Developed CMV Disease Research Articles

Leukocyte depleted, unscreened blood products give a low risk for CMV infection and disease in CMV seronegative allogeneic stem cell transplant recipients with seronegative stem cell donors.

Leukocyte depletion (LD) by blood product filtration has been shown to be similarly effective to the use of screened, CMV seronegative blood products to prevent CMV disease in CMV seronegative allogeneic stem cell transplant (SCT) patients with CMV seronegative donors. The aim of this retrospective study was to determine the risk for development of CMV infection requiring preemptive therapy and for CMV disease if unscreened products treated by prestorage LD is used. Forty-nine consecutive patients transplanted after June 1995 were included. As a control group, 33 patients transplanted from January 1992 to June 1995 in whom a combination of CMV seronegative and LD blood products were given. All patients were monitored weekly by a leukocyte-based PCR for CMV DNA detection. Preemptive therapy was initiated after two consecutively positive tests. No patient developed CMV disease in either group. CMV DNA was detected in 6/49 (p = NS) in the study group and in 3/33 patients in the historical control group. Two patients in the study group were given preemptive therapy compared to one patient in the control group. This study suggests that the risk for CMV disease and the need for preemptive therapy against CMV is low in CMV seronegative allogeneic SCT patients receiving grafts from CMV seronegative stem cell donors receiving LD blood products. Thus, this strategy can be safely used together with PCR monitoring and preemptive therapy.

Cidofovir as primary pre-emptive therapy for post-transplant cytomegalovirus infections.

Pre-emptive antiviral therapy for CMV infection following allogeneic stem cell transplantation is an effective strategy for preventing CMV disease. This entails the logistic difficulty of daily intravenous therapy with ganciclovir or foscarnet to clinically asymptomatic patients. Cidofovir (CDV) is effective against CMV in vitro and has the practical advantage of weekly administration. However, there are limited data on the pre-emptive use of CDV in CMV infections. We carried out a pilot study exploring the efficacy and toxicity of CDV as primary pre-emptive therapy for CMV infections monitored by PCR-based assays. CDV was used at 5 mg/kg with probenecid and hydration, weekly for a maximum of 4 weeks, followed by fortnightly maintenance treatment. Four patients were treated with CDV and two of them responded. Both the non-responders developed CMV disease. There was no renal toxicity noted in any of the patients, but three patients had severe vomiting and one developed uveitis, which precluded maintenance treatment in the two responders. Following failure of CDV, foscarnet was effective in controlling the CMV infection in both patients, although the infection recurred in both. Thus, larger randomised studies are required before CDV can be recommended as a primary pre-emptive therapy for post-transplant CMV infections.

CMV disease in CMV-mismatched renal transplant recipients with prophylactic low dose valaciclovir.

Valaciclovir (VACV) 2 g q.i.d. for 3 months after kidney transplantation has been shown, (Lowance et al., NEJM 1999; 340: 1462-70), to reduce CMV disease from 45 to 16% and rejection from 52 to 26% in CMV-negative (D+R-) recipients. Neurotoxic side effects, however, were frequent, and 5% of the patients experienced hallucinations. We hypothesised that a lower dosage of VACV would prevent CMV disease with fewer CNS side effects. Since September 1998 all CMV-mismatched renal transplant recipients received VACV 1 g t.i.d. for 3 months posttransplantation (PT). The incidence of CMV disease, rejection and neurotoxic side effects during 6 months PT was studied retrospectively in, up to now, 25 patients. 24% (6/25) of the patients developed CMV disease. The mean time for onset of symptoms was 145 days (92-191). Five of the patients had mild-moderate symptoms and recovered after ganciclovir therapy for 3 weeks. One patient was diagnosed with a CMV-associated retinitis on day 191 PT. The rate of biopsy-confirmed acute graft rejection was 32% (8/25). 20% (5/25) of the patients had a serum creatinine of >200 micromol/l after 6 months, including one patient on hemodialysis. CNS adverse effects were not observed. None out of nine patients with basiliximab induction and VACV developed CMV disease. One patient with basiliximab that did not receive VACV, developed a symptomatic CMV-infection. The incidence of CMV disease was lower than in historical controls at our centre, and the time to onset of symptoms was prolonged. Compared to the 8 g VACV/day study, CMV disease and graft rejection was more frequent, but no neurotoxic side effects were observed. A combination with basiliximab induction and VACV 3 g/day shows promising results, but randomised studies are needed for confirmation.

Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation.

We compared the occurrence of severe infections following 71 reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplants (PBSCT) and 123 standard myeloablative PBSCT (MINI and STAND groups, respectively) from HLA-identical siblings. The probability of 1-year infection-related mortality (IRM) was 19% in the STAND group and 10% in the MINI group (log-rank, P = 0.3). On multivariate analysis the only significant variable associated with a higher risk of IRM was the development of moderate-to-severe GVHD (P = 0.005). The probability of developing CMV infection was 39% in the STAND group and 21% in the MINI group (P = 0.03) (43% and 21%, respectively, in seropositive donor/recipient pairs, P = 0.01), and the probability of developing CMV disease was 9.5% and 1%, respectively (P = 0.05) (11% and 1%, respectively, in seropositive donor/recipient pairs, P = 0.03). Multivariate analysis of CMV infection identified four variables associated with a higher risk: CMV positive serostatus (P = 0.05), STAND transplant group (P = 0.02), the development of moderate-to-severe GVHD (P < 0.001) and a dose of CD34(+) cells infused below 6 x 10(6)/kg (P = 0.01). Invasive fungal infections and pneumonias of unknown origin did not differ between groups, and neither did other severe non-CMV viral infections and bacterial infections. Our results suggest that RIC allogeneic PBSCT may decrease the risk of dying from an opportunistic infection and reduces the occurrence of CMV infection and disease. Overall, the development of GVHD (acute or chronic) is an important risk factor for these complications. Other infections continue to pose a significant threat to recipients of RIC allografts, stressing that prophylactic and supportive measures are an important aspect in their care.

Monitoring AIDS patients for the development of cytomegalovirus (CMV) disease using multiplex PCR

The human cytomegalovirus is an important pathogen in patients infected with the human immunodeficiency virus (HIV). The CMV viral load seems to be predictor of the development of the CMV disease in these patients. We used a multiplex PCR protocol that also provides quantitative information in those samples from which a single band is amplified and contains fewer viral genomes than those from which both targets are amplified. Monthly blood samples were collected from 270 AIDS patients. From twenty patients, two CMV targets were amplified three or more consecutive times and these patients developed CMV related disease during the study. In contrast, patients who did not result positive for both viral targets, for three or more consecutive times, or who had alternating positive and negative samples during the follow up did not present CMV related disease. The results suggest that the PCR multiplex can be used for the identification of HIV positive patients with higher risk of development of CMV disease.

Comparison of the efficacy and cost effectiveness of pre-emptive therapy as directed by CMV antigenemia and prophylaxis with ganciclovir in lung transplant recipients

Background: CMV disease remains a major complication of lung transplantation and attempts to prevent it have met with marginal success. In a previous study we documented that universal prophylaxis did not prevent CMV disease but merely delayed it, and was very costly. Methods We compared the efficacy and cost of pre-emptive therapy with ganciclovir, guided by CMV antigenemia, to that of historic controls that received universal prophylaxis with ganciclovir. CMV antigenemia assay was done routinely and pre-emptive therapy was initiated if greater than 25 CMV positive cells per 100,000 polymorphonuclear cells were found. Results Nineteen patients were enrolled; 6 of whom received 12 courses of pre-emptive therapy. The incidence of CMV disease was 26% compared to 38% for the historical controls ( p = 0.51). None of the patients that received pre-emptive therapy developed CMV disease following that therapy. Antigenemia failed to predict disease in 5 patients that developed it, and thus it is unknown if pre-emptive therapy could have prevented it. There was no mortality in either the study patients or historic controls directly related to CMV. The net savings with pre-emptive therapy was $2569 per patient. Conclusion We conclude that pre-emptive therapy with ganciclovir is as safe and effective as universal prophylaxis in preventing CMV disease in lung transplant recipients, and is less expensive. The appropriate surveillance technique and timing remain to be determine to optimize the efficacy of pre-emptive therapy.

