Immune endotype linked to poorer recovery in pediatric sepsis, organ failure

A Children’s Hospital of Philadelphia (CHOP)–led study identified an immune endotype in critically ill children with multiple organ dysfunction syndrome (MODS), with or without sepsis, that was associated with more difficult recovery and increased mortality risk, according to findings published June 9 in the Journal of Clinical Investigation.¹

“Our goal is not simply to know that some children are sicker than others, but to understand the biology driving that risk so future studies can test more precise approaches,” said Robert B. Lindell, MD, lead study author and an attending physician in CHOP’s Department of Anesthesia and Critical Care.²

The observational study followed 88 children treated in CHOP pediatric and cardiac intensive care units. Investigators obtained blood samples within 48 hours of organ dysfunction onset and then twice weekly, comparing immune profiles from critically ill children with those from healthy children. The team used spectral flow cytometry and single-cell transcriptional analysis to characterize immune dysregulation patterns.^1,2

The highest-risk subgroup had marked inflammatory activation involving both interleukin 6 (IL-6) and interferon γ (IFN-γ). According to the investigators, this pattern appeared in children with sepsis and in children with organ failure from other causes, suggesting that different clinical triggers may converge on a similar immune state. The press release did not provide absolute mortality rates, effect sizes, or diagnostic performance characteristics for the proposed biomarker panel.

The study also reported abnormalities in CD8+ T cells, which typically contribute to pathogen clearance. In the sickest children, these cells appeared highly activated but also stressed and less responsive to additional stimulation. Investigators described persistent activity in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, with immune cells appearing activated at baseline but showing limited responsiveness when challenged experimentally.

To interpret the signal, researchers compared immune profiles from critically ill children with profiles from children with rare inborn errors of immunity involving STAT1 and STAT3 signaling. Sarah E. Henrickson, MD, PhD, senior author and attending physician in CHOP’s Division of Allergy and Immunology, said the comparison supports viewing pediatric sepsis “as a set of distinct immune states, rather than a uniform response to infection.”

The findings add to a broader shift in pediatric sepsis research away from syndrome-level classification alone and toward biologically defined subgroups. Sepsis is defined by life-threatening organ dysfunction resulting from a dysregulated host response to infection; updated pediatric consensus criteria have emphasized organ dysfunction-based identification and risk stratification.³ Current pediatric sepsis management remains centered on early recognition, prompt antimicrobials when infection is suspected, hemodynamic support, source control when feasible, and organ support in the ICU.⁴

Clinically, the CHOP findings are hypothesis-generating rather than practice-changing. The study did not evaluate an intervention, and no biomarker-guided treatment algorithm was tested. Although IL-6, IFN-γ, and JAK/STAT signaling are biologically plausible treatment-related pathways, the data do not establish that modulating these pathways would improve outcomes in children with MODS or sepsis. Any such approach would require prospective validation, careful attention to infection risk, and trial designs that match therapy to immune phenotype.

Nuala J. Meyer, MD, MS, study coauthor and director of the Center for Translational Lung Biology at the University of Pennsylvania Perelman School of Medicine, said the investigators identified “a small set of blood proteins that may help flag these high-risk immune patterns earlier.” That biomarker concept may be particularly relevant in pediatric critical care, where patients with similar bedside diagnoses can have substantially different immunologic trajectories.

Important limitations remain. The study population came from a single pediatric health system, and the sample size was modest. The press release described a high-risk subgroup but did not report whether the blood protein signature has been validated externally, how quickly it could be measured in routine care, or whether it distinguishes transient inflammation from a durable endotype requiring treatment. The CHOP-led team is now working to validate the signature in additional cohorts of children with sepsis.

References

1. Lindell RB, et al. Aberrant STAT signaling and T cell dysregulation define a targetable pediatric sepsis endotype. J Clin Invest. Published online June 9, 2026. doi:10.1172/JCI202867

2. Children’s Hospital of Philadelphia. Children’s Hospital of Philadelphia study may help explain why some children with sepsis or organ failure face a harder recovery. PR Newswire. Published June 10, 2026. Accessed June 12, 2026. https://www.prnewswire.com/news-releases/childrens-hospital-of-philadelphia-study-may-help-explain-why-some-children-with-sepsis-or-organ-failure-face-a-harder-recovery-302797173.html

3. Schlapbach LJ, Watson RS, Sorce LR, et al. International consensus criteria for pediatric sepsis and septic shock. JAMA. 2024;331(8):665-674. doi:10.1001/jama.2024.0179

4. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med. 2020;46(suppl 1):10-67. doi:10.1007/s00134-019-05878-6