Immune Network Dysregulation Predicts Adverse Outcomes in Infective Endocarditis

Infective endocarditis (IE) is characterized by systemic inflammation, yet the contribution of cytokine network dysregulation to clinical outcomes remains poorly understood. We aimed to evaluate cytokine co-expression patterns in IE and identify immune network signatures associated with in-hospital mortality and major complications. We conducted a prospective cohort study of adult patients hospitalized with IE at a quaternary public hospital in Brazil (2012-2024). Serum cytokines and chemokines were measured at one to three time points during hospitalization. Weighted topological overlap (wTO) and Co-expression Differential Network Analysis (CoDiNA) were used to characterize cytokine interactions in baseline. Logistic mixed-effects models assessed associations between individual cytokines and in-hospital mortality. Of 305 screened patients, 160 met inclusion criteria (41 deaths; in-hospital mortality 25.6%). Survivors exhibited dense, integrated cytokine interaction networks, whereas non-survivors showed markedly fragmented networks with loss of connectivity across multiple cytokines. IFN-γ and IL-1RA formed a preserved but isolated axis in fatal cases, while IL-7 displayed outcome-specific connectivity in patients with infectious complications. A distinct triad involving IFN-γ, IL-1RA, and IL-6 differentiated patients with cardiac complications. In multivariable models adjusted for age, sex, and sampling time, CCL2 was independently associated with in-hospital mortality. Immune network disruption is strongly associated with adverse outcomes in IE. Distinct cytokine signatures, including altered interactions of IFN-γ, IL-1RA, IL-6, IL-7, and CCL2, identify high-risk patients and reveal potential biological pathways underlying clinical deterioration.