Usefulness of pp65 antigenemia for the early diagnosis of cytomegalovirus disease in patients with AIDS.

An observational cohort study was performed to assess the effectiveness of a cytomegalovirus antigenemia (CMV-Ag) assay designed to predict clinical CMV disease in patients with AIDS. Eighty-six HIV-infected patients with CD4+ cell counts of < 100/mm3, positive CMV IgG, and no previous CMV disease were enrolled. Thirty-eight (44%) patients had at least one positive CMV antigenemia test, ten of whom eventually developed CMV focal disease. CMV disease was diagnosed in 13 (15%) patients. The CMV antigenemia assay was positive in ten of these 13 patients. Using a cut-off value of five positive cells in every 150,000 leukocytes sampled, the CMV antigenemia assay had a positive predictive value of 89% and a negative predictive value of 94%. The median time from the first positive CMV antigenemia test to the onset of CMV disease was 102 days. CMV disease probability at 6 months in patients with a CMV antigenemia value > or = 5 was 77.8% versus 6% in patients with CMV antigenemia value < 5 (log-rank test = 48.345; P < 0.001). Several independent factors were associated with the development of CMV disease: CMV antigenemia > or = 5 cells (hazard ratio: 20.44), CD4+ count < or = 25/mm3 (HR: 3.12), and sexual transmission of HIV infection (hazard ratio, 3.15). CMV antigenemia seems to be a good predictor of CMV disease in patients with AIDS.

Clinical Utility Of Cytomegalovirus (CMV) Viral Load Determination For Predicting CMV Disease In Liver Transplant Recipients

477 Background: The early detection of CMV infection after liver transplantation may form the basis of a pre-emptive strategy for prevention of active CMV disease. Methods: We prospectively analyzed the clinical utility of weekly quantitative PCR-based plasma viral load determinations and the antigenemia assay for predicting the development of active CMV disease in 97 consecutive liver transplant recipients. Results: CMV disease occurred in 21/97 (21.6%) patients. Using a positive cutoff of > 0 copies per/ml plasma, PCR had a sensitivity of 100%, specificity 47.4%, positive predictive value (PPV) 34.4%, and negative predictive value (NPV) 100% for prediction of CMV disease. Respective values for a positive antigenemia (> 0 positive cells per slide) were 95.2%, 55.3%, 37.0% and 97.7%. Different cut-off points for a positive test were analyzed using receiver-operating characteristic curves. The optimal cut-off for viral load for predicting subsequent CMV disease was in the range of 2000-5000 copies per/ml (sensitivity 85.7%, specificity 86.8%, PPV 64.3%, NPV 95.7% for > 5000 copies/ml). The optimal cut-off for antigenemia was in the range of 4-6 positive cells/slide. Mean peak viral load in symptomatic patients was 73715 copies per/ml vs. 3615 copies per/ml in patients with asymptomatic CMV reactivation (p<0.001). In a multivariate logistic regression analysis of risk factors for CMV disease (CMV serostatus, acute rejection, and induction immunosuppression), peak viral load and peak antigenemia emerged as the only significant risk factors for subsequent development of CMV disease (for PCR, OR=1.40 per 1000 copy/ml increase in viral load, p=0.0001; for antigenemia OR=1.16 per 1 positive cell/slide; p=0.007). Conclusions: Plasma viral load by quantitative PCR is a useful test for predicting CMV disease, is at least as sensitive and specific as antigenemia, and could be employed in a pre-emptive strategy.

