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. Author manuscript; available in PMC: 2024 Jun 1.
Published in final edited form as: Am J Transplant. 2023 Mar 17;23(6):794–804. doi: 10.1016/j.ajt.2023.03.008

The Effectiveness and Safety of Antibody Induction Immunosuppression in a Large Cohort of U.S. Pediatric Liver Transplant Recipients

Phoebe Wood 1, Yuan-Shung Huang 2, Lucia Sanchez 3, Eimear Kitt 4, Peter L Abt 5,6, Therese Bittermann 1,7,8
PMCID: PMC10247522  NIHMSID: NIHMS1902571  PMID: 36933831

Abstract

Data on the potential benefits and risks of induction therapy in pediatric liver transplantation (LT) are limited. This was a retrospective cohort study of 2,748 pediatric LT recipients at 26 children’s hospitals between 1/1/2006–5/31/2017 using data from the Pediatric Health Information System (PHIS) linked to the United Network for Organ Sharing database. Induction regimen was obtained from PHIS day-by-day pharmacy resource utilization. Cox proportional hazards evaluated the association of induction regimen (none/corticosteroid-only, non-depleting, depleting) on patient and graft survival. Additional outcomes, including opportunistic infections (OI) and post-transplant lymphoproliferative disorder (PTLD) were studied using multivariable logistic regression. Overall, 64.9% received none/corticosteroid-only induction, while 28.1% received non-depleting, 8.3% received depleting and 2.5% other antibody regimens. Differences in patient characteristics were small, but center practices were heterogeneous. Compared to none/corticosteroid-only induction, non-depleting induction was associated with reduced acute rejection (OR 0.53; p<0.001), but with increased PTLD (OR 1.75; p=0.021). Depleting induction was associated with improved graft survival (HR 0.64; p=0.028), but with increased non-cytomegalovirus OIs (OR 1.46; p=0.046). Depleting induction is underused yet may offer long-term benefits in this large multicenter cohort. Greater consensus guidance in this aspect of pediatric LT care is warranted.

Introduction

Induction therapy is intensive immunosuppression administered at the time of solid organ transplantation. National transplant registry data indicate that it is much less frequently utilized for pediatric liver transplantation (LT) than among pediatric recipients of other solid organs.1–4 Studies evaluating the potential benefits of induction therapy in this population have largely focused on short-term allograft outcomes, such as early acute rejection.5–7 However, longer term end-points have not been comprehensively evaluated. In parallel, safety concerns have been raised, including the potential risk for infection, cytopenia and post-transplant lymphoproliferative disorder (PTLD), among others.5,8

To date, data on the balance of benefits and risks of antibody induction in pediatric LT have been single-center and limited by small sample sizes, with few comparing multiple antibody-based therapies. This limited available evidence likely underlies the significant differences in induction practices among transplant centers. In a recent survey of 28 pediatric LT centers, induction regimens were heterogeneous and of varying intensity, ranging from no induction whatsoever to a strategy that used corticosteroids in combination with both depleting and non-depleting agents.9 In addition, there remain no consensus recommendations addressing the use of antibody induction therapy in pediatric LT.

In an effort to fill some of these knowledge gaps, our study leveraged a large multicenter cohort of pediatric LT recipients to achieve two primary objectives. First, we describe the patient and center-level factors that are associated with induction practices. Second, we examine and compare the effects of different antibody-based induction therapies with key clinical outcomes, including early acute rejection, patient and graft survival, opportunistic infections, cytopenias and PTLD.

Materials & Methods

Study design, data source & study population

This was a retrospective cohort study of pediatric LT recipients performed between January 1, 2006, and May 31, 2017, using data from the Pediatric Health Information System (PHIS) that were linked to the United Network for Organ Sharing (UNOS) national transplant registry.10,11 PHIS is an administrative database containing clinical and resource utilization data for inpatient, emergency department, ambulatory surgery and observation unit encounters from approximately 49 U.S. freestanding children’s hospitals. Patients in the PHIS database are assigned a de-identified medical record number and can be tracked across multiple hospitalizations. Specifically, PHIS contains diagnosis codes (i.e., International Classification of Diseases [ICD] 9/10 codes), procedure codes and other billed resource utilization data pertaining to inpatient hospital encounters. An advantage of PHIS is the availability of day-by-day resource utilization data, which includes medications ordered during inpatient admissions. UNOS is the private, non-profit organization that manages the U.S. national organ transplant system. The linkage of UNOS and PHIS databases has been previously described.10,11 All patients in the study cohort were aged <18 years at LT and were transplanted at a PHIS center during the study period. Follow-up in UNOS extended beyond the original study period to June 30,2021. Re-hospitalizations were captured at their LT center only. Patients were excluded if they received a multi-organ transplant or were a re-transplant recipient, given inherent differences in induction practices.

