Prediction of Hyperinflammatory Phenotypes in Critically Ill Patients via Routine Clinical Data and IL-6: Towards Personalized Anti-Inflammatory Therapy

Interleukin-6 (IL-6) is a central mediator of systemic inflammation and is markedly elevated in critical illnesses, including sepsis, acute respiratory distress syndrome, and hyperinflammatory syndromes. Patient responses to immunomodulatory therapies vary, highlighting the need to better understand IL-6 regulation and its clinical implications. We retrospectively analyzed consecutive patients admitted to a medical intensive care unit in a quaternary academic center with a comprehensive cancer program, extracting clinical and laboratory data, including inflammatory markers and plasma IL-6 levels. Plasma IL-6 concentrations were measured using an electrochemiluminescence immunoassay. Survival analyses, multivariable adaptive Lasso regression, Bayesian logistic regression, and latent class analysis were performed to define determinants of IL-6 regulation, mortality, and inflammatory phenotypes. IL-6 levels were substantially elevated in sepsis (median 1150 pg/mL) and neutropenia (median 7866 pg/mL), with extreme concentrations exceeding 20,000 pg/mL when both were present. Although IL-6 across its full range was not independently predictive of intensive care unit mortality, dichotomized thresholds (≥200 pg/mL) correlated with lower survival. Advanced modeling defined a hyperinflammatory phenotype characterized by IL-6 ≥ 100 pg/mL and predicted mortality >40%, showing mortality of 58%, alongside distinct latent subgroups with heterogeneous inflammatory activity and outcomes. These results emphasize the prominent role of sepsis and neutropenia in driving IL-6 elevations and reveal inflammatory phenotypes with potential for risk stratification and targeted anti-cytokine therapy in critical illness.