Early detection of active cytomegalovirus infection in heart/lung trans plant recipients

Although a CMV-specific T-cell response is associated with reduced risk for infection after transplantation, some patients still develop CMV disease. Thus, the characterization of additional parameters of the CMV-specific immune response that correlate with the control of CMV infection and disease and their use in defining thresholds that can be applied to clinical practice is of interest.In a cohort of high risk solid organ transplant recipients we characterized CMV-specific T-cell responses using intracellular cytokine staining upon stimulation with pp65 and IE-1 peptides, and levels of CMV-specific antibodies neutralizing infection in fibroblast (MRC-5) and epithelial (ARPE-19) cells using microneutralization assays.Although patients with a positive (≥0.25%CD8+CD69+IFN-γ+) T-cell response were 6.4 fold more protected (OR 6.4, 95% CI 1.6–25.3; p < 0.001) from CMV infection than patients without a response, 2 (4.2%) patients developed disease. We defined a cut-off titer for epithelial cell neutralizing antibodies of ≥480 that correlated with disease protection. Thus, patients with a CMV-specific T-cell response and titers ≥480 were 14.2 fold more protected from CMV infection (OR 14.2, 95% CI 5–40.2; p < 0.001) and had no episodes of CMV disease.Our results indicate that antibodies neutralizing epithelial cell infection may have an important role in long-term protection. Quantification of antibodies neutralizing epithelial cells, in addition to the T-cell response, may be useful for identifying patients with lower risk for CMV disease.

HCMV delayed-early gene activity in the absence of IE1

Background: CMV is a major clinical problem in transplant recipients. Thus, it is important to use sensitive and specific diagnostic techniques to rapidly and accurately detect CMV infection and identify patients at risk of developing CMV disease. In the present study, CMV infection after liver transplantation was monitored retrospectively by two molecular biology assays—a quantitative PCR assay and a qualitative NASBA assay. The results were compared with those obtained by prospective pp65 antigenemia determinations. Materials and Methods: 87 consecutive samples from 10 liver transplanted patients were tested for CMV by pp65 antigenemia, and CMV monitor and NASBA pp67 mRNA assay. Results: CMV infection was detected in all patients by antigenemia and CMV monitor, whereas NASBA assay identified only 8/10 patients with viremia. Furthermore, CMV infection was never detected earlier by molecular biology assays than by antigenemia. Only 5/10 patients with CMV infection developed CMV disease. Using a cut off value of 8 cells/50,000, antigenemia was found to be the assay that better identified patients at risk of developing CMV disease. However, the kinetics of the onset of infection detected by NASBA and CMV monitor seemed to have better identified patients at risk of developing CMV disease. Furthermore, before onset of disease, CMV pp67 mRNA was found to have similar or better negative and positive predictive values for the development of CMV disease. Conclusions: The present data, suggests that the concomitant use of antigenemia and pp67 mRNA assay gives the best identification of patients at risk of developing CMV disease.

PRE-EMPTIVE THERAPY AGAINST CYTOMEGALOVIRUS DISEASE IN RENAL TRANSPLANTATION - A REALISTIC OPTION?

