Surveillance of cytomegalovirus (CMV) DNAemia in pediatric allogeneic stem cell transplantation: incidence and outcome of CMV infection and disease.

Cytomegalovirus (CMV) remains a serious problem after hematopoietic stem cell transplantation (HSCT). To investigate the incidence of CMV infection and outcome we retrospectively analyzed 70 consecutive pediatric allogeneic HSCTs monitored by CMV polymerase chain reaction (PCR), with at least 1-year follow-up or until death. All patients at risk for CMV infection (CMV-seropositive patients and CMV-seronegative recipients transplanted from CMV-seropositive donors) received hyperimmune anti-CMV globulins whereas in the group of HSCT patients with both donor and recipient CMV negativity, polyvalent immunoglobulins were given, both at a dose of 400 mg/kg. All patients received acyclovir at prophylactic doses for at least 6 months. Patients were monitored twice a week by CMV PCR. Patients with 2 positive results for CMV DNAemia received ganciclovir for 14 days and continued until 2 consecutive negative results were obtained. The incidence of CMV DNAemia was 12.8% (9/70) in the whole group, with significant higher risk for patients with CMV-seropositive recipient status, 8 out of 22 (36%), vs. patients with seronegative status, 1 out of 48 (2%) (P=0.0002). Three out of 9 patients with DNAemia developed CMV disease despite adequate preemptive treatment. The transplant-related mortality was higher in the CMV-seropositive recipient group (P=0.05). Age, use of hyperimmune anti-CMV globulins at a high dose, and the low incidence of graft-versus-host disease might be contributing factors to this low incidence.     

Cytomegalovirus infection in lung transplant patients: the role of prophylaxis and recipient-donor serotype matching

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in lung transplant recipients. We investigated the incidence of CMV infection in relation to CMV prophylaxis, and recipient-donor CMV serotype, in a cohort of 250 consecutive lung transplant recipients. All patients received 3 months CMV prophylaxis with acyclovir (n = 67) or gancyclovir (n = 183). Recipient-donor CMV serotype matching was performed in patients receiving acyclovir: R+/D+(n = 38), R+/D-(n = 10), R-/D+(n = 1), R- /D-(n = 16), unknown (n = 2). Recipient-donor CMV serotype matching was not performed in patients receiving gancyclovir: R+/D+(n = 71), R+/D-(n = 42), R-/D+(n = 38), R-/D-(n = 31), unknown (n = 1). The overall incidence of CMV infection was 51% (n = 34) in the acyclovir group, and 42% (n = 77) in the gancyclovir group (p = 0.14). During the first 9 months after transplantation, the rate of CMV infection was higher in the acyclovir group (42%) compared with the gancyclovir group (30%) (p = 0.005). Multivariate analysis demonstrated the incidence of CMV infection during the first 9 months was higher for acyclovir prophylaxis (p<0.001) and R-/D+ serostatus (p<0.001) and lower with R-/D- serostatus (p = 0.02). In conclusion, gancyclovir significantly delays the onset of first CMV infection among lung transplant patients. CMV surveillance and choice of prophylaxis may be modified according to donor-recipient CMV serotype.     

High incidence of ganciclovir-resistant cytomegalovirus infection among lung transplant recipients receiving preemptive therapy.

Preemptive antiviral therapy in transplant patients is thought to be less likely to lead to antiviral resistance than is routine prophylaxis. Cytomegalovirus (CMV)-seropositive lung transplant patients (R+) were assigned to receive pp65 antigen-guided ganciclovir therapy, and seronegative recipients of organs from seropositive donors (D+/R-) were assigned to receive initially preemptive and then routine ganciclovir prophylaxis. The incidence of infection with ganciclovir-resistant (ganR) CMV was assessed retrospectively. GanR CMV infection developed in 4 (9%) of 45 patients, at a median of 4.4 months (range, 3.1-6.6 months) after transplantation, and was more common among D+/R- patients than among R+ patients (3 of 11 vs. 1 of 34; P =.04). The incidence among patients who received preemptive therapy was similar to that among patients who received routine prophylaxis. All ganR isolates contained a UL97 mutation. GanR CMV infection occurs in nearly 10% of lung transplant recipients, despite preemptive antiviral therapy, and is more common among D+/R- patients.     

