Delayed-onset Cytomegalovirus Disease Research Articles

Survey of Post-Prophylaxis Delayed-Onset Cytomegalovirus Management Strategies Among Transplant Providers.

Preventive strategies for cytomegalovirus (CMV) in the posttransplant period have changed the pattern of CMV infections, now more commonly manifesting as late-onset occurrences known as post-prophylaxis delayed-onset CMV disease (PPDOC). We conducted a survey to investigate provider practices in managing PPDOC. A web-based provider survey on the management of PPDOC was developed using Research Electronic Data Capture (REDCap). It was distributed to the online forums of the American Society of Transplantation communities of practice (COP) for Infectious Diseases (IDCOP), Kidney and Pancreas (KPCOP), Liver and Intestinal (LICOP), and Thoracic and Critical Care (TCCOP). The survey was posted twice within a span of a month. Fifty-six respondents, comprising 50 (89%) transplant physicians and 6 (11%) transplant pharmacists, from 46 distinct transplant centers, completed the survey. Universal antiviral prophylaxis (UAP) was the predominant preventive approach for both high-risk (85%) and moderate-risk (85%) transplant recipients. Out of 56, 51 respondents completed the questions regarding management of PPDOC. Regular surveillance with nucleic acid amplification tests (NAAT) (88%) was the most commonly used approach in high-risk recipients, while symptom monitoring (73%) was the most common strategy in moderate-risk recipients. Immunologic monitoring was used only by a few respondents who found it moderately useful in high-risk recipients. Management of PPDOC was highly variable among providers and strategies differed based on patient risk profile. These findings could help shape future studies and guidelines to harmonize CMV management.

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors

Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients. To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018. Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46). Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes. ClinicalTrials.gov Identifier: NCT01552369.

Sa1624 Risk Factors for Delayed-Onset Cytomegalovirus Disease in High Risk Liver Transplant Recipients Who Receive Antiviral Prophylaxis

Sa1624 Risk Factors for Delayed-Onset Cytomegalovirus Disease in High Risk Liver Transplant Recipients Who Receive Antiviral Prophylaxis

Incidence, Risk Factors and Outcomes of Delayed-onset Cytomegalovirus Disease in a Large Retrospective Cohort of Lung Transplant Recipients.

Cytomegalovirus (CMV) replication and disease commonly occur in lung transplant recipients after stopping anti-CMV prophylaxis. The epidemiology of CMV disease is not well studied, given the difficulties in assembling representative study populations with prolonged follow-up. We hypothesized that delayed-onset CMV disease (>100 days after transplantation) occurs more commonly than early-onset CMV disease in lung transplant recipients, and is associated with an increased risk of death. We assembled a large cohort of lung transplant recipients using 2004 to 2010 International Classification of Diseases, Ninth Revision, Clinical Modification billing data from 3 Agency for Healthcare Research and Quality State Inpatient Databases, and identified demographics, comorbidities, CMV disease coded during hospital readmission and inpatient death. We used Cox proportional hazard multivariate analyses to assess for an independent association between delayed-onset CMV disease and death. In the cohort of 1528 lung transplant recipients from 12 transplant centers, delayed-onset CMV disease occurred in 13.7% (n = 210) and early-onset CMV disease occurred in 3.3% (n = 51). Delayed-onset CMV pneumonitis was associated with inpatient death longer than 100 days after transplantation (adjusted hazard ratio, 1.6; 95% confidence interval [95% CI], 1.1-2.5), after adjusting for transplant failure/rejection (aHR, 2.5; 95% CI, 1.5-4.1), bacterial pneumonia (aHR, 2.8; 95% CI, 2.0-3.9), viral pneumonia (aHR, 1.5; 95% CI, 1.1-2.1), fungal pneumonia (aHR, 1.8; 95% CI, 1.3-2.3), single lung transplant (aHR, 1.3; 95% CI, 1.0-1.7), and idiopathic pulmonary fibrosis (aHR, 1.4; 95% CI, 1.0-1.8). Delayed-onset CMV disease occurred more commonly than early-onset CMV disease among lung transplant recipients. These results suggest that delayed-onset CMV pneumonitis was independently associated with an increased risk of death.

