Risk Of Cytomegalovirus Disease Research Articles

Risk of cytomegalovirus diseases among coronavirus disease survivors: A retrospective cohort study.

This study was aimed at investigating the risk of cytomegalovirus (CMV) disease among coronavirus disease 2019 (COVID-19) survivors. In this retrospective cohort study, we used the TriNetX research network to identify adults with and without COVID-19 between January 1, 2022 and December 31, 2022. Propensity score matching was used to match the patients with and without COVID-19. The primary outcome was the risk of CMV disease during the 90-day follow-up period. Two matched cohorts comprising 2 501 634 patients with balanced baseline characteristics were created using propensity score matching. During the follow-up period, patients with COVID-19 had a higher risk of CMV disease than those without COVID-19 (hazard ratio [HR], 2.55; 95% confidence interval: 2.01-3.23). The higher risk of CMV disease in the COVID-19 cohort compared with that of the non-COVID-19 cohort remained unchanged in the subgroup analyses by sex (men: HR, 1.85 [1.38-2.47]; women: HR, 2.31 [1.63-3.27]), age (18-64 years: HR, 2.21 [1.71-2.85]; ≥65 years: HR, 1.97 [1.20-3.25]), obesity (HR, 1.54 [1.04-2.30]), diabetes mellitus (HR, 1.50 [1.08-2.08]), cancer (HR, 3.10 [1.95-4.92]), glucocorticoid use (HR, 3.14 [2.45-4.02]), transplantation (HR, 1.38 [1.08-1.77]), and unvaccinated status (HR, 2.37 [1.82-3.08]). In conclusion, COVID-19 can increase the risk of CMV disease. Clinicians should be aware of the risk of CMV disease in patients with COVID-19.

Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation.

The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n= 44), mycophenolate mofetil (MMF; n= 414), or methotrexate (MTX; n= 322). Transplantation occurred between 2007 and 2018; CMV monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load and areas under the curve (AUC) within 1 year were calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was highest with MMF (mean difference= 0.125 units vs MTX group) and similar between PTCy and MTX (mean difference= 0.016 units vs MTX group). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1 year posttransplant. Although different mechanisms of immunosuppressive agents may affect CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

Specific donor HLA allotypes as predictors of cytomegalovirus disease risk in acute myeloid leukemia.

Some HLA alleles have been shown to be associated with susceptibility to cytomegalovirus (CMV) disease incidence in vitro. The objective of this study was to identify correlations between donor HLA allotypes and CMV disease incidence in patients with acute myeloid leukemia who had undergone allogeneic hematopoietic stem cell transplantation (HSCT). Methods and materials we retrospectively analyzed the medical records of 613 donors and recipients with acute myeloid leukemia who had received an allogeneic HSCT from matched sibling (n = 260), unrelated (n = 168), or haploidentical (n = 186) donors, from 2012 to 2017. The HLA-A, -B, -C, and -DRB1 allotypes in the donors were determined using sequence-based typing. Overall, CMV disease incidence was significantly associated with three genotype alleles, HLA-A*30:04:01G, -B*51:01:01G, and -DRB1*09:01:02G. In the donor CMV IgG seropositive subgroup, CMV disease incidence was significantly associated with HLA-B*51:01:01G and -DRB1*09:01:02G. In the IgG seropositive donors in the unrelated allo-HSCT subgroup CMV disease incidence was also significantly associated with HLA-B*51:01:01G. In the CMV seropositive donors in the haploidentical allo-HSCT subgroup, the incidence of CMV disease was significantly associated with HLA-A*24:02:01G and -DRB1*09:01:02G. HLA-DRB1*13:02:01G was a protective marker among IgG seropositive donors in the unrelated allo-HSCT recipient category. Discussion and conclusions The incidence of CMV disease among HSCT recipients varies according to donor HLA alleles and the donor CMV IgG serostatus. Certain donor HLA alleles can be considered to be risk or protective markers. Donors' HLA types and CMV IgG serostatus should be considered in donor selection.

Evaluation of an electronic, patient-focused management system aimed at preventing cytomegalovirus disease following solid organ transplantation.

