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Application of New Antibody-Mediated Rejection Classification (pAMR) on Pediatric Heart Transplant: A Retrospective Study*
Abstracts S73
1( 76) Donor-Specific Anti-HLA Antibodies of Immunoglobulin G3 Subclass Correlate with Cellular Rejection after Cardiac Transplantation S. Khan ,1 C. Chin,1 E. Portwood,2 P.A. Brailey,2 A. Tica,3 A.L. Girnita.4 1Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 2Transplant Immunology Division, Hoxworth Blood Center, Cincinnati, OH; 3Department of Pharmacology, University of Medicine and Pharmacy, Craiova, Romania; 4Department of Surgery, COM, Transplant Immunology Division, University of Cincinnati, Cincinnati, OH.
1( 75) Increased Frequency of Surveillance Biopsy Does Not Improve Pediatric Heart Transplant Outcomes: Time for a Change in Practice? J. Godown ,1 M. McKane,1 B.A. Mettler,2 A.C. Westrick,3 C.N. Shannon,3 H. Chen,4 S. Zhao,4 D.A. Dodd.1 1Pediatric Cardiology, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 2Pediatric Cardiothoracic Surgery, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 3Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 4Biostatistics, Vanderbilt University, Nashville, TN. Purpose: The frequency of surveillance endomyocardial biopsy (S-EMB) following pediatric heart transplant (HTx) varies significantly between centers. Based on a recent survey of PHTS centers, the frequency of S-EMB ranges from 0-9 in infants (< 6 mo of age) and 0-16 in adolescents (> 12 yrs of age) during the first year post-HTx. The aim of this study was to determine if the frequency of S-EMB in the first year post-HTx impacts patient outcomes. Methods: The SRTR database was queried for all pediatric HTx’s performed at PHTS centers from 2007 to 2013. Utilizing the previously conducted survey of S-EMB frequency, PHTS centers were classified as high or low S-EMB frequency for both infants (low ≤ 2 S-EMB/yr) and adolescents (low ≤ 6 S-EMB/yr). Key variables were compared across S-EMB frequency groups. Survival curves were generated for post-HTx mortality and compared using the log-rank test. A Cox proportional hazard regression was performed to adjust for patient characteristics and patient clusters. Results: A total of 476 infants and 654 adolescents were included in the analysis. There were no significant differences in infant populations between high and low S-EMB centers. Adolescents from high S-EMB centers were more likely to be African American, have cardiomyopathy (vs. congenital heart disease), and require VAD support compared to those at low S-EMB centers. Center frequency of S-EMB did not impact post-HTx mortality in adolescents (AHR 0.9, 95%CI 0.6 to 1.3); however, an increased center frequency of S-EMB in the first year post-HTx was associated with worse survival in infants (AHR 1.9, 95%CI 1.3 to 2.7) (Fig.). Conclusion: There is wide variation in the frequency of S-EMB between pediatric HTx centers. Increasing the frequency of S-EMB in the first year post-HTx does not improve survival, and may in fact contribute to worse outcomes in the infant population. A reduction in the use of S-EMB will decrease procedural risks and reduce cost without compromising patient outcomes.
Purpose: HLA donor-specific antibodies (DSAs) of immunoglobulin (IgG) type are associated with antibody-mediated rejection. Aim of this study was to determine if the IgG subtype was associated with cellular rejection in patients who underwent cardiac transplantation at a pediatric center. Methods: Serum samples were obtained in conjunction with endomyocardial biopsies (EMB), which were graded for cellular rejection. DSAs were identified by single-antigen beads (Luminex). A modified single antigen bead assay was used to detect the presence of individual immunoglobulin G subclasses (1-2-3-4). Rejection was classified as higher grade (HR), defined by ISHLT guidelines > grade 1B or no/low grade (NLR), defined as ISHLT guidelines < grade 2. We compared the proportions of IgG subclasses between those with HR and those with NLR. Results: Of 66 patients, 28 were positive for DSA and 38 were negative. In the DSA-positive group, 15 patients had HR and 13 patients had NLR. In the HR group, 14 patients (93.3%) were positive for IgG3 DSA, compared with only 1 patient (7.7%) in the NLR group (p value < 0.01). Furthermore, in the HR group, 14/15 (93.3%) patients exhibited DSAs of multiple IgG subtype, compared with only 3/13 (23.1%) in the NLR group (p < 0.01). The positive predictive value of the presence of IgG3 subclass for HR was 93%, negative predictive value was 92%, sensitivity was 93%, and specificity was 92%. Conclusion: The prevalence of HLA DSAs of IgG3 subtype was significantly elevated in patients with HR. High-grade rejectors were characterized by multiple IgG subtypes, while low-grade rejectors exhibited DSAs of a single subtype (non-IgG3). The determination of the IgG subclass in DSApositive patients may be a less invasive method for identifying patients at risk for higher grade cellular rejection.
