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Résumé Objectifs La pandémie de COVID-19 a influé sur la santé mentale de la population. Les familles des enfants qui ont des vulnérabilités en matière de santé ont été démesurément touchées par les politiques liées à la pandémie et les perturbations aux services, car elles s’appuient beaucoup sur le système de soins de santé et de services sociaux. Les chercheurs ont établi les répercussions de la pandémie de COVID-19 sur les enfants ayant des vulnérabilités en matière de santé physique et des incapacités, les familles et les professionnels de la santé. Méthodologie Des enfants ayant diverses vulnérabilités en matière de santé (transplantation cardiaque, affections respiratoires, anémie falciforme, trouble du spectre de l’autisme, troubles de santé mentale et approche de la fin de vie en raison d’une série de causes sous-jacentes), leurs parents et leurs professionnels de la santé ont participé à des entrevues semi-structurées. Les chercheurs ont utilisé des méthodes d’analyse qualitative et en ont extrait les thèmes liés aux effets et les recommandations en vue d’améliorer la pratique. Résultats Au total, 262 participants (30 enfants, 76 parents, 156 professionnels de la santé) ont été interviewés. Les enfants ont décrit leur solitude et leur isolement, les parents, leur épuisement, et les professionnels de la santé, la pression ressentie et un sentiment de détresse morale. Les thèmes reflétaient les effets de la pandémie sur la santé mentale des enfants, des familles et des professionnels de la santé, de même que les ressources insuffisantes pour soutenir la santé mentale, les influences organisationnelles et politiques qui ont façonné la prestation des services et les recommandations pour améliorer la prestation de ces services. Conclusion Les restrictions sanitaires imposées par la pandémie et les modifications aux soins ont eu de profondes répercussions sur la santé mentale des enfants qui ont des vulnérabilités en matière de santé, les familles et les professionnels de la santé. Les recommandations incluent la rédaction et l’adoption d’information ciblée sur la pandémie et la mise en œuvre de services de soutien en santé mentale. Ces résultats amplifient la nécessité de renforcer les capacités, y compris des stratégies proactives et la planification de mesures d’atténuation du risque dans l’éventualité d’une future pandémie.

Objectives The COVID-19 pandemic has impacted mental health at a population level. Families of children with health vulnerabilities have been disproportionately affected by pandemic-related policies and service disruptions as they substantially rely on the health and social care system. We elicited the impact of the COVID-19 pandemic on children with health and disability-related vulnerabilities, their families, and their health care providers (HCPs). Methods Children with diverse health vulnerabilities (cardiac transplantation, respiratory conditions, sickle cell disease, autism spectrum disorder, mental health issues, and nearing the end of life due to a range of underlying causes), as well as their parents and HCPs, participated in semi-structured interviews. Data were analyzed using qualitative content analysis in determining themes related to impact and recommendations for practice improvement. Results A total of 262 participants (30 children, 76 parents, 156 HCPs) were interviewed. Children described loneliness and isolation; parents described feeling burnt out; and HCPs described strain and a sense of moral distress. Themes reflected mental health impacts on children, families, and HCPs, with insufficient resources to support mental health; organizational and policy influences that shaped service delivery; and recommendations to enhance service delivery. Conclusion Children with health vulnerabilities, their families and HCPs incurred profound mental health impacts due to pandemic-imposed public health restrictions and care shifts. Recommendations include the development and application of targeted pandemic information and mental health supports. These findings amplify the need for capacity building, including proactive strategies and mitigative planning in the event of a future pandemic.

BACKGROUND There are challenges in achieving and maintaining therapeutic tacrolimus levels after solid organ transplantation (SOT). The purpose of this genome-wide association study (GWAS) was to generate an integrated clinical and genetic prediction model for tacrolimus levels in pediatric SOT. METHODS In a multicenter prospective observational cohort study (2015-18), children

CD25, the alpha chain of the IL-2 receptor, is expressed on activated effector T cells that mediate immune graft damage. Induction immunosuppression is commonly used in solid organ transplantation and can include antibodies blocking CD25. However, regulatory T cells (Tregs) also rely on CD25 for their proliferation, survival, and regulatory function. Therefore, CD25-blockade may compromise Treg protective role against rejection. We analysed in vitro the effect of basiliximab (BXM) on the viability, phenotype, proliferation and cytokine production of Treg cells. We also evaluated in vivo the effect of BXM on Treg in thymectomized heart transplant children receiving BXM in comparison to patients not receiving induction therapy. Our results show that BXM reduces Treg counts and function in vitro by affecting their proliferation, Foxp3 expression, and IL-10 secretion capacity. In pediatric heart-transplant patients, we observed decreased Treg counts and a diminished Treg/Teff ratio in BXM-treated patients up to 6-month after treatment, recovering baseline values at the end of the 12-month follow up period. These results reveal that the use of BXM could produce detrimental effects on Tregs, and support the evidence suggesting that BXM induction could impair the protective role of Tregs in the period of highest incidence of acute graft rejection.