Exposure definition

The primary exposure was antibody induction regimen. A series of steps were performed to establish each patient’s induction regimen. First, all inpatient medications received during the index LT hospital stay were tabulated. From this list, the following induction-related drugs were identified: methylprednisolone, basiliximab, daclizumab, anti-thymocyte globulin (ATG; rabbit), ATG (equine), alemtuzumab and rituximab. Of note, the use of all antibody-based induction agents is off-label in pediatric LT. Patients were defined as having received antibody induction therapy if they received any of the aforementioned antibody therapies with an associated drug billing date +/− 1 day of LT date. Second, we created the following induction categories: (i) no or steroid-only induction; (ii) IL-2 receptor antagonist (IL2Ra) +/− steroids, which included patients receiving daclizumab or basiliximab; (iii) ATG +/− steroids, which included patients receiving either rabbit or equine ATG; and (iv) other or combination, which included patients receiving alemtuzumab or rituximab or combinations of multiple induction agents (e.g., IL2Ra plus rituximab). For patients receiving IL2Ra or ATG at LT, we also computed the number of distinct, subsequent calendar days that treatment was billed for (herein named “doses”), using a maximum time horizon of 7 days from LT date. IL2Ra and ATG treatment days occurring >7 days from LT were not tabulated due to the concern that these could represent treatment for rejection.

Covariates

Demographic and clinical characteristics at LT were obtained from the UNOS database. These included: sex, age, self-reported race/ethnicity, primary liver disease, Pediatric End-stage Liver Disease (PELD) score, Model for End-stage Liver Disease (MELD) score, individual PELD/MELD laboratory components, location prior to transplant, receipt of dialysis pre-LT and transplant year. Donor covariates included: age, allograft type (whole deceased, split deceased, living donor), donation after cardiac determination of death (DCD), and donor-recipient ABO incompatibility. Maintenance immunosuppression at LT discharge was obtained from UNOS and categorized as: (i) calcineurin inhibitor (CNI) plus antimetabolite (antiM) plus steroid, (ii) CNI plus antiM, (iii) CNI plus steroid, (iv) CNI alone and (v) other. Center pediatric LT experience was ascertained by calculating the average pediatric LT volume/year, categorized into the following tertiles: <7 LTs/year, 7–14 LTs/year and ≥15 LTs/year.

Outcomes

Patient and graft survival were ascertained using UNOS data, whereby graft loss included either death or liver retransplantation. Acute rejection during the first year was also obtained from UNOS as PHIS ICD data could not full capture its occurrence due to the lack of an available ICD-9 code. Additional binary (yes/no) clinical endpoints were defined using inpatient ICD-9/10 codes available from inpatient admissions captured in PHIS (Supplemental Table 1)12–19. Opportunistic infections (OIs) included cytomegalovirus (CMV), herpes simplex virus, varicella zoster virus, Pneumocystis jirovecii and fungal infections. Cytopenias included anemia, leukopenia/neutropenia and thrombocytopenia. Presence of an OI or cytopenia was considered up to one-year post-LT, while PTLD was ascertained up to two-years post-LT. The time horizon for PTLD was determined from prior studies demonstrating that most cases occur during this time frame and given the diminishing biologic plausibility of a true association between induction therapy and PTLD with longer time horizons.20–22 Secondary outcomes included length of stay (LOS) between LT and hospital discharge and liver retransplantation during the index LT hospital admission, both obtained from UNOS data, as well as 30-day and 90-day readmission and reason for readmission using PHIS data. Given that the detection of clinical outcomes was dependent on readmissions to the transplanting center, we also computed the median number of post-LT readmissions per patient in the first year by center.

Statistical analyses

Recipient characteristics were compared across the four induction categories (none/steroid only, IL2Ra +/− steroid, ATG +/− steroid and other/combination) using chi-squared tests for categorical variables and Kruskal-Wallis tests for continuous variables. Temporal and center trends in induction use were evaluated. Differences in maintenance immunosuppression at LT hospital discharge by induction regimen were also explored.