1( 77) Application of New Antibody-Mediated Rejection Classification (pAMR) on Pediatric Heart Transplant: A Retrospective Study* M. Fedrigo ,1 A. Angelini,1 G.J. Berry.2 1Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy; 2Pathology Department, Stanford University, Stanford, CA. Purpose: To evaluate the application of new ISHLT Antibody Mediated Rejection (AMR) classification (pAMR )in a cohort of pediatric heart transplanted patients (HTx) in a single pediatric Heart Transplant center Methods: We retrospectively reviewed the Endomyocardial biopsy (EMBs) and Immunohistochemical (IHC) stains of pediatric heart transplant patients at the Lucile Packard Children’s Hospital at Stanford University who underwent cardiac transplantation from 2007 to 2014 and had IHC staining for AMR. The IHC panel consisted of the complement marker, C4d and inflammatory markers, CD68 and CD3. Five hundred and seventy EMBs of 98 pediatric HTx pts (mean age at transplant was 8,3±6,5 years) were evaluated accordingly by two expert HTx pathologists (MF,GJB) for ACR and AMR rejection (according to 1990-2005 and 2013ISHLT classifications respectively).
S74
The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016
Results: The study cohort comprised 80/570 (14%) EMBs that were positive for pAMR in 26/98 (27%) pts. The relationship between pAMR and ACR grading is summarized in Table 1. pAMR positivity was detected in 63,7% (51/80) within one year after HTx and 61% (31/51) within one month post-transplant. Eighty % (21/26) of pts showed pAMR positivity within one month, 3,8% (1/26) between 1 mo and 1 yr and 15% (4/26) later than one year with the following distribution : pAMR 1 (i+) 69% (18/26), pAMR2 11% (3/26) and pAMR3 19% (5/26). Of these, 10 EMBs (10/26, 38%) showed concurrent ACR. Macrophages were present pAMR positive EMBs in 67,5% (54/80) of cases. Sensitivity and specificity for activated mononuclear cells to predict pAMR was 71% and 87%. Conclusion: pAMR occurred more frequently within the first month after HTx in this group of pediatric patients suggesting that many were presensitized before transplant. However up to 15% of patients developed AMR after one year from HTX indicating the need to careful long-term surveillance.