Background Ventricular assist device (VAD) therapy has become an important tool for end-stage heart failure. VAD therapy has increased survival but is associated with complications including the development of human leukocyte antigen (HLA) antibodies. We sought to determine the incidence of HLA antibody development post-VAD insertion, across the age spectrum, in patients receiving leukocyte-reduced blood products, with standardized HLA antibody detection methods and to investigate factors associated with antibody development. Methods This was a retrospective analysis of all patients who underwent durable VAD placement between 2005 and 2014. Inclusion criteria included availability of pre- and post-VAD HLA antibody results. Associations between HLA antibody development in the first-year postimplant and patient factors were explored. Results Thirty-nine adult and 25 pediatric patients made up the study cohort. Following implant, 31% and 8% of patients developed new class I and class II antibodies. The proportion of newly sensitized patients was similar in adult and pediatric patients. The class I HLA panel reactive antibody only significantly increased in adults. Pre-VAD sensitization, age, sex (pediatrics), and transfusion were not associated with the development of HLA antibodies. Conclusions In a cohort of VAD patients receiving leukocyte-reduced blood products and standardized HLA antibody testing, roughly one-third developed new class I antibodies in the first-year postimplant. Adults showed significantly increased class I panel reactive antibody following VAD support. No patient-related factors were associated with HLA antibody development. Larger prospective studies are required to validate these findings and determine the clinical impact of these antibodies following VAD insertion.

BACKGOUND: B cells contribute to chronic transplant rejection by producing donor-specific antibodies and promoting T cell response, but how these processes are regulated at the transcriptional level remains unclear. Herein, we investigate the role of transcription factor interferon regulatory factor 4 (IRF4) in controlling B cell response during chronic transplant rejection. METHODS: We generated the Irf4(gfp) reporter mice to determine IRF4 expression in B cell lineage. We then used mice with B cell-specific IRF4 deletion to define the role of IRF4 in B cell response after NP-KLH immunization or allogeneic heart transplantation. In particular, graft survival and histology, as well as B and T cell responses, were evaluated after transplantation. RESULTS: IRF4 is dynamically expressed at different stages of B cell development and is absent in germinal center (GC) B cells. However, IRF4 ablation in the B cell lineage primarily eliminates GC B cells in both naïve and NP-KLH immunized mice. In the transplantation setting, IRF4 functions intrinsically in B cells and governs allogeneic B cell responses at multiple levels, including GC B cell generation, plasma cell differentiation, donor-specific antibody production, and support of T cell response. B cell-specific IRF4 deletion combined with transient CTLA4-Ig treatment abrogates acute and chronic cardiac allograft rejection in naïve recipient mice but not in donor skin-sensitized recipients. CONCLUSIONS: B cells require IRF4 to mediate chronic transplant rejection. IRF4 ablation in B cells abrogates allogeneic B cell responses and may also inhibit the ability of B cells to prime allogenic T cells. Targeting IRF4 in B cells represents a potential therapeutic strategy for eliminating chronic transplant rejection.

Purpose Patient-reported outcome measures (PROMs) are standardized instruments used to collect data about the subjective assessment of medical care from the patient perspective. Implementing PROMs within pediatric clinical settings has gained increasing importance as health services prioritize patient-centred pediatric care. This study explores the perspectives of pediatric solid organ transplant patients, caregivers, and healthcare practitioners (HCPs) on implementing PROMs into clinical practice. Methods Qualitative description methods were used to elicit stakeholder perspectives. Semi-structured interviews were conducted across five Canadian transplant centres. Purposive sampling was used to obtain maximum variation across age, gender, and transplant program for all participants, as well as discipline for HCPs. Results The study included a total of 63 participants [patients (n = 20), caregivers (n = 22) and HCPs (n = 21)]. Nearly all participants endorsed the implementation of PROMs to enhance pediatric transplant clinical care. Three primary roles for PROMs emerged: (1) to bring a transplant patient’s overall well-being into the clinical care conversation; (2) to improve patient communication and engagement; and, (3) to inform the practice of clinical pediatric transplant care. Insights for effective implementation included completing electronic PROMs remotely and prior to clinical appointments by patients who are eight to 10 years of age or older. Conclusions This study contributes to current research that supports the use of PROMs in clinical pediatric care and guides their effective implementation into practice. Future directions include the development, usability testing, and evaluation of a proposed electronic PROM platform that will inform future research initiatives.

Like other recipients of health care services, pediatric patients and their families/caregivers have been profoundly impacted by health care shifts and broader societal restrictions associated with the COVID-19 pandemic. An online roundtable discussion was facilitated with 7 pediatric clinicians and investigators of a current study examining the impacts of COVID-19 on pediatric care at multiple Canadian sites. Discussants represented a range of pediatric specialities: developmental disability, mental health, cardiac transplantation, respiratory medicine, hematology, and palliative care. We offer the transcript of the roundtable in which discussants reflected on clinical and programmatic experiences of the pandemic, including perceived impacts on children receiving care and their families, potential opportunities for improved health care delivery, impacts on health care providers, and recommendations as we move toward easing restrictions and pandemic recovery. Discussants convey a range of considerations that may have varying relevance for pediatric specialities in terms of practice and program planning.

