Epstein-Barr virus infection and immunity in bone marrow transplant recipients

Studies on patients for up to one year following allogeneic, HLA-matched bone marrow transplants have shown no increased incidence of salivary Epstein-Barr (EB) virus secretion and no significant rise in EB-virus-specific antibody titers. EB-virus-specific cytotoxic T cells could be detected in the peripheral blood of all patients by six months posttransplant. For up to one year posttransplantation in vitro EB virus infection of peripheral blood B lymphocytes from the majority of patients leads to an abortive infection followed by cell death, and without the establishment of continuously growing cell lines. This abnormality appeared to be due to patients' monocytes, which formed a defective feeder cell layer in culture, and it could be circumvented by culturing the EB-virus-infected B cells from patients on a feeder layer of x-irradiated adherent cells from normal peripheral blood. These findings may explain the relative lack of EB-virus-associated lymphoma seen in bone marrow transplant recipients when compared with other groups of transplant patients.     

Nocardial infection in immunosuppressed kidney transplant recipients

OBJECTIVE: Nocardiosis is a very rare, opportunistic infection caused by microorganisms of the genus Nocardia, and is associated with significant morbidity and mortality in kidney transplant patients receiving immunosuppressive therapy. MATERIAL AND METHODS: Since 1980, our Renal Transplant Unit has carried out 1239 kidney transplants, and five cases of Nocardia infection have occurred during this time. In this retrospective study, special consideration is given to clinical manifestations, treatment response (efficacy and side-effects) and the evolution of both the patient and the graft. Microbiological factors studied included biochemical profiles and antimicrobial sensitivity. RESULTS: Nocardiosis was observed in five men with a mean age of 49.2 years who had received immunosuppressive therapy (generally cyclosporin/azathioprine and prednisone) for a mean of 47.8 months (range 1-148 months). Four of the patients had good previous renal function. The clinical presentation of nocardiosis was as follows: pleuropulmonary pattern of infection, n = 3; subcutaneous abscess, n = 1; and fulminant multi-organ disseminated nocardiosis, n = 1. In all cases, direct observation using modified Ziehl-Neelsen staining proved positive, and in vitro culture revealed good sensitivity to trimethoprim-sulfamethoxazole and variable sensitivity to the other groups of antibiotics. Nocardia brasiliensis was isolated in two cases, and Nocardia asteroides in three. Two patients died, one due to multiple organ involvement and the other due to acute respiratory failure associated with severe hepatopathy caused by hepatitis C virus. The remaining cases improved. CONCLUSION: A low incidence of nocardiosis following kidney transplantation was observed. Fatal cases occurred in patients with bacteremia and serious comorbid medical conditions, in whom early diagnosis and specific treatment was required.     

Epstein-Barr virus reactivation in renal transplant recipients

Renal transplant recipients at Tygerberg Hospital were investigated to determine the importance of Epstein-Barr virus (EBV) as a pathogen in these patients. All 106 patients investigated were shown to have EBV antibodies before transplantation and most had serological evidence of reactivation of the infection after transplantation. A mild clinical illness was present in a few patients concomitant with EBV reactivation, which may suggest that this virus has a role in the morbidity of some renal transplant recipients. Lymphoblastoid cell lines were established from 11 renal transplant recipients; 5 of these cell lines were shown to be virus producers and 1 is thought to have unique properties.     

Epstein-Barr virus monitoring in paediatric renal transplant recipients

Prospective Epstein-Barr virus (EBV) surveillance post transplant was undertaken by qualitative polymerase chain reaction testing for EBV DNA in plasma so as to detect EBV viremia as early as possible and thereby attempt to pre-empt post-transplant lymphoproliferative disease by reduction of immunosuppression. Forty-three children (46 transplants) were followed for a median (range) of 15.5 (3-25) months. Thirty-one children (67%) were EBV seropositive pre transplant. Twenty children (44%) developed EBV viremia; of these 9 (60%) were seronegative and 11 (36%) seropositive recipients. Primary infection developed later (median difference 14.2 weeks, P=0.009), was more likely to be symptomatic (odds ratio 2.91, 95% confidence interval 0.95-4.88) and associated with a rise in serum creatinine (odds ratio 6.13, 95% confidence interval 4.13-8.13) than reactivation disease. There was a higher incidence of EBV disease in children receiving quadruple therapy and tacrolimus (odds ratio 13.2, 95% confidence interval 11.5-14.9) compared with those given cyclosporin-based immunosuppression. Immunosuppression was reduced when EBV infection was detected. All children became asymptomatic and renal function returned to normal by a median (range) of 17 (6-52) days, although mild relapses occurred in 3 children. Regular EBV surveillance allowed prompt reduction of immunosuppression and was associated with a good outcome in this group of children.     

