Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
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Volume 10 Number 1 2026
REVIEWS (Open Access)
Long COVID as a Network Disorder: Mechanisms, Biomarkers, and the Path Toward Mechanism-Anchored Clinical Stratification
Siska Ferilda 1*, Ragini Patel 2, Urvashi Jain 2
Integrative Biomedical Research 10 (1) 1-8 https://doi.org/10.25163/biomedical.10110899
Submitted: 16 November 2025 Revised: 10 May 2026 Accepted: 18 January 2026 Published: 20 January 2026
Abstract
Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), now affects several hundred million people worldwide, yet it continues to resist tidy definition and, more troublingly, effective treatment. We conducted a structured narrative synthesis of the mechanistic, biomarker, and clinical-translational literature on Long COVID and related post-acute infection syndromes, organized around five interconnected pathophysiological domains and cross-referenced against multi-omics machine learning studies reporting diagnostic performance. The evidence converges on the NF-κB pathway as a central inflammatory hub sustained by gut dysbiosis, mitochondrial mtDNA leakage, and a tryptophan-kynurenine bioenergetic bottleneck, with downstream endothelial injury and amyloid-containing microclots plausibly explaining post-exertional malaise. Machine learning classifiers built on transcriptomic, proteomic, metabolomic, and multi-omics data achieve diagnostic AUCs as high as 0.95, suggesting that objective, mechanism-anchored subtyping is already technically feasible. Long COVID appears to behave less like a single diagnosis and more like a network disorder with several biologically distinct, druggable endotypes; moving clinical trials and care pathways toward biomarker-guided stratification, rather than symptom-based enrollment, seems to be the most defensible way forward.
Keywords: Long COVID, post-acute sequelae of SARS-CoV-2, post-viral syndrome, biomarkers, NF-κB pathway, amyloid microclots, mechanism-anchored stratification
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