373 The concept of pre-emptive therapy against CMV disease requires an early indicator of CMV activity. This marker should be sensitive and specific and enable treatment before onset of disease. Eight laboratory markers were prospectively evaluated for their ability to guide pre-emptive therapy - pp65 antigenaemia (DAT), CMV IgG level, CMV IgM, Hybrid Capture assay (HCS), plasma PCR (in house PPCR, Roche Amplicor PAMP), leucocyte PCR (in house LPCR, Roche Amplicor LAMP). Patients were classified according to donor (D) and recipient (R) CMV serostatus (+ or −). 77 renal transplant recipients (D+R− 21, D−R+ 13, D+R+ 43) were followed for 12 weeks with weekly blood samples for the above tests. CMV disease was defined as confirmed organ specific illness or the presence of unexplained fever, malaise, leucopenia or thrombocytopenia in association with laboratory confirmed CMV activity. 62% (13) D+R - and 7% (4) of R+ recipients developed CMV disease (p<0.000001). In 29% D+R- recipients CMV transmission did not occur. Of the high risk category of patients (D+R−), LPCR and LAMP identified 54% and 69% of patients requiring pre-emptive therapy at a mean time of 2.3 and 8.4 days before disease onset, respectively. Plasma PCR was less sensitive (31 - 46%) and the non-PCR methods were generally positive after the onset of illness. In the low risk group (R+ groups) these markers were either not sensitive enough (DAT, IgM, IgG) or would have led to overtreatment (LPCR 35%, LAMP 50%). Viral load analysis is ongoing. Whilst none of the markers were absolutely predictive using our weekly sampling strategy, leucocyte PCRs appear to be the best and most realistic options to guide therapy in D+R- recipient. A reliable marker has yet to be found to guide therapy in the low risk recipient.

Immune reconstitution following allogeneic peripheral blood stem cell transplants.

Growth factor-mobilized peripheral blood stem cells (PBSCs) engraft rapidly in myeloablated recipients compared to conventional BM, but this procedure also mobilizes mature lymphocytes and monocytes which can impact immune reconstitution and GVHD. Hence, we serially evaluated immune reconstitution and cytokine expression in PBSCT recipients in the first year. Engraftment of neutrophils and monocytes stabilized early but NK cells, B cells and CD4+ T cell numbers were significantly (P < 0.05) low with persistently reversed CD4:CD8 ratios. NK function remained low throughout the first year. The quantitative decrease in CD4+ T cells resulted in significantly decreased proliferation in response to mitogens and alloHLA antigens. Yet, a qualitative analysis of T cell function measured by Ca++ influx after T cell activation with antiCD3 as well as T-dependent polyclonal Ig secretion by mitogen-stimulated B cells was preserved even early post transplant. TNF alpha mRNA was detected in almost all recipients in the first year. IL-10 mRNA was detected in 77%, IL-2 in 22% and IFN gamma in 44% of recipients in the first 6 months. Only 30% expressed IL-10 in the second 6 months post transplant while expression of IL-2 and IFN gamma was detected in 38% and 46% respectively. Thirty-seven percent of PBSCT recipients developed grades II-IV acute GVHD but 72% went on to develop chronic extensive GVHD at a median of 120 days. Sixty-two percent developed CMV viremia and 5.4% developed overt CMV disease in the first year post PBSCT. Lymphocyte engraftment is quantitatively delayed but CD4 functions are preserved while NK numbers and function are compromised post PBSCT. IL-10 expression decreases after the first 6 months post transplant while TNF alpha is continually expressed. The balance between quantitative lymphocyte reconstitution and qualitative lymphocyte functions as well as changes in lymphokine patterns may influence infection and GVHD and thus the clinical outcome post PBSCT.

THE IMPACT OF MYCOPHENOLATE MOFETIL (MMF) ON CYTOMEGALOVIRUS (CMV) DISEASE

597 While our group has recently shown that MMF does not increase the overall incidence of CMV infection in kidney transplant recipients, its role in CMV disease remains to be addressed. Adult kidney transplant recipients who developed CMV disease between January/1994 and June/1996, were classified according to the use of Azathioprine (AZA) or MMF, in addition to the universal use of cyclosporin A and steroids. Severity scores of CMV disease were compared using Chi-square, interval time to developing CMV disease was analyzed with Kaplan-Meier and compared with log-rank test, and categorical data was analyzed using Fisher's Exact Test. Seventeen patients on the AZA group and 12 on the MMF group developed CMV disease. Between the AZA and MMF groups there were no differences in age(mean±SD age: 43±15.4 and 41±13 years); gender(ratio male:female 9:8 and 8:4); CMV D+/R- (8/17, and 6/12), and etiology of the renal disease, respectively. Patients on AZA had more episodes of rejection (13/17 vs. 6/12) and were given OKT3 more frequently (10/17 vs. 3/12). However, patients in the MMF group had a higher frequency of organ involvement (7/12 vs. 3/17) (p=0.03), a higher severity score (5.5 vs. 4.0) (p=0.07) and a higher number of organs involved with CMV (p=0.015). In addition, there was a trend towards an earlier development of CMV disease in the MMF group (p=0.09). Conclusions from this study indicate that while MMF does not increase the overall incidence of CMV infection in renal transplant recipients, it appears to influence the rate and severity of CMV disease.