A comparison of prophylactic vs pre-emptive ganciclovir to prevent cytomegalovirus disease after T-depleted volunteer unrelated donor bone marrow transplantation

The prophylactic and pre-emptive use of ganciclovir (GCV) both reduce significantly the incidence of CMV disease after sibling BMT but it is unclear which of these strategies is best for volunteer unrelated donor (VUD) BMT patients. We reviewed 49 consecutive patients, who received a T-depleted VUD BMT (from March 1990 to March 1996) for the treatment of CML in chronic phase, and were CMV seropositive before transplant or had a CMV seropositive donor. Patients were conditioned with cyclophosphamide (120 mg/kg for 2 days) and total body irradiation (13.2-14.4 Gy). Prophylaxis for GVHD was cyclosporin A and methotrexate with ex vivo or in vivo T cell depletion. Twenty-seven patients received pre-emptive GCV if CMV infection was detected by short-term culture before day +120 post BMT. Twenty-two patients received prophylactic GCV from engraftment until day +120 post BMT. The probabilities of CMV infection and disease occurring by 1 year post-BMT were greater in the pre-emptive GCV group than in the prophylactic GCV group (73.8% and 64.0% vs 53.1% and 30.0%, respectively; P=0.04 and 0.07). The incidence of death from CMV disease was similar in both groups (3/12 (25%) vs 3/10 (30%), respectively) and there was no difference in 1 year survival (55.6% vs 54.2%, respectively). New strategies are urgently required for the prevention of CMV disease after T-depleted VUD BMT.     

Cytomegalovirus infection in renal transplant recipients

We have retrospectively analyzed the incidence of cytomegalovirus (CMV) infection in 250 consecutive renal allograft transplants performed in 244 recipients. The mean follow-up was 35.1+/-25.4 months. Immunosuppression was cyclosporine- or tacrolimus-based triple therapy. CMV infection prophylaxis with ganciclovir for 3 months post transplant was prescribed in CMV-seronegative recipients of allografts from seropositive donors (D+R-) and in all recipients treated with OKT3. CMV antigenemia was monitored by the pp65-antigen assay. Thirteen of 57 D+R- recipients (22.8%) developed CMV antigenemia. One recipient had a breakthrough of CMV antigenemia during ganciclovir prophylaxis; 12 D+R- recipients developed CMV antigenemia 147.5+/-173.8 days after transplantation. Four of 13 (30.7%) D+R- recipients had asymptomatic CMV infection, 8 (61.6%) had CMV infection with non-specific symptoms including fever, and 1 (7.7%) developed CMV pneumonia. Six of 13 (46.1%) D+R- patients had been treated with intensified immunosuppressive therapy before CMV infection. In the low-risk CMV groups (D+R+; D-R+; D-R-), 28 recipients (14.5%) developed CMV antigenemia 42.5+/-15.2 days post transplantation. Ten of the 28 (35.7%) recipients had asymptomatic CMV infection, 17 (60.7%) developed CMV infection with non-specific symptoms, and 1 (3.6%) developed CMV pneumonia. Twenty-one of 28 (75.0%) had intensified immunosuppressive therapy before CMV infection. In conclusion, ganciclovir prophylaxis diminished and delayed the onset of CMV infection but did not totally prevent it from occurring in D+R- renal transplant recipients. Clinicians should be vigilant to the possibility of CMV infection in both seronegative and seropositive recipients, especially after anti-rejection therapy.     

Prevention of CMV infection by screening for CMV antibodies in renal allograft recipients and their blood and kidney donors

The influence of the cytomegalovirus (CMV) serostatus of blood and kidney donors on patient and graft survival was studied prospectively in 73 cadaveric renal graft recipients. Six out of 12 (50%) CMV seronegative recipients receiving a kidney from a CMV seropositive donor developed CMV disease, in contrast to none of 7 CMV seronegative donor/recipient combinations. Transmission of CMV with blood products to seronegative recipients was not observed in this study. A poor graft survival of 41% 3 years after transplantation was found in CMV seronegative recipients with CMV seropositive allograft donors, compared with an actuarial 3 year graft survival of 72% in the 7 CMV seronegative donor/recipient combinations. Six patients with graft failure had a CMV infection. This study, in accordance with other studies, suggests that selection of CMV seronegative renal allograft donors for CMV seronegative recipients will improve graft survival.     

Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation

To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.     

Low‐dose valganciclovir prophylaxis for cytomegalovirus in intermediate‐risk (R+) renal transplant recipients: Single‐center experience

Renal transplant recipients (RTR) who are seropositive for CMV (R+) are considered to be at intermediate risk for CMV disease. Current guidelines recommend high‐dose valganciclovir (VGCV) prophylaxis because of limited data on the efficacy of low‐dose VGCV. We describe our experience with using low‐dose VGCV in R+ RTR. We retrospectively reviewed a cohort of 316 R+ RTR at our institution between 2002 and 2006. The primary endpoint was CMV disease at 1 year post transplant. The incidence of CMV disease at 12 months after transplantation was only 3% (6/221) in the D+R+ and 4% (4/95) in the D?R+ RTR. Low‐dose VGCV was effective at preventing CMV disease in intermediate‐risk (R+) RTR.     

Cytomegalovirus (CMV) DNA load predicts relapsing CMV infection after solid organ transplantation

Cytomegalovirus (CMV) DNA load was analyzed as a marker for relapse of CMV infection in 24 solid organ transplant patients with CMV infection or disease who received a fixed 14-day course of intravenous ganciclovir. Viral load was measured in blood samples obtained before and at the completion of treatment. Eight (33%) of 24 patients developed relapsing CMV infection. Median pretreatment viral loads were higher in the relapsing group (80,150 copies/106 leukocytes) than in the nonrelapsing group (5500 copies/106 leukocytes; P=.007). The relapsing group also had persistent detectable viral DNA (median, 5810 copies/106 leukocytes) after treatment, whereas it was undetectable in the nonrelapsing group (P<. 0001). Primary CMV infection (seronegative recipients of seropositive organs, D+R-) was an independent marker for CMV relapse (P=.03), and these patients had higher pre- and posttreatment viral loads than did non-D+/R- patients (P<.0001 and P=.0014, respectively). CMV DNA load is a useful marker for individualizing antiviral treatment of CMV infection in solid organ transplant recipients.     

High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection.

The impact of cytomegalovirus (CMV) serostatus (seropositive [(+)] or seronegative [(-)]) of the donor (D) and recipient (R) on mortality after allogeneic non-T cell-depleted stem cell transplantation (SCT) in the era of preemptive therapy was assessed among 1750 patients by means of multivariable Cox regression models. In an analysis that included only pre-SCT variables, D(+)/R(+) and D(+)/R(-) patients had the highest risk for mortality. After neutropenia or the occurrence of CMV disease was controlled for, only D(+)/R(-) patients remained at a significantly higher risk for mortality. Mortality due to bacteremia or invasive fungal infection was higher among D(+)/R(-) (18.3%) than D(-)/R(-) (9.7%) patients (P <.001). Thus, CMV serostatus remains associated with mortality; neutropenia due to ganciclovir administration and CMV disease explain the association with mortality among seropositive recipients. However, in D(+)/R(-) subjects, mortality appears to be associated with bacterial and fungal infection, indicating a possible immunomodulatory effect of primary CMV infection that was undetected despite intensive monitoring.     

High frequency of positive surveillance for cytomegalovirus (CMV) by PCR in allograft recipients at low risk of CMV

Cytomegalovirus (CMV) causes significant morbidity and mortality following allogeneic haemopoietic stem cell transplantation. A pre-emptive strategy for ganciclovir therapy is widely used, where treatment is commenced on finding positive evidence of CMV replication. Surveillance by PCR has increased the sensitivity for CMV detection, but it is not known whether this may detect cases with evidence of CMV DNAemia who have a low probability of CMV disease. We reviewed our experience of CMV infection and disease since introducing CMV surveillance by PCR. All 30 allografts received bedside leucodepleted CMV-negative blood products. Seven of 10 CMV-positive recipients of a CMV-positive graft developed CMV DNAemia, with three developing clinical disease requiring ganciclovir treatment. In contrast, of 11 low risk patients (CMV-negative recipients of CMV-negative grafts), six developed evidence of CMV DNAemia although only one had clinical evidence of CMV disease requiring ganciclovir. Transfusion records confirmed that four of these had received exclusively CMV-negative blood products. The aetiology of the CMV DNAemia in these cases is unclear. It is suggested that before commencing ganciclovir therapy, confirmatory CMV antigenaemia testing is carried out on samples which test positive for CMV DNA, unless there is high clinical suspicion of CMV disease.     

Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation

Human cytomegalovirus (CMV) is a major cause of death after transplantation. The frequency of pp65-specific T cells was examined in 38 HLA-A2+ stem cell recipients during the first year after transplantation. Patients were divided into four groups based on donor/recipient serostatus: d+/r+ (n=17), d+/r- (n=7), d-/r+ (n=9) and d-/r- (n=5). Peripheral blood mononuclear cells were stimulated with the CMVpp65 peptide NLVPMVATV, and the specific T-cell frequency was assessed by interferon gamma (IFN-gamma) ELISPOT assay. Responding T cells were characterized by flow cytometry revealing a terminal differentiated effector phenotype. Surveillance of CMV infection was carried out by real-time polymerase chain reaction (n=26) or immunofluorescence (n=12). Infection was present in 7/9 d-/r+ high-risk patients, and CMV disease occurred exclusively in this group with delayed or absent virus-specific T-cell recovery. In contrast, 16/24 intermediate-risk patients showed CMV-specific T cells. Our data suggest that CMV infection and disease rates are elevated in high-risk patients with delayed CMV-specific T-cell immune reconstitution and lower in those with early recovery of T-cell immunity. We recommend preferring CMV seropositive donors for CMV seropositive recipients, as this should lead to durable CMV-specific T-cell responses soon after transplantation with consecutive protection from CMV disease.     

Longitudinal assessment of cytomegalovirus (CMV)-specific immune responses in liver transplant recipients at high risk for late CMV disease

Cytomegalovirus (CMV)-seronegative recipients (R(-)) of a liver transplant from CMV-positive donors (D(+)) are at high risk for developing late CMV disease after discontinuation of antiviral prophylaxis. Levels of viremia and CMV-specific interferon (IFN)- gamma -producing CD4(+) and IFN- gamma -producing CD8(+) T cell responses were prospectively measured from discontinuation of antiviral prophylaxis until 1 year after transplantation in 17 consecutive D(+)/R(-) patients. CMV loads of >1000 copies/mL were strongly associated with CMV disease in the 6 symptomatic patients. Despite immunosuppression, broadly diverse T cells specific for CMV lysate or peptide libraries spanning pp65 and immediate early (IE) 1 immunodominant CMV antigens developed in all patients. A vigorous CD8(+) T cell response to pp65 and IE1 antigens characterized the D(+)/R(-) cohort. Unexpectedly, none of these responses were predictive of CMV disease or viremia. No significant lymphopenia or functional impairment of CMV-specific T cells was detected in the symptomatic patients, whose morbidity was resolved after antiviral treatment while measurable CMV immunity was maintained during the 1-year observation period.     

Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study

Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly being explored as therapy in patients who are not eligible for conventional myeloablative HSCT. Whether these transplants are associated with reduced risk of transplantation-related infections is unknown. We analyzed the incidence of posttransplantation cytomegalovirus (CMV) infections in 56 consecutive mycophenolate mofetil (MMF) patients with hematologic malignancies who underwent nonmyeloablative HSCT (TBI, 2Gy, day 0; MMF/cyclosporine after transplantation). In addition, 18 of 56 patients received 30 mg/m(2)/d fludarabine on days -4 to -2. Most donors were HLA matched and related (93%). Each case patient was matched to 2 controls who were treated by conventional HSCT during the same time period (January 1997 through April 2000). Matching criteria included CMV risk group, HSC source, donor type, age, and underlying diseases. No CMV disease occurred in the low (donor and recipient serologically negative) and intermediate (donor serologically positive and recipient negative) CMV risk groups during the first 100 days. Among cases at high risk for CMV (seropositive recipients), trends to less CMV antigenemia (P =.11), viremia (P =.16), and disease (P =.08) compared with controls were observed; all severe manifestations combined (CMV viremia and disease) were significantly reduced among cases (P =.01). However, by day 365, the overall incidence of CMV disease became similar in both groups. The onset of CMV disease was significantly delayed among case patients compared with controls (median, 130 days versus 52 days; P =.02). It was concluded that CMV disease was significantly delayed in nonmyeloablative cases, but that the overall 1-year incidence was similar to myeloablative HSCT patients. Therefore, nonmyeloablative HSCT patients should receive CMV surveillance beyond day 100 and pre-emptive ganciclovir treatment similar to that of myeloablative HSCT patients.     