Cytomegalovirus (CMV) infection is common among solid organ transplant (SOT) recipients and may cause CMV disease. To optimize the implementation of existing prevention strategies, the Management of Post-transplant Infections in Collaborating Hospitals (MATCH) program was developed. Two key performances of MATCH (diagnosing CMV infection at low viral load (VL) and before the onset of CMV disease) were assessed prior to, during and after the implementation of MATCH. The MATCH program included a personalized surveillance plan, prophylaxis and preemptive therapy determined by the recipient's risk of CMV infection. The plan was composed through predefined algorithms and implemented through harvesting of real-time data from medical records. Risk of CMV disease was compared for recipients transplanted during and after vs prior to the implementation of MATCH. Lung and non-lung transplants were analyzed separately. A total of 593, 349, 520, and 360 SOT recipients were transplanted before (2007-2010), during (2011-2012), early after (2013-2015), and late after (2016-2017) implementation of MATCH with an observed reduction of diagnostic VL (P<.001) over time. Risk of CMV disease was reduced among non-lung transplant recipients transplanted during (adjusted hazard ratios [95% CI] 0.15 [0.04-0.54], P=.003), early after (aHR 0.27 [0.11-0.63], P=.003), and late after (aHR 0.17 [0.06-0.52], P=.002) compared with prior to MATCH. No significant change was observed among lung transplants. Implementation of CMV preventive strategies through MATCH was associated with a reduced risk of CMV disease among non-lung transplant recipients. Furthermore, the limitations of VL as a sole indicator for CMV disease in lung transplants were emphasized.

MOLECULAR DETECTION OF CYTOMEGALOVIRUS IN A SAMPLE OF IRAQI PATIENTS WITH ACUTE LEUKEMIA AND STEM CELL TRANSPLANTATION

Background: Acute leukemia and hematopoietic stem cell transplantation are risk factors for opportunistic infection and reactivation of many latent infection like cytomegalovirus. Objective: Detection and quantification of cytomegalovirus viremia in patients with acute leukemia after induction chemotherapy and post allogeneic stem cell transplantation patients. Methods: A prospective study enrolled 61 patients with acute leukemia. Forty-eight of them evaluated while induction chemotherapy (group I), while the other 13 within 1-year post bone marrow transplantation (BMT) (group II). In addition, 30 apparently healthy individuals were recruited as (control group), blood samples were collected from all groups. Viral DNA was extracted from 1 ml plasma samples, and then, cytomegalovirus DNA was detected and quantitatively assessed by Taqman quantitative real-time PCR. Results: Twelve (25%) out of 48 patients in group I, 2 (15.4%) out of the 13 patients in group II, and 2 (6.7%) out of 30 in the control group had positive cytomegalovirus viremia. The mean cytomegalovirus viremia was 5.192x102, 2.71x102 and 1.60x102 copies/ml for group I, group II and controls respectively, p=0.056. Conclusion: There is a relatively high prevalence of cytomegalovirus viremia in Iraqi patients with acute leukemia after chemotherapy and post BMT. Real-time PCR assay is helpful for early diagnosis of cytomegalovirus viremia in leukemic patients and used to monitor post BMT patients at risk for cytomegalovirus disease. Keywords: HCMV, acute leukemia, stem cell transplantation, real-time PCR Citation: Al-Toban HA, Al-Marsomy HD, Al-Obaidi AB, Al Tameemi WF, Mohammed MA, Al-Saeed RM, Al-Shemary IK. Molecular detection of cytomegalovirus in a sample of iraqi patients with acute leukemia and stem cell transplantation. Iraqi JMS. 2018; 16(3): 344-352. doi: 10.22578/IJMS.16.3.14

Prolonged Low-Dose Prophylaxis With Valganciclovir in Cytomegalovirus-Negative Recipients of Kidney Transplants From Cytomegalovirus-Positive Donors Allows Seroconversion and Prevents Cytomegalovirus Disease

