Immature Neutrophil Programs Associate with Burn Mortality and Extend Across Critical Illnesses.

Area of Science:

• Immunology
• Genomics
• Critical Care Medicine

Background:

• Severe burns induce a systemic "genomic storm," but the specific cell states driving varied clinical outcomes are not well understood.
• Identifying cellular immune responses to severe burns is crucial for understanding mortality risk and developing targeted therapies.

Purpose of the Study:

• To define cell-specific immune programs associated with burn severity, inhalation injury, and mortality.
• To identify novel biomarkers for predicting mortality in burn patients and other critical illnesses.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of 73,014 blood cells from burn patients and healthy donors.
• Integration of scRNA-seq data with bulk signatures of burn size, inhalation injury, and mortality.
• Validation of clinical associations using the ABA National Burn Repository and testing a 5-gene neutrophil panel in trauma and COVID-19 cohorts.

Main Results:

• Burns induced emergency hematopoiesis, characterized by expanded immature neutrophils and plasmablasts, and depleted naïve T cells.
• Inhalation injury was a stronger predictor of mortality than burn size, with neutrophils being the most perturbed cell type in non-survivors.
• A 5-gene neutrophil signature accurately predicted mortality in burn patients (AUC >0.9) and generalized to trauma (AUC 0.81) and COVID-19 (AUC 0.75) cohorts.
• In silico analysis suggested galectin-1 inhibition as a potential therapeutic target for mortality-associated neutrophil programs.

Conclusions:

• Surges in immature neutrophils are associated with mortality in severe burns, trauma, and COVID-19, suggesting a common immune axis in critical illness.
• The 5-gene neutrophil panel may serve as a valuable biomarker for identifying high-risk patients.
• Targeting these immature neutrophil populations could represent a novel therapeutic strategy for critical illness.