A possible role for Epstein-Barr virus in tumorigenesis after immunosuppression in cases of renal transplantation

Eight secondary malignancies developing after renal transplantation were investigated in terms of a possible role of the Epstein-Barr virus (EBV). In five cases, four gastric cancers and one colonic cancer, the presence of EBV was proven by the polymerase chain reaction (PCR), all four gastric lesions being confirmed to have a massive EBV infection by in situ hydridization. Two cases demonstrated monoclonal infection with EBV, as indicated by a single band of the lymphocyte-defined membrane antigen tandem-repeat gene using PCR, and were immunohistochemically positive for the latente membrane protein 1. Our series suggests that gastrointestinal cancer predominates as a secondary malignancy in states of induced severe immunosuppression, and that EBV may play an important role in tumorigenesis as an oncovirus.Abbreviations PCR polymerase chain reaction - ISH in situ hybridization - EBV Epstein-Barr virus - IR internal repeat - LYOMA lymphocyte-determined membrane antigen     

Prospective monitoring of BK virus replication in renal transplant recipients

Background. BK virus-associated nephropathy (BKVAN) can be diagnosed only with renal graft biopsy. Definitive diagnosis of BKVAN requires demonstration of BK virus (BKV) replication in renal allograft tissues. Non-invasive analysis of urine and blood is considered essential in screening renal transplant recipients.
Patients and methods. This study evaluated prospectively the replication of BKV in plasma and urine with qualitative and quantitative real-time polymerase chain reaction in 32 de novo (group A) and 34 chronic (group B) renal transplant recipients and the long-term impact on graft function.
Results. In group A, 456 samples (228 plasma, 228 urine) were examined and BKV was detected in 31 (31/228, 14%) samples of plasma and 57 (57/228, 25%) samples of urine in 20 (20/32, 62.5%) and 23 (23/32, 72%) recipients, respectively. Incidence of viremia and viruria increased during the first 6 months presenting a peak the third postoperative month (viremia: 28% and viruria: 31%). Immune suppressive treatment with tacrolimus showed significant relation with viremia. Renal graft function in de novo renal transplant recipients remained stable throughout the follow-up period without influence of BKV replication. In group B, incidence of viremia and viruria were 3% (1/34) and 9% (3/34) correspondingly, indicating that after the first post-transplant year the risk of BKV re-activation is diminished.
Conclusion. The highest incidence of BK viremia and viruria is observed the third post-transplantation month, confirming previously published studies in Europe and the United States, and long-term follow up shows that BKV replication decreases significantly after the third post-transplant month and even transient viremia or viruria does not have an impact on renal function.     

Hepatitis E virus: an underdiagnosed cause of chronic hepatitis in renal transplant recipients

Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients leading to rapidly progressive cirrhosis. Proper diagnosis is therefore important, as reducing immunosuppressive therapy can allow clearance of the virus. We report a case of chronic HEV infection in a renal transplant recipient that went undiagnosed for many years, discuss the therapeutic options, and review the current available literature.     

Seroprevalence of hepatitis E among Iranian renal transplant recipients

Background

Renal transplant recipients are known to be susceptible to viral infections, with more severe clinical presentations compared to healthy persons. Hepatitis E is generally a self-limited disease, which is caused by hepatitis E virus. Recently, hepatitis E has become more important in organ transplant recipients, because of new findings regarding the potential for chronic infections in this patient group.

Objectives

This study aimed to evaluate the seroprevalence of anti-HEV IgG among kidney transplant recipients in Urmia, in the north-western region of Iran.

Patients and Methods

91 patients were selected randomly from amongst patients who had undergone kidney transplantation in Urmia, Iran. Each patient was tested for the presence of anti-HEV IgG antibody using an enzyme-linked immunosorbent assay (ELISA, Dia.Pro; Diagnostic Bioprobes, Italy).

Results

28 subjects (30.8%) were seropositive for anti-HEV IgG. Seropositive patients were generally older than seronegative patients (P = 0.009). There was no correlation between HEV infection and the level of education (P = 0.206), the history of blood transfusion (P = 0.164), or history of pre-transplantation hemodialysis (P = 0.228). There was no significant difference in the serum alanine aminotransferase (ALT) levels of the anti-HEV seropositive and seronegative patients. Multinomial logistic regression analysis indicated no significant relationship between HEV infection and increase in ALT levels, even after controlling for treatment with azathioprine (P = 0.79, OR = 1.12; 95% CI: 0.45–2.76).