CMV Antigenemia Directed Preemptive Prophylaxis with Oral Ganciclovir for the Prevention of CMV Disease in Liver Transplant Recipients: A Prospective, Randomized, Controlled Trial

442 The efficacy of preemptive oral ganciclovir was compared with preemptive short-course intravenous ganciclovir for the prevention of CMV disease in 50 consecutive liver transplant recipients receiving tacrolimus as primary immunosuppression. Surveillance cultures (buffy coat for CMV pp65 antigenemia) were performed on all patients at 2, 4,6, 8, 12 and 16 weeks. Patients with positive CMV antigenemia during any surveillance culture were randomized to 2 groups (stratified by the recipient and donor CMV serostatus). The experimental group received oral ganciclovir for 6 weeks(2000 mg tid ×2 weeks, then 1000 mg tid ×4 weeks) and the standard group received 7 days of IV ganciclovir. Overall, CMV shedding (+ pp65 antigenemia) occurred in 28% (14/50) and CMV disease in 7% (1/14) of those who shed CMV. CMV disease (viral syndrome) occurred in 17% (1/6) of the patients receiving IV ganciclovir vs. 0% (0/8) receiving oral ganciclovir. None of the patients, in either study group, developed tissue invasive CMV disease. The median number of pp65 + cells/105 leukocytes, at first detection of CMV antigenemia, were 3 (range 1-9) in patients with reactivation and 18 (range 1-80) in those with primary CMV infection. CMV disease occurred in 0% (0/9) of patients with reactivation infection (5 who received oral ganciclovir and 4 who received intravenous ganciclovir). CMV viral syndrome developed in 1/5 (0/3 who received oral ganciclovir and 1/2 who received intravenous ganciclovir) in patients with primary CMV. In conclusion, preemptive prophylaxis based on CMV antigenemia can effectively target the patients for CMV prophylaxis. 72% (36/50) of the patients never received antiviral prophylaxis and did not develop CMV disease; antiviral therapy instituted upon detection of antigenemia prevented tissue invasive CMV in both ganciclovir groups. Preemptively administered oral ganciclovir appeared as effective as IV ganciclovir for the prevention of CMV disease after liver transplantation.

