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

Arthurs, Supha K.; Eid, Albert J.; Pedersen, Rachel; Kremers, Walter K.; Cosio, Fernando G.; Patel, Robin; Razonable, Raymund R.

doi:10.1086/528718

Cited by 249 publications

(227 citation statements)

References 36 publications

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“…Through direct, indirect and possibly immunomodulatory mechanisms, CMV is an important predictor of mortality after transplantation [20,32,33] . Prior to the availability of intravenous (IV) and oral ganciclovir, CMV was a major cause of mortality after liver transplantation.…”

Section: Impact On Mortalitymentioning

confidence: 99%

Current concepts on cytomegalovirus infection after liver transplantation

Lee

Razonable

2010

WJH

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Cytomegalovirus (CMV) is the most common viral pathogen that negatively impacts on the outcome of liver transplantation. CMV cause febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted allograft. In addition, CMV has been significantly asso ciated with an increased predisposition to allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall pa tient and allograft survival. To negate the adverse effects of CMV on outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is regarded as an essential component to the medical management of liver transplant patients. Two recent guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver trans plant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the preven tion of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R-liver transplant recipients, and at least in one study, such occurrence of late-onset primary CMV disease was significantly associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention are needed, and aggressive treatment of CMV infection and disease should be pursued. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, one should also reduce the degree of immunosuppression. In one recent controlled clinical trial, val ganciclovir was found to be as effective and safe as intravenous ganciclovir for the treatment of mild to mo derate CMV disease in solid organ (including liver) tran splant recipients. In this article, the authors review the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.

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Section: Impact On Mortalitymentioning

confidence: 99%

Current concepts on cytomegalovirus infection after liver transplantation

Lee

Razonable

2010

WJH

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“…First, a significant number of patients (approximately 20-30% of Dþ/RÀ patients) may still develop CMV disease after discontinuation of prophylaxis (15,16). This is termed ''late-onset CMV disease'' and some studies suggest that it remains associated with poor outcomes in SOT recipients (17,18). Second, the preemptive approach, by allowing low-grade viral replication during the early posttransplant period, may not appropriately prevent the occurrence of CMV-associated indirect effects, and therefore long-term transplant outcomes might be inferior as compared to patients receiving antiviral prophylaxis (11).…”

Section: Introductionmentioning

confidence: 99%

Impact of Antiviral Preventive Strategies on the Incidence and Outcomes of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Manuel

Kralidis

Mueller

et al. 2013

American Journal of Transplantation

100

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We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant recipients.Risk factors associated with CMV disease and graft failure-free survival were analyzed using Cox regression models. One thousand two hundred thirty-nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (Dþ/RÀ vs. Rþ, hazard ratio [HR] 5.36 [95% CI 3.14-9.14], p < 0.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 [95% CI 0.63-2.17], p ¼ 0.63). CMV disease was not associated with a lower graft failure-free survival (HR 1.27 [95% CI 0.64-2.53], p ¼ 0.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure-free survival after a median of 1.05 years of follow-up (HR 1.63 [95% CI 1.01-2.64], p ¼ 0.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.

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“…Because EOD occurs mainly after a preemptive strategy, we believe that this strategy is not appropriate in D+RÀ patients and argue strongly for universal prophylaxis in these high-risk patients. Moreover, in na€ ıve D+/RÀ patients, universal prophylaxis is thought to hamper the development of a specific immune response, causing more late-onset CMV infections than the preemptive approach (3,39), with increased morbidity (10). This observation could argue for the choice of a preemptive strategy.…”

Section: Discussionmentioning

confidence: 99%

“…In one study directly comparing prophylactic and preemptive approaches, it was clearly demonstrated that late DNAemia occurs much more frequently in the prophylactic versus the preemptive setting (3,4). In addition, late DNAemia has been associated with poor prognosis, with a reduction in graft survival and higher patient mortality (5)(6)(7)(8)(9)(10). Moreover, it has been claimed that the preemptive strategy, usually associated with CMV DNAemia or early onset disease (EOD), may have the advantage of boosting antiviral immunity by exposure to asymptomatic DNAemia compared with universal prophylaxis (11).…”

Section: Introductionmentioning

confidence: 99%

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants

Kaminski

Couzi

Garrigue³

et al. 2016

American Journal of Transplantation

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Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+RÀ). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vd2-negative (Vd2 neg ) cd T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+RÀ KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vd2 neg cd T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+RÀ KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD.

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

Cited by 249 publications

References 36 publications

Current concepts on cytomegalovirus infection after liver transplantation

Current concepts on cytomegalovirus infection after liver transplantation

Impact of Antiviral Preventive Strategies on the Incidence and Outcomes of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants

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