-
[show abstract]
[hide abstract]
ABSTRACT: C4d assessment of endomyocardial biopsies (EMBs) after heart transplantation (HTx) has been widely adopted to aid in the diagnosis of antibody-mediated rejection (AMR), yet it remains unclear whether or not to assess all patients routinely and with what frequency/duration. In this study we sought to evaluate the utility of routine C4d immunostaining in the first year after pediatric and young adult HTx.
We reviewed pre-transplant alloantibody and clinical data, including serial EMB reports, on all 51 patients who received HTx at our center since we instituted routine C4d staining of all first-year EMBs. C4d was considered positive if diffuse capillary staining (≥2(+)) was present. Rare/focal capillary staining or absence of staining was considered negative.
Twenty-six of 406 first-year EMBs (6%) were C4d(+) in 6 (12%) patients. Sixty-five percent of all C4d(+) EMBs occurred by 30 days post-transplant. Five of 6 patients had pre-transplant donor-specific antibody (DSA)≥4,000 MFI. The sixth patient had neither pre-transplant anti-HLA antibodies nor a positive donor-specific cytotoxicity crossmatch (DSXM), but there was clinical concern for AMR. Among the entire cohort, 5 of 10 patients with pre-transplant DSA≥4,000 MFI and/or a positive DSXM were C4d(+) compared with only 1 of 41 without (50% vs 2%; p = 0.001).
In the first year after HTx, C4d(+) occurred early and only in children and young adults with pre-transplant DSA or with clinical suspicion of AMR. Although our data suggest that assessment limited to the first 90 days post-transplant in patients with pre-transplant DSA≥4,000 MFI may be appropriate in the absence of clinical concern for AMR, further research is needed to determine the optimum strategy for post-transplant surveillance.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2013; 32(1):92-7. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Allosensitization is associated with inferior waitlist outcomes in pediatric heart transplant candidates, presumably because of the requirement for a negative prospective crossmatch. However, there are no reports of heart transplant candidate outcomes according to prospective crossmatch requirements. METHODS: We analyzed data on all children listed for isolated heart transplantation from 1995 to 2009 in the USA according to prospective crossmatch requirement (PXMR). Primary objectives were to describe the prevalence of PXMR at and during listing and to compare waitlist and post-transplant survival for patients based on PXMR. Patients with a PXMR during listing include those with a PXMR at the time of listing as well as those who were designated by the listing center as needing a prospective crossmatch at some point after being placed onto the waitlist. RESULTS: Among 6,343 listed children, 7.7% had a requirement for a prospective crossmatch at the time of listing and 11.8% had a requirement for a prospective crossmatch during listing. After controlling for risk factors associated with inferior survival, PXMR at listing was associated with increased waitlist mortality (HR 1.32, 95% CI 1.10 to 1.56; p = 0.003). Recipients with a PXMR during listing more commonly had a positive DSXM (22.1% vs 10.3%, p < 0.0001), as did recipients who carried a PXMR throughout listing (21.7% vs 11.3%, p = 0.004). However, there was no significant difference in post-transplant survival on the basis of a PXMR during listing (HR 1.04, 95% CI 0.87 to 1.25; p = 0.67). Nearly 30% of recipients with a PXMR during listing had a peak pre-transplant PRA≤10%. CONCLUSIONS: PXMR increases the likelihood of death while awaiting, but not after, pediatric heart transplantation. Further study is necessary to understand how PXMR is applied, and changes, after listing for pediatric heart transplantation.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 11/2012; · 3.54 Impact Factor
-
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2012; 31(10):1143-4. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Thrombosis is a serious complication of heart failure for which available data on pediatric patients are scarce. This report describes the frequency and risk factors of clinically significant thrombosis (CST) for children awaiting transplantation. A retrospective study analyzed a cohort of heart recipients with CST, defined by the presence of intracardiac thrombus by imaging, explant pathology, or symptomatic clinical event. Among the 123 patients in the study, 56 % were male and 44 % had congenital heart disease. The median age at transplantation was 6.6 years (range 0-30 years). The prevalence of CST was 12.2 % (15/123), and its incidence was 32.7 events per 100 patient-years. The thromboembolic event frequencies were 2.4 % and 6.5 events per 100 patient-years. The median interval from listing to CST was eight days (range 0-113 days). The median wait-list duration was 31 days (range 8-169 days) in the CST group versus 51 days (range 0-1,743 days) in the non-CST group. Inpatient status was statistically associated with CST (14 of 15 subjects were inpatients, p = 0.03). Inotropic support (p = 0.068) and United Network for Organ Sharing (UNOS) status 1 (p = 0.061) approached significance. Clinically significant thrombosis was common in this end-stage heart failure population. Until randomized clinical trial data are available, it may be reasonable to consider anticoagulation for children admitted with decompensated heart failure and listed as UNOS status 1.
