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Four biomarkers linked to activation of CD8+ lymphocytes predict clinical outcomes in pediatric acute liver failure

Leonis, M. A.; Miethke, A. G.; Fei, L.; Maynor, S.; Chapin, C. A.; Bleesing, J. J. H.; Alonso, E. M.; Squires, R. H.

Hepatology. 2020 Apr 16

Abstract

Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim is to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome. Among 47 PALF study participants, 12 IAMs collected ≤ 6 days after enrollment were measured by flow cytometry and IMMULITE assay on blood NK and CD8+ lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort utilizing 4 of 12 IAMs which were available in all participants (% perforin(+) and % granzyme(+) CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define High (n=10), Medium (n=15), and Low IAM (n=22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% vs 20%, p<0.001). High IAM associated with higher peak serum total bilirubin levels than low IAM (median peak TB of 21.7 vs 4.8 mg/dL; p<0.001) and peak coma grades. 21-day outcomes differed between groups with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (p=0.002); no deaths were reported. In an independent validation cohort (n=71) enrolled in a prior study, segregation of IAM groups with etiology, initial biochemistries, and short-term outcomes were similar, although not statistically significant. High serum aminotransferases, total bilirubin levels and leukopenia at study entry predicted a high immune activation profile. Conclusion: Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation. These biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.

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