Initial low-dose valganciclovir as a preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients

Preemptive therapy for cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant (HSCT) patients is effective in decreasing the incidence of CMV disease. Intravenous ganciclovir is a commonly used preemptive therapy, but as we have recently shown, oral valganciclovir (VGC) is a useful alternative. However, the optimal dose of VGC has not been determined. We prospectively evaluated the efficacy and toxicity of an initial low-dose of VGC (900?mg QD) as preemptive therapy in 20 patients with low-level CMV antigenemia following allogeneic HSCT. Patients were screened weekly for CMV pp65 antigenemia after engraftment. Preemptive therapy with VGC (900?mg QD) was initiated if more than two CMV antigen-positive cells per 50,000 leukocytes were detected. CMV antigen-positive cells disappeared from all 20 patients after 14-29?days (median 20?days) of VGC treatment. None of the patients developed CMV disease nor did they require more than the conventional VGC dose (900?mg BID). Neutropenia (<500/μL) developed in three patients who required granulocyte-colony-stimulating factor support, but there were no other significant side effects. These observations suggest that the initial dose of VGC in preemptive therapy for CMV can be safely decreased to 900?mg QD for patients with low-level CMV antigenemia.     

Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients

Between March 2007 and January 2008, the safety and efficacy of oral valganciclovir (VGC) preemptive therapy for cytomegalovirus (CMV) infection was evaluated in ten consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were screened once or twice per week after engraftment using CMV pp65 antigenemia assay. When more than 2 CMV antigen-positive cells per 50,000 leukocytes were detected, preemptive therapy with oral VGC was initiated at a dose of 900 mg twice daily for 3 weeks. Nine patients (90%) completed the 3-week VGC treatment except for one patient who developed febrile neutropenia. There was no other significant toxicity. CMV antigen-positive cells were rapidly decreased in all nine patients and became undetectable by the end of the VGC treatment. None of the patients developed CMV disease. CMV infection relapsed in four of the ten patients (40%) after the VGC treatment. These observations suggest that preemptive therapy with VGC is effective for preventing CMV disease in allogeneic HSCT patients. Further studies with a large number of patients will be necessary to determine the optimal initial- and maintenance-dose of VGC.     

Sequential cytomegalovirus antigenemia monitoring in kidney transplant patients treated with antilymphocyte antibodies

BACKGROUND: Antilymphocyte antibodies (ALA) use is related to disseminated cytomegalovirus (CMV) disease after kidney transplantation. Strict surveillance of CMV infection, preemptive antiviral treatment or concomitant ganciclovir and ALA use are proposed as an attempt to prevent related clinical complications. Our objective was to describe the pattern of CMV infection, based on sequential antigenemia detection, after ALA treatment. PATIENTS AND METHODS: Thirty renal transplant patients were prospectively screened for CMV infection after ALA treatment. CMV antigenemia (pp65 antigen detection) was monitored twice a week in the first month and weekly until 60 days after the beginning of ALA therapy. Any positive value of antigenemia was considered CMV infection. RESULTS: Twenty-eight (93.3%) patients were CMV positive (IgG) before transplantation. The mean duration of ALA treatment was 12.1+/-2.4 days. Positive antigenemia was detected in 24 (80%) patients, a mean of 52.5+/-15 days after transplant and 44.7+/-14 days after the beginning of ALA treatment. The median antigenemia count was 7 positive cells/300,000 neutrophils (range: 1-227). Antigenemia preceded clinical symptoms by 5.8 days (0-28 days). Eighteen (75%) of 24 positive patients received ganciclovir treatment: 8 patients (26.7%) for viral syndrome, 2 patients (33.3%) for invasive disease, and 8 patients (26.7%) as part of preemptive therapy, asymptomatic with high antigenemia values. Six pp65-positive patients with low counts were followed up until a negative result and remained asymptomatic without any specific treatment. CONCLUSION: CMV infection was frequent after ALA treatment in this group and generally occurred late after completion of treatment. Antigenemia was a reliable tool to guide preemptive treatment in these patients, and such strategy is an alternative option compared to the prophylactic use of ganciclovir with ALA treatment.     

CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy

The incidence, treatment and outcome of CMV interstitial pneumonia (CMV-IP) were reviewed in 139 consecutive allogeneic BMT patients undergoing extended CMV antigenemia surveillance and two different ganciclovir (GCV) strategies to control CMV infection. Nineteen cases of CMV-IP were reviewed, 16 of 63 patients (25.4%) who received early GCV treatment (ET) and three of 76 patients (3.9%) who received preemptive (PE) GCV therapy. In the ET group, the median time for occurrence of CMV-IP was 55 (range 36 to 311) days. Two patients had three episodes of CMV-IP recurrences after day +100. CMV-IP-related death occurred in two patients (15.4%). In the PE group, 41 patients received pre-emptive GCV therapy prompted by the appearance of positive antigenemia > or =2 cells. The median time for the occurrence of CMV-IP was 92 (range 48 to 197) days. Response to therapy was observed when GCV was introduced within 6 days of antigenemia positivity. The use of IVIg in association with GCV did not play a major role in response to therapy. The median time for occurrence of CMV-IP was delayed during PE strategy and the cost-effectiveness of CMV surveillance after day +100 should be investigated in this population.     

A randomized trial of preemptive therapy for prevention of cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation

We studied the efficacy of two different doses of ganciclovir to prevent cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. We randomly assigned allogeneic HSCT recipients who had CMV infection to receive preemptive ganciclovir therapy with or without induction phase (5 mg/kg twice daily for 1 week). Thirty-two and thirty-six patients were randomized to the standard and the low-dose therapy group, respectively. The median time to CMV antigenemia or viremia clearance was 7 days (3–25 days) in the standard therapy group versus 11 days (3–69 days) in the low-dose therapy group (P = 0.540). The incidence of CMV disease was similar between the two groups (P = 0.366). The Kaplan–Meier estimate of event-free survival by day 180 after HSCT was 76.2% in the standard therapy group versus 66.7% in the low-dose therapy group (P = 0.590). Severe neutropenia (<0.5 × 10⁹/L) was observed in four (12.5%) patients in the standard therapy group versus two (5.6%) patients in the low-dose therapy group (P = 0.314). This study suggests that a low-dose ganciclovir preemptive therapy can be as effective as the standard-dose ganciclovir preemptive therapy for the prevention of CMV disease in allogeneic HSCT recipients.     

Significance of qualitative PCR detection method for preemptive therapy of cytomegalovirus infection in patients after allogeneic hematopoietic stem cell transplantation -- single-centre experience

Both early cytomegalovirus (CMV) monitoring and prophylactic antiviral therapy can decrease clinical complications or can prevent them in patients after allogeneic hematopoietic stem cell transplantation (HSCT). Presented paper summarizes experiences with using regular monitoring of reactivation of CMV after allogeneic HSCT by qualitative polymerase chain reaction (PCR) method to prevent the development of symptomatic CMV disease. Samples of peripheral blood leukocytes (PBL) in 71 patients were monitored. Because of retransplantation in two patients, 73 transplantations, each followed by the monitoring, were performed. Patients were monitored weekly after the transplantation for CMV DNA-emia in PBL. An episode of CMV infection representing an indication for preemptive ganciclovir (GCV) or foscarnet (FOS) therapy was defined as two consecutive positive PCR results in 4-7 days. Median time of monitoring was 313 days. The CMV infection was found in 28/73 monitorings (38.4%) and always was followed by preemptive therapy. One recurrence of CMV infection was observed in 4/28 (14.3%) monitorings and two recurrences in 1/28 (3.6%) monitorings. Presented approach resulted in complete prevention of overt CMV disease and this study enable to show that qualitative PCR method for determination of incipient CMV infection followed by preemptive therapy is suitable for preventing patients after allogeneic transplantation from CMV disease.     

Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation

Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.     

Clinical trial of quantitative real-time polymerase chain reaction for detection of cytomegalovirus in peripheral blood of allogeneic hematopoietic stem-cell transplant recipients

The preemptive therapy of cytomegalovirus (CMV) reactivation is useful for the prevention of CMV disease in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. We compared results of the pp65 CMV antigenemia test with quantitative touch-down polymerase chain reaction (Q-PCR) on unfractionated whole blood for the detection of CMV reactivation in 51 HSCT recipients. Forty episodes of reactivation in 28 patients were detected by antigenemia and treated by antiviral drugs. Q-PCR detected CMV DNA in 39 (97.5%) of 40 reactivation episodes. False-positive results occurred in 3% of tests, of which 63% were borderline positive. Q-PCR results were positive earlier than antigenemia results in 30 (77%) of 39 episodes detected by antigenemia. Q-PCR remained positive after treatment was discontinued in 14 (36%) of 39 episodes and predicted the return of CMV reactivation in 4 (31%) of 13 episodes. Q-PCR was more sensitive than the antigenemia test and had sufficient specificity for clinical use.     

Clinical significance of cytomegalovirus (CMV) antigenemia in the prediction and diagnosis of CMV gastrointestinal disease after allogeneic hematopoietic stem cell transplantation

To evaluate the clinical significance of a cytomegalovirus (CMV) antigenemia assay in the prediction and diagnosis of CMV gastrointestinal (CMV-GI) disease after hematopoietic stem cell transplantation (HSCT), 19 allogeneic HSCT recipients developing CMV-GI disease were retrospectively reviewed. All patients were monitored by a CMV antigenemia assay, at least once weekly after engraftment. The median onset of CMV-GI disease occurred 31 days post transplant (range: 19-62). Only four of 19 patients (21%) developed a positive CMV antigenemia test before developing CMV-GI diseases. Although all 19 patients subsequently developed positive CMV antigenemia tests during their clinical courses, the values remained at a low-level in nine (47%) patients. Among the 14 patients in whom results of real-time polymerase chain reaction (PCR) were available, seven (50%) yielded positive results of real-time PCR before developing CMV-GI disease. In contrast to the values of CMV antigenemia, all 14 patients exclusively yielded high viral loads (median: 2.8 x 10(4) copies/ml plasma). We conclude that CMV antigenemia testing has limited value in prediction or early diagnosis of CMV-GI disease, and that real-time PCR could have a more diagnostic significance.     

Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity

Ganciclovir effectively prevents cytomegalovirus (CMV) disease in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but late-onset CMV disease is increasingly observed. We designed a prospective cohort study to define the incidence and risk factors for late CMV infection in patients who undergo HSCT. CMV-seropositive patients were studied prospectively for CMV infection (quantitative pp65 antigenemia, quantitative CMV-DNA, blood culture), T-cell immunity (CMV-specific CD4(+) T-helper and CD8(+) cytotoxic T-lymphocyte responses, CD4 and CD8 T-cell count, absolute lymphocyte count), and other transplantation-related factors. Univariate and multivariable analyses were used to assess the risk for late CMV infection and disease and to assess overall survival. Late CMV disease developed in 26 of 146 (17.8%) patients a median of 169 days after transplantation (range, 96-784 days); the mortality rate was 46%. Thirty-eight percent of patients surviving late disease had a second episode a median of 79 days after the first episode. At 3 months after transplantation, preceding detection of CMV pp65 antigenemia, CD4 T-cell counts lower than 50 cells/mm(3), postengraftment absolute lymphopenia levels lower than 100 lymphocytes/mm(3), undetectable CMV-specific T-cell responses, and graft-versus-host disease (GVHD) were associated with late CMV disease or death. After 3 months, continued detection of pp65 antigenemia or CMV DNA in plasma or peripheral blood leukocytes and lymphopenia (fewer than 300 lymphocytes/mm(3)) were strong predictors of late CMV disease and death. In conclusion, CMV viral load, lymphopenia, and CMV-specific T-cell immunodeficiency are predictors of late CMV disease and death after allogeneic stem cell transplantation. Prevention strategies should be targeted at patients in whom CMV reactivated during the first 3 months and those with poor CMV-specific immunity or low CD4 counts.     

