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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 41  |  Issue : 2  |  Page : 94-99

Human leukocyte antigen HLA-BR16 is associated with reduced risk for cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation


Hematology/Oncology and Bone Marrow Transplantation Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission26-Oct-2015
Date of Acceptance08-Nov-2015
Date of Web Publication15-Jul-2016

Correspondence Address:
Amro M. S. El-Ghammaz
37 Mohamed Korayem Street, Nasr City, PO Box 11566, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.186413

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  Abstract 

Purpose Cytomegalovirus (CMV) infection and its associated disease are significant complications of allogeneic hematopoietic stem cell transplantation (HSCT). Many risk factors for CMV infection have been previously identified, including different human leukocyte antigens (HLAs) of donor/recipient pairs. We aimed to investigate the relation of broad HLAs of donor/recipient pairs to the occurrence of postallogeneic HSCT CMV infection and disease.
Materials and methods A total of 112 patients undergoing allogeneic HSCT from a matched sibling donor were followed up for occurrence of CMV infection and disease by performing weekly quantitative PCR-CMV-DNA and clinical examination until day 100 after transplantation.
Results CMV infection occurred in 58 patients (51.8%), whereas CMV disease occurred in 22 (19.6%). On univariate analysis, acute leukemia diagnosis (P < 0.001), donor/recipient CMV serostatus (P = 0.010), methylprednisolone administration (P = 0.002), fludarabine/cyclophosphamide/antithymocyte globulin-conditioning regimen (P = 0.002), age (P = 0.041), HLA-A1 (P = 0.037), HLA-A3 (P = 0.035), HLA-B15 (P = 0.021), HLA-B16 (P = 0.003), HLA-DR6 (P = 0.002), and HLA-Cw7 (P = 0.003) influenced the occurrence of CMV infection significantly. On multivariate analysis, HLA-A3, HLA-B16, and HLA-Cw7 significantly affected the risk for CMV infection occurrence (P = 0.025, 0.004, and 0.008, respectively). Also, HLA-B16 was associated with reduced risk for CMV disease (P = 0.048).
Conclusion HLA-B16 has a protective effect against both CMV infection and disease following allogeneic HSCT.

Keywords: allogeneic hematopoietic stem cell transplantation, cytomegalovirus disease, cytomegalovirus infection, human leukocyte antigens, risk factors


How to cite this article:
El-Ghammaz AM. Human leukocyte antigen HLA-BR16 is associated with reduced risk for cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation. Egypt J Haematol 2016;41:94-9

How to cite this URL:
El-Ghammaz AM. Human leukocyte antigen HLA-BR16 is associated with reduced risk for cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation. Egypt J Haematol [serial online] 2016 [cited 2019 Dec 11];41:94-9. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/94/186413


  Introduction Top


Human cytomegalovirus (CMV) is one of the most important opportunistic pathogens affecting hematopoietic stem cell transplantation (HSCT) recipients. CMV infection is defined as the detection of CMV, typically by quantitative PCR for CMV-DNA or pp65 antigenemia from plasma or whole blood in a CMV-seronegative patient (primary infection) or a CMV-seropositive patient (reactivation of latent virus) [1]. International definitions of CMV disease, requiring the presence of symptoms and signs compatible with CMV end-organ involvement together with the detection of CMV using a validated method in the appropriate clinical specimen, have been published [2]. Almost any organ can be involved in CMV disease - for example, pneumonia, gastrointestinal disease, CMV retinitis, and central nervous system disease [3],[4],[5]. Also, CMV infection is implicated indirectly in the higher incidence of bacterial and fungal infection and increased risk for acute graft-versus-host disease (GVHD) [6],[7].

