Abstract
Background:
End-organ disease caused by cytomegalovirus (CMV) is a significant cause of morbidity and mortality in pediatric solid organ transplant (SOT) recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre-and post-implementation of these protocols.
Methods:
We performed retrospective chart review for SOT recipients from 2009–2014 at Boston Children’s Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention.
Results:
The pre- and post-intervention periods included 141 and 109 patients respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (p<0.01). Occurrence of >1 episode of neutropenia was greater in the pre-intervention period (30% versus 10%, p<0.001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period.
Conclusions:
Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.
Keywords: CMV disease, standardized protocols, CMV DNAemia, prophylaxis, neutropenia
INTRODUCTION
Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in solid organ transplant (SOT) recipients1–3. Pediatric SOT recipients face unique challenges in the prevention and treatment of CMV infection due to factors that increase risk of infection. Young recipients who are CMV seronegative at the time of transplant are at risk for primary infection post-transplant, including donor-derived infection, while others who have been exposed remain at risk for latent CMV reactivation during periods of immunosuppression4–6. In addition to donor and recipient serostatus, other factors that influence acquisition of CMV infection in children include transplanted organ type, immunosuppression regimen, and the immunological characteristics of donor and recipient5–7. While there is consensus regarding the need for pre-transplant screening serologies of donors and recipients to aid risk stratification and the need for prevention strategies to decrease burden of post-transplant CMV disease, the types of prevention strategies employed have varied across pediatric SOT centers8,9. The main prevention strategies include: (a) universal antiviral prophylaxis for eligible patients, (b) serial viral load monitoring with preemptive antiviral therapy prior to onset of symptoms at a predetermined viral load and (c) a hybrid strategy: a combination of both approaches involving antiviral prophylaxis for a pre-fixed period followed by CMV viral load surveillance5. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation recommend the use of either universal prophylaxis or pre-emptive strategies in high-risk (i.e., donor seropositive and recipient seronegative) renal and liver transplant recipients, and the use of universal prophylaxis over pre-emptive therapy in high-risk lung and heart recipients2. However, with the exception of trials in renal transplant recipients10–13 there have been few randomized controlled trials comparing the effectiveness of these prevention strategies in other SOT recipients. Accordingly, even within SOT centers, as was the case in ours, a wide variation in practice can exist14, dependent on decisions made by individual transplant groups or providers. To address variations in practice, a virology working group (consisting of surgical and medical transplant specialists and pharmacists) was established within the Pediatric Transplant Center at our institution. This group developed evidence-based standardized protocols for CMV disease prevention. The protocols included structured approaches to pre-transplant screening, risk stratification, prophylaxis type, dose and duration, and post-prophylaxis surveillance for CMV. The purpose of this study is to report outcomes before and after standardizing CMV disease prevention protocols in a pediatric SOT population.
METHODS
We implemented standardized protocols across SOT groups in January 2012 as follows:
(A) Pre-SOT screening and serostatus assignment: Prospective SOT recipients received screening to evaluate CMV status. Screening modality was based on recipient age. Recipients <18 months received CMV shell vial culture testing from urine/saliva in addition to CMV serology testing with CMV Immunoglobulin G (IgG). Recipients >18 months received only CMV IgG testing.
(B) Post-SOT risk stratification: Risk stratification was based on CMV serostatus of recipient and donor. Seronegative recipients receiving organs from seronegative donors were considered low-risk (R−D−). Seronegative recipients receiving organs from seropositive donors were considered high-risk (R−D+). Intermediate-risk recipients were seropositive and received organs from either seronegative (R+D−) or seropositive (R+D+) donors.
(C) Prophylaxis agent and duration: CMV prophylaxis practices pre-implementation of standardized protocols and recommended strategies in the protocols are summarized in Table 1. Briefly, prior to standardization, kidney transplant recipients across all three risk categories received 1 year of valganciclovir prophylaxis whereas prophylaxis practices for low-risk non-kidney recipients varied with some receiving prophylaxis and others not receiving any. It was also common practice for low-risk liver recipients to receive acyclovir prophylaxis for 3 months if their donors were seropositive for Herpes Simplex Virus (HSV). Typical durations of prophylaxis provided to high-and intermediate-risk non-kidney recipients in the pre-intervention period are indicated in Table 1. These durations were however arbitrary and often provider dependent. Additionally, CMV immune globulin was routinely used by some SOT groups as an adjunctive prophylaxis agent. In the standardized protocols, we recommended no prophylaxis for all low-risk recipients and eliminated the use of CMV immune globulin for prophylaxis. Recommendations on duration of prophylaxis for high-and intermediate-risk recipients by organ group are noted in Table 1.
Table 1.
CMV prevention strategies according to organ type, donor and recipient (D/R) status, risk stratification and year of transplant
| Risk category/Transplant type | Pre-intervention practice (prior to 2012) | Standardized protocol recommendations (2012 and later) |
|---|---|---|
| Low Risk (D-R-) | ||
| Kidney | 12 months prophylaxis | Clinical follow-up |
| Lung/Liver/Heart/Multi-visceral | Variable practice with some recipients receiving valganciclovir prophylaxis 3 months acyclovir prophylaxis for liver recipients (if donor HSV+) |
Clinical follow-up |
| High Risk (D+R-) | ||
| Kidney | 12 months prophylaxis | 6 months prophylaxis |
| Heart | 3 months prophylaxis | 6 months prophylaxis |
| Liver/ Multi-visceral (without intestine) | 6 months prophylaxis | 6 months prophylaxis |
| High Risk (D+R-) | ||
| Lung/ Intestine/ Multi-visceral (with intestine) | 6–12 months prophylaxis | 12 months prophylaxis |
| Intermediate Risk (R+D-/R+D+) | ||
| Kidney | 12 months prophylaxis | 3 months prophylaxis |
| Liver/Heart/Multi-visceral (without intestine) | 3 months prophylaxis | 3 months prophylaxis |
| Intermediate-risk (R+D-/R+D+) | ||
| Lung/Intestine/Multi-visceral (with intestine) | 6 months prophylaxis | 6–12 months prophylaxis |
Dosage recommendations for prophylaxis were as follows: Valganciclovir was provided at 15mg/kg/dose daily for patients weighing <15 kg or 500mg/m2/dose daily for patients weighing >15 kg (maximum dose of 900mg). Valganciclovir dose was adjusted for creatinine clearance in patients with renal impairment. We recommended laboratory tests (Complete blood count (CBC with differential), blood urea nitrogen (BUN), creatinine, and hepatic transaminases (AST and ALT)) to monitor medication toxicity in patients receiving prophylaxis. These tests were performed every 1–2 weeks in the first month post-transplant and monthly thereafter until completion of prophylaxis.