BackgroundCytomegalovirus-negative recipients of kidneys from cytomegalovirus (CMV)-positive donors (D+/R−) are at high risk to develop severe clinical manifestations of CMV disease. Long-term data about incidence and timing of CMV seroconversion, CMV disease, and the influence of prolonged valganciclovir prophylaxis on the clinical course of CMV infection are missing. MethodsWe conducted a retrospective long-term study of 89 consecutive CMV D+/R− kidney transplant recipients transplanted between 2003 and 2012. All recipients received valganciclovir prophylaxis after transplantation (median 187 [126-261] days) with a median dose of 213 (181-338) mg/d. Long-term outcome was assessed over a maximum of 10 years post-transplant. ResultsDuring follow-up (median 62 months) 60 of 89 (67%) patients had CMV seroconversion, and 29 of 89 (33%) developed symptomatic CMV disease. In addition, in 38 of the 60 (63%), seroconversion occurred during prophylaxis (median 154 days post-transplant), and in 22 patients, after the end of prophylaxis (median 320 days after transplantation). Baseline characteristics of the 2 groups did not differ significantly. Seroconversion during prophylaxis vs seroconversion after the end of prophylaxis was associated with significantly lower incidence of CMV disease (34% vs 73%, P = .007), less severe CMV disease (16% vs 64%, P < .001), and fewer organ manifestations (26% vs 64%, P = .006). The risk of CMV disease was limited to the first 475 days after transplantation. Valganciclovir resistance occurred in just 1 case (1%). ConclusionsProlonged prophylaxis with low-dose valganciclovir allowed CMV seroconversion during prophylaxis in a high proportion of D+/R− patients. Seroconversion occurred after a median of 154 days and was associated with significantly lower incidence of CMV disease, less severe CMV disease, and fewer CMV complications.

Clinical significance of the single nucleotide polymorphism TLR2 R753Q in heart transplant recipients at risk for cytomegalovirus disease

BackgroundThe toll-like receptor 2 (TLR2) is a significant component of innate immunity against cytomegalovirus (CMV) infection but information on the clinical significance of the single nucleotide polymorphism (SNP) (R753Q) is conflicting. ObjectivesThe inconsistent observations of the immunological and clinical significance of the TLR2 R753Q polymorphism for CMV infection indicates the influence of confounders. Study designThe presence of the TLR2 polymorphism was determined by a genotyping assay of 175 HTX patients and 281 healthy blood donors and evaluated in relation to selected virological and clinical parameters. ResultsRelative frequency of TLR2 polymorphism was similar in HTX patients and blood donors (homozygous wild-type, 94.3% vs. 94.0%; heterozygous, 5.1% vs. 5.7%; homozygous mutated, <1%). CMV viremia was detectable in 108 (61.7%) of HTX patients. The TLR2 polymorphism was neither associated with occurrence or level of CMV infection nor with survival, graft failure or rejection, or CMV serostatus of patient before transplantation. Nevertheless, CMV viremia occurred in 83.1% of R+/D+, 77.1% of R+/D-, and 64.3% of R-/D+ patients. Time of first CMV viremia was in R-/D+ patients later than in CMV-seropositive patients (median, 182days versus 23 days; P<0.001) corresponding to the duration of antiviral prophylaxis in R-/D+ patients. ConclusionsThe TLR2 R753Q polymorphism is extremely rare in the general population and HTX patients. Screening for this risk factor of CMV disease may not be cost-effective in contrast to testing for CMV viremia.

Does cytomegalovirus viral load in stem-cell transplant recipients matter?

The question of cytomegalovirus (CMV) viral load on outcome after allogeneic stem-cell transplantation has been discussed since the development of quantitative techniques for assessing CMV DNA more than 15 years ago. Emery and colleagues did groundbreaking work in this area that was published in 2000 showing that initial viral load and the rate of viral load increase were predictive of subsequent development of CMV disease in diff erent types of transplant recipients. However, most patients were not given pre-emptive antiviral therapy. Ljungman and colleagues studied recipients of stem-cell transplants who were receiving PCR-based pre-emptive antiviral therapy and were unable to show an eff ect of pretreatment viral load on the risk for CMV disease but that the rate of decrease in viral load predicted development of CMV disease during later CMV replication episodes. Other studies have also addressed this question, providing support for viral load on outcome development of CMV disease, but data for hard endpoints such as survival are lacking. Why is this question important? New drugs against CMV are urgently needed because presently licensed antiviral drugs have important side-eff ects. Until now, regulatory authorities have required hard clinical endpoints in pivotal studies such as survival or development of CMV disease. However, due to developments in the fi eld of CMV management (eg, in pre-emptive therapy) the frequency of these complications has decreased to levels that make it very diffi cult to do such trials because of the large number of patients required. Establishment of a surrogate endpoint such as viral load for studies of CMV would therefore be of major importance, such as is the case for HIV and HCV. A report in The Lancet Haematology by Margaret Green and colleagues provides important information in this regard. First, they used a standardised assay using the international standard to analyse their material. Second, they noted a clear viral-load dependent negative eff ect on outcome measured by hard endpoints such as overall and non-relapse mortality. Third, they identifi ed that commencement of antiviral therapy when CMV replication has started might be too late, because even low viral loads had a negative eff ect on outcome. The fi ndings of this study therefore support the use of viral load as an important study endpoint in future clinical trials and that prevention of CMV replication rather than pre-emptive therapy should be the goal when managing recipients of stem-cell transplants. The limitation of this study is its retrospective design. However, prospective studies of CMV prophylaxis are ongoing and verifi cation of the fi ndings from Green and colleagues’ retrospective study might be possible through analysis of the data from these studies.

