Abstract Background and aims Patients with ischemic stroke face a high risk of poor outcome and mortality, driven by inflammatory, stress, and tissue-damage mechanisms. Within the European CiRculating mEdiators of Stroke reCurrence anD aetiOlogies (CRESCENDO) consortium, we assessed early serum biomarkers representing inflammation (IL1β, IL6, CRP), stress (copeptin), and damage-associated signalling (HMGB1) as predictors of 3month functional outcome and mortality. Methods Harmonized prospective cohorts from Germany, Spain and Switzerland included 4,854 ischemic stroke patients with serum obtained within 24h of onset. IL1β, IL6, CRP, copeptin, and HMGB1 levels were quantified. Prognostic value for unfavorable outcome (mRS 3–6) and mortality at 3months was evaluated by the change in area under the curve (ΔAUC) between clinical model (NIHSS, age, sex, EssenStrokeRiskScore) and biomarker-augmented models. Results At 3months, 1,603 patients had unfavorable outcomes and 384 had died. For unfavorable outcome, IL-6 showed superior additive value (ΔAUC = 1.2%, 95% CI 0.7–1.7%), followed by copeptin (ΔAUC = 1.0%, 95% CI 0.5–1.5%) and CRP (ΔAUC = 0.6%, 95% CI 0.2–1.0%); the combination of HMGB1, copeptin, and IL6 yielded a ΔAUC = 1.8% (95% CI 1.1–2.4%). For mortality, IL6 performed best (ΔAUC = 3.1%, 95% CI 1.6–4.5%), followed by copeptin (ΔAUC = 2.6%, 95% CI 1.2–4.0%) and CRP (ΔAUC = 2.3%, 95% CI 0.8–3.7%). Combining HMGB1, copeptin and IL6 achieved a ΔAUC = 4.5% (95% CI 2.8–6.2%). Early serum IL6, copeptin, and CRP demonstrated additional prognostic yield for 3month functional outcome and mortality after ischemic stroke, with synergistic performance in combination. Conflict of interest “Johannes Teller: : nothing to disclose”, “Johanna Ernst: : nothing to disclose”, “Alejandro Fernández-Vega: : nothing to disclose”, “Johannes Frenger:: nothing to disclose”, “Hui Jeong Jung:: nothing to disclose”, “Catherine Jutzeler,:: nothing to disclose” “Ralf Lichtinghagen:: nothing to disclose”, “Gerrit M. Grosse:: nothing to disclose”, “Joan Montaner:: nothing to disclose”, “Mira Katan:: nothing to disclose”, on behalf of the CRESCENDO investigators (“Markus Arnold:: nothing to disclose”, “Marcel Arnold:: nothing to disclose”, “Carlo Cereda:: nothing to disclose”, “Carmen Del Río Mercado:: nothing to disclose”, “Gian Marco De Marchis:: nothing to disclose”, “Alejandro Gonzalez:: nothing to disclose”, “Timo Kahles:: nothing to disclose”, “Georg Kägi:: nothing to disclose”, “Francisco Moniche:: nothing to disclose”, “Soledad Perez-Sanchez:: nothing to disclose”, “Ramona Schuppner: nothing to disclose”, “Katharina Spanaus: nothing to disclose”, “Hans Worthmann: nothing to disclose”, “Karin Weissenborn: nothing to disclose”)
Teller et al. (2026) studied this question.