A systems-theoretic, phenotype-guided intervention protocol for ME/CFS and Long COVID

Persistent post-infectious syndromes such as ME/CFS and Long COVID are characterized by regulatory fragility, heterogeneous trajectories, and frequent intolerance to standard therapeutic approaches. Conventional randomized controlled trials, which assume population-level homogeneity and ethically neutral non-intervention, are poorly suited to these conditions. This preprint presents a mechanistic, state-based intervention protocol designed to explore the feasibility, safety, and interpretability of sequential, phenotype-guided pharmacological modulation in individuals with post-infectious systemic dysregulation. The protocol conceptualizes illness persistence as a failure of adaptive recovery within tightly coupled autonomic, metabolic, and neuroimmune regulatory systems, rather than as a fixed disease entity. Participants undergo conservative functional screening followed by baseline physiological monitoring to support provisional, state-based stratification. Interventions are introduced sequentially at low doses, guided by predefined decision rules based on objective trends in autonomic, metabolic, and recovery-related markers. Explicit PROCEED, HOLD, and STEP-BACK criteria are specified a priori to govern phase transitions, accommodate delayed system responses, and minimize the risk of cumulative destabilization. Patient-reported outcomes are used contextually to support interpretation but do not drive progression decisions. The protocol is intentionally non-confirmatory and does not aim to establish causal efficacy of individual agents. Instead, it seeks to determine whether controlled, sequential perturbation of dominant regulatory domains can be conducted safely and yield mechanistically interpretable trajectories in a fragile population. Inability to tolerate or progress through the intervention sequence is treated as a valid and informative outcome rather than protocol failure. This work is intended as a methodological bridge between symptomatic management and confirmatory trials, offering a structured framework for ethically responsible exploration of system-level interventions in post-infectious illness.