The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Ending the HIV Epidemic in Black America: Qualitative Insights Following COVID-19.

BACKGROUND: The disproportionate effects of the human immunodeficiency virus (HIV) and the Coronavirus 2019 (COVID-19) on Black American communities highlight structural systems rooted in racism and must be addressed with national strategies that improve both biomedicine and social determinants of health. PURPOSE: The purpose of this study was to qualitatively examine the experiences and interpretations of experts in the HIV workforce (local, state, and national HIV-related organizations) regarding the state of HIV and COVID-19 among Black Americans. METHODS: Within key informant interviews and a focus group recorded and transcribed verbatim, fifteen members of the HIV workforce and Black community described their experiences and provided insights to inform ending the negative outcomes resulting from HIV and COVID-19. RESULTS: Data were analyzed using NVivo software, and eight themes emerged to address disease disproportionality through a Black lens. Themes reflected (1) accessing information and care; (2) key potential partners/stakeholders; (3) investing in Black communities; (4) governmental support; (5) increasing engagement and advocacy; (6) HIV-related community conversations; (7) developments since COVID-19; and (8) the Ending the HIV Epidemic (EHE) trajectory. CONCLUSIONS: Themes directly speak to recommendations to adjust education and policy strategies for HIV and COVID-19 prevention and intervention. Such recommendations, (1) amplifying Black voices, (2) investing sustainable dollars into Black communities, and (3) leaning into advocacy, can bolster the foundation for the HIV workforce and Black community to break ineffective response patterns and lead the fight against these systemic issues of inequity.

The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

The IPTA Nashville consensus conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: II-consensus guidelines for prevention.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.

COVID-19 diagnosis and testing in pediatric heart transplant recipients.

Pediatric heart transplant recipients have been expected to be at higher risk of adverse events from developing COVID-19 infection. COVID-19 RNA PCR and antibody testing has been performed in our cohort of patients since March 15, 2020 and outcomes were reviewed. COVID-19 infection in our population of pediatric heart transplant recipients is common (21%), despite recommendations to avoid contact with others. Asymptomatic COVID-19 infection is common as well (55%). Despite the frequency of infection, COVID-19 is well tolerated in this population (5% admission from home; 0% mortality). A suppressed immune system does not significantly inhibit an antibody response in pediatric heart transplant recipients (>70% antibody seroconversion) and appears to persist, similar to those without transplantation (>90 days). Routine testing for COVID-19 via PCR and antibody testing enhances the ability to detect COVID-19 infection in asymptomatic patients and may help reduce unintended transmission to more susceptible individuals.

Primary Transplantation for Congenital Heart Disease in the Neonatal Period: Long-term Outcomes.

BACKGROUND: Primary transplantation was developed in the 1980s as an alternative therapy to palliative reconstruction of uncorrectable congenital heart disease. Although transplantation achieved more favorable results, its utilization has been limited by the availability of donor organs. This review examines the long-term outcomes of heart transplantation in neonates at our institution. METHODS: The institutional pediatric heart transplant database was queried for all neonatal heart transplants performed between 1985 and 2017. Follow-up was obtained from medical records and an annually administered questionnaire. Overall survival and time to development of complications were estimated using the Kaplan Meier method. Univariate and multivariate analyses were performed to identify independent predictors of survival. RESULTS: Heart transplantation was performed in 104 neonates. Median age was 17 days. Hypoplastic left heart syndrome (classic or variant) was the primary diagnosis in 77.8% of patients. Survival at 10 years and 25 years was 73.9% and 55.8%, respectively. At 20 years, freedom from allograft vasculopathy and lymphoproliferative disease was 72.0% and 81.9%, respectively. Freedom from re-transplantation was 81.4% at 20 years. Eight patients (7.6%) developed end-stage renal disease. By multivariate analysis, lower glomerular filtration rate and allograft vasculopathy were the only significant predictors of death. CONCLUSIONS: Neonatal heart transplantation remains a durable therapy with very acceptable long-term survival. Children transplanted in the newborn period have the potential to reach adulthood with minimal need for reintervention.

Toward a solution for cardiac failure in the newborn.

The newborn infant with severe cardiac failure owed to congenital structural heart disease or cardiomyopathy poses a daunting therapeutic challenge. The ideal solution for both might be cardiac transplantation if availability of hearts was not limiting and if tolerance could be induced, obviating toxicity of immunosuppressive therapy. If one could safely and effectively exploit neonatal tolerance for successful xenotransplantation of the heart, the challenge of severe cardiac failure in the newborn infant might be met. We discuss the need, the potential for applying neonatal tolerance in the setting of xenotransplantation and the possibility that other approaches to this problem might emerge.

Calcineurin inhibitor- and corticosteroid-free immunosuppression in pediatric heart transplant patients.