Delayed-onset cytomegalovirus disease coded during hospital readmission in a multicenter, retrospective cohort of liver transplant recipients.

Delayed-onset cytomegalovirus (CMV) disease can occur among liver transplant recipients after CMV prophylaxis is stopped. We hypothesized that delayed-onset CMV disease (>100 days after transplant) occurs more commonly than early-onset CMV disease and is associated with clinical sepsis and death. Using 2004-2010 International Classification of Diseases, Ninth Revision, Clinical Modification billing data from 4 Healthcare Cost and Utilization Project state inpatient databases, we assembled a large and more representative cohort of 7229 adult liver transplant recipients from 26 transplant centers, and we identified demographics, comorbidities, CMV disease, and clinical sepsis coded during readmission and inpatient death. Multivariate analysis was performed with Cox proportional hazards models. Delayed-onset CMV disease occurred in 4.3% (n = 309), whereas early-onset CMV disease occurred in 2% (n = 142). Delayed-onset CMV disease was associated with previous transplant failure or rejection [adjusted hazard ratio (aHR), 1.4; 95% confidence interval (CI), 1.1-1.7]. Clinical sepsis > 100 days after transplant was associated with previous CMV disease (aHR, 1.3; 95% CI; 1.0-1.7), previous transplant failure or rejection (aHR, 2.1; 95% CI; 1.8-2.4), female sex (aHR, 1.3; 95% CI; 1.1-1.5), and several comorbidities. Death > 100 days after transplant was associated with delayed-onset CMV disease (aHR, 2.0; 95% CI; 1.6-2.6), transplant failure or rejection (aHR, 4.3; 95% CI; 3.4-5.5), increasing age by decade (aHR, 1.1; 95% CI; 1.0-1.2), and some comorbidities. In conclusion, delayed-onset CMV disease is more common than early-onset CMV disease among liver transplant recipients. Previous CMV disease may be a risk factor for clinical sepsis > 100 days after transplant, and delayed-onset CMV disease may be a risk factor for death > 100 days after transplant.

Efficacy of Extended Valganciclovir Prophylaxis in Preventing Cytomegalovirus Infection in Pediatric Kidney Transplantation

Cytomegalovirus (CMV) is one of the most frequent opportunistic infection in renal transplant (RTx) recipients. Valganciclovir (VGC) has been showed to be safe and highly effective in prophylaxis of CMV infection in RTx recipients. Recently, an increase in delayed onset CMV disease has been noted with some arguing that longer prophylaxis may decrease the late-onset disease. We retrospectively tested the hypothesis that extended term prophylaxis (ETP) of VGC for 12 months is more effective than short term prophylaxis (STP) of 6 months in preventing CMV infection and disease in pediatric RTx performed at the University of Florida from July 2003 to December 2010. In this period, all recipients underwent prospective CMV PCR (Polymerase Chain Reaction) monitoring and were maintained on similar immunosuppression. Eighty six patients received RTx during that period. All eligible subjects had to have at least 12 months of graft survival and 18 months of follow up, leaving 73 eligible subjects in final study group. CMV infection or disease occurred in 6/29 (20%) in the STP group vs 6/44 (14%) in the ETP group with no statistical significant difference (P= 0.42). Donor positive/recipients negative CMV serology status (D+/R-) were associated with a higher risk of CMV infection in both univariate and multivariate analysis (P=0.01). Anemia and Leucopenia directly associated with VGC were similar in both groups (P=0.58 and P=0.2 respectively). Biopsy-proven acute rejection was also non-significant in both groups (P=0.39). Although ETP for CMV from 6 months to 12 months is safe and has minimal adverse effect, it did not reduce CMV infection or disease. Further controlled studies in pediatrics age group are considered to compare longer versus shorter periods of prophylaxis and their impact on prevention of CMV infection, resistance, cost, and toxicity.