(D) Post-SOT surveillance: Prior to standardized surveillance, SOT groups only performed CMV testing in the context of febrile illness or when there was clinical suspicion for CMV disease. We instituted recommendations for post-prophylaxis surveillance that were organ and risk specific. High-and intermediate-risk lung and multivisceral with intestine transplant recipients received CMV quantitative PCR testing every 2 weeks for 3 months followed by monthly CMV quantitative PCR until 12 months post-prophylaxis. High-and intermediate-risk kidney, heart and liver transplant recipients received monthly CMV quantitative PCR until 12 months post-prophylaxis. Low-risk recipients across SOT groups did not receive any surveillance. All recipients regardless of risk status received CMV quantitative PCR testing at the time of any febrile illness.
Infectious diseases (ID) consultation for further guidance on testing and provision of treatment or prophylaxis was recommended in the following scenarios: (i) CMV DNAemia detected during the surveillance period – if therapy was instituted at the recommendations of the ID team, it was continued until resolution of DNAemia, (ii) Rejection episodes needing augmented immunosuppression, and (iii) concern for CMV end organ disease symptoms.
These standardized protocols were widely disseminated in the following ways: 1) medication and lab orders were incorporated into electronic order sets used by hospital staff, 2) standardized protocols were available as clinical guidelines in the hospital intranet, and 3) multiple education sessions were held for staff of SOT groups over a three-month period prior to implementation. In the pre-and post-intervention periods, transplant pharmacists participated daily in multi-disciplinary rounds and provided medication oversight including recommendations for dosage adjustment in renal impairment.
CMV DNAemia monitoring: Due to non-availability of in-house assays, in the pre-intervention period, CMV DNAemia was detected via the CMV pp65 antigen immunofluorescence assay performed by standard procedures as previously described15,16 at the University of Pittsburgh. The results of this test are expressed as the number of CMV-antigen positive cells per 200,000 polymorphonuclear leukocytes (PMN) with 1 CMV-antigen positive cell per 200,000 PMN constituting the lowest limit of assay detection. In the post-intervention period, blood sample testing for CMV quantitative PCR in whole blood was performed in the Boston Children’s Hospital Virology Laboratory using our laboratory validated test containing primers and probes selective for the detection of CMV glycoprotein b gene. Using a 5’ nuclease assay, viral DNA is detected using the primers and fluorescent probes by means of real time PCR in a Cepheid SmartCycler (Cepheid, Sunnyvale, CA). The lower limit of quantification in this test is 500 copies of the CMV genome per mL.
After receiving approval from the Institution Review Board at Boston Children’s Hospital, a retrospective chart review was conducted for all SOT recipients between January 1, 2009 to December 30, 2011 (pre-intervention period) and July 1, 2012 to June 30, 2014 (post-intervention period). We excluded patients who had more than one consecutive transplant within the time periods included in the study and therefore may have had prior valganciclovir exposure and instituted a washout period between January 1, 2012 and June 30, 2012. We compared the pre- and post-intervention groups for the following outcomes: 1) provision of appropriate prophylaxis, 2) development of neutropenia while receiving prophylaxis and associated complications, including febrile neutropenia requiring hospitalization and blood stream infections and 3) development of CMV DNAemia and CMV disease. Outcomes were measured for the follow-up duration of 12 months for each patient. We excluded patients who had either died or were lost to follow-up before completion of 12 months in the analysis. None of the censored patients in the former group had CMV DNAemia and/or CMV disease. There was no overlap in patients between the two periods.
DEFINITIONS
Neutropenia: Absolute neutrophil count (ANC) <1000 cells/mm3 at any point while receiving prophylaxis.
CMV DNAemia: Either the presence of CMV pp65 antigenemia or CMV DNAemia measured by quantitative PCR. CMV pp65 antigenemia was defined as the presence of any number of cells that stained positive for CMV antigen per 200,000 PMN. CMV DNAemia was defined as CMV DNA > 500 copies of the CMV genome per mL, the lower level of quantification of this test.
CMV disease defined “a priori” to chart review: evidence of CMV infection with attributable symptoms. This was further characterized as a viral syndrome (i.e., fever, leukopenia, malaise, and/or thrombocytopenia), or as tissue invasive “end-organ” disease. Late onset CMV disease was defined as disease occurring after discontinuation of prophylaxis.
Appropriate prophylaxis: Evaluated as (1) adherence to recommended prophylaxis agent (valganciclovir) and (2) adherence to recommended duration and dosage.
STATISTICAL ANALYSIS
Data was analyzed using SPSS version 24.0 (IBM technologies, Armonk, New York). Summary characteristics regarding demographics, serostatus, allograft type, induction treatment, transplant number (1st, 2nd or 3rd) and occurrence of acute cellular rejection were created for patients pre- and post-intervention. Baseline characteristics and the outcomes of interest were compared between the two periods using the Fisher’s exact/chi-square test for categorical variables and the independent samples median test/ Mann-Whitney U test for medians (i.e., median number of days of prophylaxis and median number of days to development of neutropenia). For each CMV disease episode, we performed a chart review to understand factors which may have led to development of disease. Specifically, we inquired if appropriate dose and duration of prophylaxis had been provided, and whether prophylaxis was stopped prematurely for any reason.
RESULTS
Population Characteristics
There were no differences in median age of patients, gender distribution, CMV risk status distribution, graft type distribution, or number of transplants received between the pre-and post-intervention periods (Table 2). Heart and lung recipients received the same induction treatment (anti-thymocyte globulin) in both periods. The majority of liver recipients received basiliximab in both periods although there was significantly greater daclizumab use in the pre-intervention period (prior to discontinuation of this drug in 2009). In kidney recipients, steroid minimization/avoidance protocols were used in both periods, with the use of alemtuzumab or daclizumab as induction therapies in the pre-intervention period and the use of alemtuzumab exclusively in the post-intervention period. Basiliximab was used for patients who did not meet criteria for steroid minimization/avoidance protocols in both periods. Differences in induction regimens used in multivisceral transplant recipients were not statistically significant given the small number of patients.
