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Multicenter, cross-sectional, observational study on Epstein–Barr viral infection status and thiopurine use by age group in patients with inflammatory bowel disease in Japan (EBISU study)

Abstract

Background

The Epstein–Barr virus (EBV) infection status in patients with inflammatory bowel disease (IBD), particularly those using thiopurines, may be associated with the risk of lymphoproliferative disorder and hemophagocytic lymphohistiocytosis. This was the first multicenter survey of EBV infection in Japanese patients with IBD. Factors related to the EBV infection status were also investigated.

Methods

Five tertiary institutions in Japan participated in this study to examine pediatric and adult patients with IBD. Serum EBV anti-viral capsid antigen (VCA) IgG, EBV anti-VCA IgM, and anti-EBV nuclear antigen–antibody were measured in 495 patients with IBD. The patients’ information was obtained from their medical records. Prior EBV infection was defined as anti-VCA IgM negativity and anti-VCA IgG positivity (UMIN000033004).

Results

The patients’ median age was 25 years (range 0–92 years). Of the 495 patients, nine were anti-VCA IgM-positive and 354 were anti-VCA IgG-positive (seroprevalence: 72.8%). The proportion of patients with prior EBV infection was 0% for those aged < 5 years, < 60% for those aged < 30 years, and > 90% for those aged > 30 years. The proportion of EBV-uninfected patients using thiopurines was 28.4% (52/183) for all patients and 51.8% (44/85) for pediatric patients. Age was significantly associated with anti-VCA IgG seropositivity (p < 0.01, odds ratio: 0.902, 95% confidence interval: 0.880–0.925). No cases of lymphoproliferative disorder, hemophagocytic lymphohistiocytosis, or chronic active EBV infection were reported.

Conclusions

Approximately 30% of Japanese patients with IBD were EBV-uninfected, including those using thiopurines. Age was a significant factor for anti-VCA IgG seropositivity.

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Fig. 1

Abbreviations

CD:

Crohn’s disease

EBNA:

Epstein–Barr virus nuclear antigen

EBV:

Epstein–Barr virus

HLH:

Hemophagocytic lymphohistiocytosis

IBD:

Inflammatory bowel disease

IBDU:

Inflammatory bowel disease unclassified

LPD:

Lymphoproliferative disorder

UC:

Ulcerative colitis

VCA:

Viral capsid antigen

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Acknowledgements

We thank Traci Raley, MS, ELS and Angela Morben, DVM, ELS, from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported in part by grants from the Japan Sciences Research Grant for Research on Intractable Diseases (Japanese Inflammatory Bowel Disease Research Group) affiliated with the Japan Ministry of Health, Labour and Welfare.

Author information

Affiliations

Authors

Contributions

Concept and design of the study: TH, MMi, HS, KA, II, HN, and TS; acquisition of data: TH, MMi, HS, DS, TK, DH, MY, KA, II, HN, and TS; analysis and interpretation of data: TH, MMi, JM, MMa, KA, II, HN, and TS; drafting of the manuscript: MMi, TH, JM, and MMa; critical revision of the manuscript for important intellectual content: KA, II, HN, and TS; statistical analyses: JM; study supervision: TH, KA, II, HN, and TS.

Corresponding author

Correspondence to Tadakazu Hisamatsu.

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Conflict of interest

Tadakazu Hisamatsu has performed joint research with Alfresa Pharma Co., Ltd. and EA Pharma Co., Ltd.; received grant support from Mitsubishi Tanabe Pharma Corporation, EA Pharma Co., Ltd., AbbVie GK, JIMRO Co., Ltd., Zeria Pharmaceutical Co., Ltd., Daiichi-Sankyo, Kyorin Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., and Mochida Pharmaceutical Co., Ltd.; and received consulting and lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, Celgene K.K., EA Pharma Co., Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Inc. Jun Miyoshi received lecture fees from JIMRO Co. and Takeda Pharmaceutical Co., Ltd. Minoru Matsuura received commercial research funding from AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and JIMRO Co. and received lecture fees from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, AbbVie GK, Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Viatris Inc., Sandoz K.K., JIMRO Co., Nippon Kayaku Co., Ltd., Kissei Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., and Zeria Pharmaceutical Co., Ltd. Katsuhiro Arai received grant support from Nippon Kayaku Co., Ltd. and received consulting and lecture fees from Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., EA Pharma Co., Ltd., AbbVie GK, Zeria Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., Alfresa Pharma Corporation, Eli Lilly Japan K.K., and Nobelpharma Co., Ltd. Hirotaka Shimizu received grant support from Nippon Kayaku Co., Ltd. Hiroshi Nakase received honoraria from Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., and Abbvie GK and commercial research funding from Hoya Group Pentax Medical, Boehringer Ingelheim GmbH, and Daticho-Sankyo Co., Ltd. Toshiaki Shimizu received research grants from Otsuka Pharmaceutical Co., Ltd., Japan Blood Products Organization, EA Pharma Co., Ltd., and Kissei Pharmaceutical Co., Ltd. Miki Miura, Daisuke Saito, Yoshida Masashi, Takahiro Kudo, Daisuke Hirayama, Masashi Yoshida, and Itaru Iwama have no conflicts of interest.

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Supplementary file1 (DOCX 29 KB)

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Supplementary file2 Supplemental Fig. 1 Flowchart of patients in this study. UC ulcerative colitis; CD Crohn’s disease; IBDU inflammatory bowel disease unclassified; VCA viral capsid antigen (PPTX 42 KB)

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Miura, M., Shimizu, H., Saito, D. et al. Multicenter, cross-sectional, observational study on Epstein–Barr viral infection status and thiopurine use by age group in patients with inflammatory bowel disease in Japan (EBISU study). J Gastroenterol 56, 1080–1091 (2021). https://doi.org/10.1007/s00535-021-01832-w

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Keywords

  • Epstein–Barr virus
  • Thiopurine
  • Inflammatory bowel disease