BK virus infection in kidney transplant recipients

INTRODUCTION: Nephropathy associated with the polyomavirus type BK virus (BKV) has emerged as a cause of allograft failure linked to immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). The outcome in BKV nephropathy is generally unfavorable, namely 50% of patients lose graft function. We herein report nine cases of BKV nephropathy after kidney transplantation. METHODS: From October 1998 to May 2003, 138 of 169 consecutive kidney transplant patients received tacrolimus-based immunosuppression, and 31 received cyclosporine-based immunosuppression. Additionally, 88.2% of the patients received mycophenolate mofetil (MMF). The diagnosis of BK infection was made by the presence of decoy cells in the urine and by allograft biopsy. RESULTS: There were nine cases of BKV nephropathy in kidney transplant recipients, an incidence of 5.3%. All patients with BKV nephropathy received tacrolimus, MMF, and steroids. The median time to diagnosis of BKV infection was 7.8 months after transplantation. All patients experienced an elevated serum creatinine, which stabilized or decreased in seven patients with altered or decreased immunosuppression. After a mean follow-up of 11.1 months, 2 (22.2%) of nine patients lost the graft. CONCLUSION: Because BKV nephropathy is a rare but serious complication after kidney transplantation, it should be included in the clinical differential of transplant dysfunction. In the absence of documented antiviral treatment, early diagnosis and judicious use of immunosuppressive agents is indicated to minimize the occurrence of BKV infection.     

Epstein-Barr virus latency in kidney specimens from transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) infection is common in immunosuppressed patients and can lead to life threatening lymphoproliferative diseases. Small numbers of cells infected by EBV have been detected in human tissues, transplanted or non-transplanted. Little is known about EBV latency in the allograft kidneys of patients without post-transplant lymphoproliferative disease (PTLD). The aims of this study were to look for the presence of EBV-encoded small RNAs (EBER) in allograft kidneys and to quantify their expression. METHODS: We analysed 62 allograft nephrectomies and 20 native kidneys to determine the presence of EBV; we also quantified its expression and calculated its ratios to CD45 and CD20 cells. The techniques used were: tissue microarray, EBER-1- and 2-specific in situ hybridization and immunohistochemistry. RESULTS: EBER expression was detected in 30.6% of transplanted kidneys and 5% of non-transplanted kidneys. In the positive specimens, a mean of 8.2 cells/1.57 mm(2) expressed the EBERs (range 1-38 cells). The ratios of EBER-positive (+) cells to CD45 or CD20 cells were 1.7 +/- 2.4% (range 0.1-8.1%) and 8.4 +/- 10.9% (range 0.5-34.4%), respectively. No relationship was found between anti-T-cell treatment and EBER expression in the failed allografts. CONCLUSIONS: In failed kidney allografts, a small number of lymphocytes can express EBV latency. The number of EBER+ cells is smaller than in PTLD. Studies of functioning grafts are necessary to better understand the clinical relevance of this expression.     

Herpes simplex virus infection in heart-lung transplant recipients

We report our experience of herpes simplex virus infection in a series of 51 recipients of heart lung transplantation (HLT). Nine patients, all of whom were seropositive for the virus preoperatively, developed HSV infection. Seven episodes of culture-proved mucocutaneous HSV infection without evidence of pulmonary involvement occurred in four patients. Six episodes of HSV pneumonia were seen in a further five patients, one of whom died. Diagnosis of HSV pneumonia was by histological appearances on transbronchial biopsy, together with culture of lung tissue or bronchoalveolar lavage. Concomitant cytomegalovirus infection occurred in four patients. All patients who developed HSV pneumonia did so within the first two postoperative months; in four patients following augmented immunosuppression. We now suggest that HLT recipients who are HSV antibody-positive should receive prophylactic acyclovir for the first two months after surgery and at times of augmented immunosuppression.     

Epstein-Barr virus antibody responses and clinical illness in renal transplant recipients.

Among 88 renal transplant recipients evaluated for a change in Epstein-Barr virus (EBV) antibody status in the period after transplant, 22 showed a 4-fold rise and eight showed an 8-fold or greater rise in EBV antibody. Among the patients with an 8-fold or greater EBV ANTIBODY RISE, THE OCCURRENCE OF FEVER WAS FREQUENT, ONE PATIENT DEVELOPED A LYMPHOPROLIFERATIVE reaction, and one died with a malignant EBV infection. Patients without pretransplant antibody showed a longer mean time to antibody rise (104 +/- 23 days) than did those patients with pretransplant antibody (19 +/- 7 days). The longer incubation period in patients without pretransplant antibody was in the expected range for primary EBV infections. Both primary and secondary (reactivation) EBV infections occur in renal transplant patients. These infections may be assoicated with prolonged fever, and in unusual circumstances, may cause dramatic lymphoproliferative disease.     

