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Year : 2021  |  Volume : 17  |  Issue : 1  |  Page : 40-42

Spontaneous regression of chronic epstein –Barr virus infection-related lymphoproliferative disease

Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India

Date of Submission22-Jan-2021
Date of Decision25-Mar-2021
Date of Acceptance27-Mar-2021
Date of Web Publication17-Aug-2021

Correspondence Address:
Dr. Manicka Saravanan Subramanian
Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiag.jiag_1_21

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Chronic active Epstein–Barr virus infection (CAEBV) is relatively uncommon and can be associated with lymphoproliferative diseases (LPD's) of NK/T cell and B cell type. In the western world, the disease is less common, while it is found to be more prevalent in the East Asian, South, and Central American population. The presentation widely varies from skin rashes, fever, lymphadenopathy to major organ involvement and usually takes a fulminant course. Here, we describe a 70-year-old Indian male, who was diagnosed as CAEBV-related LPD with spontaneous regression with a brief review of the literature.

Keywords: Antitumor immune response, chronic active Epstein–Barr virus, lymphoproliferative diseases, older adult, spontaneous regression, spontaneous remission

How to cite this article:
Kumari B, Rao A, Subramanian MS, Dey AB. Spontaneous regression of chronic epstein –Barr virus infection-related lymphoproliferative disease. J Indian Acad Geriatr 2021;17:40-2

How to cite this URL:
Kumari B, Rao A, Subramanian MS, Dey AB. Spontaneous regression of chronic epstein –Barr virus infection-related lymphoproliferative disease. J Indian Acad Geriatr [serial online] 2021 [cited 2021 Oct 24];17:40-2. Available from: http://www.jiag.com/text.asp?2021/17/1/40/323937

  Introduction Top

Chronic active Epstein–Barr virus infection (CAEBV) is one of the rare manifestations of Epstein–Barr virus. EBV usually has B cell tropism, but the NK/T cell tropism subtype is usually associated with a wide range of lymphoproliferative disorders (LPDs), which are usually rare and life-threatening[1] and widely prevalent in East Asia, Central and South America.[2] The presentation varies from fever, hepatomegaly, splenomegaly, thrombocytopenia, anemia, and lymphadenopathy to life-threatening complications such as hemophagocytic syndrome (HLH), interstitial pneumonia, coagulopathy, malignant lymphoma, coronary aneurysms, and sepsis.[1],[2] Studies have shown that antiviral therapy is ineffective, and chemotherapy has only a transient effect. Hematopoietic stem cell transplant (HSCT) increased the overall survival rate in inactive disease and is remaining as the only option.[3]

We report a 70-year-old Indian male, diagnosed as chronic active EBV infection-related LPD with spontaneous resolution.

  Case Report Top

A 70-year-old male patient presented with a history of fever with chills for 1 month, loss of weight and appetite for the past 20 days, and flu-like symptoms for 4 days. He had a history of tuberculosis, which was treated 40 years ago and no other comorbidities. His vital signs were within the normal range. His inguinal lymph nodes were palpable bilaterally, largest measuring 3 cm × 2 cm, hard, nontender and fixed on the left side. Pallor was present. He had hepatosplenomegaly as well. HIV enzyme-linked immunosorbent assay test was negative. Blood and urine cultures were sterile.

Based on the initial evaluation, he was found to have lymphadenopathy, pancytopenia with neutropenia [Table 1] and renal impairment. The patient was admitted, and febrile neutropenia was managed with strict aseptic precautions and oral hygiene, broad spectrum antibiotics, antifungals and antiviral agents as per the local hospital policy. After 6 days of admission, the patient progressed to develop severe neutropenia. The patient was given Granulocyte colony-stimulating factor (G-CSF, Filgrastim) 300 mcg subcutaneously (5 mcg/kg/day) for 5 days, the leukocyte counts gradually improved. Meanwhile the patient was evaluated for pancytopenia and lymphadenopathy. Bone marrow aspirate showed adequate trilineage haematopoiesis and no blasts. Bone marrow biopsy revealed a normocellular marrow with adequate trilineage haematopoiesis with reactive changes. Computed tomography (CT) of the chest revealed fibro parenchymal opacities in bilateral apical lobes with predominantly upper lobe bronchiectasis and some calcified subcentimetric lymph nodes, suggestive of old tuberculosis infection. Positron emission tomography (PET) scan [Figure 1] revealed metabolically active lymph nodes on both sides of the diaphragm. Left inguinal lymph node biopsy [Figure 2] revealed binucleate atypical cells, and cells immunopositive for CD30, EBV-latent membrane protein (LMP1), CD15 (occasional) and CD20 (variable) with background proliferation of CD3 lymphocytes all suggestive of classical Hodgkin's lymphoma/angioimmunoblastic T cell lymphoma. On immunohistochemical evaluation, T cells are immunopositive for CD4, immune negative for CD10, CD8 and Bcl 6, suggestive of Classical Hodgkin's lymphoma, nodular sclerosis type. EBV-DNA copy number in whole blood, as measured by real-time polymerase chain reaction (RT-PCR), was 1701 copies/ml. A diagnosis of Classical Hodgkin's lymphoma, nodular sclerosis type, causing pancytopenia with febrile neutropenia with acute kidney injury (likely due to auto tumor lysis) was made. After discussion with the patient about treatment options and potential complications, he refused to undergo further treatment. He was asymptomatic, with normal renal parameters as on 20th day of admission and hence discharged and advised to follow-up after 1 month with a PET scan and EBV DNA reports.
Table 1: Haematological and biochemical parameters of the patient

