Background and aimsThe majority of indeterminate pediatric acute liver failure (PALF) cases are secondary to immune dysregulation, labeled activated T-cell hepatitis (TC-Hep). We aimed to describe a cohort of children with acute severe hepatitis and PALF and define how clinical immune labs may help identify the TC-Hep group. MethodsRetrospective review of children with acute hepatitis and PALF between March 2020 and August 2022. Patients were classified as known diagnosis, indeterminate hepatitis (IND-Hep), or TC-Hep (defined by liver biopsy with predominant CD8 T-cell inflammation or development of aplastic anemia). Results124 patients were identified: 83 with known diagnoses, 16 with TC-Hep, and 25 with IND-Hep. Patients with TC-Hep had significantly increased median total bilirubin levels (7.5 mg/dL (IQR 6.8-8.9) vs 1.5 mg/dL (IQR 1.0-3.6), p<0.0001), soluble interleukin-2 receptor levels (4512 IU/mL (IQR 4073-5771) vs 2997 IU/mL (IQR 1957-3237), p=0.02), and percent of CD8+ T-cells expressing perforin (14.5% (IQR 8.0-20.0) vs 1.0% (IQR 0.8-1.0), p=0.004) and granzyme (37.5% (IQR 15.8-54.8) vs 4.0% (IQR 2.5-5.5), p=0.004) compared to IND-Hep patients. Clinical flow cytometry showed that TC-Hep patients had significantly increased percent CD8+ T cells (29.0% (IQR 24.5-33.5) vs 23.6% (IQR 19.8-25.8), p=0.04) and HLA-DR+ (16.0% (IQR 14.5-24.5) vs 2.7 (1.8-5.3), p<0.001) compared to IND-Hep patients indicative of increase in CD8+ T cells that are activated. ConclusionsPeripheral blood clinical immune studies demonstrate increased markers of CD8 T-cell activation, proliferation, and cytotoxic function for TC-Hep patients. These readily available immune function labs can be used to help distinguish patients with TC-Hep from those with other causes. This provides a non-invasive tool for early detection of potential TC-Hep before progression to liver failure.