Patients with refractory cytomegalovirus (CMV) infection following allogeneic haematopoietic stem cell transplantation are at high risk for CMV disease and non-relapse mortality

Pre-emptive therapy is an effective approach for cytomegalovirus (CMV) control; however, refractory CMV still occurs in a considerable group of recipients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Until now, hardly any data have been available about the clinical characteristics and risk factors of refractory CMV, or its potential harmful impact on the clinical outcome following allo-HSCT. We studied transplant factors affecting refractory CMV in the 100 days after allo-HSCT, and the impact of refractory CMV on the risk of CMV disease and non-relapse mortality (NRM). We retrospectively studied 488 consecutive patients with CMV infection after allo-HSCT. Patients with refractory CMV in the 100 days after allo-HSCT had a higher incidence of CMV disease and NRM than those without refractory CMV (11.9% vs. 0.8% and 17.1% vs. 8.3%, respectively). Multivariate analysis showed that refractory CMV infection in the 100 days after allo-HSCT was an independent risk factor for CMV disease (hazard ratio (HR) 10.539, 95% CI 2.467–45.015, p 0.001), and that refractory CMV infection within 60–100 days after allo-HSCT was an independent risk factor for NRM (HR 8.435, 95% CI 1.511–47.099, p 0.015). Clinical factors impacting on the risk of refractory CMV infection included receiving transplants from human leukocyte antigen-mismatched family donors (HR 2.012, 95% CI 1.603–2.546, p <0.001) and acute graft-versus-host disease (HR 1.905, 95% CI 1.352–2.686, p <0.001). We conclude that patients with refractory CMV infection during the early stage after allo-HSCT are at high risk for both CMV disease and NRM.

Pre-transplant thymic function is associated with the risk of cytomegalovirus disease after solid organ transplantation

Cytomegalovirus (CMV) disease is an important complication in solid organ transplant recipients. Thymic function in adults is associated with specific T-cell immunity. Pre-transplant thymic function was analysed in 75 solid organ transplant patients by the use of nested PCR. The primary outcome was the incidence of CMV disease 12 months after transplantation. Using multivariable logistic regression, we studied whether pre-transplant thymic function is an independent risk factor for CMV disease after transplantation. Thymic function was related to the risk of CMV disease in CMV-seropositive recipients. In these recipients, pre-transplant thymic function of <9.5 (OR 11.27, 95% CI 1.11–114.43, p 0.040) and the use of thymoglobulin (OR 8.21, 95% CI 1.09–61.84, p 0.041) were independent risk factors for CMV disease at 12 months after transplantation. Patients with pre-transplant thymic function values of <9.5 had a higher subsequent incidence of CMV disease (24%) than patients with values of ≥9.5 (3%) (log-rank test: 5.727; p 0.017). The positive and negative predictive values of these pre-transplant thymic function cut-offs were 0.24 (95% CI 0.10–0.45) and 0.97 (95% CI 0.82–1.00), respectively. Pre-transplant thymic function in CMV-seropositive candidates could be useful in determining the risk of post-transplant CMV disease in solid organ transplant patients, selecting a group of low-risk candidates.

