Cytomegalovirus infection and specific cell-mediated immunity after marrow transplant

Patients were studied prospectively after marrow transplant to correlate cytomegalovirus (CMV) infection with the in vitro lymphocyte transformation response to CMV antigen. Ninety-two (58%) of 158 patients developed CMV infection. The lymphocyte response to CMV antigen of patients who were seropositive before transplant was significantly suppressed immediately after transplant. Isolation of CMV was associated with further suppression of responses; seroconversion to CMV was associated with a significant increase. The lymphocyte response of 73 long-term survivors was similar to that of normal persons. The presence of antibody to CMV in the donor before transplant had little effect on the lymphocyte response of patients after transplant even though the patients' lymphocyte s were of donor origin. As in previously reported studies of immunity to other herpesviruses after marrow transplant, it was concluded that recovery of the response to CMV antigen is related primarily to active virus infection and not to patient or donor pretransplant immunity.     

Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease

Among 181 patients undergoing allogeneic bone marrow transplantation over a five-year period (1978 through 1982), cytomegalovirus (CMV) infection was a frequent and often lethal complication. Recipient pretransplant serology was the most important predictor of posttransplant CMV infection. CMV infection occurred in 26/137 seronegative recipients and in 28/44 seropositive recipients (P less than .001). Among patients who developed CMV infection, the time to infection was identical in seronegative and seropositive patients (median, 71 days post transplant). Bone marrow donor CMV serology did not significantly influence CMV infection rate. CMV infection was strongly associated with acute graft-v-host disease (AGVHD), occurring in 34/81 patients with AGVHD and 20/100 without GVHD (P less than .001). AGVHD preceded CMV infection by 33.7 days (mean) in patients developing both complications. Patients who developed CMV infections had also received more cellular blood products post transplant. These data suggest that CMV infection may occur through reactivation of latent virus (in seropositive recipients) or through exogenous exposure, possibly through transfused blood products, but that duration of immunoincompetence may be more critical than route of exposure in timing of clinically evident CMV infection. Prophylaxis tailored to the likely infectious source and more effective GVHD prevention both may be critical in preventing CMV infection after bone marrow transplantation.     

Cytomegalovirus infection after autologous bone marrow transplantation: occurrence of cytomegalovirus disease and effect on engraftment

Epidemiologic and clinical characteristics of cytomegalovirus (CMV) infection and disease were analyzed retrospectively in 159 autologous marrow transplant recipients. The probability of CMV infection by day 100 after transplant was 22.5% in patients seronegative to CMV before transplant versus 61.1% in seropositive patients (P less than .0001 by logrank test). Multivariate analysis identified positive pretransplant CMV serology as the only definable risk factor for CMV infection (relative risk 1.4, P less than .0001). CMV pneumonia developed in 11 patients at a median time of 100 days after transplant and was fatal in nine cases. CMV pneumonia was associated with significantly decreased probability of survival by day 100 after transplant (relative risk of death of 16.7, P less than .0001). In contrast to earlier reports, CMV infection had no significant effect on the rapidity of platelet or neutrophil recovery after transplant as assessed by time-dependent multivariate analysis. Because the incidence of severe CMV disease is not negligible after autologous marrow transplantation, preventive measures against CMV infection are warranted, as in allogeneic marrow transplantation.     

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).     

Identification of patients with increased risk of infection with herpes simplex virus after renal transplantation.

Forty-nine recipients of renal allografts were studied for infection with herpes simplex virus (HSV) before and at sequential intervals after transplantation. Forty-four (90%) of the patients studied were initially seropositive for neutralizing antibody to HSV type 1. HSV was not shed prior to transplantation nor by any of the five seronegative recipients after transplantation. Twenty-nine (66%) of the 44 seropositive patients shed virus postoperatively: 23 in saliva, three in urine, and three in both sites. Twenty (63%) of 32 seropositive patients examined developed herpetic mucocutaneous lesions. Both viral shedding and lesions were most prevalent during the first four weeks after transplantation. Twenty-nine (85%) of 34 patients with antibody titers of 1:256-1:4,096 and zero of 10 with titers of 1:8-1:128 shed HSV postoperatively (P less than 0.0001). The group with high antibody titers before transplantation were also more likely to develop lesions after transplantation (P = 0.002) as were those with a positive history (P = 0.017). The ability to predict symptomatic HSV recurrences in renal transplant patients could be a valuable aid in identifying individuals with which to evaluate antiviral compounds.     