The relationship between pAMR and ACR grading ACR/pAMR
1 (h+)n (%)
1 (i+)n (%)
2n (%)
3 n (%)
Total
0 1A 1B 2 3A 3B Total
1 (17) 3 (50) 2 (33) 0 0 0 6 (7,5)
25 (53) 11 (23) 6 (13) 2 (4) 3 (7) 0 47 (58,7)
10 (45) 3 (14) 4 (18) 1 (4) 2 (9) 2 (9) 22 (27,5)
5 (100) 0 0 0 0 0 5 (6,3)
41 17 12 3 5 2 80
1( 78) Pediatric Heart Transplant Waitlist Time Is Increased and Survival Is Decreased in Overweight-Obese (BMI> 85%) Individuals T.D. Ryan , F. Zafar, R.M. Siegel, C.R. Villa, R. Bryant, C. Chin. The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. Purpose: Studies in adult heart transplant show that level of obesity at listing negatively affects outcomes, with those with extreme obesity (BMI> 35) having increased waitlist time and decreased long-term survival compared to those with normal weight (BMI< 25). Pediatric studies show variable results using BMI cut-off of 95%ile for age. This does not account for distinction between overweight (BMI= 85-95%ile) and obese (BMI> 95%ile) individuals. We analyzed the effect of BMI on waitlist time and survival. Methods: The UNOS database was queried for patients < 19-years-old listed for heart transplant and they were stratified according to recently defined ranges: normal (BMI< /= 85%ile), overweight (BMI= 86-95%ile), obese level 1 (BMI= 100-120% of 95%ile), level 2 (BMI= 121-140% of 95%ile), and level 3 (BMI> 140% of 95%ile). To study effect of donor:recipient weight ratio, patients were grouped as < /= 0.8, 0.81-1.2, and > 1.2. Waitlist and transplant outcomes were studied. Results: 6249 individuals listed for transplant were identified, with 77% normal and 23% overweight-obese (OvOb). Among OvOb, 45% were overweight, 36% level 1, 13% level 2, and 6% level 3. Time on the waitlist was longer for OvOb vs. normal [Median (IQR): 54(17-189) vs 48 (15-149) days, p= 0.009] with no difference within OvOb. Long-term survival was decreased in OvOb (Figure); there was no survival difference within OvOb. Mean donor:recipient weight was lower in OvOb [1.02 (0.88-1.25) vs 1.24 (1.041.53), p< 0.001]. Long-term survival was significantly decreased in OvOb for donor:recipient < /= 0.8 and 0.81-1.2, with no difference within groups at > 1.2. Conclusion: We demonstrate that stricter definition of normal weight reveals a negative effect of being OvOb on pediatric heart transplant outcomes. Distinction between levels of obesity is not clear, but numbers are small. These data also give guidance when considering donor weight range, with undersized hearts showing worse long-term outcomes in OvOb patients.
1( 79) Heart Transplantation in Adolescents: Does Pediatric Experience Improve Outcomes? R.R. Davies ,1 S.J. Kindel,2 M.A. McCulloch,1 C. Pizarro,1 W.T. Mahle,3 D.L. Morales.4 1Nemours/A.I. duPont Hospital for Children, Wilmington, DE; 2Children’s Hospital of Wisconsin, Milwaukee, WI; 3Children’s Healthcare of Atlanta, Atlanta, GA; 4Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. Purpose: There is ongoing controversy regarding potential effects of defining specific criteria for UNOS designation of pediatric transplant (TX) centers. The impact of proposed criteria on access or outcomes for adolescents is uncertain; little data exists to guide this policy debate. Methods: We reviewed UNOS listings (2000-2015) for primary heart transplant (HTX) among adolescents (13-18 yrs). In order to limit casemix variation, waitlist and transplant outcomes were compared for dilated cardiomyopathy (DCM) transplanted at adult vs. pediatric centers. Pediatric centers were defined (based on UNOS Pediatric Transplant Committee proposals) as those performing at least 1 HTX in a child under 6 years of age for HTX (PEDS, n= 60; ADULT, n= 51). Results: Of 966 adolescents with DCM, 113 (11.7%) were listed at adult centers. Median additional distance to a pediatric center compared to an adult listing center was 0.6 miles (IQR -1.6-84.4); 70% were listed within 30 miles of a pediatric center. Likelihood of transplantation was higher when listed at a pediatric center (OR 1.8, 95% CI 1.1-2.9); wait-list mortality was lower but did not reach statistical significance (OR 0.6, 95%CI 0.3-1.2, p= 0.1). Multivariable analysis demonstrated decreased risk of discharge mortality post-transplant at pediatric centers (OR 0.3, 95%CI 0.1-0.95). Long-term post-transplant survival was unaffected by center type (FIGURE). Conclusion: Listing and transplantation at a pediatric center is associated with improved outcomes among DCM HTx recipients. The additional travel distance to a pediatric heart transplant center was minimal for most patients. These data help inform the debate on the need for pediatric thoracic transplant center designation.