Purpose Socioeconomic disparities negatively impacts outcomes in heart transplantation (HTx). However, the impact of insurance status and the social construct of race in pediatric patients has not been well studied. Methods The Pediatric Heart Transplant Society registry was queried between January 1, 2000- December 31, 2019. Patients were stratified by insurance status: US government (USG), US private (USP) and Single Payer (SP, UK & Canada) and race (black, white, other). Patients with a selection of more than one race were classified as other. Outcomes after HTx were assessed by Kaplan Meier log rank test including graft survival, time to first cardiac allograft vasculopathy (CAV), rejection, hemodynamic compromised (HC) rejection, and malignancy. Results 5879 children underwent HTx with insurance status as follows: 2800 USG (48%), 2431 USP (41%) and 648 SP (11%). Race breakdown included: 4086 white, 1052 black and 936 other. At 10 years post-transplant, graft survival (65.8% USG, 72.6% USP, 77% SP, p= .0005), time to first CAV (73.5% USG, 77.7% USP, 94.6% SP, p Conclusion In this multinational analysis of pediatric HTx patients, USG was associated with worse post-HTx outcomes. When stratified by race, graft survival was worse in black patients with USG and USP insurance. Both insurance and the social construct of race contribute to worse outcomes post heart transplant and may represent disparity in access to care and other racial bias. These results highlight the importance of further work in this area.

Purpose There are limited data reporting outcomes of children with trisomy 21 undergoing heart transplantation (HTx). This project reports the waitlist and post-HTx outcomes of children with trisomy 21. Methods This is a retrospective cohort study of children with trisomy 21 listed for or who underwent HTx at 11 centers within North America and internationally. Demographic, medical, surgical, and post-HTx outcome data were collected and described. Results Twenty-one patients with trisomy 21 were listed for HTx from 1992 through 2019 (median age 8.5y, 43% male, 52% white). High-risk or failed repair of congenital heart disease was the indication for transplant in 16 (76%) patients with atrioventricular septal defect being the most common (N=12). Other diagnoses included dilated cardiomyopathy in 4 patients (secondary to anthracyclines in 2) and myocarditis in 1 patient. A total of 18 (86%) patients survived to transplant. Of this group, support at the time of transplant included inotropes (N=10, 56%), ventricular assist device (N=7, 39%), and mechanical ventilation (N=2, 11%). No patients required post-operative extracorporeal membrane oxygenation or dialysis. All centers reported the use of standard immunosuppression without alterations secondary to trisomy 21. All transplanted patients survived to hospital discharge with a median post-HTx length of stay of 19d. With a median follow-up of 2.9y, 16 (89%) patients were alive, 5 (28%) had rejection within the 1st year post-HTx, 2 (11%) developed post-transplant lymphoproliferative disorder (PTLD), and 7 (39%) were hospitalized for infection within the 1st year post-HTx. For the two post-HTx mortalities, the causes of death were 1) coronary allograft vasculopathy at 22y post-HTx and 2) multiple episodes of rejection and PTLD at 1.5y post-HTx (Figure). Conclusion Waitlist and intermediate post-HTx outcomes are acceptable in children with trisomy 21. The presence of trisomy 21 should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.

Background Glutaraldehyde (GA) treatment of allografts used for arch reconstruction prevents the immunologic sensitization that occurs with untreated allografts, but its use may cause tissue changes that predispose to recurrent obstruction. The objective was to determine whether GA treatment of allografts used in Norwood procedures increases the risk of recurrent aortic obstruction. Methods All infants who underwent a Norwood procedure between 2000 and 2015 were included. Cryopreserved pulmonary allografts were used for all arch reconstructions; starting in 2005 all were treated with GA before use. Complete follow-up was obtained, including survival, transplantation, and all repeat procedures. Competing risks analyses were used to assess for differences in aortic reintervention over time. Results Two hundred six infants (132 male) were included. There were 60 deaths and 14 transplantations; 5-year transplantation-free survival was 71.9%. GA treatment of patches (n = 142, 68.9%) was not predictive of death (hazard ratio [HR] 1.38, 95% confidence interval [CI]: 0.61 to 3.08). Fifty-five patients had at least one aortic reintervention and 31 patients (15.0%) required surgical aortic reintervention. At 1-year, freedom from all aortic reintervention was similar between patients with and without treated patches, but freedom from surgical aortic reintervention was lower in the treated group (87.6% versus 95.3%, p = 0.0256). GA treatment was not associated with the combined end point of catheter-based or surgical reintervention but was associated with specific need for surgical reintervention (HR 4.05, 95% CI: 1.19 to 13.77). Conclusions GA treatment is associated with increased late surgical aortic reintervention. The advantages of decreased sensitization with GA treatment need to be balanced against the risk of aortic reobstruction.

