Occurrence of post-transplant lymphoproliferative disorders among over thousand adult recipients: any role for hepatitis C infection?

BACKGROUND: Post-transplant lymphoproliferative disorders represent an increasingly important complication of organ transplantation. Although the majority of the post-transplant lymphoproliferative disorder are etiologically related to Epstein-Barr virus infection other factors may play a role. Hepatitis C virus may induce clonal expansion of B-lymphocytes and has been associated with extrahepatic lymphoproliferative disorders. OBJECTIVES: In this study, we have evaluated: (i) the prevalence of post-transplant lymphoproliferative disorder; (ii) presence of Epstein-Barr virus in post-transplant lymphoproliferative disorder tissue; and (iii) the potential association between post-transplant lymphoproliferative disorder development and hepatitis C virus infection in a large cohort of adult solid organ transplant recipients. METHODS: The study involved 1011 liver, heart and kidney-transplanted patients. Different immunosuppression therapy was recorded from all patients, all were screened for hepatitis C virus infection. When post-transplant lymphoproliferative disorder developed, Epstein-Barr virus encoded RNA by in-situ hybridization and EBNA-1 and gp220 by polymerase chain reaction was assessed in tissue samples. RESULTS: The overall prevalence of post-transplant lymphoproliferative disorder was 1.4% (2.5% in heart, 0.9% in liver and 0.8% in kidney-transplanted patients) and significantly higher in hepatitis C virus positive than in hepatitis C virus negative patients (3.6 % vs 1.2 %; P=0.04). Epstein-Barr virus was present in 10 (77%) out of 13 tumors tested. Two out of three Epstein-Barr virus-negative post-transplant lymphoproliferative disorder developed in hepatitis C virus-positive patients. Thirteen out of 15 (86%) post-transplant lymphoproliferative disorder patients had undergone antithymocyte globulin/OKT3 induction therapy. CONCLUSIONS: Epstein-Barr virus, induction immunosuppression, rejection therapy and also hepatitis C virus infection may play a role in the multifactorial pathogenesis of post-transplant lymphoproliferative disorder.     

Interferon and BK Papovavirus--clinical and laboratory studies

The effects of human leukocyte interferon on BK papovavirus (BKV) infection in 41 recipients of renal transplants were studied as part of a randomized, double-blind, placebo-controlled trial. Eight transplant recipients demonstrated fourfold or greater rises in antibody to BKV, and three excreted BKV in urine. Neither seroconversion nor excretion was reduced by interferon administration. No clinical syndromes could be clearly linked to BKV infection. BKV was also relatively resistant to the in vitro effects of interferon. Pretreatment of interferon-sensitive human fibroblasts with up to 620 units of interferon/ml resulted in a loss of viral infectivity of one log or less. Continuous exposure of infected cultures to these interferon levels reduced BKV titers by 1.5-2.9 logs, whereas continuous exposure to lower concentrations of interferon had less effects. The levels shown to be marginally effective in vitro were considerably higher than those achieved in these patients' sera.     

Impaired lymphocyte transformation response to cytomegalovirus and phytohemagglutinin in recipients of renal transplants: association with antithymocyte globulin

Cell-mediated immunity was assessed in 38 seropositive recipients of renal transplants by measuring the in vitro lymphocyte transformation response (LTR) to cytomegalovirus (CMV) and to phytohemagglutinin; results were correlated with clinical course, viral excretion, and immunosuppressive treatment. Thirteen seropositive controls all responded to CMV with a mean stimulation index of 31 +/- 6; 14 seronegative controls all had stimulation indices of less than 3. LTR to CMV was found to require both thymus-derived lymphocytes and macrophages. Before immunosuppression, responses of patients were similar to those of controls. After renal transplantation mean LTRs to CMV were dramatically reduced up to 18 months postoperatively, especially in patients treated with antithymocyte globulin. Viremia and CMV-related illness were significantly more frequent in recipients of antithymocyte globulin. Although there was only a rough correlation between clinical events and LTR to CMV, five deaths were noted among seven patients (all treated with antithymocyte globulin) who failed to respond to phytohemagglutinin on two consecutive tests.     