1( 76) Donor-Specific Anti-HLA Antibodies of Immunoglobulin G3 Subclass Correlate with Cellular Rejection after Cardiac Transplantation S. Khan ,1 C. Chin,1 E. Portwood,2 P.A. Brailey,2 A. Tica,3 A.L. Girnita.4 1Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 2Transplant Immunology Division, Hoxworth Blood Center, Cincinnati, OH; 3Department of Pharmacology, University of Medicine and Pharmacy, Craiova, Romania; 4Department of Surgery, COM, Transplant Immunology Division, University of Cincinnati, Cincinnati, OH.
1( 75) Increased Frequency of Surveillance Biopsy Does Not Improve Pediatric Heart Transplant Outcomes: Time for a Change in Practice? J. Godown ,1 M. McKane,1 B.A. Mettler,2 A.C. Westrick,3 C.N. Shannon,3 H. Chen,4 S. Zhao,4 D.A. Dodd.1 1Pediatric Cardiology, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 2Pediatric Cardiothoracic Surgery, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 3Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 4Biostatistics, Vanderbilt University, Nashville, TN. Purpose: The frequency of surveillance endomyocardial biopsy (S-EMB) following pediatric heart transplant (HTx) varies significantly between centers. Based on a recent survey of PHTS centers, the frequency of S-EMB ranges from 0-9 in infants (< 6 mo of age) and 0-16 in adolescents (> 12 yrs of age) during the first year post-HTx. The aim of this study was to determine if the frequency of S-EMB in the first year post-HTx impacts patient outcomes. Methods: The SRTR database was queried for all pediatric HTx’s performed at PHTS centers from 2007 to 2013. Utilizing the previously conducted survey of S-EMB frequency, PHTS centers were classified as high or low S-EMB frequency for both infants (low ≤ 2 S-EMB/yr) and adolescents (low ≤ 6 S-EMB/yr). Key variables were compared across S-EMB frequency groups. Survival curves were generated for post-HTx mortality and compared using the log-rank test. A Cox proportional hazard regression was performed to adjust for patient characteristics and patient clusters. Results: A total of 476 infants and 654 adolescents were included in the analysis. There were no significant differences in infant populations between high and low S-EMB centers. Adolescents from high S-EMB centers were more likely to be African American, have cardiomyopathy (vs. congenital heart disease), and require VAD support compared to those at low S-EMB centers. Center frequency of S-EMB did not impact post-HTx mortality in adolescents (AHR 0.9, 95%CI 0.6 to 1.3); however, an increased center frequency of S-EMB in the first year post-HTx was associated with worse survival in infants (AHR 1.9, 95%CI 1.3 to 2.7) (Fig.). Conclusion: There is wide variation in the frequency of S-EMB between pediatric HTx centers. Increasing the frequency of S-EMB in the first year post-HTx does not improve survival, and may in fact contribute to worse outcomes in the infant population. A reduction in the use of S-EMB will decrease procedural risks and reduce cost without compromising patient outcomes.
Purpose: HLA donor-specific antibodies (DSAs) of immunoglobulin (IgG) type are associated with antibody-mediated rejection. Aim of this study was to determine if the IgG subtype was associated with cellular rejection in patients who underwent cardiac transplantation at a pediatric center. Methods: Serum samples were obtained in conjunction with endomyocardial biopsies (EMB), which were graded for cellular rejection. DSAs were identified by single-antigen beads (Luminex). A modified single antigen bead assay was used to detect the presence of individual immunoglobulin G subclasses (1-2-3-4). Rejection was classified as higher grade (HR), defined by ISHLT guidelines > grade 1B or no/low grade (NLR), defined as ISHLT guidelines < grade 2. We compared the proportions of IgG subclasses between those with HR and those with NLR. Results: Of 66 patients, 28 were positive for DSA and 38 were negative. In the DSA-positive group, 15 patients had HR and 13 patients had NLR. In the HR group, 14 patients (93.3%) were positive for IgG3 DSA, compared with only 1 patient (7.7%) in the NLR group (p value < 0.01). Furthermore, in the HR group, 14/15 (93.3%) patients exhibited DSAs of multiple IgG subtype, compared with only 3/13 (23.1%) in the NLR group (p < 0.01). The positive predictive value of the presence of IgG3 subclass for HR was 93%, negative predictive value was 92%, sensitivity was 93%, and specificity was 92%. Conclusion: The prevalence of HLA DSAs of IgG3 subtype was significantly elevated in patients with HR. High-grade rejectors were characterized by multiple IgG subtypes, while low-grade rejectors exhibited DSAs of a single subtype (non-IgG3). The determination of the IgG subclass in DSApositive patients may be a less invasive method for identifying patients at risk for higher grade cellular rejection.
