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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 1  |  Page : 41-45
Occurrence of Cytomegalovirus Infection and Factors Causing Reactivation of the Infection among Renal Transplant Recipients: A Single Center Study

Assistant Professor of Virology, Urmia University of Medical Sciences, Iran

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Reactivation of infection with the cytomegalovirus (CMV) in renal transplant recipients may cause significant morbidity and mortality. To evaluate factors associated with activation of CMV replication, we followed prospectively a group of 68 renal transplant recipients for 12 months. The control group consisted of healthy blood donors (n = 37). Sera were collected periodically from these patients and analyzed for the presence of specific anti-CMV antibodies. Enzyme-linked immunoassay based on recombinant CMV proteins was used to detect the following antibody specificities: IgG and IgM. During the first year after transplantation, reactivation of CMV occurred in 48 recipients (70.6%). Detailed analysis did not show any association of reactivation with the type of basic immunosuppressive therapy, prophylactic or therapeutic use of anti-lymphocyte antibodies, as well as occurrence of acute rejection episodes. There was a borderline association (P=0.068) between the presence of CMV infection and EBV reactivation. In conclusion, results of our study suggest that CMV infection may represent a factor activating EBV replication

Keywords: Cytomegalovirus, Reactivation, Acute rejection, Epstein-Barr virus, Immunosuppressive therapy

How to cite this article:
Khameneh ZR. Occurrence of Cytomegalovirus Infection and Factors Causing Reactivation of the Infection among Renal Transplant Recipients: A Single Center Study. Saudi J Kidney Dis Transpl 2008;19:41-5

How to cite this URL:
Khameneh ZR. Occurrence of Cytomegalovirus Infection and Factors Causing Reactivation of the Infection among Renal Transplant Recipients: A Single Center Study. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Jun 24];19:41-5. Available from: https://www.sjkdt.org/text.asp?2008/19/1/41/37431

   Introduction Top

Viral infections constitute the single greatest cause of infectious-disease related morbidity and mortality in organ transplant recipients. [1]

Cytomegalovirus (CMV), which frequently causes latent asymptomatic infection in healthy adults, may evade immune survei­llance in immune compromised patients and start to replicate. Reactivation of chronic Epstein Barr Virus (EBV) infection some­times results in clinical symptoms (fever, leukopenia, pharyngitis, hepatitis, lymphade­nopathy) and eventually may lead to un­controlled proliferation of B cells terminating in post-transplant lymphoproliferative disease (PTLD). [2],[3],[4],[5],[6] The risk of PTLD is mostly deter-mined by the prevalence of anti-EBV sero-positivity in transplanted population. The probability of PTLD is further increased by concomitant use of anti­lymphocytic anti-bodies (ALG) and infection with the CMV.

It has been assumed that similar factors may affect the rates of reactivation of EBV during the post-transplant course. We therefore undertook this prospective study in a group of kidney allograft recipients to investigate the effect of type of immunosuppressive regimen, incidence of CMV infection and the number of rejection episodes, on EBV reactivation as assessed by serological markers.

   Patients and Methods Top

We studied 68 renal allograft recipients (38 male and 30 female) who were transplanted at The Transplantation Institute, Medical University of Urmia. The most frequent causes of renal insufficiency of the native kidneys in the studied patients were chronic glome­rulonephritis, pyelonephritis, and polycystic kidney disease. Immunosuppressive regimen consisted of cyclosporine (CsA), azathioprine (Aza), prednisone (Pred) and mycophenolate mofetil (MMF). Thirty-five patients received triple drug immunosuppression (Aza, CsA and Pred), eight patients received (Pred, CsA and MMF), while 25 patients were administered double drug regimen (Pred and CsA). A total of 19 episodes of acute rejection were diagnosed; all were treated with 0.5 to 1.0 gm of methylprednisolone, given for three days. In eight cases of resistant rejection, antibody therapy in the form of ALG was used in addition. None of the 68 study recipients had clinically evident active EBV infection. There were no cases of PTLD, or infectious mononucleosis among the patients studied.

A total of 35 healthy blood donors (n = 35; mean age 34.31 ± 11.46 years; range: 19-35 19-35 years) constituted the control group.