In multivariable analyses, we excluded children receiving other or combination induction therapy given the inherent heterogeneity of this group. In these analyses, IL2Ra +/− steroids and ATG +/− steroids were compared to the reference of none/steroid only induction. Unadjusted patient and graft survival by induction regimen was investigated using Kaplan-Meier curves. Multivariable Cox regression evaluated the association of induction regimen with patient and graft survival. Logistic regression evaluated the association of induction regimen with the following 1-year post-LT outcomes: acute rejection, hospitalization for CMV infection, hospitalization for non-CMV OI, hospitalization with anemia, hospitalization with leukopenia/neutropenia, and hospitalization with thrombocytopenia. Logistic regression was also employed to study PTLD within 2-years of LT. All multivariable models were adjusted for: sex, age, race/ethnicity, primary liver disease etiology, serum bilirubin, international normalized ratio (INR), serum creatinine, location prior to LT, donor age, allograft type, DCD allograft, ABO incompatibility, LT era and center average yearly volume tertile. The multivariable model evaluating PTLD was also adjusted for recipient Epstein-Barr virus antibody status. The relationship between induction regimen and secondary outcomes was described.

This study was approved by the Institutional Review Board of the Children’s Hospital of Philadelphia. All analyses were conducted using Stata version 16 (College Station, TX).

Results

Overall study cohort

The final study cohort included 2,748 children undergoing first LT alone at 26 PHIS transplant centers from 1/1/2006–5/31/2017, representing 53.1% of the national pediatric LT volume during the study period. The cohort was 50.5% female, 53.7% White, and with 36.9% being 1–5 years of age at LT. Primary LT indication consisted of: 42.5% biliary atresia (BA), 17.8% metabolic disease, 10.7% tumor, 12.9% acute liver failure (ALF), and 16.1% other causes. Average yearly center volume was <7 LTs/year at 12 (46.2%) centers, 7–14 LTs/year at 8 centers (30.8%) and ≥15 LTs/year at 6 (23.1%) centers. There were small differences in patient characteristics between patients included in the PHIS cohort versus pediatric LT recipients nationally (Supplemental Table 2). For example, the PHIS cohort included fewer Black recipients (12.1% vs 19.8%; p<0.001 in pairwise comparisons) and a greater proportion of patients transplanted for metabolic disease (17.8% vs 13.3%; p<0.001 in pairwise comparisons).

Recipient characteristics associated with induction

Overall, 1,609 (64.9%) LT recipients received steroid-only or no induction, while 772 (28.1%) received IL2Ra +/− steroids, 229 (8.3%) received ATG +/− steroids, and 68 (2.5%) received a combination of or other form of antibody induction therapy. Details regarding each induction regimen are available in Supplemental Table 3. Age and liver diagnosis in the none/steroid-only group closely mirrored that of the IL2Ra group (Table 1). In contrast, children receiving ATG +/− steroids were frequently older with 45.2% aged ≥6 years (vs 29.9% none/steroid-only and 31.5% ILR2a induction) and less often of Black race (8.0% vs 11.5% vs 14.9%, respectively). Additionally, the ATG group included a greater proportion of children with metabolic disease (22.4% vs 17.4% none/steroid-only vs 16.5% IL2Ra induction) or ALF (17.7% vs 11.3% vs 13.5%, respectively), and fewer with liver tumors (3.0% vs 11.8% vs 11.3%, respectively; p<0.001 in overall pairwise comparisons).

Table 1.

Differences in recipient characteristics by induction regimen (N=2,748)