Risk of cytomegalovirus disease in high‐risk liver transplant recipients on valganciclovir prophylaxis: A systematic review and meta‐analysis

Valganciclovir (VGC) was approved by the Food and Drug Administration in 2004 as cytomegalovirus (CMV) prophylaxis except for liver transplant recipients because of their high incidence of CMV disease with this drug. However, surveys have shown its common off-label use for CMV prophylaxis in liver transplant recipients. We aimed to evaluate the risk of CMV disease with VGC prophylaxis in liver transplant recipients. All studies that evaluated liver transplant recipients and used VGC (900 or 450 mg daily) for the prevention of CMV disease were included. Five controlled studies (n = 483) were pooled with a random effects model; five single-arm studies (n = 380) were pooled for the prevalence rate of CMV disease. The risk of CMV disease with VGC versus ganciclovir was 1.81 [95% confidence interval (CI) = 1.00-3.29, P = 0.05, I(2) = 0%]. For high-risk (donor-positive/recipient-negative) patients, the risk of CMV disease was 1.96 (95% CI = 1.05-3.67, P = 0.035, I(2) = 0%). The risk of CMV disease remained significant with 900 mg of VGC daily (P = 0.04) but not with 450 mg of VGC daily (P = 0.76). The risk of leukopenia with VGC was 1.87 (95% CI = 1.03-3.37, P = 0.04, I(2) = 0%). In single-arm trials, the overall CMV disease rate was 12% (95% CI = 9%-16%, P < 0.001), and the rate for high-risk patients was 20% (95% CI = 10%-38%, P = 0.002). In conclusion, 900 mg of VGC daily may not be safe as CMV prophylaxis in high-risk liver transplant recipients because of the significant 2-fold increase in the risk of CMV disease and the 1.9-fold increase in the risk of leukopenia. Alternative CMV prophylaxis should be used for liver transplant recipients.

Low levels of mannan-binding lectin or ficolins are not associated with an increased risk of cytomegalovirus disease in HIV-infected patients – A case–control study nested within the Swiss HIV Cohort Study

Low levels of mannan-binding lectin or ficolins are not associated with an increased risk of cytomegalovirus disease in HIV-infected patients – A case–control study nested within the Swiss HIV Cohort Study

Efficacy of a Viral Load-Based, Risk-Adapted, Preemptive Treatment Strategy for Prevention of Cytomegalovirus Disease after Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) surveillance and preemptive therapy is the most commonly used strategy for CMV disease prevention in hematopoietic cell transplantation recipients. In 2007, we introduced a CMV prevention strategy for patients at risk for CMV disease using quantitative PCR surveillance, with treatment thresholds determined by patient risk factors. Patients (N=367) received preemptive therapy either at a plasma viral load of ≥500 copies/mL, at ≥100 copies/mL if receiving ≥1 mg/kg of prednisone or anti-T cell therapies, or if a ≥5-fold viral load increase from baseline was detected. Compared with patients before 2007 undergoing antigenemia-based surveillance (n=690) with preemptive therapy initiated for any positive level, the risk-adapted PCR-based strategy resulted in similar use of antiviral agents, and similar risks of CMV disease, toxicity, and nonrelapse mortality in multivariable models. The cumulative incidence of CMV disease by day 100 was 5.2% in the PCR group compared with 5.8% in the antigenemia group (1 year: 9.1% PCR vs 9.6% antigenemia). Breakthrough CMV disease in the PCR group was predominantly in the gastrointestinal (GI) tract (15 of 19 cases; 79%). However, unlike CMV pneumonia, CMV GI disease was not associated with increased nonrelapse mortality (adjusted hazard ratio, 1.19; P=.70 [GI disease] vs 8.18; P<.001 [pneumonia]). Thus, the transition to a preemptive therapy strategy based on CMV viral load and host risk factors successfully prevented CMV disease without increasing the proportion of patients receiving preemptive therapy and attributable toxicity. Breakthrough disease in PCR-based preemptive therapy occurs at a low incidence and presents primarily as GI disease, which is more likely to be responsive to antiviral therapy.