   Diagnostic Assays of Cytomegalovirus Infection Top

Serum samples were collected prospectively from all patients before transplantation and at 3, 6, 9 months and 1 year after transplantation. Sera were stored at -70 o Celsius. The samples were tested for IgG and IgM anti-CMV anti­bodies. The levels of antibodies were deter­mined using commercially available sensitive enzyme-linked immunosorbent assay (ELISA) method.

   Statistical analysis Top

Data were analyzed using Student's t-test or Mann-Whitney test where appropriate. Rates were compared by means of chi-square test.

   Results Top

Pre-transplant CMV serology

Both renal allograft recipients and subjects from the control group had high rate of seropositivity against CMV. At the time of transplantation, 94.1% of the recipients had serological evidence of previous infection in comparison to the 88.6% positivity among healthy blood donors. Additionally, sero­logical evidence of reactivation (appearance of anti-IgM in previously seropositive patients) was detected in 5.9% of the recipients, which was lower than among the control group (8.6%): these frequencies, however, were not significantly different.

Serological evidence of reactivation of CMV infection in the post-transplant period

In the sera collected before transplantation, 8.8% of the samples among the study subjects tested positive for CMV-IgM as against 13.5% among the control group. However, 12 months after transplantation, the CMV-IgM positivity rate increased from 8.8% to 72.1%. Although this increase in seropositivity did not reach statistical significance (X 2 =2.53, P=0.112), it shows that in some recipients, reactivation of CMV infection occurred during the post­transplant period.

The effect of immunosuppressive therapy on CMV serology

A total of 40 recipients (58.8%) had sero­logical evidence of reactivation. In this group, 20 subjects were treated with Pred + Aza + CsA, 17 patients received Pred + CsA, while three recipients were treated with Pred + MMF + CsA. There was no statistically significant difference in the frequency of reactivation in the patient-groups receiving different immunosuppressive regimens.

The effect of acute rejection on CMV infection

Among the 68 patients studied, acute rejec­tion was diagnosed in 19. The acute rejection episodes occurred after a mean period of 3.78 ± 0.12 months following transplantation. All these patients received therapy with pulse methylprednisolone, while eight recipients with steroid-resistant rejection were treated with ALG in addition.

Ten recipients had serological markers of previous CMV infection in sera collected prior to the occurrence of the rejection epi­sode. In serum samples obtained after a rejection episode and therapy, only three patients had serological markers of reacti­vation of CMV infection. Rejection episodes as well as anti-rejection therapy did not affect the serological status of CMV infection. Also, there was no effect of ALG administration on serological markers of CMV infection

The effect of EBV infection on CMV activation

Reactivation of, or occurrence of primary EBV infection is a common complication during the post-transplant course. Before transplantation, 85.3% of the recipients were latently infected with EBV while only 14.7% of the recipients had serological evidence of EBV reactivation just prior to transplantation. During the first 12 months after transplan­tation, reactivation of EBV infection occurred in 40 recipients (58.8%). No primary infec­tion with EBV was diagnosed during this period.

Since EBV infection causes a transient immunosuppression, which may exacerbate CMV replication, analysis of relationship between CMV and EBV infection was carried out. Among the 40 patients who had reactivation of EBV infection, serological markers of CMV reactivation and replication developed in 23 recipients. Although this prevalence is not statistically significant (X 2 = 3.22, p=0.068), it indicates that EBV infec­tion may play a role in reactivation of CMV infection.

   Discussion Top

In this study, we studied CMV serology during the post-transplant period in sera consecutively collected over a period of one year. At the time of transplantation, four subjects (5.9%) had serological evidence of reactivation of latent infection. During the first post-transplant year the number of recipients who developed reactivation doubled up to 48 patients (70.6%). The diagnosis of reactivation was based on seroconversion of anti IgM. Using the same parameter, Hornef detected reactivation in 24.4% reci­pients observed during 10-59 weeks after transplantation. In another group of renal allograft recipients, reactivation occurred in 29.5% of patients during 649 days of observation. [3],[4],[5] For comparison, in a retros­pective study conducted on 67 heart-lung and 295 heart transplant recipients, Gray et al. [4] found reactivation of past infection in 17.4% of the recipients. This is a very interesting finding since these recipients were routinely treated with prophylactic ALG despite which the rate of reactivation was at the same level as in patients in our study, most of whom did not receive ALG or OKT3. There is a common notion that intensification of immunosuppression increases the risk of reactivation of CMV. [8],[9] There was no significant difference noted in the rate of reactivation among our patients who received different basic immuno­suppressive protocols. Unfortunately, the number of recipients in our study is too small to draw any conclusions but our data provide some suggestions regarding the effect of basic immunosuppression with MMF on the rate of CMV reactivation. It seems that the use of MMF increases the risk of CMV reactivation.

