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Adult patients with chronic active EBV-like features
adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.
Introduction
Epstein-Barr virus (EBV) generally infects almost all people by early adulthood. Although EBV infection in childhood is asymptomatic in most people, some develop infectious mononucleosis (the so-called "kissing dis- ease"). Almost all of them recover spontaneously after EBV-specific immunity is established.1
In addition, EBV has been reported to be involved in transformation from reactive to neoplastic or abnormal proliferation in some immunocompetent hosts after it infects B cells, T cells, and natural killer (NK) cells. This results in a wide range of conditions known as EBV-asso- ciated lymphoproliferative diseases (EBV-LPD),1,2 includ- ing chronic active Epstein-Barr virus infection (CAEBV), which produces infectious mononucleosis-like symp- toms such as chronic persistent or recurrent fever, lym- phadenopathy, skin rash, liver dysfunction, and hepatosplenomegaly, and has been reported to have a high mortality rate.3-5 In CAEBV, EBV-infected T cells and NK cells play important roles. Hypersensitivity to mos- quito bites, the presence of hydroa vacciniforme (HV), high EBV-related antibody titers, and a high EBV-deoxyri- bonucleic acid (DNA) copy number in peripheral blood have been reported to be characteristic of CAEBV; how- ever, there is often no discernable immunological abnor- mality, or history thereof until the patient has been diag- nosed, at which point symptoms have rapidly pro- gressed.6-8 Although the mechanism of onset is still unknown, CAEBV is thought to progress to an EBV-asso- ciated T/NK-cell lymphoproliferative disorder by clonal expansion of T cells or NK cells infected with EBV.9 In addition, CAEBV can have potentially fatal complications such as hemophagocytic syndrome, interstitial pneumo- nia, malignant lymphoma, myocarditis, and central nerv- ous system infiltration.4,7,10,11 This entity is currently defined as systemic EBV-positive T-LPD of childhood because almost all diagnoses are made in pediatric patients.12,13 However, similar clinical conditions have also been reported in adults (EBV-T/NK-LPD with CAEBV- like features in adult; adult-onset CAEBV).14,15
Most pediatric patients with EBV-T/NK-LPD show symptoms of CAEBV, although lymphomas are rarely observed.16 Conversely, adult-onset EBV-T/NK-LPD shows very diverse clinical manifestations, such as extra- nodal NK/T-cell lymphoma (ENKTL) and aggressive NK- cell leukemia (ANKL), which both follow a relatively rapid clinical course. CAEBV, however, has a chronic clin- ical course. In cases in which there is clonal expansion due to CAEBV, it may be difficult to distinguish it patho- logically from ENKTL without detailed clinical informa- tion. A thorough medical interview and careful examina- tion by physicians are, therefore, very important for the diagnosis of adult-onset CAEBV. However, because of its rarity, the clinical features of adult-onset CAEBV have been poorly detailed, and there is no consensus as to
whether there are clinical differences between adult- onset and pediatric-onset CAEBV.
The purpose of this study was to characterize the clin- icopathological features of EBV-T/NK-LPD with CAEBV- like features in adults (adult-onset CAEBV) by comparing the features to those of patients with pediatric-onset CAEBV and ENKTL. In addition, we compared the prog- nosis of adult patients with CAEBV to that of patients with ENKTL.
Methods
Patients
We enrolled 54 patients who were diagnosed with adult- onset CAEBV at the Department of Pathology, Kurume University between January 2005 and December 2015. Patients with adult-onset CAEBV were defined as those whose estimat- ed age at onset was 15 years or older, and who met the criteria for the diagnosis of systemic EBV-T-LPD of childhood according to the 2008 and 2016 World Health Organization (WHO) classi- fications of lymphoid neoplasms.12 Consequently, patients with pediatric-onset CAEBV were defined as those with an estimated age at onset of less than 15 years. All patients with CAEBV sat- isfied the following diagnostic criteria, based on the previous report by Kimura et al.17 (with the exception of EBV-DNA viral load, which was measured in plasma in this study as previously reported18): (i) sustained or recurrent infectious mononucleosis- like symptoms lasting more than three months: fever (≥38.3oC or ≥101oF), liver dysfunction (elevated liver enzymes), lym- phadenopathy, hepatosplenomegaly, cytopenia, interstitial pneumonia, hydroa vacciniforme, and hypersensitivity to mos- quito bites; (ii) increased quantities of EBV in affected tissues [i.e. detection of EBV-DNA in tissues or peripheral blood by Southern blot hybridization, or EB-encoded small RNA 1 (EBER)-positive cells detected in affected tissues by microscopy (≥10 cells/high power field)], or in peripheral blood [i.e. EBV- DNA detected in plasma (≥2×102 copies/mL in plasma)]; and (iii) no evidence of any previous immunological abnormalities or any other infections that could otherwise explain the condition. We confirmed negativity for human immunodeficiency virus antibody and human T-cell lymphoma virus 1 antibody in all patients. Hemophagocytic syndrome was diagnosed according to the HLH 2004 guidelines;19 all patients with hemophagocytic syndrome met the study criteria.
This study was carried out in accordance with the recommen- dations of the Declaration of Helsinki and was approved by the ethics review committee of Kurume University (approval num- ber: 291).
The methodological details regarding determination of the EBV-DNA viral load in peripheral blood,18 Southern blot hybridization,8,20 T-cell receptor gamma gene rearrangement,21,22 in situ hybridization for EBER,21 histology and immunophenotyp- ing,9 determination of EBV-infected cell type,6,22 and statistical analysis23 were based on previous reports, as described in the Online Supplementary Appendix.
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