Pediatric Cardiology 08/2012; · 1.30 Impact Factor
-
Steven A Webber,
Steven E Lipshultz,
Lynn A Sleeper,
Minmin Lu,
James D Wilkinson,
Linda J Addonizio,
Charles E Canter,
Steven D Colan,
Melanie D Everitt,
John Lynn Jefferies,
Paul F Kantor,
Jacqueline M Lamour,
Renee Margossian,
Elfriede Pahl,
Paolo G Rusconi,
Jeffrey A Towbin
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Restrictive cardiomyopathy (RCM) has been associated with poor prognosis in childhood. The goal of the present analysis was to use the Pediatric Cardiomyopathy Registry to analyze outcomes of childhood RCM, with a focus on the impact of phenotype comparing pure RCM with cases that have additional features of hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We analyzed the Pediatric Cardiomyopathy Registry database (1990-2008; N=3375) for cases of RCM. Cases were defined as pure when RCM was the only assigned diagnosis. Additional documentation of HCM at any time was used as the criterion for RCM/HCM phenotype. RCM accounted for 4.5% of cases of cardiomyopathy. In 101 (66%), pure RCM was diagnosed; in 51 (34%), there was a mixed phenotype. Age at diagnosis was not different between groups, but 10% of the pure RCM group was diagnosed in infancy versus 24% of the RCM/HCM group. Freedom from death was comparable between groups with 1-, 2-, and 5-year survival of RCM 82%, 80%, and 68% versus RCM/HCM 77%, 74%, and 68%. Transplant-free survival was 48%, 34%, and 22% and 65%, 53%, and 43%, respectively (P=0.011). Independent risk factors at diagnosis for lower transplant-free survival were heart failure (hazard ratio 2.20, P=0.005), lower fractional shortening z score (hazard ratio 1.12 per 1 SD decrease in z score, P=0.014), and higher posterior wall thickness in the RCM/HCM group only (hazard ratio 1.32, P<0.001). Overall, outcomes were worse than for all other forms of cardiomyopathy. CONCLUSIONS: Transplant-free survival is poor for RCM in childhood. Survival is independent of phenotype; however, the RCM/HCM phenotype has significantly better transplant-free survival. CLINICAL TRIALS REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00005391.
Circulation 07/2012; 126(10):1237-1244. · 14.74 Impact Factor
-
Brian Feingold,
Maria M Brooks,
Adriana Zeevi,
Erin L Ohmann,
Gilbert J Burckart,
Robert E Ferrell,
Richard Chinnock,
Charles Canter,
Linda Addonizio,
Daniel Bernstein,
James K Kirklin,
David C Naftel, Steven A Webber
[show abstract]
[hide abstract]
ABSTRACT: Common genetic variations influence rejection, infection, drug metabolism, and side effect profiles after pediatric heart transplantation. Reports in adults suggest that genetic background may influence post-transplant renal function. In this multicenter study, we investigated the association of genetic polymorphisms (GPs) in a panel of candidate genes on renal function in 453 pediatric heart transplant recipients.
