Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients

BACKGROUND: Treatment with prophylactic oral acyclovir, intravenous ganciclovir, or immunoglobulins to prevent cytomegalovirus (CMV) infection and disease in renal transplantation is associated with variable efficacy and significant expense. We studied control of CMV in renal transplant recipients using either prophylactic oral ganciclovir or deferred therapy with intensive monitoring with polymerase chain reaction (PCR) analysis. METHODS: Forty-two recipients were followed for 6 months after transplantation. Ganciclovir (1000 mg p.o. t.i.d.; n=19) or acyclovir (200 mg p.o. b.i.d.; n=23) was begun at transplantation and continued for 12 weeks. PCR for CMV was performed on buffy-coat specimens every week for 15 weeks and at months 5 and 6. RESULTS: No patients in the ganciclovir group, compared with 14 of 23 patients (61%) in the deferred-therapy group (P<0.0001), developed CMV disease during the first 12 weeks. In the ganciclovir group, 4 of 19 patients (21%) subsequently experienced 5 episodes, whereas 14 patients in the deferred-therapy group experienced 18 episodes (P=0.013 for subjects and P=0.026 for episodes). The time to disease was also delayed in the ganciclovir group compared with the deferred-therapy group (133+/-17 days vs. 51+/-7 days; P<0.0001). Oral ganciclovir also prevented CMV viremia during prophylaxis (2/19 patients [11%] vs. 23/23 patients [100%]). Time to CMV viremia was delayed in the ganciclovir group; however, 13/19 patients (68%) ultimately showed PCR evidence for CMV viremia (P=0.005). CONCLUSIONS: An initial 12-week course of oral ganciclovir prevents CMV disease and infection in renal transplant recipients during prophylaxis, and the benefits persist after discontinuation.     

A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients

BACKGROUND: Posttransplantation cytomegalovirus (CMV) infection remains a significant cause of morbidity in kidney transplant recipients. We performed a randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for CMV prophylaxis in a group of renal allograft recipients considered at high risk for CMV disease due to the use of OKT3 induction therapy. METHODS: A total of 101 recipients of cadaveric (83) and zero haplotype-matched live donor (18) kidney transplants were entered into the trial. A total of 22 D-R- patients received no prophylaxis. Twenty-seven D+R-, 29 D+R+, and 23 D-R+ patients were randomized to receive 3 months of either oral acyclovir (800 mg q.i.d.) or oral ganciclovir (1000 mg t.i.d.). Doses were adjusted according to the level of renal function. The D+R- patients were also given CMV immune globulin biweekly for 16 weeks. Surveillance blood cultures were obtained at transplantation, at months 1, 2, 3, and 6, and when clinically indicated. The primary study end points were time to CMV infection and disease the first 6 months after transplantation. RESULTS: The mean follow up was 14.4 months. Both agents were well tolerated, and no drug interruptions for toxicity occurred. CMV was isolated in 14 of 39 (35.9%) acyclovir-treated and 1 of 40 (2.5%) ganciclovir-treated recipients by 6 months (P=0.0001). Symptomatic CMV disease occurred in 9 of 14 (64%) of the acyclovir patients, two with tissue-invasive disease. Infection rates for acyclovir vs. ganciclovir, respectively, stratified by CMV serology were: D+R-, 54 vs. 0%, P=0.0008; D+R+, 43 vs. 6.6%, P=0.01; D-R+, 8.3 vs. 0%, P=NS. No patient developed CMV infection while taking oral ganciclovir, however three delayed infections occurred 2-7 months after finishing therapy. Each patient had been previously treated for acute rejection. CONCLUSIONS: Oral acyclovir provides effective CMV prophylaxis only for recipients of seronegative donor kidneys. Oral ganciclovir is a superior agent providing effective CMV prophylaxis for recipients of seropositive donor kidneys. Recipients who are treated for acute rejection are at risk for delayed CMV infection during the first posttransplantation year.     

