Association Between Epstein-Barr Virus Infection and B-Cell Lymphoproliferative Diseases: A Case-Control Study

Seyyed Hamid Hashemi; Mohammad Abbasi; Mehrdad Hajilooi; Jalal Poorolajal; Lida Lakzadeh

doi:10.17795/ajcmi-23059

Association Between Epstein-Barr Virus Infection and B-Cell Lymphoproliferative Diseases: A Case-Control Study

Seyyed Hamid Hashemi ^{1 , *} , Mohammad Abbasi ² , Mehrdad Hajilooi ³ , Jalal Poorolajal ⁴ and Lida Lakzadeh ¹

Authors Information

¹ Brucellosis Research Center, Department of Infectious Diseases, Hamadan University of Medical Sciences, Hamadan, IR Iran

² Department of Oncology, Hamadan University of Medical Sciences, Hamadan, IR Iran

³ Department of Immunology, Hamadan University of Medical Sciences, Hamadan, IR Iran

⁴ Research Center for Health Sciences, Department of Epidemiology and Biostatics, School of Public Health, Hamadan University of Medical Sciences, Hamadan, IR Iran

Article Notes and Dates

Avicenna Journal of Clinical Microbiology and Infection: March 2015, 2 (1); e23059.Published Online: February 14, 2015

Article Type: Research Article; Received : August 25, 2014; Revised : October 15, 2014; Accepted : October 20, 2014
DOI: http://dx.doi.org/10.17795/ajcmi-23059

To Cite : Hashemi S H, Abbasi M, Hajilooi M, Poorolajal J, Lakzadeh L. et al. Association Between Epstein-Barr Virus Infection and B-Cell Lymphoproliferative Diseases: A Case-Control Study, Avicenna J Clin Microb Infec. 2015 ;2(1):e23059. doi: 10.17795/ajcmi-23059.

Abstract

Copyright: Copyright © 0, Avicenna Journal of Clinical Microbiology and Infection. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Epstein-Barr Virus (EBV) is a member of the Herpesviridae family . EBV infections occur worldwide. Most of these infections arise in early childhood, with a second peak in late teenage years. By adulthood, more than 90% of individuals have been infected and have antibodies to the virus (1). EBV, as well as the other herpes viruses, may play an important role in some hematologic malignancies due to their ability to modulate the host’s immune system. Particularly, four herpes viruses including cytomegalovirus, EBV, human herpes virus -6 and -7 have the multiple mechanisms to modulate the host’s immune system, allowing them to create latency in B lymphocytes (2, 3). EBV is the first virus described as carcinogen. It is now considered etiologically associated with the endemic Burkitt's lymphoma, Hodgkin disease, and nasopharyngeal carcinoma (4). Previous studies showed that EBV interferes with cellular DNA repair mechanisms and could lead to genetic changes in the infected cells (5). Years after primary EBV infection, a wide variety of B-cell-derived lymphoid malignancies, such as Burkitt's lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma can emerge. These cancers can initiate from a clone of EBV-infected cells. The role of EBV in these late-onset malignancies is complicated (4). On the other hand, there is evidence that persistent EBV infection may reduce its pathogenicity; therefore, causal relationships between the virus and malignancies should be interpreted with care (6). Recent findings show a variety of results regarding the relationship between EBV infection and non-Hodgkin lymphoma (7, 8). To verify these relationships further studies are required.

2. Objectives

3. Patients and Methods

In the current case-control study, conducted in 2013, a total of 43 patients with B-cell lymphoproliferative disorders including Hodgkin and non-Hodgkin lymphoma, and multiple myeloma referred to the Oncology Center of Hamadan, West of Iran, were enrolled in the study. In addition, 46 age/sex-matched healthy controls were also included. Subjects with the background of malignancies, chemotherapy, radiotherapy, blood transfusion in the recent year, or HIV infection were excluded. After taking written consent, serum samples were taken from all subjects and stored at -20°C until use. As a serologic marker of EBV, IgG against viral capsid antigen (VCA) was measured by ELISA using a specific kit for anti-VCA (Bioprob Srl., Milan, Italy). Antibody titers higher than 5 U/mL were considered positive. Data were analyzed using Stata11 software. The association between EBV seropositivity and each factor was estimated using logistic regression analysis with 95% confidence intervals; P value < 0.05 was considered significant. The study protocol and the informed consent were approved by the Ethics Committee of Hamadan University of Medical Sciences, Hamadan, Iran.