None or steroid-only (N=1,609) IL2Ra +/− steroids (N=772) ATG +/− steroids (N=299) Other or combination (N=68) p-value
Female sex 822 (51.1%) 394 (51.0%) 136 (45.5%) 35 (51.5%) 0.342
Age at LT (years)
 Median (iQr) 2 (0–7) 2 (0–8) 4 (0–11) 2 (0–11) 0.001
 Category 0.001
  <1 509 (31.6%) 246 (31.8%) 79 (26.4%) 20 (29.4%)
  1–5 619 (38.5%) 283 (36.7%) 85 (28.4%) 27 (39.7%)
  6–10 196 (12.2%) 105 (13.6%) 54 (18.1%) 8 (11.8%)
  11–17 285 (17.7%) 138 (17.9%) 81 (27.1%) 13 (19.1%)
Race/ethnicity <0.001
 White 854 (53.1%) 409 (53.0%) 175 (58.5%) 39 (57.4%)
 Black 185 (11.5%) 115 (14.9%) 24 (8.0%) 8 (11.8%)
 Hispanic 417 (25.9%) 157 (20.3%) 61 (20.4%) 16 (23.5%)
 Asian 108 (6.7%) 63 (8.2%) 15 (5.0%) 3 (4.4%)
 Other 45 (2.8%) 28 (3.6%) 24 (8.0%) 2 (2.9%)
Liver Disease <0.001
 BA 697 (43.4%) 339 (43.9%) 113 (37.8%) 20 (20.4%)
 Metabolic 280 (17.4%) 127 (16.5%) 67 (22.4%) 14 (20.6%)
 Tumor 190 (11.8%) 87 (11.3%) 9 (3.0%) 7 (10.3%)
 ALF 181 (11.3%) 104 (13.5%) 53 (17.7%) 17 (25.0%)
 Other 261 (16.2%) 115 (14.9%) 57 (19.1%) 10 (14.7%)
PELD at LT
 Median (IQR) 11 (−1 to 23) 14 (0–25) 15 (1–24) 12 (0–27) 0.331
MELD at LT
 Median (IQR) 16 (10–24) 18 (11–31) 19 (13–28) 16 (13–22) 0.093
Dialysis at LT 39 (2.5%) 47 (6.2%) 19 (6.7%) 6 (8.8%) <0.001
ABO incompatible 38 (2.4%) 56 (7.2%) 24 (8.0%) 25 (36.8%) <0.001
Location prior to LT <0.001
 Home 1,055 (65.6%) 460 (60.6%) 185 (61.9%) 40 (58.8%)
 Inpatient 296 (18.4%) 141 (18.3%) 41 (13.7%) 10 (14.7%)
 ICU 258 (16.0%) 171 (22.2%) 73 (24.4%) 18 (26.5%)
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While native PELD and MELD scores at LT were not different by induction group (p=0.331 and p=0.093, respectively), differences in other markers of illness severity were evident (Table 1). For example, patients receiving none/steroid-only induction were least commonly in the intensive care unit (ICU; 16.0% vs 22.2% IL2Ra vs 24.4% ATG vs 26.5% other/combination induction; p<0.001 in pairwise comparisons) and least likely to be on dialysis pre-LT (2.5% vs 6.2% vs 6.7% vs 8.8%, respectively; p<0.001). The other/combination group included a high proportion of ABO-incompatible LTs (36.8% vs 2.4% in none/steroid-only vs 7.2% IL2Ra vs 8.0% ATG; p<0.001).

Maintenance immunosuppression regimen at LT hospital discharge was comparable between the none/steroid-only and IL2Ra induction groups, with the majority receiving either a CNI+steroid (53.7% and 48.2%, respectively) or CNI+antiM+steroid (19.3% and 16.9%, respectively; Supplemental Figure 1). Children receiving ATG induction were more often discharged on CNI alone (34.5%) or CNI+steroid (26.7%), while those receiving other/combination induction regimens most often received CNI+antiM (52.4%; p<0.001 comparing maintenance regimen by induction therapy overall).

Temporal and geographic factors associated with induction

Unlike trends observed in the adult LT population, there was minimal change in induction practices over time (Figure 1A).23 Among the 24 centers performing ≥10 pediatric LTs during the study period, induction practice heterogeneity was observed with many employing a single induction strategy for their patients (Figure 1B). At 9/24 centers, >90% of children received any induction use, while at 5/24 centers induction use was <10%. Among the remaining 10 centers, induction use ranged 11.8% to 68.2% with patients receiving any form of induction being more often either very young (<1 year, 35.0% vs 30.9% no induction) or older (11–17 years, 22.7% vs 16.8%), less likely to have tumor as their LT indication (7.3% vs 12.9%), more likely to be on dialysis (11.8% vs 1.9%) or in the ICU pre-LT (28.4% vs 14.2%; Supplemental Table 4).

Figure 1 –

Figure 1 –

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Panel A: Temporal trends in antibody induction use in pediatric LTs from 2006–2017 (n=2,748 children); Panel B: Center differences in induction practices (n=24 centers)*; Panel C: Center antibody induction practices according to average pediatric LT volume per year (n=26 centers)

*Panel B excludes two centers that performed <10 pediatric LTs during the study period and centers are ranked left to right by increasing transplant volume

Low-volume (<7 LTs/year) centers favored IL2Ra induction, while intermediate- (7–14 LTs/year) and high-volume (≥15 LTs/year) centers often employed a none/steroid-only approach (Figure 1C). Use of ATG induction was unaffected by center LT volume. Low-volume centers often used more intensive maintenance immunosuppression (e.g., CNI+antiM+steroid) at LT hospital discharge than intermediate- and high-volume centers, irrespective of whether patients received no/steroid-only, IL2Ra or ATG induction (Supplemental Figure 2).

