Clinical and Pathological Characteristics of Severe EBV Infection in Japanese Children; a Disease Spectrum from Acute Liver Failure to Hemophagocytic Lymphohistiocytosis
Authors: Murata Yo , Yamada Masaki , Haga Chizuko , Ide Kentaro , Gocho Yoshihiro , Uchida Hajime , Yoshioka Takako , Imadome Ken-Ichi , Kasahara Mureo 
Published: November 2023

Abstract

Background
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus known as a cause of infectious mononucleosis (IM). While most EBV infection is mild and self-limited, severe EBV diseases such as severe IM, EBV-associated hemophagocytic lymphohistiocytosis (HLH) and EBV-associated acute liver failure (ALF) may occur on rare occasions. Interestingly, the severe EBV disease with ALF may occasionally present with overlapping features of HLH; however, it remains unknown if the presence or absence of HLH reflects a distinctive underlying pathophysiology of EBV infection. To investigate the clinical and pathological characteristics of EBV-associated ALF among children, we conducted a single-center, retrospective study at the largest tertiary children’s hospital in Japan.

Methods
We enrolled children under 18 years old who required medical management in the intensive care unit due to primary EBV infection between January 2010 and April 2021. Patients with underlying immunodeficiencies and other medical conditions were excluded. Clinical data, type of EBV-infected cell lineage, and pathological exam were reviewed.
Fourteen patients with EBV-associated ALF were identified in the initial screening, and two were excluded (due to underlying medical conditions). Thus, the details of 12 patients were further analyzed. Five patients fulfilled the criteria for HLH, while seven presented as isolated ALF only.

Results
The most common symptoms of these patients include fever (92%), vomiting (58%), and consciousness disturbance (100%). EBV loads were higher when HLH co-existed (median 2,700 copies/μg of DNA vs. 130,000 copies/μg of DNA, p = 0.01). Identification of EBV-infected cells revealed that the most common cell type was CD8+T cells (8/12, 80%), followed by CD3+T cells (1/12, 10%), and CD19+ cells (2/12, 20%). EBV infected in both CD8+T and CD19+ cells in one case and EBV-infected cells were not identified in two cases. In addition, an increase of activated CD8+ T cells (CD3+CD8+HLA-DR+) was observed in both HLH and ALF cases. Among 12 patients with ALF, seven patients underwent life-saving liver transplantation (LT) due to ALF. Of five patients with ALF+HLH, all patients received corticosteroid, four received cyclosporin or etoposide, and one underwent hematopoietic stem cell transplantation (HSCT). Overall mortality is 17% (2/12 patients), and both patients were complicated with HLH.

Conclusion
This study suggests that HLH and ALF can be an indistinguishable spectrum of severe EBV disease, and the underlying pathogenesis may be associated with the unusual type of EBV-infected cells. Hence, the identification of EBV-infected cells should be considered to guide the diagnosis and treatment. Our study also revealed that LT and cytotoxic anti-inflammatory therapy effectively treated patients with EBV-associated ALF with or without HLH, given the high mortality (&gt;70%) of this disease spectrum. Further studies investigating EBV-associated ALF pathology are warranted to determine optimal management.