Symptom Clusters in ME/CFS Reflect Distinct Neuroimmune and Autonomic Pathophysiological Mechanisms: A Translational Model

Abstract Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disease characterized by heterogeneous symptom patterns. Previous work suggested that specific symptoms tend to co‑occur, pointing toward underlying biological mechanisms. This study aimed to empirically validate literature‑based, hypothesis‑driven symptom clusters and assess whether they reflect distinct neuroimmune and autonomic pathophysiological pathways. Methods Symptom data from 748 adults with ME/CFS (≥ 20 years) participating in the APAV‑ME/CFS study were analyzed. Symptoms were assigned to predefined mechanistic groups informed by current pathophysiological hypotheses. Exploratory and Confirmatory Factor Analyses, followed by Structural Equation Modeling (SEM), evaluated the coherence, distinctiveness, and hierarchical structure of each cluster. Robustness was tested using a stratified, randomized training dataset. Results A coherent Brain factor (brain fog, sensory hypersensitivity, visual disturbances, sleep disturbances, headaches) showed excellent fit (RMSEA = 0.021; CFI = 0.996). Gastrointestinal symptoms demonstrated stronger internal consistency than Immune symptoms, and model comparisons supported a two‑factor Gut – Immune structure. Across all analyses, symptom groups emerged as internally consistent and statistically distinct. A higher‑order SEM including a common latent factor yielded excellent fit for the Vegetative (autonomic) symptom complex. Conclusions The findings support ME/CFS as a complex neuroimmune and autonomic multisystem disorder and demonstrate that symptom clusters map onto functional biological systems. Mechanism‑aligned symptom subgrouping may facilitate pathophysiology‑guided diagnostics, stratification, and individualized therapeutic development.