A randomised trial comparing cytomegalovirus antigenemia assay vs screening bronchoscopy for the early detection and prevention of disease in allogeneic bone marrow and peripheral blood stem cell transplant recipients

Preemptive antiviral therapy is often employed for CMV prevention following allogeneic BMT. Two common strategies are a screening bronchoscopy for CMV post-BMT or regular CMV antigenemia testing with ganciclovir administration for a positive result. In a randomised trial, we prospectively compared the efficacy of these two preemptive strategies. Consecutive patients were randomised to either a bronchoscopy for CMV on day 35 post BMT or weekly CMV antigenemia testing. If the bronchoscopy was positive for CMV, patients received preemptive ganciclovir for 8-10 weeks. If the antigenemia was positive for CMV, patients received a minimum of 2 weeks of preemptive ganciclovir. The primary endpoint was the development of active CMV disease. One hundred and eighteen allogeneic BMT patients were enrolled (60 in the antigenemia arm and 58 in the bronchoscopy arm). The two groups were comparable with respect to baseline demographic data, underlying disease, conditioning regimen, and immunosuppression. Active CMV disease developed in 7/58 (12.1%) patients in the bronchoscopy arm vs 1/60 patients (1.7%) in the CMV antigenemia arm (P = 0.022). Based on the screening test, 13.8% of patients received preemptive ganciclovir in the bronchoscopy arm vs 48.3% of patients in the antigenemia arm (P < 0.001). There was no significant difference in the rate of graft-versus-host disease, bacteremia, invasive fungal infections or mortality between the two groups. Preemptive therapy based on regular CMV antigenemia monitoring is superior to screening bronchoscopy for the prevention of CMV disease after allogeneic BMT.     

Comparison of serology, antigenemia assay and the polymerase chain reaction for monitoring active cytomegalovirus infections in hematopoietic stem cell transplantation patients

Forty-six allogeneic hematopoietic stem cell transplantation (HSCT) patients were monitored for the presence of CMV antibodies, CMV-DNA and CMV antigens after transplantation. Immunoenzymatic serological tests were used to detect IgM and the increase in CMV IgG antibodies (increase IgG), a nested polymerase chain reaction (N-PCR) was used to detect CMV-DNA, and an antigenemia assay (AGM) was used to detect CMV antigens. The presence of CMV-IgM and/or CMV-increase IgG antibodies was detected in 12/46 (26.1%) patients, with a median time between HSCT and the detection of positive serology of 81.5 days. A positive AGM was detected in 24/46 (52.2%) patients, with a median time between HSCT and antigen detection of 62 days. Two or more consecutive positive N-PCR results were detected in 32/46 (69.5%) patients, with a median time between HSCT and the first positive PCR of 50.5 days. These results confirmed that AGM and mainly PCR are superior to serology for the early diagnosis of CMV infection. Six patients had CMV-IgM and/or CMV-increase IgG with a negative AGM (five cases) or N-PCR assay (one case). In five of these cases the serological markers were detected during the first 100 days after HSCT, the period of highest risk. These findings support the idea that serology may be useful for monitoring CMV infections in HSCT patients, especially when PCR is unavailable.     

