Inclusion Criteria (Screening Cohort):

• Age: Participants must be ≥ 1 year of age at the time of screening.
• Evidence of Severe Hepatic Injury of all etiology (not just iSH/ iSH-T): Serum alanine aminotransferase (ALT) ≥ 1000 U/L documented within 7 days prior to enrollment.

Exclusion Criteria (Screening Cohort):

• Any condition impairing informed consent/assent or protocol compliance

Inclusion Criteria (Intervention Cohort; patients who meet Intervention Cohort eligibility can bypass Screening Cohort enrollment):

• Steroid-refractory, steroid-dependent, or relapse of hepatitis after stopping steroids and have an Indeterminate etiology of hepatitis based on standard of care, age appropriate evaluation

• Age: ≥ 1 year

• ALT ≥ 1000 U/L prior to initiation of any immune modulatory therapy

• Evidence of T-cell activation at initial diagnosis, as indicated by one of the following:

  • sIL2R > 2× upper limit of normal (ULN)
  • CXCL9 > 5× ULN
  • CD8+ T-cell infiltration in the liver

• INR < 2.0 without evidence of hepatic encephalopathy

Exclusion Criteria (Intervention Cohort; patients who meet Intervention Cohort eligibility can bypass Screening Cohort enrollment):

• Patients with known Liver failure (defined as INR >2 on two consecutive occasions without hepatic encephalopathy (HE), or INR ≥1.5 with evidence of HE)

• Evidence of chronic liver disease or parenchymal nodularity as demonstrated on imaging (US, CT, or MRI)

• Evidence of hepatic encephalopathy

• Severe acquired aplastic anemia at presentation

• Organ dysfunction assessment defined below:

  • Renal dysfunction: eGFR < 30 mL/min/1.73m² or
  • Mechanical Ventilation

• Persistent systemic infection despite appropriate antimicrobial therapy

• Active infection with Hepatitis A, B, C, HIV, or herpes simplex virus

• Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Herpes zoster infections.

• Patients with positive respiratory viral infection, including adenovirus, rhinovirus/enterovirus, SARS-CoV-2, influenza, and respiratory syncytial virus, only if they also have declining respiratory function needing positive pressure support. Suspected primary hemophagocytic lymphohistiocytosis based on patients with a history of consanguinity and/or central nervous system dysfunction or other clinical manifestations that is exaggerated compared to the degree of liver dysfunction (as judged by the site investigator and study team)

• Diagnosis of Autoimmune Hepatitis, Wilson Disease, inborn error of metabolism, acute drug or toxin-induced liver injury, or ischemic liver injury

• History of severe hypersensitivity or allergy to any component of this study regimen

• History of confirmed malignancy

• History of recreational drug use within the past 4 weeks, excluding cannabinoids

• Therapy with an immunosuppressive agent or an experimental drug within the past 6 weeks

• Pregnant, planning to become pregnant during study window, or breastfeeding at time of study entry

• Patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method (e.g. hormonal contraceptives, intrauterine device, or double-barrier method) for the duration of their study participation. Patients must maintain adequate contraception for at least 4 weeks after their last dose of emapalumab.

• Live-virus vaccination within 4 weeks of study entry or anticipated need for a live or live attenuated vaccine within 4 weeks after the last dose of emapalumab

• Peceived Bacillus Calmette-Guerin vaccine within 12 weeks prior to screening

• Patient or parent/guardian unable to give informed consent or unable to comply with the treatment protocol

• Prisoners will be excluded