Efficacy of Extended Valganciclovir Prophylaxis in Preventing Cytomegalovirus Infection in Pediatric Kidney Transplantation.

Cytomegalovirus (CMV) is one of the most frequent opportunistic infection in renal transplant (RTx) recipients. Valganciclovir (VGC) has been showed to be safe and highly effective in prophylaxis of CMV infection in RTx recipients. Recently, an increase in delayed onset CMV disease has been noted with some arguing that longer prophylaxis may decrease the late-onset disease.We retrospectively tested the hypothesis that extended term prophylaxis (ETP) of VGC for 12 months is more effective than short term prophylaxis (STP) of 6 months in preventing CMV infection and disease in pediatric RTx performed at the University of Florida from July 2003 to December 2010. In this period, all recipients underwent prospective CMV PCR (Polymerase Chain Reaction) monitoring and were maintained on similar immunosuppression.Eighty six patients received RTx during that period. All eligible subjects had to have at least 12 months of graft survival and 18 months of follow up, leaving 73 eligible subjects in final study group. CMV infection or disease occurred in 6/29 (20%) in the STP group vs 6/44 (14%) in the ETP group with no statistical significant difference (P= 0.42). Donor positive/recipients negative CMV serology status (D+/R-) were associated with a higher risk of CMV infection in both univariate and multivariate analysis (P=0.01). Anemia and Leucopenia directly associated with VGC were similar in both groups (P=0.58 and P=0.2 respectively). Biopsy-proven acute rejection was also non-significant in both groups (P=0.39).Although ETP for CMV from 6 months to 12 months is safe and has minimal adverse effect, it did not reduce CMV infection or disease. Further controlled studies in pediatrics age group are considered to compare longer versus shorter periods of prophylaxis and their impact on prevention of CMV infection, resistance, cost, and toxicity.

Incidence, Risk Factors, and Outcomes of Delayed-Onset Cytomegalovirus Disease in a Large, Retrospective Cohort of Heart Transplant Recipients

BackgroundDelayed-onset cytomegalovirus (CMV) disease can occur among heart transplant recipients after stopping anti-CMV prophylaxis. We evaluated a large, retrospective cohort of heart transplant recipients in the United States through the use of billing data from 3 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) to determine the epidemiology of delayed-onset CMV disease coded during hospital readmission. MethodsWe identified 2280 adult heart transplant recipients from 2004 to 2010 through the use of the California, Florida, and New York SID. Demographics, comorbidities, heart failure etiology, CMV disease, and inpatient death were identified. CMV disease was classified as early-onset (≤100 days) or delayed-onset (>100 days after transplant). Possible tissue invasion by CMV was determined through the use of codes for CMV pneumonitis, hepatitis, and gastrointestinal endoscopy. Multivariate analysis was performed with the use of Cox proportional hazards models. ResultsDelayed-onset CMV disease occurred in 7.5% (170/2280) and early-onset CMV disease occurred in 2.0% (45/2280) of heart transplant recipients. Risk factors for delayed-onset CMV disease included residence in a non-metropolitan locale (aHR. 1.8; 95% confidence interval [CI], 1.0–3.3) and ischemic cardiomyopathy as heart failure etiology (aHR, 1.8; 95% CI, 1.3–2.5). Inpatient death >100 days after transplant was associated with delayed-onset CMV disease with possible tissue invasion (aHR, 2.0; 95% CI, 1.1–3.8), transplant failure or rejection (aHR, 4.0; 95% CI, 2.7–5.8), and renal failure (aHR, 1.5; 95% CI, 1.1–2.0). ConclusionsDelayed-onset CMV disease is more common than early-onset CMV disease among heart transplant recipients. These results suggest that delayed-onset tissue-invasive CMV disease may be associated with an increased risk of death.