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Figure 1: Positron Emission Tomography (PET) scan of the patient. (a) 18-fluorodeoxyglucose (FDG) PET scan showing multiple FDG avid cervical, axillary, mediastinal, abdominal and pelvic lymph nodes. (b) 18FDG PET scan showing near-complete resolution in mediastinal, abdominal and pelvic lymph nodes and a significant reduction in size, number and FDG avidity in cervical, axillary and inguinal and pelvic lymph nodes

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Figure 2: Histopathological examination of the lymph node biopsy. Excision biopsy of left Inguinal lymph node shows thick capsule and effacement of architecture with the expansion of paracortical zones, comprises of small lymphocytes, histiocytes, few mononuclear and binucleate atypical cells along with many endothelial vessels. In Immunohistochemistry, these cells are immunopositive for CD30, EBVLMP 1, CD15 (occasional) and CD20 (variable) and the background show CD3 positive lymphocytes

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The patient underwent a repeat PET Scan [Figure 1] after 28 days which revealed near-complete resolution of mediastinal, abdominal, and pelvic lymph nodes in comparison to previous PET scan and cervical, axillary, inguinal and pelvic lymph nodes showed a significant reduction in size, number and fluorodeoxyglucose (FDG) avidity and no new lesions were seen. Serial EBV RT PCR count increased from 1701 copies/ml to 15,390 copies/ml and to 95,400 copies/ml in 3 months.

A final diagnosis of chronic active EBV infection with lymphoproliferative disorder with spontaneous resolution was made. His current EBV DNA counts being stabilized (40,000 copies/ml). Post remission contrast-enhanced CT and PET scan showed no lymph nodes amenable for biopsy. He is under surveillance and asymptomatic at present.

  Discussion Top

Revised diagnostic criteria for CAEBV encompasses, EBV like illness including infectious mononucleosis for 3 months, high EBV DNA titers (>102.5 copies) in peripheral blood, detection of EBV RNA in tissues as well as excluding other immunodeficiency states.[4] Even though the pathophysiology is unclear, it is believed to be multifactorial involving altered oncogene expression, immune evasion, altered genome expression and cytokine production resulting in abnormal proliferation of NK/T/B cells resulting in malignant neoplasms.[5] In the Western world, the CAEBV is associated with B cell proliferation whereas in the Eastern part and Asia it is more commonly associated with the NK/T cell subtype, with incidences even in the forties and sixties. The CAEBV is well documented in these regions ranging from 2.6% to 15% of all Non-Hodgkin's lymphoma in Japan.[6] The NK/T cell CAEBV also believed to be the precursor for the development of adult-onset NK/T cell lymphomas.[7],[8]

It has been reported that EBV has an affinity for T lymphocytes and some of the infected cells express LMP and these T lymphocytes are responsible for the cytokine production.[9],[10]

Various treatment options have been tried for CAEBV related LPD's ranging from antivirals, chemotherapeutics, immunomodulators and allogeneic stem cell transplant. Allogeneic stem cell transplant is the only treatment that has been successful in CAEBV infection but has its pitfalls such as increased mortality, subject to donor availability, high cost, and the fulminant disease.[11],[12] In conclusion, CAEBV-associated LPD's carry poorer prognosis and need aggressive and structured regimen.[13] However, we would like to report there was a spontaneous resolution of the disease, without any treatment. There have been previous reports about the spontaneous resolution of tumors. However, the mechanism is unclear. A variety of mechanisms such as immunomodulation, trauma, concurrent infection, and increased tumor vigilance were postulated.[14],[15]

