SEARCH

SEARCH BY CITATION

Keywords:

  • Cytomegalovirus;
  • pediatric transplantation;
  • preemptive therapy;
  • prophylaxis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

Cytomegalovirus (CMV) continues to be a significant posttransplant infectious complication after pediatric liver transplant (PLT). The optimal prevention strategy is not currently known. To assess current CMV prevention practices, a web-based survey was conducted within the North American Studies in Pediatric Liver Transplantation (SPLIT) network. Twenty-nine of the 31 centers (94%) surveyed responded. Only seven centers reported evidence-based development of protocols. For most at-risk (donor or recipient CMV seropositive) PLT recipients, a prophylactic strategy predominates current practice. For high-risk (D+/R−), only three centers used nonprophylaxis-based protocols: one preemptive and two sequential/hybrid. Duration of prophylaxis ranged from 84 to 730 days with 14 centers using around 100 days and nine centers using around 200 days. Initial therapy with ganciclovir followed by valganciclovir was the most common strategy. For lower-risk recipients (CMV D−/R−), more centers (10/29) employed a preemptive strategy while the remainder described prophylaxis (15) and sequential/hybrid (3) strategies. Prophylaxis predominates current CMV prevention strategies for at-risk recipients within SPLIT. The variation in duration of therapy provides the opportunity to perform comparative effectiveness studies within SPLIT.


Abbreviations
CMV

cytomegalovirus

CMVIG

CMV-hyperimmune globulin

D

donor

PLT

pediatric liver transplant

R

recipient

SPLIT

Studies in Pediatric Liver Transplantation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

Cytomegalovirus (CMV) is a significant posttransplant infection after pediatric liver transplant (PLT) with up to 30% of patients developing an episode of CMV infection or disease [1-4]. While prevention strategies can decrease the incidence of early posttransplant infections, the optimal strategy for CMV prevention is uncertain with limited literature in PLT recipients. Further, comparisons between strategies have focused mainly on the use of different antivirals using historical control groups or small single-center studies [1, 5]. To evaluate the potential for planning a comparative effectiveness study for CMV prevention strategies, a survey of the North American Studies in Pediatric Liver Transplantation (SPLIT) was conducted. SPLIT was chosen for its commitment to open collaboration and quality improvement in the focus to improve outcomes after PLT [6].

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

A survey was developed in conjunction with infectious disease and hepatology at Cincinnati Children's Hospital Medical Center with review from the local Institutional Review Board and approval from the SPLIT Research Committee. The survey focused on strategies to prevent CMV infection including protocol development processes, screening and laboratory use, antiviral choices and adjunctive therapies. A REDCap survey [7] was sent electronically to one individual at each of 31 centers participating in SPLIT as provided by the data-coordinating center (EMMES Corporation, Rockville, MD). Requests were sent weekly until a response was received for 3 weeks preceding the 2013 Annual SPLIT meeting (September 2013). The interim findings were provided at the 2013 Annual SPLIT meeting after which an additional e-mail request was sent with up to three reminders to the centers that had not yet replied. Centers provided contact information for clarification as part of the survey. Data are reported in aggregate using descriptive statistics.

Definitions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

Survey participants were requested to use common definitions for CMV prevention strategies that were provided in the survey.

Prophylaxis: antiviral medication for a specified period of time. Prophylaxis can be universal (given to all recipients) or targeted (given based on risk profile to selected groups of recipients).

Preemptive therapy: serial monitoring for CMV replication with initiation of therapy at a predetermined threshold viral load.

Sequential/hybrid therapy: short-course prophylaxis followed by serial monitoring and preemptive therapy as above.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

Responder demographics

Twenty-nine SPLIT centers responded to the survey (94%): 27 from the United States and 2 from Canada. The majority of responders (15; 52%) were hepatologists. The remainder were coordinators/nurses (7; 24%), surgeons (5; 17%) and infectious diseases specialists (2; 7%).

Protocol development process

A series of questions focused on the process of protocol development and evaluation. The majority of centers had guidelines or protocols related to the prevention of CMV after transplantation including pretransplant screening (28/29), CMV prevention strategy (27/29), CMV monitoring (24/29) and viral load threshold for intervention (19/29). Seven centers reported using formal evidence-based medicine review to develop strategies; outcomes of these reviews produced different strategies ranging from preemptive therapy to prolonged prophylaxis for up to 2 years. Formal or informal periodic review of CMV prevention practices was reported at 19 centers. Most centers collected CMV-related metrics including donor–recipient serostatus (23), CMV monitoring (20) and CMV incidence (17) while only three reported collecting no CMV-related metrics. Formal protocol development and systematic review of practices driven by ongoing CMV metrics were not common.