Heart transplantation from ABO incompatible (ABOi) donors has evolved into a progressively accepted therapy in young children. We assessed the recent practice of ABOi listing impact on waitlist and post-transplant outcomes.Using the Pediatric Heart Transplant Society registry, we compared clinical presentation, waitlist parameters, and post-transplant survival of children2 years of age listed for ABOi vs ABO compatible (ABOc) heart transplant between January 2010 and June 2018 with sub-analysis of blood group O recipients.Among 2,039 patients, ABOi listing increased significantly with time from 49% (2010) to 72% (2017). ABOi-listed patients had lower age and body surface area, and higher proportion of congenital heart disease, mechanical ventilation, and high urgency status (all p0.01). Use of mechanical circulatory support was similar between groups. Of 1,288 patients reaching transplant, 239 (18.6%) received an ABOi organ (15%-40%/year). Death while waiting, removal from the waitlist, and waitlist survival were similar between groups. Time to transplant was significantly shorter for ABOi listing in blood group O patients (p0.02), approaching significance (p = 0.057) for all blood groups. Post-transplant survival was similar except for lower survival of patients listed ABOc but transplanted ABOi. These patients showed increasing need for mechanical circulatory support and high urgency listing while waiting.In the current era, primary listing for ABOi heart transplant has become routine for the majority of children2 years old, resulting in shorter waitlist time, especially in blood group O. Post-transplant survival is similar despite ABOi-listed children still showing a higher risk profile.

Passive antibodies, maternal or transfusion-acquired, make serologic determination of pretransplant cytomegalovirus (CMV) status unreliable. We evaluated 3 assays unaffected by passive antibodies, in assignment of CMV infection status in children awaiting solid organ transplant and in controls: (1) CMV nucleic acid amplification testing (NAAT), (2) quantification of CMV-specific CD4+ T cells, and (3) quantification of CD27-CD28-CD4+ T cells. Our results highlight that CMV NAAT, from urine and oropharynx, is useful in confirming positive CMV status. Detection of CMV-specific CD4+ T cells was sensitive and specific in children >18 months but was less sensitive in children

Background Despite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults. Methods In this prospective observational cohort study, we recruited pediatric and young adult solid organ transplant, pediatric allogeneic hematopoietic stem cell transplant recipients, and matched living and deceased organ donors from 14 transplant centers across Canada. Clinical data, questionnaires, biospecimens, and pharmacy records were collected at serial time points: (1) to identify genetic and host immune factors that influence immunosuppression dose requirements across different ages and transplant types, (2) to identify viral-host interactions that increase susceptibility to Epstein-Barr virus infection, and (3) to define care processes and structures associated with medication adherence in adolescents and young adults. Results From 2015 to 2018, 1662 new and prevalent transplant recipients were screened, 1166 were recruited for the various aims, including 370 liver, 445 kidney, 277 heart, 19 lung, 19 multiple, and 36 hematopoietic stem cell transplant transplants. Twelve percent were younger than 2 years, 30% were 2 to 10 years, 42% were 10 to 18 years, and 16% were 18 to 24 years at enrollment. Nine hundred thirty-one consented to participation in aims 1 and 2 (90% consent rate), 287 to aim 3 (82% consent rate). Biospecimens collected included 898 for DNA, 276 for immunoassays, and 717 for biomarker studies. Seventy percent participants have completed follow-up; 30% are pending study completion. Conclusions The design of this national multicenter cross-organ network helped maximize recruitment of a large patient cohort for studying age and organ-related differences in immunosuppression needs that would not otherwise be feasible. Leveraging the unique clinical, biological, environmental, and behavioral characteristics of this cohort will help develop precision medicine strategies for individualizing posttransplant immunosuppression.

Background. Despite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults. Methods. In this prospective observational cohort study, we recruited pediatric and young adult solid organ transplant, pediatric allogeneic hematopoietic stem cell transplant recipients, and matched living and deceased organ donors from 14 transplant centers across Canada. Clinical data, questionnaires, biospecimens, and pharmacy records were collected at serial time points: (1) to identify genetic and host immune factors that influence immunosuppression dose requirements across different ages and transplant types, (2) to identify viral-host interactions that increase susceptibility to Epstein-Barr virus infection, and (3) to define care processes and structures associated with medication adherence in adolescents and young adults. Results. From 2015 to 2018, 1662 new and prevalent transplant recipients were screened, 1166 were recruited for the various aims, including 370 liver, 445 kidney, 277 heart, 19 lung, 19 multiple, and 36 hematopoietic stem cell transplant transplants. Twelve percent were younger than 2 years, 30% were 2 to 10 years, 42% were 10 to 18 years, and 16% were 18 to 24 years at enrollment. Nine hundred thirty-one consented to participation in aims 1 and 2 (90% consent rate), 287 to aim 3 (82% consent rate). Biospecimens collected included 898 for DNA, 276 for immunoassays, and 717 for biomarker studies. Seventy percent participants have completed follow-up; 30% are pending study completion. Conclusions. The design of this national multicenter cross-organ network helped maximize recruitment of a large patient cohort for studying age and organ-related differences in immunosuppression needs that would not otherwise be feasible. Leveraging the unique clinical, biological, environmental, and behavioral characteristics of this cohort will help develop precision medicine strategies for individualizing posttransplant immunosuppression.