Cytomegalovirus preemptive therapy with ganciclovir in renal transplant patients treated with OKT3

In an attempt to decrease the prevalence and severity of cytomegalovirus (CMV) disease, preemptive therapy with ganciclovir was administered to all renal transplant patients treated with OKT3 between February 1993 and December 1994 (26 patients). The results were compared with those of a historical group treated with OKT3 but not with ganciclovir (29 patients). Both groups were similar in age, sex, number of previous transplants, number of rejections, serological status of donor and recipient and OKT3 dose. Ganciclovir was administered during the period of treatment with OKT3. Only 2 (7.7%) treated patients developed CMV disease versus 11 (37.9%) of the control group (p = 0.01). In the control group the intensity of the disease was severe in 7 (63.6%) cases, whereas in the treated patients it was always of slight intensity (p = 0.01). In conclusion, preemptive therapy with ganciclovir during treatment with OKT3 decreases the prevalence and severity of CMV disease.     

Self-inflicted intramyocardial injury with a sewing needle: a rare cause of pneumothorax

Ganciclovir susceptibilities and UL97 sequences were analyzed in 20 cytomegalovirus (CMV) isolates recovered from 15 bone marrow transplant recipients with active CMV infection after prophylaxis with acyclovir (group I; 12 isolates) or after acyclovir prophylaxis followed by ganciclovir therapy (group II; 8 isolates). All group I isolates were susceptible to ganciclovir. Five group II isolates were susceptible to ganciclovir, and 3 isolates (all from the same person) were resistant to ganciclovir (IC50 > 12 microM). Ganciclovir resistance UL97 mutations were found in 4 group II isolates, including a ganciclovir-susceptible isolate obtained from 1 patient after 41 days of therapy with ganciclovir and 3 ganciclovir-resistant isolates obtained from another patient after 73, 116, and 132 days of treatment with ganciclovir. Ganciclovir-resistant CMV isolates may emerge rapidly in bone marrow transplant recipients who are treated with ganciclovir after receiving prophylaxis with acyclovir.     

Psychiatric diseases presenting as infectious diseases

BACKGROUND: Cytomegalovirus (CMV) disease is an important cause of organ transplant-related morbidity and mortality. During the last 5 years at our institution, prophylactic ganciclovir and hyperimmune globulin have been routinely administered to lung transplant recipients whenever the donor or the recipient was CMV antibody-positive. We sought to assess the efficacy of prophylaxis on viremia, CMV disease, and bronchiolitis obliterans syndrome (BOS). METHODS: A retrospective chart review of 61 consecutive lung transplants performed between recipients between January 1993 and August 1995 was performed. Fifty-six patients who survived at least 1 month were analyzed. Patients were considered at risk for CMV disease whenever pretransplant donor or recipient serology was positive. RESULTS: Fourteen of the 39 patients at risk (36%) had viremia while on prophylaxis. The rate of CMV disease was 13% during the first 6 months following transplantation. A donor whose CMV serology was positive appeared to increase the risk of BOS in a Cox regression model (relative risk=2.4; 95% confidence interval=0.86-6.74; p=0.0957). Neither age, CMV infection (viremia or a positive specimen from BAL), recipient's serology at the time of transplantation, or CMV disease was associated with BOS. None of these variables was associated with mortality on Cox regression analysis or univariate analysis. CONCLUSIONS: Administration of combination ganciclovir and hyperimmune globulin prophylactic therapy to lung transplant recipients at risk for CMV infection and disease is associated with a relatively low incidence of disease, which appears only after prophylaxis treatment with ganciclovir is completed. Ganciclovir prophylaxis does not prevent CMV viremia; however, viremia while on prophylaxis is not predictive of disease.     

