Research Square · Feb 17, 2026
Additive Interaction Between Systemic Inflammation and Functional Dependency on In-Hospital Mortality: A "Double-Hit" Phenotype in 8,409 Geriatric Inpatients
By Huaping W, Haihong Z, Hui Z et al.
Background Systemic inflammation and functional status are two critical prognostic domains in geriatric medicine. However, whether these two domains interact synergistically—particularly on an additive scale—to influence short-term outcomes in secondary care geriatric inpatients remains unclear.as regional facilities focusing on subacute care, rehabilitation, and management of chronic multimorbidity, serving as a critical bridge between tertiary acute care and community care. Methods This retrospective cohort study included 8,409 patients aged ≥ 65 years admitted to a secondary geriatric hospital in China between January 2022 and December 2025. Systemic inflammation was assessed using the C-reactive protein-to-albumin ratio (CAR), and functional status was evaluated by the Barthel Index (BI). Both multiplicative and additive interaction analyses were performed, with additive interaction quantified using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Restricted cubic spline (RCS) models were applied to explore non-linear associations. Results CAR was independently associated with in-hospital mortality (adjusted OR 1.35, 95% CI 1.31–1.40). Although the multiplicative interaction between CAR and BI was not statistically significant ( P = 0.262), a pronounced additive interaction was observed. Compared with patients with low CAR and high BI, those with both high CAR and severe functional dependency exhibited a markedly increased mortality risk (36.3%; adjusted RR 55.75, 95% CI 33.33–93.26). The RERI was 29.54, AP was 53.0%, and SI was 2.17, indicating that over half of the excess mortality was attributable to their synergistic effect. The combined CAR–BI model demonstrated excellent discrimination (AUC 0.890), outperforming models using either component alone. Conclusion Systemic inflammation and functional dependency exert a strong additive synergistic effect on in-hospital mortality in secondary care geriatric patients. Integrating CAR and BI identifies a clinically meaningful “double-hit” phenotype that substantially improves risk stratification and may guide targeted multidisciplinary interventions.