Acyclovir prophylaxis against cytomegalovirus in high risk paediatric kidney transplant recipients

Aims Cytomegalovirus (CMV) is an important infectious pathogen after kidney transplantation causing significant morbidity and mortality. Several prophylactic antiviral treatments are used and the aim of this study was to review the efficacy of acyclovir prophylaxis to prevent CMV infection in paediatric kidney transplant recipients. Methods The clinical records of kidney transplant recipients over a 20 year period were reviewed. Details of recipient and donor CMV serostatus were recorded together with information regarding prophylaxis received, evidence of CMV infection, and CMV related complications. All patients were scheduled to receive 5 mg/kg loading dose acyclovir peri-operatively and then acyclovir 200 mg qds for 90 days. Results 192 kidney transplants were performed in 177 children between 1991 and 2010. Only first grafts were considered in subsequent analysis. 36 recipients were identified as being at risk of CMV after transplant (i.e. recipient CMV IgG negative, donor CMV IgG positive). All of these patients received oral acyclovir prophylaxis and 58% received an intravenous loading dose. Of these 36 patients, 9 (25%) developed CMV viraemia with a positive CMV PCR. 7 patients met the criteria for CMV disease. 8 of the 9 patients developed viraemia whilst on acyclovir indicating active CMV replication despite treatment. There were no cases of severe infection or tissue invasive disease. There was no graft loss as a consequence of CMV infection. Conclusions The evidence supporting the choice of prophylactic treatment for CMV in paediatric kidney transplant recipients is limited. Recent data from the adult population indicate rates of disease are substantially lower in kidney transplant recipients treated with valganciclovir. These data indicate that in high risk individuals there is substantial risk of CMV disease despite prophylaxis with acyclovir and suggest that prophylaxis with valganciclovir is likely to result in significantly lower rates of CMV disease.

Development of a therapeutic vaccine to prevent cytomegalovirus infection in transplant recipients

August 20-22, 2012 A is a DNA vaccine designed to prevent cytomegalovirus (CMV) infection in both hematopoietic and solid organ transplant recipients at risk for CMV disease. The vaccine consists of two plasmids which encode the tegument protein pp65 and the surface protein gB of CMV. pp65 induces cell-mediated responses and gB induces humoral responses in persons infected with CMV. A Phase 1, dose-ranging trial evaluated safety and immunogenicity of the vaccine in CMV-seronegative and CMVseropositive healthy volunteers. No significant safety events occurred and a cultured ELISPOT assay detected T cell responses in 56-62.5 % of seronegative subjects. A Phase 2 exploratory, double-blind, placebo-controlled trial evaluated the efficacy, immunogenicity, and safety of the vaccine in cytomegalovirus-seropositive hematopoietic cell recipients. 108 transplant recipients received the vaccine. The efficacy population comprises 74 subjects: 34 in the placebo arm and 40 in the ASP0113 treatment arm. The safety population comprises the 108 subjects treated. 19 (48%) of the ASP0113 recipients received cytomegalovirusspecific CMV anti-viral therapy compared with 21 (62%) of placebo recipients (p=0.145). 13(33%) of the ASP0113 recipients reached > 500 copies/mL of CMV by central assay compared with 21 (62%) of placebo recipients (p=0.008). In addition, there was a reduction in the number of CMV infection episodes (p=0.017) and the time to initial viremia (p=0.003). One subject discontinued the vaccine after a hypersensitivity reaction but responded well to conservative medical therapy. Based on these positive findings, further evaluation of the efficacy and safety of the vaccine is planned.

Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8+ T cells during cytomegalovirus infection

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and both CD4(+) and CD8(+) CMV-specific T cells are essential. These virus-specific T cells persist in exceptionally large numbers during the infection, traffic into peripheral tissues and remain functional, making CMV an attractive vaccine vector for driving "CMV-like" T cell responses against recombinant antigens of choice. However, the mechanisms by which these T cells persist and differentiate while remaining functional are still poorly understood, and we have no means to promote their development in immune-compromised patients at risk for CMV disease. In this review, I will briefly summarize our current knowledge of CMV-specific CD8(+) T cells and propose a mechanism that may explain their maintenance and preservation of function during chronic infection.