Purpose ABO-incompatible (ABOi) heart transplantation (HTx) has become a standard approach for infants with low isohemagglutinin titers (ISO). ABOi HTx may also be safe for older pediatric patients with altered immune response, however, thresholds are yet to be defined. Methods Data on management, clinical course and ISO were analyzed from two patients undergoing ABOi HTx beyond infancy. Results A 4-yr old ABO-O girl with hypoplastic left heart syndrome developed refractive protein-losing enteropathy, effusions and edema shortly after Fontan palliation, in the context of AV valve regurgitation and ventricular dysfunction. She was listed for HTx and deemed high-risk due to elevated pulmonary vascular resistance, HLA sensitization (cPRA 81 %), and need for ventilatory support. Despite her age, ISO titers were only moderately high (anti-A 1:32; anti-B 1:16); she underwent ABOi HTx (donor ABO-B) with plasmapheresis, ATG and methylprednisolone induction which was expanded for rituximab and IVIG. She required temporary right ventricular support and dialysis after HTx. Immunosuppression was maintained with tacrolimus and mycophenolate mofetil (MMF), modified during the clinical course to now receiving sirolimus / MMF for the past 6 years. Her B-ISO titres never exceeded 1:2 post-transplant. She remains free of rejection and graft vasculopathy now 9.5 years post-HTx. Another 4-yr old ABO-O girl with microdeletion 22q11 syndrome, pulmonary atresia, ventricular septal defect and MAPCAs sustained coronary artery injury resulting in ventricular dysfunction, requiring ECMO followed by milrinone dependency. She was listed for HTx and was highly HLA sensitized (cPRA 92%). Desensitisation was initiated with rituximab and IVIG; her A-ISO (peak anti-A 1:128) dropped to 1:16 at which point her listing was opened to ABOi. She received an ABOi HTx (donor ABO-A) at age 5 11/12 years, not crossing donor-specific HLA antibodies, receiving plasma exchange, ATG induction and methylprednisolone. Maintenance therapy included tacrolimus and MMF. She remains free of rejection now 1.5 years post-HTx with anti-A titre never exceeding 1:4. Conclusion ABOi HTx can be performed safely in selected older pediatric patients if ISO are low even secondary to immune manipulation. This approach may offer a long-term HTx option for older children who are highly sensitized or in urgent need of transplantation.

ABO-incompatible (ABOi) heart transplantation (HTx) in young children has evolved from an experimental approach to a standard allocation option in many countries. Clinical and immunological research in ABOi transplantation has revealed insight into the immature immune system and its role in superior graft acceptance in childhood and antigen-specific tolerance.Multicenter experience has confirmed equal actuarial survival, freedom from rejection, and graft vasculopathy comparing ABOi with ABO-compatible HTx. Observations of reduced antibody production and B-cell immunity toward the donor blood group have been confirmed in long-term follow-up. Mechanisms contributing to tolerance in this setting involve the interplay between B-cells and the complement system and the development of B-cell memory. Better characterization of the ABH polysaccharide antigens has improved diagnostic methods and clinical assessment of blood group antibodies. Boundaries regarding age, immune maturity, and therapeutic interventions to extend the applicability of ABOi HTx have been explored and resulted in data that may be useful for HTx patients beyond infancy and ABOi transplantation of other organs. Tolerance of ABH antigens possibly extends to HLA response.The review provides insight into the clinical evolution of ABOi HTx and associated immunologic discoveries. Current experiences and boundaries are discussed together with recent and potential future developments for utilization in other patient and age groups.

Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD).This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival.Statin use was variable among participating centers with only 30% to 35% of patients ≥10 years of age started on a statin at1 year post-transplant. After the first year post-transplant, statin-treated children (average age at transplant 13.24 ± 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 ± 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small.Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted.

The analysis and validation of flow cytometry–based biomarkers in clinical studies are limited by the lack of standardized protocols that are reproducible across multiple centers and suitable for use with either unfractionated blood or cryopreserved PBMCs. Here we report the development of a platform that standardizes a set of flow cytometry panels across multiple centers, with high reproducibility in blood or PBMCs from either healthy subjects or patients 100 days after hematopoietic stem cell transplantation. Inter-center comparisons of replicate samples showed low variation, with interindividual variation exceeding inter-center variation for most populations (coefficients of variability 0.75). Exceptions included low-abundance populations defined by markers with indistinct expression boundaries (e.g., plasmablasts, monocyte subsets) or populations defined by markers sensitive to cryopreservation, such as CD62L and CD45RA. Automated gating pipelines were developed and validated on an independent data set, revealing high Spearman’s correlations (rs >0.9) with manual analyses. This workflow, which includes pre-formatted antibody cocktails, standardized protocols for acquisition, and validated automated analysis pipelines, can be readily implemented in multicenter clinical trials. This approach facilitates the collection of robust immune phenotyping data and comparison of data from independent studies.