Several risk factors for CMV infection have been recognized, including the serologic status of the donor and recipient, T-cell depletion, acute and chronic GVHD, the use of mismatched or unrelated donors, drugs used for GVHD prophylaxis, and umbilical cord blood transplantation [1]. Identifying new factors that modify the immune response against CMV might be of importance in HSCT recipients. The human leukocyte antigen (HLA) has long been shown to be an important host genetic risk factor in infectious disease as well as in a variety of autoimmune diseases and cancers. Several of these diseases have a viral etiology [8]. The role of HLA in immunologic susceptibility to viral infection was originally discovered by Zinkernagel and Doherty [9]. They determined that virus-specific cytotoxic T cells recognize both a viral antigen and a polymorphic HLA molecule (HLA restriction). In turn, HLA restriction with cytotoxic T-cell lymphocytes plays a major role in destruction of virally infected cells [9]. The impact of various HLAs on risk for CMV infection and disease after allogeneic HSCT remains unclear and needs further research. Hence, we investigated the relation of broad HLA of donor/recipient pairs to the occurrence of postallogeneic HSCT CMV infection and disease.


  Materials and methods Top


Patients

This study included 112 patients undergoing peripheral blood allogeneic HSCT from a matched sibling donor in the period 2010-2014. All recipients and donors had undergone serologic determination of CMV-specific antibodies (immunoglobulins G and M) and PCR for CMV-DNA before transplantation.

HLA typing

Before transplantation, HLA typing for patients and their siblings was performed serologically (using the standard microlymphocytotoxicity method for class I antigens and microdroplet B lymphocyte cytotoxicity test for class II antigens) and molecularly (using DNA-based PCR-sequence-specific primer technique for HLA-DR antigens and in case of ambiguous results).

Treatment plan

For acute leukemia patients, the conditioning regimen consisted of fractionated total body irradiation/cyclophosphamide (Cy), busulfan (Bu)/fludarabine (Flu), or Bu/Cy. Aplastic anemia patients received Flu/Cy/rabbit antithymocyte globulin (ATG). GVHD prophylaxis consisted of methotrexate and cyclosporine. Methylprednisolone has been used for prophylaxis against hypersensitivity from ATG and for treatment of acute GVHD. All patients received irradiated blood products when needed. Acyclovir was used for antiviral prophylaxis.

Follow-up and detection of CMV infection and disease

During hospitalization and after discharge, patients were followed up weekly for 100 days by quantitative PCR for CMV-DNA (QIAGEN GmbH, Hilden, Germany). The cutoff level for CMV infection was defined at least 1000 copies/΅l in peripheral blood or rapid increase of viral load by quantitative real-time PCR [2],[10],[11]. CMV disease was defined according to Ljungman et al. [2]. Briefly, CMV pneumonia was diagnosed when either a bronchoalveolar lavage or a lung biopsy was positive for CMV in a patient with characteristic symptoms and chest radiographic findings; CMV enterocolitis was diagnosed by gastrointestinal symptoms with histologic demonstration of CMV on biopsy materials obtained by endoscopy; CMV cystitis was defined by the identification of conventional histologic features of CMV infection together with immunohistochemical analysis for CMV on a bladder biopsy specimen obtained from a patient with hemorrhagic cystitis [2]. Those patients who developed CMV infection and/or disease received pre-emptive ganciclovir treatment.

Statistical analysis

Only broad HLAs were included in the analysis. Descriptive statistical analysis of variables was performed (mean, SD, range, number, and percentage). Univariate analysis of variables was performed using the unpaired t-test (for continuous variables) and the χ2 -test (for categorical variables). Binary logistic regression was used for multivariate analysis of significant variables obtained from univariate analyses. Statistical significance was determined at the 0.05 level. All P values were two sided. Standard computer program SPSS for Windows, release 17.0 (SPSS Inc., Chicago, Illinois, USA), was used for data entry and analysis.

Compliance with ethical standards

All the procedures followed were in accordance with the ethical standards of the institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from adult participants and an assent was obtained for children aged below 16 years before participating in the study.


  Results Top


Patient characteristics

The median age of the studied patients was 27 years (range = 4-52). Fifty-four patients (48.2%) were male. Ninety patients (80.4%) had acute leukemia and 22 (19.6%) had aplastic anemia. All leukemia patients were in complete remission at the time of transplantation. Ninety-eight patients (87.5%) were CMV-seropositive before transplantation and 14 (12.5%) were CMV-seronegative. Sixty-two patients (55.4%) received Bu/Flu, 14 (12.5%) received total body irradiation/Cy, 14 (12.5%) received Bu/Cy, and 22 (19.6%) received Flu/Cy/ATG. Thirty-six patients (32.1%) developed grades II-IV acute GVHD.

