Late Cytomegalovirus Research Articles

Immunologic Predictors of Late Cytomegalovirus Disease after Solid Organ Transplantation—An Elusive Goal?

Late cytomegalovirus (CMV) disease is a well-described clinical problem after solid organ transplantation in the era of universal prophylaxis with ganciclovir and valganciclovir [1-3]. This complication occurs after liver, heart, lung, kidney-pancreas, and kidney transplantation and is most significant in CMV-seronegative recipients of a graft from a seropositive donor (D+/R-), with '-25%-30% of these patients developing late CMV disease at a median of 5 months after transplantation [1, 2, 4-9]. An association of late CMV disease with drug-resistant virus has been reported in D+/R transplant recipients following oral ganciclovir prophylaxis, and after lung transplantation [2, 5, 10]. Late CMV disease has also been associated with

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.

Prophylactic Versus Preemptive Oral Valganciclovir for the Management of Cytomegalovirus Infection in Adult Renal Transplant Recipients

Prophylaxis reduces cytomegalovirus (CMV) disease, but is associated with increased costs and risks for side effects, viral resistance and late onset CMV disease. Preemptive therapy avoids drug costs but requires frequent monitoring and may not prevent complications of asymptomatic CMV replication. Kidney transplant recipients at risk for CMV (D+/R-, D+/R+, D-/R+) were randomized to prophylaxis (valganciclovir 900 mg q.d. for 100 days, n=49) or preemptive therapy (900 mg b.i.d. for 21 days, n=49) for CMV DNAemia (CMV DNA level>2000 copies/mL in >or=1 whole blood specimens by quantitative PCR) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. More patients in the preemptive group, 29 (59%) than in the prophylaxis group, 14 (29%) developed CMV DNAemia, p=0.004. Late onset of CMV DNAemia (>100 days after transplant) occurred in 11 (24%) randomized to prophylaxis, and none randomized to preemptive therapy. Symptomatic infection occurred in five patients, four (3 D+/R- and 1 D+/R+) in the prophylactic group and one (D+/R-) in the preemptive group. Peak CMV levels were highest in the D+/R- patients. Both strategies were effective in preventing symptomatic CMV. Overall costs were similar and insensitive to wide fluctuations in costs of either monitoring or drug.

Impact of Cytomegalovirus in Organ Transplant Recipients in the Era of Antiviral Prophylaxis

Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

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.

Increased sensitivity of two-step cytomegalovirus PCR analysis on peripheral blood leukocytes permits detailed analysis of reactivation and immune reconstitution

Increased sensitivity of two-step cytomegalovirus PCR analysis on peripheral blood leukocytes permits detailed analysis of reactivation and immune reconstitution

Viral Infections in Patients with Hematological Malignancies

Viral infections are important causes of morbidity and mortality for patients with a hematological malignancy. However, the true incidence and consequences of viral infections for these patients who undergo conventional nontransplant therapy are poorly defined. The difference in incidence and outcome of viral infections among patient groups is wide, but dependent upon the intensity and duration of T-cell-mediated immune suppression. Infections caused by cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), respiratory syncytial virus (RSV), parainfluenza viruses and influenza viruses have been intensely studied, yet newly recognized aspects of these viral infections including late CMV infection; the emergence of new viral pathogens (human herpesvirus-6, BK virus, adenovirus, and human metapneumovirus); the development of molecular diagnostic techniques, and the potential of new agents for viral prophylaxis (maribavir), or preemptive therapy (valganciclovir) form the basis of this review. Well-designed prospective studies are needed to better clarify the spectrum of these viral infections and develop effective prevention and treatment strategies. Yet the increased use of agents like alemtuzumab that induce profound T-cell depletion demands that we develop a better understanding of viral infections that occur in patients with hematological malignancy who receive nontransplant therapy.