Short-term hospitalization outcomes with induction therapy

Children receiving ATG had longer post-LT LOS (median 17 vs 14 for none/steroid-only vs 16 days for IL2Ra; p<0.001; Table 2). There was no difference in the rate of liver retransplantation during the index LT admission between induction groups (p=0.320). Patients receiving ATG or other/combination induction were more likely to be readmitted within 30- and 90-days. For example, 57.9% and 52.4% of ATG and other/combination induction patients were readmitted at 30-days post-LT versus 44.3% of none/steroid-only and 46.3% of IL2Ra induction patients (p<0.001).

Table 2.

Short-term post-LT outcomes according to induction regimen received

None or steroid-only (N=1,609) IL2Ra +/− steroids (N=772) ATG +/− steroids (N=299) Other or combination (N=68) p-value
Post-LT length of stay (days), median (IQR)* 14 (9–24) 16 (11–26) 17 (12–29) 17 (10–28) <0.001
Liver retransplant during index LT admission 50 (3.1%) 30 (3.9%) 5 (1.7%) 2 (3.0%) 0.320
Readmitted within 30 days of LT discharge* 672 (44.3%) 336 (46.3%) 168 (57.9%) 33 (52.4%) <0.001
Readmitted within 90 days of LT discharge* 866 (57.1%) 464 (64.0%) 204 (70.3%) 44 (69.8%) <0.001
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*

Excludes patients who died or were retransplanted during their index admission (N=2,596).

Common reasons for readmission across all induction groups at 30- and 90-days were: non-specific complications of LT, electrolyte or acid/base disturbances and failure to thrive (Supplemental Tables 5 and 6, respectively). Non-OI viral or other unspecified infections were possibly less frequent in the ATG group both at 30-days (17.3% vs 19.8% in IL2Ra vs 30.4% in none/steroid only induction) and at 90-days (17.5% vs 25.8% vs 23.0%, respectively). However, in the ATG group, 30-day readmissions with acute cardiopulmonary illness and 90-day readmissions with biliary complications appeared more frequent (26.7% vs 12.3% IL2Ra vs 12.2% none/steroid only and 25.3% vs 20.2% IL2Ra vs 15.7% none/steroid only, respectively).

Long-term patient and graft survival with induction therapy

Induction regimen was not associated with unadjusted patient survival (log-rank p=0.200; Figure 2A) nor with adjusted patient survival (p=0.257 for exposure overall; Table 3 and Figure 2C). However, induction regimen was associated with unadjusted graft survival (log-rank p=0.024; Figure 2B). In multivariable analyses, ATG induction was associated with improved graft survival compared to none/steroid-only induction (HR 0.64, 95% CI: 0.43–0.95, p=0.028; Table 3 and Figure 2D). There was no interaction between age and induction regimen for either patient or graft survival (all p>0.1).

Figure 2 –

Figure 2 –

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Panel A: Unadjusted patient survival by induction strategy (N=2,748); Panel B: Unadjusted graft survival by induction strategy (N=2,748); Panel C: Adjusted patient survival by induction strategy (N=2,597); Panel D: Adjusted graft survival by induction strategy (N=2,597) Note: Multivariable models adjusted for sex, age, race/ethnicity, primary liver disease etiology, serum bilirubin, international normalized ratio (INR), serum creatinine, location prior to LT, donor age, allograft type, DCD allograft, ABO incompatibility, LT era and center average yearly volume tertile.

Table 3.

Association of induction regimen with unadjusted and adjusted patient and graft survival

Patient survival, HR (95% CI) p-value Graft survival, HR (95% CI) p-value
Unadjusted (N=2,676)
 None/steroid-only Reference Reference
 IL2RA +/− steroid 1.10 (0.82–1.50) 0.510 1.99 (0.97–1.48) 0.094
 ATG +/− steroid 0.67 (0.40–1.13) 0.136 0.72 (0.50–1.04) 0.084
Adjusted* (N=2,597)
 None/steroid-only Reference Reference
 IL2RA +/− steroid 0.91 (0.65–1.27) 0.579 1.01 (0.80–1.28) 0.900
 ATG +/− steroid 0.63 (0.36–1.10) 0.101 0.64 (0.43–0.95) 0.028
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*

Multivariable model adjusted for sex, age, race/ethnicity, diagnosis, bilirubin at LT, creatine at LT, INR at LT, patient location at LT, donor age, graft type, DCD donor, ABO compatibility, LT era, center average yearly volume tertile

Impact of induction therapy on acute rejection and hospitalization-related outcomes

Compared to none/steroid only induction, IL2Ra induction was associated with reduced acute rejection at 1-year post-LT: adjusted odds ratio (OR) 0.53 (95% CI: 0.43–0.67, p<0.001; Table 4). However, IL2Ra induction was also associated with a higher risk of hospitalization for PTLD in the first 2 years post-LT: adjusted OR 1.75 (95% CI: 1.09–2.81, p=0.021) versus none/steroid-only induction. Of note, no relationship was seen between the proportion patients who developed PTLD and the number of IL2Ra doses received (p=0.647) or the maintenance regimen used at LT hospital discharge (p=0.364).