Conclusion

The anti-HEV IgG antibody has a high prevalence in Iranian kidney transplant recipients, and it is significantly higher in comparison with previous studies in the general population or in hemodialysis patients.     

Tuberculosis in renal transplant recipients

Tuberculosis (TB) is a frequent infectious complication in patients on renal replacement therapy, as a result of immunosuppression from uremia and drugs in the post-transplantation period. A retrospective study of all renal transplantation patients from 1989 to date was conducted. This study tried to examine the prevalence, course, and outcome of TB in renal transplant recipients. A comparison with the occurrence of TB in other modalities of renal replacement therapy was also made. We also discussed the treatment protocols for TB in this group of patients. No difference in the prevalence, age, or male/female ratio of TB was seen among the 3 modes of renal replacement therapy. TB of the lung was the more favored site of infection in patients on hemodialysis (77.3%), when compared with those on CAPD (30%) and renal transplant recipients (33.3%). In renal transplant recipients, no deaths occurred due to TB. In 7 patients there was co-infection with cytomegalovirus and in 3 patients there was Aspergillus lung infection.     

Epstein-Barr virus in familial Hodgkin's disease

Summary Hodgkin's disease (HD) has been found to be linked to Epstein-Barr virus (EBV). Familial HD (FHD) may be related to a possible unknown agent. We have determined whether EBV small RNAs (EBERs) were found in Reed-Sternberg cells from FHD. Five families were studied for histological subtype and EBER presence. There was a striking similarity in FHD subtypes of each family and 3/11 (27%) of the cases were EBER positive. In conclusion, EBV EBERs are only infrequently found in FHD and other factors including viruses different from EBV should be further investigated in FHD.     

Nutritional management in renal transplant recipients: A transplant team opportunity to improve graft survival

Aims

The nutritional management of renal transplant recipients (RTR) represents a complex problem either because the recovery of renal function is not complete and for the appearance of “unavoidable” metabolic side effects of immunosuppressive drugs. Nevertheless, it remains a neglected problem, whereas an appropriate dietary intervention could favorably affect graft survival.

Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult

Liver involvement is nearly universal in healthy persons with Epstein-Barr Virus (EBV) infection-induced infectious mononucleosis. It is usually mild, undetected clinically and resolves spontaneously. Jaundice is distinctly uncommon and may reflect either more severe hepatitis or an associated hemolytic anemia. Cholestatic hepatitis due to EBV infection is infrequently reported and may pose a diagnostic quandary. We describe a patient who presented with jaundice and a markedly elevated serum alkaline phosphatase level due to serologically confirmed acute infection with EBV. Imaging studies excluded biliary obstruction. Symptoms and laboratory abnormalities resolved spontaneously. EBV infection should be included in the differential diagnosis of cholestatic hepatitis in adults.     

Monthly screening for BK viremia is an effective strategy to prevent BK virus nephropathy in renal transplant recipients

C. Alméras, F. Vetromile, V. Garrigue, I. Szwarc, V. Foulongne, G. Mourad. Monthly screening for BK viremia is an effective strategy to prevent BK virus nephropathy in renal transplant recipients.
Transpl Infect Dis 2011: 13: 101–108. All rights reserved Abstract: Background. BK polyomavirus virus (BKV) nephropathy (BKVN) is the most common viral infection that affects renal allografts. Because a specific antiviral therapy is lacking, BKVN may result in graft dysfunction and/or loss. We prospectively analyzed whether monthly nucleic acid testing (NAT) for BKV replication in blood and immediate reduction of immunosuppression (IS) could prevent BKVN. Methods. NAT was performed at monthly intervals for 6 months and then at 12 months in 119 de novo renal transplant recipients. In viremic patients (presumptive BKVN), a graft biopsy was systematically performed and IS was immediately reduced. Results. BKV viremia occurred in 13 (10.9%) patients after a median time of 90 days (23–241); 77% of patients were viremic before month 4. After reduction of IS, viral load was undetectable in 11 patients, remained low in 1, and continued to increase in 1 patient who developed definitive BKVN despite reduction of IS, and finally returned to dialysis 6 months after transplantation. Conclusion. BKV infection is an early complication. Monthly NAT in blood during the first 6 months and immediate reduction of IS in viremic patients almost completely prevent definitive BKVN.     