Post-transplant CMV infection and disease

CMV infection occurred in 58 patients (51.8%). The mean timing of CMV infection was 51.1 ± 23.1 days (range = 4-99). CMV disease occurred in 22 patients (19.6%).

Univariate analysis of risk factors for CMV infection

CMV infection occurred more frequently in acute leukemia than in aplastic anemia patients (P < 0.001), donor-negative/recipient-positive CMV serostatus pairs (P = 0.010), and in patients who did not receive methylprednisolone (P = 0.002), and less frequently in patients who received Flu/Cy/ATG-conditioning regimen (P = 0.002) ([Table 1]). Also, the mean age of patients who developed CMV infection was significantly higher than that of those who did not develop CMV infection (P = 0.041) ([Table 1]).
Table 1 Comparison of CMV infection-positive and CMV infection-negative patients with respect to transplant risk factors


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Impact of HLA on post-transplant CMV infection risk

HLA-A1 negativity was associated with higher rate of absent CMV infection (P = 0.037), whereas HLA-A3, HLA-B15, HLA-B16, and HLA-DR6 positivity was associated with lower rate of CMV infection (P = 0.035, 0.021, 0.003, and 0.002, respectively) ([Table 2]). HLA-Cw7 positivity was associated with higher rate of CMV infection (P = 0.003) ([Table 2]).
Table 2 Comparison of broad HLA among CMV infection-positive and CMV infection-negative patients


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Multivariate analysis of risk factors for CMV infection

On multivariate analysis of diagnosis, donor/recipient CMV serostatus, use of methylprednisolone, conditioning regimen, age, HLA-A1, HLA-A3, HLA-B15, HLA-B16, HLA-Cw7 and HLA-DR6, HLA-A3, HLA-B16 and HLA-Cw7 significantly affected the risk for CMV infection occurrence (P = 0.025, 0.004, and 0.008, respectively) ([Table 3]).
Table 3 Multivariate analysis of broad HLA and other variables with respect to CMV infection risk


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Analysis of impact of HLA-A3, HLA-B16, and HLA-Cw7 on risk for CMV disease occurrence

On univariate analysis, only HLA-B16 was associated with reduced risk for CMV disease (P = 0.048) ([Table 4]).
Table 4 Univariate analysis of HLA-A3, HLA-B16, and HLA-Cw7 with respect to CMV disease risk


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  Discussion Top


CMV infection and disease remain two of the most important complications of allogeneic HSCT, although the impact on morbidity and mortality has reduced during the last two decades as a result of improvements in management [12]. In our study, CMV infection occurred in 58 patients (51.8%). The infection rate was lower than that in a Japanese study (70.1%) [13]. In contrast, a Turkish study reported a much lower CMV infection rate (24.9%) than the Japanese and our studies and the authors suggested that genetic factors, whether HLA or non-HLA factors, might be responsible for the discrepancies in reactivation rates in different parts of the world [14]. CMV disease was higher in our study than in the other two studies (19.6 vs. 7.5 and 2.7%, respectively). These differences can be attributed to the different CMV detection technique used in the Japanese study and to the different PCR cutoff point used for defining CMV infection and disease in the Turkish study [13],[14].

There have been many reports on the risk factors affecting CMV infection following allogeneic HSCT [1]. CMV seropositivity of the recipient has been recognized as the most striking risk factor for CMV infections [15],[16],[17]. In univariate analysis, we found more frequent CMV infections in donor-negative/recipient-positive CMV serostatus pairs. It has been previously hypothesized that the use of stem cells from a seropositive donor may be preferred in the seropositive recipient because of delayed reconstitution of CMV-specific T-cell immunity in case of negative donor serostatus [18],[19]. However, upon performing multivariate analysis, the impact of donor/recipient CMV serostatus lost its significance. Other significant risk factors in univariate analysis included acute leukemia diagnosis, lack of administration of methylprednisolone, administration of Flu/Cy/ATG-conditioning regimen, and age. However, none of these risk factors had a significant impact on CMV infection risk in multivariate analysis.

