Persistent Inflammation, Immunosuppression, and Catabolism Syndrome in Children: Associations With Outcomes in a Secondary Analysis of a 2019–2024 Cohort

Objectives: To identify the clinical and physiologic factors associated with mortality in pediatric patients with persistent inflammation, immunosuppression, and catabolism syndrome (PIICS). Design: Secondary analysis of a single-center cohort, 2019–2024. Setting: PICU at a tertiary children’s hospital in Japan. Patients: We reviewed data on all patients younger than 21 years who had been admitted to the PICU for greater than or equal to 15 consecutive days between 2019 and 2024. Pediatric PIICS was defined as: C-reactive protein greater than 2 mg/dL, albumin less than 3 g/dL, and lymphocyte count less than 800/µL. Interventions: None. Measurements and Main Results: Among 536 patients, we identified 64 who met criteria for pediatric PIICS. Cox proportional hazards models were used to examine factors associated with greater hazard of mortality, and proportional hazards assumptions were assessed using hazard smoothing. In the primary time-to-event analysis, severity of diarrhea, maximum heart rate ratio (mHR-r), and cumulative hypotension exposure were associated with greater hazard of mortality. The Youden-derived cutoffs were 6.5 for diarrheal severity, 1.67 for mHR-r, and 63 hours for cumulative hypotension exposure. Analysis of Kaplan-Meier curves showed that lower survival was associated with data above these thresholds. However, in the sensitivity analyses evaluating confounding by case-mix and baseline severity, we failed to identify that diarrhea was associated with greater odds of mortality. Cumulative hypotension exposure and mHR-r remained consistent physiologic markers associated with greater hazard of mortality. Conclusions: In this secondary analysis of pediatric patients with PIICS, the mHR-r and cumulative hypotension exposure were associated with greater hazard of mortality. Severe diarrhea showed an association with mortality in the primary time-to-event analysis, but we failed to identify such an association after adjustment for case-mix and baseline severity. These findings suggest that diarrhea may be a clinically relevant marker of gastrointestinal dysfunction, but its prognostic role remains uncertain. Larger multicenter studies are needed.