Cytomegalovirus infection after allogeneic stem cell transplant in children

The aim of this study was to examine the frequency and the course of cytomegalovirus (CMV) infection and CMV disease in a group of pediatric and adolescent patients after allogeneic stem cell transplantation. Patients were treated according to a protocol including prophylactic high-dose acyclovir in combination with preemptive administration of ganciclovir, based on weekly examinations of CMV antigenemia. A total of 110 consecutively transplanted patients, with a mean age of 9 yr (range 0-20) were treated according to the protocol. All patients were transplanted between March 1993 and January 2000 at the only Danish allotransplantation center. CMV infection occurred in 21.8% (24 of 110) of the patients. Three patients [12.5% (3/24)] developed CMV disease, all with pneumonitis and one with gastrointestinal disease as well. Mean time of disease onset was day +58. Treatment with ganciclovir was in general well tolerated. Late onset CMV disease was not documented. Multivariate analysis revealed that the use of unrelated donor transplants was significantly associated with an increased risk for CMV infection [hazard ratio (HR) 2.90, p = 0.03] and CMV infection was found to be a risk factor for transplant related mortality before day +100 (HR 10.70, p = 0.0015). Although high-dose acyclovir in combination with antigenemia based preemptive treatment with ganciclovir resulted in a low incidence of CMV disease in pediatric and adolescent patients, CMV infection was a significant risk factor in stem cell transplantation with unrelated donors.

Cytomegalovirus Reactivation in Pediatric Hemopoietic Progenitors Transplant

Cytomegalovirus (CMV) disease is an important infectious complication after allogeneic hemopoietic progenitors transplant (HPT), but few data are available in children. To investigate the factors influencing CMV reactivation, subsequent relapses of positive antigenemia, and the development of organ disease in children, the authors retrospectively analyzed 108 children who received allogeneic HPT for malignant conditions at one center. Of these, 41 were CMV serology positive (donor or recipient) before HPT. All those with CMV-positive serology received high-dose acyclovir in conjunction with weekly CMV phosphoprotein-pp65 antigen monitoring of the peripheral blood during the first 3 months. Those with CMV reactivation (positive antigenemia) received preemptive treatment with ganciclovir and/or foscarnet to prevent CMV disease. The incidence of positive antigenemia in this cohort was 41.5% at a mean of 44 +/- 31.6 days after HPT. Two patients (4.9%) subsequently developed late CMV disease. Recipient CMV status was significantly (P = 0.0001) more relevant to reactivation than donor status. Reactivations were significantly more common in single recipient seropositive than double (donor and recipient) positive pairs (P = 0.05). Reactivations were significantly more common in recipients of unrelated donor grafts than matched-related donor grafts (P = 0.025). Reactivations also occurred significantly more in T-cell-depleted graft recipients (P = 0.004) than recipients of unmanipulated grafts. The subsequent development of disease was more common in a CMV-seropositive recipient receiving a CMV-seronegative, T-cell-depleted, unrelated donor graft, and after transplantation receiving treatment for acute graft-versus-host disease. Patients with identified high risk factors for CMV reactivation and disease should be monitored by CMV PCR, and early preemptive treatment should be instigated to prevent the development of disease.

A simplified strategy for clinical management of late cytomegalovirus infection after oral ganciclovir prophylaxis in renal recipients

Late cytomegalovirus disease after completion of prophylactic therapy occurs in 5-21% of renal allograft recipients within the first year post-transplantation. Identifying patients at risk for late infection is clinically difficult; prolonged cytomegalovirus (CMV) monitoring is costly and cumbersome as follow-up intervals lengthen. We performed a prospective 1 year study in 54 de novo renal recipients to assess the minimum CMV monitoring frequency for identifying patients at risk. CMV DNA PCR monitoring on the last day, and again 2 weeks after conclusion of oral ganciclovir prophylaxis, seemed sufficient for identifying recipients at risk for developing clinically relevant late CMV disease and for whom closer clinical follow-up is warranted.

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 Model to Predict Risk for Late Cytomegalovirus Reactivation after Allogeneic Stem Cell Transplantation for Hematological Malignancies.

