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Mechanisms and modulation of sepsis-induced immune dysfunction in children

Abstract

Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. Sepsis has a direct impact on the immune system due to adverse alteration of the production, maturation, function, and apoptosis of immune cells. Dysregulation in both the innate and adaptive immune responses during sepsis leads to a range of phenotypes consisting of both hyperinflammation and immunosuppression that can result in immunoparalysis. In this review, we discuss components of immune dysregulation in sepsis, biomarkers and functional immune assays to aid in immunophenotyping patients, and evolving immunomodulatory therapies. Important research gaps for the future include: (1) Defining how age, host factors including prior exposures, and genetics impact the trajectory of sepsis in children, (2) Developing tools for rapid assessment of immune function in sepsis, and (3) Assessing how evolving pediatric sepsis endotypes respond differently to immunomodulation. Although multiple promising immunomodulatory agents exist or are in development, access to rapid immunophenotyping will be needed to identify which children are most likely to benefit from which therapy. Advancements in the ability to perform multidimensional endotyping will be key to developing a personalized approach to children with sepsis.

Impact

  • Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. The resulting spectrum of immunoparalysis that can occur due to sepsis can increase morbidity and mortality in children and adults.

  • This narrative review summarizes the current literature surrounding biomarkers and functional immunologic assays for immune dysregulation in sepsis, with a focus on immunomodulatory therapies that have been evaluated in sepsis.

  • A precision approach toward diagnostic endotyping and therapeutics, including gene expression, will allow for optimal clinical trials to evaluate the efficacy of individualized and targeted treatments for pediatric sepsis.

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Fig. 1: Pathways of immune dysfunction associated with sepsis.
Fig. 2: Targeted immunomodulatory therapies in sepsis.
Fig. 3: Representative monocyte HLA-DR expression before and after GM-CSF treatment in sepsis.

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Acknowledgements

We would like to thank the Program in Inflammation, Immunity and the Microbiome (PrIIMe) team and acknowledge the Lurie Children’s Immunology Lab. The following authors are supported by National Institutes of Health awards: NHLBI K08HL143127 (Coates), NIAID K08AI123524 (Arshad), and NIAID K23AI139337 (Mithal).

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Mithal, L.B., Arshad, M., Swigart, L.R. et al. Mechanisms and modulation of sepsis-induced immune dysfunction in children. Pediatr Res 91, 447–453 (2022). https://doi.org/10.1038/s41390-021-01879-8

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