Delayed-Onset Cytomegalovirus Disease Coded During Hospital Readmission After Kidney Transplantation

Use of prophylactic anti-CMV therapy for 3 to 6 months after kidney transplantation can result in delayed-onset CMV disease. We hypothesized that delayed-onset CMV disease (occurring >100 days posttransplant) occurs more commonly than early-onset CMV disease and that it is associated with death. We assembled a retrospective cohort of 15,848 adult kidney transplant recipients using 2004 to 2010 administrative data from the California and Florida Healthcare Cost and Utilization Project State Inpatient Databases. We identified demographic data, comorbidities, CMV disease coded during readmission, and inpatient death. We used multivariate Cox proportional hazards modeling to determine risk factors for delayed-onset CMV disease and inpatient death. Delayed-onset CMV disease was identified in 4.0%, and early-onset CMV disease was identified in 1.2% of the kidney transplant recipients. Risk factors for delayed-onset CMV disease included previous transplant failure or rejection (HR 1.4) and residence in the lowest-income ZIP codes (HR 1.2). Inpatient death was associated with CMV disease occurring 101 to 365 days posttransplant (HR 1.5), CMV disease occurring greater than 365 days posttransplant (HR 2.1), increasing age (by decade: HR 1.5), nonwhite race (HR 1.2), residence in the lowest-income ZIP codes (HR 1.2), transplant failure or rejection (HR 3.2), previous solid organ transplant (HR 1.7), and several comorbidities. These data showed that delayed-onset CMV disease occurred more commonly than early-onset CMV disease and that transplant failure or rejection is a risk factor for delayed-onset CMV disease. Further research should be done to determine if delayed-onset CMV disease is independently associated with death.

444Incidence, Risk Factors and Outcomes of Delayed-Onset Cytomegalovirus Disease in a Large Retrospective Cohort of Lung Transplant Recipients

444Incidence, Risk Factors and Outcomes of Delayed-Onset Cytomegalovirus Disease in a Large Retrospective Cohort of Lung Transplant Recipients

24 Weeks of Valganciclovir Prophylaxis in Children After Renal Transplantation: A 4-Year Experience

Cytomegalovirus (CMV) is the most common opportunistic infection after solid-organ transplant. Valganciclovir prophylaxis significantly reduces disease, but limited data are available on its use in children. Recently, an increase in delayed-onset CMV disease has been noted with some arguing that longer prophylaxis may decrease late-onset disease. Single-center, retrospective analysis of pediatric renal transplant patients receiving 24 weeks valganciclovir prophylaxis (15 mg/kg/day, maximum 900 mg/day) from January 2004 to December 2008, aiming to measure the incidence of CMV disease and toxicity of valganciclovir. We enrolled 111 patients, 60% males, 46% African Americans, and median age at transplant 14.5 years (range 1.4-20.4 years). Sixty-nine percent of donors and 44% of recipients were seropositive pretransplant. Median duration of valganciclovir use was 5.9 months (range 0.5-24 months). CMV viremia and disease occurred in 27% and 4.5%, respectively. All patients with disease presented after prophylaxis ended and all were D+/R-. Thymoglobulin use (P = 0.04) and positive donor CMV status (P = 0.02) were associated with a higher risk of CMV viremia. Twenty-four percent had hematologic toxicity directly associated with valganciclovir. Valganciclovir use in children was effective as prophylaxis against CMV disease; no children at our institution developed disease while on therapy. Our regimen of 24 weeks of prophylaxis was associated with a lower rate of late-onset disease than previous reports with 12-week regimens. Further controlled studies should be considered to compare longer versus shorter periods of prophylaxis and dose reductions and their impact on prevention of late-onset disease, resistance, cost, and toxicity.

New Developments in the Management of Cytomegalovirus Infection after Solid Organ Transplantation