Laboratory and assay use

Issues with inter-laboratory variation were addressed in a series of questions about the laboratory sites and sample specimens. Of the 26 centers responding to this section, 23 sites sent specimens only to an on-site laboratory while 2 used an outside but single central laboratory. One center allowed patients to use a laboratory in their local community but collected viral load, units of measure and the laboratory site used to assess for inter-laboratory variation. A CMV PCR-based assay was most commonly used with 13 reporting whole-blood samples and 10 reporting plasma samples for this assay. The majority of laboratories (17 of 25 responding centers) still reported viral loads in copies/mL while only five centers had transition to international units (IU)/mL as suggested in international guideline documents [8].

Pretransplant screening

Pretransplant screening focused mainly on serologic assays for both infants (26/29 centers) and children older than 12 months (27/29 centers). Other assays for infant screening included blood CMV PCR (12 sites), urine CMV PCR (1), urine viral culture (5) and CMV antigenemia (3). Two of these centers used these alternatives in place of serology in infants while an additional 12 centers used them in conjunction with serology. For toddlers and older children, supplemental assays were reported by 11 centers, blood CMV PCR (9), urine CMV PCR (1), urine viral culture (1) and CMV antigenemia (3).

Stratification by donor–recipient CMV serostatus

To gauge individual center practice, prevention strategies were surveyed for all potential donor–recipient serostatus combinations (D+/R−, D+/R+, D−/R+, D−/R−). Major distinctions within centers were seen for most centers only when differentiating those with either donor and/or recipient seropositivity (D+ and/or R+) compared to lower-risk D−/R− groups. Only minor variations existed within individual centers for the patient groups with any seropositivity (D+ or R+). The variations consisted primarily of adjunctive therapy (immunoglobulin) use and antiviral choice.

Types of prevention strategy

Prevention strategies for SPLIT centers focused predominantly on prophylaxis to avert CMV (Table 1). Twenty-six of the 29 responders used prophylaxis for any CMV donor or recipient (D or R) seropositive patients. The majority of centers (16) initiated prophylaxis with intravenous ganciclovir for 1–14 days followed by transition to oral prophylaxis. However, as perceived risk decreased from CMV D+/R− mismatches to CMV D+/R+ or CMV D−/R+ groups, one center transitioned from a sequential/hybrid strategy to a preemptive strategy, while two other centers transitioned to the use of oral acyclovir or valacyclovir to complete prophylaxis after a short course of intravenous ganciclovir. The duration of prophylaxis varied based on D/R serostatus, but most centers used prophylaxis for either 80–120 days or 200 days (Table 2).

Table 1. CMV prevention strategies based on antivirals and durations reported
CMV serotypeProphylaxisPreemptiveSequential/hybrid
  1. CMV, cytomegalovirus; D, donor; R, recipient.

D+/R−2612
D+/R+ or D−/R+2621
D−/R−15103
Table 2. Duration of prophylaxis by donor/recipient (D/R) serostatus
D/R serostatus80–120 days of prophylaxis180+ days of prophylaxis
D+/R−1410
D+/R+177
D−/R+186

Prevention strategies for CMV D−/R− PLT recipients were substantially different with 10 centers reporting a preemptive approach, 3 using a sequential/hybrid plan with antivirals for less than 6 weeks and the remainder (15) employing prophylaxis for at least 3 months or longer. Of those 15 centers with prophylaxis strategies, 6 centers reported using acyclovir or valacyclovir as the antiviral used for the largest proportion of the prophylactic period.

Sequential and preemptive strategies

Fewer centers reported using sequential/hybrid or preemptive strategies for CMV prevention after PLT. A uniform sequential/hybrid approach was reported at one center with 14 days of intravenous ganciclovir followed by CMV viral load monitoring every 2 weeks for all donor or recipient CMV seropositive patients.

Preemptive therapy was reported by only two sites as primary CMV prevention strategy. Sites monitored every 1–2 weeks and used variable thresholds for intervention. Lower viral loads prompted intervention for D+/R− compared with other D/R serostatus.

Sequential and preemptive strategies are uncommon in pediatric transplant centers within SPLIT.

Adjunctive therapy, monitoring and variations for T cell induction

Adjunctive therapy and monitoring were employed variably across responding centers. Six centers reported administration of CMV-hyperimmune globulin (CMVIG) as part of prophylaxis for higher-risk D+/R− patients. Fewer centers included CMVIG in prophylaxis for D+/R+ or D−/R+ patients, four and three, respectively. One center used CMVIG for D−/R− subjects as the sole prophylactic agent. No centers reported using intravenous immunoglobulin preparations in their routine prophylactic schemes.

Twenty-one centers of the 26 centers using prophylactic strategies reported CMV viral load monitoring during and after prophylaxis. An additional two centers monitored CMV viral loads in higher-risk D+/R− patients after completion of antiviral prophylaxis. Where reported, monitoring schedules ranged from weekly to every 3 months and varied based on clinical visits and symptoms (Table 3).

