SEPSIS immune responses follow three distinct states that may not align with a patient’s clinical stage.
Researchers analyzed blood samples collected at four time points between critical care admission and discharge from adults with sepsis. The longitudinal approach was designed to capture how the immune system changes throughout illness and recovery, instead of relying on a single clinical snapshot.
The team constructed detailed immune profiles by integrating information on immune cells, gene expression, and protein expression. Machine learning methods combined these biological layers to characterize the changing sepsis immune response more comprehensively.
This analysis identified three sepsis temporal immune states, termed STImS1, STImS2, and STImS3. Each state displayed distinct immune cell activity and immune response programs. STImS1 showed the strongest innate immune responses, elevated pathogen resistance programs, and variable programs associated with tolerance to disease.
Crucially, the three immune states did not consistently correspond to the recognized clinical stages of sepsis. A patient considered to have early sepsis based on the timing of diagnosis, for example, was not necessarily in the earliest biological immune state.
This asynchrony suggests that time since diagnosis or critical care admission may not accurately indicate what is occurring within an individual patient’s immune system. Consequently, patients who appear clinically similar could occupy different immune states and potentially respond differently to immune directed treatment.
The findings may help explain why previous efforts to modify the dysregulated sepsis immune response have not improved patient outcomes. Current management focuses on treating the underlying infection with antimicrobials and supporting failing organs, while successful immunomodulatory therapies remain unavailable.
Repeated immune profiling could ultimately help clinicians determine which components of the immune system are altered and when a targeted intervention might be most effective. However, the findings do not establish a new clinical test or treatment strategy and require further investigation before bedside application.
The researchers next aim to determine what drives immune changes between infection onset and the development of sepsis. Clarifying these transitions could reveal therapeutic targets for preventing progression, reducing disease severity, and advancing more individualized sepsis care.
Reference
Fish M et al. Temporal analyses of immune responses in sepsis reveal asynchrony between clinical stage of illness and immune states. Immunity. 2026. doi:10.1016/j.immuni.2026.08.003.
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