Despite remarkable advances in the diagnostic and therapeutic modalities for its management, cytomegalovirus (CMV) remains one of the most important pathogens impacting on the outcome of transplantation. Not only does CMV directly cause morbidity and occasional mortality, it also influences many short-term and long-term indirect effects that collectively contribute to reduced allograft and patient survival. Prevention of CMV infection and disease is therefore key in ensuring the successful outcome of solid organ transplantation (SOT). In this regard, antiviral prophylaxis and pre-emptive therapy are similarly effective in preventing CMV disease after transplantation. However, current guidelines prefer antiviral prophylaxis over pre-emptive therapy in preventing CMV disease in high-risk SOT recipients, such as CMV-seronegative recipients of organs from CMV-seropositive donors (CMV D+/R-), and lung, intestinal and pancreas transplant recipients. Antiviral prophylaxis has the benefits of reducing not only the incidence of CMV disease, but also the indirect effects of CMV on allograft and patient survival. The major drawback of antiviral prophylaxis is delayed-onset CMV disease, which occurs in 15-38% of CMV D+/R- SOT recipients who received 3 months of prophylaxis. Allograft rejection, over-immunosuppression and lack of CMV-specific immunity are factors that predispose patients to delayed-onset CMV disease. A recent randomized trial in CMV D+/R- kidney recipients demonstrates a significant reduction in the incidence of CMV disease when valganciclovir prophylaxis is extended to 200 days (compared with the standard 100 days) after transplantation; however, the safety and cost of this prolonged approach has yet to be assessed. In some studies, delayed-onset CMV disease has been significantly associated with allograft loss and mortality. In the vast majority of patients, CMV disease responds to treatment with intravenous ganciclovir. Recently, oral valganciclovir was demonstrated to have an efficacy that is comparable to intravenous ganciclovir in treating mild to moderate cases of CMV disease in SOT recipients. Reduction in the degree of immunosuppression should complement antiviral treatment of CMV disease. Although it remains rare, ganciclovir-resistant CMV disease is increasingly seen in clinical practice, potentially fostered by the prolonged use of antivirals in high-risk over-immunosuppressed transplant recipients. Treatment of drug-resistant CMV is currently non-standardized and may include foscarnet, cidofovir, CMV hyperimmune globulins or leflunomide. The investigational drug marivabir had the potential to treat ganciclovir-resistant CMV disease as it acts through a different mechanism. However, the recent phase III clinical trial in allogeneic bone marrow transplant recipients showed that maribavir was not significantly better than placebo for the prevention of CMV disease. Similarly, the preliminary data in a liver transplant population suggests that maribavir was inferior to oral ganciclovir for the prevention of CMV disease. This article reviews the recent data and other developments in the management of CMV infection after SOT.

A prospective longitudinal analysis of cytomegalovirus (CMV)-specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection

Cytomegalovirus (CMV)-specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV-specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine-flow cytometry, we enumerated interferon-gamma producing CMV-specific CD4+ and CD8+ T cells at serial time points among CMV-mismatched (D+/R-) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (+ or - SD) time of 151 (+ or - 33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue-invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R-) status (HR: 13, 95% CI: 1.6-106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1-27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change-over-time in CMV-specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE-1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV-specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV-specific T cell assays will need to be assessed in a larger cohort of CMV D+/R- kidney recipients who remain at high-risk of delayed-onset CMV disease.

Deficiency of cytomegalovirus (CMV)‐specific CD8+ T cells in patients presenting with late‐onset CMV disease several years after transplantation

Cytomegalovirus (CMV) is a major cause of morbidity and mortality among transplant recipients. The routine use of anti-CMV prophylaxis has modified the epidemiology of post-transplant CMV infection by delaying the onset of clinical disease. While the majority of delayed-onset CMV disease still occurs during the first year after transplant, reports of late-onset CMV disease presenting many years after transplantation are increasing. Here, we describe 2 CMV-seropositive transplant recipients who presented with late-onset CMV disease at 8 and 11 years after transplantation. To determine whether CMV disease occurring at a very late period after transplantation is related to immune competence, we assessed global and CMV-specific cellular immunity by evaluating the activation capability of CD8+ T cells to a mitogenic stimulus and by quantitative and functional analysis (as assessed by intracellular cytokine production and degranulation) of CMV-specific CD8+ T cells. In both patients, we demonstrated the absence or marked deficiency of CMV-specific T-cell immunity despite CMV seropositivity, and in one patient, a partial defect in the immune response to phorbol myristate acetate and ionomycin suggesting impaired global immune competence. Hence, our data suggest that late-onset CMV disease occurring many years after transplantation remains related to defects in the immune competence of patients. Measurement of CMV-specific cellular immune competence may therefore provide an additional tool to screen for patients at high risk of developing late-onset CMV disease. The clinical utility of this assay, however, will need to be evaluated in larger prospective studies.