Pediatric heart transplant patients at our institution are immunosuppressed with a CNI and another immune-modulating agent without utilizing corticosteroids. Patients whose renal function worsened and who did not respond to CNI minimization had their CNI discontinued. The clinical history of 35 pediatric heart transplant patients with significant renal insufficiency whose CNI was discontinued was retrospectively analyzed. Data including serum creatinine and weight were collected before, at time of, and every 3-6 months after CNI discontinuation. This was used to calculate an eGFR. Cardiac allograft rejection and mortality data were also collected. CNI discontinuation occurred 39 times in 35 patients. The median eGFR significantly increased by 14 mL/min 3 months after CNI discontinuation and the increase continued to be significant (P≤.05) at 5 years. Freedom from rejection analysis showed no difference between graft rejection 2 years before versus after CNI discontinuation (P=.437). No mortality was associated with CNI discontinuation. Immunosuppression free of CNIs and corticosteroids appears to be a safe alternative in pediatric heart transplant patients with significant renal insufficiency. Furthermore, this strategy can significantly reverse renal insufficiency, even late after transplantation.

Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients.

The introduction of cyclosporine revolutionized the practice of immunosuppression for solid organ transplant recipients, and has resulted in a significant increase in survival. While CNI use has been the mainstay of immunosuppressive therapy in pediatric heart transplantation, CNIs have been associated with an increased risk of nephropathy leading to significant morbidity and mortality. We evaluated the effect on renal function of a CNI minimization protocol using SRL in pediatric heart transplant patients with CNI induced renal insufficiency. An IRB approved retrospective chart review and case control study was performed. There were 20 patients identified with renal insufficiency who had been converted to SRL (target 5-8 ng/mL) and cyclosporine (target 50-75 vs. 125-150 ng/mL). Renal insufficiency was defined as isotopic (Indium 111 DTPA) GFR <60 mL/min per 1.73 m(2) or sCr >1 mg/dL. Outcome variables evaluated were GFR and sCr at time of conversion and at two yr post conversion. Comparison was made with case control subjects matched for age at Tx, time from Tx to conversion, and initial GFR. The median age at Tx = 81 days (S.D. ±26), median time of conversion after Tx = 10 yrs (s.d. ±0.65). Self-limited/treatable side effects included hypercholesterolemia (10), neutropenia (6), aphthous ulcer (3), edema (2), anemia (2), and tremor (1). One patient rejected in the two yr prior to conversion, and one patient had two rejection episodes following conversion. GFR at conversion for study group was 51 ± 14 vs. 60 ± 2 at two yr, p = 0.018. GFR at inclusion for control group was 56 ± 20 vs. 53 ± 21, p = 0.253. This report demonstrates that minimizing CNI exposure by addition of SRL to the immunosuppressant regimen in pediatric heart transplant recipients result in improved renal function in comparison to historically managed patients. Furthermore, immunotherapy with SRL and lower-dose CNI can effectively prevent rejection with an acceptable side-effect profile.

Heart transplantation for congenital heart disease in the first year of life.

Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance.

Cause of death in pediatric and infant heart transplant recipients: review of a 20-year, single-institution cohort.

BACKGROUND: As infant and pediatric heart transplantation becomes more common, there is a growing need to better understand the causes of failure or death, if we are to continue to improve the outcome in these children. METHODS: A multidisciplinary team reviewed all deaths occurring in the cohort of infants and children transplanted during the first 20 years of the Loma Linda Pediatric Heart Transplant program, with 2 additional years of follow-up beyond the 20-year accrual period, and classified them as to cause. RESULTS: There were 169 deaths among 421 recipients, with a median follow-up of 9.7 years. Autopsy was performed in 128 cases. The causes of death, in decreasing order of frequency, included acute rejection (26.0%), infection (16.0%), cardiac allograft vasculopathy (CAV) (14.2%), technical issues (8.3%), acute graft dysfunction (6.5%), neoplasm (7.1%), chronic graft dysfunction (4.7%) and miscellaneous factors (10.1%), and in twelve deaths (7.1%) the cause was unclassified. Acute graft dysfunction and technical issues accounted for nearly two-thirds of the deaths in the first 30 days after transplant, while acute rejection resulted in the largest number of deaths after the first year (30.4%), with CAV a close second (23.5%). CONCLUSIONS: Acute graft dysfunction and technical issues were the most frequent cause of early death. Late deaths were most often due to acute rejection and CAV, which differs somewhat from the experience reported in adults. Acute rejection was the single most important cause of late mortality, and resulted in a significant number of late sudden and unexpected deaths.

Pediatric transplantation using hearts refused on the basis of donor quality.