VARIABLES AFFECTING THE RISK OF CMV INFECTION OR SEROCONVERSION IN THE UNEXPOSED PEDIATRIC LIVER TRANSPLANT RECIPIENT

340 The relative low incidence of CMV in pretransplant pediatric patients in comparison to that of adults implies a higher probability of exposure and seroconversion early or late after transplantation. This study focuses on the fate of the previously unexposed pediatric recipient, and intends to determine whether post-transplant seroconversion is associated with a higher incidence of clinical CMV disease. Methods: The pretransplant recipient and donor CMV serological status was determined by detection of CMV IgG by enzyme immunoassay. The study group included 50 pediatric liver recipients ages 2 weeks to 18 years. Routine post-transplant CMV prophylaxis included gammaglobulin or ganciclovir using previously published protocols. Post-transplant CMV status was determined either following clinical findings indicative of possible CMV disease, or as part of the completion of this study. Variables to be examined included the risk of exposure, the rate of seroconversion, and the incidence of clinical CMV disease. Results: The incidence of CMV positive serologies in our pediatric population is 32% (approx. 70% in adults), and is lower in candidates under the age of 5 (19%). CMV seropositivity is high (52%) in the donor pool available for this population, and is not attributed to the increased used of reduced size grafts from seropositive adults (53%) in this series. Of the previously unexposed recipients, seroconversion is observed in 38%, and in the majority (78%), directly related to donor transmission. Of these, only a minority of the seroconverted patients were found to suffer from clinical CMV disease (22%). Conclusions: Pediatric patients under the age of 5 are at high risk for CMV exposure and seroconversion. Frequent post-transplant seroconversion occurs in the majority of these patients and is donor-related transmission or environmental exposure. Despite that, only a small group of immunosuppressed recipients develop CMV disease, a finding that may be attributed to more liberal use of prophylaxis protocols.

THE IMPACT OF MYCOPHENOLATE MOFETIL (MMF) ON CYTOMEGALOVIRUS (CMV) DISEASE.

597 While our group has recently shown that MMF does not increase the overall incidence of CMV infection in kidney transplant recipients, its role in CMV disease remains to be addressed. Adult kidney transplant recipients who developed CMV disease between January/1994 and June/1996, were classified according to the use of Azathioprine (AZA) or MMF, in addition to the universal use of cyclosporin A and steroids. Severity scores of CMV disease were compared using Chi-square, interval time to developing CMV disease was analyzed with Kaplan-Meier and compared with log-rank test, and categorical data was analyzed using Fisher's Exact Test. Seventeen patients on the AZA group and 12 on the MMF group developed CMV disease. Between the AZA and MMF groups there were no differences in age(mean±SD age: 43±15.4 and 41±13 years); gender (ratio male:female 9:8 and 8:4); CMV D+/R- (8/17, and 6/12), and etiology of the renal disease, respectively. Patients on AZA had more episodes of rejection(13/17 vs. 6/12) and were given OKT3 more frequently (10/17 vs. 3/12). However, patients in the MMF group had a higher frequency of organ involvement(7/12 vs. 3/17) (p=0.03), a higher severity score (5.5 vs. 4.0) (p=0.07) and a higher number of organs involved with CMV (p=0.015). In addition, there was a trend towards an earlier development of CMV disease in the MMF group(p=0.09). Conclusions from this study indicate that while MMF does not increase the overall incidence of CMV infection in renal transplant recipients, it appears to influence the rate and severity of CMV disease.

VARIABLES AFFECTING THE RISK OF CMV INFECTION OR SEROCONVERSION IN THE UNEXPOSED PEDIATRIC LIVER TRANSPLANT RECIPIENT

340 The relative low incidence of CMV in pretransplant pediatric patients in comparison to that of adults implies a higher probability of exposure and seroconversion early or late after transplantation. This study focuses on the fate of the previously unexposed pediatric recipient, and intends to determine whether post-transplant seroconversion is associated with a higher incidence of clinical CMV disease. Methods: The pretransplant recipient and donor CMV serological status was determined by detection of CMV IgG by enzyme immunoassay. The study group included 50 pediatric liver recipients ages 2 weeks to 18 years. Routine post-transplant CMV prophylaxis included gammaglobulin or ganciclovir using previously published protocols. Post-transplant CMV status was determined either following clinical findings indicative of possible CMV disease, or as part of the completion of this study. Variables to be examined included the risk of exposure, the rate of seroconversion, and the incidence of clinical CMV disease. Results: The incidence of CMV positive serologies in our pediatric population is 32% (approx. 70% in adults), and is lower in candidates under the age of 5 (19%). CMV seropositivity is high (52%) in the donor pool available for this population, and is not attributed to the increased used of reduced size grafts from seropositive adults (53%) in this series. Of the previously unexposed recipients, seroconversion is observed in 38%, and in the majority (78%), directly related to donor transmission. Of these, only a minority of the seroconverted patients were found to suffer from clinical CMV disease (22%). Conclusions: Pediatric patients under the age of 5 are at high risk for CMV exposure and seroconversion. Frequent post-transplant seroconversion occurs in the majority of these patients and is donor-related transmission or environmental exposure. Despite that, only a small group of immunosuppressed recipients develop CMV disease, a finding that may be attributed to more liberal use of prophylaxis protocols.

