Researchers pinpointed a key immune pathway that could help identify high-risk children and guide future precision treatments

PHILADELPHIA, June 10, 2026 /PRNewswire/ -- A Children's Hospital of Philadelphia (CHOP) research team, working with collaborators across Penn and several national institutions, reported that many critically ill children who develop multiple organ dysfunction syndrome (MODS) – with or without sepsis – share a measurable immune system pattern linked to harder recovery and a higher risk of mortality. The findings were published this week in the Journal of Clinical Investigation.

Sepsis is a life-threatening condition that occurs when the body's immune response to infection contributes to organ injury. It remains a major cause of serious illness and death in pediatric intensive care units worldwide. However, not every child with sepsis has the same immune response, and organ failure can also occur in critically ill children without sepsis. To better understand these differences, the research team looked beyond labels and instead focused on what was happening within children's immune systems during critical illness.

In this study, Robert B. Lindell, MD, the lead study author and an attending physician in CHOP's Department of Anesthesia and Critical Care, worked with colleagues in the Henrickson lab in the Department of Pediatrics to follow 88 children treated in CHOP's pediatric and cardiac intensive care units. Using blood samples collected within 48 hours of onset of organ dysfunction, and then twice weekly thereafter, the team compared critically ill children with healthy children and used spectral flow cytometry and single cell transcriptional analysis to define underlying patterns of immune dysregulation.

The study reflects a highly interdisciplinary effort across the CHOP campus.

"This work was possible because CHOP has a unique environment where clinicians caring for critically ill children can work side-by-side with immunologists, computational scientists, and translational laboratory teams," said Lindell. "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."

The study identified one group that stood out as the highest risk. These children showed an extreme inflammatory response marked by high activity of both interleukin‑6 (IL‑6) and interferon-gamma (IFN-γ), immune signals that help coordinate the body's response to infection or injury. When these signals are too strong or persist for too long, they can contribute to an overactive immune state associated with organ injury, slower recovery, and higher mortality. Importantly, this immune pattern was present in children with sepsis as well as children with organ failure from other causes, suggesting different triggers can lead to a similarly harmful immune response.

"We identified a small set of blood proteins that may help flag these high-risk immune patterns earlier," said Nuala J. Meyer, MD, MS, study co-author and Director of the Center for Translational Lung Biology at the University of Pennsylvania Perelman School of Medicine. "Reducing a complex immune response to a measurable biomarker signal is an important step toward real-time, biology-based treatments in the ICU."

When the team examined immune cells, the sickest children had major disruption in CD8⁺ T cells, which normally help the body clear infections. These cells showed signs that they were being strongly activated by inflammation, but they also appeared stressed and less able to respond normally. The study also found persistently high activity of a major immune signaling pathway, called JAK/STAT. The cells looked turned on at rest, but when researchers tried to activate them, they barely responded. To better understand this pattern, the researchers compared the critically ill children's immune profiles with those from children who have rare inborn errors of immunity affecting the same STAT1 and STAT3 signaling pathways.

"Patients with rare inborn errors of immunity (IEIs) can teach us what happens to the immune system when specific immune pathways are turned up or down," said Sarah E. Henrickson, MD, PhD, senior author of the study and an attending physician in the Division of Allergy and Immunology. "Seeing similarities between specific IEIs and this high-risk sepsis endotype helps us understand sepsis as a set of distinct immune states, rather than a uniform response to infection, and this may help us improve our treatment strategies in the future."

Building on these findings, the CHOP-led team is working to validate the blood protein signature in additional groups of children with sepsis. The long-term goal is to develop rapid biomarker tools that could identify immune endotypes in real time and support future clinical trials of targeted, biomarker-guided therapies.

This work was supported by the National Institutes of Health (NIH) grants (K12HD047349), (K23GM159013) and (K08AI135091). Foundation grants included the Thrasher Research Fund, Burroughs Wellcome Fund, Barbara Brodsky Foundation and the CHOP Research Institute.

Lindell et al. "Aberrant STAT signaling and T cell dysregulation define a targetable pediatric sepsis endotype." J Clin Invest. Online June 9, 2026. DOI: 10.1172/JCI202867.

About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

Contact: Amanda DiPaolo Bradley
Children's Hospital of Philadelphia
267-391-8599
dipaoloa@chop.edu

View original content to download multimedia: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

SOURCE Children's Hospital of Philadelphia