University of Oulu

Honkila, M., Niinimäki, R., Taskinen, M. et al. A nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine: a case report and review of literature. BMC Infect Dis 19, 404 (2019).

A nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine : a case report and review of literature

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Author: Honkila, Minna1,2; Niinimäki, Riitta1,2; Taskinen, Mervi3;
Organizations: 1Department of Children and Adolescents, Oulu University Hospital, P.O. Box 23, FIN-90029 OYS, Oulu, Finland
2PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland
3Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland
4Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
5Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
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Language: English
Published: Springer Nature, 2019
Publish Date: 2020-04-14


Background: Symptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.

Case presentation: An 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine.

Conclusions: We found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.

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Series: BMC infectious diseases
ISSN: 1471-2334
ISSN-E: 1471-2334
ISSN-L: 1471-2334
Volume: 19
Article number: 404
DOI: 10.1186/s12879-019-4022-3
Type of Publication: A2 Review article in a scientific journal
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3123 Gynaecology and paediatrics
Copyright information: © The Author(s). 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.