GANCICLOVIR PROPHYLAXIS IS MORE EFFECTIVE THAN INTRAVENOUS IMMUNOGLOBULIN(IVIG) IN PREVENTING CYTOMEGALOVIRUS (CMV) DISEASE IN RENAL TRANSPLANT RECIPIENTS

605 CMV disease is the most important infectious complication in renal transplantation that is associated with increased morbidity and mortality. We compared the effectiveness of two different prophylactic protocols(Ganciclovir vs IVIG) against CMV disease in renal transplant recipients. Sixty-nine renal transplant recipients at risk of developing CMV disease were identified retrospectively. These were CMV- recipients of CMV + donor kidneys (R-D+) and CMV + recipients of either CMV + (R+D+) or CMV-(R+D-) donor kidneys who received immunosuppression with antilymphocyte globulin. Patients received either IVIG(n=42) or Ganciclovir (n=30) prophylaxis. IVIG (GAMMAR, ARMOUR, Kankakee, IL) dose was 500mg/kg at weeks 1, 2, and 4 post transplant, then 250mg/kg wks 6 and 8. Ganciclovir was given during hospital stay and in conjunction with antilymphocyte therapy at a dose of 2.5mg/kg every 1-3 days depending on serum creatinine. All patients received Acyclovir 600-3200 mg/day depending on weight and serum creatinine for 12 weeks post transplant. CMV disease was defined as CMV + buffy coat plus any 2 combinations: Leukopenia<3000 mm3, fever > 38 °C for > 3 days, increased liver function tests, tissue involvement on biopsy (renal, bronchial, etc.) Incidence of CMV disease was as follows: TableThese data demonstrate that Ganciclovir is more effective than IVIG in the prevention of CMV disease in high risk renal transplant patients (R-D+).

Screening for CMV-specific T cell proliferation to identify patients at risk of developing late onset CMV disease.

Thirty patients undergoing allogeneic BMT were screened post-transplant together with their marrow donors for CMV-specific T cell proliferation and the occurrence of CMV disease. Twenty-one of these patients received a marrow transplant from an HLA-matched sibling donor, and nine from an HLA-matched unrelated donor. All these patients were either CMV seropositive and/or had received a transplant from a CMV-seropositive donor. Patients were monitored for CMV-viraemia until day +100 post-BMT by PCR and virus culture, and thereafter by virus culture only when clinically indicated. The proliferative T cell response was investigated at regular monthly intervals beginning on day +30. A proliferative response to HCMV (median, day +123) was documented in these patients between day +37 and +730 post-BMT. None of the patients with a documented CMV-specific T cell proliferation on day 120 (n = 17) developed CMV disease in the later post-transplant period, but of the patients lacking CMV-specific proliferation (n = 13), 30.8% developed CMV disease after day 120. Thus, patients lacking a CMV-specific T-helper cell response might benefit from sensitive screening for CMV infection and pre-emptive therapy after day +100.

Clinical strategies for the management of cytomegalovirus infection and disease in allogeneic bone marrow transplant.

Four clinical strategies are proposed for the management of CMV disease: prophylaxis, suppression, pre-emptive therapy and treatment. The degree of risk of developing CMV disease and the safety profile of the presently available drugs need to be considered when deciding on the most appropriate approach. We conclude that a prophylactic strategy employing a drug with a safe toxicity profile followed by pre-emptive treatment with an effective antiviral drug for failure of prophylaxis gives the best outcome in allogeneic HLA matched bone marrow transplant recipients.