Epstein-Barr virus infection in Richter's transformation

Chronic lymphocytic leukemia (CLL) may convert to a diffuse large cell lymphoma (Richter's syndrome) over time. In occasional cases of Richter's transformation, Epstein-Barr virus (EBV) has been identified in the lymphoma cells. To evaluate the association of EBV infection with Richter's syndrome, the biopsy specimens and clinical records of 25 patients who were seen at the Mayo Clinic between 1984–1996 were retrospectively evaluated for the presence of EBV by immunoperoxidase staining for expression of EBV latent membrane protein (LMP), as well as the expression of EBV RNA and DNA in the cells by in situ hybridization. Four of the 25 patients showed evidence of EBV in the diffuse large cell lymphoma cells—three patients with a B-cell phenotype were positive for LMP, EBV DNA, and RNA; and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells. The Richter's syndrome was treated with combination chemotherapy in 15 patients, three received radiotherapy, three were followed without further therapy after a splenectomy, two died before treatment could be started, and one patient had insufficient follow-up. One patient with evidence of EBV in large cell lymphoma cells was treated with acyclovir as initial therapy. The median survival of EBV-positive patients was three months compared with nine months for EBV-negative patients, but this difference was not statistically significant (P = 0.385). Evidence for EBV infection related to Richter's transformation was present in 16% of the patients in this study and may be associated with a poorer outcome. Primary therapy with acyclovir in one patient did not seem to be beneficial and other therapeutic modalities in patients with EBV-positive Richter's transformation need to be explored. Am J. Hematol. 60:99–104, 1999. © 1999 Wiley-Liss, Inc.     

肾移植患者外周血巨细胞病毒抗体检测

为及时诊断肾移植后活动性巨细胞病毒感染，采用酶联免疫吸附法对４５例肾移植患者的１１４份血标本进行了抗人巨细胞病毒ＩｇＭ和ＩｇＧ的检测。     

Cytomegalovirus-associated bleeding diathesis in renal transplant recipients

Cytomegalovirus (CMV) infection is reported to be capable of modifying endothelial surface with subsequent increased risk of thromboembolic complications. Nevertheless, there are only sparse reports on its role in the development of bleeding diathesis. Here we report two renal transplant recipients who manifested severe coagulation disorders associated with acute CMV infection. Antiviral therapy was followed by consistent correction of coagulation abnormalities.     

The pathogenesis and management of influenza virus infection in organ transplant recipients

Abstract: Infection with influenza viruses poses specific problems in adult and pediatric organ transplant recipients, including a higher rate of pulmonary and extra-pulmonary complications. Also, data suggest that influenza is associated with acute cellular rejection and chronic allograft dysfunction. The main strategy of influenza prevention has been influenza immunization in order to stimulate local and systemic antibodies. However, studies have shown that antibody response to inactivated influenza vaccine is decreased in all groups of organ transplant recipients. A live attenuated influenza virus vaccine is nearing approval in the United States. However, studies are needed in organ transplant recipients to determine whether the live attenuated influenza virus vaccine can enable these patients to mount a protective immune response and what degree of protection or amelioration of illness is provided by such vaccine. It is also important to verify the safety of this vaccine in organ transplant recipients because live virus may cause severe disease in these patients. Therefore, other modalities of prevention against influenza, such as chemoprophylaxis with antiviral drugs, should be considered in this patient population. The current review provides an overview of the incidence, clinical manifestations, and strategies for the prevention and management of influenza in organ transplant recipients.     

