Significant advances have been made in the management of posttransplant cytomegalovirus (CMV); however, it remains one of the most common complications affecting organ transplant recipients, with significant morbidity and occasional mortality. The adverse impact of CMV infection on graft function underscores the importance of CMV on transplant outcomes. Concurrent with recent advances in molecular diagnostics, antiviral therapies, and evolving immunosuppression regimens, management of CMV varies considerably among transplant centers. In December 2008, a panel of experts on CMV and solid organ transplant (SOT) was convened by The Infectious Diseases Section of The Transplantation Society to develop consensus guidelines on CMV management. Topics include diagnostics, immunology, prevention, treatment, resistance, and pediatrics. Each section used a scoring system to rate the quality of evidence on which recommendations are based (1) (Table 1). For clarity, the following definitions, which are consistent with the American Society of Transplantation recommendations for use in clinical trials (2), are used in this document.
- 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 a viral syndrome with fever, malaise, leukopenia, and thrombocytopenia or as a tissue-invasive disease.
CMV serology should be performed pretransplant on both the organ donor and the recipient. A test that measures anti-CMV IgG should be used, because IgG serologic tests have better specificity than IgM tests or tests combining IgG and IgM, neither of which should be used for screening. False-positive IgM reactions may significantly decrease the specificity of the screen (3–5). Because donor and recipient serostatus (cited as D/R) are such key predictors of infection risk and management, it is imperative that a test with high sensitivity and specificity be used. Not all serologic tests are equivalent, and thus, it is important to understand the performance characteristics of the specific test used (6). A change in the serologic test requires an evaluation of the test performance, including comparison with the previously used test. If the donor or recipient is seronegative during the pretransplant evaluation, serology should be repeated at the time of the transplant if there is a significant time interval between screening and the transplant. Interpretation of serology results can be difficult in donors and recipients with recent transfusion of blood products, as passive transfer of antibody can lead to transient false-positive serologic results (7); a pretransfusion sample is preferable if available.
In adults, an equivocal serologic assay result in the donor should be assumed to be positive, whereas this result in the recipient should be assumed to be negative. This strategy will ensure that the recipient is assigned to the highest appropriate CMV risk group for posttransplant management decisions.
Posttransplant Role of Diagnostics
Serology has no role in the diagnosis of active CMV disease posttransplantation. Viral culture of blood for CMV has limited clinical utility for diagnosis of disease due to poor sensitivity. There is no role for CMV urine culture in the diagnosis of disease due to poor specificity (8). A positive culture from bronchoalveolar lavage specimens in lung transplant recipients may reflect viral secretion and may not reflect pulmonary disease (9, 10). Culture of tissue specimens remains an option for diagnosis of tissue-invasive disease, particularly for gastrointestinal samples, whereas antigenemia or polymerase chain reaction (PCR) testing on blood may not always be positive.
The CMV pp65 antigenemia test is a semiquantitative test that is useful for the diagnosis of clinical disease, initiating preemptive therapy, and monitoring response to therapy (11–15). Studies have shown that higher numbers of positive staining cells correlate better with disease (11, 12), although tissue-invasive disease can occur with low or negative cell counts. Only one study showed a positive correlation between the number of pp65-positive cells and CMV disease for D+/R+ cases, because 82% of the D+/R− patients developed CMV disease (16). The antigenemia test has advantages in some settings, because it does not require expensive equipment and the assay is relatively easy to perform. There are problems with a lack of assay standardization, including subjective result interpretation, and it is unlikely that better standardization of this assay will occur, as more laboratories move toward molecular methods. The assay may not be possible to perform when the absolute neutrophil count is less than 1000 neutrophils/μL. The test is labor intensive, and the blood specimen has limited stability and should be processed within 6 to 8 hr of collection to avoid a decrease in test sensitivity. Transplant centers where many patients live far away and whose blood samples are mailed to the laboratory may prefer to use quantitative nucleic acid testing (QNAT) rather than antigenemia, given the decreased yield of antigenemia over time.
QNAT for CMV (also known as CMV viral load testing) is the main alternate option for diagnosis, making decisions regarding preemptive therapy, and monitoring response to therapy (17–23). Most laboratories that perform viral load testing are moving to real-time PCR technologies, because they have better precision, broader linear range, faster turnaround time, higher throughput, and less risk of carry over contamination compared with conventional PCR tests (24). The testing requires expensive equipment and reagents, specialized expertise, and may not be appropriate for all laboratories. Plasma and whole-blood specimens both provide prognostic and diagnostic information regarding CMV disease (25–28). When using whole blood, the consensus opinion is to report values as copies per milliliter of blood, although there are no data directly comparing the impact of reporting results based on volume of blood, micrograms of DNA, or number of cells. CMV DNA is detected earlier and usually in greater quantitative amounts in whole blood compared with plasma. For this reason, one specimen type should be used when serially monitoring patients.
The pp67 test (bioMerieux, Marcy l'Etoile, France) detects pp67 late mRNA in whole blood; there are limited data on the clinical utility of this test (14, 17). As a qualitative assay, it may be more appropriate for diagnosis of disease than for monitoring treatment response. Qualitative PCR is an option for surveillance if this is the only testing option available, as there are problems with clinical specificity of this test and it is generally not recommended.
Currently, there is poor interinstitutional correlation of QNAT viral load values, partly due to the lack of an international reference standard and variation in assay design (29). This prevents the establishment of broadly applicable cutoffs for clinical decision making, particularly for preemptive strategies. It is imperative that laboratories use an external quantitative standard material (independent of that provided by the manufacturer) to monitor quantification across different lots of reagents to ensure consistency of assay performance. If the laboratory changes QNAT viral load tests or extraction method, there must be an evaluation of the performance characteristics of the new tests compared with the old tests. Interinstitutional comparison of QNAT values requires cross-referencing of values by specimen exchange or use of common external reference material (30).
Natural history studies have shown that higher viral load values correlate with increased risk for the development of disease (21, 22). One study (22) established a cutoff for predicting disease of 2000 to 5000 copies/mL in CMV- seropositive liver transplant recipients; this study was performed, however, using a commercial QNAT viral load test (Cobas Amplicor Monitor; Roche, Basel, Switzerland) and so may not be applicable in setting where other assays are used or in different populations and risk groups. Several recent publications reporting equal efficacy of preemptive therapy to universal prophylaxis in randomized trials in renal allograft recipients used trigger points for intervention of more than 2000 copies/mL of whole blood (9, 31, 32). Trends in viral loads over time may be more important in predicting disease than any absolute viral load value (21). The limit of detection varies among the different viral load tests; a lower limit of detection of greater than 1000 copies/mL (using either whole blood or plasma) may be inadequate to detect disease (33) because some patients with end-organ disease may have very low or even undetectable viral load values. Conversely, a sensitive test (limit of detection <10 copies/mL) may detect latent virus, particularly if whole blood specimens are used, which limits the clinical utility of an extremely sensitive test. QNAT viral load tests should be linear throughout the important range of clinical values (up to ∼1 million copies/mL). The precision of QNAT viral load tests are such that changes in values should be at least 3-fold (0.5 log10 copies/mL) to represent biologically important changes in viral replication (34). QNAT variability is greatest for low viral loads; thus for viral load values at or near the limit of quantification, QNAT viral load changes may need to be greater than 5-fold (0.7 log10 copies/mL) to be considered significant.
