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References
1. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-492.
2. Williams H, Crawford DH. Epstein-Barr virus: the impact of scientific advances on clinical practice. Blood. 2006;107(3):862-869.
3. Straus SE. The chronic mononucleosis syn- drome. J Infect Dis. 1988;157(3):405-412.
4. Jones JF, Shurin S, Abramowsky C, et al. T-
cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein- Barr virus infections. N Engl J Med. 1988;318(12):733-741.
5. Okano M, Kawa K, Kimura H, et al. Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. Am J Hematol. 2005;80(1):64-69.
6. Kimura H, Hoshino Y, Kanegane H, et al. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood. 2001;98(2):280-286.
7. Schooley RT, Carey RW, Miller G, et al. Chronic Epstein-Barr virus infection associ- ated with fever and interstitial pneumoni- tis. Clinical and serologic features and response to antiviral chemotherapy. Ann Intern Med. 1986;104(5):636-643.
8. Tsuge I, Morishima T, Morita M, Kimura
K, Matsuoka H. of Epstein-Barr virus
haematologica | 2018; 103(6)
H, Kuzushima
Characterization
(EBV)-infected natural killer (NK) cell prolif- eration in patients with severe mosquito allergy; establishment of an IL-2-dependent NK-like cell line. Clin Exp Immunol. 1999;115(3):385-392.
9. Ohshima K, Kimura H, Yoshino T, et al. Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in chil- dren and young adults: overlap with chron- ic active EBV infection and infantile fulmi- nant EBV T-LPD. Pathol Int. 2008;58(4):209-217.
10. Kikuta H, Taguchi Y, Tomizawa K, et al. Epstein-Barr virus genome-positive T lym- phocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease. Nature. 1988;333(6172):455-457.
11. Okano M, Matsumoto S, Osato T, Sakiyama Y, Thiele GM, Purtilo DT. Severe chronic active Epstein-Barr virus infection syndrome. Clin Microbiol Rev. 1991;4(1):129-135.
13. Hong M, Ko YH, Yoo KH, et al. EBV- Positive T/NK-cell lymphoproliferative dis- ease of childhood. Korean J Pathol. 2013;47(2):137-147.
14. Yamada H, Kohno S, Koga H, et al. An adult case of severe chronic active Epstein- Barr virus infection syndrome. Intern Med. 1992;31(12):1381-1386.
15. Saburi M, Ogata M, Satou T, et al. Successful cord blood stem cell transplanta- tion for an adult case of chronic active Epstein-Barr virus infection. Intern Med. 2016;55(23):3499-3504.
16. Huang Y, Xie J, Ding Y, Zhou X. Extranodal Natural killer/T-cell lymphoma in children and adolescents: a report of 17 cases in China. Am J Clin Pathol. 2016;145(1):46-54.
17. Kimura H, Ito Y, Kawabe S, et al. EBV-asso- ciated T/NK-cell lymphoproliferative dis- eases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood. 2012;119(3):673-686.
18. Ohga S, Kimura N, Takada H, et al. Restricted diversification of T-cells in chronic active Epstein-Barr virus infection: potential inclination to T-lymphoprolifera- tive disease. Am J Hematol. 1999;61(1):26-
12. Swerdlow SH, Campo E, Pileri SA, et al.
The 2016 revision of the World Health Organization classification of lymphoid 33.
neoplasms. Blood. 2016;127(20):2375-2390.
19. Henter JI, Horne A, Arico M, et al. HLH-
Adult patients with chronic active EBV-like features
EBV-related lymphoproliferative diseases could be related to an immune escape mechanism in the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) path- way.35,36 In fact, it has been reported that an anti-PD-1 monoclonal inhibitor is effective in Hodgkin lymphoma and ENKTL.37-39 The existence of such an immune escape mechanism in CAEBV is presumed. Unfortunately, it was impossible to investigate the immune background of the EBV infection in the present study because of a lack of specimens. With further accumulation of cases, we hope to investigate the immune response against EBV infection in the future, and examine the differences in immunolog- ical background between patients with CAEBV and healthy individuals.
Almost all of the Asian cases have a T-cell or NK-cell ori- gin.17 In contrast, the most common type of CAEBV in the USA originates from B cells.28 There may be racial differ- ences in susceptibility to EBV infection and host immuni- ty. In the future, it will be necessary to clarify these genetic backgrounds. In the present study we confirmed that adult-onset CAEBV has a poorer prognosis than ENKTL. Although adult EBV-positive T/NK-cell LPD includes vari- ous lymphomas, such as ENKTL and EBV-positive PTCL- NOS,12 we found that CAEBV needs to be distinguished by detailed interview and medical history because of the differences in prognosis and treatment strategies. However, at present, CAEBV and ENKTL can only be dis- tinguished by differences in their clinical courses, given that differences in biological mechanisms of action are not known. Although it is thought that a simple prognostic comparison should not be performed because the treat- ments are quite different, the present study showed there was no statistical difference in the prognosis between non-nasal type ENKTL and adult-onset CAEBV. In fact, there was a report in which it was difficult to distinguish between the two diseases.40 In future, further research is necessary to establish novel testing methods to improve the differential diagnosis of these two diseases.
The reasons why adult-onset CAEBV has a poor prog- nosis may be as follows: (i) recognition of adult-onset CAEBV by physicians is poor, so the condition is often regarded as an unknown fever; (ii) remissions and exacer- bations recur for a long period; (iii) treatments are per- formed after systemic conditions worsen and/or life- threatening complications develop, including hemophago- cytic syndrome; (iv) not much is known about the patho- biology; and (v) there is no fundamental treatment.
The accumulation of more cases may help in the recog- nition of adult-onset CAEBV by revealing the clinical fea- tures and elucidating the mechanisms of the molecular pathogenesis.
The following proposed diagnostic criteria for adult- onset CAEBV are very simple and are based on the pedi- atric-onset disease: (i) several symptoms of infectious mononucleosis are present, such as fever, lym- phadenopathies, and hepatosplenomegaly; (ii) exacerbation and remission of symptoms repeat within a certain period; (iii) proven EBV infection in T cells or NK cells in the affect- ed lesions. Hydroa vacciniforme or hypersensitivity to mos- quito bites are not essential for the diagnosis, as these symptoms are present in only approximately 30% of cases, even in pediatric-onset CAEBV. The foregoing criteria may help the timely diagnosis of adult-onset CAEBV.
Although there were clinical differences between adult- and pediatric-onset CAEBV, we confirmed that CAEBV is a disease with a varying age of onset. In addition, the prognosis of adult-onset CAEBV appears to be very poor. Therefore, a prescise, early diagnosis and appropriate treatment strategies are critical for adult patients.
Acknowledgments
The authors thank Fumiko Arakawa, Kazutaka Nakashima, Mayumi Miura, Kanoko Miyazaki, Yuki Morotomi, Chie Kuroki, and Kaoruko Nagatomo for their technical assistance. This work was partly supported by The Tsukada Medical Foundation and The Yasuda Medical Foundation.
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