Cytomegalovirus infections in patients after liver transplantation: determination of risk groups]

The goal of this study was to identify high-risk groups for cytomegalovirus infection after liver transplantation. Sixty-one patients were evaluated. Twenty-five patients (41 percent) had infection. Among the 16 patients who were seronegative for the virus before transplantation, 11 received a liver graft and blood products from seronegative donors and none of them developed infection. All seronegative recipients of a liver from seropositive donors (5/5) developed primary infection. Among the 45 patients seropositive before transplantation, 20 developed a cytomegalovirus infection, whatever the donor serologic status. The incidence of symptomatic reactivation or reinfection was high (14/20), and, for 12/14 of them, associated with early acute rejection. Two high-risk groups of patients, eligible for cytomegalovirus prophylaxis, were identified: seronegative recipients of seropositive donors and seropositive recipients with early acute rejection.     

Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical course

Bone marrow transplant recipients are at risk for acquiring hepatitis C infection from the donated marrow. Twelve patients who were hepatitis C virus (HCV) RNA-negative pretransplant received marrow from anti-HCV seropositive donors. HCV RNA was present in the sera of seven of these donors. After transplant, serial serum specimens were obtained from all marrow recipients for determination of HCV RNA and aminotransferase levels. All seven recipients of marrow from HCV RNA-positive donors were HCV RNA-positive after marrow infusion; none cleared virus from the serum. All five recipients of marrow from anti-HCV seropositive, HCV RNA-negative donors remained free of HCV RNA in serum up to day 100. Abnormal serum aminotransferases were common in both HCV RNA- negative and HCV RNA-positive marrow recipients. One HCV-infected recipient developed marked elevation in aminotransferases after immunosuppressive drugs were stopped. We conclude that the presence of HCV RNA in the serum of marrow donors is an accurate predictor of HCV infection in marrow recipients. The acute infection was subclinical in all patients. The long-term risk of chronic hepatitis C virus infection in these patients remains to be determined.     

Risk factors for cytomegalovirus infection after human marrow transplantation

The records of 545 patients were reviewed for risk factors associated with cytomegalovirus (CMV) infection after marrow transplant. CMV infection occurred among 36% of seronegative patients and 69% of seropositive patients. Among seronegative patients, significant risk factors for CMV infection included positive serology of the marrow donor (relative rate, 2.3) and the use of granulocyte transfusions from seropositive donors (relative rate, 2.5). Among both seronegative and seropositive patients, the occurrence of acute graft-versus-host disease (GVHD) significantly increased the risk of CMV infection (average relative rate, 1.8) and of subsequent CMV pneumonia (average relative rate, 2.6). CMV excretion and viremia were each associated with subsequent pneumonia, but the positive predictive values were low. One-third of long-term survivors excreted CMV at greater than 250 days after transplantation. The only risk factor for late excretion was CMV infection that occurred in the first 150 days after transplantation. In contrast to the effect of acute GVHD on CMV infection, CMV infection did not increase the risk of either acute or chronic GVHD.     

Graft-versus-leukaemia activity associated with cytomegalovirus seropositive bone marrow donors but separated from graft-versus-host disease in allograft recipients with AML

To elucidate whether a relationship existed between bone marrow donor cytomegalovirus (CMV) immune status and the probability of staying in remission after transplantation, a retrospective multicentre analysis was performed in 69 patients who received allogeneic bone marrow transplantation during relapse or second remission of AML, or second remission of ALL. None of 12 AML patients with CMV seropositive donors had posttransplant relapse, in contrast to 7 of 10 AML patients with seronegative donors. Kaplan-Meier estimates of the 2-yr probability of staying in remission for the two groups were 100% and 0%, respectively (p less than 0.0005). This effect was independent of disease stage, donor and recipient age, recipient pretransplant CMV immune status and the occurrence of posttransplant CMV infection in recipients, and was not mediated through an increased occurrence of overt graft-versus-host disease (GvHD) in recipients with CMV seropositive donors. The increased probability of staying in remission was associated with an increased probability of 3-yr disease-free survival (p less than 0.01). No similar effect was observed in patients with ALL. This study may suggest an allograft-versus-leukaemia effect in AML, associated with CMV seropositive donors, which seems separate from GvHD and independent of the occurrence of posttransplant CMV infection.     

Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up.