Cytomegalovirus infection in patients with renal transplants: potentiation by antithymocyte globulin and an incompatible graft

Fifty-six of 67 patients with antibody to cytomegalovirus before transplantation shed cytomegalovirus from urine and/or saliva postoperatively. Symptomatic reactivation occurred in 17 (25%) patients, five of whom had pneumonitis. The symptomatic patients were more likely to have received a cadaver kidney (P = 0.004) and high-dosage antithymocyte globulin (P = 0.003) and to be viremic (P < 0.0001), compared to patients with silent infection. Forty-eight of 49 patients treated with antithymocyte globulin received cadaver or parent donor kidneys. Twenty-four were given a low-dosage intramuscular regimen, and 25 received a higher dosage intravenously. In the latter group 48% experienced symptomatic reactivation adn 48% viremia, compared to 21% and 17%, respectively, in the former group (P < 0.05 for both comparisons). There were no symptomatic cytomegaloviral infections among 18 patients not treated with antithymocyte globulin, all of whom received related donor kidneys. Renal transplant patients who receive both a poorly matched graft and antithymocyte globulin are at increased risk of morbidity due to cytomegalovirus.     

Primary and reactivated toxoplasma infection in patients with cardiac transplants. Clinical spectrum and problems in diagnosis in a defined population

We have attempted to define the serologic criteria for diagnosis of toxoplasmosis in heart transplant recipients. Of 31 patients who were seronegative before transplantation, 4 received a heart from a seropositive donor, and 3 of these 4 had seroconversion and developed life-threatening toxoplasmosis; the remaining 27 did not have seroconversion or develop clinical toxoplasmosis. Of 19 patients who had antibodies to Toxoplasma before transplantation, 10 developed significant increases in test titers of the dye test or double-sandwich IgM enzyme-linked immunosorbent assay but did not develop a clinical illness that could be attributed to toxoplasma infection. Significant serologic changes occurred more often in patients who received azathioprine, corticosteroids, and antithymocyte globulin than in those who received cyclosporine, corticosteroids, and antithymocyte globulin (p less than 0.05). These data show the wide clinical spectrum and differences in kinetics of antibody response of patients who develop toxoplasma infection after transplantation, and suggest that clinical disease occurs in those who have seroconversion but is rare in patients with preexisting antibody who have serologic evidence of recrudescence.     

Malignant neoplasms following bone marrow transplantation

We undertook an analysis of 2,150 recipients of bone marrow transplant (BMT) at the University of Minnesota to determine the incidence of post- BMT malignant neoplasms (MNs). Fifty-one patients developed 53 MNs, compared with 4.3 expected from general population rates (standardized incidence ratio [SIR], 11.6, 95% confidence interval [CI], 8.2-14.5). These included 22 occurrences of B-cell lymphoproliferative disorder (BLPD), 17 solid nonhematopoietic tumors, 10 myelodysplastic syndromes (MDS), 1 acute myelogenous leukemia (AML), 2 non-Hodgkin's lymphoma (NHL), and 1 Hodgkin's disease (HD). The estimated actuarial incidence of any post-BMT malignancy was 9.9% +/- 2.3% at 13 years posttransplant. The cumulative probability of BLPD plateaued at 1.6% +/- 0.3% by 4 years from transplant and factors independently associated with increased risk included in vitro T-cell depletion of marrow (relative risk (RR) = 11.9, P < .001), HLA mismatch (RR = 8.9, P < .001), use of antithymocyte globulin (ATG) for graft versus host disease (GVHD) prophylaxis (RR = 5.9, P < .001) or in the preparative regimen (RR = 3.1, P = .03) and primary immunodeficiency (RR = 2.5, P = .06). The cumulative probability of developing solid malignancy was 5.6% +/- 2.2% at 13 years from BMT. Malignant melanomas were the most common (SIR, 10.3, 95% CI 1.9 to 25.4). The actuarial incidence of MDS/AML plateaued at 2.1% +/- 0.8% at 9 years and was seen most often in older patients receiving autologous peripheral blood stem cells for HD or NHL. These data document that BMT recipients are at an increased risk of later malignancy, which may add significant morbidity and mortality to the transplant process. Methods for screening and identification of individuals at increased risk need to be addressed in future studies.     