The immunogenicity of standard intramuscular (IM) influenza vaccine is suboptimal in transplant recipients. Also, recent studies suggest that alloantibody may be upregulated due to vaccination. We evaluated a novel high-dose intradermal (ID) vaccine strategy. In conjunction, we assessed alloimmunity. Transplant recipients were randomized to receive IM or high-dose ID vaccine. Strain-specific serology and HLA alloantibody production was determined pre- and postimmunization. In 212 evaluable patients (105 IM, 107 ID), seroprotection to H1N1, H3N2 and B strains was 70.5%, 63.8% and 52.4% in the IM group, and 71.0%, 70.1%, 63.6% in the ID group (p=ns). Seroconversion to ≥1 antigen was 46.7% and 51.4% in the IM and ID groups respectively (p=0.49). Response was more likely in those≥6 months posttransplant (53.2% vs. 19.2%; p=0.001). Use of mycophenolate mofetil was inversely associated with vaccine response in a dose-dependent manner (p

Deutsche Forschungsgemeinschaft (Bonn, Germany) European Commission (Brussels, Belgium) National Institutes of Health/National Institute of Allergy and Infectious Diseases Primary Immunodeficiency Association (PIA; London, United Kingdom) Medical Research Council (MRC; London, United Kingdom) The Wellcome Trust (London, United Kingdom) Swedish Research Council (Stockholm, Sweden) Fondazione C. Golgi (Brescia, Italy) Swiss National Science Foundation (Bern, Switzerland) Grant Colciencias (Bogota, Colombia) NIH Jeffrey Modell Foundation (New York, NY) Intramural Research Program of the National Institutes of Health, National Library of Medicine TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. the genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. the most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the patients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P < .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation. (Blood. 2009; 113: 1967-1976) Univ Hosp Freiburg, Dept Rheumatol & Clin Immunol, Freiburg, Germany Inst Child Hlth, Mol Immunol Unit, London, England Karolinska Univ Hosp Huddinge, Karolinska Inst, Div Clin Immunol, Stockholm, Sweden Univ Brescia, Pediat Clin, Brescia, Italy Spedali Civil Brescia, Ist Med Mol Angelo Nocivelli, I-25125 Brescia, Italy Royal Free Hosp, Dept Immunol & Mol Pathol, London NW3 2QG, England UCL, London, England Allergy Asthma & Immunol Clin, Irving, TX USA Oxford Radcliffe Hosp, Nuffield Dept Med, Oxford, England Royal Victoria Infirm, Dept Immunol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England Univ Washington, Reg Med Ctr, Seattle, WA 98195 USA Childrens Hosp, Seattle, WA USA Univ Munich, Div Infect Dis & Immunol, Univ Childrens Hosp, Munich, Germany Addenbrookes Hosp, Dept Clin Immunol, Cambridge, England Universidade Federal de São Paulo, Dept Pediat, São Paulo, Brazil Univ Oslo, Natl Hosp, Internal Med Res Inst, Oslo, Norway Univ Antioquia, Grp Immunodeficiencias Primarias, Medellin, Colombia Charite Humboldt Univ, Dept Paediat Pneumol & Immunol, Berlin, Germany Univ Lausanne, Dept Biochem, Lausanne, Switzerland Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, US Dept HHS, Bethesda, MD 20894 USA Universidade Federal de São Paulo, Dept Pediat, São Paulo, Brazil Deutsche Forschungsgemeinschaft (Bonn, Germany): GR1617/3 Deutsche Forschungsgemeinschaft (Bonn, Germany): SFB620/C2 Deutsche Forschungsgemeinschaft (Bonn, Germany): SFB620/Z1 Deutsche Forschungsgemeinschaft (Bonn, Germany): SFB620/C1 European Commission (Brussels, Belgium): SP23-CT-2005-006411 European Commission (Brussels, Belgium): MEXT-CT-2006-042316 European Commission (Brussels, Belgium): HEALTH-F2-2008-201549 National Institutes of Health/National Institute of Allergy and Infectious Diseases: NO1-A130070 Fondazione C. Golgi (Brescia, Italy): PRIN2006 Grant Colciencias (Bogota, Colombia): 1115-05-16784 NIH: HD 37091 Web of Science

Coronary allograft vasculopathy is the current leading cause for late graft loss following cardiac transplantation. Its pathogenesis is multifactorial, including immune, constitutional and genetic factors, metabolism, infection, as well as potential injury from routine immunosuppressive therapy. Children represent a patient group with unique differences: their pretransplant history rarely includes ischemic heart disease and risk factors for atherosclerotic heart disease, but many are presensitized from use of allograft material during reconstructive cardiac surgeries. Compared with older children and adults, infants and young children show significantly lower rates of graft vasculopathy that may be related to the relative immaturity of their immune system. This review summarizes the current concepts of coronary allograft vasculopathy derived mainly from animal models and adult clinical observations. It provides an overview of confirmed risk factors and explains their interactions. The characteristics and unique clinical findings among pediatric transplant recipients will be explored within the context of recent, albeit limited, scientific investigations.