BACKGROUND: There is always more demand than supply of organs in pediatric heart transplantation. Yet, potential donor organs are regularly declined for a variety of reasons, among them donor organ quality as determined by United Network for Organ Sharing (UNOS) refusal code 830 or its equivalent. METHODS: For the study group institutional and UNOS databases (July 2000 to December 2008) were reviewed to examine outcomes of pediatric heart transplantation using donor hearts that had been previously refused one or more times because of organ quality. Variation between outcomes of this cohort and recipients who received primarily offered heart grafts in a single institution was analyzed. RESULTS: In 29 recipients, transplantation or retransplantation was with heart grafts previously declined on the basis of quality. Recovery distances (p < 0.002) and graft cold ischemic times (p < 0.001) were significantly longer for declined hearts. Operative survival was 93% +/- 5.0% (27 of 29). Seven-year actuarial survival was 74% +/- 10.5%. At the present time, 24 of the 29 recipients (83%) are alive. These results do not vary statistically from those experienced by 84 recipients of 86 primarily offered donor organs during the same time. CONCLUSIONS: Despite longer distance recovery (ie, longer graft cold ischemic times), outcomes of pediatric heart transplantation using donor heart grafts refused on the basis of organ quality are highly competitive. Pediatric donor hearts should seldom be declined on the basis of organ quality (UNOS code 830).

Developmental outcomes after pediatric heart transplantation.

BACKGROUND: Pediatric heart transplantation has now been successfully performed for more than 20 years. As survival rates have improved, more attention is now focused on long-term outcomes. METHODS: This report reviews the literature on developmental outcomes after pediatric heart transplantation. RESULTS: Pediatric patients undergoing heart transplantation generally can be expected to have developmental outcomes in the low-normal range, consistent with outcomes seen in other children with complex congenital heart disease requiring surgical intervention. When these children reach school age, or return to school, most can be expected to function reasonably well in mainstream school settings. A significant minority will require additional educational assistance. Approximately 10% will have significant neurologic impairment. In school, particular attention should be paid to evaluating the child for deficits in arithmetic and verbal skills. Performance may be better than predicted from IQ testing. Behavioral issues are common, with depression, concerns about social competence, and attention difficulties most frequently endorsed. This may pre-date transplantation in those who undergo transplantation during childhood and may improve with time. Parents more often report problem behaviors than teachers. Family resources and family coping skills are also strongly correlated with the child's emotions and coping skills. CONCLUSION: The pediatric heart transplant recipient's ability to transition from childhood into a happy and productive adult life can be significantly affected by his or her cognitive abilities, learning experiences, sense of self, and emotions. Attention to these factors is an important part of caring for these children.

Late outcomes of pediatric heart transplantation are independent of pre-transplant diagnosis and prior cardiac surgical intervention.

BACKGROUND: An increasing number of children are being referred for cardiac transplantation after (1) failing conventional corrective or palliative surgical reconstruction, (2) after stabilization with mechanical circulatory support devices, and (3) when primary graft failure or advanced cardiac allograft vasculopathy are established. METHODS: The records of 417 infants and children (age range, 0-18 years) who underwent cardiac transplantation from November 1985 through December 2005 at Loma Linda University Children's Hospital were retrospectively reviewed. The pre-transplantation diagnosis was used to divide patients into 3 groups: primary cardiomyopathy (CM), 103; hypoplastic left heart syndrome (HLHS), 154; and other complex congenital heart disease (CCHD), 160. These groups were compared and analyzed for differences in early and late morbidity and mortality. RESULTS: Operative mortality was significantly lower in the CM group compared with the HLHS (p < 0.02;) and CCHD groups (p < 0.01). Long-term actuarial recipient survival, however, was similar for all groups. The 15-year actuarial survival was 59% for the CM Group, 57% for the HLHS Group, and 50% for the CCHD Group. Actuarial survival after retransplantation is not statistically different from that with primary cardiac transplantation. CONCLUSION: Although peri-operative survival was lower in infants and children with HLHS and CCHD compared with those with CM, long-term survival has been the same for all groups. Late survival after retransplantation was not statistically different than among those with primary cardiac transplantation.

Decreased exercise performance with age in children with hypoplastic left heart syndrome.

OBJECTIVE: Children born with hypoplastic left heart syndrome (HLHS) may experience cardiac dysfunction after staged surgery or transplantation, which may worsen with age. We examined the hypothesis that exercise testing can address cardiovascular capacity and suggest interventions to improve quality of life. STUDY DESIGN: Children with HLHS > or = 8 years old performed treadmill or bicycle ergometric testing at 4 centers. Results were compared with norms for age and sex. RESULTS: Of the 42 participants, the mean age was 12.9 years (range, 8.5-17.0 years), 64% were boys, 20 had staged surgery, and 34 completed metabolic assessment. The percent of predicted maximal oxygen uptake (mVO2) was higher in younger children. Children aged 8 to 12 years achieved 70% of predicted mVO2; children aged 13 to 17 years achieved 60% of predicted mVO2 (P = .02). The percent of predicted peak heart rate trended higher in younger patients (83% versus 75%, P = .07). Electrocardiographic changes were more common in older children. In treadmill testing, patients who had a transplant had better exercise performance than patients who underwent staged surgery in percent of predicted exercise time (82% versus 54%, P < .0001) and peak rate-pressure product (241 x 10(3) versus 195 x 10(3), P = .02). The percent of predicted mVO2 did not differ between patients who had a transplant (66%) and patients who underwent staged surgery (61%, P = .25). CONCLUSION: Children with HLHS showed considerable age-related decline in exercise performance, regardless of surgical strategy.