巨细胞病毒pp65抗原血症检测

目的：评估巨细胞病毒（CMV）pp65白细胞抗原血症在骨髓移植或外周血干细胞移植后活动性CMV感染早期诊断和CMV 病的预测、指导CMV亚临床期感染的抗病毒治疗及抗病毒疗效判断中的价值。方法：1999年9月－2000年4月共收集 210份乙二胺四乙酸（EDTA）抗凝血，骨髓移植或外周血干细胞移植患者36例。移植前用ELISA法检测患者CMV特异性抗体IgG和IgM，移植后3周起采用CMV Brite试验盒每周检测1次CMV pp65抗原血症，并计数抗原 阳性细胞，直到移植后100d或治疗后抗原阴转、死亡或出院。移植后患者第1次检测到bp65抗原阳性细胞即开始更昔洛韦抗病毒治疗。结果：36例骨髓移植或干细胞移植患者于移植前CMV特异性抗体IgG均阳性，IgM均阴性；移植后16例出现CMV pp65抗原血症，其中15例 出现有症状的CMV感染或CMV病，14例接受更昔洛韦抗病毒治疗，12例治疗后抗原血症阴转、症状消失、死亡2例（病死率14．2％），未经抗病毒治疗者2例均死亡（P＜0．01）。16例pp65抗原阳性患者中，仅2例CMV特异性抗体IgM阳性。10名健康对照组的CMV特异性抗体IgG均阳性，IgM均阴性；pp65抗原血症 检测均阴性。结论：本研究结果提示，人CMV pp65白细胞抗原血症检测可作为骨髓移植后CMV病的预测指标，指导移植后抗病毒治疗的开展和疗效评价。pp65白细胞抗原症出现即开始抗病毒治疗可明显降低病死率。     

Risk-Adapted Preemptive Therapy for Cytomegalovirus Disease after Allogeneic Stem Cell Transplantation: A Single-Center Experience in Korea

Cytomegalovirus (CMV) remains a major cause of infection in recipients of hematopoietic stem cell transplants (HSCT) and results in significant mortality and morbidity. We present the results of CMV pp65 antigenemia-guided, risk-adapted preemptive therapy aimed at preventing CMV disease in allogeneic HSCT. Preemptive ganciclovir treatment was started when more than 5 CMV antigen-positive cells were detected in the low-risk group (with grade 0-I acute GVHD and matched related HSCT) and when any antigen-positive cells were seen in the high-risk group (with grade II-IV acute GVHD or matched unrelated HSCT). At least 1 episode of antigenemia was observed in 53 (59.6%) of 89 patients before day 100, and preemptive therapy was performed in 33 patients. CMV disease occurred in 6 patients (5 in the high-risk group and 1 in the low-risk group), and late CMV disease developed in 4 patients. Only 1 patient died of CMV pneumonitis before day 100. Neutropenia was observed in 51.5% of ganciclovir-treated patients, and coinfection/superinfection was observed in 42.4%. A strategy of ganciclovir treatment focusing on patients at higher risk could reduce the toxicity from the antiviral drug and be cost-effective. Extended surveillance for CMV disease using more sensitive diagnostic methods is necessary in high-risk patients.     

A short-term preemptive treatment for cytomegalovirus infection in seropositive patients after liver transplantation

Background/purpose

Cytomegalovirus (CMV) infection remains a challenge following liver transplantation. Preemptive treatment is an effective strategy for CMV infection. However, how long preemptive treatment should be applied is not defined.

Methods

Clinical records of preemptive treatment for CMV infection in patients who underwent liver transplantation were collected. CMV antigenemia (pp65) was monitored weekly during hospital stay and subsequently on follow up whenever indicated clinically. Antiviral treatment was administered based on positive antigenemia (>1 positive cell per 500,000 leukocytes) and discontinued when antigenemia became negative.

Results

CMV infection was diagnosed in 58 (43.9%) of 132 liver transplantation patients. All 58 patients were seropositive for CMV before transplantation. CMV infection was first diagnosed at a median time of 20?days (interquartile range [IQR] 15.3?C26) after transplantation. Twelve (20.7%) patients developed repeated infections. Only one of 58 patients (1.7%) was suspected to have invasive disease. The median (IQR) duration of antiviral treatment was 7 (7?C12) days. Of these patients with CMV infection, 14 (24.1%) patients developed acute rejection peri-anti-CMV treatment and 36 (62.1%) developed other infectious complications.