Specific B-cell tolerance toward donor blood group antigens develops in infants after ABO-incompatible heart transplantation, whereas their immune response toward protein antigens such as HLA has not been investigated. We assessed de novo HLA-antibodies in 122 patients after pediatric thoracic transplantation (28 ABO-incompatible) and 36 controls. Median age at transplantation was 1.7 years (1 day to 17.8 year) and samples were collected at median 3.48 years after transplantation. Antibodies were detected against HLA-class I in 21 patients (17.2%), class II in 18 (14.8%) and against both classes in 10 (8.2%). Using single-antigen beads, donor-specific antibodies (DSAs) were identified in six patients (all class II, one additional class I). Patients with DSAs were significantly older at time of transplantation. In patients who had undergone pretransplant cardiac surgeries, class II antibodies were more frequent, although use of homografts or mechanical heart support had no influence. DSAs were absent in ABO-incompatible recipients and class II antibodies were significantly less frequent than in children with ABO-compatible transplants. This difference was present also when comparing only children transplanted below 2 years of age. Therefore, tolerance toward the donor blood group appears to be associated with an altered response to HLA beyond age-related effects.

Summary We investigated whether children after heart- (HTx) or heart–lung transplantation (HLTx) show protective antibody levels against recommended vaccinations, whether vaccination schedules are completed and which factors influence serologic immunity. We performed a cross sectional ELISA – quantification of specific antibodies in 46 patients after pediatric thoracic Tx. Findings were correlated to vaccination history, age at Tx, clinical course and immunosuppressive regimen. We found protective antibody levels against diphtheria in 74% of patients, against tetanus in 22%, against Haemophilus influenzae type b in 30% and against Streptococcus pneumoniae in 59%. Antibody concentrations against live attenuated vaccines were significantly lower in children transplanted in the first 2 years of life. Antibodies were absent for measles in 55% of late – and 81% of early transplanted children, for mumps in 66%/94%, for rubella in 30%/56% and for Varicella in 34%/63%. We found significant correlation of low antibody concentrations and age at Tx. Patients without protective antibody concentrations had significantly longer use of steroids. Vaccination schedules were incomplete or delayed in the majority of patients associated with more days in hospital pre-Tx. Our study shows that closer adherence to pretransplantation vaccination schedules and also post-transplantation monitoring of antibody levels are required in transplant patients.

Background Quantitative measurement of DNA levels of persistent highly prevalent viral infections such as Torque Teno Virus (TTV) and Epstein–Barr Virus (EBV) that are highly dependent on T-cell responses for control have been proposed as possible biomarkers of “net immunosuppression.” Methods We examined factors influencing TTV in 51 adult patients awaiting solid organ transplantation (15 kidney, 15 liver/small bowel, 10 heart, 11 lung) and 51 healthy age- and sex-matched controls. Samples from all patients were tested for TTV DNA (plasma) using quantitative nucleic acid testing (QNAT), EBV and cytomegalovirus (CMV) serology, CMV DNA (QNAT of plasma, urine, saliva), and EBV DNA (QNAT of whole blood [WB], saliva). Effects of age, sex, organ, CMV serology, and EBV DNA on TTV DNA were explored in univariate and multivariate models. Results Patients and controls were well-matched for age (median 48.4 vs. 49.2 years), sex 64.7% M, both CMV seropositivity (45.1% vs. 51%) and EBV seropositivity (94.1% vs. 98.0%), and detection of EBV DNA in saliva (52.9% vs. 50.0%) and WB (28.6% vs. 16.3%). TTV DNA was detected more frequently and at higher levels (Figure 1) in patients (86.3%) vs. controls (66.7%). TTV DNA plasma levels were age-dependent for patients but not controls (50 years, P = 0.021), and were only higher in patients >50 years vs. controls (P = 0.003). Only two patients and no controls had CMV DNA detected. Neither CMV serostatus nor sex impacted TTV DNA levels in patients or controls. Patients awaiting lung transplant had lower TTV levels compared with those awaiting liver (P = 0.04) or heart transplant (P = 0.03). A significant correlation between plasma TTV DNA levels and WB EBV DNA (r = 0.28, P = 0.05) but not saliva EBV DNA levels was observed in patients (Figure 2); only WB EBV DNA level was a significant predictor of high (≥3rd quartile of control) TTV DNA levels in patients in multivariate analysis (P = 0.026). Four of the five patients tested before and 27–285 days after transplant had a significant post-transplant rise in TTV DNA levels (Figure 3). Conclusion Measurement of TTV DNA in plasma alone or combined with EBV DNA in WB may be a useful marker for measuring global immunosuppression including age-related immunosenescence in subjects not receiving exogenous immunosuppression. Disclosures All authors: No reported disclosures.

A girl received an ABO-incompatible heart transplantation (ABOiHTx) at the age of 3.5 years for failed univentricular palliation with protein-losing enteropathy (PLE). She was born with a hypoplastic left heart syndrome and underwent multistage palliation to a Fontan circulation at 2½ years of age. After the Fontan surgery, she developed PLE, necessitating a Fontan revision, followed by a Fontan takedown and eventually HTx, which was performed with a blood group B heart into an O recipient. Right ventricular (RV) failure secondary to increased pulmonary vascular resistance (PVR) evolved immediately after HTx. A temporary right ventricular assist device (RVAD) was implanted and later switched to a pneumatic pulsatile RVAD. With the adaption of PVR on the RVAD, the PLE resolved and the RVAD was explanted. In the following 12 months, she developed multiple relapses of PLE which eventually resolved after exchange of the calcineurin inhibitor.