Geometric disproportion of cardiac structure and graft ischemia affect tricuspid valve regurgitation early after neonatal heart transplantation.

BACKGROUND: Although tricuspid valve regurgitation (TR) after heart transplantation is a known complication, there has been little discussion of this subject in neonatal heart transplantation. We aim to elucidate the prevalence, etiology, and evolution of TR early after transplant in neonates. METHODS: Eighty-five neonatal recipients were studied retrospectively by two-dimensional and Doppler echocardiography. The semiquantitative grading of TR was based on the ratio of regurgitation jet area to right atrial area. RESULTS: Immediately after neonatal heart transplantation, TR was recognized in 47 patients (grade 1, n = 18; grade 2, n = 22; grade 3, n = 7; and grade 4, n = 0). Tricuspid regurgitation prevalence diminished from 55% to 19% with reduction in severity 1 year after transplantation. The prevalence of TR (grade 2 and grade 3) was affected by a donor/recipient body weight ratio of more than 2.0 (p = 0.004) and graft ischemia for more than 3 hours (p = 0.014). The ratio of donor and recipient right atria portion, which had a correlation with donor/recipient body weight ratio (r2 = 0.415, p < 0.0001), separated the four subgroups in terms of TR grade immediately after transplantation (p = 0.0064) and also at 1 year after transplantation in all surviving grafts from 1.48 +/- 0.54 to 0.8 +/- 0.32 (p < 0.0001). The Cox model found no significance for early posttransplant TR as a risk factor for graft survival. CONCLUSIONS: Early posttransplant TR was affected by atria geometrical disproportion and by graft ischemia. Tricuspid regurgitation was not a risk factor for graft survival because of its amelioration over time, perhaps induced by recipient growth and recovery of myocardial injury relating to graft procurement.

Postmortem intracranial neuropathology in children following cardiac transplantation.

At Loma Linda University Children's Hospital, the medical information of 405 pediatric patients who received orthotopic cardiac transplantation were reviewed. Of those who died (n=136), 86% (n=117) underwent postmortem examinations, and the brain was examined in 61% (n=82, male=39). The number and type of intracranial lesions present were compiled, and these were matched to underlying functional cardiac disease categories. Intracranial abnormalities were present in 87%. Infarct was the most common primary central nervous system pathology in hypoplastic left heart syndrome (41%) but was also observed frequently in children with obstructive lesions (37%), cyanotic disease (31%), or cardiac shunting (29%). Secondary findings included extraparenchymal hemorrhage in obstructive lesions (31%); hypoxic changes occurred in 15% of patients with cyanotic disease and in 14% of those with cardiac shunting. Thirty-three percent of children with restrictive lesions had no neuropathology reported. Postmortem examination brain weights were matched against age and sex norms, with 29% of females and 36% of males below two standard deviations. These findings revealed that intracranial pathology was present in the majority of transplanted children who underwent postmortem examination, and that infarctive changes constituted the most common neuropathologic abnormality. Additionally, a number of children had significantly reduced brain weight.

Cardiac allograft vasculopathy in pediatric heart transplant recipients.

Metabolic parameters for coronary allograft vasculopathy (CAV) have not been well defined in children. CAV (by angiography or autopsy) was studied in 337 heart recipients on a cyclosporine-based steroid-sparing regimen. Freedom from CAV for all was 79% at 10 years. Fifty-nine patients (18%) developed CAV at a mean of 6.5 +/- 3 years post-transplant. First year rejections were significantly higher in CAV, mean 2.3 vs. 1.4, P = 0.003, odds ratio (OR) 1.8. Rejection with hemodynamic compromise beyond 1 year post-transplant was associated with CAV, P < 0.001, OR 8.4. There was no significant correlation among human leukocyte antigen DR (HLA DR) mismatch, pacemaker use or homocysteine levels and the development of CAV. Maximum cholesterol and low density lipoprotein (LDL) levels were not significantly different. Neither diabetes nor hypertension was significant predictors of CAV on multivariate logistic regression analysis. In conclusion, frequent and severe rejection episodes may predict pediatric CAV. Neither glucose intolerance nor lipid abnormalities appeared to alter risk for CAV in this population.