Human polyomavirus infections with JC virus and BK virus in renal transplant patients

Infection with the human polyomaviruses JC virus and BK virus was studied in 61 immunosuppressed renal transplant patients. Urine cytologic studies, indirect immunofluorescence microscopy, electron microscopy, and serologic studies were used to assess viral activity. Patients records were abstracted for events associated with polyomavirus infections. Polyomavirus excretion in urine was detected in 12 of 61 patients (20%). Eleven excreted JC virus and nine, BK virus. Fourfold hemagglutination-inhibition antibody titer rises occurred in 25 of 61 patients (41%). The serologic data suggested that most JC virus infections were primary, whereas most BK virus infections resulted from virus reactivation. During this 2-year study, 32 of 61 patients (52%) had evidence of active viral replication. Urinary tract excretion was associated with drug-requiring diabetes mellitus (P = 0.001), arterial occlusive disease (P = 0.03), and ureteral stricture with loss of renal function (P = 0.02). Antibody increases to BK virus were associated with a rising seurum creatinine (P = 0.02) and need for transplant biopsy (P = 0.02). Polyomavirus replication was therefore associated with an increased frequency of transplant related complications.     

Role of hepatitis C virus in lymphoproliferative disorders after liver transplantation.

It has been suggested that hepatitis C virus (HCV) infection could be associated with B-cell clonal expansion. The aim of this study was to analyze the relationship between lymphoproliferative disorders and HCV infection in liver transplant recipients. We studied 157 patients receiving a liver transplant between January 1989 and May 1997 with a follow-up longer than 3 months. The incidence of posttransplant lymphoproliferative disorders (PTLDs) was analyzed with reference to the indication for liver transplantation, the induction and maintenance immunosuppression, the incidence of acute rejection episodes, and Epstein-Barr virus (EBV) infection. Six PTLDs occurred after a median posttransplant follow-up of 7 months (3.8%). Four of the 6 PTLDs occurred among the 38 patients transplanted for HCV-related cirrhosis, and 2 PTLDs occurred in the 119 patients receiving a liver transplant for non-HCV liver diseases (10.5% vs. 1.7%, respectively; P =.03). The 4-year probability of PTLD was significantly higher in patients receiving a liver transplant for HCV-related cirrhosis than non-HCV liver diseases (12.3% vs. 2.2%, respectively; P =.015). Patients receiving a liver transplant for HCV-related cirrhosis were more likely to receive antithymocyte globulins (ATG). However, in patients treated with ATG, the 4-year probability of PTLD was higher among those patients receiving a liver transplant for HCV-related cirrhosis than for non-HCV liver diseases (27.1% vs. 6.4%, respectively; P =.08). EBV gene products were detected in tumor tissues in 3 of 4 patients with HCV-associated PTLD. Our data suggest that, in addition to EBV infection, 2 mutually nonexclusive factors, i.e., the use of ATG and HCV infection, could play a role in the occurrence of PTLD after a liver transplant for HCV-related cirrhosis.     

Oropharyngeal excretion of Epstein-Barr virus by patients with lymphoproliferative disorders and by recipients of renal homografts.

In an attempt to associate oropharyngeal excretion of Epstein-Barr (EB) virus with lymphoproliferative disorders other than infectious mononucleosis, we tested throat gargles collected from adult subjects for the EB virus. Nine (16%) of 55 healthy persons were positive. High EB virus-excretion rates were found among patients with active acute lymphocytic leukemia (6/6, 100%), among renal homograft recipients during the third to 12th month after transplantation (26/30, 87%), and among critically ill patients with leukemia-lymphoma (14/19, 74%). Moderately high excretion rates were found among patients with myeloma (7/16, 44%), patients with poorly differentiated lymphocytic lymphoma (5/11, 44%), critically ill patients with solid cancers (15/37, 41%), and patients with chronic myelogenous leukemia (8/21, 38%). Our data suggested that the higher than normal excretion rate is realted to the basic disease process and to the general health status but not to the duration of cancer chemotherapy.     