Table 4.

Association of induction therapy with unadjusted and adjusted one- and two-year clinical outcomes

Unadjusted OR, (95% CI) p-value Adjusted* OR, (95% CI) p-value
Acute rejection in first year
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 0.59 (0.48–0.72) <0.001 0.53 (0.43–0.67) <0.001
 ATG +/− steroid 1.28 (0.99–1.66) 0.062 1.27 (0.97–1.69) 0.084
Hospitalization for CMV infection in first year
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 0.95 (0.77–1.17) 0.611 0.96 (0.76–1.22) 0.734
 ATG +/− steroid 0.94 (0.70–1.28) 0.693 1.10 (0.79–1.53) 0.575
Hospitalization for non-CMV OI† in first year
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 1.20 (0.93–1.54) 0.171 1.11 (0.83–1.48) 0.485
 ATG +/− steroid 1.44 (1.02–2.02) 0.036 1.46 (1.01–2.12) 0.046
Hospitalization with anemia in first year
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 1.16 (0.97–1.39) 0.103 1.07 (0.87–1.31) 0.515
 ATG +/− steroid 1.27 (0.68–0.83) 0.069 1.42 (1.07–1.88) 0.014
Hospitalization with leukopenia or neutropenia in first year
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 1.13 (0.90–1.43) 0.298 1.13 (0.87–1.48) 0.349
 ATG +/− steroid 1.04 (0.75–1.46) 0.806 1.19 (0.82–1.73) 0.354
Hospitalization with thrombocytopenia in first year
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 1.30 (1.07–1.57) 0.009 1.15 (0.92–1.43) 0.214
 ATG +/− steroid 1.37 (1.05–1.80) 0.022 1.37 (1.01–1.85) 0.040
PTLD in first 2 years post-LT ‡
 None/steroid-only Reference Reference
 IL2Ra +/− steroid 1.33 (0.87–2.04) 0.188 1.75 (1.09–2.81) 0.021
 ATG +/− steroid 0.80 (0.39–1.63) 0.539 0.94 (0.43–2.08) 0.880
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*

Multivariable model adjusted for sex, age, race/ethnicity, diagnosis, bilirubin at LT, creatine at LT, INR at LT, patient location at LT, donor age, graft type, DCD donor, ABO compatibility, transplant year, center average volume tertile

†

Includes: HSV, VZV, pneumocystis jirovecii, fungal infections

‡

Multivariable model additionally adjusted for recipient Epstein-Barr virus antibody status

ATG induction was associated with increased non-CMV OI hospitalization in the first year (adjusted OR 1.46 vs none/steroid-only, 95% CI: 1.01–2.12, p=0.046) and of certain hematologic issues: adjusted OR 1.42 (95% CI: 1.07–1.88, p=0.014) for anemia and OR 1.37 (95% CI: 1.01–1.85, p=0.040) for thrombocytopenia. There was no association between induction regimen and hospitalization for CMV infection in the first year (p=0.724 in adjusted model for exposure overall) or with leukopenia or neutropenia (p=0.461 in adjusted model for exposure overall).

An interaction between age and induction regimen was observed for CMV infection and thrombocytopenia in the first year (p=0.028 for both interactions), and possibly also for non-CMV infection (p=0.08). Results of interaction analyses are shown in Supplemental Table 7. For example, the odds of CMV infection were higher with ATG in recipients aged 11–17 years (OR 2.22 vs none/steroid-only induction, 95% CI: 1.09–4.52; p=0.028). There was no interaction between age and induction regimen for the other outcomes studied (all p>0.1).

Discussion

Due to concerns over their increased risks of rejection and PTLD, among others, LT immunosuppression management presents unique challenges in pediatric recipients.24 This decision-making therefore cannot solely rely on the evidence obtained from studies of adult LT recipients. Our study is the first to comprehensively assess the impact of antibody induction therapy on multiple clinical outcomes in a large, multicenter and representative pediatric LT cohort. Taken together, our results suggest that depleting induction with ATG may offer improvements in long-term graft survival, which likely outweigh the potential risks of cytopenias, non-CMV OI and early post-LT readmissions. In contrast, while IL2Ra was observed to reduce the risk of early acute rejection, it was also associated with an increased risk of PTLD. Our findings bring important new insights to the pediatric transplant community. In addition, we also found considerable heterogeneity in induction practices and patient factors played a lesser role in determining the induction strategy used. This highlights the need for more comprehensive consensus guidance on the optimal and individualized approach to induction use in pediatric LT.