Before the introduction of routine blood donor screening in 1991, marrow transplant recipients were at significant transfusion-associated risk for infection with hepatitis C virus (HCV). We followed a cohort of 355 patients undergoing transplant in Seattle during 1987 to 1988 to determine (1) the impact of pretransplant HCV infection on the occurrence and severity of venocclusive disease (VOD); (2) the impact of HCV infection on liver dysfunction, other than VOD, occurring between 21 and 60 days after transplantation; and (3) the natural history of post-transplant HCV liver disease with a 10-year follow-up. HCV-RNA status was determined on serum stored before transplant and at day 100 post-transplant. Sixty-two (17%) patients were HCV-RNA positive before transplant, and 113 (32%) were HCV-RNA positive by day 100 post-transplant (or before death). Severe VOD developed in 22 of 46 (48%) evaluable patients with pretransplant HCV infection and in 150 of 229 (14%) evaluable patients without HCV (P <.0001). In multivariable analysis of risk factors for developing VOD, pretransplant HCV infection associated with elevated serum aspartate transaminase (AST) levels predicted the development of severe VOD (relative risk, 9.6; P =.0001). The presence of HCV with normal AST levels before transplant was not a risk factor for severe VOD. Between 21 and 60 days after transplant, HCV-RNA positive-patients had higher AST levels (median 101 U/L), but similar alkaline phosphatase and total bilirubin levels compared with HCV-negative patients, suggesting that cholestatic liver disease (particularly graft-versus-host disease [GVHD]) was not related to HCV infection. An acute flare of hepatitis (AST >10 times the upper limit of normal) developed at a mean of 136 +/- 58 days in 31% of HCV-positive patients; no patients developed fulminant hepatitis. Between 5 and 10 years after transplant, 57% of HCV-positive and 6% of HCV-negative patients had mild to moderate elevations of AST (P <. 0001), but HCV infection was not associated with excess mortality between 3 and 10 years after bone marrow transplantation. In summary, HCV infection with elevated AST levels is a significant risk factor for severe VOD after marrow transplant. However, the decision to proceed to transplantation in HCV-positive patients must balance the absolute risk of death from VOD against the risks of the underlying disease. In long-term survivors, HCV infection is not associated with excess mortality over 10 years of follow-up.     

Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency.

Wild-type strains of Epstein-Barr virus (EBV) can be distinguished on the basis of variations in the molecular weight of virus-encoded, growth transformation-associated proteins. This approach was used to study the persistence of EBV in two seropositive recipients of allogeneic bone marrow transplants. The first patient received marrow from her EBV-seronegative brother, became EBV seronegative after grafting, and remained so for greater than 1200 days. Subsequently, she became infected with a new EBV strain that differed from her pretransplant strain but was indistinguishable from the virus isolated from her husband. The second patient received marrow from his EBV-seropositive brother. This patient showed only a transient decrease in IgG antibodies to EBV capsid antigen. His pretransplant strain differed from the virus of his donor. On days 252 and 915 after transplantation, lymphoblastoid cell lines were grown from the peripheral blood of the patient and were found to carry exclusively the virus of the donor. These results suggest that the latently EBV-infected host cells reside in a cellular compartment that can be destroyed by graft-versus-host reactivity, irradiation, or cytotoxic drugs. Hemopoietic tissue is the most likely candidate.     

Toxoplasma infection after human allogeneic bone marrow transplantation: clinical and serological study of 80 patients

Systematic clinical and serological studies to evaluate the frequency of toxoplasmosis in bone marrow transplant recipients were performed in 80 consecutive patients. Antitoxoplasma antibody titres were measured in donors and recipients before transplant and subsequently post-transplant. Before bone marrow transplant, 54 recipients were seropositive and 26 were seronegative, whereas 35 donors were seropositive and 45 were seronegative. After bone marrow transplant, the frequency of clinical and serological manifestations of toxoplasmosis appeared closely related to the recipient's serological status before transplant. In the seronegative group of patients before transplant the incidence of toxoplasmosis was low: only two patients experienced seroconversion 3 months after bone marrow transplant and one developed clinical symptoms consistent with toxoplasmosis but without cerebral involvement. Clinical toxoplasmosis or secondary elevation of antibody titres was mostly observed in pre-bone marrow transplant seropositive patients; in this group, cerebral toxoplasmosis occurred in four patients and a significant secondary rise of antibody titres was observed in 16 patients. It thus appears that toxoplasmosis is most often related to a reactivation of latent cysts. Prophylactic treatment may be useful in patients presenting serological evidence of past or latent infection before bone marrow transplant.     

