A Nationwide Survey on Chronic Active Epstein-Barr Virus Infection in Japan Based on New Diagnostic Criteria: Clinical Features and Treatment Strategies
Authors: Arai Ayako , Yonese Ichiro , Sakashita Chizuko , Imadome Ken-Ichi , Kobayashi Tohru , Sawada Akihisa , Ito Yoshinori , Ohga Shouichi , Kimura Hiroshi , Fujiwara Shigeyoshi 
Published: October 2019

Abstract
Background and aims
Chronic active Epstein-Barr virus infection (CAEBV) is classified into T- or NK-cell neoplasms in the new WHO classification revised in 2017. Allogeneic stem cell transplantation (allo-HSCT) has recently been reported to be an effective treatment for this disorder. Conversely, effects of chemotherapies on CAEBV have not yet been examined in a large number of patients. To clarify clinical features and the current state of chemotherapies for CAEBV under the new definition of the disease, we performed a nationwide survey in Japan.
Methods
Questionnaires were sent to all educational hospitals certified by the Japanese Society of Hematology and the Japanese Pediatric Society. Subjects were patients newly diagnosed with CAEBV between January 2003 and March 2016. CAEBV was diagnosed according to criteria suggested by the Research group of Measures against Intractable Diseases by Ministry of Health, Labour and Welfare of Japan in 2016: (1) elevated EBV DNA load in peripheral blood (PB) (>102.5 copies/μg DNA); (2) detection of EBV infection in T or NK cells from the affected tissues or PB; (3) systemic inflammatory symptoms (such as fever, lymphadenopathy, liver dysfunction, progressive skin lesions, vasculitis, and uveitis) persisting for >3 months; and (4) exclusion of other possible diagnoses, such as primary EBV infection, autoimmune disease, immunodeficiencies, and lymphomas. Patients who fulfilled (1)-(4) were diagnosed with CAEBV. These criteria were established based on those proposed by Okano et al.(Am J Hematol. 2005;80,p64) and Kimura et al.(Blood. 2012;119,p673) and were compatible with the definition of CAEBV described by WHO in 2017. The disease activity was defined according to the previous reports (Blood. 2012;119,p673 and BMT. 2016;51,p879) as follows: positive for fever, ALT level elevation, vasculitis, progressive skin lesions, or uveitis. Effects of treatments were evaluated as follows: partial response (PR), partial resolution of disease activity; complete response (CR), complete resolution of disease activity with EBV load in PB remaining high (>102.5 copies/μg DNA, which is the upper limit for healthy people); virological CR (vCR), CR with a significant decrease in the EBV DNA load in PB (<102.5 copies/μg DNA).
Results
Completed questionnaires were returned by 29 institutes and 100 patients were evaluated. They were 53 males and 47 females aged 1-78 (median, 21) years. Types of EBV-infected cells were as follows: CD4 (n = 25), CD8 (n = 13), and CD56 (n = 28). The 3-year overall survival (OS) from diagnosis was 58%.
Because different outcomes have been reported between children and adults with CAEBV, we divided patients into three groups according to their onset ages: childhood onset (CO) with patients aged <9 years, adolescent- and adult-onset (AAO), and advanced age-onset (AO) with patients aged >45 years. Seventy-eight percent patients in the CO group were males. Conversely, 85% patients in the AO group were females. The 3-year OS from diagnosis in the CO, AAO, and AO groups were 83%, 57%, and 31%, respectively. The prognosis of CO of CAEBV was significantly better than that of AAO (p = 0.0151) and AO (p = 0.0034) of CAEBV. Spontaneous regression was not observed in patients with active disease. Main chemotherapies employed were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 patients and CHOP in 45 patients. The rate of CR + PR was as follows: cooling therapy, 57% and CHOP, 39%. Viral CR was not observed. Three-year OS from the start of treatment was 0% in patients treated with only chemotherapy (n = 20) and 69% in those who received allo-HSCT (n = 59).
Conclusions
Based on the difference in OS and increased prevalence of males in the CO group, it can be concluded that CO of CAEBV may be independent from AO and AAO of CAEBV. Chemotherapy alone is currently insufficient for eradicating infected cells and resolving CAEBV. The development of an effective treatment reagent is an urgent issue.

Disclosures
No relevant conflicts of interest to declare.