Epstein-Barr virus-associated syndromes in immunosuppressed liver transplant recipients. Clinical profile and recognition on routine allograft biopsy

The clinical profile and histopathologic changes in needle biopsies of the liver were studied in 10 cases of acute Epstein-Barr virus infection occurring in liver transplant recipients. The systemic viral syndrome in four cases resembled that seen in infectious mononucleosis, whereas in six others it was characterized by atypical signs and symptoms in the form of jaw pain, arthralgias, joint space effusions, diarrhea, encephalitis, pneumonitis, mediastinal lymphodenopathy, and ascites. Laboratory investigation showed marked elevations in hepatocellular enzymes and circulating atypical lymphocytes in the peripheral blood. Pancytopenia was noted in eight cases. A range of histopathologic changes was noted in the allografts ranging from alterations typically observed in infectious mononucleosis to a distinctive constellation characterized by (a) mixed mononuclear portal and sinusoidal infiltrates containing atypical large noncleaved cells and immunoblasts; (b) associated lobular activity indicative of a hepatitic process, and (c) relatively mild duct damage not in proportion to the severity of the inflammatory infiltrates. The patients responded to reduced immunosuppression, but recurrent viral syndromes occurred in four instances and one patient died of systemic lymphoproliferative disease.     

Viremia and excretion of TT virus in immunosuppressed heart transplant recipients and in immunocompetent individuals

BACKGROUND: The TT virus (TTV) was discovered in patients with symptomatic posttransfusion hepatitis, but many viremic individuals are asymptomatic. Inadvertent transfusion-associated transmission must therefore be anticipated. We screened blood donors and heart transplant recipients for TTV infections. METHODS: Nested polymerase chain reaction was used to detect TTV DNA in plasma, serum, urine, and fecal samples from 600 blood donors, from 100 healthy individuals, and from 495 heart transplant recipients. RESULTS: A total of 3.2% of the blood donors, but 25% of the heart transplant recipients were viremic. TTV subtypes G1a/b and G2a/b were observed in both groups, but the subtype distributions were discrepant. A severe, acute infection with TTV subtype 3 was observed in one blood donor. The prevalence of TTV infections in heart transplant recipients was not correlated to transfusion frequency. Nine viremic heart transplant recipients and their 75 blood donors were studied in detail. Seven blood donors were viremic, but only two "pairs" of viremic blood donors and transfusion recipients had identical TTV isolates. TTV DNA was detected in the feces of 5% (5/100) of immunocompetent individuals (staff), in 46% (52/112) of viremic heart transplant recipients, and in the urine of 55% (20/36). TTV DNA was detected in six of six batches of pooled "virus-inactivated" plasma (solvent/detergent treated), and in none of eight batches of commercial immunoglobulins. CONCLUSION: Although TTV is transfusion-transmissible, the parenteral transmission rate may have been overestimated. Many TTV infections are apparently acquired by nonparenteral routes. Immunoglobulins are safe but pooled plasma is not safe regarding TTV transmission.     

Epstein-Barr virus infection is associated with endothelial Bcl-2 expression in transplant liver allografts

INTRODUCTION: In liver transplant recipients with Epstein-Barr virus (EBV) disease, we reported a low rate of acute rejection after stopping or markedly lowering immunosuppression. This observation led to the hypothesis that EBV, as a means of viral persistence, induces expression of antiapoptotic factors and these factors, in turn, confer protection to the transplanted organ. Bcl-2, an antiapoptotic factor induced by EBV in various host cells, is not normally expressed in the liver. We questioned whether bcl-2 is expressed in the transplanted liver and whether its expression is modified by EBV. MATERIALS AND METHODS: Retrospective liver biopsy specimen from liver transplant patients diagnosed with EBV (n=12) were examined for the presence of bcl-2 by immunohistochemistry and compared with EBV (-) transplant (n=15), and nontransplant (n=13) livers. RESULTS: The most significant finding was the presence of endothelial bcl-2 expression in the majority of EBV (+) transplant samples examined (67%) and its relative absence in the other two groups (P<0.005). There was also bcl-2 expression in the hepatocytes and lymphocytes of the majority of transplant liver samples, irrespective of EBV status. DISCUSSION: We have identified a strong association between EBV infection and endothelial bcl-2 expression in transplant livers. We also found that transplantation, in itself, was associated with bcl-2 expression in the hepatocytes and lymphocytes of liver allografts.     