Both the antigenemia and the QNAT viral load tests have clinical utility, are widely available, and in general there is a good but not uniform correlation between CMV antigenemia levels and QNAT viral load values (17, 24, 35). One recent study directly compared a whole-blood QNAT viral load test and the antigenemia test for use in initiating preemptive therapy (36) in SOT recipients and found that use of the viral load test for initiating preemptive therapy significantly reduced the number of patients requiring treatment with no increase in CMV disease. The decision regarding which test to use will depend on many factors including available resources, technical expertise, patient population, required turnaround time, volume of samples tested, and cost. Ideally, CMV QNAT and antigenemia tests should be available within 24 to 48 hr for diagnosis of disease. For viral load testing, reporting results as both integers and log10 transformed data may help clinicians avoid overinterpreting small changes in viral load.
Diagnostics for Tissue-Invasive Disease
Specimens from specific body sites may provide additional information about CMV infection. Identification of inclusion bodies or viral antigens in biopsy material by immunohistochemistry (37, 38) or in bronchoalveolar lavage specimens cells by immunocytochemistry may improve the predictive value of a positive culture. The diagnosis of tissue invasive CMV disease, such as hepatitis and gastrointestinal infection, should be confirmed by immunohistochemistry or in situ DNA hybridization (39–41). When performing histopathology of biopsy specimens, immunostaining should be routinely performed to maximize sensitivity. Not all antibodies have equal sensitivity, and the performance may also differ between fresh and formalin-fixed, paraffin-embedded tissue (41).
For bronchoalveolar lavage and biopsy specimens, laboratories should be moving toward QNAT testing because it provides quantitative results, improved sensitivity without loss of specificity, and faster turn around time compared with culture (42, 43). The quantitative nature of QNAT may allow the establishment of a viral load cutoff to predict the development of disease, without loss of specificity. At present, there are no randomized clinical data regarding the interpretation of QNAT viral load testing in bronchoalveolar lavage specimens, although several studies suggest it may be helpful in predicting pneumonitis (38, 43, 44).
Central nervous system disease in SOT recipients is extremely rare. In the absence of extensive clinical studies, the presence of CMV DNA in the cerebrospinal fluid (CSF) likely represents CMV disease and should be treated. The diagnosis of retinitis is based on ophthalmologic examination; viral load in blood or plasma or other laboratory tests are rarely useful as predictors of CMV eye disease although they may be positive before and at the time of diagnosis of CMV retinitis.
Numerous questions remain unanswered in this field. Future studies are needed to:
- Compare the performance characteristics of the different serologic tests; assess the utility of cell-mediated immunity assays (45) for the interpretation of passive immunity due to transfusion of blood products and in sorting out serostatus in donors and recipients less than 18 months of age.
- Correlate viral load levels with immunohistopathology, in situ hybridization, and clinical outcome.
- Determine the characteristics of an international reference standard that would optimize agreement between viral load values obtained with different tests.
- Determine the viral form (virions, fragmented, or genomic CMV) in cellular and acellular compartments and viral kinetics in peripheral blood compartments.
- Directly compare QNAT viral load monitoring in plasma and whole blood with respect to disease prediction and monitoring response to therapy.
- Determine the role of antigenic variability among strains and coinfection in predicting disease, relapse, and therapy response.
- Pretransplant donor and recipient serology should be performed. If pretransplant serology of the recipient is negative, retest at time of transplant (III). If the pretransplant serology is equivocal in the donor, assume it is positive, and if the result is equivocal in the recipient, assume it is negative (III). (For guidance on infants and children less than 18 months, see Pediatrics section.)
- Viral culture of blood or urine has a limited role for the diagnosis of disease. Culture of tissue specimens has some role in the diagnosis of invasive disease. Positive culture of bronchoalveolar lavage samples may not always correlate with disease (II-2).
- Histopathologic examination of tissue should routinely include immunostaining (II-2).
- Both antigenemia and QNAT viral load tests are acceptable options for diagnosis, decisions regarding preemptive therapy, and monitoring response to therapy (II-1/II-2). Transplant centers where many patients live far away and whose blood samples are mailed to the laboratory may prefer to use QNAT rather than antigenemia, given the decreased yield of antigenemia over time.
- Either plasma or whole blood is an acceptable specimen for QNAT viral load testing, but there needs to be an appreciation of the differences in viral load values and viral kinetics in the two compartments. Specimen type should not be changed when monitoring patients (II-2).
- A universal cutoff for initiating therapy has not been established due to issues outlined earlier. It is likely that an international reference standard and consensus on specimen type would improve the determination of appropriate standardized trigger points for intervention. In the interim, laboratories must establish their own cutoffs and audit clinical outcomes to verify the trigger points used (III).
IMMUNOLOGIC MONITORING FOR CMV AND CMV VACCINES
Immunologic Control of CMV
The immunologic control of CMV in the immunocompromised host is complex and involves both the innate and adaptive immune systems (46–48). Polymorphisms of Toll-like receptor-2 and Toll-like receptor-4 as well as deficiencies of complement proteins and mannose binding lectin are associated with increased risk of CMV disease (49–51). Natural killer cells play a critical role in control of primary and recurrent CMV infection, typically increasing in response to viral replication (52, 53).
Adaptive immune responses of B and T lymphocytes are critical in controlling CMV replication. The methods to monitor the adaptive immune response to CMV may allow for early identification of patients at increased risk of viral replication. B cells are important in the humoral response to CMV, producing neutralizing antibodies that primarily target glycoprotein B (gB) and glycoprotein H (46, 47). There is emerging evidence that a significant number of posttransplant patients develop hypogammaglobulinemia (26%–70% in some series), although a link with CMV risk is controversial. Hypogammaglobulinemia was a risk factor for CMV infection in heart and lung transplant recipients but not in a large cohort of patients postliver transplant (54–56).
T-cell responses, including both CD4+ and CD8+ T cells, are critically important components of the immune system for control of CMV. Both CD4+ T cells and CD8+ cytotoxic T lymphocytes protect against replication (46–48). T-cell reactivity has been shown to be directed toward a wide range of CMV antigens such as pp65, pp50, IE-1, gB, and others (57). The key role of T cells in the control of CMV has been demonstrated through the use of adoptive immunotherapy for both prophylaxis and therapy of CMV infection, primarily in the hematopoeitic stem-cell transplantation (HSCT) setting. For immunotherapy, donor T cells are stimulated in vitro using viral lysate or CMV-specific peptides and then transfused into the patient, resulting in control of CMV replication in most cases (58). There are no data available for the SOT population; this may be an experimental strategy for CMV disease in those who are unresponsive to standard therapies.
Immune monitoring of CMV-specific T-cell responses may predict individuals at increased risk of CMV disease posttransplant and be useful in guiding prophylaxis and preemptive therapies. There are a variety of T-cell assays for CMV. Most of these assays have been used in experimental settings, and widespread clinical application is still under investigation. The majority of assays rely on the detection of interferon (IFN)-γ after stimulation with CMV specific antigens (46–48). In addition to IFN-γ, other markers, including interleukin (IL)-2, CD107, tumor necrosis factor-α, programmed death (PD)-1, and CD154, can be used to correlate the CMV-specific response with the risk of CMV. An ideal assay should provide both CMV-specific CD4+ and CD8+ T-cell quantitation (number of CMV-specific T cells) and function (number of CMV-specific cells that are functional). For ideal clinical application, an assay should be simple to perform, inexpensive, highly reproducible, and amenable to either widely available platforms or shipping to specialized reference laboratories.
Each of the assays currently under investigation have specific advantages and limitations and have been studied in various clinical applications to predict disease or viremia (Table 2). The QuantiFERON-CMV assay (Cellestis Inc., Melbourne, Australia) is currently the only commercially available kit and is an ELISA-based IFN-γ release assay that consists of three tubes: negative control, mitogen or positive control, and a tube with specific peptides targeting CMV specific CD8+ T cells. The assay has been evaluated in clinical studies and shown to have some predictive value for disease (59, 60) but not viremia. Interpretation of the test is unclear if a posttransplant patient does not respond to the mitogen control. Nonresponse to mitogen may potentially be a marker for global immunosuppression, however, and warrants further study. Test sensitivity decreases in lymphopenic patients because an adequate number of cells are required for the production of IFN-γ.