While there are few studies simultaneously comparing multiple induction approaches in pediatric LT recipients, our results are largely consistent with the available literature. For example, IL2Ra has been shown to offer benefits (vs no/steroid-only induction) with regards to early acute rejection in several studies of pediatric LT recipients (all <100 patients).7,25,26 Two single-center studies have also reported numerically but not statistically higher rates of PTLD among IL2Ra treated pediatric liver and/or intestine recipients (vs ATG or none/steroid only induction).6,27 In our analysis on induction regimen and PTLD, we were not able to account for potential differences in maintenance immunosuppression beyond the LT hospital discharge to confirm the observed association with IL2Ra induction. This warrants further investigation to better guide treatment.

Pediatric LT and non-liver adult transplant studies have also demonstrated increased cytopenias, particularly thrombocytopenia and lymphopenia, with ATG (vs other regimens).6,28,29 Limited evidence on the potential association of induction therapy with infection risk in pediatric LT recipients has suggested no increased risk, in contrast to studies of other transplant populations in which infections appear more frequent with antibody induction.6,30–33 Regarding long-term outcomes, improved graft survival with ATG induction as compared to IL2Ra has been shown in several studies of pediatric non-liver transplant recipients and also in adult LT recipients, consistent with our results.23,34–37 However, existing evidence in pediatric LT patients remains limited.24,38 The overall readmission rates and reasons for rehospitalization were also congruent with prior studies of pediatric LT recipients, though none have evaluated these in the context of induction immunosuppression.39,40

This study had limitations worth noting. First, as this is a retrospective cohort study, the findings obtained should be interpreted as associations, rather than cause-effect. Regarding missing data, the completeness of UNOS-derived covariates was ≥97.5%. The primary weaknesses of UNOS data are in the assessment of post-LT outcomes other than patient/graft survival, which is why we also relied on PHIS data. However, the presence of acute rejection in the first year could solely be derived from UNOS data given the lack of an available ICD-9 code. UNOS capture of acute rejection events has inherent limitations. In a prior study of adult LT recipients, approximately 15% of acute rejection events were missed in UNOS (missingness unknown in children).41 In addition, mild acute rejection events that are treated with immunosuppression escalation without liver biopsy may not be regularly reported in UNOS.

While induction regimen is captured in UNOS, we chose to rely on billed pharmacy resource utilization data from PHIS, which are based on hospital financial charges. PHIS resource utilization data are known to be highly reliable. For example, these data are regularly used for peer hospital comparisons, to develop multicenter research cohorts and to examine clinical trial-related resource utilization (e.g., Children’s Oncology Group).42–46 We allowed for a window of up to 7 days post-LT to evaluate for receipt of induction therapy to account for potential discrepancy between billed drug date and drug administration date. In prior chart-validated pediatric cancer cohorts, investigators found good reliability when capturing chemotherapy regimens +/− 1 day.45–47

While PHIS data has numerous advantages over UNOS data, it is largely an inpatient database. Therefore, occurrences of PHIS-derived endpoints (OIs, cytopenias, PTLD) in the outpatient setting or at local hospitals were not able to be captured, which is an inherent limitation. Readmissions in the first year in PHIS were overall high (81.9% with ≥1 readmission) and we found minimal differences in the center-level readmission rate, suggesting a good likelihood of capturing inpatient events. We also hypothesized that complications warranting readmission in the early post-LT period would preferentially be managed at the transplanting center. Nevertheless, it is possible that the absolute inpatient event rates were underestimated. Overall, we suspect this missingness was non-differential by induction regimen, and thus led to minimal bias with respect to point estimates obtained, though may have decreased power. Moreover, while we used previously validated ICD codes to identify the outcomes studied, their sensitivity is not well established in pediatric patients, which could have also contributed to missingness.

The lack of available outpatient data likely also selected for more severe presentations of the outcomes of interest (e.g., OIs, cytopenias). We hypothesize that those warranting hospitalization would be of greatest interest to transplant physicians, patients and their caregivers. Yet, it is also possible that induction regimens have differential risks of milder versus more severe presentations, such that the magnitude and/or statistical significance of the point estimates obtained herein would differ if outpatient events were also captured. Thus, it is important to interpret the associations found (or lack thereof) in the context of being hospitalized for each of the post-LT complications studied.