False-positive Histoplasma antigenemia caused by antithymocyte globulin antibodies

False-positive Histoplasma antigen results were identified in two patients who received rabbit antithymocyte globulin (ATG, Thymoglobulin(R)) to prevent allograft rejection. To determine the prevalence of false-positive results following the administration of Thymoglobulin, sequential specimens were tested from a cohort of transplant recipients. Of 107 such patients, 17 (15.9%) demonstrated false-positive tests for Histoplasma antigenemia. False antigenemia peaked at 2-4 weeks after ATG administration and cleared over the next few months. Physicians should be aware of the potential for false-positive results in specimens from patients who have received ATG.     

Polyomavirus JC Urinary Shedding in Kidney and Liver Transplant Recipients Associated With Reduced Creatinine Clearance

Background.?Polyomavirus reactivation can cause significant morbidity in solid organ transplant recipients, particularly BK virus (BKV) in kidney transplant patients. Less is known about dynamics of John Cunningham virus (JCV) in nonkidney organ transplant patients. Methods.?We examined the frequency of urinary shedding of polyomaviruses BKV and JCV and their relationship to creatinine clearance (CrCl) in a longitudinal study of 41 kidney and 33 liver transplant recipients. Results.?Any polyomavirus urinary shedding was more frequent in liver than kidney recipients (64% vs 39%; P?=?.03). JCV was excreted more frequently by liver than kidney recipients (71% vs 38%), whereas BKV was shed more often by kidney than liver patients (69% vs 52%). Mean JCV loads were significantly higher than those of BKV in both patient groups (P?相似文献   

Epstein-Barr virus infections in homosexual men with chronic, persistent generalized lymphadenopathy

The status of infection by the Epstein-Barr virus (EBV) in 20 patients with chronic, persistent generalized lymphadenopathy was evaluated with use of three parameters: antibodies to EBV, EBV excretion, and EB virocytemia. Results were compared with those obtained from two groups of control subjects: patients with infectious mononucleosis and healthy EBV-seropositive adults. Profiles of antibody to EBV and the prevalence of EBV excretion were essentially similar for study subjects and healthy control subjects, but the level of EB virocytemia was significantly higher in study subjects than in healthy control subjects.     

Interstitial pneumonitis in allogeneic bone marrow transplantation: a report from the Japanese BMT Study Group

One hundred and four patients with acute leukemia treated by allogeneic bone marrow transplantation in Japan were analysed for the incidence of interstitial pneumonitis (IP). Thirty-six (35%) of 104 marrow graft recipients developed IP. Cytomegalovirus (CMV) was the most frequent organism (61%). Using multivariate analysis, remission at transplant (P = 0.0001) and use of cyclosporin A to prevent graft-versus-host disease (P = 0.0363) were found to be significant factors associated with a decreased incidence of IP. For preventing IP, anti-CMV hyperimmune globulin was effective, while interferon and acyclovir were not.     

Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: transmission by donated organ and the effect of OKT3 antibodies

One hundred twenty-one adult liver transplant recipients were studied for the incidence, risk factors, and morbidity associated with herpesviruses infections after transplantation. The overall incidence of infection was 59% for cytomegalovirus (CMV), 35% for herpes simplex virus (HSV), 25% for Epstein-Barr virus (EBV), and 7% for varicella-zoster virus (VZV). Primary CMV infection occurred in 46% and reactivation CMV infection in 67% of the susceptible recipients. Symptomatic and disseminated CMV diseases were more common when patients developed primary infection (P less than .01, for both comparisons). The donor organ appeared to be the only important source of CMV infection in seronegative recipients. The use of OKT3 antibodies was associated with disseminated CMV disease in patients with primary infection (P = .04) but not with reactivation infection (P greater than .10). Although most HSV infections were oral or genital reactivations, three cases of HSV hepatitis occurred--one was a primary infection. Symptomatic reactivations of HSV were observed in 53% of HSV-seropositive recipients who received OKT3, versus 31% of seropositive recipients who did not receive OKT3 (P = .05).     

Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment

One-hundred fifty-three recipients of HLA-identical sibling marrow transplants for aplastic anemia or hematologic malignancy were injected with bacteriophage phi X174 (phage), pneumococcal polysaccharide antigen (PPA), or keyhole limpet hemocyanin (KLH). Antibody levels were determined several times in the 6 wk after injection. Multiple regression techniques were used to determine what factors played significant roles in the antibody response. The most significant factors were the time elapsed from transplantation, chronic graft- versus-host disease (GVHD), and antithymocyte globulin (ATG) treatment. All patients had low antibody responses to all antigens in the first 180 days from transplant. Beyond 180 days patients without chronic GVHD showed antibody responses indistinguishable from those of normal donors. However, patients with chronic GVHD had the following impairments: (1) primary response to phage, (2) conversion from IgM to IgG in secondary response to phage, (3) secondary response to KLH, and (4) response to PPA. ATG treatment given to patients either prophylactically or therapeutically for acute GVHD was followed by lower primary responses to phage in the first 180 days and poor ability to switch from IgM to IgG antibody in the secondary response beyond 180 days postgrafting. Other factors did not yield additional significant information about ability to predict antibody responses including diagnosis, conditioning regimen, treatment in or out of laminar air flow rooms, transplantation, pretransplant refractoriness of the recipient to platelet transfusions from random donors, donor age or donor sex, and steroid administration for treatment for prevention of GVHD. The data indicate that, given enough time after transplantation, the ability to produce normal antibody function recovers except in those patients experiencing chronic GVHD.     

A randomized double-blind placebo controlled trial of oral acyclovir in renal allograft recipients

Fifty renal transplant patients were randomized to receive either 800 mg acyclovir by mouth four times daily or identical placebo tablets for prophylaxis of herpes simplex infection. Patients were followed weekly to assess reactivation of herpes simplex, varicella zoster virus, Epstein-Barr virus or cytomegalovirus (CMV) infections. The patients received standard immunosuppressive regimens including cyclosporine A. Acyclovir suppressed secretion of herpes simplex virus in treated patients (P=0.001). Three episodes of mucocutaneous herpes simplex virus occurred in placebo recipients and one in a noncompliant acyclovir recipient. A clinically important difference in graft survival was demonstrated, but because of sample size failed to reach statistical significance (P=0.11). No reactivation of varicella zoster virus, Epstein-Barr virus or CMV infection was detected in either group. Toxicity was limited to central nervous irritability. The authors conclude that high dose oral acyclovir provides effective prophylaxis for prevention of herpes simplex virus infections in renal transplantation and may be associated with increased graft survival, perhaps from suppression of CMV infection.     

Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children

Some prospective studies showed that rabbit antithymocyte globulin was inferior to horse antithymocyte globulin as first-line therapy for patients with severe aplastic anemia. We retrospectively analyzed the clinical outcome of 455 children with severe aplastic anemia who received horse antithymocyte globulin (n=297) or rabbit antithymocyte globulin (n=158) combined with cyclosporine as first-line therapy between 1992 and 2010. The response rates were comparable between the horse and rabbit antithymocyte globulin groups at 3 months [46% (136/294) versus 42% (66/153), P=0.55] and 6 months [60% (178/292) versus 55% (87/143), P=1.0]. Using multivariate analysis, differences in antithymocyte globulin preparations were not associated with response rates. However, 2-year and 10-year overall survival rates in the horse antithymocyte globulin group were significantly better than those in the rabbit antithymocyte globulin group (2-year overall survival: 96% versus 87%, 10-year overall survival: 92% versus 84%, P=0.004). On the basis of multivariate analysis, use of rabbit antithymocyte globulin was a significant adverse factor for overall survival (hazard ratio = 3.56, 95% confidence interval, 1.53 – 8.28, P=0.003). Rabbit antithymocyte globulin caused more profound immunosuppression, which might be responsible for the higher incidence of severe infections. Considering that there are no studies showing the superiority of rabbit antithymocyte globulin over horse antithymocyte globulin, horse antithymocyte globulin should be recommended as a first-line therapy. However, our results justify the use of rabbit antithymocyte globulin as first-line therapy if horse antithymocyte globulin is not available.     

