Methodist Children’s Hospital

Inborn errors of immunity (IEI) are characterized by impaired lymphoid or myeloid immune cell function, resulting in recurrent infections, end-organ damage, and increased premature mortality. Allogeneic hematopoietic cell transplantation (allo-HCT) constitutes a curative treatment option for many IEI. Allo-HCT in this patient population poses unique challenges that necessitate the utilization of a conditioning regimen that affords rapid and stable engraftment, reduced organ toxicity, and low rates of graft-versus-host disease (GVHD). Evaluate survival, engraftment, and toxicity after reduced intensity conditioning (RIC) allo-HCT in patients with IEI. This IRB-approved, multicenter phase 2 clinical trial aimed to estimate the overall (OS) and characterize longitudinal engraftment of patients with IEI undergoing allo-HCT using an optimized reduced-intensity conditioning (RIC) regimen. The regimen consisted of alemtuzumab on days -14 through -12 (cumulative dose 45 mg in patients weighing ≥ 10 kg, 30 mg if < 10 kg), fludarabine on days -8 through -4 (150 mg/m² or 5 mg/kg in patients weighing <10 kg), thiotepa on day -4 (8 mg/kg total) and melphalan on day -3 (140 mg/m² or 4.7 mg/kg in patients weighing <10 kg). Graft sources included bone marrow (BM), peripheral blood stem cells (PBSCs), or umbilical cord blood (UCB). Twenty-eight pediatric and young adult patients with IEI received study treatment. The 1-year and 3-year overall survival (OS) for the entire cohort was 96.3% (95% CI: 76.5 to 99.5) and 87.5% (95% CI: 66.0 to 95.8), respectively. Event-free survival (EFS) was significantly lower in infants [1-year EFS 57.1% (95% CI: 17.2 to 83.7) and 3-year EFS 38.1% (95% CI: 6.1 to 71.6)] compared to older children [1-year EFS 90.5% (95% CI: 67.0 to 97.5) and 3-year EFS 84.4% (95% CI: 58.7 to 94.8)] (P = .0007) owing to higher rates of treatment failure (TF, loss of donor chimerism or recurrence of IEI). The cumulative incidence of TF in infants was 42.9% (95% CI: 7.6% to 75.7%) at 1 year and 61.9% (95% CI: 10.4% to 90.3%) at 3 years compared to 9.5% (95% CI: 1.5% to 26.6%) at 1 and 3 years in older children (P = .004). Most infants (4/5,80%) with TF were successfully salvaged with second allo-HCT. The cumulative incidence of Grade II-IV acute and chronic GVHD was 10.7% (95% CI: 2.6 to 25.4) and 12.9% (95% CI: 3.0 to 30.2), respectively. Immune reconstitution was robust in most patients, with timely lymphocyte subset recovery, restored thymopoiesis, and independence of immunoglobulin administration. This RIC allo-HCT regimen for treatment of IEI had excellent OS with resolution of underlying immune abnormality, reconstitution of normal immune function, and low rates of GVHD. Future efforts will focus on optimizing engraftment in infants.

Hematopoietic stem cell transplantation (HCT) is potentially curative for numerous malignant and non-malignant diseases but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. Bronchoalveolar lavage (BAL) is the most commonly used procedure for diagnostic sampling of the lung but is invasive, cannot be performed in medically fragile patients, and is challenging to perform serially. We previously showed that BAL transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality outcomes. However, whether peripheral blood testing is a suitable minimally-invasive surrogate for pulmonary sampling in the HCT population remains unknown. To address this question, we compared 210 paired BAL and peripheral blood transcriptomes obtained from 166 pediatric HCT patients at 27 children's hospitals. BAL and blood mRNA abundance showed minimal overall correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, expression of innate and adaptive immune pathways was tightly co-regulated with expression of epithelial mesenchymal transition and hypoxia pathways, and these signatures were associated with mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups, of which one group showed twice the rate of hypoxia and significantly worse outcomes within 7 days of enrollment. These findings reveal a compartmentalized injury response, where BAL and peripheral blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.

The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. We find no support for an increased risk of BPD with iron supplementation. NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Children and young people (CYP) within the Child Welfare System (CWS) often experience a range of trauma‐related difficulties. However, systematic use of evidence‐based measures to support mental health assessment and care planning appeared to be lacking within CWS in Singapore. This study evaluated the use of evidence‐based measures to inform care planning in out‐of‐home residential care in Singapore. Participants were 65 CYP in care. Measures consisted of the Child PTSD Symptom Scale for DSM‐5 (CPSS‐5), Assessment Checklist for Children (ACC) and Adolescents (ACA), Child Behavior Checklist (CBCL) and Youth Self‐Report (YSR). Care plans were identified based on the measures' clinical criteria and validated against the Child and Adolescent Needs and Strengths (CANS) and Adverse Childhood Experience (ACE) questionnaire. More intensive measurement‐based care plans were associated with higher service needs and lower strengths on the CANS, and higher ACE exposure. However, there was limited support for the validity of care plans when evaluated against the CANS and ACE questionnaire. Methodological implications for mental health assessment are discussed. Compared to service‐allocation‐as‐usual, measurement‐based care plans identified more cases that may require intensive psychological intervention. Overall, study findings provided some support for the use of assessment measures to supplement care planning in residential care.‘This study evaluated the use of evidence‐based measures to inform care planning in out‐of‐home residential care in Singapore’Key Practitioner Messages A comprehensive approach to care planning for CYP in out‐of‐home residential care should include the use of multi‐informant evidence‐based mental health assessment measures. The use of mental health assessment measures may reduce information gaps and complement the use of service needs assessment tools. Measurement‐based care planning may provide added value to supplement existing standard psychological care planning practices in out‐of‐home residential care.