IL-6, IFN-γ, IL-17A elevations and glutathione depletion predict severe MODS and mortality in critically ill children with COVID-19 and bacterial sepsis: a prospective cohort study from the Brazilian Amazon

Abstract

Background: Multiple organ dysfunction syndrome (MODS) remains a major cause of morbidity and mortality in pediatric intensive care units (PICUs), particularly when triggered by SARS-CoV-2 or bacterial sepsis. This study aimed to investigate the association between inflammatory and oxidative stress biomarkers and the development and outcome of MODS in critically ill children with confirmed SARS-CoV-2 or bacterial infections.

Methods: In this prospective, single-center cohort study (May 2020-December 2024), 62 pediatric patients (29 days to <18 years) were stratified into three groups: SARS-CoV-2 without MODS (n = 22), SARS-CoV-2 with MODS (n = 20), and bacterial MODS (n = 20). Circulating cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-17A) and oxidative stress markers (GSH, TBARS, TEAC) were quantified at PICU admission and on day 5. Associations with organ dysfunction and 28-day mortality were assessed using non-parametric statistical analyses and Kaplan-Meier survival estimates.

Results: MODS groups exhibited on day 1 sustained elevations in TNF-α, IFN-γ, and IL-17A-most pronounced in bacterial MODS (Group 3; p < 0.0001). IFN-γ was notably increased in viral MODS (Group 2). Group 3 also showed marked elevations in IL-6, IL-2, and IL-10 (p < 0.0001). By day 5, both MODS groups demonstrated significant reduced GSH and TEAC and elevated TBARS, the most severe in Group 3. In contrast, Group 1 exhibited stable cytokine profiles and preserved antioxidant status throughout. Non-survivors showed persistently elevated IL-6, TNF-α, IFN-γ, and IL-17A, coupled with sustained depletion of GSH and TEAC, and increased TBARS levels (all p < 0.0001). IL-6 and IFN-γ were particularly elevated in non-survivors with bacterial and viral MODS, respectively. Biomarker trajectories diverged between survivors and non-survivors by day 5, with failure to normalize immune-redox profiles associated with mortality. Accessible indices such as NLR, CAR, and VIS correlated with biomarker levels and disease severity. Kaplan-Meier analysis confirmed reduced survival in MODS groups (p = 0.0005).

Conclusions: A distinct cytokine and oxidative stress signature-marked by early and sustained elevations in IL-6, TNF-α, IFN-γ, IL-17A, and TBARS, and depletion of GSH and TEAC-is associated with mortality in pediatric MODS. Bacterial MODS was distinguished by the most severe immune-redox imbalance. Integrated immune-redox profiling offers prognostic value and may inform precision-targeted interventions, particularly in resource-limited settings.

Keywords: COVID-19; Cytokines; Multiple organ dysfunction; Oxidative stress; Pediatric intensive care unit; Sepsis; Shock.