We performed genotyping for functional GPs in 19 candidate genes. Renal function was determined annually after transplantation by calculation of the estimated glomerular filtration rate (eGFR). Mixed-effects and Cox proportional hazard models were used to assess recipient characteristics and the effect of GPs on longitudinal eGFR and time to eGFR < 60 mL/min/1.73m(2).
Mean age at transplantation was 6.2 ± 6.1 years. Mean follow-up was 5.1 ± 2.5 years. Older age at transplant and black race were independently associated with post-transplant renal dysfunction. Univariate analyses showed FASL (C-843T) T allele (p = 0.014) and HO-1 (A326G) G allele (p = 0.0017) were associated with decreased renal function. After adjusting for age and race, these associations were attenuated (FASL, p = 0.075; HO-1, p = 0.053). We found no associations of other GPs with post-transplant renal function, including GPs in TGFβ1, CYP3A5, ABCB1, and ACE.
In this multicenter, large, sample of pediatric heart transplant recipients, we found no strong associations between GPs in 19 candidate genes and post-transplant renal function. Our findings contradict reported associations of CYP3A5 and TGFβ1 with renal function and suggest that genotyping for these GPs will not facilitate individualized immunosuppression for the purpose of protecting renal function after pediatric heart transplantation.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 07/2012; 31(9):1003-8. · 3.54 Impact Factor
-
Elfriede Pahl,
Lynn A Sleeper,
Charles E Canter,
Daphne T Hsu,
Minmin Lu, Steven A Webber,
Steven D Colan,
Paul F Kantor,
Melanie D Everitt,
Jeffrey A Towbin,
John L Jefferies,
Beth D Kaufman,
James D Wilkinson,
Steven E Lipshultz
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to establish the incidence of and risk factors for sudden cardiac death (SCD) in pediatric dilated cardiomyopathy (DCM).
The incidence of SCD in children with DCM is unknown. The ability to predict patients at high risk of SCD will help to define who may benefit most from implantable cardioverter-defibrillators.
The cohort was 1,803 children in the PCMR (Pediatric Cardiomyopathy Registry) with a diagnosis of DCM from 1990 to 2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using Classification and Regression Tree methodology.
The 5-year incidence rates were 29% for heart transplantation, 12.1% non-SCD, 4.0% death from unknown cause, and 2.4% for SCD. Of 280 deaths, 35 were SCD, and the cause was unknown for 56. The 5-year incidence rate for SCD incorporating a subset of the unknown deaths is 3%. Patients receiving antiarrhythmic medication were at higher risk of SCD (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.3, p = 0.025). A risk stratification model based on most recent echocardiographic values had 86% sensitivity and 57% specificity. Thirty of 35 SCDs occurred in patients who met all these criteria: left ventricular (LV) end-systolic dimension z-score >2.6, age at diagnosis younger than 14.3 years, and the LV posterior wall thickness to end-diastolic dimension ratio <0.14. Sex, ethnicity, cause of DCM, and family history were not associated with SCD.
The 5-year incidence rate of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included age at diagnosis younger than 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for implantable cardioverter-defibrillator placement.
Journal of the American College of Cardiology 02/2012; 59(6):607-15. · 14.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Post-transplantation lymphoproliferative disorders (PTLD) are life-threatening complications of organ transplantation caused by EBV infection and the use of chronic immunosuppression. While T-cell impairment is known to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of NK cells is still under investigation. Here, we have characterized NK-cell phenotype and function in peripheral blood from asymptomatic pediatric thoracic transplant patients, patients with PTLD, and healthy controls. Overall, asymptomatic pediatric solid organ transplant (Tx) patients presented significant expansion of the CD56(bright) CD16(±) subset and displayed effective NK-cell function, while PTLD patients accumulated CD56(dim) CD16(-) and CD56(-) CD16(+) NK-cell subsets. In addition, NK cells from PTLD patients down-regulated NKp46 and NKG2D, and significantly up-regulated PD-1. These phenotypic changes were associated with NK functional impairment, resembling cellular exhaustion. Disrupting PD-1 inhibitory pathway improved IFN-γ release, but did not enhance cytotoxicity in PTLD patients, suggesting that these defects were partially PD-1 independent. Our results indicate the important role of NK cells during EBV surveillance post-transplantation, with implications for the immunopathogenesis of EBV complications, and suggest that monitoring NK cells in transplant patients may hold clinical value.
