Cytomegalovirus in Solid Organ Transplant Recipients

CMV infection is a major cause of morbidity in patients receiving solid organ transplants. CMV is widely distributed in the general population with seroprevalence ranging from 30 to 97% (1-3). After primary infection, CMV establishes life-long latency. Without some form of prevention, CMV infection primarily occurs in the first 3 months following transplant. Onset may be delayed in patients receiving CMV prophylaxis. The following definitions are commonly used in the transplant literature and are consistent with the AST recommendations for use in clinical trials (4): CMV infection: evidence of CMV replication regardless of symptoms (differs from latent CMV). CMV disease: evidence of CMV infection with attributable symptoms. CMV disease can be further categorized as either a viral syndrome with fever and/or malaise, leukopenia, thrombocytopenia or as tissue invasive disease (e.g. pneumonitis, hepatitis, retinitis, gastrointestinal disease). In addition, several features unique to pediatric transplantation are discussed separately in this document. CMV has a predilection to invade the allograft, likely in part due to an aberrant immune response within the allograft (1). To directly attributable morbidity, CMV likely also has an immunomodulatory effect, and active CMV infection has been found to be an independent risk factor for the development of other infectious complications, such as bacteremia, invasive fungal disease and EBV-related PTLD (5, 6). CMV has also been implicated as a cause of acute and chronic allograft injury. There is evidence that CMV may play a crucial role in chronic graft vasculopathy resulting in lesions, such as chronic allograft nephropathy, bronchiolitis obliterans (lung transplant) and accelerated coronary artery disease (heart transplant) (5, 6). The risk of CMV disease is highest in donor-positive, recipient-seronegative (D+R–) solid organ transplant patients who lack cellular and humoral immunity to CMV. Other risk factors for disease include the recipient's overall state of immunosuppression determined by the immunosuppressive protocol (e.g. type of drug, dose, timing, duration) and various host factors (e.g. age, comorbidity, neutropenia). Antilymphocyte antibodies (ALA) (such as thymoglobulin) as either induction or antirejection therapy are associated with high rates of CMV disease (1-3). The risk is maximal when ALA therapy is used for the treatment of organ rejection, with CMV disease being diagnosed three to four times more frequently than in patients not receiving ALA therapy (2). The risk of CMV also varies with the type of transplant. Lung, small intestinal and pancreas transplant recipients have the highest risk for CMV while liver and kidney recipients are at lower risk for CMV disease. This may be due to the degree of immunosuppression, and/or the viral load present in the transplanted allograft. Co-infection with related viruses such as HHV-6 and 7 may also be an important risk factor for CMV disease (1). The lowest risk of CMV disease occurs in the D–/R– setting, provided these patients are given CMV negative blood or leukodepleted blood products (1). Pretransplant CMV IgG screening of donors and recipients should be performed to allow for risk stratification (II-1). CMV D–/R– transplant recipients should receive CMV negative blood or leukodepleted blood during and posttransplant (II-1). The diagnosis of CMV infection and disease has evolved considerably. Historically, the diagnosis of CMV disease has been made by histopathology. This approach is limited, however, by the fact that an invasive procedure is required to obtain samples. Serologic assays appear to have limited clinical utility posttransplant, and should not be used to diagnose acute disease in SOT patients (7). For years, culture-based methods (tissue culture and shell-vial centrifugation culture) were used for CMV diagnosis. Tissue culture can take weeks, however, and the shell-vial centrifugation assay is insensitive by comparison with molecular assays (8). Tissue culture methods may still useful in growing CMV isolates in the laboratory for phenotypic antiviral resistance testing, although the latter technique has been replaced predominantly by genotypic resistance testing. The pp65 antigenemia assay is a semi-quantitative fluorescent assay based on detection of infected cells in peripheral blood. This assay has far higher sensitivity and specificity than culture-based methods (8), and is comparable in sensitivity to CMV PCR (see further) (9). Though not fully quantitative, it can provide an estimate of the magnitude of viral load from the number of infected cells. Molecular diagnostic tests may detect DNA or RNA and can be qualitative and quantitative. The majority of these tests are quite sensitive for the detection of CMV. Measurement