The ELISPOT assay quantitates T-cells producing IFN-γ in response to CMV. Purified peripheral blood monocyte cells (PBMCs) are stimulated with CMV-specific peptides or whole antigen lysates; IFN-γ is then captured, detected, and quantified using a labeled antibody. As with the QuantiFERON assay, a mitogen control assays general T-cell responsiveness. The ELISPOT assay cannot differentiate CD4+ and CD8+ T cells. Various in-house ELISPOT assays have been evaluated and shown to be predictive of disease but not viremia (61). There is currently no standardized ELISPOT assay commercially available.
Most studies that have analyzed CMV-specific T-cell responses have used intracellular cytokine staining (ICS) for IFN-γ using flow cytometry. Whole blood or isolated PBMCs are stimulated with CMV peptides or CMV lysate. If whole antigen lysate is used, the assay is not human leukocyte antigen (HLA)-restricted and knowledge of patient HLA type is not required. Stimulated cells are stained with monoclonal antibodies directed against IFN-γ. This technique is fast, versatile, and can be expanded to include other cytokines and cell surface molecules. Unlike the ELISPOT assay, ICS (and QuantiFERON) can provide both quantitative and qualitative characteristics of CMV-specific T cells. Clinical studies have shown that this technique can predict both CMV disease and viremia. Several studies in SOT recipients showed an increased risk of CMV disease in patients with low levels of specific T-cell immunity (62–64). Similarly, the absence of anti-CMV T-cell response by this technique correlates with the inability to clear viremia (62, 65, 66). Stable levels of CMV specific CD4+ T cells were associated with lower risk of CMV replication (62, 66, 67). The development of T-cell immunity has also been shown to be associated with freedom from CMV disease after lung transplantation (68). The predictive value for viremia may be improved when the analysis of IFN-γ is combined with other cytokines such as IL-2 and additional markers such as PD-1 (69, 70).
Major histocompatibility complex (MHC)-multimer-based assays directly stain peptide-specific T cells using peptide-conjugated MHC class I tetramers or pentamers. They can determine CD8+ T-cell responses but are epitope- specific and require knowledge of the patient's HLA type. Multimer assays combined with analysis of surface markers such as PD-1 have been shown to predict viremia and CMV disease (69, 71). Both ICS and MHC-multimer staining require a fluorescence-activated cell sorting facility, which may limit widespread use in transplant centers.
The Cylex ImmunKnow assay (Cylex Inc., Columbia, MD) is not specific for CMV. This assay, which is commercially available in the United States and in some European countries, measures overall immune response and serves as a marker of immunosuppression by determining the amount of ATP produced in response to whole-blood stimulation by phytohemagglutinin. A Cylex assay specific to CMV is available for research purposes and has been studied in a cohort of lung transplant recipients to monitor CMV-specific responses overtime posttransplant (72). This assay has not yet been studied, however, to determine whether it is predictive of CMV viremia or disease.
Several CMV vaccines are under development; none are currently available for routine clinical use. Types of vaccines includes live attenuated, DNA, subunit, and recombinant viral vaccines (48). A live attenuated vaccine based on the Towne strain of CMV was found to be safe during clinical testing but had a suboptimal antibody response, and although CMV disease was attenuated, the vaccine failed to prevent infection (73, 74). Recombinant gB vaccine with adjuvant has been shown to induce neutralizing antibodies (75) and prevent infection (76). Canarypox gB and pp65 vaccines produce T-cell responses and neutralizing antibodies (77, 78). An alphavirus replicon vector system has been used to produce viral particles expressing gB and pp65/IE-1 fusion protein; initial studies in mice and rabbits have shown the development of neutralizing antibodies (79). An adenoviral chimeric vaccine-based replication deficient adenovirus encoding gB and multiple CMV epitopes was able to produce a robust cellular response and neutralizing antibodies in mice (80). Currently, clinical trials in HSCT are underway with a gB/pp65-based DNA vaccine (www.clinicaltrials.gov). A previous study with this vaccine in both seropositive and seronegative healthy volunteers showed promising results (81). Because CMV vaccines are in a preliminary phase, recommendations for the development and testing of vaccines were made based on expert opinion.
- Hypogammaglobulinemia may play a role in CMV disease posttransplant; the measurement of immunoglobulins may be considered posttransplant if CMV is difficult to control (II-2).
- Adoptive T-cell therapy has been used on an experimental basis in HSCT recipients. No clinical studies for CMV in SOT exist. This is an area where further study is needed (III).
- An ideal immune monitoring assay should provide CD4+ and CD8+ T-cell quantitation and function. Optimally, the assay should measure IFN-γ; additional markers such as IL-2, PD-1, CD107, tumor necrosis factor-α may have predictive value for viremia. Clinically, an ideal assay should be simple to do, rapid turnaround time, cost-effective, reproducible, and potentially amenable to allow shipping of specimens to a specialized referral laboratory (III).
- Current evidence suggests that certain immunologic monitoring tests can predict risk of CMV viremia and disease in the postprophylaxis and preemptive setting (II-2/II-3). Few tests specific for CMV were commercially available at the time of this consensus meeting.
- At present, there are no clinical studies demonstrating that management decisions based on immunologic monitoring affect patient outcomes. Therefore, based on current evidence, immunologic monitoring cannot be recommended on a routine basis. Studies should be conducted to understand the role of immune monitoring in making clinical decisions about the prevention and management of CMV viremia and disease (III).
- CMV vaccines are in preclinical and phase I trials. The primary goal of a CMV vaccine should be to prevent CMV viremia or CMV disease and prevent secondary endpoints such as rejection and graft loss (III). In theory, it is possible that vaccination may reduce burden of disease or impact the course of latent CMV infection in seropositive patients, and vaccination trials should, therefore, focus both on seronegative and seropositive recipients (III). Until further evidence is available, no recommendation can be made with regards to type of vaccine or timing of vaccination.
PREVENTION OF CMV
CMV prevention strategies have resulted in significant reductions in CMV disease and CMV-related mortality. The improvements in the “indirect effects” of CMV infection have also been attributed to the use of CMV prevention. Two major strategies are commonly used for prevention of CMV: universal prophylaxis and preemptive therapy. Within each of these strategies, significant variation in clinical practice exists, and hybrid models using both strategies are possible.
Universal prophylaxis involves the administration of antiviral medication to all patients or a subset of “at-risk” patients. Antivirals are usually begun in the immediate or very early posttransplant period and continued for a finite period of time, often in the range of 3 to 6 months. Several antivirals have been evaluated for universal prophylaxis, including acyclovir, valacyclovir, intravenous (IV) ganciclovir, oral ganciclovir, and valganciclovir. In early studies, acyclovir was determined to be inferior to ganciclovir for prevention of CMV (82). A subsequent large study comparing oral ganciclovir with valganciclovir in D+/R− transplant patients demonstrated equivalent efficacy of the two regimens, although concern was raised regarding an increased incidence of tissue-invasive disease in the liver transplant patients who received valganciclovir (83). Late onset CMV disease has been the most significant finding in all studies evaluating universal prophylaxis, defined as disease occurring after the discontinuation of prophylaxis. In the PV16000 study, late-onset CMV disease occurred in 18% at 12 months (and in closer to 30% when including investigator treated disease) (83). The determinants of late-onset CMV disease in patients receiving prophylaxis have not been fully elucidated, but are likely related to ongoing significant immunosuppression, accompanied by a lack of development of significant CMV specific cell-mediated immunity. Risk factors for late- onset disease include D+/R− serostatus, higher levels of immunosuppression, and allograft rejection (84).