  Conclusion Top

We report an unusual presentation of CAEBV infection in an older adult presenting as Hodgkin's lymphoma. We diagnosed our patient with CAEBV, by the clinical features, expression of EBV-LMP 1 in lymph node biopsy and the high titers of EBV DNA in peripheral blood. Though FDG PET showed an increased uptake in various lymph nodes which suggests high metabolic activity in the lymph nodes, it is not a specific diagnostic finding of CAEBV/lymphoma. The patient who refused any further treatment had spontaneous resolution of LPD. This case highlights the rare spontaneous resolution of LPD in a CAEBV patient.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Kim HJ, Ko YH, Kim JE, Lee SS, Lee H, Park G, et al. Epstein-Barr Virus-associated lymphoproliferative disorders: Review and update on 2016 WHO Classification. J Pathol Transl Med 2017;51:352-8.  Back to cited text no. 1
Cohen JI, Kimura H, Nakamura S, Ko YH, Jaffe ES. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: A status report and summary of an international meeting, 8-9 September 2008. Ann Oncol 2009;20:1472-82.  Back to cited text no. 2
Kimura H, Ito Y, Kawabe S, Gotoh K, Takahashi Y, Kojima S, et al. EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: Prospective analysis of 108 cases. Blood 2012;119:673-86.  Back to cited text no. 3
Frontiers | Advances in the Study of Chronic Active Epstein-Barr Virus Infection: Clinical Features Under the 2016 WHO Classification and Mechanisms of Development | Pediatrics. Available from: https://www.frontiersin.org/articles/10.3389/fped. 2019.00014/full. [Last accessed on 2020 Jan 31].  Back to cited text no. 4
Worth AJ, Houldcroft CJ, Booth C. Severe Epstein-Barr virus infection in primary immunodeficiency and the normal host. Br J Haematol 2016;175:559-76.  Back to cited text no. 5
Park S, Ko YH. Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders. J Dermatol 2014;41:29-39.  Back to cited text no. 6
Isobe Y, Aritaka N, Setoguchi Y, Ito Y, Kimura H, Hamano Y, et al. T/NK cell type chronic active Epstein-Barr virus disease in adults: An underlying condition for Epstein-Barr virus-associated T/NK-cell lymphoma. J Clin Pathol 2012;65:278-82.  Back to cited text no. 7
Cho EY, Kim KH, Kim WS, Yoo KH, Koo HH, Ko YH. The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: Incidence of disease entities by age groups. J Korean Med Sci 2008;23:185-92.  Back to cited text no. 8
Ohshima K, Suzumiya J, Sugihara M, Nagafuchi S, Ohga S, Kikuchi M. Clinicopathological study of severe chronic active Epstein-Barr virus infection that developed in association with lymphoproliferative disorder and/or hemophagocytic syndrome. Pathol Int 1998;48:934-43.  Back to cited text no. 9
Toriihara A, Nakajima R, Arai A, Nakadate M, Abe K, Kubota K, et al. Pathogenesis and FDG-PET/CT findings of Epstein-Barr virus-related lymphoid neoplasms. Ann Nucl Med 2017;31:425-36.  Back to cited text no. 10
Cohen JI. Optimal treatment for chronic active Epstein-Barr virus disease. Pediatr Transplant 2009;13:393-6.  Back to cited text no. 11
Kawa K, Sawada A, Sato M, Okamura T, Sakata N, Kondo O, et al. Excellent outcome of allogeneic hematopoietic SCT with reduced-intensity conditioning for the treatment of chronic active EBV infection. Bone Marrow Transplant 2011;46:77-83.  Back to cited text no. 12
Kimura H, Morishima T, Kanegane H, Ohga S, Hoshino Y, Maeda A, et al. Prognostic factors for chronic active Epstein-Barr virus infection. J Infect Dis 2003;187:527-33.  Back to cited text no. 13
Buckner TW, Dunphy C, Fedoriw YD, van Deventer HW, Foster MC, Richards KL, et al. Complete spontaneous remission of diffuse large B-cell lymphoma of the maxillary sinus after concurrent infections. Clin Lymphoma Myeloma Leuk 2012;12:455-8.  Back to cited text no. 14
Snijder J, Mihyawi N, Frolov A, Ewton A, Rivero G. Spontaneous remission in diffuse large cell lymphoma: A case report. J Med Case Rep 2019;13:28.  Back to cited text no. 15


  [Figure 1], [Figure 2]

  [Table 1]


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