Long COVID as a network disorder: a mechanism-anchored framework for biological stratification and therapeutic targeting

Abstract

Long COVID is increasingly recognized as a biologically heterogeneous, multisystem condition with wide variability in symptom expression and treatment response. Although symptom-based phenotyping has advanced descriptive and epidemiologic understanding, similarity in clinical presentation does not necessarily imply shared upstream pathophysiology. Therapeutic cohorts defined solely by symptom clusters may therefore combine biologically distinct mechanisms, potentially diluting treatment effects and complicating interpretation of interventional trials. This manuscript proposes a complementary, mechanism-anchored framework centered on recurrent and biologically measurable domains: autonomic dysfunction, mitochondrial and bioenergetic impairment, endothelial and microvascular dysfunction, gut dysbiosis and barrier disruption, mast cell–mediated signaling, and neuroendocrine dysregulation. These primary domains are conceptualized as physiologically coherent systems capable of generating multisystem symptom patterns in biologically enriched subsets. Secondary amplifying processes, including persistent immune activation, viral antigen persistence without established replication, autoantibody formation, neuroinflammation, and sleep-related destabilization, are positioned as network-coupling processes that may sustain or amplify dysregulation across domains. Within a network-based framework, Long COVID is conceptualized as a network disorder in which interacting regulatory nodes are hypothesized to generate self-reinforcing feedback loops that maintain symptom persistence even after resolution of acute infection. The model accommodates heterogeneity across mechanisms and alternative explanatory hypotheses. It provides an operational structure for organizing mechanistic heterogeneity and generating testable predictions. A prototype, unvalidated screening instrument is included to illustrate a potential pathway toward mechanism-informed stratification and prospective trial enrichment. Future research should evaluate whether biologically enriched cohorts demonstrate differential therapeutic responsiveness compared with symptom-defined populations. Prospective validation using standardized physiological metrics will be essential to determine whether mechanism-guided stratification improves translational precision and clarifies actionable pathophysiology in Long COVID.