Cytomegalovirus (CMV) reactivation is associated with increased morbidity and mortality after allogeneic stem cell transplantation (SCT). The incidence of “late” CMV reactivation occurring after post-SCT day 100 has increased over time. We analyzed clinical factors associated with the occurrence of late CMV antigenemia in a group of consecutive recipients of allogeneic SCT for hematological malignancies at the M.D. Anderson Cancer Center surviving at least 100 days after SCT. Recipients of T cell depleted, syngeneic or cord blood grafts were excluded. 269 subjects at risk for CMV reactivation were studied with a median follow-up of 14 months after SCT; of these, 144 subjects (54%) experienced early CMV reactivation while 89 subjects (33%) experienced late CMV reactivation. In univariate analyses, factors associated with a significantly increased risk of late CMV reactivation included prior early CMV antigenemia, SCT for a lymphoid diagnosis (HR=2.4, p=0.002), use of a matched unrelated donor (MUD) or mismatched-related (MMR) donor (HR 1.8 vs. recipients of matched-related (MR) allografts, p=0.003), day 100 lymphocyte count<900/μl (HR 1.9, p=0.01), prior acute GVHD (HR=1.5, p=0.003) and the occurrence of chronic GVHD considered as a time-dependent variable (HR=4.2, p<0.001). As expected, early CMV reactivation was a strong risk factor for late CMV reactivation. 65 of the 144 patients (45%) with early CMV reactivation also experienced late reactivation; only 19 of 125 patients (15%) without antecedent early reactivation experienced late antigenemia (HR=4.1, 95% CI 2.4–7). In 132 subjects experiencing early CMV reactivation, we performed a Cox multivariate analysis of risk factors for late CMV reactivation, after excluding subjects who experienced an episode of early CMV reactivation that continued through day +100. We examined the rate of CMV reactivation in groups stratified according to three clinical factors that were independently associated with increased risk in the multivariate analysis: 1) history of acute GVHD; 2) the use of a MMR or MUD donor rather than a MR donor; and 3) transplantation for a lymphoid rather than myeloid malignancy. The rate of late CMV reactivation was lowest for those subjects transplanted for a myeloid malignancy, who had a MR donor and had no history of acute GVHD (n=33, cumulative incidence 10%). In comparison to this group, we observed an increasing rate of late CMV reactivation in subjects with a MR donor, no history of acute GVHD transplanted for lymphoid malignancy (n=18, incidence 22%, HR=2.3, p=0.1); and in subjects with MMR or MUD donor, positive history of acute GVHD transplanted for a myeloid malignancy (n=46, incidence 30% HR=2.8, p=0.04). The rate was highest in lymphoid malignancy patients who received a MMR or MUD allograft and who experienced acute GVHD (n=35, incidence 50%, HR=7.3, p<0.001). If confirmed, the risk assessment model developed here should be useful for the optimization of monitoring and therapeutic strategies designed to minimize the morbidity and mortality associated with late CMV reactivation after allogeneic SCT. [Display omitted]

Attenuated Preemptive Therapy Against Cytomegalovirus (CMV) Reactivation/Disease Consisting of a Higher Cutoff Point and a Lower Initial Dose of Ganciclovir after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with an HLA-Identical Sibling Donor.

CMV continues to be a major cause of morbidity following allogeneic HSCT. Although preemptive ganciclovir therapy is widely used to prevent CMV disease, the optimal initial dose and timing of ganciclovir administration have not yet been determined. Unnecessary routine ganciclovir therapy is not acceptable, since it can cause considerable neutropenia and may impair the de novo recovery of CMV-specific T cell immunity. We performed a prospective study to evaluate the safety and effectiveness of a novel preemptive protocol with a higher cutoff point to initiate therapy and a lower initial dose of ganciclovir. The primary endpoint of this study was defined as the occurrence of CMV disease. CMV antigenemia was measured weekly after engraftment. The decision to start ganciclovir was based on the detection of ≥10 positive cells per 50,000 cells by the antigenemia assay, or by the clinical diagnosis of CMV disease with apparent infection-related symptoms. Intravenous ganciclovir was started at 5 mg/kg/day three times per week, and was continued until the positive cell count had decreased to < 10 per 50,000 cells. If the number of positive cells increased or CMV-related symptoms worsened, the dose of ganciclovir was increased. Forty-six consecutive patients undergoing allogeneic HSCT from an HLA-identical sibling at National Cancer Center Hospital between April 2003 and March 2004 were enrolled. The median age of the patients was 51 years (range, 17 to 68 years). There were 40 cases of hematological malignancy and 6 solid tumor. The risk status of CMV was recipient (R) +/donor (D)+ in 39, R+/D- in 4, R−/D+ in 1, and R−/D− in 2. Fludarabine- or cladribine-based reduced-intensity regimens were used in 35 patients and conventional myeloablative in 11. All patients were given acyclovir 750 mg/day orally from day −7 to the discontinuation of GVHD prophylaxis. The median follow-up was 275 days (26 – 481). Twenty-six patients (57%) developed positive antigenemia at a median of 42 days (12 – 151) after transplantation. In 10 patients (22%), ≥10 positive cells per 50,000 cells were detected by the antigenemia assay, and these patients, except two with renal dysfunction, received low-dose ganciclovir. The dose of ganciclovir was increased in 5 patients. Three patients developed overt CMV gastroenteritis which was successfully treated with a regular therapeutic dose of ganciclovir at 10 mg/kg/day. No case of late CMV disease was observed in this study. Overall, the total dose of ganciclovir was significantly less than that in a previous protocol using a conventional double dose (5 mg/kg twice daily) of ganciclovir (111 mg/kg vs. 225 mg/kg on average, P=0.006), reducing the cost by as much as $ 1,500 per patient. The incidence of neutropenia after ganciclovir was significantly less than that in the previous approach (0% vs. 11% (4/36), P=0.038). In a multivariate analysis, factors associated with ≥10 positive antigenemia included grade II – IV acute GVHD (P < 0.0001), the use of systemic steroid of ≥1.0 mg/kg/day (P < 0.0001), and a reduced- intensity conditioning regimen (P =0.036). In conclusion, our attenuated preemptive treatment protocol appeared to be safe, better tolerated, less expensive, and effective at controlling CMV infection.

