BACKGROUNDSevere hepatitis cases in children are increasingly recognized, but the exact etiology remains unknown in a significant proportion of patients. Cases of indeterminate severe hepatitis (iSH) may progress to indeterminate pediatric acute liver failure (iPALF), so understanding its immunobiology is critical to preventing disease progression. Hemophagocytic lymphohistiocytosis (HLH) is a systemic hyperinflammatory disorder associated with T-cell and macrophage activation with liver injury.OBJECTIVESWe hypothesized that a high proportion of patients with iSH demonstrate systemic T-cell activation similar to HLH before developing iPALF and that the degree of T-cell activation in iSH might correlate with outcomes.METHODSFrom 2019 to 2022, 14 patients with iSH and 7 patients with PALF of known, nonimmune etiology were prospectively enrolled. We compared immune signatures of iSH, HLH, known PALF, and healthy controls.RESULTSWe found that patients with iSH have increased CD8+ T-cell activation and high IFN-γ activity similar to HLH. The amplitude of CD8+ T-cell activation was predictive of iSH progression to iPALF. We also found that in patients with iSH, ferritin had only modest elevation. However, the ratio of age-normalized plasma soluble IL-2 receptor to ferritin level can distinguish iSH from known PALF and HLH. As proof of concept, we report that in 3 patients with steroid-refractory iSH, emapalumab, an IFN-γ blocking antibody used in combination with steroids, improved liver function and may have prevented progression to PALF.CONCLUSIONSFlow-based T-cell activation markers could help in early identification and risk stratification for targeted intervention in patients with iSH.