Table 2.
Demographic and clinical characteristics of pediatric solid organ transplant recipients pre- and post-intervention
| Pre-intervention | n (%) | |||||
|---|---|---|---|---|---|---|
| Transplant Type | ||||||
| All SOT | Kidney | Liver | Heart | Lung | Multivisceral | |
| N | 141 | 68 (48%) | 29 (21%) | 24 (17%) | 12 (9%) | 8 (6%) |
| Age (years), median (Q1, Q3) | 8.4 (2.1, 15.3) | 12.3 (3.1, 17.3) | 3.7 (0.9, 10.1) | 6.8 (1.7, 15.4) | 17.4 (8.4, 18.2) | 1.9 (1.1, 9.0) |
| Male Sex | 76 (53%) | 39 (57%) | 16 (55%) | 12 (50%) | 6 (50%) | 3 (38%) |
| CMV Risk Status | ||||||
| High | 49 (35%) | 24 (35%) | 9 (31%) | 11 (46%) | 4 (33%) | 1 (12%) |
| Intermediate | 41 (29%) | 18 (27%) | 9 (31%) | 5 (21%) | 4 (33%) | 5 (63%) |
| Low | 51 (36%) | 26 (38%) | 11 (38%) | 8 (33%) | 4 (33%) | 2 (25%) |
| Induction treatment | ||||||
| Thymoglobulin | 44 (31%) | 1 (1%) | 1 (3%) | 24 (100%) | 12 (100%) | 6 (75%) |
| Basiliximab | 33 (23%) | 13 (19%) | 20 (69%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Alemtuzumab | 28 (20%) | 28 (41%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Daclizumab | 34 (24%) | 25 (37%) | 7 (24%) | 0 (0%) | 0 (0%) | 2 (25%) |
| None | 2 (1%) | 1 (1%) | 1 (3%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Graft type | ||||||
| Deceased donor | 106 (75%) | 35 (51%) | 27 (93%) | 24 (100%) | 12 (100%) | 8 (100%) |
| Living donor | 35 (25%) | 33 (49%) | 2 (7%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Transplant Number | ||||||
| 1st transplant | 134 (95%) | 63 (93%) | 27 (93%) | 24 (100%) | 12 (100%) | 8 (100%) |
| 2nd transplant | 6 (4%) | 4 (6%) | 2 (7%) | 0 (0%) | 0 (0%) | 0 (0%) |
| 3rd transplant | 1 (1%) | 1 (1%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Acute cellular rejection | 12 (9%) | 3 (4%) | 7 (24%) | 2 (8%) | 0 (0%) | 0 (0%) |
| >Post-intervention | >n (%) | |||||
| >Transplant Type | ||||||
| >All SOT | >Kidney | >Liver | >Heart | >Lung | >Multivisceral | |
| N | 109 | 44 (40%) | 23 (21%) | 27 (25%) | 12 (11%) | 3 (3%) |
| Age (years), median (Q1, Q3) | 10.4 (2.4, 15.9) | 14.7 (8.9, 17.0) | 1.0 (0.6, 11.5) | 5.2 (0.9, 14.0) | 14.3 (8.3, 19.2) | 17.0 (8.4, 20.2) |
| Male Sex | 62 (57%) | 24 (55%) | 12 (52%) | 15 (56%) | 9 (75%) | 2 (67%) |
| CMV Risk Status | ||||||
| High | 41 (38%) | 19 (43%) | 9 (40%) | 9 (33%) | 2 (17%) | 2 (67%) |
| Intermediate | 37 (34%) | 14 (32%) | 7 (30%) | 6 (22%) | 9 (75%) | 1 (33%) |
| Low | 31 (28%) | 11 (25%) | 7 (30%) | 12 (45%) | 1 (8%) | 0 (0%) |
| Induction treatment | ||||||
| Thymoglobulin | 39 (36%) | 0 (0%) | 0 (0%) | 27 (100%) | 12 (100%) | 0 (0%) |
| Basiliximab | 28 (26%) | 5 (11%) | 23 (100%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Alemtuzumab | 42 (38%) | 39 (89%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (100%) |
| Daclizumab | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| None | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Graft type | ||||||
| Deceased donor | 86 (79%) | 24 (55%) | 20 (87%) | 27 (100%) | 12 (100%) | 3 (100%) |
| Living donor | 23 (21%) | 20 (45%) | 3 (13%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Transplant Number | ||||||
| 1st transplant | 97 (89%) | 37 (84%) | 22 (96%) | 27 (100%) | 8 (67%) | 3 (100%) |
| 2nd transplant | 12 (11%) | 7 (16%) | 1 (4%) | 0 (0%) | 4 (33%) | 0 (0%) |
| 3rd transplant | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Acute cellular rejection | 24 (22%) | 4 (9%) | 8 (35%) | 8 (30%) | 2 (17%) | 2 (67%) |
No statistically significant differences in patient characteristics including median age, gender distribution, CMV risk status, type of graft and number of transplants between the pre-and post-intervention periods
Significantly greater daclizumab use in the pre-intervention period (among kidney and liver recipients in 2009 prior to discontinuation of the drug), whereas significantly greater use of alemtuzumab in the post-intervention period (among kidney recipients); Significantly greater acute cellular rejection among patients in the post-intervention period; p<0.01 from fisher’s exact/chi-square testing for difference in categorical variables pre-and post-intervention.
Maintenance immunosuppression was tacrolimus monotherapy for liver recipients (with prednisone added if required for rejection) and triple therapy with the addition of mycophenolate mofetil and prednisone for all other allograft types (including kidney recipients who received basiliximab for induction). Kidney recipients who received alemtuzumab were prescribed tacrolimus and mycophenolate mofetil (without the addition of prednisone), with a switch from tacrolimus to sirolimus at 8–12 weeks after transplant in recipients of living donor grafts who remained rejection-free. There were no statistically significant differences in the proportion of kidney patients who received steroid-free maintenance immunosuppression regimens in both periods (pre-intervention: 51 patients (76%), post-intervention: 39 patients (89%), p=0.10). Similarly, there were no statistically significant differences in the proportion who received sirolimus in both periods (pre-intervention: 15 patients (22%), post-intervention: 16 patients (36%), p= 0.10). There was significantly greater acute cellular rejection overall in the post-intervention period.
