Abstract
Background and Aims: Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome. Approach and Results: Among 47 PALF study participants, 12 IAMs collected ≤6 days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8–positive (CD8+) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive 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% versus 20%, P < 0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8 mg/dL, P < 0.001) and peak coma grades. The 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 by etiology, initial biochemistries, and short-term outcomes was 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 233-246 |
| Number of pages | 14 |
| Journal | Hepatology |
| Volume | 73 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
Funding
The work was made possible by the collaborative effort of the following current and former principal and coinvestigators of the Pediatric Acute Liver Failure Study (by site) and research coordinators at the University of Pittsburgh: Robert H. Squires, M.D., and Benjamin L. Shneider, M.D., Cincinnati Children’s Hospital: John Bucuvalas, M.D., and Mike Leonis, M.D., Ph.D., Ann & Robert H. Lurie Children’s Hospital of Chicago: Estella Alonso, M.D., University of Texas Southwestern: Norberto Rodriguez-Baez, M.D., Seattle Children’s Hospital: Karen Murray, M.D., and Simon Horslen, M.D., Children’s Hospital Colorado (Aurora): Michael R. Narkewicz, M.D., St Louis Children’s Hospital: David Rudnick, M.D., Ph.D., and Ross W. Shepherd, M.D., University of California at San Francisco: Philip Rosenthal, M.D., Hospital for Sick Children (Canada): Vicky Ng, M.D., Riley Hospital for Children (Indianapolis): Girish Subbarao, M.D., Emory University: Rene Romero, M.D., Children’s Hospital of Philadelphia: Elizabeth Rand, M.D., and Kathy Loomis, M.D., Kings College-London (England): Anil Dhawan, M.D., Birmingham Children’s Hospital (England): Dominic Dell Olio, M.D., and Deirdre A. Kelly, M.D., Texas Children’s Hospital: Saul Karpen, M.D., Ph.D., Mt. Sinai Medical Center: Nanda Kerkar, M.D., University of Michigan: M. James Lopez, M.D., Ph.D., Children’s Hospital Medical Center (Boston): Scott Elisofon, M.D., and Maureen Jonas, M.D., Johns Hopkins University: Kathleen Schwarz, M.D., Columbia University: Steven Lobritto, M.D., and the Epidemiology Data Center (Pittsburgh): Steven H. Belle, Ph.D.
ASJC Scopus subject areas
- Hepatology