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K. Kawamoto et al.
Comparative analysis of clinical features of adult-onset and pediatric-onset patients
Comparison of clinical features of adult-, and pediatric- onset patients is shown in Table 3. Patients with adult- onset CAEBV had a significantly lower frequency of fever, and more frequent occurrence of skin lesions (erythema), compared to pediatric-onset patients (P=0.005 and P<0.001, respectively). Hypersensitivity to mosquito bites and hydroa vacciniforme were also statistically less fre- quent in patients with adult-onset CAEBV (P<0.001 and P=0.0238, respectively). As regards laboratory results at initial diagnosis, while elevated liver enzymes were more frequently observed in patients with pediatric-onset type CAEBV (P<0.001), hemophagocytic syndrome was observed in bone marrow biopsies in patients with adult- onset CAEBV (P=0.0073).
Indicators for predicting prognosis of patients with adult-onset chronic active Epstein-Barr virus infection
We searched for indicators to predict prognosis at initial diagnosis because at that stage, there is no indication of the severity of CAEBV disease progression.
In log-rank test analysis (Figure 2A-E), thrombocytope- nia (platelet count <100×109/L), EBNA antibody titer ≥40, and the presence of hemophagocytic syndrome at initial diagnosis were associated with a poor prognosis (i.e. decreased overall survival; P=0.0087, P=0.0236, and P=0.0149, respectively); however, type of infected cell and histological classification were not prognostic factors for overall survival (P=0.587 and P=0.822, respectively). In terms of treatment for CAEBV, although many cases were initially treated with various chemotherapeutic regimens (Online Supplementary Table S8), allogeneic hematopoietic stem cell transplantation (HSCT) was found to be the most effective treatment for improving survival (P=0.0289) (Figure 2F and Online Supplementary Figure S3).
In both univariate and multivariate analyses for predict- ing overall survival, log-rank tests yielded similar results (Table 4). Age (> 60 years), high-risk Performance Status (2-4), type of infected cell, elevated lactate dehydrogenase level, number of EBV-DNA copies in peripheral blood, EBER-positive cell counts per high power field, and EBV detected by Southern blot using a terminal repeat probe were not prognostic factors in univariate analysis. Conversely, thrombocytopenia (platelet count <100×109/L; hazard ratio=6.157, 95% confidence interval: 2.433–15.58; P<0.001), high EBNA titer (≥40; hazard ratio=2.815, 95% confidence interval: 1.225-2.497, P=0.0148), and not receiving HSCT (hazard ratio=5.410, 95% confidence interval: 1.892–15.47, P=0.0016) were independent poor prognostic factors.
Statistical comparison of overall survival
We compared the overall survival between pediatric- onset CAEBV and ENKTL. Overall survival of patients with adult-onset CAEBV (n=54), pediatric-onset CAEBV (n=75), and ENKTL (n=82) is depicted in Figure 3. Adult-onset CAEBV had a poorer prognosis compared to both pediatric- onset CAEBV and ENKTL (P<0.001 and P=0.0484, respec- tively). Even when survival rate was stratified by allogeneic HSCT, significant differences in prognosis were observed between adult-onset and pediatric-onset CAEBV (P<0.001) (Online Supplementary Figure S3). Furthermore, the prognosis for non-nasal-type ENKTL and adult-onset CAEBV appeared to be comparable (P=0.972) (Figure 4).
Discussion
In the present study, we analyzed 54 patients with adult-onset CAEBV meeting the diagnostic criteria out- lined in the Methods section. Non-nasal-type ENKTL, ANKL, and cytotoxic-type and EBV-positive peripheral T- cell lymphomas not otherwise specified (PTCL-NOS) did not meet the diagnostic criteria. As the clinical stage pro- gresses, adult-onset CAEBV may eventually show find- ings similar to those of malignant lymphomas such as ENKTL, ANKL, and cytotoxic-type and EBV-positive PTCL-NOS. However, it is critical to diagnose CAEBV as early as possible, before fatal complications, such as hemophagocytic syndrome and malignant lymphoma, have developed. The present study showed that adult- onset CAEBV is more weakly associated with some char- acteristics, such as hypersensitivity to mosquito bites and hydroa vacciniforme, compared to pediatric-onset CAEBV. Although it appears that adult-onset CAEBV overlaps clinically with ENKTL, ANKL, and PTCL-NOS (cytotoxic-type and EBV-positive), many CAEBV cases were diagnosed only after progression to malignant lym- phomas. In addition, histopathological analysis alone may make it difficult to differentiate among these diseases; however, CAEBV may be considered symptomatically and clinically completely different because of its unique symptoms.
Of the patients diagnosed with adult-onset CAEBV in this study, 18 (33.3%) were diagnosed with malignant lymphoma (ANKL, ENKTL, and EBV + PTCL-NOS) at the time of diagnosis of the CAEBV. When the clinical course of the disease showed the presentation of CAEBV symptoms for diagnosis, the cases were considered to have developed malignant lymphomas during the clinical course of CAEBV. In our analysis, adult-onset CAEBV had a poor prognosis even in cases in which malignant lymphoma has not developed at the time of diagnosis. Simple diagnostic criteria are considered to be necessary
Table 3. Comparison of adult-onset and pediatric-onset chronic active Epstein- Barr virus (EBV) infection patients.
Patients’ characteristics
Sex Male,n(%)/female,n(%)
Symptoms and involved sites Fever, n (%)
Splenomegaly, n (%) Lymphadenopathy, n (%) Skin rash, n (%)
Lung, n (%)
Oral lesion, n (%)
Central nervous system, n (%) Myocarditis, n (%)
Past medical history
Hypersensitivity to mosquito bites, n (%) Hydroa vacciniforme, n (%)
35 (64.8) 28 (51.9) 21 (38.9) 21 (38.9) 8 (14.8) 2 (3.7)
1 (1.9)
1 (1.9)
4 (7.4) 2 (3.7)
26 (48.1) 22 (40.7) 25 (46.3)
65 (86.7) 44 (58.7) 30 (40.0) 9 (12.0) 9 (12.0) 4 (5.3)
4 (5.3)
6 (8.0)
27 (36.0) 13 (17.3)
34 (45.3) 54 (72.0) 17 (22.7)
0.005* 0.476 1
< 0.001* 0.793 1 0.399 0.238
< 0.001* 0.0238*
0.481 < 0.001* 0.0073*
Adult onset Pediatric onset P (n=54) (n=75)
31(57.4)/23(42.6)39(52.0)/36(48.0) 0.593
Laboratory test at initial diagnosis Thrombocytopenia, n (%) Transaminase elevation, n (%) Hemophagocytic syndrome, n (%) T-celltype/NK-celltype,n(%)
22(40.7)/32(59.3)34(45.3)/41(54.7) 0.153
1024
CAEBV: chronic active EBV infection, *Statistically significant difference. Thrombocytepenia: platelet count < 100×109 /L.
haematologica | 2018; 103(6)