Provision of Appropriate Prophylaxis
Overall, among non-kidney recipients, provision of appropriate prophylaxis with the use of recommended agent and recommended duration and dose improved in the post-intervention period (Table 3). However, there were differences in provision of appropriate prophylaxis by organ and risk. Pre-intervention, all high-risk liver, heart, lung and multivisceral transplant recipients received valganciclovir. However, a proportion of low-risk heart, lung, multivisceral and liver transplant recipients received prophylaxis although none was necessary (Table 3). Reasons for providing valganciclovir to these patients included beliefs of benefit in epstein-barr virus (EBV) seropositive and naïve recipients at risk for natural EBV infection or infection from grafts of EBV seropositive donors, and concern for CMV acquisition from transfusions, although our center uses leukocyte depleted blood. Reasons for provision of acyclovir prophylaxis included concern for HSV acquisition (in the case of low-risk liver recipients with HSV seropositive donors) despite evidence that HSV transmission in the absence of donor HSV viremia is unlikely. Post-intervention, although a proportion of low-risk liver recipients continued to receive acyclovir prophylaxis, the majority of low-risk liver and other non-kidney recipients were only followed clinically as recommended (p<0.01). The impact of the standardized protocols on duration of prophylaxis was significant for high-risk non-kidney SOT with a greater proportion of recipients receiving the appropriate duration in the post-intervention period (p<0.01). The standardized protocols however did not impact provision of appropriate prophylaxis duration for intermediate-risk non-kidney recipients, who received longer than necessary prophylaxis in the post-intervention period. Reasons for provision of longer duration of valganiclovir in these recipients included similar beliefs of benefit against EBV infection (in EBV infected and naïve recipients). Notably, all kidney recipients continued to receive a year of prophylaxis regardless of risk status with no change in practice. However, the use of CMV immune globulin for prophylaxis significantly decreased across all SOT. Pre-intervention, 20% of patients received CMV immune globulin whereas none received it post-intervention (p<0.001).
Table 3.
Duration of prophylaxis and provision of appropriate prophylaxis by organ group and risk status pre-and post-intervention
| Transplant Type and Risk | Median duration of prophylaxis (days) (Q1,Q3) |
Appropriate prophylaxis (appropriate agent for risk status) n (%) |
Appropriate prophylaxis (appropriate duration and dose) n (%) |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pre | Post | p-value* | Pre | Post | p-value** | Pre | Post | p-value** | |||||
| Yes | No | Yes | No | Yes | No | Yes | No | ||||||
| Kidney | |||||||||||||
| High | 363(355,368) | 365(354,379) | 0.45 | 24(100%) | 0(0%) | 19(100%) | 0(0%) | -- | 1(4%) | 23(96%)† | 0(0%) | 19(100%)† | 0.99 |
| Intermediate | 365(364,378) | 365(360,371) | 0.39 | 18(100%) | 0(0%) | 14(100%) | 0(0%) | -- | 0(0%) | 18(100%)† | 0(0%) | 14(100%)† | -- |
| Low | 371(364,522) | 367(365,369) | 0.54 | 0(0%) | 26(100%)† | 1(9%) | 10(91%)† | 0.30 | -- | -- | -- | -- | -- |
| Liver | |||||||||||||
| High | 90(84,136) | 183(173,195) | <0.01 | 9(100%) | 0(0%) | 9(100%) | 0(0%) | -- | 1(11%) | 8(89%)‡ | 8(89%) | 1(11%)‡ | <0.01 |
| Intermediate | 89(84,125) | 178(66,183) | 0.62 | 8(89%) | 1(11%)‡ | 7(100%) | 0(0%) | 0.99 | 7(78%) | 2(22%)‡ | 2(29%) | 5(71%)‡ | 0.13 |
| Low | -- | -- | -- | 0(0%) | 11(100%)‡ | 4(57%) | 3(43%)‡ | 0.01 | -- | -- | -- | -- | |
| Lung | |||||||||||||
| High | 396(299,504) | 242 | 0.40 | 4(100%) | 0(0%) | 2(100%) | 0(0%) | -- | 3(75%) | 1(25%)Ψ | 2(100%) | 0(0%) | 0.99 |
| Intermediate | 550(294,842) | 395(201,508) | 1.00 | 4(100%) | 0(0%) | 8(89%) | 1(11%)Ψ | 0.99 | 2(50%) | 2(50%)Ψ | 3(33%) | 6(67%)Ψ | 0.99 |
| Low | -- | -- | -- | 1(25%) | 3(75%)Ψ | 1(100%) | 0(0%) | 0.40 | -- | -- | -- | -- | -- |
| Heart | |||||||||||||
| High | 90(86–118) | 125(86,251) | 1.00 | 11(100%) | 0(0%) | 9(100%) | 0(0%) | -- | 2(18%) | 9(82%)κ | 3(33%) | 6(67%)κ | 0.62 |
| Intermediate | 88(81–100) | 147(95,189) | 0.24 | 5(100%) | 0(0%) | 6(100%) | 0(0%) | -- | 5(100%) | 0(0%) | 3(50%) | 3(50%)κ | 0.18 |
| Low | -- | -- | -- | 4(50%) | 4(50%)κ | 11(92%) | 1(8%)κ | 0.11 | -- | -- | -- | -- | -- |
| Multivisceral | |||||||||||||
| High | 1376 | 292 | 0.33 | 1(100%) | 0(0%) | 2(100%) | 0(0%) | -- | 0(0%) | 1(100%)β | 1(50%) | 1(50%)β | 0.99 |
| Intermediate | 509(227,1281) | 687 | 1.00 | 5(100%) | 0(0%) | 1(100%) | 0(0%) | -- | 1(20%) | 4(80%)β | 0(0%) | 1(100%)β | 0.99 |
| Low | -- | -- | -- | 0(0%) | 2(100%)β | 0(0%) | 0(0%) | -- | -- | -- | -- | -- | -- |
| Non-kidney grafts | -- | -- | -- | 52(71%) | 21(29%) | 60(92%) | 5(8%) | <0.01 | 21(43%) | 27(56%) | 22(49%) | 23(51%) | 0.62 |
| High | 97(90,277) | 182(136,234) | 0.03 | 25(100%) | 0(0%) | 22(100%) | 0(0%) | -- | 6(24%) | 19(76%) | 14(64%) | 8(36%) | <0.01 |
| Intermediate | 115(87,405) | 182(95,380) | 0.37 | 22(96%) | 1(4%) | 22(96%) | 1(4%) | 0.99 | 15(65%) | 8(35%) | 8(35%) | 15(65%) | 0.04 |
| Low | -- | -- | -- | 5(20%) | 20(80%) | 16(80%) | 4(20%) | <0.01 | -- | -- | -- | -- | -- |
p-value from independent samples median test;
p-value from fisher’s exact/chi-square test testing for difference in categorical variables pre- and post-intervention.