Table 3. Viral load monitoring for prophylactic strategies during and after antiviral prophylaxis
MonitoringD+/R−D+/R+D−/R+
PrePostPrePostPrePost
  1. D, donor; R, recipient.

Weekly5 4 4 
Every 2 weeks839392
Monthly511510610
Every 2–3 months121112
With clinic visits/for symptoms/routinely262616

Alterations in CMV prevention strategies were rarely reported for patients who received T cell induction; however, some modifications were described. In two centers, preemptive therapy reverted to prevention strategies used in higher-risk D+/R− groups while an additional center included CMVIG in its prophylactic strategy when T cell induction was administered.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

CMV remains a significant posttransplant infection in PLT recipients. Optimal methods to prevent CMV are not well described in this population. Current international CMV consensus guidelines suggest that any of three strategies (prophylaxis, preemptive/hybrid) may be safely used to prevent CMV disease in PLT recipients [8] based on single-institution reports of the safety of hybrid/sequential strategy [5], choice of antiviral [1, 9] and preemptive therapy in special populations [10]. However, comprehensive multi-center pediatric-specific evaluation of CMV prevention has not yet been accomplished. This survey provides salient information about current practices within an ongoing collaborative of PLT centers with the infrastructure to develop and perform future comparative effectiveness studies. The use of observational registries to investigate comparisons of clinical practice is emerging as an important, if flawed, tool in clinical effectiveness research. Adaptive study design utilizing these databases, like SPLIT, have potential to address complex questions with limited finances [11].

Importantly, a comparison within SPLIT between prophylaxis and other strategies is unlikely to be successful as prophylaxis is the overwhelming choice for CMV prevention. However, evaluation of the antiviral prophylaxis duration is possible with a significant division between centers using prophylaxis for 90–120 days compared to those using 180–200 days. Transplant volumes at the centers participating in the survey indicate the potential for an adequate comparison between these two durations of prophylaxis. Further exploration of feasibility within SPLIT is warranted.

The underlying reasons that prophylaxis dominated current practice were not explored in the survey. We hypothesize that the choice was primarily driven by perceived process and resource issues required to ensure timely monitoring and institution of preemptive therapy as outlined in international guidelines [8]. As many as 23 centers performed CMV viral load monitoring during antiviral prophylaxis but at a less frequent interval than that recommended by current guidelines [8].

While classification of prevention strategy (prophylaxis, preemptive therapy, sequential/hybrid) based on recent international CMV guidelines [8] was included for reference in the survey, responders at five centers misidentified their local strategy when choosing the strategy type upon central review of their strategy details. This indicates continued difficulty with semantics around CMV prevention that could potentially impact reporting and interpretation of the literature.

Seven centers reported evidence-based medicine as the basis for protocol development, but the outcomes of these reviews differed across the sites. All seven sites currently use prophylaxis but duration varies from 90 to 730 days at these centers. Only one center is known to have submitted their local protocol for review by the National Guideline Clearinghouse overseen by the Agency for Healthcare Research and Quality. Differences are likely related to the scant literature specific to PLT and broad extrapolation from adult-oriented studies. Issues related to definitions discussed above could potentially explain the different strategies emanating from similar evidence-based medicine. Another correlate to limited reflection on current literature is evidenced in the use of CMVIG as adjunctive therapy for prophylaxis at several centers. In the current era of antiviral prophylaxis, the addition of CMVIG to antivirals as part of a CMV prevention strategy has little supportive evidence in the literature and is not currently recommended by a pediatric international consensus panel after evidenced-based review [8].

As with any study, limitations to the study design exist. SPLIT participants actively participated in this survey with 94% of surveyed centers responding. Missing information or incomplete answers were addressed by targeted e-mails to clarify protocols as needed, leading to minimal missing variables. Finally, reported protocols may not reflect current practice, and prospective measurement of prevention strategy and CMV-specific metrics would be needed to evaluate the impact of specific prevention plans.

In conclusion, prophylaxis was the dominant prevention strategy reported by SPLIT members participating in this survey. Significant differences existed in the duration of antiviral prophylaxis across sites providing an opportunity to prospectively evaluate these strategies within the SPLIT community through a comparative effectiveness study.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

We thankfully acknowledge the support of the SPLIT research committee, the participation of SPLIT centers and information provided by Jeff Mitchell at EMMES Corporation that allowed the completion of this survey. We also thank Elizabeth Heubi for her technical expertise with REDCap survey. This project was supported by an Institutional Clinical and Translational Science Award, NIH/NCATS Grant Number 8UL1TR000077-04. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Definitions
  6. Results
  7. Discussion
  8. Acknowledgments
  9. Disclosure
  10. References