Favourable Impact on Acute and Chronic Graft-Versus-Host Disease with Cyclophosphamide and In-Vivo Anti-CD52 Monoclonal Antibodies for Marrow Transplantation from HLA-Identical Sibling Donors for Acquired Aplastic Anaemia.

Despite excellent long-term results of bone marrow transplantation (BMT) in acquired severe aplastic anemia (SAA), graft-versus-host disease (GVHD) continues to remain a major concern. Approximately 30–40% patients experience chronic GVHD resulting in long-term complications and impaired quality of life. At St. George's Hospital, we investigated the role of anti-CD52 monoclonal antibodies (MoAb) in transplant protocols for SAA. The CD52 antigen is expressed widely on virtually all lymphocytes including T and B-cells, NK cells, dendritic cells, eosinophils and macrophages but is absent from erythrocytes, platelets and marrow progenitors. Between Aug 1989 and Nov 2003, 33 patients at our centre with acquired SAA underwent BMT from HLA-identical sibling donors using cyclophosphamide (CY) 50 mg/kg x 4 (days −5 to −2) and anti-CD52 MoAb 0.75–1 mg/KgBW as conditioning. Prior to 1999, rat derived anti-CD52 MoAb (Campath-1G) was used. We switched to humanized version of anti-CD52 MoAb (Alemtuzumab) when it became available in 1999. Median age at BMT was 17 yrs (range 4–46). Prior to BMT, 58% were heavily transfused (>50 transfusions) and 42% had previously failed anti-thymocyte globulin (ATG) based immunosuppressive therapy. Unmanipulated bone marrow was used as source of stem cells in all except one. GVHD prophylaxis was with cyclosporine (CSA) alone in 19 (58%) patients; 14 received anti-CD52 MoAb in addition to CSA. The conditioning regimen was well tolerated without significant acute toxicity. Graft failure was seen in 8 (24%) patients (primary,4; secondary, 4). Graft failure was non-significantly higher in heavily transfused patients and those receiving CSA and anti-CD52 MoAb as GVHD prophylaxis. Of those failing grafts, 4 survived long-term (complete autologous recovery, 2; autotransplant from previous stored marrow, 1; second allograft, 1). Acute grade II-IV GVHD and chronic GVHD was seen in 13% and 4%, respectively. None developed extensive chronic GVHD. Of the 19 recipients positive for cytomegalovirus (CMV), reactivation was seen in 5(26%) with in 100 days. No cases of late CMV reactivation were observed. Six patients died of complications related to BMT at a median of 248 days (range 47–414). With a median follow-up of 59 months, the 5-year survival was 81% (95% C.I. 68–96). There was a non-significant trend towards improved survival in patients transplanted after 1995 (93% vs. 74%). The performance status of all survivors is 100% except one who developed avascular necrosis of hip.We conclude that the conditioning regimen containing CY and anti-CD52 MoAb is well tolerated and efficacious for acquired SAA using HLA-matched sibling donors. The long-term survival with this conditioning appears to be equivalent to current standard conditioning for acquired AA (CY and ATG) and the impact on acute and chronic GVHD is particularly notable. Based on the results of our study we are further investigating the role of Alemtuzumab in the transplant protocols for AA using CSA alone as GVHD prophylaxis.

Late-Onset Cytomegalovirus Disease in Liver Transplant Recipients Despite Antiviral Prophylaxis1

The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.

Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: Donor lymphocyte infusion and previous history of early CMV infection

6648 Background: An increased incidence of late cytomegalovirus (CMV) infection has been reported during the last decade since the introduction of ganciclovir (GCV) prophylaxis or GCV pre-emptive t...

Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: Donor lymphocyte infusion and previous history of early CMV infection

Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: Donor lymphocyte infusion and previous history of early CMV infection

Late cytomegalovirus disease with atypical presentation in renal transplant patients: Case reports

Cytomegalovirus (CMV) disease typically occurs 1 to 4 months (median 35 days) after solid organ transplantation. Recent reports documented that the natural history of CMV disease associated with solid organ transplantation has been modified as a result of the widespread use of potent immunosuppressents and antiviral prophylaxis. We herein report three pretransplant CMV seropositive recipients (with unknown donor status) who were diagnosed recently to display late and atypical CMV disease. Two men and one woman included two patients who presented with allograft dysfunction at 12 years and at 3 years after transplantation. Both patients showed increased serum creatinine approximately from baseline 200 to >400 μmol/L over 3 months in the absence of features of rejection or cyclosporine toxicity. A renal biopsy was refused by both patients. Two of the three patients presented with symptoms of enterocolitis (diarrhea, nausea, weight loss), which had persisted for more than 6 months. Other symptoms and signs of overt CMV disease (fever, leukopenia) were absent. None had pulmonary, hepatic, or other major organ involvement. In all patients IgG antibodies and CMV DNA by polymerase chain reaction were positive with negative IgM antibodies. The immunosuppressive regimen consisted of mycophenolate mofetil (MMF), steroids, and calcineurin inhibitors. The kidney function significantly improved in both patients with renal dysfunction. Gastrointestinal symptoms resolved completely with gradual weight gain. The recognition and early diagnosis of late atypical CMV disease in kidney transplant patients presenting with allograft dysfunction and/or other organ systems is important. The MMF has a red herring effect in our cases due to its GI side effects.

Recent advances in the prevention of CMV infection and disease after hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) remains an important pathogen in hematopoietic stem cell transplant (HCT) recipients in the current era of antiviral prophylaxis and preemptive therapy, despite the almost complete elimination of CMV disease during the first 3 months after transplantation. Pretransplant CMV serostatus of the donor and/or recipient remains an important risk factor for poor post-transplant outcome, especially in highly immunodeficient patients (e.g. recipients of ex vivo or in vivo T-cell depletion). Prevention of late CMV disease continues to be a challenge in selected high-risk populations, and indirect immunomodulatory effects of CMV (e.g. invasive bacterial and fungal infections) appear to contribute to the poor outcome. The risk of developing antiviral resistance remains low in most patients; however, in a setting of intense immunosuppression (e.g. after transplantation from a haploidentical donor) the incidence may be as high as 8%. Transfusion-transmitted CMV infection can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1-2% of CMV disease remains. Surveillance and preemptive therapy is effective in preventing transfusion-related CMV disease. The development of new drugs and immunologic strategies (adoptive transfer of CMV-specific T-cells and donor/recipient vaccination strategies) are important goals for the elimination of the negative impact of CMV in the HCT setting.

Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: donor lymphocyte infusion and previous history of early CMV infection.

An increased incidence of late cytomegalovirus (CMV) infection has been reported during the last decade since the introduction of ganciclovir (GCV) prophylaxis or GCV pre-emptive therapy. Given that a donor lymphocyte infusion (DLI) can induce more severe GVHD, this may predispose a patient to late CMV infection. In all, 64 patients (median age 36, M/F 38/26) underwent allogeneic stem cell transplantation (SCT) using a matched sibling donor with bone marrow (n=9) or peripheral blood stem cells (n=55). The overall incidence of CMV infection, early and late CMV infection was 46.9 (30/64), 42.2 (27/64), and 16.4% (9/55), respectively. Early CMV infection was treated with GCV pre-emptive therapy that produced a 92.6% success rate. Among the 20 patients who received 35 DLIs, late CMV infection developed in eight (42.1%) of 19 evaluable cases with a median onset at 127 days post transplant. Risk factors for late CMV infection in a logistic regression analysis included DLIs (P=0.001) and a previous history of CMV infection (P=0.006). In conclusion, late CMV infection was strongly associated with DLIs and a previous history of early CMV infection. Accordingly, extended surveillance of CMV antigenemia is recommended for patients receiving DLIs or who have a previous history of CMV infection.