Kidney: All low risk recipients received 12 months of valganciclovir prophylaxis when none was recommended in the standardized protocols; High and intermediate risk recipients received longer than recommended duration of prophylaxis
Liver: 7 out of 8 high risk patients who received inappropriate duration of prophylaxis in the pre-intervention period received shorter than recommended duration while 1 high-risk patient in the post-intervention period received longer than recommended duration; 1 intermediate risk patient in the pre-intervention period received inappropriate agent (acyclovir) while 1 received longer than necessary prophylaxis. 4 out of 5 intermediate risk patients who received inappropriate duration of prophylaxis in the post-intervention period received longer than recommended duration while 1 received shorter than recommended duration. 11 low risk recipients in the pre-intervention period received acyclovir prophylaxis while 3 out of 7 low risk recipients in the post-intervention period received acyclovir prophylaxis when none was recommended.
Lung: 1 high risk patient and 2 intermediate risk patients who received inappropriate duration of prophylaxis in the pre-intervention period received longer than recommended duration. 1 intermediate risk patient in the post-intervention period received acyclovir instead of valganciclovir prophylaxis. 4 out of 6 intermediate risk patients who received inappropriate duration of prophylaxis in the post-intervention period received longer than necessary prophylaxis. 3 out of 4 low risk patients in the pre-intervention period received valganciclovir prophylaxis when none was recommended.
Heart: 7 out of 9 high risk patients who received inappropriate duration of prophylaxis in the pre-intervention period and 4 out of 6 high risk patients who received inappropriate duration of prophylaxis in the post-intervention period received shorter than recommended duration. All 3 intermediate risk patients who received inappropriate duration of prophylaxis in the post-intervention period received longer than recommended duration. 4 out of 8 low risk patients in the pre-intervention period and 1 out of 12 low risk patients in the post-intervention period received prophylaxis when none was recommended.
Multivisceral: Both low risk patients in the pre-intervention period received valganciclovir prophylaxis when none was recommended. All high and intermediate risk patients who had received inappropriate duration of prophylaxis in both periods received longer than recommended duration.
Occurrence of neutropenia and associated complications
While the proportion of patients experiencing any neutropenia was comparable pre- and post-intervention, a significantly greater proportion in the pre-intervention experienced more than one episode of neutropenia (Table 4). There were no significant differences in the use of granulocyte colony stimulating factor (G-CSF) for neutrophil recovery. Nearly half of the patients who developed neutropenia had at least one episode with fever needing hospitalization pre-intervention; this proportion significantly decreased post-intervention. There were few documented blood stream infections during neutropenia. Neutropenia was most frequent among kidney transplant recipients in both periods.
Table 4.
Occurrence of neutropenia and associated complications pre- and post-intervention
| Neutropenia Characteristics | n (%) | p-value* | |
|---|---|---|---|
| Pre-intervention (n=141) |
Post-intervention (n=109) |
||
| Patients with any neutropenia | 80 (57%) | 61 (56%) | 0.90 |
| Patients with any neutropenia receiving chemotherapy | 6 (8%) | 2 (3%) | 0.47 |
| Patients with >1 episode | 42 (30%) | 11 (10%) | <0.001 |
| Patients with >1 episode receiving chemotherapy† | 5 (12%) | 0 (0%) | 0.57 |
| Days post-transplant to first neutropenia episode, Median (Q1, Q3)** | 83.0 (60.0, 137.0) | 99.0 (52.0, 141.0) | 0.23 |
| Ever received GCSF for neutropenia | 32 (40%) | 28 (46%) | 0.48 |
| Ever Neutropenia with fever | 25 (31%) | 15 (25%) | 0.39 |
| Ever Neutropenia requiring hospitalization | 38 (48%) | 18 (30%) | 0.03 |
| Ever Documented blood stream infection | 2 (3%) | 1 (2%) | 0.99 |
| Neutropenia by transplant type | 0.10 | ||
| Kidney | 47 (59%) | 27 (44%) | |
| Liver | 13 (16%) | 13 (21%) | |
| Heart | 6 (7.5%) | 12 (20%) | |
| Lung | 7 (9%) | 7 (12%) | |
| Multivisceral | 7 (9%) | 2 (3%) | |
All patients who received chemotherapy had received a liver transplant for hepatoblastoma or other hepatic tumors
p-value from fisher’s exact/chi-square test testing for difference in categorical variables pre- and post-intervention.
p-value from Mann-Whitney U test comparing distribution of days post-transplant between pre- and post-intervention periods.
Occurrence of CMV DNAemia and CMV disease
There was no significant difference in occurrence of CMV DNAemia in both periods (Table 5), which occurred in ~10% of recipients. No episodes of CMV DNAemia developed in low-risk recipients. In patients who had received inadequate prophylaxis and developed CMVDNAemia, main reasons for inadequate prophylaxis included under-dosage, shorter than recommended prophylaxis duration and prematurely terminated prophylaxis due to renal dysfunction. Pre-intervention, as CMV DNAemia was only checked in the presence of a suggestive illness, all these patients were symptomatic with either CMV syndrome or disease. Post-intervention, with routine surveillance, the majority (75%) of patients who developed CMV DNAemia were asymptomatic and received preemptive therapy. Development of CMV disease was low and occurred exclusively in high-and intermediate-risk patients. In the pre-intervention period, both patients who developed CMV disease while on prophylaxis were multivisceral recipients receiving intensified immunosuppression for intestinal rejection. All three patients with CMV disease in the post-intervention period developed late-onset disease and had received inadequate prophylaxis (under-dosage or short duration). Under-dosage resulted from dosage modifications for renal dysfunction initially but failure to resume appropriate dose following resolution.
Table 5.