Hepatitis E virus infection and rejection in kidney transplant recipients

BackgroundHepatitis E virus (HEV) infection has been associated with immune-mediated kidney diseases in developing countries. However, its relationship with kidney transplant outcomes has never been studied. We investigated the association between HEV infection and kidney graft rejection among kidney transplant recipients (KTRs).MethodsWe conducted a matched cohort and longitudinal study utilizing banked sera following kidney transplantation during 1988–2012. Studies with evidence of post-transplantation HEV infection were identified by positive ELISA tests (anti-HEV IgM or anti-HEV IgG seroconversion) or positive HEV PCR and matched to KTR controls with negative HEV ELISA and PCR tests in a 1:5 ratio by age, sex, crossmatch status, immunosuppression era, and time of HEV testing. Outcome data collected included time to first kidney graft rejection, transaminases, and glomerular filtration rates. Log-ranked test was used to analyze survival.ResultsOf 271 KTRs, 9 (3%) had evidence of post-transplantation HEV infection and were compared to 45 negative, matched controls. Median age at transplantation was 46 years. Kidney graft rejection was reported in 8 (89%) of cases and 21 (47%) of controls. Median time to first episode of kidney graft rejection was 17.4 months in cases and 30.8 months in controls (p = 0.029), with a higher hazard of developing kidney graft rejection in cases (HR = 3.23, 95% CI: 1.19–8.79). Lower mean glomerular filtration rates over time were observed in cases (35 mL/min/1.73m²) versus controls (42.4 mL/min/1.73m²) but did not reach significance (p = 0.24).ConclusionSubjects with evidence of post-transplantation HEV infection demonstrated earlier kidney graft rejection compared to controls.     

肾移植受者BK病毒的感染特点

Objective To investigate the characteristics of BK virus (BKV) infection in renal transplant recipients. Methods A total of 243 renal recipients from our clinic within 48 months after transplantation were enrolled as the trial group and 82 healthy people as the control group. Urine and peripheral blood samples of these two groups were harvested for urinary sediment BKV cytology by Decoy cell counting and BKV DNA by real-time PCR. Results The positive rates of urinary Decoy cell, BKV viruria and viremia were 35.4%, 36.6% and 16.9% in trial group, and 4.9%, 20.7% and 2.9% in control group, respectively. In trial group, the medians of urinary Decoy cell, urinary BKV and peripheral blood BKV were 6/10 HPF, 1.00×104 copy/ml and 6.87×103 copy/ml respectively, while in control group, they were 2/10 HPF, 1.10×104 copy/ml and 2.24×1(3 copy/ml. Compared with the healthy people, the positive rates and the levels of BKV DNA in urine and peripheral blood of recipients were significantly higher. The amount of urinary Decoy cells was positively correlated to urinary BKV load (r=0.636, P＜0.01). Conclusions BKV replication is easier to happen in renal recipients as compared to healthy people. Counting of urinary Decoy cells is convenient, useful and sensitive to evaluate BK viruria and viremia in renaltransplant recipients. BKV DNA detection in urine and peripheral blood can be used to screen the evidence of BK reaction in order to prevent irreversible graft damage by BKV.[ Key words ] Kidney transplantation; BK virus; Kidney diseases; Decoy cells     

肾移植受者BK病毒的感染特点

Objective To investigate the characteristics of BK virus (BKV) infection in renal transplant recipients. Methods A total of 243 renal recipients from our clinic within 48 months after transplantation were enrolled as the trial group and 82 healthy people as the control group. Urine and peripheral blood samples of these two groups were harvested for urinary sediment BKV cytology by Decoy cell counting and BKV DNA by real-time PCR. Results The positive rates of urinary Decoy cell, BKV viruria and viremia were 35.4%, 36.6% and 16.9% in trial group, and 4.9%, 20.7% and 2.9% in control group, respectively. In trial group, the medians of urinary Decoy cell, urinary BKV and peripheral blood BKV were 6/10 HPF, 1.00×104 copy/ml and 6.87×103 copy/ml respectively, while in control group, they were 2/10 HPF, 1.10×104 copy/ml and 2.24×1(3 copy/ml. Compared with the healthy people, the positive rates and the levels of BKV DNA in urine and peripheral blood of recipients were significantly higher. The amount of urinary Decoy cells was positively correlated to urinary BKV load (r=0.636, P＜0.01). Conclusions BKV replication is easier to happen in renal recipients as compared to healthy people. Counting of urinary Decoy cells is convenient, useful and sensitive to evaluate BK viruria and viremia in renaltransplant recipients. BKV DNA detection in urine and peripheral blood can be used to screen the evidence of BK reaction in order to prevent irreversible graft damage by BKV.[ Key words ] Kidney transplantation; BK virus; Kidney diseases; Decoy cells