Conclusion

Preemptive treatment is an effective way to halt the progression of asymptomatic CMV infection. A brief course of antiviral treatment is enough for seropositive patients with CMV infection after liver transplantation.     

Cytomegalovirus infection after autologous stem cell transplantation: incidence and outcome in a group of patients undergoing a surveillance program

This study was performed to evaluate the incidence, risk factors, and outcome of cytomegalovirus (CMV) infection in autologous stem cell transplantation (ASCT), with the aim of performing preemptive therapy in patients with antigenemia. Starting from 2001, 171 consecutive ASCTs were performed in 136 patients; 102 of these patients were seropositive for CMV at the onset of hematological disease. In all these patients, a CMV pp65 antigenemia assay was determined weekly, starting from the day when the absolute neutrophil count went above 500/microL, and until day 60 after ASCT; subsequently, antigenemia was determined only when a CMV infection was suspected. Among the 136 transplanted patients, 40 (29.4%) presented a positive antigenemia; all of them were seropositive for CMV before ASCT; and no cases of primary infection were seen. The incidence of CMV infection in the seropositive population was 40/102 (39.3%); 6 patients (5 with multiple myeloma and 1 with non-Hodgkin's lymphoma) who received 2 ASCTs developed CMV infections after both transplantations, so that positive antigenemia developed after 46/171 (26.9%) transplantations. First positive antigenemia presented a median of 32 days (range 7-57) after stem cell reinfusion. The median antigenemia level at the first appearance was 2/200,000 (range 1-1000). No significant prognostic factors could be shown. Enteritis was present in 5 patients; 2 of them also had fever, and 1 of them also had thrombocytopenia. In 5 patients fever without any other clinical signs or symptoms was present; 30 patients were asymptomatic. Fourteen patients were treated with anti-CMV drugs. CMV reactivation was successfully treated in all patients, and no patient died from CMV disease.     

Predictors for persistent cytomegalovirus reactivation after T-cell-depleted allogeneic hematopoietic stem cell transplantation

Cytomegalovirus (CMV) reactivation occurs in up to 60% of CMV-seropositive recipients after allogeneic hematopoietic stem cell transplantation (HSCT). The incidence of CMV disease among T-cell-depleted HSCT patients has been reported from 5-15%. The incidence of reactivation refractory to antivirals in this population is not well studied. METHODS: In this retrospective study we characterized the outcome of CMV reactivation in a cohort of 255 adult and pediatric patients who underwent T-cell-depleted HSCT at Memorial Sloan-Kettering Cancer Center from September 1999 through August 2004. CMV infection was monitored by the pp65 antigenemia assay (CMV Ag). Persistent reactivation was defined as antigenemia positivity >21 days on antiviral therapy. RESULTS: Of 118 CMV-seropositive recipients, 69 (58.4%) had reactivated CMV. Twenty of 69 (29%) developed persistent reactivation at first episode of reactivation, and 7 (10%) in subsequent episode. All patients with persistent reactivation received >/=2 antivirals and CMV hyperimmune globulin; 45% received combination antiviral therapy. The median duration of persistent reactivation was 98 days, range 31-256 days. In multivariate analysis, maximum CMV Ag >25 cells/slide was associated with persistent reactivation (odds ratio 16.2%, 95% confidence interval 4-64, P<0.0001). CMV disease occurred in 6/27 (22%) patients with persistent reactivation. Patients with persistent reactivation had lower CD4(+) and CD8(+) lymphocyte counts compared with those with non-persistent reactivation at day +90 post HSCT (P=0.01 and 0.02, respectively). CONCLUSIONS: Persistent reactivation occurred in 39% of T-cell-depleted HSCT despite treatment with currently available antivirals. Maximum CMV Ag >25 cells/slide was associated with persistent CMV reactivation. More effective treatment modalities are needed for this high-risk population to reduce CMV-associated morbidity and mortality.     

Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation

The present study compared foscarnet with ganciclovir for preemptive therapy of cytomegalovirus (CMV) infection after allogeneic blood or marrow stem cell transplantation (SCT). Patients with CMV infection, as detected by weekly antigenemia or polymerase chain reaction (PCR) in blood leukocytes, were randomized to intravenous therapy for 2 weeks with either foscarnet at 60 mg/kg or ganciclovir at 5 mg/kg administered every 12 hours; if CMV infection remained detectable, patients received an additional 2 weeks of intravenous foscarnet at 90 mg/kg or ganciclovir at 6 mg/kg given once daily for 5 days per week, after which therapy was stopped. Primary efficacy endpoint was the occurrence of CMV disease or death from any cause within 180 days after SCT. A total of 213 patients were treated with either foscarnet (n = 110) or ganciclovir (n = 103). Kaplan-Meier estimates of event-free survival within 180 days after SCT were similar in the 2 treatment groups (P =.6). During study treatment, severe neutropenia (< 0.5 x 10(9)/L) occurred in 11 (11%) patients on ganciclovir versus 4 (4%) patients on foscarnet (P =.04), and impaired renal function was observed in 5 (5%) patients on foscarnet versus 2 (2%) patients on ganciclovir (P =.4). Neutropenia or thrombocytopenia required discontinuation of ganciclovir in 6 (6%) patients but in no foscarnet-treated patient (P =.03). After allogeneic SCT, preemptive therapy of CMV infection with foscarnet shows similar efficacy as with ganciclovir, but is associated with a lower proportion of patients who develop severe neutropenia and who require discontinuation of antiviral therapy due to hematotoxicity.     

Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation

CMV disease remains a major infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate the relationship between CMV antigenemia, treatment with ganciclovir (GCV), and outcome, we retrospectively analyzed 241 consecutive patients at risk for CMV infection who underwent allogeneic HSCT. Antigenemia-guided pre-emptive strategy with GCV was used for all patients. CMV antigenemia developed in 169 patients (70.1%), and CMV disease in 18 patients (7.5%). Multivariate analysis showed that acute GVHD (grades II-IV) was the only risk factor for developing antigenemia, and acute GVHD and advanced age for CMV disease. GCV use, as well as acute GVHD and advanced age, significantly increased the risk for bacterial and fungal infection after engraftment. Those who developed CMV antigenemia had a poorer outcome than those who did not (log-rank, P=0.0269), although the development of CMV disease worsened the outcome with only borderline significance (log-rank, P=0.0526). In conclusion, detection of antigenemia proved to be a poor prognostic factor for HSCT patients, which may be attributed to a combination of factors, including CMV disease itself, the effect of treatment, and a host status that allows for reactivation of CMV. Optimal pre-emptive strategy needs to be determined.     

异基因造血干细胞移植后巨细胞病毒感染的预先治疗

目的:探讨预防治疗及预先治疗对异基因造血干细胞移植后CMV感染的干预作用.方法:225例异基因造血干细胞移植患者中160例接受预先治疗,65例接受预防治疗,用logistic回归模型分析影响CMV感染的危险因素.结果:预先治疗组与预防治疗组比较,CMVpp65抗原血症、CMV病和CMV病死亡率分别为28.1%(35.3%,P>0.05),1.9%(12.3%,P<0.05)和0.6%(10.7%,P<0.01).单倍体相合移植组出现CM-Vpp65血症33.0%(40.0%,P>0.05)、CMV病发生率1.9%(12.0%,P<0.05)、死亡率0.0%(10.0%,P<0.05),均低于相合移植.单倍体相合移植组中CMVpp65阳性发生的主要危险因素为重症GVHD、移植前给予抗CMV治疗以及是否混合其他严重感染.结论:异基因移植后预先治疗优于预防治疗,可以明显减低CMV病的发生和死亡.