Occurrence of CMV DNAemia and CMV Disease pre-and post-intervention
| CMV DNAemia | n (%) | p-value* | |
|---|---|---|---|
| Pre-intervention (n=141) |
Post-intervention (n=109) |
||
| Patients with any CMV DNAemia (positive pp65/CMV PCR) | 16 (11%) | 12 (11%) | 0.93 |
| Adequate prophylaxis in patients with any CMV DNAemia | 0.45 | ||
| Yes | 9 (56%) | 5(42%) | |
| No | 7 (44%)† | 7 (58%)‡ | |
| Acute cellular rejection in patients with any CMV DNAemia | 1 (6%) | 5 (42%) | 0.06 |
| Patients with >1 episode of CMV DNAemia (all SOT) | 5 (4%) | 2 (2%) | 0.71 |
| Occurrence of any CMV DNAemia by transplant type | 0.38 | ||
| Kidney | 2 (13%) | 4 (33%) | |
| Liver | 5 (31%) | 2 (17%) | |
| Heart | 5 (31%) | 2 (17%) | |
| Lung | 1 (6%) | 3 (25%) | |
| Multivisceral | 3 (19%) | 1 (8%) | |
| CMV DNAemia by risk | 0.91 | ||
| High | 9 (56%) | 7 (58%) | |
| Intermediate | 7 (44%) | 5 (42%) | |
| Low | 0 (0%) | 0 (0%) | -- |
| Ever developed CMV syndrome (all SOT) | 14 (10%) | 0 (0%) | <0.001 |
| Ever developed CMV disease (all SOT) | 2 (1%) | 3 (3%) | 0.66 |
| CMV syndrome/disease by risk | 0.26 | ||
| High | 9 (56%) | 3 (100%) | |
| Intermediate | 7 (44%) | 0 (0%) | |
| Low | 0 (0%) | 0 (0%) | -- |
p-value from fisher’s exact/chi-square test testing for difference in categorical variables pre- and post-intervention.
1 patient with 2nd transplant. In 2 patient – prophylaxis stopped prematurely due to renal dysfunction; In 2 patients – prophylaxis under-dosed albeit appropriate duration; in 3 patients – shorter than recommended duration of prophylaxis albeit appropriate dose.
3 patients with 2nd transplants; In 1 patient – prophylaxis stopped prematurely; in 5 patients – prophylaxis under-dosed albeit appropriate duration; in 1 patient – shorter than recommended duration of prophylaxis albeit appropriate dose.
DISCUSSION
In this study comparing outcomes pre- and post-implementation of standardized protocols for CMV disease prevention in a pediatric transplant center, we were able to evaluate practice changes and challenges, and the impact of a bundled CMV prevention strategy.
Overall, we found practice improvements in the post-intervention period. Provision of CMV immune globulin, an inferior and expensive strategy for prophylaxis, was completely eliminated. Provision of appropriate prophylaxis generally improved although stratified analysis by organ and risk offered data on areas where standardization was not effective. Among low-risk non-kidney recipients, the use of unnecessary prophylaxis significantly decreased in the post-intervention period. However, a proportion of low-risk liver recipients continued to receive acyclovir prophylaxis. Although almost universally, high-and intermediate-risk recipients across all SOT received valganciclovir (i.e., the appropriate agent), the standardized protocols only seemed to impact duration of prophylaxis in high-risk non-kidney recipients. In the post intervention period, a significantly greater proportion of non-kidney intermediate-risk recipients received longer than necessary prophylaxis. Our intervention also had no impact on the prophylaxis practices of kidney transplant providers with low-risk kidney recipients continuing to receive prophylaxis and high-and intermediate-risk recipients receiving longer than necessary prophylaxis. These examples highlight the challenges of standardization of practice in a large transplant center such as ours, where long-established practices are difficult to change. We offer some reasons for providing low-risk recipients with prophylaxis or continuing prophylaxis longer than necessary in high-and intermediate-risk recipients (e.g., donor and/or recipient EBV seropositivity, donor HSV seropositivity, concern for acquisition of CMV from blood products etc.). It should be noted that these perspectives were gleaned from chart review for this study as well as discussions outside of this study with various SOT groups. A formal study that employs rigorous qualitative methodology is needed to offer in-depth perspectives on non-adherence to recommended protocols among providers.
Although we included a prospective CMV surveillance strategy in our standardized protocols, our intervention cannot be considered a strictly hybrid strategy. We used longer durations of prophylaxis for high-and intermediate-risk recipients than in other studies employing hybrid strategies17–19. Pre-intervention, all intermediate- and high-risk patients in general received a minimum of 3–6-months prophylaxis although post-prophylaxis surveillance was rare. With both strategies, there was no difference in occurrence of CMV infection and disease, which were both low. In the post-intervention period, there was no early onset disease akin to reports in other pediatric studies employing similar prophylaxis strategies17–26. However, given the low burden of CMV infection and disease, we were likely not powered to determine if a longer duration of prophylaxis could have impacted occurrence of either outcome. Our prospective surveillance strategy did allow for treatment of asymptomatic patients with CMV DNAemia preemptively. Whether this resulted in decreased CMV disease is hard to determine given the low number of patients with disease. The significantly higher proportion of patients with symptoms at the time of CMV detection in the pre-intervention period, however, raises concerns regarding the potential risk for progression to disease in the absence of active surveillance. Preemptive therapy in asymptomatic patients is likely beneficial in alleviating this risk. Of note, the majority of CMV disease cases in our study were late-onset. All such cases occurred in patients receiving either a reduced dosage or an inadequate duration of prophylaxis, reasons that along with reduced CMV-specific cell mediated immunity have been attributed to occurrence of late-onset disease27,28. We note several instances of under-dosage occurring in the setting of renal dysfunction, where dose modifications were initially made appropriately but not adjusted subsequently pointing to the need for continued vigilance and reassessment by providers in patients with changing renal function. No low-risk patients in our population developed either CMV DNAemia or CMV disease. However, all kidney recipients in both periods received prophylaxis for a year. This extended duration may have been influenced by the increasing use of lymphocyte depleting agents such as alemtuzumab which could augment risk for CMV infection despite favorable risk status in low-risk recipients. Since low-risk kidney recipients constituted between ~40–50% of all low-risk recipients in our study, the risk for CMV DNAemia and CMV disease may have been masked. Nevertheless, other studies have also observed low rates of CMV DNAemia and disease among low-risk recipients without any prophylaxis, suggesting that aggressive strategies for CMV disease prevention are not needed for this risk group. Data from our low-risk non-kidney recipients lends support for these observations.