Reconstitution of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell responses affording protection from CMV DNAemia following allogeneic hematopoietic SCT

Threshold levels of CMV-specific T-cell populations presumably affording protection from active CMV infection in allo-SCT recipients have been proposed, but lack extensive validation. We quantified CMV pp65 and immediate-early 1-specific IFN-γ CD8(+) and CD4(+) T cell responses at days +30, +60 and +90 after transplantation in 133 patients, and established cutoff cell levels protecting from CMV DNAemia within the first 120 days after transplantation. No patients showing IFN-γ CD8(+) or IFN-γ CD4(+) T-cell counts >1.0 and >1.2?cells/μL, respectively, developed a subsequent episode of CMV DNAemia. Initial or recurrent episodes of CMV DNAemia occurred in the face of IFN-γ T-cell levels below defined thresholds. Negative predictive values at day +30 for the IFN-γ CD8(+) and CD4(+) T-cell markers were 68.1 and 61.8%, respectively. Recipients of grafts from CMV seropositive, related or HLA-matched donors, or receiving non-myeloablative conditioning had nonsignificant tendencies to reach more frequently protective levels of both T-cell subsets at early and late (day +365) times after transplantation. The use of anti-thymocyte globulin and umbilical cord blood transplantation were associated with impaired CMV-specific T-cell reconstitution. CMV-specific IFN-γ CD8(+) and CD4(+) T-cell recovery occurred irrespective of detectable CMV DNAemia.     

Polymerase chain reaction in detection of CMV DNA in renal allograft recipients

This study investigates the w of polymerase chain reaction (PCR) in comparison with viral culture and serology for monitoring of cytomegalovirus (CMV) infection in 21 consecutive renal allograft recipients mated with a quadruple immunosuppression protocol. In addition, an attempt is made to explore the significance of quantitation of CMV signals obtained from peripheral blood leucocytes.
CMV infection developed in 16 patients with seven of the patients having organ involve mat. All of these 16 patients bad a fourfold rise in antibody as well as positive identification of CMV DNA in peripheral blood leucocytes by PCR. Blood viral cultures were negative in two of these patients. All five patients who remained PCR negative also remained culture negative with no antibody change. PCR detected CMV infection on average 15 days and 20 days earlier than viral culture and serology respectively. All except one of the patients with CMV organ involvement had an initial peak of CMV DNA followed by prolonged carriage of detectable CMV. The majority of patients with fever only or asymptomatic CMV infection had a transient peak of CMV DNA.
A high incidence of CMV disease with organ involvement occurred in seronegative recipients of kidneys from seropositive donors (3/5) and in seropositive recipients Of kidneys from seronegative donors (3/7). OKT3 was associated with a higher incidence of CMV organ involvement compared to Antilymphocytic globulin (3/5 v 4/16) but there was a higher incidence of CMV mismatched patients in the OKT3 created group.
This study confirmed the high incidence of CMV infection in renal allograft recipients on an aggressive immunosuppression regimen. The detection of CMV DNA in peripheral blood leucocytes by PCR is a sensitive and specific marker of CMV infection. It enables an earlier diagnosis of CMV infection. The precise role for monitoring of CMV DNA levels is yet to be fully defined.     