Strategies for the prevention of cytomegalovirus disease after marrow transplantation

The purposes of this review are to examine the epidemiology of disease due to cytomegalovirus (CMV) in recipients of autologous and allogeneic marrow transplants and to compare different antiviral regimens used for the prevention of such disease in recipients of allogeneic marrow transplants, with an emphasis on ganciclovir. In seven studies, ganciclovir reduced the incidence of CMV infection and disease after allogeneic marrow transplantation. In one study mortality after transplantation was reduced because of a decreased rate of CMV-related death among ganciclovir-treated patients. Ganciclovir was effective when given to all CMV-seropositive patients (prophylaxis) or to patients who were considered at high risk for CMV disease on the basis of a positive surveillance culture (early treatment). The effectiveness of ganciclovir for the prevention of CMV infection and disease is limited by drug-induced neutropenia. Experience with other antiviral agents, such as foscarnet, has been limited. Initial studies of the adoptive transfer of CMV-specific CD8+ cytotoxic T cells have been conducted. In short, ganciclovir is currently effective for the prevention of CMV disease in allogeneic marrow transplant recipients, but its usefulness is limited by neutropenia. Future studies must be aimed at confining the toxicity of ganciclovir to patients at the highest risk for CMV disease.     

Quantitative polymerase chain reaction to predict occurrence of symptomatic cytomegalovirus infection and assess response to ganciclovir therapy in renal transplant recipients

Cytomegalovirus (CMV) DNA levels were measured by quantitative-competitive polymerase chain reaction (PCR) in weekly leukocyte samples from 50 renal transplant recipients, including 23 with symptomatic and 27 with asymptomatic CMV infection. Peak and week 4 CMV DNA levels were higher in symptomatic subjects (P = .07 and .02, respectively). In a logistic regression model, the logarithm of the week 4 level independently predicted symptomatic infection (odds ratio, 1.78 for a 1 log10 increase; 95% confidence interval, 1.14-2.78; P = .01). All subjects whose week 4 level exceeded 1000 copies/100,000 leukocytes developed symptoms. In subjects with adequate samples for analysis, CMV levels declined exponentially with ganciclovir treatment, with an average half-life of 3.3 days. Levels exceeding 10,000 copies were associated with prolonged time to clearing of CMV DNA. Potential clinical applications of quantitative CMV PCR include predicting occurrence of symptomatic first episodes after transplantation and individualizing duration of antiviral therapy.     

Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation

Cytomegalovirus (CMV) infection is associated with an increased incidence of other opportunistic infections in organ transplant recipients. Whether this is related to immunomodulating effects of CMV or independent of CMV but associated with a host risk factor common to both infections is unclear. The purpose of this study was to determine whether the reduction in CMV infections seen with prophylactic ganciclovir treatment after heart transplantation is associated with a reduced incidence of other opportunistic infections. Of 149 patients prospectively enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of ganciclovir to prevent CMV disease, 74 patients enrolled at this center (33 control and 41 ganciclovir-treated) were retrospectively identified. All received prophylactic OKT-3 and standard 3 drug maintenance immunosuppressive therapy. Actuarial survival and rejection rates and incidence of opportunistic infections (bacterial, fungal, and protozoal) for the 2 treatment groups were determined and compared using Cox-Mantel analysis. CMV disease occurred 2.5 times more frequently in the control group. There were no significant differences in survival or rejection rates nor in bacterial or protozoal infection incidence between the 2 groups. Bacterial infections occurred in 54% of control and 39% of ganciclovir-treated patients (P = 0.18). There were significantly fewer fungal infections in the ganciclovir-treated group (7% vs. 27%, P = 0.0071). CMV and fungal infections were both significantly reduced in patients who received ganciclovir prophylaxis. This suggests that active CMV disease may be causally associated with the development of opportunistic fungal infections.     

Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (CMV) disease in CMV high-risk renal transplant recipients

Recent studies showed contradictory results concerning the efficacy of oral acyclovir in the prevention or amelioration of cytomegalovirus (CMV) disease after renal transplantation (TX). This study evaluated the incidence and severity of CMV disease within the first year after TX in high-risk renal transplant recipients (CMV-seropositive donor, seronegative recipient) treated prophylactically with oral acyclovir (800 to 3200 mg/day) over a period of 12 wk (ACY, N = 22), compared with high-risk patients randomly assigned as controls (CO, N = 10). Follow-up for CMV infection included serological determination of CMV-specific immunoglobulin G and immunoglobulin M antibodies, antigen detection in peripheral blood leukocytes (PP 65), shell vial culture (blood), and virus isolation/early antigen detection (urine). Severity of CMV disease was quantified by a scoring system for CMV-related symptoms. Nine patients (40.1%) in the acyclovir group and four patients (40%) in the control group developed CMV disease. Neither severity (ACY, 11.4 versus CO; 12.5 points score), nor duration of disease (ACY, 21 days; CO, 22 days), nor transplant function at the end of the observation period differed significantly. The onst of CMV disease was not delayed significantly in acyclovir-treated patients compared with controls (ACY, 47 +/- 34 days versus CO, 27 +/- 14 days after TX, not significant). Our results show no beneficial effect of oral acyclovir prophylaxis in CMV high-risk renal transplant recipients.     

Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. Prior work suggested that a peripheral blood monitoring strategy detecting peripheral B lymphoproliferation was effective in the early diagnosis of PTLD among 7 of 179 (3.9%) consecutive transplant recipients. Each of those seven patients received at least one course of antithymocyte globulin, Minnesota antilymphocyte globulin, or OKT3 before developing PTLD. METHODS: To determine whether antiviral prophylaxis might reduce the incidence of PTLD, a subsequent group of 198 consecutive recipients received either ganciclovir or acyclovir during antilymphocyte antibody administration. When the donor or recipient were cytomegalovirus-seropositive, ganciclovir was given; acyclovir was used when both were cytomegalovirus-seronegative. Baseline and protocol posttransplant cell surface profiles were obtained using immunofluorescence and flow cytometry to detect T cells, lymphocyte activation markers, and the CD19 B cell antigen. RESULTS: Demographic factors, including the incidence of recipients more than 50 years of age, non-Caucasians, previous transplantation, and diabetes mellitus, were similar in both groups. Additionally, the number of patients receiving antilymphocyte preparations was similar. However, only one patient (0.5%) from the latter group who received preemptive antiviral therapy developed PTLD. Although elevations in CD19+ B cells preceded clinical PTLD among each of the seven earlier patients, evidence of peripheral B cell proliferation was not demonstrated for the sole patient from the latter group, which suggests a possible effect of antiviral therapy. CONCLUSIONS: Prophylactic antiviral therapy may reduce the sensitivity of peripheral monitoring for B lymphoproliferation, but the dramatic reduction in PTLD incidence strongly supports its use among transplant recipients at risk.     

Randomized comparison of ganciclovir plus intravenous immune globulin (IVIG) with IVIG alone for prevention of primary cytomegalovirus disease in children receiving liver transplants

A randomized placebo-controlled trial was conducted to determine the benefit of ganciclovir (5 mg/[kg x d]) for 30 days in addition to intravenous immune globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV) disease in children receiving liver transplants. Patients were monitored for 6 months after transplantation. The two groups of patients (recipients of 29 ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of age, sex, and underlying disease. The incidence of CMV disease among the ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%, respectively, and the time to disease in these recipients was 46 days and 32 days, respectively. There was no difference between groups in terms of survival; episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents; and incidence of leukopenia or thrombocytopenia. These results suggest that a 4-week course of ganciclovir with IVIG is not more effective than IVIG alone for prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir may delay the onset of CMV disease, further studies with a longer course of ganciclovir prophylaxis are warranted.     

Experimental syringomyelia: late ultrastructural changes of spinal cord tissue and magnetic resonance imaging evaluation

Seroprevalence for CMV varies from 70% in the general population to more than 90% in HIV infected patients. Immunodepression whatever its origin, either post therapeutic as in transplant recipients, or induced by HIV, leads to the reactivation of this virus, present in a latent form in the host. In CMV-seronegative patients, the main prevention is based on donor matching before a graft (graft of seronegative donor) and on the use of seronegative blood products or deleukocyted blood. Since the availability of efficient strategies of prophylaxis (before infection) or of early treatment (pre-emptive therapy), CMV disease is now infrequent in most transplantation centers. A real prophylaxis with ganciclovir is usually selected in high risk patients (lung, bone marrow transplants in case of a CMV seropositive recipient or seronegative but with a seropositive donor). It has replaced in most centers aciclovir that has only a modest efficacy. A pre-emptive therapy by ganciclovir is proposed in case of lower risk of CMV disease (kidney, liver or heart transplants) or if the local virology laboratory provides sensitive virological markers to detect the first signs of CMV reactivation. Besides viremia or pp65 antigenemia, currently used to initiate a pre-emptive therapy, the standardisation of other virological markers such as leukocytic or plasmatic PCR is in progress. The prophylaxis of CMV disease in less developed for HIV infected patients. Immunosuppression, continuously progressing in absence of antiretroviral agents, requires a continuous prophylaxis for months or years, treatment that is difficult to propose at the present time considering the modest activity of oral ganciclovir, the only oral agent available. Future progresses in this field will be obtained when a sensitive and reproductible CMV marker will allow to identify the patients at highest risk of CMV disease, and with new anti-CMV agents having a good oral bioavailability.     

