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

Limaye, Ajit P.; Bakthavatsalam, Ramasamy; Kim, Hyung W.; Randolph, Sara E.; Halldorson, Jeffrey B.; Healey, Patrick J.; Kuhr, Christian S.; Lévy, A; Perkins, James D.; Reyes, Jorgé; Boeckh, Michael

doi:10.1097/01.tp.0000226071.12562.1a

Cited by 222 publications

(192 citation statements)

References 35 publications

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“…Factors such as age [3] , female gender [3,78] , renal dysfunction [78] , and allograft rejection [13] predisposed to the development of delayedonset primary CMV disease. Delayedonset CMV disease appears to be clinically less severe, although it is associated with signifi cant mortality after li ver transplantation [33] . Because of the negati ve effect of late onset CMV dis ease on overall outcome, a better method for CMV pre vention is needed among CMV D+/R li ver transplant re cipients.…”

Section: Delayed-and Late-onset CMV Diseasementioning

confidence: 99%

“…Indeed, several metaanalyses have demons trated that the use of antiCMV drugs, either through antiviral prophylaxis or preemptive therapy, is associated with significant reductions in mortality after transplan tation [20,3436] . Despite these improvements in outcome with the widespread use of anti viral drugs, CMV disease occurring at a delayed onset after prophylaxis remains a common problem, and notably, remains significantly associated with increased risk of mortality after li ver transplantation [33] . In an analysis of 437 li ver transplant recipients, CMV disease occurred in 37 patients (8.5%) and its occurrence was in dependently associated with a 5fold increased risk of all cause mortality, and an 11fold increased risk of infection related mortality [33] .…”

Section: Impact On Mortalitymentioning

confidence: 99%

“…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%

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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: Delayed-and Late-onset CMV Diseasementioning

confidence: 99%

Section: Impact On Mortalitymentioning

confidence: 99%

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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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“…The disadvantages of universal prophylaxis include prolonged drug expose, the development of resistance and perhaps most importantly, the development of delayed and late-onset CMV disease. [111][112][113] Prophylaxis does not prevent the development of primary CMV infection; it only delays the onset of viral replication, and primary CMV infections are relatively common after the cessation of prophylaxis. Preemptive therapy is time and cost intensive, requiring repeated and vigilant blood testing.…”

Section: Cytomegalovirusmentioning

confidence: 99%

Infections After Orthotopic Liver Transplantation

Pedersen

Seetharam

2014

Journal of Clinical and Experimental Hepatology

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Opportunistic infections are a leading cause of morbidity and mortality after orthotopic liver transplantation. Systemic immunosuppression renders the liver recipient susceptible to de novo infection with bacteria, viruses and fungi post-transplantation as well to reactivation of pre-existing, latent disease. Pathogens are also transmissible via the donor organ. The time from transplantation and degree of immunosuppression may guide the differential diagnosis of potential infectious agents. However, typical systemic signs and symptoms of infection are often absent or blunted after transplant and a high index of suspicion is needed. Invasive procedures are often required to procure tissue for culture and guide antimicrobial therapy. Antimicrobial prophylaxis reduces the incidence of opportunistic infections and is routinely employed in the care of patients after liver transplant. In this review, we survey common bacterial, fungal, and viral infections after orthotopic liver transplantation and highlight recent developments in their diagnosis and management. ( J CLIN EXP HEPATOL 2014;4:347-360) I nfection after orthotopic liver transplantation (OLT) is a major cause of morbidity and mortality. Infection is estimated to occur in upto 80% of organ recipients. Bacterial infections are most frequent (70%), followed by viral (20%) and fungal infections (8%). 1,2,3 In addition to direct effects of infection and end-organ inflammation, pathogens may have a number of indirect effects that result in allograft injury, rejection and opportunistic superinfection.The risk of infection in liver transplant recipients is determined by the intensity of exposure to infectious agents and the overall level of immunosuppression. 4 In addition, conditions attendant to end-stage liver disease in the immediate perioperative period may render a recipient vulnerable to infection and include: neutropenia, deficits in mucocutaneous barrier integrity, presence of necrotic tissue, ischemia, diabetes mellitus, immunomodulating viruses, uremia, and protein-calorie malnutrition. 5 Infectious exposures come from many sources post liver transplant including: de novo (acquired acute) in the recipient, reactivation in the recipient, the donor organ, and nosocomial and time from transplant may provide clues to etiology (Figure 1). The overall level of immunosuppression is dependent upon the dose, duration, and choice of immunosuppression as well as underlying immune deficiencies. 6 Inflammatory responses to invading pathogens are often blunted by immunosuppressive therapy, and as a result, the classic signs or symptoms of infection may be absent. A high index of suspicion is need in the liver recipient, and a low threshold to perform invasive diagnostic procedures is often required. It is critical to identify clinical factors that predispose recipients to infection and much interest centers on identifying risk factors for infection after liver transplant. GENETIC POLYMORPHISMS IN THE INNATE IMMUNE SYSTEMIn addition to clinical factors that promote ...

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

Abstract: 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.

Cited by 222 publications

References 35 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

Infections After Orthotopic Liver Transplantation

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