of quantitative CMV-DNA levels has become popular at many centres. Commonly used assays include plasma or whole blood based PCR testing which is either commercially available or developed in-house. Whole blood assays will often have higher viral loads than those using plasma. Generally, the highest viral loads are associated with tissue-invasive disease, while the lowest are seen with asymptomatic CMV infection, and intermediate-range viral loads seen in patients with CMV syndrome (10); there is wide overlap, however, between these categories. In addition to the absolute value of viral load, the rate of rise is also an important factor (11). Occasionally patients with tissue invasive disease (especially gastrointestinal or retinal disease) will have undetectable blood viral loads. Both the pp65 antigenemia assay and quantitative CMV viral load testing can be utilized in preemptive protocols, for diagnosis of CMV disease, and to guide management of CMV disease (8-12). A lack of standardization between different centers is a major problem with all assays. A recent multicenter comparison of viral load assays demonstrated up to a 3-log10 variation among different assays. Standardization may be achieved in the future with quantitative viral load assays (13). Culture based assays of blood and urine are of limited utility for prediction, diagnosis and management of CMV disease (II-2). Either the pp65 Antigenemia assay or a quantitative viral load assay should be used for most areas of management. Lack of standardization across different laboratories is a problem for both tests and centres need to validate their own threshold values (II-2). Approaches in the prevention of CMV in solid organ transplantation, and the results obtained, vary widely among different transplant programs. Reasons for this include insufficient large trials (especially comparing prophylaxis vs. preemptive therapy), different end-point definitions, multiple nonstandardized testing methodologies and differing patient populations. Two strategies are commonly used for CMV prevention: (1) universal prophylaxis and (2) preemptive therapy. Universal prophylaxis involves giving antiviral therapy to all ‘at-risk’ patients (or a specified subset) beginning in the early posttransplant period for a defined duration (e.g. 3–6 months). In preemptive therapy, patients are monitored at regular intervals (often weekly) for early evidence of CMV replication by use of a laboratory assay. Patients with early replication are then treated with antiviral therapy to prevent symptomatic disease. Each approach has advantages and disadvantages that must be considered in the context of the patient and the allograft (14, 15) (Table 1). Preemptive therapy may decrease drug costs and toxicity, but requires excellent logistic coordination, in order to obtain, receive, and act on results in a timely fashion, which can be difficult if patients live quite some distance from the transplant center. In addition, due to a lack of standardization of diagnostic testing, optimal threshold values for initiation of preemptive therapy have not been defined. Prophylaxis might have the theoretical advantage of preventing reactivation of other viruses such as HHV-6 and may be more likely to prevent indirect effects of CMV. Metanalyses have demonstrated that antiviral prophylaxis is associated with decreased rates of graft loss, improvement in survival and decreased incidence of opportunistic infections (16, 17). Late-onset CMV disease is a potential problem with prophylaxis (see further). CMV resistance has been observed with both strategies (18, 19). There are very few comparative randomized trials comparing preemptive therapy versus prophylaxis. Khoury et al. (20) randomized 98 kidney transplant recipients (D+/R– n = 29) to preemptive therapy (valganciclovir) versus prophylaxis (valganciclovir 100 days). Both strategies were equally effective in preventing CMV disease. Kliem et al. (21) randomized 148 renal transplant patients to preemptive therapy (I.V. ganciclovir) versus prophylaxis (3-months oral ganciclovir). Long-term graft survival at 4-years posttransplant was significantly improved in the prophylaxis group. In another study prophylactic valacyclovir was equivalent to preemptive valganciclovir in kidney transplant recipients (n = 70) for the prevention of CMV disease but the prophylactic regimen had a significant lower rate of biopsy proven rejection (15% vs. 36%, p = 0.034) (22). Drugs that have been evaluated for universal prophylaxis include ganciclovir, valganciclovir, acyclovir, valacyclovir and immune globulin preparations (Table 2). Ganciclovir is available in both oral and intravenous formulations. There have been a number of randomized trials with varying agents that have been previously reviewed (1). Several large multicenter randomized trials of prophylaxis