European Journal of Immunology 11/2011; 42(2):541-50. · 5.10 Impact Factor
-
Pediatric Critical Care Medicine 11/2011; 12(6):683-4. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 2005 ISHLT rejection grading system merged grades 1A, 1B, and 2 into a single grade (1R) assuming equivalent prognostic significance. We hypothesized that recurrent 1B ACR is associated with adverse outcomes. Data on all heart transplant recipients at our center from 1990 to 2007 were reviewed. Patients were excluded if they had more than one grade ≥ 3A/2R biopsy in the first six wk or any grade ≥ 3A/2R biopsies during the first year thereafter. Patients with ≥ 2 grade 1B biopsies from six wk to one yr were classified as "recurrent 1B." Outcomes were freedom from late (greater than one yr) ACR (grade ≥ 3A/2R), CAD, retransplantation/death, and a composite end-point. Sixty-two patients (53 non-recurrent 1B, nine recurrent 1B) met inclusion criteria. In univariate analyses, recurrent 1B status was associated with decreased freedom from late ACR (p < 0.001), CAD (p = 0.004), and the composite outcome (p < 0.001). There was no difference in freedom from retransplantation/death (p = 0.48). After controlling for demographic differences between the groups, recurrent 1B status was independently associated with late ACR (HR 5.90; p = 0.002) and the composite outcome (HR 4.52; p = 0.002). These data suggest that further study of the impact of removal of the 1B classification from the ISHLT grading scheme is warranted.
Pediatric Transplantation 09/2011; 15(6):589-93. · 1.48 Impact Factor
-
Jorge A Alvarez,
E John Orav,
James D Wilkinson,
Lora E Fleming,
David J Lee,
Lynn A Sleeper,
Paolo G Rusconi,
Steven D Colan,
Daphne T Hsu,
Charles E Canter, Steven A Webber,
Gerald F Cox,
John L Jefferies,
Jeffrey A Towbin,
Steven E Lipshultz
[show abstract]
[hide abstract]
ABSTRACT: Pediatric dilated cardiomyopathy (DCM) is the leading indication for heart transplantation after 1 year of age. Risk factors by etiology at clinical presentation have not been determined separately for death and transplantation in population-based studies. Competing risks analysis may inform patient prioritization for transplantation listing.
The Pediatric Cardiomyopathy Registry enrolled 1731 children diagnosed with DCM from 1990 to 2007. Etiologic, demographic, and echocardiographic data collected at diagnosis were analyzed with competing risks methods stratified by DCM etiology to identify predictors of death and transplantation. For idiopathic DCM (n=1192), diagnosis after 6 years of age, congestive heart failure, and lower left ventricular (LV) fractional shortening z score were independently associated with both death and transplantation equally. In contrast, increased LV end-diastolic dimension z score was associated only with transplantation, whereas lower height-for-age z score was associated only with death. For neuromuscular disease (n=139), lower LV fractional shortening was associated equally with both end points, but increased LV end-diastolic dimension was associated only with transplantation. The risks of death and transplantation were increased equally for older age at diagnosis, congestive heart failure, and increased LV end-diastolic dimension among those with myocarditis (n=272) and for congestive heart failure and decreased LV fractional shortening among those with familial DCM (n=79).
Risk factors for death and transplantation in children varied by DCM etiology. For idiopathic DCM, increased LV end-diastolic dimension was associated with increased transplantation risk but not mortality. Conversely, short stature was significantly related to death but not transplantation. These findings may present an opportunity to improve the transplantation selection algorithm.
