Biomarkers of post-acute infection syndrome: a systematic literature review

Post-acute infection syndrome (PAIS) remained underrecognized before the COVID-19 pandemic, which further increased exposure by introducing a novel global cause. The global burden of post-acute COVID syndrome (PACS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) alone is estimated at several tens of millions affected worldwide. Biomarker discovery is central to improving PAIS diagnosis and may provide therapeutic targets. This review summarizes current knowledge on biomarkers for PAIS, including PACS and ME/CFS.

A systematic literature search was conducted in PubMed and Web of Science. Inclusion criteria were: (1) studies including PAIS patients; (2) reporting laboratory or omics biomarkers; and (3) investigating biomarkers or pathomechanisms of PAIS. Although Guillain-Barré syndrome (GBS) is not PAIS, we have included it as a separate mechanistic comparator due to its prevalence in search results and its clinical and immunological similarities to PAIS.

A total of 142 studies analyzing PAIS biomarkers were included. GBS was analyzed separately and later compared with the other results. Overall, the reviewed studies employed heterogeneous approaches. While similar types of data were frequently investigated, analytical methods varied and often focused only on a subset of molecules. The results indicate that amino acid, energy, and lipid metabolism, microbiome, mitochondrial stress, and miRNA networks are affected. All pathways are connected via NF-κB.

PAIS is a multisystem disorder rooted in persistent immune activation, metabolic reprogramming, and systemic inflammation, driven not by active viral infection, but by dysregulated host responses. The NF-κB pathway serves as a unifying hub, connecting molecular, cellular, and clinical phenotypes. Our framework enables a shift from symptom-based to mechanism-based classification, paving the way for biologically grounded interventions.

This review synthesizes a broad spectrum of biomarkers in PAIS, integrating findings across pathogens and molecular levels rather than restricting to individual conditions or symptom clusters. This study highlights the differences and commonalities among pathogens and diseases that lead to post-acute sequelae, fills a critical knowledge gap, and provides a foundation for future research and clinical practice. Future studies incorporating multi-omics approaches, longitudinal designs, and larger patient cohorts are needed to validate specific biomarkers and advance the understanding of PAIS.