Comparative study of cytomegalovirus (CMV) antigenemia assay, polymerase chain reaction, serology, and shell vial assay in the early diagnosis and monitoring of CMV infection after renal transplantation

BACKGROUND: Early diagnosis of cytomegalovirus (CMV) infection, which is an important cause of morbidity and mortality in renal transplant recipients, remains of great importance. This prospective study was performed in kidney transplant recipients to determine the diagnostic value of the CMV antigenemia assay in comparison with polymerase chain reaction (PCR), serology, and shell vial assay. METHODS: Seventy-five consecutive renal transplant recipients were enrolled in this study and monitored by both antigenemia assay and serology. The initial 34 of the 75 patients were subjected to PCR and shell vial assay. RESULTS: Antigenemia, PCR, and shell vial assay became positive before the onset of CMV-related symptoms in 31/34 (89%), 13/16 (81%), and 2/16 (13%), respectively. None of the 34 patients who had symptomatic CMV disease showed a significant increase in IgG or IgM before the onset of symptoms. Antigenemia and PCR assays turned positive, 7 and 11 days (median), respectively, before the onset of clinical symptoms. Serology and shell vial assay became positive 21 and 25 days (median), respectively, after the onset of CMV-related clinical symptoms. To examine the clinical value of these assays, "good correlation" was defined based on the correlation between the clinical course and the results of the assays. Good correlation with the antigenemia assay was observed in 33 (96%) out of 34 renal transplant recipients who recovered from their CMV disease after ganciclovir therapy. Only one of 16 (7%) patients showed good correlation by shell vial assay, whereas PCR and serology did not show a good correlation. Consequently, antigenemia was considered the best way to monitor CMV infections after kidney transplantation. CONCLUSIONS: Only the CMV antigenemia assay can be successfully employed after renal transplantation for the early diagnosis and extensive monitoring of active CMV infection.     

Use of laboratory assays to predict cytomegalovirus disease in renal transplant recipients

Eight laboratory assays, viz., the pp65 direct antigenemia test, a quantitative cytomegalovirus (CMV)-specific immunoglobulin G (IgG) assay (Biomerieux VIDAS), a CMV-specific IgM assay (Biomerieux VIDAS), the Hybrid Capture system (Murex), an in-house PCR with plasma (P-PCR) and leukocytes (L-PCR), and a commercial PCR (Roche AMPLICOR) with plasma (P-AMP) and leukocytes (L-AMP), were compared for their abilities to predict CMV disease before the onset of illness in a prospective study of 37 renal transplant recipients. By using an expanded criterion for active infection (two or more of the markers positive) and a clinical definition of disease, 22 (59%) patients were identified as having active CMV infection and 13 (35%) were identified as having CMV disease. Of the 13 CMV-seronegative recipients who received seropositive kidneys (R- group), 8 had active infection and disease. All assays were 100% specific and 100% predictive of CMV disease in the R- group. The leukocyte PCRs (L-PCR and L-AMP) were the most sensitive assays, had positive results an average of between 8 and 13 days before the onset of illness, and were the assays of choice. The performance of the assays was less satisfactory for the 24 patients who were CMV seropositive before transplantation (R+ group). A negative result was more useful for this group. Overall, P-AMP had the best results, and it could be the assay of choice for monitoring R+ patients. The non-PCR-based methods generally had high specificities but often gave late positive results and were not sensitive enough for use as prediction tools for either group of patients.     