Resurgence of BK virus following Covid‐19 in kidney transplant recipients

Kidney transplant recipients have been supposed vulnerable to severe Covid‐19 infection, due to their comorbidities and immunosuppressive therapies. Mild‐term complications of Covid‐19 are currently unknown, especially in this population. Herein, we report two cases of BKV replication after non‐severe SARS‐CoV‐2 infection. The first case was a 59‐year‐old man, transplanted 3 months ago, with recent history of slight BKV viremia (3.3 log₁₀ DNA copies/ml). Despite strong reduction of maintenance immunosuppression (interruption of mycophenolic acid and important decrease of calcineurin inhibitors), BKV replication largely increased after Covid‐19 and viremia persisted at 4.5 log copy/ml few months later. The second case was a 53‐year‐old woman, transplanted 15 years ago. She had a recent history of BKV cystitis, which resolved with a decrease of MPA dosage. Few weeks after SARS‐CoV‐2 infection, she presented recurrence of lower urinary tract symptoms. Our reports highlight that SARS‐CoV‐2 infection, even without severity, could disrupt immune system and particularly lymphocytes, thus leading to viral replication. Monitoring of viral replications after Covid‐19 in kidney transplant recipients could permit to confirm these preliminary observations.     

Cytomegalovirus infection in renal transplant recipients

We have retrospectively analyzed the incidence of cytomegalovirus (CMV) infection in 250 consecutive renal allograft transplants performed in 244 recipients. The mean follow-up was 35.1+/-25.4 months. Immunosuppression was cyclosporine- or tacrolimus-based triple therapy. CMV infection prophylaxis with ganciclovir for 3 months post transplant was prescribed in CMV-seronegative recipients of allografts from seropositive donors (D+R-) and in all recipients treated with OKT3. CMV antigenemia was monitored by the pp65-antigen assay. Thirteen of 57 D+R- recipients (22.8%) developed CMV antigenemia. One recipient had a breakthrough of CMV antigenemia during ganciclovir prophylaxis; 12 D+R- recipients developed CMV antigenemia 147.5+/-173.8 days after transplantation. Four of 13 (30.7%) D+R- recipients had asymptomatic CMV infection, 8 (61.6%) had CMV infection with non-specific symptoms including fever, and 1 (7.7%) developed CMV pneumonia. Six of 13 (46.1%) D+R- patients had been treated with intensified immunosuppressive therapy before CMV infection. In the low-risk CMV groups (D+R+; D-R+; D-R-), 28 recipients (14.5%) developed CMV antigenemia 42.5+/-15.2 days post transplantation. Ten of the 28 (35.7%) recipients had asymptomatic CMV infection, 17 (60.7%) developed CMV infection with non-specific symptoms, and 1 (3.6%) developed CMV pneumonia. Twenty-one of 28 (75.0%) had intensified immunosuppressive therapy before CMV infection. In conclusion, ganciclovir prophylaxis diminished and delayed the onset of CMV infection but did not totally prevent it from occurring in D+R- renal transplant recipients. Clinicians should be vigilant to the possibility of CMV infection in both seronegative and seropositive recipients, especially after anti-rejection therapy.     

Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients

IntroductionThere is scarce information regarding clinical evolution of HBV infection in renal transplant patients.AimsTo evaluate the prevalence of acute exacerbation in HBV-infected renal transplant patients and its association with the time after transplantation, presence of viral replication, clinical evolution, and use of antiviral prophylaxis.Materials and methodsHBV infected renal transplant patients who underwent regular follow-up visits at 6-month intervals were included in the study. The criteria adopted to characterize exacerbation were: ALT >5× ULN and/or >3× baseline level. Predictive factors of exacerbation evaluated were age, gender, time on dialysis, type of donor, post-transplant time, ALT, HBeAg, HBV-DNA, HCV-RNA, immunosuppressive therapy, and use of antiviral prophylaxis.Results140 HBV-infected renal transplant patients were included (71% males; age 46 ± 10 years; post-renal transplant time 8 ± 5 years). During follow-up, 25% (35/140) of the patients presented exacerbation within 3.4 ± 3 years after renal transplant. Viral replication was observed in all patients with exacerbation. Clinical and/or laboratory signs of hepatic insufficiency were present in 17% (6/35) of the patients. Three patients died as a consequence of liver failure. In univariate analysis variables associated with exacerbation were less frequent use of prophylactic/preemptive lamivudine and of mycophenolate mofetil. Lamivudine use was the only variable independently associated with exacerbation, with a protective effect.ConclusionsAcute exacerbation was a frequent and severe event in HBV-infected renal transplant patients. Prophylactic/preemptive therapy with antiviral drugs should be indicated for all HBsAg-positive renal transplant patients.