1( 77) Application of New Antibody-Mediated Rejection Classification (pAMR) on Pediatric Heart Transplant: A Retrospective Study* M. Fedrigo ,1 A. Angelini,1 G.J. Berry.2 1Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy; 2Pathology Department, Stanford University, Stanford, CA. Purpose: To evaluate the application of new ISHLT Antibody Mediated Rejection (AMR) classification (pAMR )in a cohort of pediatric heart transplanted patients (HTx) in a single pediatric Heart Transplant center Methods: We retrospectively reviewed the Endomyocardial biopsy (EMBs) and Immunohistochemical (IHC) stains of pediatric heart transplant patients at the Lucile Packard Children’s Hospital at Stanford University who underwent cardiac transplantation from 2007 to 2014 and had IHC staining for AMR. The IHC panel consisted of the complement marker, C4d and inflammatory markers, CD68 and CD3. Five hundred and seventy EMBs of 98 pediatric HTx pts (mean age at transplant was 8,3±6,5 years) were evaluated accordingly by two expert HTx pathologists (MF,GJB) for ACR and AMR rejection (according to 1990-2005 and 2013ISHLT classifications respectively).
S74
The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016
Results: The study cohort comprised 80/570 (14%) EMBs that were positive for pAMR in 26/98 (27%) pts. The relationship between pAMR and ACR grading is summarized in Table 1. pAMR positivity was detected in 63,7% (51/80) within one year after HTx and 61% (31/51) within one month post-transplant. Eighty % (21/26) of pts showed pAMR positivity within one month, 3,8% (1/26) between 1 mo and 1 yr and 15% (4/26) later than one year with the following distribution : pAMR 1 (i+) 69% (18/26), pAMR2 11% (3/26) and pAMR3 19% (5/26). Of these, 10 EMBs (10/26, 38%) showed concurrent ACR. Macrophages were present pAMR positive EMBs in 67,5% (54/80) of cases. Sensitivity and specificity for activated mononuclear cells to predict pAMR was 71% and 87%. Conclusion: pAMR occurred more frequently within the first month after HTx in this group of pediatric patients suggesting that many were presensitized before transplant. However up to 15% of patients developed AMR after one year from HTX indicating the need to careful long-term surveillance.