There are only few studies in the literature estimating the rates of seroconversion with the use of different immunosuppressive pro­tocols. Hornef et al. [7] did not find any differ­rence in seroconversion rate (IgM) between recipients treated or not treated with ALG induction therapy. However, when they ana­lyzed their data including the rise in anti­IgG OD value as well as a two-fold rise in anti-IgA value, an increase in the reactivation rate was noted in the group on quadruple immunosuppression.

Rejection can be associated with activation of some infections. This may be due to injury induced by alloantigen-driven inflammation or intensification of immunosuppressive regimen as part of anti-rejection therapy. Also, viral infections may facilitate the development of rejection. In our study, rejection episodes occurred in 19 recipients, all of whom received therapy with high doses of methylprednisolone while eight patients with steroid-resistant rejection were treated with anti-lymphocyte antibodies, in addition. No change was detected in viral serology in the sera collected before and after rejection. These data suggest no significant association between rejection episodes and EBV reacti­vation. On the contrary, Hornef et al. found 43.3% reactivation rate in recipients with acute rejection. They found that serological evidence of reactivation preceded the occurrence of acute rejection in some patients (23.1%) while in others (76.9%), the rejection episodes were followed by serological signs of CMV reactivation. The authors also described a significant corre­lation between groups of patients who had experienced at least one rejection episode versus patients who did not have any, and the incidence of a greater than four-fold rise of the anti-IgG OD value. In their data, patients suffering from graft rejection showed constant high amounts of anti- EA-IgG.

These apparent discrepancies between our data and of Hornef et al. may be explained by some differences in the patient population studied. In the group of patients studied by Hornef et al, [7] there was a much higher pro­portion of recipients who lost their grafts and who had received much more intensified immunosuppressive regimen. Also, Hornef et al [7] detected serological evidence of CMV reactivation in sera collected even after 205 days after the rejection episode. In the majo­rity of their patients, reactivation occurred after rejection, suggesting causal role of anti-rejection therapy. Also, the majority of rejection episodes were detected during the first post-transplant month while in our study the mean time of diagnosis of acute rejection was 3.78 months. Therefore, it is possible that at least in some recipients in our study, serological symptoms of reacti­vation could have been detected if their sera had been collected after longer duration than the one year as in our study.

In a small group of pediatric renal allograft recipients, Acott et al [11] found CMV reactivation in only one of the eight patients who had acute rejection, which matches our data on very low rate of CMV reactivation during acute rejection. In this short communication, the authors did not provide any data on the changes in CMV serological status during longitudinal observation.

Nine patients (13.8%) in our study had active CMV infection. Unfortunately, there is no data on donor's CMV serology, and thus it cannot be established if the trans­planted kidney was a source of the virus in these cases. Six patients with active CMV infection developed serological evidence of EBV reactivation in the post-transplant period; of the remaining recipients only 10 had EBV reactivation. This difference reaches the border of statistical significance (X 2 =3.22, p=0.088), and might indicate association bet­ween CMV infection and EBV reactivation.

This relationship is also suggested by other authors. Hornef et al, found a striking coin­cidence of active, and particularly sympto­matic CMV infection and serological evi­dence of EBV reactivation. According to their data, serological reactivation of EBV infection generally occurred within a short period of CMV infection (less than 3 weeks). O'Neill and Shirodaria [13] have reported on higher anti-VCA IgG titers in renal allograft recipients without CMV infection than in patients with CMV infection. In the majority of their patients, they found a significant increase in anti-VCA IgG and anti-EA IgG as well as appearance of anti-VCA IgM. They also concluded that these findings might represent reactivation of these viruses during CMV infection.

