Dynamic sepsis endotypes: instability or expected signal of biological progression? Author's reply
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By
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Emma Rademaker
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Harm-Jan de Grooth
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Olaf L. Cremer
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February 17, 2026
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Clinical Scorecard: Evolving Endotypes of Sepsis: Are Fluctuations Indicative of Biological Progression? Response from the Author
At a Glance
| Category | Detail |
|---|
| Condition | Sepsis |
| Key Mechanisms | Frequent transitions between immune profiles; classification error vs biological evolution |
| Target Population | ICU patients with sepsis |
| Care Setting | Intensive Care Unit (ICU) |
Key Highlights
- Observed 8-hourly immune profile transition rates (22-41%) exceed biologically plausible variation (15-25%).
- Rapid immune profile changes likely reflect classification error rather than true biological progression.
- Limited temporal cohesion (Rand index 0.65) undermines reliability of immune endotypes for targeted therapy.
Guideline-Based Recommendations
Diagnosis
- Be cautious interpreting frequent immune profile changes as biological progression in sepsis.
- Consider potential classification errors when assigning immune endotypes.
Management
- Avoid relying solely on immune endotype classification for patient selection in immune-modulating therapies.
- Recognize that patients with identical baseline profiles may diverge rapidly, complicating targeted treatment.
Monitoring & Follow-up
- Monitor immune profiles with awareness of potential instability and classification noise over short intervals.
- Use serial immunological measurements critically, considering their limitations in reflecting true biological changes.
Risks
- Risk of inappropriate immunomodulatory therapy due to unstable and rapidly changing immune profile assignments.
- Potential misclassification leading to ineffective or harmful treatment decisions.
Patient & Prescribing Data
Sepsis patients in ICU with immune profiling data
Rapid divergence in immune profiles suggests limited utility of current endotype-based immunomodulatory therapies for consistent patient targeting.
Clinical Best Practices
- Interpret immune endotype data with caution, acknowledging classification instability.
- Integrate immune profiling with clinical context rather than relying on discrete subgroup assignments alone.
- Prioritize validation of immune profiling methods to reduce classification error before clinical application.
References