Primary herpes simplex virus type-2 infection as a cause of liver failure after liver transplantation

We report a case of fatal primary herpes simplex virus type-2 (HSV-2) infection following liver transplantation, which manifested with fever and liver failure in the absence of muco-cutaneous disease. The infection was characterized by high levels of HSV DNA in blood and the patient's inability to mount HSV-specific T-cell responses while showing preserved T-cell responses against cytomegalovirus. The donor was HSV-1 immunoglobulin G (IgG) seronegative and HSV-2 IgG seropositive, whereas the recipient was HSV-1 and HSV-2 IgG seronegative, suggesting that the graft may have been the source of the infection. In HSV-seronegative recipients of grafts from HSV-seropositive donors, HSV infection should be included in the differential diagnosis of a febrile illness, regardless of the absence of muco-cutaneous disease. In this setting, real-time polymerase chain reaction applied to blood samples provides a sensitive, rapid, and quantitative diagnostic tool.     

Cytomegalovirus infections and toxoplasmosis in heart transplant recipients in Sweden.

The morbidity of cytomegalovirus (CMV) infection and toxoplasmosis was evaluated in 75 heart transplant recipients. Among the 73 patients who survived more than one week after transplantation, 16 (22%) acquired primary CMV infection and 30 (41%) had evidence of secondary infection. All CMV seronegative recipients receiving hearts from seropositive donors developed CMV infection. The majority of infections (42/46) occurred during the first 4 months after transplantation. Overall, the incidence of symptomatic CMV disease was 44%. The infections were generally mild and only 1 death was attributed to primary CMV disease complicated by bacterial septicaemia and multiple organ failure. The severity of CMV disease was greatest among those with primary infection. There were 3 cases of toxoplasmosis. Two patients were toxoplasma seronegative before transplantation and developed clinical and serological signs of infection 2-3 months after transplantation despite receiving organs from seronegative donors. Of toxoplasma seronegative recipients receiving allografts from seropositive donors 3/4 were prophylactically treated with pyrimethamine for 6 weeks. None developed clinical or serological signs of toxoplasmosis while one patient who received trimethoprim-sulfamethoxazole had a subclinical infection.     

Prevention of cytomegalovirus infection by cytomegalovirus immune globulin after marrow transplantation

In an effort to prevent cytomegalovirus infection among seronegative patients having marrow transplants, a globulin with high antibody levels against cytomegalovirus was given before and for 11 weeks after transplantation in a randomized trial. Among 36 patients who received no prophylactic granulocyte transfusions, globulin recipients had significantly fewer infections than controls (2 of 17 versus 8 of 19, p = 0.05 by Fisher's exact test and p = 0.03 by Mantel-Cox test). Conversely, infection rates were high and unchanged by globulin use among patients who received granulocytes from seropositive donors (7 of 8 recipients versus 6 of 7 controls). The lack of effect of the globulin among patients receiving transfusions of granulocytes from seropositive donors may suggest that the dose of antibody was insufficient or that antibody is ineffective against virus transmitted in granulocytes. We conclude that cytomegalovirus infection can be prevented by immunoprophylaxis in seronegative patients having marrow transplants who are not given granulocyte transfusions.     

Transient residence of a seropositive organ is sufficient to transfer human cytomegalovirus to a seronegative recipient

Many aspects of the pathogenesis of human cytomegalovirus (HCMV) infection in liver transplantation remain unclear. This study examined the transfer of HCMV from the transient residence of a seropositive organ in seronegative recipients. All subjects receiving >1 orthotopic liver transplant (LT) were identified from an LT database. The patients of interest were HCMV‐seronegative LT recipients who received their first organ from a seropositive donor, and subsequently a second LT from a seronegative donor within 30 days. Of 98 patients identified, 6 met these criteria and 4 developed viremia; in 2 cases, after the seropositive organ was in situ for 28 and 109 h. We can therefore conclude that 28 h is sufficient to allow HCMV to transmit, but the minimum time has not yet been defined.     

Effect of Towne live virus vaccine on cytomegalovirus disease after renal transplant. A controlled trial

OBJECTIVE: To test the efficacy of vaccination with the Towne live attenuated cytomegalovirus vaccine. DESIGN: A double-blind, randomized, placebo-controlled trial in candidates for renal transplantation. The cytomegalovirus serologic status of both recipients and donors were determined, and the recipients were followed for periods of 6 months to 7 years after transplant. SETTING: A university transplant center. PATIENTS: The analyses were made on 237 patients who were given either vaccine or placebo, received renal transplants, and were followed for at least 6 months. INTERVENTION: Subcutaneous inoculation with Towne live attenuated virus or with placebo. MAIN OUTCOME MEASURES: The presence of cytomegalovirus infection was defined by virus isolation and antibody tests. If infection occurred, a prearranged scoring system for cytomegalovirus disease was used to objectify disease severity. RESULTS: The vaccine was well tolerated, and there were no discernible long-term adverse effects. Recipients who were originally seropositive did not clearly benefit from vaccination. Protective efficacy was analyzed in the group at highest risk for cytomegalovirus disease; recipients who were seronegative at the time of vaccination and who received a kidney from a seropositive donor. Compared with placebo recipients, vaccinated patients in this group had significantly less severe cytomegalovirus disease, with a significant reduction in disease scores (P = 0.03) and 85% decrease in the most severe disease (95% CI, 35% to 96%), although infection rates were similar. Graft survival at 36 months was improved in vaccinated recipients of cadaver kidneys (8 of 16) compared with unvaccinated recipients (4 of 16) (P = 0.04). CONCLUSIONS: Previous vaccination of seronegative renal transplant recipients with live cytomegalovirus results in reduction of disease severity mimicking the action of naturally derived immunity.     