Circulation 08/2011; 124(7):814-23. · 14.74 Impact Factor
-
Diana M Girnita,
Erin L Ohmann,
Maria M Brooks, Steven A Webber,
Gilbert J Burckart,
Robert E Ferrell,
Sarangarajan Ranganathan,
Richard Chinnock,
Charles Canter,
Linda Addonizio,
Daniel Bernstein,
James K Kirklin,
David C Naftel,
Adriana Zeevi
[show abstract]
[hide abstract]
ABSTRACT: Rejection with hemodynamic compromise (RHC) is associated with high mortality in heart recipients. This study investigates the association between genetic polymorphisms and RHC in pediatric heart recipients.
Data from 532 pediatric heart recipients from six centers in the Pediatric Heart Transplant Study were analyzed for time to RHC by recipient race, age at transplantation, and genotype at 13 genetic polymorphisms (TNF-α A-308G, IL-6 G-174C, INF-γ T+874A, IL-10 G-1082A, C-819T, and C-592A; FAS A-670G, FASL C-843T, and ACE I/D; and VEGF A-2578C, C-1451T, C+405G, and -2549 I/D).
RHC occurred in 126 (23.7%) patients during the study period. Adjusting for age and race, IL-10 G-1082A, FAS A-670G, and ACE I/D genotypes were associated with RHC. IL-10 G-1082A GG genotype was associated with decreased risk of RHC with an adjusted hazard ratio (HR) of 0.49 (95% confidence interval [CI], 0.27-0.90; P=0.020). FAS A-670G AA genotype was associated with increased risk of RHC with an adjusted HR of 1.84 (95% CI, 1.25-2.69; P=0.002). ACE II genotype was associated with decreased risk of RHC with an adjusted HR of 0.58 (95% CI, 0.36-0.95; P=0.031).
Recipients with a high anti-inflammatory and immune-regulatory genetic profile (high interleukin-10) were protected from RHC. Conversely, recipients with a pro-apoptotic genetic profile (high Fas) or high angiotensin-1-converting enzyme producing genotype were at increased risk of RHC. This represents progress toward understanding the genetic risk factors of posttransplantation outcomes in pediatric heart recipients.
Transplantation 06/2011; 91(12):1326-32. · 4.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Failure to develop antibodies to nonself A and B blood group antigens is well described after infant ABO-incompatible heart transplantation and suggests that exposure to incompatible ABO antigens early in life may lead to tolerance rather than immunogenicity. If this finding is also true following ABO-incompatible cryopreserved homograft implantation, then such patients who require transplantation may be able to accept certain ABO-incompatible organs. In this study, we measured anti-A and -B antibody titers (isohemagglutinins) and allosensitization to human leukocyte antigens (HLA) in 21 patients after homograft placement (12 of whom were <1 year of age at initial homograft exposure) in childhood. We also examined homograft explant specimens for endothelial preservation and expression of HLA and A and B blood group antigens. We observed no differences in isohemagglutinins between patients who received ABO-incompatible versus ABO-compatible homografts. Allosensitization to HLA was present in 88% of patients (9 of 9 ABO-incompatible recipients and 5 of 7 ABO-compatible recipients). In 7 homograft explant specimens (median implant duration 10.1 years), the vasa vasorum endothelium was intact with ABO blood group antigen expression on 3 of 5 non-O homografts. These data suggest that tolerance to incompatible A and B blood group antigens does not occur following placement of ABO-incompatible homografts in childhood.