Delayed-Onset Primary Cytomegalovirus Disease and the Risk of Allograft Failure and Mortality after Kidney Transplantation

During the contemporary era of antiviral prophylaxis, the impact of delayed-onset primary cytomegalovirus (CMV) disease on the outcome of kidney transplantation is not known. We evaluated the incidence, clinical features, risk factors, and outcomes of CMV disease among high-risk kidney transplant recipients. The medical records of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors were reviewed. Cox proportional hazards regression was used to identify factors associated with CMV disease and to assess its impact on allograft loss and mortality. None of the 176 CMV-seronegative recipients of kidney transplants from CMV-seropositive donors developed breakthrough CMV disease during a median of 92 days (interquartile range, 90-92 days) of oral ganciclovir or valganciclovir prophylaxis. Thereafter, 51 patients (29%) developed CMV disease at a median of 61 days (interquartile range, 40-143 days) after stopping antiviral prophylaxis. Early-onset bacterial and fungal infection (hazard ratio, 3.61; 95% confidence interval, 1.78-7.33; p < .001) and a Charlson comorbidity index > or =3 (hazard ratio, 2.21; 95% confidence interval, 1.15-4.22; p = .011) were associated with a higher risk of delayed-onset primary CMV disease, and postrejection antiviral prophylaxis (hazard ratio, 0.29; 95% confidence interval, 0.09-0.94; P = .039) was associated with a lower risk of such CMV disease. A time-dependent Cox regression analysis revealed a statistically significant association between tissue-invasive CMV disease and allograft loss or mortality (hazard ratio, 2.85; 95% confidence interval, 1.22-6.67; P = .016). This study of a large cohort of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors illustrates the ongoing challenge of delayed-onset primary CMV disease and its impact on transplantation outcomes despite antiviral prophylaxis. Better strategies for CMV disease prevention after kidney transplantation are warranted.

Cytomegalovirus infection after liver transplantation: Current concepts and challenges

Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.

Cytomegalovirus disease in solid organ transplant recipients: advances lead to new challenges and opportunities

Purpose of review Despite advances in its management, cytomegalovirus remains a significant pathogen that influences the outcome of solid organ transplantation. Herein, the current epidemiology of cytomegalovirus disease and its prevention and treatment are discussed. Recent findings Antiviral prophylaxis is preferred over preemptive therapy in preventing cytomegalovirus disease in cytomegalovirus donor seropositive/recipient seronegative (D+/R−) solid organ transplantation recipients. Antiviral prophylaxis is complicated by delayed-onset cytomegalovirus disease. Risk factors for delayed-onset cytomegalovirus disease include cytomegalovirus D+/R− status, allograft rejection, and severe immunosuppression. The potential roles of innate and adaptive immune responses in cytomegalovirus predisposition are being recognized. Delayed-onset cytomegalovirus disease is associated with allograft loss and mortality, and in some cases, the disease is due to drug-resistant virus. The optimal method for preventing delayed-onset cytomegalovirus disease is not defined. Randomized trials comparing 100 versus 200 days of valganciclovir prophylaxis, and maribavir versus ganciclovir prophylaxis are underway. A recent trial demonstrated comparable efficacy between valganciclovir and intravenous ganciclovir in treating cytomegalovirus disease in solid organ transplantation recipients. Summary The clinical impact of cytomegalovirus on the outcome of solid organ transplantation remains evident in the era of antiviral prophylaxis. The challenges of delayed disease and drug resistance provide opportunities for optimizing the current management of cytomegalovirus disease after solid organ transplantation.