Betaherpesvirus (Cmv, Hhv-6 and Hhv-7) Active Infections in Brazilian Hematopoietic Stem Cell Transplant Patients

Cytomegalovirus (CMV) is one of the most prevalent infectious pathogen in transplant recipients, including those receiving bone marrow or stem cell grafts. Rapid diagnostic tests to identify active CMV infection and preemptive treatment are significant improvements in the management of CMV. Two newly identified beta herpesviruses, hu - man herpesvirus-6 (HHV-6) and human betaherpesvirus-7 (HHV-7), are genetically more closely related to each other than to CMV and have been frequently detected in the blood of allogeneic HSCT. HHV-6 reactivation has been associated with fever, rash, delayed engraftment and encephalitis. Also, HHV-7 has been reported as a cause of severe central nervous system disease and with severe GVHD and sepsis secondary to immune suppression. Nested polymerase chain reaction in blood samples (serum or leukocytes) was used to monitor active CMV, HHV-6 and HHV-7 infections and disease in forty-three HSCT patients for up to 150 days after transplant. All adult recipients with a risk for CMV disease (D+/R+; D+/R-) were enrolled in this study. Acyclovir was used at low doses prior to the transplant as herpes virus prophylactic therapy. Patients who were at least 2 consecutive N-PCR positive for CMV received preemptive therapy with ganciclovir. The prevalence’s of positive active CMV, HHV-6 and HHV-7 infec- tions were 72%, 4.6% and 13.9%, respectively. Thirteen patients died (30.2%). Biopsies confirmed CMV disease occurred in 8 out of 43 patients (18.6%), in the gastrointestinal tract. All of them presented active CMV infection and one presented active CMV+HHV-6 infection. None of these patients presented active HHV-7 infection. One patient with CMV disease died by disseminated CMV. Detection of active HHV-6 and HHV-7 infections was low and clini cally significant complications were rare. CMV disease remains the most prominent disease associated with HSCT. Results show that surveillance with N-PCR a sensitive, non-invasive and low-cost technique for detection of active beta herpesvirus infections can be used when antigenemia or DNA quantitative methods are unavailable, because patients with a propensity for developing CMV disease can be readily identified and pre-emptive therapy started.

Considering Prophylaxis for Cytomegalovirus Disease in Cytomegalovirus Positive Renal Transplant Recipients from Positive Donors in a Resource Limited South African Public Hospital

Giving cytomegalovirus (CMV) prophylaxis to CMV positive recipients is expensive in a resource-limited setting like South Africa. We report a retrospective analysis of CMV disease in 47 CMV donor/recipient positive (D+/R+) adult renal transplant patients (> 80% African Blacks) from February 2000 to November 2004 who had received four drug induction immune suppression. We commenced routine valganciclovir prophylaxis for 3 months post renal transplant in January 2007 and reviewed incidence of CMV disease from January 2007, in similar patients, until October 2009. Before prophylaxis, incidence of CMV disease was 32% in D+/R+ and was similar to recipient negative/donor positive (D-/R+) patients, however graft survival analysis adjusted for CMV disease showed that D+/R+ recipients had a hazard ratio of 2.8 (p=0.03) for poor graft outcome. After prophylaxis, among deceased donor recipients the incidence of CMV disease over a mean follow up of 17.3 months was 6% (n=2), and nil in live donor recipients. Our immunosuppressive therapy carries a risk of CMV disease in approximately a third of patients and is associated with poorer graft outcomes. CMV prophylaxis has been highly effective at reducing the incidence of CMV disease, and is important in a setting with ever decreasing availability of organs for transplantation.

Cytomegalovirus prophylaxis: how long is enough?

Extending the duration of cytomegalovirus prophylaxis to 6 months in virus-seronegative organ recipients who receive transplants from seropositive donors decreases the risk of cytomegalovirus disease. But is prophylaxis extension the best approach to preventing late-onset cytomegalovirus disease?

Six-Month Prophylaxis Is Cost Effective in Transplant Patients at High Risk for Cytomegalovirus Infection

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of $34,362 and $16,215 per case of infection and disease avoided, respectively, and $8,304 per one quality adjusted life-year gained. Sensitivity analyses supported the cost effectiveness of 6-mo prophylaxis over a wide range of valganciclovir and hospital costs, as well as variation in the incidence of CMV disease. In summary, 6-mo prophylaxis with valganciclovir combined with a one-time determination of viremia is cost effective in reducing CMV infection and disease in seronegative recipients of seropositive kidney and/or pancreas transplants.