Human immunology 06/2011; 72(10):835-40. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Serial EBV load monitoring of clinically asymptomatic pediatric thoracic organ transplant patients has identified three groups of children who exhibit undetectable (<100 copies/ml), chronic low (100-16,000 copies/ml), or chronic high (>16,000 copies/ml) EBV loads in peripheral blood. Chronic high EBV load patients have a 45% rate of progression to late-onset posttransplant lymphoproliferative disorders. In this article, we report that asymptomatic patients carrying EBV loads (low and high) expressed increased frequencies of EBV-specific CD8(+) T cells, as compared with patients with undetectable EBV loads. Although patients with low viral load displayed EBV-specific CD8(+) T cells with moderate signs of activation (CD38(+/-)/CD127(+/-)), programmed death 1 upregulation and effective IFN-γ secretion, high EBV load carriers showed significant CD38(+) upregulation, features of cellular exhaustion (programmed death 1(+)/CD127(-)) accompanied by a decline in IFN-γ release. Immunopolarization of EBV-specific CD8(+) T cells was skewed from the expected type 1 (IFN-γ) toward type 0 (IFN-γ/IL-5) in patients, and Tr1 (IL-10) in high load carriers. These results indicate the importance of chronic EBV load and of the levels of antigenic pressure in shaping EBV-specific memory CD8(+) T cells. Concomitant phenotypic and functional EBV monitoring is critical for identifying the complex "functional" versus "exhausted" signature of EBV-specific CD8(+) T cells, with implications for immunologic monitoring in the clinic.
The Journal of Immunology 04/2011; 186(10):5854-62. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: CONTEXT: Characteristic adolescent risk-taking behavior, including nonadherence with prescribed medications, can be life-threatening for transplant recipients. Suggestions for managing nonadherence in teen recipients include providing them and their parents with adequate information about medications, talking with and listening to pediatric recipients about problems with the comprehensive regimen, and encouraging age-appropriate responsibility for maintaining health. OBJECTIVE: The clinical goal of this project was to develop a structured age-appropriate educational program to prepare pediatric transplant recipients and their families for the patient's life as a responsible, independent individual. Our primary research goal was to assess patients' and parents' knowledge about critical aspects of heart transplantation and the treatment regimen with brief questionnaires before and after they received the educational materials from their primary nurse coordinator. DESIGN, SETTING, PARTICIPANTS: This descriptive pre-post test study was done to assess the effectiveness of an innovative family-centered educational program among 20 pediatric heart transplant recipients and their parents at Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center. MAIN OUTCOME MEASURE, RESULTS: Percentage change in children's scores on questionnaires given before and after the educational intervention ranged from -8% to 300% (mean, 64.1%). Percentage change in scores from before to after for parents ranged from -19% to 53.8% (mean, 7.2%).
Progress in transplantation (Aliso Viejo, Calif.) 03/2011; 21(1):61-6. · 1.03 Impact Factor
-
Erin L Ohmann,
Maria M Brooks, Steven A Webber,
Diana M Girnita,
Robert E Ferrell,
Gilbert J Burckart,
Richard Chinnock,
Charles Canter,
Linda Addonizio,
Daniel Bernstein,
James K Kirklin,
David C Naftel,
Adriana Zeevi
[show abstract]
[hide abstract]
ABSTRACT: Late infections are common causes of morbidity and mortality after pediatric heart transplantation. In this multicenter study from 6 centers, we investigated the association between genetic polymorphisms (GPs) in immune response genes and late post-transplantation infections in 524 patients.
Late infection was defined as a clinical infectious process occurring >60 days after transplantation and requiring hospitalization, intravenous antimicrobial therapy, or a life-threatening infection requiring oral therapy. All patients provided a blood sample for GP analyses of 18 GPs in cytokine, growth factor, and effector molecule genes by single specific primer-polymerase chain reaction and/or sequencing. Significant associations in univariable analyses were tested in multivariable Cox regression models.
Late infection was common, with 48.7% of patients experiencing ≥ 1 late infection, 25.2% had ≥ 1 late bacterial infection, and 30.5% had ≥ 1 late viral infection. Older age at transplantation was a protective factor for late infection, both bacterial and viral (hazard ratio [HR] 0.89-0.92 per 1-year age increase, p < 0.001). Adjusting for age, race, and transplant etiology, late bacterial infection was associated with HMOX1 A+326G AG and GG genotypes (HR, 2.41, 95% confidence interval [CI] 1.35-4.30; p = 0.003) and GZMB A-295G AA genotype (HR, 1.47; 95% CI; 1.03-2.1; p = 0.036). Late viral infection was associated with FAS A-670G GG genotype (HR, 1.42; 95% CI, 1.00-2.00; p = 0.050) in the adjusted model and with CTLA4 A+49G AA and AG genotypes (HR, 1.49; 95% CI, 1.02-2.19; p = 0.041) in univariable analysis.