The use of PHIS data additionally limited the cohort to pediatric LT centers at freestanding children’s hospitals, which may have impacted the generalizability and/or transportability of our findings. As a result, it is not known whether the practices or the effectiveness and safety of induction immunosuppression differed at other types of pediatric LT centers. Nevertheless, our study did include centers spanning a wide range of pediatric LT experience, which provided important insights into the role of center volume and induction practices. We opted to pursue only a limited analysis of patients receiving other or combination induction regimens, primarily due to the heterogeneous nature of this small group and also given its larger prevalence of ABO-mismatched LTs, in which the use of induction immunosuppression has inherently different objectives. Lastly, maintenance immunosuppression regimen is not reliable in UNOS beyond LT hospital discharge48 and was not available from PHIS data. Thus, our approach to studying the effects of antibody induction should viewed as being comparable to an intention-to-treat analysis.

In conclusion, this large and real-world analysis of the trends, practices and outcomes of induction therapy among pediatric LT recipients augments the existing evidence that supports early immunosuppression decision-making for this patient population. While IL2Ra and ATG induction are infrequently used in children undergoing LT overall, at some centers this is the dominant strategy employed. We find that there are key benefits to induction therapy in pediatric LT recipients that likely warrants greater consideration of this approach moving forward. However, our observation of IL2Ra induction being associated with an increased risk of PTLD, a finding that has been also reported in smaller studies, may favor the use of ATG in this setting. Though, further studies of large pediatric LT cohorts, such as via other administrative data sources and/or patient registries, should be pursued to help validate our findings.

Supplementary Material

1

Supplemental Figure 1 – Maintenance immunosuppression regimen at LT hospital discharge by induction strategy (N=2,596)

Note: excludes patients who died or were retransplanted prior to discharge; p<0.001 comparing maintenance regimen by induction strategy

2

Supplemental Figure 2 – Maintenance immunosuppression regimen at LT hospital discharge by induction strategy and by center volume (N=2,596)

Note: excludes patients who died or were retransplanted prior to discharge

3
4
5
6
7
8
9

Acknowledgments

This study was funded by a Pilot Award from the Fred and Suzanne Biesecker Pediatric Liver Center at the Children’s Hospital of Pennsylvania (PI: Therese Bittermann). Dr. Therese Bittermann is also supported by a National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award K08-DK117013.

Abbreviations:

antiM

antimetabolite

ATG

anti-thymocyte globulin

BA

biliary atresia

CMV

cytomegalovirus

CNI

calcineurin inhibitor

DCD

donation after cardiac determination of death

ICD

International Classification of Diseases

ICU

intensive care unit

IL2Ra

IL-2 receptor antagonist

INR

international normalized ratio

LT

liver transplantation

LOS

length of stay

MELD

Model for End-stage Liver Disease

OI

opportunistic infection

PELD

Pediatric End-stage Liver Disease

PHIS

Pediatric Health Information System

PTLD

posttransplant lymphoproliferative disorder

UNOS

United Network for Organ Sharing

Footnotes

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Data Availability Statement

The data that support the findings of this study are publicly available from the United Network for Organ Sharing (https://unos.org) and the Pediatric Health Information System (https://www.childrenshospitals.org/content/analytics/product-program/pediatric-health-information-system).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1

Supplemental Figure 1 – Maintenance immunosuppression regimen at LT hospital discharge by induction strategy (N=2,596)

Note: excludes patients who died or were retransplanted prior to discharge; p<0.001 comparing maintenance regimen by induction strategy

NIHMS1902571-supplement-1.tif (341KB, tif)
2

Supplemental Figure 2 – Maintenance immunosuppression regimen at LT hospital discharge by induction strategy and by center volume (N=2,596)

Note: excludes patients who died or were retransplanted prior to discharge

NIHMS1902571-supplement-2.tif (516.2KB, tif)
3
NIHMS1902571-supplement-3.docx (26.9KB, docx)
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NIHMS1902571-supplement-4.docx (13.7KB, docx)
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NIHMS1902571-supplement-5.docx (14.3KB, docx)
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NIHMS1902571-supplement-6.docx (30.2KB, docx)
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NIHMS1902571-supplement-7.docx (36.5KB, docx)
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NIHMS1902571-supplement-8.docx (37.2KB, docx)
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NIHMS1902571-supplement-9.docx (35.1KB, docx)

Data Availability Statement

The data that support the findings of this study are publicly available from the United Network for Organ Sharing (https://unos.org) and the Pediatric Health Information System (https://www.childrenshospitals.org/content/analytics/product-program/pediatric-health-information-system).

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