In preemptive therapy, laboratory monitoring is performed at regular intervals to detect early, asymptomatic viral replication. Once viral replication reaches a certain assay threshold, and hopefully before the development of symptoms, antiviral therapy is initiated to prevent the progression to clinical disease. The advantages of preemptive therapy include more selective drug targeting, decreased drug cost, and associated toxicities. Theoretically, a preemptive strategy may promote the development and maintenance of CMV-specific cell-mediated immunity by allowing low-level viral replication. Preemptive therapy is more difficult to coordinate because it requires weekly laboratory monitoring and a short turnaround time in the laboratory. In addition, optimal threshold values for antigenemia or viral load are assay dependent and have not been well established. In settings where viral doubling time is rapid, there may be insufficient time to diagnose and begin treatment for CMV viremia before the development of symptoms. One of the major concerns with preemptive therapy is that it may not prevent the indirect effects of CMV infection, including effects on graft and patient survival (85, 86). In addition, second episodes of replication are observed in approximately 30% of patients treated for CMV disease, some of which require further therapeutic intervention (87). Patients who are D+/R−, certain transplant types (e.g., lung) and those on highly potent immunosuppression are likely more prone to recurrent episodes of viremia.
Universal Prophylaxis Versus Preemptive Therapy
A comparison of universal prophylaxis with preemptive therapy is provided in Table 3. There are only relatively small comparative trials of the two strategies. In one study comparing oral ganciclovir prophylaxis to preemptive IV ganciclovir in kidney transplant patients, prophylaxis reduced CMV infection by 65% (13 vs. 33 patients), and graft survival was improved at 4 years posttransplant suggesting a possible beneficial effect of prophylaxis (85).
The majority of consensus conference participants favored the use of prophylaxis over preemptive therapy in the highest risk recipients (e.g., D+/R−), based on the available data suggesting better graft survival and clinical outcomes. Individual transplant centers should weigh the risks and benefits of each strategy, based on their frequency of CMV disease, ability to monitor recipients (i.e., logistics), cost of antiviral medications, frequency of late onset CMV disease, relapse failure rates with preemptive therapy, and rates of other opportunistic infections (which may be increased by CMV disease), graft loss, rejection, and mortality. To mitigate risk, some centers use a hybrid approach, especially for those recipients felt to be at high risk for late CMV disease, that is, preemptive therapy with treatment followed by secondary prophylaxis or prophylaxis followed by preemptive therapy.
Use of Prophylaxis Versus Preemptive Therapy
- Both universal prophylaxis and preemptive strategies are viable approaches for prevention of CMV disease (I).
- For the highest risk patients (D+/R−), prophylaxis may have some advantages over preemptive therapy (II/III).
- Preemptive therapy has not been well studied in some subpopulations including lung transplant, intestinal transplant, and pediatric transplant.
When a prophylaxis strategy is used for prevention in D+/R− patients, the following durations are recommended:
- The duration of prophylaxis in D+/R− patients should be generally between 3 months (I) and 6 months (I). The decision to use 3 vs. 6 months may depend on degree of immunosuppression, including the using of antilymphocyte antibodies for induction. The Improved Protection Against Cytomegalovirus in Transplantation (IMPACT) study compared 100 vs. 200 days of prophylaxis in 316 D+/R− kidney patients. The incidence of CMV disease was reduced from 36.8% to 16.1% (88).
- A minimum of 6 months of prophylaxis is recommended for lung (II-2) and small intestine (III) transplant recipients.
When a prophylaxis strategy is used for prevention in D+/R− patients, the following antiviral medications are recommended:
- Kidney transplant: valganciclovir, IV or oral ganciclovir, or valacyclovir (I).
- Pancreas transplant (including kidney/pancreas): valganciclovir and IV or oral ganciclovir (II).
- Liver transplant: oral ganciclovir (I) or valganciclovir (III). In a subgroup analysis, valganciclovir was associated with a higher rate of tissue-invasive disease in liver transplant recipients (83), but its use is still recommended based on expert opinion; in one survey, it was the most commonly used drug for CMV prevention in liver transplant recipients (89).
- Heart transplant: valganciclovir, IV or oral ganciclovir (II), ±CMV immunoglobulin (III).
- Lung transplant: valganciclovir or IV ganciclovir (II), ±CMV immunoglobulin (III).
- Intestinal transplant: valganciclovir, IV or oral ganciclovir, ±CMV immunoglobulin (III).
When used for prophylaxis, the usual dose of valganciclovir is 900 mg a day, versus treatment dose which is 900 mg twice daily; both should be adjusted for renal function. There are limited data to support the use of CMV immunoglobulin for prophylaxis when appropriate antivirals are given. However, some centers use these products in conjunction with antiviral therapy, especially for thoracic transplant recipients (III).
Important Considerations for Prophylaxis for D+/R− Patients
Dosing of antiviral medication should be based on standard recommended dosing algorithms and adjusted for renal function. “Mini-dosing” strategies (i.e., valganciclovir 450 mg a day with normal renal function) are not recommended. Most centers do not test for CMV viremia in asymptomatic patients on antiviral prophylaxis. The occurrence of late-onset disease after discontinuing prophylaxis is an important issue and is associated with higher rates of mortality (90) and graft loss (91). Transplant centers should monitor clinically for signs and symptoms of late-onset CMV disease; additional strategies to prevent late onset disease may be considered, including PCR or antigenemia monitoring after completion of prophylaxis, or prolonging prophylaxis from 3 up to 6 months or longer in certain subgroups of patients.
Prophylaxis of R+
- When a prophylaxis strategy is used for prevention in R+ patients (with either D+ or D−), a majority of the experts felt that 3 months of antiviral medication should be used for kidney, pancreas, liver, and heart transplant recipients (I/II).
- In those receiving antilymphocyte antibody induction, or lung and intestinal transplant recipients, between 3 and 6 months of prophylaxis can be used (III). The same medications are recommended for this cohort as for D+R−.
- While D+R+ patients are discussed here together with the D−/R+ group, the former group is usually at higher risk for developing CMV disease.
Prophylaxis of D−R−
In general, this population is at low risk for CMV disease. Extensive transfusion of blood products increases the risk of CMV disease (especially if not CMV screened or leukodepleted), and transplant centers may wish to monitor such recipients with weekly CMV PCR or antigenemia. The use of leukodepleted blood products and CMV-seronegative blood products is recommended for these recipients to decrease the risk of transfusion transmitted CMV (II). Some transplant centers may give CMV antiviral prophylaxis in patients who receive extensive transfusions (III).
- Antiviral prophylaxis against other herpes infections (varicella and herpes simplex) should be considered.
Preemptive Therapy Strategy
- When a preemptive therapy strategy is used, it is recommended that the center develop and validate their local protocol. Because preemptive therapy relies on laboratory monitoring, it is important that an appropriate threshold value be chosen for the specific assay that is used. There is currently insufficient evidence to recommend universal threshold values for assays that are used in preemptive therapy. For optimal preemptive therapy, there was strong consensus that kidney, pancreas, liver, and heart transplants should be monitored by either CMV PCR or antigenemia every week for 3 months after transplant.
- Once a certain positive threshold (variable by assay used) is reached, therapy with treatment dose (not prophylactic dose) valganciclovir (I) or IV ganciclovir (I) should be started and continued until one or two negative tests are obtained. Testing while on treatment is often performed once or twice a week.