We found an association between late bacterial infection and GP of HMOX1, which may control macrophage activation. A weaker association was also found between late viral infection and GP of CTLA4, a regulator of T-cell activation. This represents progress toward understanding the clinical and genetic risk factors of outcomes after transplantation.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2010; 29(12):1342-51. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: MMF, the most commonly used adjuvant immunosuppressant in pediatric heart transplantation, has frequent GI adverse events. SNPs in inosine 5'-monophosphate dehydrogenase I (IMPDH1) may contribute to MMF GI intolerance. Phased haplotypes may have more utility than individual SNPs in candidate gene association studies for complex traits. This study defined common IMPDH1 haplotypes and investigated whether these haplotypes influence MMF GI intolerance in 59 pediatric heart recipients. Genotypes were assessed by Taqman analysis of IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294, and rs2228075, and haplotypes were inferred using Arlequin 3.01 software. GI intolerance was defined as diarrhea, vomiting, nausea, or abdominal pain requiring MMF dose holding for > 48 h or MMF discontinuation. GI intolerance occurred in 21 patients (35.6%). Ten IMPDH1 haplotypes were identified in this population. In univariable analyses, one haplotype was strongly associated with MMF GI intolerance with 59.1% of carriers of this haplotype experiencing MMF GI intolerance compared to 21.6% of non-carriers (p = 0.005). In this study, we identify a common IMPDH1 haplotype associated with MMF GI intolerance in a population of pediatric heart transplant patients. This haplotype of interest did not demonstrate stronger association with MMF GI intolerance than an individual IMPDH1 SNP.
Pediatric Transplantation 11/2010; 14(7):891-5. · 1.48 Impact Factor
-
Susan R Foerster,
Charles E Canter,
Amy Cinar,
Lynn A Sleeper, Steven A Webber,
Elfriede Pahl,
Paul F Kantor,
Jorge A Alvarez,
Steven D Colan,
John L Jefferies,
Jacqueline M Lamour,
Renee Margossian,
Jane E Messere,
Paolo G Rusconi,
Robert E Shaddy,
Jeffrey A Towbin,
James D Wilkinson,
Steven E Lipshultz
[show abstract]
[hide abstract]
ABSTRACT: Myocarditis is a cause of a new-onset dilated cardiomyopathy phenotype in children, with small studies reporting high rates of recovery of left ventricular (LV) function.
The presenting characteristics and outcomes of children with myocarditis diagnosed clinically and with biopsy confirmation (n=119) or with probable myocarditis diagnosed clinically or by biopsy alone (n=253) were compared with children with idiopathic dilated cardiomyopathy (n=1123). Characteristics at presentation were assessed as possible predictors of outcomes. The distributions of time to death, transplantation, and echocardiographic normalization in the biopsy-confirmed myocarditis and probable myocarditis groups did not differ (P≥0.5), but both groups differed significantly from the idiopathic dilated cardiomyopathy group (all P≤0.003). In children with myocarditis, lower LV fractional shortening z-score at presentation predicted greater mortality (hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98; P=0.03) and greater LV posterior wall thickness predicted transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02 to 1.35; P=0.03). In those with decreased LV fractional shortening at presentation, independent predictors of echocardiographic normalization were presentation with an LV end-diastolic dimension z-score >2 (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58; P<0.001) and greater septal wall thickness (hazard ratio, 1.16; 95% confidence interval, 1.01 to 1.34; P=0.04).
Children with biopsy-confirmed or probable myocarditis had similar proportions of death, transplantation, and echocardiographic normalization 3 years after presentation and better outcomes than those of children with idiopathic dilated cardiomyopathy. In children with myocarditis who had impaired LV ejection at presentation, rates of echocardiographic normalization were greater in those without LV dilation and in those with greater septal wall thickness at presentation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005391.