Antibody response to human cytomegalovirus glycoproteins gB and gH after natural infection in humans.

Antibody to the recombinant gB (rgB) and recombinant gH (rgH) glycoproteins of human cytomegalovirus (CMV) was studied in immunocompetent and immunocompromised humans by immunoprecipitating [35S]methionine-labeled CHO cell lines stably expressing rgB and rgH. Antibody to the rgB precursor was present in greater than 60% of immunocompetent individuals. However rgH antibody was detected in less than 10% of these patients. Antibody to both the rgB and rgH was detected during convalescence in three immunocompetent individuals with symptomatic CMV mononucleosis but to a lesser extent in three others who seroconverted to CMV without symptoms. Antibody to rgB and rgH in heart and heart-and-lung transplant recipients was detected in both primary and recurrent CMV infections but not with the same intensity as in immunocompetent individuals. Selected lots of immune serum globulin, administered prophylactically to bone marrow transplant recipients, were frequently deficient in antibody to rgH but not to rgB.     

Infection with varicella-zoster virus after marrow transplantation

Infection with varicella-zoster virus (VZV) occurred in 231 (16.6%) of 1,394 patients undergoing marrow transplantation in Seattle, Washington, between 1969 and 1982. The probability of VZV infection was 30% by one year after transplant. Eighty percent of infections occurred within the first nine months after transplant, and of these cases 45% had cutaneous or visceral dissemination. Twenty-three deaths were associated with VZV infection, all within the initial nine months after transplant. Postherpetic neuralgia, scarring, and bacterial superinfection were also significantly more frequent among patients with VZV in the first nine months after transplant (32%) than among patients with later infection (19%; P less than .05). By multivariate analysis, allogeneic transplant, acute or chronic graft-vs.-host disease, patient age between 10 and 29 years, diagnosis other than chronic myelogenous leukemia, and posttransplant use of antithymocyte globulin were each risk factors for VZV infection. Among infected patients, the only significant risk factor for VZV dissemination or death was acute graft-vs.-host disease (P less than .03 and P less than .0002, respectively.     

Early infections in adults undergoing matched related and matched unrelated/mismatched donor stem cell transplantation: a comparison of incidence

We compared the incidence of early infectious complications between matched related (MR) and matched unrelated/mismatched (MU/MM) allogeneic stem cell transplant (allo-SCT) recipients in a single centre over a 6-year period in 214 consecutive adult patients. Early infections were defined as occurring from hospital admission for SCT until discharge. One hundred and fifty-nine patients received an allograft from MR donors and 55 patients received MU/MM allo-SCT. One hundred and eight of 214 patients had 147 episodes of fever. Ninety-three episodes (63%) were due to clinically or microbiologically documented infections and 54 episodes (37%) to fever not related to infection. Patients undergoing MU/MM transplantation tended to have more documented infections compared to recipients of MR allo-SCT (P = 0.06). Significantly more MU/MM transplant recipients had breakthrough infections with Herpes simplex virus type 1 (HSV-1, P = 0.003), and more CMV reactivation (P = 0.015). The mortality rate in all patients during hospitalisation post-SCT was 6.3% in MR and 18.2% in MU/MM allo-SCT recipients (P = 0.009). Early mortality was associated with infection in 70% of the patients, with a similar distribution between MR and MU/MM transplant recipients. However, MU/MM transplant recipients had significantly more early deaths due to toxic causes (P < 0.001). We conclude that early post-transplant MU/MM transplant recipients tend to have more documented infections, and have significantly more breakthrough infections with HSV-1 and more CMV reactivation. MU/MM transplant recipients are at higher risk of early mortality, especially due to toxic causes.