Cell-mediated immunity of cytomegalovirus infection in normal subjects and cardiac transplant patients.

Two assays of cell-mediated immunity, lymphocyte transformation and interferon production, were adapted to test for specific immunity to cytomegalovirus (CMV). Normal individuals seropositive for CMV had a mean transformation index of 7.9 in response to antigen of the Davis strain of CMV, whereas all of 14 seronegative normal individuals had transformation indexes of less than or equal to 3.0. Interferon production in seropositive and seronegative individuals was not statistically different. One to two months after CMV mononucleosis (after the termination of viruria), normal individuals had increased transformation indexes. Recipients of cardiac transplants within six months after transplant had normal levels of antibody to CMV; lymphocyte transformation and interferon production in these subjects were markedly decreased and returned to normal by three years and between one and three years after transplant, respectively. A syndrome of unexplained fever, hepatitis, pneumonitis, leukopenia, and atypical lymphocytes was common in a group of recipients with primary CMV infection. Shedding of virus was frequent in these symptomatic patients and in patients with repeat infection during the first three years after transplant. These assays appear to identify periods of immune deficits correlating with increased incidence of infection with CMV.     

Immunity to and immunization against measles, rubella and mumps in patients after autologous bone marrow transplantation.

Humoral immunity to measles, rubella and mumps was studied in 63, 36 and 16 patients 1, 2 and 3 years, respectively after autologous bone marrow transplantation (ABMT). Serologic examination was performed using antibody-ELISA. One year after ABMT, 7/57 patients (12%) who were seropositive to measles before ABMT, became seronegative, 8/44 (18%) to rubella and 3/51 (6%) to mumps. Among patients who were retested at 2 and 3 years, three more patients became seronegative to measles, one to rubella, and three to mumps. Nine of 12 children who had previously been immunized against measles were seropositive before ABMT, 3/7 to rubella and 5/7 to mumps, respectively. After ABMT, 5/9 became seronegative to measles, none to rubella and 2/5 to mumps. Six seronegative children were immunized with a live trivalent attenuated measles, mumps, and rubella vaccine 1 to 2 years after ABMT. Two children seroconverted to measles, six to rubella, and four to mumps. No side effects were observed. Most adult patients who have had the diseases of measles, rubella, or mumps naturally remain seropositive, while children who have been immunized commonly lose their immunity after ABMT.     

The course of Helicobacter pylori infection in kidney transplantation patients

BACKGROUND: Helicobacter pylori has been found to be only a minor risk factor for gastroduodenal complications in kidney transplantation patients. The aim of the study was to follow up the course of H. pylori infection in a group of immunosuppressed kidney transplantation patients. METHODS: After a median follow-up of 6.8 years, control serum samples were taken from 93 originally seropositive and 88 originally seronegative kidney transplant recipients. H. pylori antibodies of the IgG and IgA classes and serum pepsinogen I levels were measured from pretransplant and follow-up samples in parallel. In addition, CagA antibodies were measured from the baseline samples of the seropositive patients. RESULTS: 83 of the 93 seropositive patients were also cagA-positive. In addition to the 10 patients who received H. pylori eradication therapy, 27 (29%) of the 92 patients with originally elevated H. pylori IgG antibody titres showed IgG titres at normal level or levels decreased by more than 70% and below 2000 (regarded as seroreverters) after the follow-up. One of the originally seronegative patients seroconverted during the study period. After transplantation, the decrease of serum pepsinogen I values was in accordance with improved kidney function. Patients with lower serum pepsinogen I levels before the transplantation seroreverted more easily. CONCLUSIONS: A spontaneous H. pylori seroreversion occurred in 29% of the immunosuppressed kidney transplantation patients. After a successful kidney transplantation, serum pepsinogen I values declined significantly.