- Whether to reinitiate subsequent monitoring or secondary antiviral prophylaxis after the end of treatment should be an institutional decision. Occasional low-level unsustained viremia (i.e., below the institutional threshold for preemptive treatment) may be seen and should not result in the initiation of antiviral treatment unless the patient is symptomatic; such low viremia may respond to a reduction in immunosuppression.
Prevention During Treatment of Rejection
- There was consensus that treatment of rejection with antilymphocyte antibodies in at-risk recipients should result in reinitiation of prophylaxis or preemptive therapy for 1 to 3 months (II/III); a similar strategy may be considered during treatment of rejection with high-dose steroids (III).
IV ganciclovir has been the “gold standard” for treatment of CMV disease for some years. Previously, foscarnet was commonly used but toxicity generally limits use in SOT recipients, especially the nephrotoxic effect in those receiving concomitant calcineurin inhibitors (92). The Valcyte in CMV-disease Treatment of solid Organ Recipients (VICTOR) trial recently showed that oral valganciclovir is noninferior to IV ganciclovir for treatment of CMV disease in a population of SOT recipients (74% of whom were renal transplant recipients) with generally nonlife-threatening disease as determined by the investigator (48% had CMV syndrome and 49% had tissue-invasive CMV disease) (33). In patients with life-threatening CMV disease and in children, IV ganciclovir is still the preferred drug, because data on the effect of oral treatment are limited. IV ganciclovir should also be used in patients who do not tolerate oral treatment or when absorption of valganciclovir is suboptimal.
It is important to give appropriate doses of valganciclovir or ganciclovir. Inadequate dosing may result in lack of clinical efficacy and promote resistance (93). Supratherapeutic doses may result in toxicity (94). Twice daily dosing should be used for treatment of disease in patients with normal renal function. Once daily dosing is appropriate for secondary prophylaxis (see later). Optimal length of treatment should be achieved by monitoring weekly viral loads and treating until one or two consecutive negative samples are obtained, but not shorter than 2 weeks. With this treatment algorithm, the risk for development of resistance and recurrence of CMV disease is minimized (87, 95, 96). The use of secondary prophylaxis is variable across transplant centers, but it is often recommended (range 1–3 months) (87, 33). Duration should reflect the likelihood of recurrent CMV infection. In cases of serious disease and in tissue-invasive disease without viremia, longer treatment periods with clinical monitoring of the specific disease manifestation are recommended. In cases of recurrent CMV disease, prophylaxis after retreatment may need to be prolonged.
Clinical trials over the years have established several risk factors for recurrence of CMV include: primary CMV infection (e.g., CMV IgG seronegative at start of treatment of CMV disease), deceased donor transplantation, high baseline viral load, persistent viremia when transferred to secondary prophylaxis, multiorgan disease, and treatment of rejection (87, 96–98). Knowledge of these risk factors allows for some individualization of the treatment, but only as a supplement to clinical and virologic monitoring of the patient.
- For nonsevere CMV disease, oral valganciclovir (900 mg orally every 12 hr) or IV ganciclovir (5 mg/kg every 12 hr) are recommended as first-line treatment (I, ). In children, in patients with severe or life-threatening disease, and when the oral formulation of the drug is not tolerated or its absorption may be suboptimal, IV ganciclovir should be used, because there are no efficacy data for oral treatment in these cases (III). Conversion between the two drugs (i.e., from IV ganciclovir to oral valganciclovir) may be performed without dosing interruption (III). Oral ganciclovir, acyclovir, or valacyclovir should not be used for treatment of CMV disease (III). Renal function should be monitored frequently during treatment, with estimated or measured glomerular filtration rate. The doses should be adjusted as per the package label (noting that there are different cutoffs for IV ganciclovir and oral valganciclovir) (II-1, ). Dose reduction of antiviral treatment due to side effects such as leukopenia should be avoided as much as possible. A reduction of mycophenolic acid products, mammalian target of rapamycin inhibitors, azathioprine, and possibly also trimethoprim-sulfamethoxazole dosages should be considered before valganciclovir/ganciclovir reduction (III). Granulocyte colony-stimulating factor (G-CSF) may be considered for severe leukopenia, especially if the absolute neutrophil count is less than 1000/mm3 (III). Redosing of G-CSF depends on individual response to therapy.
- Treatment with twice daily valganciclovir or IV ganciclovir should be continued until viral eradication is achieved, but not shorter than 2 weeks (II-1, [23, 87, 33]). Risk factors indicating a possible need for longer treatment length are CMV IgG seronegativity and high baseline viral load at the start of treatment (II-1, ). Secondary prophylaxis with 900 mg valganciclovir once daily for 1 to 3 months may be given, with the longer duration deployed in high-risk patients (II-3, ); dose adjustment based on estimated or measured renal function should be made per the package insert.
- Laboratory monitoring of CMV should be applied weekly during the treatment phase with a QNAT or antigenemia-based assay to monitor response and the possible development of resistance (II-1, [23, 33]). Trends of serial monitoring are easier to interpret than an individual test result. Two consecutive negative samples (preferably sampled one week apart) ensure viral clearance (III). Periodic viral load monitoring should also be performed during secondary prophylaxis (III); the correct time interval for monitoring is not known, but more frequent monitoring should be done in those at high risk for breakthrough disease. Because the lower limits of detection of QNAT assays are variable, “undetectable” is an assay-specific term. At present, when using extremely sensitive viral load assays (which may detect latent virus), it is not known whether treatment to “undetectable” QNAT viral load is required to minimize relapse risk.
- Dose reduction of the immunosuppressive therapy should be individualized but should be considered in severe CMV disease, in nonresponding patients, in patients with high viral loads, and with leukopenia (II-2, ). If the immunosuppressive therapy is reduced, clinicians may wish to return to standard immunosuppressive treatment when adequate clinical and viral response is obtained (III). In case of recurrent CMV disease, a general evaluation of the overall immunosuppressive status of the patient should be performed and immunosuppression adjusted when indicated (III).
- The role of CMV immunoglobulin in the treatment of CMV disease is unclear. It may be considered as adjunctive therapy for severe forms of CMV disease such as pneumonitis (III).
ANTIVIRAL DRUG RESISTANCE
Risk Factors for CMV Drug Resistance, Observed Frequency, and Clinical Consequences
Published series identify the risk factors for drug resistance as prolonged antiviral drug exposure (usually several months, median is 5 to 6 months) and ongoing active viral replication as permitted by host immunosuppression or immunodeficiency, lack of prior CMV immunity (D+R−), or inadequate antiviral drug delivery as with oral ganciclovir (evidence II-2) (92, 101–105). Among adult SOT recipients, ganciclovir resistance occurs overwhelmingly in the D+R− subset where the usual incidence of resistance is 5% to 10% (92, 102) and seems to be higher in lung transplant recipients (103, 106). There are no large studies comparing the outcomes of infection with drug-resistant versus drug-sensitive CMV strains. Reported outcomes of drug-resistant CMV infection range from asymptomatic to severe or fatal disease (92, 102, 107, 108). Tissue-invasive CMV disease is frequently encountered in those who are infected with drug-resistant virus. Virulent disease is common despite potential loss of viral fitness due to the resistance mutation(s) present (93).
Diagnosis of Drug Resistance
Antiviral drug resistance is suspected when increasing or high-level CMV viremia or progressive clinical disease is observed during prolonged antiviral therapy. The increases in viral loads, especially in the first weeks of treatment, are not reliable indicators of drug resistance (109). Although the clinical risk factors for drug resistance are becoming better defined, accurate diagnosis requires diagnostic laboratory testing.