Similar common occurrence (around 40%) of EBV reactivation and CMV disease was reported in a study by Merlino et al. [14] Also, the role of CMV infection in PTLD has been implicated. Results from liver and heart transplant recipients show that the risk of this complication is significantly increased when primary EBV infection is accompanied by CMV disease. [15]

It must be emphasized that immuno competent individuals with acute primary CMV infection also show the serological parameters of EBV reactivation in 40% of cases. [16] Only two recipients in our study had CMV disease with EBV reactivation, associated with prior anti-lymphocyte therapy. From these data, it does not seem that ALG therapy predisposes to concomitant activation of both viral infections.

In conclusion, results of our study suggest that CMV infection may represent a factor activating EBV replication. We did not make any effort to evaluate the potential mecha­nisms of this interaction. Even in the available literature, there are no data, which may explain this phenomenon and further studies are required in this regard.

   References Top

1.Robert H, Rubin N. Infectious complication of renal transplantation. Kidney Int 1993; 44:221-36.  Back to cited text no. 1    
2.Ho M, Miller G, Atchison W. Epstein - Barr virus infections and DNA Hybridization studies in post-transplantation lymphoma and lymphoproliferative lesions: The role of primary infection. J Infect Dis 1985;152: 876-86.  Back to cited text no. 2    
3.Kaden J, Petersen S, Kaden K, May G. Epstein- Barr virus infection after kidney transplantation. Transplant Int 1998;11:S119­-24.  Back to cited text no. 3    
4.Gray J, Werghitt TG, Pavel P. Epstein - Barr virus infection in heart and heart-lung transplant recipient: incidence and clinical impact. J Heart Lung Transplant 1995;14: 640-6.  Back to cited text no. 4    
5.Marker SC, Ascher NL, Kalis JM. Epstein­Barr virus antibody responses and clinical illness in renal allograft recipients. Surgery 1979;85:433.  Back to cited text no. 5    
6.HO M, Jaffe R, Miller G. The frequency of Barr virus infection and associated lympho­proliferative syndrome after transplantation and its manifestations in children. Trans­plantation 1988; 45:719-27.  Back to cited text no. 6    
7.Homef M, Bein G, Fricke L. Coincidence of Epstein-Barr virus reactivation, Cyto­megalovirus infection, and rejection episodes in renal transplant recipients. Transplantation 1995;60:474-80.  Back to cited text no. 7    
8.Penn I. Lymphomas complication in organ transplantation. Transplantation 1983;15: 574-9.  Back to cited text no. 8    
9.Swerdlow S. Post transplant lympho­prolifetative disorders: A morphologic and genotypic spectrum of disease. Histo­pathology 2002;20:373-85.  Back to cited text no. 9    
10.Birkeland SA. Steroid-free immuno­suppression after kidney transplantation with antithymocyte globulin induction and cyclosporin and mycophenolate mofetil maintenance therapy. Transplantation 1998;66:1207-10.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Acott D, Lee S, Suermann B. Infection concomitant with pediatric renal allograft rejection. Transplantation 1996;62:689-98.  Back to cited text no. 11    
12.Van Son WJ. Cytomegalovirus infection after organ transplantation. Transplant Int 1989; 2:147-59.  Back to cited text no. 12    
13.O'Neill HJ, Shirodaria PV. Virus-specific antibodies to Epstein-Barr virus, varicella zoster virus and rubella virus in renal transplant patients with Cytomegalovirus infections. J Infect 1992;24:301-39.  Back to cited text no. 13  [PUBMED]  
14.Merlino C, Giacchino F, Tognarelli G. Epstein-Barr virus infection and lympho­proliferative disorders in patients after renal transplanation. Minerva Urol Nephrol 1996;48:139-43.  Back to cited text no. 14    
15.Manez R, Breining M, Linden K, et al. Post-transplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: The role of cyto­megalovirus disease. J Infect Dis 1997;176: 1462-7.  Back to cited text no. 15    
16.Farber I, Wutzer P, Wohlrabe P, et al. Serological diagnosis of infectious mononucleosis using three anti-Epstein- Barr virus recombinant ELISA. J Virol Method 1993;42:301-12.  Back to cited text no. 16    

Correspondence Address:
Zakieh Rostamzadeh Khameneh
Assistant Professor of Virology, Urmia University of Medical Sciences, Urmia
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PMID: 18087121

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