with agents including oral ganciclovir, valganciclovir and valacyclovir have also been performed (23-25). Valganciclovir is a valine ester prodrug of ganciclovir with improved bioavailability (50–60%) compared with oral ganciclovir (6–9%). In a trial of 372 D+/R– SOT recipients randomized to 3 months of prophylaxis with oral ganciclovir versus oral valganciclovir (PV16000), the rate of CMV disease at 6 and 12 months was comparable in the 2 arms (17.2% valganciclovir vs. 18.4% ganciclovir at 12 months) (25). In a trial comparing 200 versus 100 days of valganciclovir prophylaxis in 318 D+/R– kidney transplant recipients (Impact study), the incidence of confirmed CMV disease was 16.1% versus 36.8%, respectively (26). Less data are available in lung transplant recipients, but studies suggest that rates of viremia and disease are high with short courses of prophylaxis and lower with longer courses of prophylaxis (6 months or more) (27, 28). Benefit for indirect effects has been more difficult to demonstrate in individual studies. Valacyclovir (8 g/day, adjusted for renal function) administered for 90 days reduced the incidence of biopsy-proven acute rejection in CMV-seronegative patients (24). Acyclovir has less activity and is not recommended specifically for CMV prophylaxis. The efficacy of prophylaxis with either CMV immune globulin (CMVIG) or intravenous immune globulin (IVIG) in solid organ transplant recipients has been investigated in relatively few trials (29, 30), and the majority of those conducted have been randomized, but nonblinded. Further research is needed to delineate the benefit of adding immune globulin to current CMV prophylaxis regimens. The major problem with CMV prophylaxis continues to be late-onset CMV disease. This can be defined as disease occurring sometime after discontinuation of antiviral prophylaxis. For 3-month prophylaxis regimens, this typically occurs between 3 and 6 months posttransplant or sometimes later (25). Disease presenting late may be missed due to difficulties in diagnosis, especially for patients living at geographical locations removed from their primary transplant program. Late onset disease contributes to morbidity and has been shown to be associated with higher overall mortality (31). The incidence of late-onset disease with a standard 3-month course of prophylaxis is estimated to be approximately 17–37% among D+/R– recipients, with higher rates when current definitions of CMV disease are used (25, 32). Potential options for dealing with late-onset CMV disease are as follows: Careful clinical follow-up with treatment of disease as soon as symptoms occur. Virologic monitoring after completion of prophylaxis. Check antigenemia or viral load periodically for 8–12 weeks after completion of prophylaxis. However, studies evaluating the utility of monitoring after prophylaxis have demonstrated poor sensitivity and specificity for prediction of CMV disease (33). Weekly monitoring would likely be required to be successful. Prolong prophylaxis from 3 to 6 months in D+/R–. The Impact trial demonstrated a significant reduction in CMV disease using 200 days of prophylaxis versus 100 days in D+/R– kidney transplant recipients (32). Further research is needed to extrapolate this to R+ patients. All doses should be adjusted based on renal function. Specific anti-CMV prophylaxis in D–/R– patients is generally not needed provided CMV negative blood or leukodepleted blood products are used. In D+/R– kidneys and livers, valganciclovir 900 mg/day, oral ganciclovir (3 g/day), or intravenous ganciclovir (5 mg (kg/day)) prophylaxis are effective for prevention of CMV disease (I). In kidney transplant recipients, valacyclovir 8 g/day is an alternative (I). The FDA has a caution against the use of valganciclovir in liver transplant patients but many experts still recommend its use in this setting and it is used in 60% of U.S. transplant centers (34) Start prophylaxis within 10 days posttransplant and continue until ∼3 to 6 months posttransplant (I). In R+ kidney or livers, oral ganciclovir, valganciclovir, intravenous ganciclovir, or valacyclovir (kidneys) for 3 months decreases the rate of CMV disease (same doses). For D+/R– heart transplant recipients valganciclovir (900 mg/day), oral ganciclovir (3 g/day) or intravenous ganciclovir (5 mg/(kg day)) for 3–6 months can be used for prophylaxis (I). Some centers add CMVIG for prophylaxis (II-2) In R+ recipients, oral valganciclovir (II-2), intravenous ganciclovir (II-1), or oral ganciclovir for 3 months are effective (same doses). There is limited RCT data in pancreas transplant recipients, but generally they are thought to be at high risk for CMV disease. Options include for D+/R– or R+: valganciclovir (900 mg/day) (II-2), intravenous ganciclovir (5 mg/kg/day) or oral ganciclovir (3 g/day) for 3–6 months (II-2). There is limited