Circulation Heart Failure 11/2010; 3(6):689-97. · 6.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OPINION STATEMENT: Outcomes following cardiac transplantation in childhood continue to improve. Advances in immunosuppressive therapy over the past two decades likely have contributed to this trend. The evolution in the management of immunosuppression in children has been based on clinical experience rather than on evidence-based medicine; indeed, there have been no pivotal randomized controlled trials of any form of immunosuppression in pediatric thoracic transplantation. Important trends in immunosuppressive therapy and transplant outcomes have been obtained from large transplant registries. Several trends have been identified since the last review of this topic in this journal. First, there is increased knowledge of the pharmacodynamics and pharmacokinetics of immunosuppressive drugs in children, with notable advances in the field of pharmacogenomics. These studies help explain individual variations in drug exposure, efficacy, and adverse events. They also help explain racial and ethnic variations in drug metabolism and efficacy. Second, there have been clear trends in the use of specific immunosuppressive medications. Use of induction therapy, especially polyclonal T cell-depleting antibody preparations, has increased significantly in recent years. The calcineurin inhibitor (CNI) tacrolimus is being used as the cornerstone of maintenance therapy in lieu of cyclosporine in more and more centers. Mounting evidence suggests that use of adjunctive agents (notably mycophenolate mofetil [MMF]) may improve outcomes, including survival, suggesting that monotherapy with CNIs is not the ideal maintenance therapy. Despite its increased cost, MMF has largely replaced azathioprine as the adjunctive agent of choice. Inhibitors of the mammalian target of rapamycin (i.e., sirolimus and everolimus) have not yet assumed a major place as adjunctive agents, as their safety and efficacy have not been well established in children. With the improvements in immunosuppressive therapy, the justification for routine corticosteroid use is far from clear, and many centers have shown excellent outcomes with complete steroid avoidance. Third, there is increasing interest in the importance of anti-HLA antibodies as important risk factors for adverse graft and patient outcomes. This is generating intense interest in treatments that target B cells and plasma cells. Finally, there is increasing realization that the "one size fits all" approach to immunosuppressive therapy is an obsolete concept and that the ultimate goal is to tailor immunosuppressive therapy to the needs of the individual patient. The development of reliable biomarkers of the patient's immune response to the allograft will be essential for optimal individualized immunosuppressive management.
Current Treatment Options in Cardiovascular Medicine 10/2010; 12(5):489-502.
-
James D Wilkinson,
David C Landy,
Steven D Colan,
Jeffrey A Towbin,
Lynn A Sleeper,
E John Orav,
Gerald F Cox,
Charles E Canter,
Daphne T Hsu, Steven A Webber,
Steven E Lipshultz
[show abstract]
[hide abstract]
ABSTRACT: Cardiomyopathy is a serious disorder of the heart muscle and, although rare, is a common cause of heart failure in children and the most common cause for heart transplantation in children older than 1 year of age. Funded by the National Heart Lung and Blood Institute since 1994, the Pediatric Cardiomyopathy Registry (PCMR) has followed more than 3500 North American children with cardiomyopathy. Early analyses determined estimates for the incidence of pediatric cardiomyopathy (1.13 cases per 100,000 children per year), risk factors for cardiomyopathy (age <1 year, male sex, black race, and living in New England as opposed to the central southwestern states), the prevalence of heart failure at diagnosis (6%-84% depending on cause), and 10-year survival (29%-94% depending on cause). More recent analyses explored cause-specific functional status, survival and transplant outcomes, and risk factors in greater detail. For many topics these analyses are based on the largest and best-documented samples of children with disease such as the muscular dystrophies, mitochondrial disorders, and Noonan syndrome. Data from the PCMR continue to provide valuable information that guides clinical management and the use of life-saving therapies, such as cardiac transplantation and approaches to treating heart failure, and prepares children, their families, and their caregivers to deal with this serious condition.
Heart Failure Clinics 10/2010; 6(4):401-13, vii.
