Integrating Pulmonary and Systemic Transcriptomic Profiles to Characterize Lung Injury after Pediatric Hematopoietic...

Hematopoietic stem cell transplantation (HCT) is potentially curative for numerous malignant and non-malignant diseases but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. Bronchoalveolar lavage (BAL) is the most commonly used procedure for diagnostic sampling of the lung but is invasive, cannot be performed in medically fragile patients, and is challenging to perform serially. We previously showed that BAL transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality outcomes. However, whether peripheral blood testing is a suitable minimally-invasive surrogate for pulmonary sampling in the HCT population remains unknown. To address this question, we compared 210 paired BAL and peripheral blood transcriptomes obtained from 166 pediatric HCT patients at 27 children's hospitals. BAL and blood mRNA abundance showed minimal overall correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, expression of innate and adaptive immune pathways was tightly co-regulated with expression of epithelial mesenchymal transition and hypoxia pathways, and these signatures were associated with mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups, of which one group showed twice the rate of hypoxia and significantly worse outcomes within 7 days of enrollment. These findings reveal a compartmentalized injury response, where BAL and peripheral blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.