randomized clinical trial data for lung transplant in these patients are at the highest risk for CMV disease. D+/R– lung transplant recipients may be given prophylaxis with intravenous ganciclovir (5 mg/kg/day) or oral valganciclovir (900 mg/day) for 6 months (II-2). the high rate of late onset CMV disease in this some centres the duration of prophylaxis 6 months (II-2). For lung transplant recipients, prophylaxis with oral valganciclovir, intravenous ganciclovir, or oral ganciclovir for 3–6 months may be used (II-2) (same doses as CMVIG is used by some centres in to antiviral therapy in high risk lung transplant recipients (II-2). There are more limited data in this patient For D+/R– and for valganciclovir (900 mg/day), intravenous ganciclovir (5 mg/(kg day)) or oral ganciclovir (3 g/day) for 3–6 months are recommended CMVIG is used by some centers in to antiviral therapy Preemptive therapy involves monitoring of patients for early evidence of CMV replication with early treatment to prevent symptomatic disease (Table (1-3). Preemptive therapy has the potential advantage of therapy to the highest risk patients and drug costs and Several up a preemptive including (see (1) of the population for preemptive therapy, (2) the optimal laboratory and duration of monitoring and the and duration of an antiviral on current a preemptive is shown in Either the pp65 antigenemia assay or CMV viral load testing should be and assay threshold values for initiation of preemptive therapy should be to of a preemptive protocol for preemptive therapy. viremia is treatment with either valganciclovir or intravenous ganciclovir should be In a randomized trial comparing the agents for treatment of to CMV disease, both agents had efficacy preemptive therapy should asymptomatic oral valganciclovir is likely to intravenous ganciclovir for logistic Preemptive therapy is a for patients at risk for CMV disease (I). the population in which to use a preemptive prophylaxis for the higher risk D+/R– while the potential utility of preemptive therapy in the R+ group. The laboratory for monitoring is either a CMV viral load or a pp65 antigenemia assay (II-2). The optimal monitoring is approximately testing for 12 weeks posttransplant (II-2). The optimal for preemptive therapy are oral valganciclovir (900 mg times a or intravenous ganciclovir (5 times a (I). should be until viremia is undetectable (II-2). Further studies are required to comparative efficacy of preemptive therapy versus especially the indirect of CMV. The use of ALA therapy is a major risk factor for CMV disease especially when used for the treatment of on antiviral efficacy has been in three trials in solid organ transplant recipients In of the in which intravenous ganciclovir was compared with therapy in kidney transplant recipients receiving ALA there was evidence of a of Prophylaxis with antiviral therapy should be given in patients receiving ALA therapy either as induction or for the treatment of rejection (I). The optimal duration of antiviral therapy is not Options include valganciclovir oral ganciclovir or intravenous ganciclovir for approximately a preemptive therapy protocol can be in these patients In patients treated for acute rejection with high of prophylaxis or a preemptive may be considered as ganciclovir has been used in 30 trials to solid organ transplant recipients with CMV disease and has been considered the for therapy. The of intravenous ganciclovir for treatment is The duration of therapy in trials from 2 to Valganciclovir at a of 900 mg levels to intravenous ganciclovir In a randomized trial comparing 3 weeks of oral valganciclovir to ganciclovir for the treatment of CMV disease in organ transplant patients majority were kidney transplant with to CMV disease, both had efficacy for the of viremia at days In the a significant number of patients had viremia at longer courses of therapy should be administered in many patients. oral ganciclovir has been shown to prevent CMV disease, its utility in the treatment of CMV disease is not molecular diagnostic tests can be used to the duration of antiviral therapy in patient based on of CMV viral load or This risk of is lower in patients who have CMV viral load at the of therapy than for those with CMV viral load patients with evidence of CMV viremia should be on therapy until viremia either by antigenemia or has the negative threshold value for a given this negative threshold value has not been defined. In solid transplant CMV disease should be treated with either intravenous ganciclovir (5 times a or oral valganciclovir (900 mg times a until the following are of symptoms Virologic a threshold negative value patients with viral load or pp65 antigenemia a 2 weeks of ganciclovir is to oral valganciclovir in patients with or disease, or in patients who may have a problem with gastrointestinal of oral drug (e.g. significant Acyclovir and oral ganciclovir are not effective in CMV disease in transplant recipients (II-2). ganciclovir treatment in the of CMV replication may to of ganciclovir CMV (II-2). is addition of or CMVIG to treatment has a benefit for solid organ transplant recipients (II-2) but may be considered for patients with CMV and other of disease. After completion of a course of prophylaxis may be considered on the clinical clinical and/or follow-up after discontinuation of treatment is an Ganciclovir by a viral by the After by cellular the active drug CMV DNA by the in and less commonly in can ganciclovir often have resistance to ganciclovir on the of and response may still be observed in some and often have resistance to is a anti-CMV and has activity against most ganciclovir of CMV. There are far studies of in solid organ transplant recipients than there are of however, the majority of transplant patients treated with either or in with ganciclovir, multiple of CMV disease by ganciclovir CMV have been treated with The major problem in transplant patients is significant The of effects of in solid organ transplantation to be is used for the treatment of CMV infection in with and although evaluated in transplant studies have been has significant as CMV isolates with may sensitive to and may in resistance to these on the of the The incidence of ganciclovir CMV generally in most after solid organ transplant. In the study the overall rate of resistance was in those who oral ganciclovir versus among those receiving valganciclovir in some (especially lung higher rates of resistance have been factors for resistance include oral prophylaxis (e.g. with ganciclovir or D+/R– of immunosuppression and lung transplantation should be if (1) the patient has antiviral (2) the viral load to decrease or weeks of antiviral therapy and patients have other risk factors for resistance as resistance testing may be very in CMV. for treatment of ganciclovir resistance CMV disease is in for treatment of ganciclovir Patients who CMV disease after courses of ganciclovir or valganciclovir prophylaxis and those to to standard ganciclovir treatment should be of ganciclovir testing for resistance should be performed should be reduced or options include the of intravenous ganciclovir to 10 times a or or in with ganciclovir) (see (II-2). For or options may be considered and include and The role of CMVIG in this setting is but may be considered In general there are less data available for pediatric transplant with to CMV prevention and In addition, other such as prevention of EBV-related may be of more in this population and the of CMV prevention more pediatric patients are at risk of primary CMV infection and disease by of being CMV-seronegative to many donors for pediatric patients will also be the use of or decreased in liver results in a of high risk pediatric organ The following recommendations to pediatric patients can be transplant recipients months of may have culture should be urine culture based on the highest risk for the of CMV prevention For donors months age, if is (II-2). The and recommendations for the use of prophylaxis and therapy in recipients are generally to pediatric organ transplant recipients with the following are limited the efficacy of therapy in pediatric organ transplant are on the and efficacy of oral ganciclovir and oral valganciclovir in and prevention strategies continue to be based primarily on intravenous ganciclovir especially in The duration of intravenous ganciclovir is by the risk of infections in some The duration of prophylaxis is also by other factors that vary across centres. factors include the of organ the with CMV disease in their patient immunosuppressive and the prophylaxis regimen (I). In this there is standard of as this to the duration of prophylaxis. The duration of intravenous ganciclovir prophylaxis in major centres varies from a of days to 3 months (II-2). of CMV disease in should be with intravenous ganciclovir due to a lack of efficacy data of oral therapy in the pediatric CMVIG is considered by some experts in with ganciclovir for the treatment of CMV disease in and for treatment of more of CMV disease There are a number of areas that are being in and clinical research A number of and some commercially available assays for the of immunity to CMV are being evaluated for their to the development of CMV disease. is that these assays will allow of patients and allow more prevention and strategies being evaluated include CMV and The drug to development is an of CMV In a 2 study in transplant recipients, prophylaxis was to for the prevention of CMV viremia However, a 3 studies in recipients to its primary and the future of this drug is further studies of CMV prevention and treatment are required for pediatric transplant and/or

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