Quantitation of cytomegalovirus: methodologic aspects and clinical applications

Cytomegalovirus (CMV) is an important pathogen in transplant recipients and human immunodeficiency virus (HIV)-infected individuals. Major progress has been made in developing quantitative detection methods for CMV in recent years. Due to their high sensitivity, these assays can detect CMV early, and quantitation may be useful in predicting the patient's risk for disease and in monitoring the effect of antiviral therapy. This review discusses methodological aspects of currently used quantitative assays for CMV (i.e., viral culture techniques, antigen detection assays, DNA detection assays including PCR, branched-DNA assay, and the DNA hybrid capture assay) and addresses the correlation of systemic and site-specific CMV load and CMV disease in different populations of immunosuppressed patients as well as the response to antiviral treatment. To date, direct antigen detection and molecular techniques have largely replaced traditional culture-based techniques for CMV quantitation. In general, a high systemic CMV load is correlated with CMV disease. This correlation is strong in the HIV-infected population and in solid-organ transplant recipients but less clear in allogeneic marrow transplant recipients. Measuring the viral load at specific anatomic sites may be an alternative way to assess disease activity in situations where the systemic viral load correlates poorly with disease activity. A reduction of the systemic CMV load also correlates with a response to antiviral treatment, but more research is needed to evaluate the role of viral load as a surrogate marker for drug resistance. Due to the widespread use of quantitative CMV detection techniques to direct and monitor antiviral treatment, there is a great need for an assessment of the reproducibility of test results and better standardization of the assays.     

Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients

This study was designed to investigate the interaction between high-dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open-label, randomized, three-period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration-time curve (AUC0-12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady-state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.     

Evolution of the Sry genes

Cytomegalovirus (CMV) infection is a major cause of morbidity and occasionally of mortality in immunosuppressed allograft recipients. At the University of Cincinnati Medical Center, ganciclovir has been administered for the prevention of CMV infection since July 1992. Forty-six recipients of cadaveric renal allografts (Group I) received ganciclovir at a dose of 2.5 or 5 mg/kg/day (adjusted for renal function) for 14-21 days, during induction treatment and during antirejection treatment with monoclonal or polyclonal antilymphocyte preparations. In this retrospective study, these 46 patients were compared with 77 recipients of cadaveric renal allografts transplanted prior to July 1992 (Group II) for the prevalence, severity and time of CMV occurrence after transplantation. CMV diagnosis was based on clinical evaluation and was confirmed by blood cultures, CMV antigen immunofluorescence assay and/or histology. Patients were stratified according to CMV serology (+) or (-) in donor and recipient. CMV infection developed in 16 of 46 (35%) patients in Group I vs. 27 of 77 (35%) patients in Group II (p = 0.97). A total of 25 episodes of CMV infection occurred in Group I compared to 44 in Group II (p = 0.76). CMV infection was diagnosed an average of 97.4 days after transplant in Group I compared to 48.3 days in Group II (p = 0.0003). Tissue-invasive CMV infection occurred in 3 patients in Group I (19%) vs. 12 in Group II (44%) (p = 0.5). In conclusion, ganciclovir prophylaxis resulted in a delayed onset of clinical CMV infection with a trend towards less severe infection in patients treated with antilymphocyte antibody preparations.     

Diagnosis of cytomegalovirus infections by shell vial assay and conventional cell culture during antiviral prophylaxis

A total of 3,552 specimens for conventional cytomegalovirus (CMV) culture and shell vial assay for CMV immediate-early antigen were obtained during a prospective randomized trial for prophylaxis of CMV disease after liver transplantation. Prophylaxis with ganciclovir for 2 weeks and then high-dose acyclovir for 2.5 months was compared with high-dose acyclovir alone for 3 months. During the first 12 weeks after transplantation, when the patients were on prophylaxis, there were significantly more clinical samples positive by the shell vial assay and negative by standard culture in comparison with the number of samples obtained from weeks 13 to 24, after prophylaxis was discontinued, that were positive by the shell vial assay and negative by standard culture. In contrast, significantly fewer samples were positive by both the shell vial assay and standard culture during the first 12 weeks compared with the number obtained 13 to 24 weeks after transplantation that were positive by both methods. Samples positive by the shell vial assay only were obtained significantly more frequently from patients with asymptomatic than symptomatic CMV infections, while samples positive by both methods were obtained significantly more often from patients with symptomatic CMV infection. It was concluded that antiviral prophylaxis with high-dose acyclovir or ganciclovir and then high-dose acyclovir and asymptomatic CMV infection are associated with a decrease in the level of CMV isolation by standard cell culture in comparison with that by the shell vial assay.     

