Systemic T-cell activation and IFN-γ activity in indeterminate severe hepatitis are reminiscent of hemophagocytic lymphohistiocytosis: Implications for T-cell– and IFN-γ–directed therapies - 07/10/24

Doi : 10.1016/j.jaci.2024.08.029

Thinh H. Nguyen, MD, PhD ^a, Prakash Satwani, MD ^b, Deepak Kumar, PhD ^a, Urvi Kapoor, MD ^b, Sakshi Malik, PhD ^a, Chengyu Prince, BS ^a, Taylor Montminy, MD ^c, Kristi Smiley, BS ^d, Mercedes Martinez, MD ^e, Dana Goldner, MD ^e, Rebecca Marsh, MD ^d, Helen E. Remotti, MD ^f, Ladan Fazlollahi, MD ^f, Heather B. Rytting, MD ^g, Rene Romero, MD ^c, Shanmuganathan Chandrakasan, MD ^a,^⁎
^a Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
^b Division of Pediatric Hematology–Oncology, Columbia University, New York, NY
^c Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Ga
^d Division of Bone Marrow Transplantation and Immune Deficiency, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
^e Division of Pediatric Gastroenterology, Hepatology and Nutrition, NewYork-Presbyterian Hospital, Columbia University, New York, NY
^f Department of Pathology and Cell Biology, Columbia University, New York, NY
^g Department of Pediatrics, Division of Pediatric Pathology, Children’s Healthcare of Atlanta, Atlanta, Ga

^∗Corresponding author: Shanmuganathan Chandrakasan, MD, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, 2015 Uppergate Dr, Rm 434A, Atlanta, GA 30322.Aflac Cancer and Blood Disorders CenterChildren’s Healthcare of AtlantaDepartment of PediatricsEmory University2015 Uppergate DrRm 434AAtlantaGA30322

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Monday 07 October 2024

Graphical abstract

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Abstract

Background

Severe 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.

Objectives

We 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.

Methods

From 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.

Results

We 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.

Conclusions

Flow-based T-cell activation markers could help in early identification and risk stratification for targeted intervention in patients with iSH.

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Key words : Indeterminate severe hepatitis, hemophagocytic lymphohistiocytosis, indeterminate pediatric acute liver failure, CD8⁺ T-cell activation, soluble interleukin-2 receptor, ferritin, posthepatitis aplastic anemia

Abbreviations used : ALC, ALF, ALT, ANA, ANC, AST, CI, CXCL, EM, HC, Hgb, HLA, HLH, INR, iPALF, iSH, PALF, sIL-2R, T_EM, WBC