The traditional plaque reduction (phenotypic) sensitivity assay is used to determine the drug concentration required to inhibit the growth of a viral isolate by 50% (IC50). This assay is impractical for routine patient care, because of technical complexity, difficulties with standardization, and slow turnaround time (at least several weeks). Phenotypic assays are required as reference standards for comparing the drug sensitivity of viral strains, assessing the significance of previously uncharacterized mutations, and setting cutoff criteria for diagnosing viral drug resistance.
Genotypic assays for rapid antiviral resistance testing are useful to identify characteristic viral mutations indicative of drug resistance. Such assays are being performed by an increasing number of commercial laboratories and can be performed on viral sequences directly amplified from blood (whole blood, plasma, and PBMC), fluids (CSF and bronchoalveolar lavage), tissue specimens, or CMV culture isolates. The turnaround time for such assays varies depending on the laboratory and geographical constraints. There are a few reports of discordant resistance mutations in different body compartments (110). This testing is more reliable if the CMV load in the specimen is at least 1000 copies/mL. Standard sequencing technologies enable the detection of a mutant viral sequence when it increases to approximately 20% of the total sequence population (111). Amplification directly from clinical specimens allows determination of the UL97 kinase (codons 400–670) and (optionally) the UL54 pol (codons 300–1000) sequences. A large and evolving database of characterized CMV drug resistance mutations has been accumulated (112–115). Existing data indicate that more than 90% of ganciclovir-resistant CMV isolates contain UL97 mutations at codons 460, 520, or 590 to 607. Mutations M460V/I, C592G, A594V, L595S, and C603W are the most common and confer a 5- to 10-fold increase in ganciclovir IC50, except for C592G that confers only approximately a 2.5-fold increased IC50, considered low-grade resistance. Less common sequence changes at codons 590 to 607 may confer various degrees of ganciclovir resistance or no significant resistance. In the viral DNA polymerase gene (UL54, pol), drug resistance mutations tend to occur in the conserved functional domains and may confer resistance to any or all of the current drugs ganciclovir, foscarnet, or cidofovir. Mutations that confer ganciclovir and cidofovir resistance are clustered in the exonuclease domains and region V, whereas those conferring foscarnet resistance are often located in or between regions II, III, and VI. Some foscarnet resistance mutations in region III confer a low-grade ganciclovir cross-resistance. In patients initially treated with ganciclovir, UL97 mutations usually appear first, followed later by the addition of pol mutations that confer increased ganciclovir resistance and cross-resistance to cidofovir or foscarnet (116–118). When interpreting genotypic assays, it is important to distinguish baseline sequence polymorphisms of CMV strains (119, 120) from mutations that are proven to confer drug resistance (121, 122). The status of many observed sequence changes in UL97 and pol remain unresolved.
Selection of Alternate Therapy for Drug-Resistant CMV
No controlled trial data support a best practice for selection of alternate therapy when evidence of drug resistance is present. An algorithm is proposed (Fig. 1) based on consensus opinion assembled for this publication (III). Clinically, antiviral drug resistance is suspected when high or rising viral loads and progressive CMV disease are observed after substantial cumulative antiviral drug exposure and several weeks of antiviral therapy. This finding is sometimes called “clinical resistance,” but many such cases reveal no virologic (genotypic or phenotypic) evidence of drug resistance, especially when the duration of drug exposure is less than several months. Antiviral therapy may be insufficient to suppress viral replication in the presence of adverse host factors (e.g., immune impairment, inadequate drug levels), independent of viral drug resistance. In this situation, the first recommended therapeutic change is to decrease immunosuppressive therapy to the lowest feasible amount. Then, depending on the severity of the CMV disease (whether life or sight threatening) and host risk factors (D+R−, lung transplantation, and severe immunosuppression), an empiric therapy is begun, pending return of genotypic resistance test data. In a high-risk clinical setting, empiric combination ganciclovir and foscarnet therapy is reasonable (at either partial or standard doses) (123, 124) or foscarnet alone. Alternatively, for more mild CMV disease, ganciclovir can be increased to higher than standard doses (up to 10 mg/kg twice daily for normal renal function).
If genotypic resistance testing reveals a major UL97 mutation (>5-fold increased ganciclovir resistance), a switch to foscarnet is suggested. UL97 mutations conferring lesser degrees of resistance may permit the continued use of ganciclovir at higher doses (125) (between 5 and 10 mg/kg twice daily for normal renal function), but genotypic testing for a viral UL54 pol mutation is suggested. If a pol mutation is present that confers added ganciclovir resistance (and usually cidofovir cross-resistance), switching to foscarnet is recommended. Because of the demonstrated frequency of ganciclovir-cidofovir cross-resistance from pol mutations, cidofovir is not recommended as an alternate therapy for ganciclovir-resistant CMV, unless pol mutations are shown to be absent and the disease is not clinically severe. There is little information on the efficacy of cidofovir in SOT; its use in HSCT gave mixed results (126). Additional guidance appears in Figure 1.
Adjunctive treatments, defined as those without a specific CMV antiviral drug target, have not been adequately evaluated. Immunoglobulins containing CMV antibodies and adoptive infusions of CMV-specific T-cells (58) may improve antiviral host defenses. Several small molecule drugs, including sirolimus (127, 128), leflunomide, and artesunate (129), have shown anti-CMV effects, probably by altering host cell physiology to a less permissive condition for viral replication (130). Leflunomide was reported to clear CMV viremia in a HSCT and renal transplant recipients with drug-resistant CMV (130, 131), but also to have failed in another HSCT recipient (132). Prolonged leflunomide treatment may be needed to clear CMV viremia (133).
Experimental CMV Antiviral Agents
Maribavir (MBV) is an orally administered benzimidazole l-riboside that is a potent inhibitor of the CMV UL97 kinase (134, 135). A phase II trial showed significant reduction of active CMV infection when MBV was given as prophylaxis after HSCT (136). Phase III trials were initiated to confirm this effect in larger groups of HSCT and liver transplant recipients, but they were halted when MBV was found to have similar outcomes compared with placebo in HSCT. Because there is no known cross-resistance between current drugs and MBV (137), it has been used as salvage therapy for those who have developed multidrug resistant CMV infection, with too few cases to assess efficacy.
Future Research and Clinical Practice Needs
Because of the relative infrequency of CMV drug resistance, adequate prospective studies have not been performed to define the outcomes of drug-resistant CMV. Genotypic resistance testing needs to be made more widely available, with improved interpretation of the degree of resistance conferred to various drugs by the mutations present in a given clinical specimen. A validated and continuously updated public database of these mutations would be a valuable resource. New therapeutic options lacking cross-resistance with current drugs are needed.
Figure 1 explains the management of suspected ganciclovir resistance (III).
PEDIATRIC ISSUES IN CMV MANAGEMENT
Management of CMV infection and disease in pediatric organ transplant recipients presents a number of specific challenges. The pediatric group considered and adopted issues that were common to both children and adults, taking into account existing guidelines (138, 139). For the purposes of this document, the pediatric age group was defined as 12 years or less. It should be noted that this age cutoff will not be applicable to all children, taking into account other factors, including body weight.
Current Burden of CMV-Associated Disease in Children
CMV infection and disease remain important causes of morbidity and occasional mortality among pediatric organ transplant recipients. Data on the precise burden in pediatric organ transplant recipients are limited, however, by wide differences in data collection and reporting. In addition, nonuniform approaches to the laboratory diagnosis and definition of CMV disease in retrospective studies affect the ability to interpret available data. In five centers in the United States, 10% to 20% of liver transplant patients experienced CMV disease within 2 years after transplantation (140). These patients had received 2 weeks of prophylaxis with ganciclovir with or without immune globulin. A review of first-time pediatric lung transplant patients indicated that among at-risk subjects, the incidence of CMV viremia was 29% to 32%, whereas that of CMV pneumonitis was 20% in the first year after transplantation (141, 142).