Unesterified cholesterol content of human sperm regulates the response of the acrosome to the agonist, progesterone

A prospective virologic follow-up of solid organ transplant patients was designed to determine the usefulness of antigenemia and viremia as virologic markers for the diagnosis of cytomegalovirus (CMV) infections, and also for monitoring CMV disease and therapy control. A total of 629 blood samples from 127 patients (60 liver, 47 kidney, and 20 heart transplant recipients) were studied by tube and shell vial cultures, and by antigenemia assay. This later was carried out by an indirect immunofluorescent assay method for formalin-fixed cytospin slides containing 2 x 10(5) leukocytes, using a monoclonal antibody directed against the CMV pp65 antigen. CMV was detected by at least one of the three methods in 238 specimens (37.8%) from a total of 63 patients. The antigenemia assay was positive in 215 (90.3% of positive samples). A total of 94 samples were detected only by this marker, which occurred either in samples with low positive counts (70.2% with antigenemia counts < 10 positive cells/10(5) leukocytes) or in specimens from treated patients. There were 30 episodes of CMV disease in 23 patients. Antigenemia was positive in all these episodes, 27 of them with counts > 20 positive cells/10(5) leukocytes. With this cut-off, positive and negative predictive values for symptomatic CMV infection were 100% and 97.2%, respectively. The antigenemia assay is a rapid, sensitive, specific, and early marker of CMV infection in transplantees. Cultures became negative with antiviral therapy while remaining antigenemia detectable. There was an association between highest quantitative antigenemia test results and clinical symptoms in our patients. In its quantitative version, the assay is useful to detect symptomatic infection and appears to be a helpful tool in managing patients at risk and in guiding antiviral therapy.     

Management of posttransplant lymphoproliferative disease in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) after pediatric liver transplantation has been associated with high mortality rates. METHODS: The present study examined 282 consecutive pediatric liver transplant recipients from October 1989 to June 1996 who received primary tacrolimus immunosuppression. The aim was to determine the incidence of PTLD, management strategies, and patient outcome. RESULTS: The incidence of PTLD was 13% (361282) with a mean age of 5.5+/-0.7 years (range 0.6 to 15) at diagnosis. The average time from transplantation to PTLD was 10.1+/-2.1 months. Initial treatment of PTLD consisted of reduction (3 patients) or discontinuation (33 patients) of tacrolimus and initiation of antiviral therapy (intravenous ganciclovir, 14 patients; intravenous acyclovir, 22 patients; or both, 5 patients). Alpha-interferon was used in four patients (two successfully). One patient also received gamma-interferon, chemotherapy, and radiation for a central nervous system lesion. Chemotherapy was also used in one patient with Burkitt's, whereas one patient with a pulmonary lesion received additional radiation therapy. Three patients received supportive surgery for gastrointestinal involvement, and one patient had a splenectomy for hemolysis. Overall mortality was 22% (8/36) with 5 (14%) PTLD-related deaths (disseminated disease, 4 patients; bowel perforation, 1 patient). Of 31 survivors, 23 had acute rejection at a median time of 24 days after PTLD, with 2 patients developing chronic rejection. One patient required retransplantation. Present immunosuppression consists of tacrolimus monotherapy in 14 patients, tacrolimus/prednisone in 8 patients, and none in 6 patients. CONCLUSION: In summary, PTLD can be successfully treated with reduction of immunosuppression and administration of antiviral agents in most patients. The management of rejection after PTLD requires reassessment of disease status and judicious reintroduction of immunosuppression therapy.