HLA molecules are essential in immune regulation, especially in defense against viruses [20]. Certain HLA alleles were associated with slow disease progression and even in protection against HIV infection, in a high rate of spontaneous viral clearance in hepatitis B and C virus infections, in protection against Epstein-Barr virus infection, and in increased or reduced risk for Epstein-Barr virus-related Hodgkin's lymphoma [21],[22],[23],[24],[25],[26]. Many studies reported that the risk for CMV infection is increased in association with HLA-A30, HLA-B14, HLA-B40, HLA-DRB1*01, HLA-DRB1*09, HLA-DRB1*13, and HLA-DRB1*1 [14],[27],[28]. Others reported that CMV infection is reduced in association with HLA-A11 and HLA-DRB1*04 [14],[29].

In our study, HLA-A1, HLA-A3, HLA-B15, HLA-B16, HLA-DR6, and HLA-Cw7 had a significant impact on CMV infection risk in univariate analysis. On performing multivariate analysis, HLA-A3, HLA-B16, and HLA-Cw7 significantly affected the risk for CMV infection occurrence. Our results were not in agreement with the results of the aforementioned studies [14],[27],[28],[29]. In one study, none of the HLAs found to be significant in univariate analysis maintained their significance in multivariate analysis [14]. The authors in another study restricted their analysis to seven HLA alleles, which were the most frequent ones in the studied patient sample [27]. Also, the third study excluded patients who developed acute GVHD, which is a significant risk factor for the development of CMV infection in allogeneic HSCT recipients [1],[28]. Moreover, the fourth study depended on CMV antigenemia for detection of CMV infection [29]. CMV antigenemia is less sensitive than quantitative PCR used in our study and is known to have limitations [1],[30].

In contrast, we agreed with other studies in the association of HLA-B16 with reduced risk for CMV infection and disease, but these were in the settings of allogeneic liver and renal transplantations [31],[32]. The impact of HLA-Cw7 on risk for CMV infection was controversial as it was associated with increased risk in our study and with nonsignificant risk in another study [33]. HLA-Cw7 was found to be protective against CMV retinitis in AIDS patients but had no influence on the risk for CMV disease in our study [34]. To our knowledge, HLA-A3 was not found to influence CMV infection or disease risks in HSCT or solid-organ transplantation recipients. Minor differences observed by different authors might be caused by the subtype differences of human CMV.

Major histocompatibility complex molecules are critical for antigen uptaking, processing, and presenting. The association of some HLA with active CMV infection might be due to differential presentation of CMV peptides (glycoprotein B or immediate early-1 antigens) by HLA molecules or differential recognition by host CD8+ and CD4+ T lymphocytes [31],[32]. A Japanese study suggested that the deficient production of neutralizing antibodies against CMV in certain HLA types may lead to increased susceptibility [35]. Others suppose that distinct HLA types may enhance the production of tumour necrosis factor α giving rise to CMV end-organ diseases [36].


  Conclusion Top


Certain HLA antigens influence the risk of CMV infection and disease following HSCT. HLA-A3 is protective against CMV infection, whereas HLA-Cw7 is associated with increased risk. HLA-B16 is protective against both infection and disease. However, larger studies are needed to confirm these results. The mechanisms underlying such effects of HLA on the risk for CMV infection and disease following allogeneic HSCT are still not understood and should be researched. We recommend risk-adapted prophylactic strategies based on genetic factors including HLA for patients undergoing allogeneic HSCT.

Acknowledgements

The author has contributed substantially to the conception and design of the study, to the acquisition, analysis, and interpretation of data, to the drafting of the article and revising it critically for important intellectual content, and to giving the final approval for the version to be published. The manuscript has been read and approved by the author. The requirements for authorship have been met. The author believes that the manuscript represents honest work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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