Coronary allograft vasculopathy is the current leading cause for late graft loss following cardiac transplantation. Its pathogenesis is multifactorial, including immune, constitutional and genetic factors, metabolism, infection, as well as potential injury from routine immunosuppressive therapy. Children represent a patient group with unique differences: their pretransplant history rarely includes ischemic heart disease and risk factors for atherosclerotic heart disease, but many are presensitized from use of allograft material during reconstructive cardiac surgeries. Compared with older children and adults, infants and young children show significantly lower rates of graft vasculopathy that may be related to the relative immaturity of their immune system. This review summarizes the current concepts of coronary allograft vasculopathy derived mainly from animal models and adult clinical observations. It provides an overview of confirmed risk factors and explains their interactions. The characteristics and unique clinical findings among pediatric transplant recipients will be explored within the context of recent, albeit limited, scientific investigations.

Objective:The populationofchildren who receivedrightventricle-to-pulmonaryartery shunt (RV-PA) atNorwood procedure (NP)is growing,but limited data are available regarding the long-term outcome. Theaim of this study was to present operative outcomes and mid-term hemodynamics and to assess the impact of the residual aortic obstruction on the results in patients undergoing three-staged surgery with RV-PA application at NP. Methods: Between June 2001 and June 2009, 229 children with hypoplastic left heart syndrome (HLHS) and variants underwent NP with RV-PA; 172 have proceeded to stage II and 95 to stage III. The medical records (clinical data, echocardiographic records, cardiac catheterization reports, electrocardiograms, and surgical notes) were retrospectively reviewed. Results: The later era of NP was associated with significantly better outcome (2001—2004: 1- and 5-years’ survival were 64.3% and 59.8%, respectively; 2005—2009: 1- and 4-years’ survival were 93.1% and 86.9%, respectively) (p < 0.001). There was no association between long-term survival and diagnosis (HLHS/HLHS variant) (p = 0.39). The incidence of depressed ventricular function and moderate or severe systemic atrioventricular valve regurgitation among the children who required balloon aortoplasty (BA) before stage IIsurgerywassignificantlyhigher than inchildren without aorticarchobstruction(p =0 .027,p = 0.008,respectively). In midterm follow-up, BA had no significant influence on the actuarial survival (p = 0.089). No ventricular arrhythmias were noticed at any stage. Conclusions: The RV-PA shunt is a safe technique that does not seem to impair systolic or electrical ventricular function; its outcomes continue to improve with growing experience. Combined cardiologic interventional and surgical procedures are required to optimize the outcomes. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

We investigated whether children after heart- (HTx) or heart-lung transplantation (HLTx) show protective antibody levels against recommended vaccinations, whether vaccination schedules are completed and which factors influence serologic immunity. We performed a cross sectional ELISA - quantification of specific antibodies in 46 patients after pediatric thoracic Tx. Findings were correlated to vaccination history, age at Tx, clinical course and immunosuppressive regimen. We found protective antibody levels against diphtheria in 74% of patients, against tetanus in 22%, against Haemophilus influenzae type b in 30% and against Streptococcus pneumoniae in 59%. Antibody concentrations against live attenuated vaccines were significantly lower in children transplanted in the first 2 years of life. Antibodies were absent for measles in 55% of late - and 81% of early transplanted children, for mumps in 66%/94%, for rubella in 30%/56% and for Varicella in 34%/63%. We found significant correlation of low antibody concentrations and age at Tx. Patients without protective antibody concentrations had significantly longer use of steroids. Vaccination schedules were incomplete or delayed in the majority of patients associated with more days in hospital pre-Tx. Our study shows that closer adherence to pretransplantation vaccination schedules and also post-transplantation monitoring of antibody levels are required in transplant patients.

Objective: In HIV-infected adults Pneumocystis jirovecii pneumonia (PCP) prophylaxis can be safely withdrawn after immune reconstitution due to the introduction of highly active antiretroviral therapy (HAART). With regard to children only a small amount of data has been published. The present study investigated whether the withdrawal of PCP prophylaxis after immune reconstitution is safe in HIV-infected children. Methods: A retrospective analysis at 10 European centers belonging to the Pediatric European Network on the treatment of AIDS (PENTA) using a standardized questionnaire. Results: A total of 113 questionnaires were received. In 82 children the indication for PCP prophylaxis was provided following Centers for Disease Control (CDC) guidelines (72 primary and 10 secondary). Prophylaxis was withdrawn after the CD4 cell count increased above the age-related CDC thresholds. The observation period off prophylaxis was 335 years (300 years for primary and 35 years for secondary prophylaxis) and the median time per patient off prophylaxis was 4.1 years (range, 0.3-7.7 years). No episode of PCP occurred during the study period. In comparison with the incidence rate from historical data before the introduction of PCP prophylaxis and HAART, this was a significant reduction (P < 0.05). Conclusions: The increase in CD4 cell count provides functional reconstitution of the immune system in children. Our data suggests that the risk of developing a PCP after immune reconstitution is sufficiently low to withdraw PCP prophylaxis.