In general, we observed higher rates of neutropenia compared to what has been reported in the literature20,26. This may be due to several reasons. In this study, we employed a liberal definition of neutropenia (i.e., ANC <1000cells/mm3). Our neutropenia findings were also influenced by kidney recipients who constituted nearly half of all SOT. Prolonged duration of prophylaxis across all risk groups may be one reason why kidney recipients had the highest rates of neutropenia. The additive effects of alemtuzumab and valganciclovir resulting in leukopenia has been previously reported29 and is likely the mechanism of neutropenia among our kidney recipients. While the proportion of patients with any episode of neutropenia was comparable pre- and post-intervention, standardization of practice allowed for reduction in the proportion of patients experiencing >1 episode of neutropenia. This may have been influenced by the improvement in practice among low-risk non-kidney recipients who did not receive unnecessary prophylaxis.
The use of G-CSF for neutrophil recovery for ANC<500/mm3 cells was also common in our population. This finding was again influenced by kidney recipients. The use of alemtuzumab with prolonged duration valganciclovir likely led to greater depth of neutropenia in kidney recipients which may explain our relatively high rates of G-CSF use. While the proportion of patients with febrile neutropenia was comparable pre- and post-intervention, the proportion requiring hospitalization was significantly lower post-intervention. Importantly, despite concerns for a serious bacterial infection in the setting of febrile neutropenia, few patients in our population actually developed a documented blood stream infection (BSI). While the tendency at our center is to hospitalize patients with febrile neutropenia and start antibiotics, the relative rarity of a BSI offers evidence that select patients could be monitored without hospitalization.
Our study has several limitations. While we measured practice improvements, the implementation of standardized protocols did not strictly follow a quality improvement framework that included rapid cycle improvement models such as plan-do-study-act (PDSA) cycles. Therefore, this study cannot be viewed as a quality report. We also did not include patients with incomplete follow-up and therefore may have underestimated the occurrence of CMV DNAemia and disease. The CMV testing methodology was distinct in the pre-and post-intervention periods which may have impacted outcomes related to incidence of CMV infection. The small number of patients within certain SOT groups restricted power to examine differences between the pre- and post-intervention periods. Similarly, we were limited in power to examine the impact of greater occurrence of acute cellular rejection in the post-intervention period, or greater alemtuzumab use among kidney recipients in the post-intervention period on occurrence of CMV DNAemia and CMV disease. However, our study has notable strengths. We describe an effort of implementing standardized protocols that brought together various groups to work collaboratively that can be adopted at other centers. While ours is a single center retrospective study, it is one of the few pediatric studies that has included patients across all SOT groups and also has equivalent representation of patients across all risk-statuses. Although other studies have reported the common hematological toxicities associated with valganciclovir use, we have additionally attempted to delineate the clinical significance of neutropenia which has been reported less commonly in the literature. Given the paucity of pediatric data on CMV disease prevention and outcomes, particularly with the use of surveillance strategies, our study is a contribution to existing literature.
Overall, standardizing risk-stratified approaches to CMV disease prevention in a large pediatric transplant center is effective and reduces the use of ineffective prophylaxis strategies and the use of unnecessary prophylaxis in low-risk recipients while balancing the adverse events associated with use of effective agents for prophylaxis and the costs associated with regular surveillance of medication toxicities and CMV DNAemia. Further research is needed to delineate interventions for non-adherence to such standardized protocols among providers. Further multicenter studies are also needed to assess the impact of testing and treating episodes of asymptomatic CMV DNAemia on the occurrence of late onset CMV disease in patients who complete an adequate duration of prophylaxis.
Acknowledgements
This study was supported by a fellowship grant from the Program for Patient Quality and Safety (PPSQ) at Boston Children’s Hospital. The project was also supported by a Harvard HIV T32 post-doctoral fellowship (T32AI007433) from the National Institute of Allergy and Infectious Diseases and The Aerosmith Research Endowment Fund from Boston Children’s Hospital. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors wish to thank research assistants Danielle Coloma and Robin Zaboulian who assisted with data collection.
Abbreviations
- CMV
cytomegalovirus
- SOT
solid organ transplant
- IgG
Immunoglobulin G
- EBV
epstein-barr virus
- HSV
herpes simplex virus
- CBC
complete blood count
- BUN
Blood urea nitrogen
- PMN
polymorphonuclear leukocytes
- G-CSF
granulocyte colony stimulating factor
- ANC
absolute neutrophil count
- PCR
polymerase chain reaction
Footnotes
Conflict of Interest Statement
All authors have no conflicts of interest to disclose.