Primary Risk Factors for the Development of CMV Disease in Children
Adult and pediatric patients share similar risk factors for the development of CMV disease after transplantation (143). Compared with adult transplant recipients, children have an increased likelihood of acquiring primary CMV infection because children are more often CMV naïve at the time of transplant. Characterizing donor and recipient serostatus in children less than 18 months of age is complicated by the variable persistence of transplacental maternal CMV antibodies. CMV D−R− pediatric SOT recipients remain at ongoing risk of de novo infection due to environmental CMV exposures in the posttransplant period. In addition, leukocyte-reduced or CMV-negative blood products should be considered for special populations (e.g., bowel, lungs, and hearts) and in CMV D−/R− patients. Similar to adult SOT recipients, pediatric patients who receive antilymphocyte globulin or OKT3 for rejection are at increased risk of CMV disease. Of special note, the implications of starting children with developing immune systems on immunosuppression are unclear and are in need of further study, as it has been observed by some experts that young children may seem to be more immunosuppressed than what would be predicted from the dose of immunosuppressive drugs received.
Optimal Methods for the Diagnosis of Pediatric CMV Infection/Disease
The approach to the diagnosis of CMV infection/disease in children is similar to that among adults (143), with a few caveats. The amount of blood obtained by venipuncture may be limited (thus QNAT may be easier than antigenemia). In children, some invasive diagnostic procedures are more difficult (e.g., transbronchial biopsies in young infants).
Prevention of Pediatric CMV Disease
Both preemptive therapy and antiviral prophylaxis are used to prevent CMV infection in pediatric SOT recipients. Data on the use of preemptive IV or oral therapy to prevent CMV disease in this population are lacking. In general, there is more collective experience with IV ganciclovir for preemptive treatment in children.
Antiviral prophylaxis is more commonly used and includes both IV ganciclovir and oral valganciclovir. IV ganciclovir is usually dosed at 5 mg/kg per day; some centers start with 10 mg/kg in two divided doses for the initial 2 weeks of the prophylaxis period. Prolonged IV ganciclovir (12 weeks) has been used safely in pediatric transplant recipients (144). Valganciclovir has emerged as a viable option for prevention of CMV infection in adult SOT recipients, and emerging data in pediatric patients help to address issues relating to formulation and pharmacokinetics (145–147). Data regarding the efficacy of valganciclovir in pediatric SOT recipients in these situations are still necessary, particularly due to the potential for inadvertently achieving low levels and the risk of ganciclovir resistance. Prolonged valganciclovir use has not been the subject of randomized studies in children, but it has been evaluated in individuals older than 16 years (88). Absorption issues might be of particular concern in bowel transplant recipients. Valganciclovir use is more likely to be associated with prolonged courses compared with the IV route due to convenience. This is of theoretical concern, given the known carcinogenicity in animals at high doses and unknown consequences of prolonged ganciclovir therapy in young infants (Product Monograph Cytovene; Genentech, formerly Hoffmann-La Roche Limited, Basel, Switzerland).
CMV immunoglobulin is sometimes used with antivirals for the prevention of CMV infection and disease after pediatric organ transplantation. Evidence is often extrapolated from data derived from adult populations. A recently published meta-analysis of randomized trials demonstrated a beneficial effect of prophylactic CMV immunoglobulin on total survival and prevention of CMV-associated death in SOT recipients except kidney transplant recipients (148). The occurrence of CMV disease was significantly less in all recipients receiving prophylactic CMV immunoglobulin, but it had no effect on CMV-infections and clinically relevant rejections. None of these trials compared the efficacy of CMV immunoglobulin with ganciclovir or valganciclovir. Limited published data address the potential benefit of the addition of CMV immunoglobulin to ganciclovir in the prevention of CMV. In one pediatric study that primarily targeted Epstein-Barr virus, the addition of CMV immunoglobulin to 2 weeks of IV ganciclovir did not seem to have a significant impact on the development of CMV disease, although there was a trend toward a higher 2-year CMV disease-free rate in R+ children (140). In another randomized trial that also targeted Epstein-Barr virus (149), CMV infection (but not disease) developed in 18.8% of pediatric patients receiving ganciclovir alone and 5.6% in those given ganciclovir with CMV immunoglobulin; this difference was not statistically significant. Despite the lack of available data, many pediatric centers currently use CMV immunoglobulin as part of their CMV preventive strategies. This is evidenced by a recent survey of eight pediatric lung transplant programs that indicated that 50% use CMV immunoglobulin as a part of a CMV prevention strategy that also includes the use of ganciclovir (150). Overall, there are no large randomized trials that show CMV immunoglobulin is of benefit when standard antiviral prophylaxis is used.
Treatment of Pediatric CMV Disease
In the treatment of CMV disease in children, there is a profound lack of data on which to base firm recommendations, notably as this relates to the role of IV versus oral therapy. Many principles that guide therapy are similar to those among adults and are outlined elsewhere in this document. The concept of initial treatment followed by secondary prophylaxis is advocated by some experts (151).
Ganciclovir Resistance in Pediatric Organ Transplant
Because of the high likelihood of CMV D+R− status in children, ganciclovir resistance is of significant theoretical concern (115). Based on data from children with severe combined immunodeficiency states and pediatric HSCT recipients, there are anecdotal reports of the rapid emergence of resistance to ganciclovir. There are few reports, however, describing ganciclovir resistance among pediatric SOT recipients. It is unclear if this is due to low resistance burden, lack of generated data, or underreporting. Similar to adult patients, the currently available agents for the treatment of ganciclovir-resistant CMV in children include foscarnet and cidofovir. The use of these agents is limited by nephrotoxicity. Other investigational agents, with little or no pediatric data, include MBV, leflunomide, and artesunate.
While recognizing that the ability to generate pediatric data is challenging, it is recommended that:
- Given the challenge of characterizing donor and recipient serostatus in those less than 18 months of age, risk assessment in this age group should assume the highest risk level for purposes of CMV prevention (III). Donors who are less than 18 months of age should be regarded as CMV seropositive if the CMV serologic test is positive. Similarly, any CMV seropositive recipient who is less than 18 months of age should be assumed to be seronegative, as maternal antibody may account for this finding. CMV urine culture or QNAT should be obtained from seropositive recipients less than 18 months of age, because a positive result would confirm prior CMV exposure. Negative CMV urine culture, however, may result from intermittent shedding of virus.
- In general, the principles that guide the use of prophylaxis in adults are similar in children as defined by CMV donor and recipient serostatus. Table 4 provides a suggested approach to CMV prevention with antivirals±CMV immunoglobulin in children. CMV D−R− patients are excluded given the low risk (<5%) of CMV disease. Recommended regimens are largely based on expert opinion and extrapolation from adult studies.
- Prophylaxis is preferred over preemptive treatment for the majority of pediatric patients (III). Most experts recommend at least 3 months of prophylaxis. Shorter courses are used in some centers. Longer durations have been evaluated in adults (I) and represent acceptable alternate courses of action for children (III). A valganciclovir-dosing algorithm that adjusted for body surface area and renal function and which provided ganciclovir exposures similar to those established as safe and effective in adults has been published recently (146). The dosing, pharmacokinetics, and efficacy of CMV prevention using valganciclovir require further study in children. Use of this agent may be considered for CMV prophylaxis in older children more than 12 years of age (III).
- The initial treatment of CMV disease in children should be with IV ganciclovir at a dose of 5 mg/kg every 12 hr (II-3). In situations where secondary prophylaxis is used, IV ganciclovir is preferred (5 mg/kg/day; II-3). Given the absence of prospective data, no firm recommendations can be made regarding the use of oral therapy for the treatment of CMV disease in children (III). Some experts consider oral therapy for some older children and adolescents toward the end of their treatment courses (III).