High-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation

We evaluated high-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation. One hundred and seventy-four consecutive patients who were at risk for CMV infection (either recipient or donor seropositive) and received either intensive chemoradiotherapy and a T cell-depleted stem cell transplant followed by delayed add-back of donor T cells (TCDT: n = 98), or a non-myeloablative preparative regimen followed by an unmanipulated peripheral blood stem cell transplant (NMT: n = 76) from an HLA-identical sibling donor were studied. All received high-dose acyclovir (HDACV) from day - 7 for 3 months post-transplant in conjunction with weekly CMV pp65 antigenemia monitoring and pre-emptive treatment with intravenous immunoglobulin (not CMV-specific) and ganciclovir. The actuarial probabilities of developing pp65 antigenemia were 83 +/- 4% after TCDT and 41 +/- 6% after NMT (P < 0.00001) with reactivation occurring earlier in the TCDT group (the median 36 days vs 55 days). We observed no reactivation of CMV in seronegative recipients with a seropositive donor (n = 23). A total of 11 patients (5 in TCDT, 6 in NMT) developed CMV disease within 400 days after transplantation, and one death was clearly attributable to CMV interstitial pneumonitis (IP). This strategy was associated with effective control of CMV antigenemia in the majority of patients and near-complete eradication of fatal CMV IP.     

The clinical utility of CMV surveillance cultures and antigenemia following bone marrow transplantation

At our institution, the cytomegalovirus (CMV) prophylaxis protocol for allogeneic bone marrow transplant (BMT) recipients who are CMV-seropositive or receive marrow from a CMV-seropositive donor consists of a surveillance bronchoscopy approximately 35 days posttransplant. Patients with a positive surveillance bronchoscopy for CMV receive pre-emptive ganciclovir. In order to determine the utility of other screening methods for CMV, we prospectively performed weekly CMV antigenemia, and blood, urine and throat cultures from time of engraftment to day 120 post-BMT in 126 consecutive patients. Pre-emptive ganciclovir was given to 11/81 patients (13.6%) because of a positive surveillance bronchoscopy for CMV. Results of CMV blood, urine and throat cultures and the antigenemia assay done prior to or at the time of the surveillance bronchoscopy were analyzed for their ability to predict the bronchoscopy result. The antigenemia test had the highest positive and negative predictive values (72% and 96%, respectively). The ability of these tests to predict CMV disease was evaluated in the 70 patients with a negative surveillance bronchoscopy who did not receive pre-emptive ganciclovir. Of 19 cases of active CMV disease, CMV antigenemia was positive in 15 patients (79%) a mean of 34 days preceding symptoms. Blood cultures were positive in 14/19 patients (74%) a mean of 31 days before onset of disease. CMV antigenemia is useful for predicting the surveillance bronchoscopy result, and also predicts the development of CMV disease in the majority of patients missed by the surveillance bronchoscopy.     

Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogeneic stem cell transplantation

Mycophenolate mofetil (MMF) is increasingly used for prophylaxis and therapy of GVHD in allogeneic stem cell transplantation. In some recent reports of use of MMF in solid organ transplantation a high incidence of CMV disease has been described. We evaluated the frequency and course of active CMV infection in patients who received MMF compared to those who did not receive MMF after allogeneic stem cell transplantation. We retrospectively analyzed 48 adult patients who consecutively underwent unmanipulated allogeneic bone marrow (n = 15) or peripheral stem cell transplantation (n = 33) from HLA-compatible family donors (n = 30) or unrelated donors (n = 18) from February 1997 to September 2000 at our institution. Only patients who were evaluable for the first 100 days were included in this analysis. Sixteen patients received MMF post transplant (MMF+). CMV-antigenemia was monitored by CMV-pp65 antigen. CMV-antigenemia occurred in 14 patients and was virtually only observed in CMV-IgG+ recipients (13/23, 56%). CMV-IgG+/MMF+ patients developed a higher incidence of CMV-antigenemia (8/9, 89%) compared to the CMV-IgG+/MMF- patients (5/14, 35%; P < 0.05). Moreover, five of six patients with persistent or recurrent CMV-antigenemia received MMF. No patient in either group developed CMV disease or died of CMV-related complications. In multivariate analysis including MMF treatment, unrelated vs related donor, GVHD, CMV-serostatus of the donor and stem cell graft type, only MMF treatment was found to be a significant risk factor for both overall and complicated CMV infection.