REFERENCES
- 1.Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2013;13 Suppl 4:93–106. doi: 10.1111/ajt.12103 [DOI] [PubMed] [Google Scholar]
- 2.Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018;102(6):900–931. doi: 10.1097/TP.0000000000002191 [DOI] [PubMed] [Google Scholar]
- 3.Paya CV. Indirect effects of CMV in the solid organ transplant patient. Transpl Infect Dis Off J Transplant Soc. 1999;1 Suppl 1:8–12. [PubMed] [Google Scholar]
- 4.Danziger-Isakov LA, Worley S, Michaels MG, et al. The risk, prevention, and outcome of cytomegalovirus after pediatric lung transplantation. Transplantation. 2009;87(10):1541–1548. doi: 10.1097/TP.0b013e3181a492e8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Tsai KC, Danziger-Isakov LA, Banach DB. Cytomegalovirus Infection in Pediatric Solid Organ Transplant Recipients: a Focus on Prevention. Curr Infect Dis Rep. 2016;18(2):5. doi: 10.1007/s11908-015-0511-8 [DOI] [PubMed] [Google Scholar]
- 6.Martin JM, Danziger-Isakov LA. Cytomegalovirus risk, prevention, and management in pediatric solid organ transplantation. Pediatr Transplant. 2011;15(3):229–236. doi: 10.1111/j.1399-3046.2010.01454.x [DOI] [PubMed] [Google Scholar]
- 7.Lumbreras C, Manuel O, Len O, ten Berge IJM, Sgarabotto D, Hirsch HH. Cytomegalovirus infection in solid organ transplant recipients. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2014;20 Suppl 7:19–26. [DOI] [PubMed] [Google Scholar]
- 8.Hodson EM, Ladhani M, Webster AC, Strippoli GFM, Craig JC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2013;(2):CD003774. doi: 10.1002/14651858.CD003774.pub4 [DOI] [PubMed] [Google Scholar]
- 9.Le Page AK, Jager MM, Kotton CN, Simoons-Smit A, Rawlinson WD. International survey of cytomegalovirus management in solid organ transplantation after the publication of consensus guidelines. Transplantation. 2013;95(12):1455–1460. doi: 10.1097/TP.0b013e31828ee12e [DOI] [PubMed] [Google Scholar]
- 10.Khoury JA, Storch GA, Bohl DL, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2006;6(9):2134–2143. doi: 10.1111/j.1600-6143.2006.01413.x [DOI] [PubMed] [Google Scholar]
- 11.Reischig T, Jindra P, Hes O, Svecová M, Klaboch J, Treska V. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2008;8(1):69–77. doi: 10.1111/j.1600-6143.2007.02031.x [DOI] [PubMed] [Google Scholar]
- 12.Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2008;8(5):975–983. doi: 10.1111/j.1600-6143.2007.02133.x [DOI] [PubMed] [Google Scholar]
- 13.Witzke O, Hauser IA, Bartels M, et al. Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial. Transplantation. 2012;93(1):61–68. doi: 10.1097/TP.0b013e318238dab3 [DOI] [PubMed] [Google Scholar]
- 14.Danziger-Isakov L, Bucavalas J. Current prevention strategies against cytomegalovirus in the studies in pediatric liver transplantation (SPLIT) centers. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2014;14(8):1908–1911. doi: 10.1111/ajt.12755 [DOI] [PubMed] [Google Scholar]
- 15.Mazzulli T, Rubin RH, Ferraro MJ, et al. Cytomegalovirus antigenemia: clinical correlations in transplant recipients and in persons with AIDS. J Clin Microbiol. 1993;31(10):2824–2827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.St George K, Rinaldo CR. Comparison of commercially available antibody reagents for the cytomegalovirus pp65 antigenemia assay. Clin Diagn Virol. 1997;7(3):147–152. [DOI] [PubMed] [Google Scholar]
- 17.Lin A, Worley S, Brubaker J, et al. Assessment of Cytomegalovirus Hybrid Preventative Strategy in Pediatric Heart Transplant Patients. J Pediatr Infect Dis Soc. 2012;1(4):278–283. doi: 10.1093/jpids/pis056 [DOI] [PubMed] [Google Scholar]
- 18.Madan RP, Campbell AL, Shust GF, et al. A hybrid strategy for the prevention of cytomegalovirus-related complications in pediatric liver transplantation recipients. Transplantation. 2009;87(9):1318–1324. doi: 10.1097/TP.0b013e3181a19cda [DOI] [PubMed] [Google Scholar]
- 19.Gerna G, Lilleri D, Callegaro A, et al. Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation. Transplantation. 2008;86(1):163–166. doi: 10.1097/TP.0b013e31817889e4 [DOI] [PubMed] [Google Scholar]
- 20.Camacho-Gonzalez AF, Gutman J, Hymes LC, Leong T, Hilinski JA. 24 weeks of valganciclovir prophylaxis in children after renal transplantation: a 4-year experience. Transplantation. 2011;91(2):245–250. doi: 10.1097/TP.0b013e3181ffffd3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lapidus-Krol E, Shapiro R, Amir J, et al. The efficacy and safety of valganciclovir vs. oral ganciclovir in the prevention of symptomatic CMV infection in children after solid organ transplantation. Pediatr Transplant. 2010;14(6):753–760. doi: 10.1111/j.1399-3046.2010.01330.x [DOI] [PubMed] [Google Scholar]
- 22.Bedel AN, Hemmelgarn TS, Kohli R. Retrospective review of the incidence of cytomegalovirus infection and disease after liver transplantation in pediatric patients: comparison of prophylactic oral ganciclovir and oral valganciclovir. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2012;18(3):347–354. doi: 10.1002/lt.22471 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Jongsma H, Bouts AH, Cornelissen EAM, Beersma MFC, Cransberg K. Cytomegalovirus prophylaxis in pediatric kidney transplantation: the Dutch experience. Pediatr Transplant. 2013;17(6):510–517. doi: 10.1111/petr.12115 [DOI] [PubMed] [Google Scholar]
- 24.Höcker B, Zencke S, Krupka K, et al. Cytomegalovirus Infection in Pediatric Renal Transplantation and the Impact of Chemoprophylaxis With (Val-)Ganciclovir. Transplantation. 2016;100(4):862–870. doi: 10.1097/TP.0000000000000888 [DOI] [PubMed] [Google Scholar]
- 25.Fijo-López-Viota J, Espinosa-Román L, Herrero-Hernando C, Sanahuja-Ibáñez MJ, Vila-Santandreu A, Praena-Fernández JM. Cytomegalovirus and paediatric renal transplants: is this a current issue? Nefrol Publicacion Of Soc Espanola Nefrol. 2013;33(1):7–13. doi: 10.3265/Nefrologia.pre2012.Sep.11470 [DOI] [PubMed] [Google Scholar]
- 26.Suresh S, Lee BE, Robinson JL, Akinwumi MS, Preiksaitis JK. A risk-stratified approach to cytomegalovirus prevention in pediatric solid organ transplant recipients. Pediatr Transplant. 2016;20(7):970–980. doi: 10.1111/petr.12786 [DOI] [PubMed] [Google Scholar]
- 27.Humar A, Limaye AP, Blumberg EA, et al. Extended valganciclovir prophylaxis in D+/R- kidney transplant recipients is associated with long-term reduction in cytomegalovirus disease: two-year results of the IMPACT study. Transplantation. 2010;90(12):1427–1431. [DOI] [PubMed] [Google Scholar]
- 28.Razonable RR, Rivero A, Rodriguez A, et al. Allograft rejection predicts the occurrence of late-onset cytomegalovirus (CMV) disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral ganciclovir. J Infect Dis. 2001;184(11):1461–1464. doi: 10.1086/324516 [DOI] [PubMed] [Google Scholar]
- 29.Walker JK, Scholz LM, Scheetz MH, et al. Leukopenia complicates cytomegalovirus prevention after renal transplantation with alemtuzumab induction. Transplantation. 2007;83(7):874–882. doi: 10.1097/01.tp.0000257923.69422.4d [DOI] [PubMed] [Google Scholar]