4. Results

Forty-three patients with lymphoproliferative disorders and 46 age/sex-matched control subjects participated in the study. Mean anti-VCA antibody titers in the patients and controls are shown in Table 1. There was no statistically significant difference between the mean anti-EBV titers in the case and control groups. Positive titers of anti-VCA were detected in 27 (62.7%) of the case and 35 (76%) of the control groups. As shown in Table 2, no significant relationship was observed between seropositivity of anti-VCA and lymphoprolferative diseases. In addition, there was no relationship between the types of diseases including lymphoma, Hodgkin, multiple myeloma, and anti-VCA positivity.

Table 1. Correlation Between Anti-EBV Antibody and Lymphoproliferative Diseases

Groups	Number	Mean	P Value
Two groups			0.252 a
Controls	46	41.99 ± 34.44
Cases (all patients)	43	33.04 ± 38.86
Four groups			0.040 b
Normal	46	41.99 ± 34.44
Lymphoma	24	43.57 ± 42.07
Hodgkin	13	28.54 ± 23.52
Multiple Myeloma	06	00.64 ± 01.57

^at-test.

^bANOVA test.

Table 2. Relationship Between Anti-VCA Seropositivity and Lymphoproliferative Diseases

Groups	Anti-EBV Antibody, U/mL
Groups	Negative, < 5	Positive, ≥ 5	OR	95% CI	P Value
Normal	11	35	1.00
Lymphoma	06	18	0.94	0.27, 3.64	0.920
Hodgkin	04	09	0.71	0.16, 3.79	0.616
Multiple Myeloma	06	00	-	-	-
Lymphoma/Hodgkin	10	27	0.85	0.28, 2.60	0.746
All cases	16	27	0.53	0.19, 1.46	0.172

5. Discussion

The present study found no relationship between the seropositivity of EBV and lymphoma, Hodgkin, or multiple myeloma. The current study results were in contrast with the previous reports regarding the relationship between seropositivity of EBV antibodies and the risk of hematologic malignancies. High level of anti-EBV antibodies are detected in patients with non-Hodgkin’s lymphoma, Hodgkin, and nasopharyngeal carcinoma (9). Few studies determined the role of EVB in multiple myeloma. A recent case-control study demonstrated this relationship by detecting EBV-DNA in bone marrow cells of the patients with multiple myeloma (10). On the other hand, there is supporting evidence regarding the increased risk of lymphoma in patients with EBV infection and underlying severe immunodeficiency. Some types of primary immunodeficiency disorders are predisposing factors for the development of EBV-associated hematological diseases (11). Moreover, reactivation of EBV infection in the patients with bone marrow transplant results in fatal lymphoproliferative diseases (12, 13). These observations indicate potential oncogenicity of EBV. Several studies showed the relationship between lymphoma and EBV. In a case-control study by Mueller et al. seropositivity of anti-VCA IgG was associated with the increased risk of non-Hodgkin’s lymphoma (14). In a prospective study, Lehtinen et al. reported the relationship between the elevated levels of antibodies to EBV-early antigen (EA) and Epstein-Barr nuclear antigen (EBNA) and the increased risk of lymphoma/leukemia (15). Furthermore, increased risk of lymphoma was shown in patients with anti-EA IgG positive, in a prospective study by Rothman et al. (16). Hardell et al. (17) reported a significantly increased level of IgG anti-EA and no significant elevation of anti-VCA IgG in patients with lymphoma. In a study by Gonzalez et al. (18), no relationship was found between anti –EBNA seropositivity and lymphoma, Hodgkin, or multiple myeloma. In a recent case-control study, Bertrand et al. (7) reported no relationship between serum levels of anti-VCA, anti-EA, or anti-EBNA and the risk of non-Hodgkin lymphoma. Although the results of the current study were compatible with some of above-mentioned ones, it is difficult to compare the results because of the different employed methods. Moreover, one of the limitations of the present study was the small sample size which limited of the comparison of the variables in subgroups. Another limitation of the current study was the seropositivity of EBV which is considered as only a marker of latent infection, and does not necessarily mean the reactivation of latent EBV infection. However, studies based on viral markers suggest that EBV viremia may be related with lymphoma and Hodgkin (19-21). In conclusion, according to the obtained results, the relationship between EBV infection and B-cell lymphoproliferative diseases is still controversial. To evaluate the role of EBV in lymphoproliferative disorders further studies with larger population and detection of viral DNA are necessary.

Acknowledgements

Footnote

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Avicenna Journal of Clinical Microbiology and Infection

Published by: Kowsar

Association Between Epstein-Barr Virus Infection and B-Cell Lymphoproliferative Diseases: A Case-Control Study

Abstract

1. Background

2. Objectives

3. Patients and Methods

4. Results

5. Discussion

Acknowledgements

Footnote

References

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