysregulation, autonomic imbalance, impaired thymic function, and possible viral persistence.

OBJECTIVE: This study aims to systematically synthesise current evidence on the immunopathogenesis of PCS and to critically evaluate the application of artificial intelligence (AI) and machine learning (ML) approaches for its prediction and clinical stratification.

METHODS: A PRISMA 2020-informed systematic review was conducted using PubMed/MEDLINE, Scopus, Web of Science, elibrary.ru and Embase databases (January 2020-December 2025). Studies addressing immunopathological mechanisms and AI/ML applications in PCS were selected based on predefined eligibility criteria. Risk of bias in prediction studies was assessed using the PROBAST tool. Due to heterogeneity, a structured qualitative synthesis was performed. Current evidence indicates that PCS may result from sustained systemic inflammation, cytokine dysregulation, autoimmunity, and delayed restoration of T-cell homeostasis, including reduced thymic output of naïve T lymphocytes. Persistent thymic dysfunction may contribute to prolonged immune imbalance, increased susceptibility to secondary infections, and reactivation of latent viruses. AI/ML approaches-including gradient boosting, ensemble learning, deep neural networks, and natural language processing-have demonstrated promising performance across multimodal datasets. However, significant limitations were identified, including small sample sizes, overfitting, lack of external validation, and heterogeneity in outcome definitions.

CONCLUSIONS: The integration of immunopathological insights with data-driven modelling highlights the potential of combined approaches for improving PCS risk stratification. However, current AI models remain insufficiently validated for clinical implementation. Future research should prioritise methodological standardisation, external validation, and incorporation of mechanistically informed biomarkers.