- CMV immunoglobulin is recommended for the treatment of CMV pneumonitis and enteritis in children and for hypogammaglobulinemia (II-2). For other clinical entities, CMV immunoglobulin is recommended on a more selective basis (III).
- Studies of the indirect effects of CMV are needed, given the uncertain impact in pediatrics (III).
The CMV Consensus Conference was organized by The Infectious Diseases Section of The Transplantation Society. An independent, nonrestricted grant from Roche made this conference possible. The authors thank Filomena Picciano, Frank Lindo Verissimo, and Catherin Parker of The Transplantation Society for their administrative support.
CMV Consensus Meeting participants' conflict of interest: Upton Allen, Hospital for Sick Children: grant application to Hoffmann—La Roche from 2007 to 2008. Khalid Almeshari, King Faisal Specialist Hospital & Research Center: consultant for Genzyme for 1 year and consultant for Wyeth for 3 years. Anders Åsberg, University of Oslo: consultant for Roche from 2004 to 2008. Fausto Baldanti, Fondazione IRCCS Policlinico San Matteo: declares no conflict of interest. Guy Boivin, Centre de recherche du CHUL: grant application to Roche from 2001 to 2008. Angela Caliendo, Emory University School of Medicine: Scientific advisor for Roche Molecular Diagnostics, Nanogen, Siemens, and Qiagen. Sunwen Chou, VA Medical Center: speaker for Robert Michael Education Institute 2007 to 2008, research contract with ViroPharma for resistance testing services done. Lara Danziger- Isakov,; Cleveland Clinic: supported by grant CSL Behring from 2004 to 2008. Elias David-Neto, University of Sao Paulo. Vincent Emery, University College London (UCL), Centre for Virology: consultant and speaker for Roche for 10 years and consultant and speaker for ViroPharma for 1 year. Jay A. Fishman, Massachussetts General Hospital: SAB for Primera since 2007 and speaker for Roche in 2008. Michael Green, Division of Infectious Diseases, Children's Hospital of Pittsburgh of UPMC. Anders Hartmann, Rikshospitalet University Hospital. Atul Humar, University of Alberta: supported by grant from Roche from 2006 to 2009, honoraria from Roche in 2008, and speaker for ViroPharma in 2008. Michael Ison, Northwestern University: speaker for Viracor since 2007, speaker for Abbott molecular in 2008, PI for Roche since 2005, PI for Biocryst and ViroPharma since 2006, PI for Pfizer since 2007, and PI for Adma since 2008. Alan Jardine, BHF Cardiovascular Research Centre: consultant for Roche since 2000, consultant for Novartis since 1996, consultant for AstraZeneca since 2003, consultant and speaker for Wyeth since 2002, and speaker for Astellas since 2008. Nassim Kamar, Department of Nephrology, Dialysis & Multi-Organ Transplantation, Toulouse University Hospital: honoraria from Roche. Rajiv Khanna, Queensland Institute of Medical Research: consultant for Cellestis in 2005. Camille Kotton, Massachusetts General Hospital: honoraria from ViroPharma in 2009. Deepali Kumar, University of Alberta: research funding from Hoffmann-LaRoche and Cellestis Inc. Roberta Lattes: declares no conflict of interest. Irmeli Lautenschlager, Helsinki University Central Hospital: declares no conflict of interest. Tiziana Lazzarotto, Bologna St. Orsola Malpighi General Hospital: declares no conflict of interest. Christophe Legendre, Hôpital Necker: consultant for Roche. Hildebrando Leguizamon S., Columbiana de Transplantes from Colombia: declares no conflict of interest. Daniele Lilleri, Fondazione IRCCS Policlinico San Matteo: declares no conflict of interest. Ajit Limaye, University of Washington: speaker for Robert Michael Education Institute in 2008 and research contract from Roche and ViroPharma. Carlos Lumbraras, Universidad Europea de Madrid: declares no conflict of interest. Nell Lurain, Department of Immunology/Microbiology, Rush University Medical Center: consultant for Abbott from 2006 to 2008. Oriol Manuel, University Hospital of Lausanne (CHUV): TID fellowship from Roche for 2 years (2006). Miguel Montejo, Hospital de Cruces: declares no conflict of interest. Nicolas J. Mueller, Division of Infectious Diseases, University Hospital Zurich: declares no conflict of interest. Patricia Muñoz; Hospital General Universitario Gregorio Marañón: declares no conflict of interest. Mark Pescovitz, Indiana University: PI, consultant, and speaker for Roche for 10 years, PI and consultant for ViroPharma for 3 years, and consultant for Vical for 1 year. Jutta K. Preiksaitis, Provincial Laboratory for Public Health: declares no conflict of interest. Raymund R. Razonable, Mayo Clinic: supported by Roche in 2008 and PI for ViroPharma since 2008. Halvor Rollag, Institute of Microbiology, Rikshospitalet: member of Victor Steering Committee for Roche since 2004. Martina Sester, Department of Transplant and Infection Immunology, University of Saarland: declares no conflict of interest. Dino Sgarabotto, Padua General Hospital: speaker for Roche and Bayer for 3 year and, speaker for Pfizer for 4 year. Nina Singh, Pittsburgh VA Medical Center/University of Pittsburgh Medical Center: data safety monitoring board for Viropharma study 1263-300. David R. Snydman, Tufts Medical Center: consultant for CSL Behring since 2008 and supported by Roche from 2003 to 2005. Cecilia Söderberg-Nauclér, Karolinska Institutet: investigational grant and occasional speaker for Roche for 6 year and speaker honorarium for CME in 2008. Julián Torres-Cisneros, UGC of Infectious Disease, Hospital Universitario Reina Sofia: speaker bureau and supported by Roche from 2007 to 2009. Huseyin Toz, Division of Nephrology, Ege University Medical School: declares no conflict of interest. Glen Westall, Alfred Hospital: supported by Cellestis for 2 year, consultant for CSC in 2007, and speaker bureau from Roche in 2008.
The Consensus contributors are as follows: Leaders: Camille N. Kotton (US) and Atul Humar (Canada); diagnostics: Angela M. Caliendo (leader, US), Vincent Emery (UK), Irmeli Lautenschlager (Finland), Tiziana Lazzarotto (Italy), Jutta Preiksaitis (Canada), Raymund Razonable (US), and Halvor Rollag (Norway); immunology: Deepali Kumar (leader, Canada), Michael G. Ison (US), Rajiv Khanna (Australia), Oriol Manuel (Switzerland), Cecilia Soderberg- Naucler (Sweden), Martina Sester (Germany), Julian Torre-Cisneros (Spain), and Glen Westall (Australia); prevention: David R. Snydman (leader, US), Khalid Almeshari (Saudi Arabia), Mark D. Pescovitz (US), Jay A. Fishman (US), Alan Jardine (UK), Nassim Kamar (France), Roberta Lattes (Argentina), Christophe Legendre (France), Daniele Lilleri (Italy), Carlos Lumbreras (Spain), Nicolas Mueller (Switzerland), Elias David-Neto (Brazil), Nina Singh (US); treatment: Anders Åsberg (leader, Norway), Anders Hartmann (Norway), Hildebrando Leguizamon (Colombia), Miguel Montejo (Spain), Patricia Munoz (Spain), Dino Sgarabotto (Italy), and Hüseyin Töz (Turkey); resistance: Sunwen Chou (leader, US), Fausto Baldanti (Italy), Guy Boivin (Canada), Ajit Limaye (US), and Nell Lurain (US); pediatrics: Upton Allen (leader, Canada), Lara Danziger-Isakov (US), and Michael Green (US).
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