Clinical Features and Outcomes of Delayed-onset Primary Cytomegalovirus Disease in Cardiac Transplant Recipients

Cytomegalovirus (CMV)-seronegative recipients of cardiac allografts from CMV-seropositive donors (CMV D(+)/R(-)) are at highest risk of CMV disease after transplantation. This study was conducted to investigate the incidence, clinical features, risk factors and outcome of delayed-onset primary CMV disease in cardiac recipients who received anti-CMV prophylaxis. This study enrolled all CMV D(+)/R(-) cardiac recipients during the period from 2000 to 2004. The medical records of patients were reviewed to assess clinical variables and outcomes. The data were analyzed using descriptive statistics and survival analysis. During the 5-year study period, a total of 31 cardiac recipients had CMV D(+)/R(-) serostatus (mean age +/- SD: 49.2 +/- 13.7 years; 74% male). All patients received oral ganciclovir (n = 6) or valganciclovir (n = 25) prophylaxis for a median duration of 95 days (interquartile range: 90 to 100). No breakthrough CMV disease was observed. However, 9 (29%) patients developed delayed-onset primary CMV disease (3 with CMV syndrome, 6 with gastrointestinal disease) during the period from 120 to 444 days after transplantation. No demographic or clinical variable was significantly associated with delayed-onset primary CMV disease. However, acute rejection with a severity of Grade >or=2 showed a trend toward association with CMV disease (hazards ratio: 2.46; 95% confidence interval: 0.66 to 9.2; p = 0.18). During the mean (+/-SD) follow-up period of 2.9 (+/-1.68) years, 3 patients died. CMV disease was not associated with all-cause mortality. In the contemporary era of anti-viral prophylaxis, delayed-onset primary CMV disease remains a common complication among CMV D(+)/R(-) cardiac recipients. This finding warrants a better strategy for CMV prevention.

Emergence of drug‐resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes

Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir-resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug-resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis. The medical records of all CMV D+/R- kidney, pancreas, liver, and heart recipients were screened for CMV disease, and the clinical course and outcomes of patients with drug-resistant CMV were reviewed. During a four-yr-study period, a total of 225 CMV D+/R- transplant patients received valganciclovir prophylaxis for a median of 92 d. Sixty-five (29%) of the 225 patients developed delayed-onset primary CMV disease, including nine (14%) suspected to have drug-resistant virus. Four (6.2%) had confirmed UL97 or UL54 mutations. All except one patient manifested gastrointestinal tissue-invasive disease. Together with reduction in immunosuppression, intravenous foscarnet with or without CMV hyperimmunoglobulin was the most common treatment. Drug-associated nephrotoxicity was commonly observed and resulted in allograft loss in two patients. During the mean follow-up of 2.2 yr, allograft loss and mortality occurred in two of four patients with proven and in three of five patients with clinically suspected drug-resistant CMV. Cytomegalovirus disease because of clinically suspected or genotypically confirmed drug-resistant CMV is not uncommon in CMV D+/R- solid organ transplant patients who received valganciclovir prophylaxis. Because of its significant morbidity and mortality, an optimized strategy of CMV prevention is warranted to reduce the negative impact of drug-resistant CMV on the successful outcome of organ transplantation.

Delayed-onset primary cytomegalovirus disease after liver transplantation

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor-positive/recipient-negative (D+/R-) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R- liver transplant recipients who received antiviral prophylaxis. Sixty-seven CMV D+/R- liver transplant recipients (mean age+/-standard deviation: 49.5+/-11.4 years; 75% male) received oral ganciclovir [n=9 (13%)] or valganciclovir [n=58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91-100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed-onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P=0.01) and younger age at transplant (P=0.03) were associated with an increased risk, whereas diabetes mellitus (P<0.001) was significantly associated with a lower risk of delayed-onset primary CMV disease. Allograft loss or mortality occurred in 8 (12%) patients during the median follow-up period of 3.31 (range: 0.8-5.9) years. No significant association was observed between CMV disease and patient and allograft survival. In conclusion, CMV disease remains a common complication in CMV D+/R- liver transplant patients during the contemporary era of antiviral prophylaxis. Female patients and younger patients are at increased risk of delayed-onset primary CMV disease.