Early T Cell Depletion and Mortality in Children

During the initial phase of an infection, innate immune system cells (e.g., macrophages, neutrophils) dominate cytokine production. Then, the adaptive immune system, made up of lymphocytes, assumes the regulatory role in fighting the infection, ensuring homeostasis between pro- and antiinflammatory cytokines. However, the phenomenon of immunoparalysis occurring in some adult patients with sepsis has been linked to T cell depletion and subsequent increased mortality from severe infections.¹ Low T cell counts and subsequent cytokine expression patterns in children with severe infections are poorly understood. This study sought to determine whether T cell depletion is associated with mortality in critically ill children with severe infections and, if so, what cytokine profile mediates this process.²

In this prospective observational cohort, the authors recruited patients from a pediatric intensive care unit (PICU) in the Children’s Hospital of Fudan University in China between May 2022 and August 2024. The patients were children between the ages of 28 days and 18 years who were admitted to the PICU with suspected or confirmed infection and at least one dysfunctional organ. Children with immune deficiencies or malignancies or those who had received a transplant were excluded. Information acquired for these children during the first 24 hours of admission included demographic, laboratory, disease severity, steroid use, and clinical outcome data. Mortalities were recorded at 30, 60, and 90 days after admission.

The authors collected data from 252 patients. First, the authors developed restricted cubic spline models and applied them to examine the association between T cell counts (including subsets) and mortality. They discovered that the hazard ratio for mortality was higher with low total (CD3+) T cells, CD4+ cells, and CB8+ cells (at counts of 705, 411, and 248 cells/μL, respectively). The CD3+ value was then used as an inflection point to study lower versus higher T cell groups. They found a trend toward increased severity of illness and the use of extracorporeal membrane oxygenation and continuous renal replacement therapy in patients with lower T cell counts, and the use of vasoactive agents was significantly higher. More importantly, the lower T cell counts were associated with mortality at 30, 60, and 90 days. Kaplan-Meier curves demonstrated lower survival probability in the lower T cell group, showing the breaks in survival around days 7 through 10. Steroid use had no effect on T cell numbers.

To ascertain possible mechanisms for this association, the authors performed cytokine profiling on a subset of 80 patients, looking at levels of 46 different cytokines followed by correlation analyses with T cell counts and ultimately mortality. Platelet-derived growth factor (PDGF)-AA and PDGF-AB/BB were found to be significantly decreased in nonsurvivors. To determine whether these low cytokines were just co-occurring with low T cells or whether they were low because of diminished T cells, the authors used causal mediation analysis and determined that 71% of the relationship between lower T cells counts and 90-day mortality was driven by these low cytokines.

Immunoparalysis can occur in 30% to 50% of critically ill children with septic shock. In adults with severe infections, T cell lymphopenia has been shown to contribute to immunoparalysis and is associated with worse outcomes. In this study, the authors demonstrated that total T cell depletion (as well as decreased CD4+ and CD8+) within the first 24 hours of PICU admission is associated with 30-, 60-, and 90-day mortality in children with severe infections. In addition, the authors were able to link decreased PDGF-AA and PDGF-AB/BB, cytokines typically involved in maintaining and healing vascular integrity and tissue remodeling, with low T cells counts and mortality.

Limitations of this study include its single-center design and the lack of age-stratified and endotype-specific analyses. The authors clarify that this study should be considered exploratory and can provide the framework for future validation studies. Alone, this study already provides evidence affirming the use T cell numbers (easily obtained by flow cytometry) for prognostic purposes and suggests a mechanism that can be elucidated in the future.


References

1. Jensen IJ, Sjaastad FV, Griffith TS, Badovinac VP. Sepsis-induced T cell immunoparalysis: the ins and outs of impaired T cell immunity. J Immunol. 2018 Mar 1;200(5):1543-1553.
2. Cheng Z, Wang J, Zhang C, et al. Early T-lymphocyte depletion predicts mortality in critically ill children with severe infections: an exploratory analysis of cytokine pathways. Crit Care Med. 2026 Apr 1;54(4):848-859.