The relationship between pAMR and ACR grading ACR/pAMR
1 (h+)n (%)
1 (i+)n (%)
2n (%)
3 n (%)
Total
0 1A 1B 2 3A 3B Total
1 (17) 3 (50) 2 (33) 0 0 0 6 (7,5)
25 (53) 11 (23) 6 (13) 2 (4) 3 (7) 0 47 (58,7)
10 (45) 3 (14) 4 (18) 1 (4) 2 (9) 2 (9) 22 (27,5)
5 (100) 0 0 0 0 0 5 (6,3)
41 17 12 3 5 2 80
1( 78) Pediatric Heart Transplant Waitlist Time Is Increased and Survival Is Decreased in Overweight-Obese (BMI> 85%) Individuals T.D. Ryan , F. Zafar, R.M. Siegel, C.R. Villa, R. Bryant, C. Chin. The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. Purpose: Studies in adult heart transplant show that level of obesity at listing negatively affects outcomes, with those with extreme obesity (BMI> 35) having increased waitlist time and decreased long-term survival compared to those with normal weight (BMI< 25). Pediatric studies show variable results using BMI cut-off of 95%ile for age. This does not account for distinction between overweight (BMI= 85-95%ile) and obese (BMI> 95%ile) individuals. We analyzed the effect of BMI on waitlist time and survival. Methods: The UNOS database was queried for patients < 19-years-old listed for heart transplant and they were stratified according to recently defined ranges: normal (BMI< /= 85%ile), overweight (BMI= 86-95%ile), obese level 1 (BMI= 100-120% of 95%ile), level 2 (BMI= 121-140% of 95%ile), and level 3 (BMI> 140% of 95%ile). To study effect of donor:recipient weight ratio, patients were grouped as < /= 0.8, 0.81-1.2, and > 1.2. Waitlist and transplant outcomes were studied. Results: 6249 individuals listed for transplant were identified, with 77% normal and 23% overweight-obese (OvOb). Among OvOb, 45% were overweight, 36% level 1, 13% level 2, and 6% level 3. Time on the waitlist was longer for OvOb vs. normal [Median (IQR): 54(17-189) vs 48 (15-149) days, p= 0.009] with no difference within OvOb. Long-term survival was decreased in OvOb (Figure); there was no survival difference within OvOb. Mean donor:recipient weight was lower in OvOb [1.02 (0.88-1.25) vs 1.24 (1.041.53), p< 0.001]. Long-term survival was significantly decreased in OvOb for donor:recipient < /= 0.8 and 0.81-1.2, with no difference within groups at > 1.2. Conclusion: We demonstrate that stricter definition of normal weight reveals a negative effect of being OvOb on pediatric heart transplant outcomes. Distinction between levels of obesity is not clear, but numbers are small. These data also give guidance when considering donor weight range, with undersized hearts showing worse long-term outcomes in OvOb patients.
1( 79) Heart Transplantation in Adolescents: Does Pediatric Experience Improve Outcomes? R.R. Davies ,1 S.J. Kindel,2 M.A. McCulloch,1 C. Pizarro,1 W.T. Mahle,3 D.L. Morales.4 1Nemours/A.I. duPont Hospital for Children, Wilmington, DE; 2Children’s Hospital of Wisconsin, Milwaukee, WI; 3Children’s Healthcare of Atlanta, Atlanta, GA; 4Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. Purpose: There is ongoing controversy regarding potential effects of defining specific criteria for UNOS designation of pediatric transplant (TX) centers. The impact of proposed criteria on access or outcomes for adolescents is uncertain; little data exists to guide this policy debate. Methods: We reviewed UNOS listings (2000-2015) for primary heart transplant (HTX) among adolescents (13-18 yrs). In order to limit casemix variation, waitlist and transplant outcomes were compared for dilated cardiomyopathy (DCM) transplanted at adult vs. pediatric centers. Pediatric centers were defined (based on UNOS Pediatric Transplant Committee proposals) as those performing at least 1 HTX in a child under 6 years of age for HTX (PEDS, n= 60; ADULT, n= 51). Results: Of 966 adolescents with DCM, 113 (11.7%) were listed at adult centers. Median additional distance to a pediatric center compared to an adult listing center was 0.6 miles (IQR -1.6-84.4); 70% were listed within 30 miles of a pediatric center. Likelihood of transplantation was higher when listed at a pediatric center (OR 1.8, 95% CI 1.1-2.9); wait-list mortality was lower but did not reach statistical significance (OR 0.6, 95%CI 0.3-1.2, p= 0.1). Multivariable analysis demonstrated decreased risk of discharge mortality post-transplant at pediatric centers (OR 0.3, 95%CI 0.1-0.95). Long-term post-transplant survival was unaffected by center type (FIGURE). Conclusion: Listing and transplantation at a pediatric center is associated with improved outcomes among DCM HTx recipients. The additional travel distance to a pediatric heart transplant center was minimal for most patients. These data help inform the debate on the need for pediatric thoracic transplant center designation.