Immune-state transition pharmacology in severe infection: From static endotypes to dynamic treatment targets

Precision immunotherapy in severe infection has historically targeted static molecular endotypes identified at admission. However, critical illness represents a rapidly moving target where inflammatory tissue damage, myeloid paralysis, lymphocyte depletion, and repair mechanisms evolve asynchronously along divergent trajectories. Consequently, interventions prescribed from an admission snapshot often exert their peak biological effect only after the host's therapeutic priorities have already shifted. Synthesizing contemporary evidence from longitudinal patient cohorts, recent biomarker-guided randomized trials, and critical-illness pharmacokinetics, we introduce an organizing translational framework: immune-state transition pharmacology. Rather than assigning patients to fixed categories, this paradigm treats reproducible, within-patient functional transitions as dynamic therapeutic targets over defined operational intervals. We demonstrate that successful immunomodulation requires decoupling three distinct pharmacological clocks: plasma clearance half-life, receptor occupancy, and functional biological response duration. While prolonged target engagement by long-acting antibodies risks causing fatal immunosuppression during secondary infections, short-acting antagonists provide the temporal agility required to manage fluctuating host states. To operationalize this approach, we outline a pragmatic bedside pathway integrating calibrated serial biomarkers, particularly standardized monocyte human leukocyte antigen-DR, with emerging rapid microfluidics, explicitly accounting for analytical turnaround times and residual drug exposure. We further propose sequential multiple assignment randomized trial designs to rigorously evaluate adaptive decision rules for initiating, switching, or discontinuing immunotherapies based on real-time functional trajectories. Ultimately, by synchronizing therapeutic kinetics with evolving host pathophysiology, immune-state transition pharmacology transforms sepsis management from static snapshot phenotyping into trajectory-matched precision medicine, balancing pathogen eradication with tissue preservation and durable functional recovery.