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K. Kawamoto et al.
Table 4. Univariate and multivariate analyses for predicting overall survival of adult-onset chronic active Epstein-Barr virus (EBV) infection patients.
EBNA antibody titer ≥ 40
EBV-DNA in PB ≥ 103 copies/mL EBV monoclonality by Southern blot EBER-positive cells ≥30 /HPF
Univariate analysis Hazard ratio (95% CI)
P
Multivariate analysis Hazard ratio (95% CI)
Age ≥ 61 years
PS High (2-4)
T-cell type
Thrombocytopenia (< 100×109 /L) Elevated LDH
1.340 (0.698-2.574)
1.719 (0.885-3.342) 1.190 (0.623-2.274) 2.277 (1.187-4.368) 1.610 (0.762-3.402) 2.341 (0.329-2.497) 0.866 (0.361-2.078) 0.789 (0.229-2.719) 0.637 (0.329-1.235)
2.524 (1.044-6.104)
0.3793
0.1101
0.5989 0.0133* 0.2125 0.0351* 0.7470 0.7069 0.1821 0.0398*
6.157 (2.433-15.58) 2.815 (1.225-8.468)
5.410 (1.892-15.47)
P
<0.001* 0.0148*
0.0016*
Treatment without HSCT
1026
CAEBV: chronic active EBV infection; EBNA: Epstein–Barr virus nuclear antigen 1; EBV-DNA: EBV-deoxyribonucleic acid; PS: Performance Status; EBER: Epstein-Barr virus-encoded RNA; LDH: lactate dehydrogenase; HSCT: hematopoietic stem cell transplantation. *Statistically significant difference; PB: peripheral blood (plasma); HPF: high power field.
that direct verification of increased quantitative EBV val- ues may be important for diagnosis. If EBV infection in T cells or NK cells and an increase in plasma EBV-DNA level are proven, it may be necessary to diagnose CAEBV.
Many differences in the clinical features between adult- onset, and pediatric-onset type CAEBV were elucidated. As for other infectious diseases, there was a lower fre- quency of fever in adult-onset CAEBV, than in pediatric- onset CAEBV.27 The frequency of skin lesions was higher in the adult-onset type, while hypersensitivity to mosqui- to bites and hydroa vacciniforme were significantly much less frequent in adult-onset CAEBV than in pediatric-onset CAEBV. Although there was a difference in the appear- ance of skin lesions between adult-onset and pediatric- onset CAEBV, it is not known whether this could be explained only by the difference in age at onset. It should be noted that many patients with adult-onset CAEBV do not have a history of hypersensitivity to mosquito bites and hydroa vacciniforme, despite these symptoms having been thought to be clues to the diagnosis of CAEBV.
Adult- and pediatric-onset CAEBV may constitute a continuous spectrum because the diagnostic criteria for adult-onset CAEBV in this analysis were the WHO criteria for “Systemic EBV positive T-cell lymphoproliferative dis- orders of childhood”. Comparing clinical features, CAEBV patients over 50 years old were considered to share the pathogenesis with that of their young and adult-onset counterparts. However, the clinical and molecular details are still unknown. In this analysis, we did not perform molecular biology to investigate the common features. In future, we would like to investigate whether the molecu- lar background of adult- and pediatric-onset CAEBV is the same.
This study suggests that thrombocytopenia, high EBNA antibody titer (≥40), and the presence of hemophagocytic syndrome at the initial diagnosis of CAEBV are prognostic factors in adult patients, as previously reported in children and young adults, and further suggested to be indicators for aggressive therapeutic intervention including allogene- ic HSCT.17,28 It has been reported that patients with clini- cally aggressive CAEBV have a high level of expression of EBNA-1;29 this report may support our results. It has also been reported that treatment with EBNA-1-specific T cells
may be effective.30 This may be a treatment option for CAEBV patients with high EBNA antibody levels. Conversely, no difference in prognosis was detected depending on the type of cell infected by EBV in patients with adult-onset CAEBV, which contradicts previous find- ings in children and young adults.6,17 Precursor T cells are reported to have the potential to differentiate into NK cells, suggesting that phenotype could be changed.31 Moreover, it has been proven that a single EBV clonotype can infect multiple NK-cell and T-cell subsets.32 The iden- tification of infected cells in patients with adult-onset dis- ease may not be very important. In this study, there were 2 patients who did not express cytotoxic molecules such as TIA-1 and granzyme B from their T cells, as determined by immunohistochemistry. Although we could not further characterize the clinical features of these cases because of their small number, further studies are necessary to deter- mine the significance of EBV-infected cells. In addition, there were no differences in prognosis among the three histological classifications (A1, A2, and A3).9 Regardless of histological category, this study suggests that treatment including allogeneic HSCT is the cure for CAEBV. Although allogeneic HSCT has been reported to be effec- tive,6,15,17 there is still controversy about when the trans- plant should be performed and further research is, there- fore, needed.
Genetic analysis by next-generation sequencing is a very important issue in order to evaluate subtypes and dif- ferent genetic abnormalities which result in CAEBV. According to the results of genetic analysis of terminal repeats of EBV, since it was suggested that CAEBV in the early stage has a polyclonal state, genetic analysis by sequencing was not necessarily valid.9 Although other research groups have detected genetic abnormalities, such as those of the T-cell receptor β repertoire and perforin,33,34 these genetic abnormalities are not useful for explaining the development and mechanism of progression of CAEBV. In situations in which the actual condition of the disease is unclear, we believe it is important to recognize that there are various types of disease. Next-generation sequencing to analyze the genetic landscape of CAEBV will be necessary and important in the future.
It has been suggested recently that the development of
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