In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors and 258 non-transplanted controls. CH was detected in 16% of HCT recipients and 8% of controls, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older hematopoietic age (odds ratio: 1.07, p<0.001) and the HCT procedure (odds ratio: 2.53, p=0.02) independently increased the risk of CH, indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after a cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival.
Chronic kidney disease (CKD) is an important sequela of hematopoietic stem cell transplantation (HSCT), but data regarding CKD after pediatric HSCT are limited. In this single center cohort study, we evaluated the estimated glomerular filtration rate (eGFR) dynamics, proteinuria and hypertension in the first decade after HSCT and assessed risk factors for CKD in 216 pediatric HSCT survivors, transplanted 2002-2012. The eGFR decreased from a median of 148 to 116 ml/min/1.73 m2 between pre-HSCT to ten years post-HSCT. CKD (KDIGO stages G2 or A2 or more; eGFR under 90 ml/min/1.73m2 and/or albuminuria) occurred in 17% of patients. In multivariate analysis, severe prolonged stage 2 or more acute kidney injury (AKI), with an eGFR under 60ml/min/1.73m2 and duration of 28 days or more, was the main risk factor for CKD (hazard ratio 9.5, 95% confidence interval 3.4-27). Stage 2 or more AKI with an eGFR of 60ml/min/1.73m2 or more and KDIGO stage 2 or more AKI with eGFR under 60ml/min/1.73m2 but recovery within 28 days were not associated with CKD. Furthermore, hematological malignancy as HSCT indication was an independent risk factor for CKD. One third of patients had both CKD criteria, one third had isolated eGFR reduction and one third only had albuminuria. Hypertension occurred in 27% of patients with CKD compared to 4.4% of patients without. Tubular proteinuria was present in 7% of a subgroup of 71 patients with available β2-microglobulinuria. Thus, a significant proportion of pediatric HSCT recipients developed CKD within ten years. Our data stress the importance of structural long-term monitoring of eGFR, urine and blood pressure after HSCT to identify patients with incipient CKD who can benefit from nephroprotective interventions.
Objective: After paediatric haematopoietic stem cell transplantation (HSCT) adenovirus (HAdV) infection is a severe complication with high morbidity and mortality rate. By intensive surveillance patients at high risk for developing HAdV disease can early be identified in order to start preemptive therapy with antiviral medication in an early stage. Methods: In a prospective study, we determined the predictive value of HAdV DNA positivity in nasopharyngeal fluid preceding HSCT to identify patients at risk for a plasma HAdV reactivation after HSCT. We weekly monitored Adenovirus DNA loads in plasma after HSCT. HAdV reactivation was defined as plasma viral DNA load >1000cp/mL. Secondly, the association between plasma HAdV reactivation and alloreactive disease (Graft-versus-Host disease and/or idiopathic pulmonary syndrome) was analyzed, using Cox proportional hazard models. Results: A total of 62 patients were included: 37 (60%) recipients received bone marrow (17/37, 46%, matched family donor) or unrelated peripheral blood stem cells while 25 (40%) recipients received unrelated cord blood stem cells. 42/62 (68%) recipients received HLA-matched stem cells (for BM/PBSC high resolution typing, for CB intermediate: HLA-A and B on low and HLA-DR on high resolution). All patients received myeloablative conditioning and standardized Graft-versus-host disease prophylaxis. The median follow-up time was 47 (5–150) weeks. Prior to HSCT, HAdV DNA could be detected in nasopharyngeal fluid of 8/62 patients (13%). In all these patients (100%), plasma HAdV reactivation occurred during isolated hospitalization at a median time of 12.5 days (range 5–72 days) after HSCT. Additionally, 11 (18%) patients developed plasma HAdV reactivation at a median time of 40 (14–160) days after HSCT. In multivariate analysis HAdV DNA positivity in nasopharyngeal fluid was the only significant predictor for plasma HAdV reactivation after HSCT (HR 9,7; 95%CI 3,4–27,4; p = 0.000). Plasma HAdV reactivation was a predictor for allo-reactive disease (HR 2.6; 95% CI 1,2–5,4; p = 0.013). Conclusions: HAdV positivity in nasopharyngeal fluid pre-HSCT is a very strong predictor for the development of plasma HAdV reactivation after HSCT. Prevention or early pre-emptive treatment with antiviral therapy might contribute to prevent HAdV disease and / or HSCT associated problems after HSCT.
The assessment of using patient-reported outcomes (PROs) within comprehensive care follow-up programmes, specifically focused on health screening, remains largely unexplored. PROs were implemented in our late effects and comprehensive care programme after paediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. The programme focuses solely on screening of physical and mental health and on discussing PROs during the consultation.
Objective: Haematopoietic stem cell transplantation (HSCT) is frequently complicated by early Human herpesvirus type 6 (HHV6) reactivation and is associated with poor survival and severe acute Graft-versus-host-disease (aGvHD). We hypothesized that HHV6 may be a trigger for immunedysregulation, resulting in alloreactivity. We investigated total T-cell numbers and HHV6-specific Interferon-γ (IFNγ) producing T-cells in children with or without HHV6-reactivation after HSCT using a newly developed enzyme-linked immunospot (ELISPOT) technique. Methods: Prospectively, HHV6, Cytomegalovirus, Adenovirus and Epstein Barr virus DNA-loads were weekly monitored by quantitative realtime-PCR and clinical data were collected. HHV6 reactivation was defined as HHV6 DNA-load >250cp/mL. T-cell reconstitution was prospectively measured every other week by immunophenotyping (markers CD3, CD4 and CD8). Numbers of IFNγ-producing T-cells in PBMCs were retrospectively determined by ELISPOT after overnight stimulation with HHV6-virus lysate (ABI, Columbia, Maryland, USA) 2 months after HSCT. Results: Twenty-one HSCT patients were analyzed (median age 4.4 years; range 1–16.5yrs). Within the first two months, 13/21 (62%) patients developed HHV6 reactivation; median time of reactivation was 14 (range 1–41) days. The development of other virusreactivations did not differ between the two groups; 4/13 versus 3/8 respectively. The median number of IFNγ-producing specific HHV6 T-cells 2 months after HSCT was significantly increased in the patients with HHV6-reactivation; 40 (0–362) versus 0 (0–25) specific T-cells per million PBMCs (p = 0.006). Additionally, the median CD3+ T-cell numbers were significantly increased in these patients; 393 (32–5514) versus 93 (0–641) T-cells/uL (p = 0.03), including median CD8+ T-cells; 79% (6–87 %) versus 33% (0–83%) (p = 0.03). Conclusions: Patients with HHV6 reactivation had significantly higher numbers of IFNγ-producing HHV6-specific T-cells and more CD3+T-cells/uL, among which mainly CD8+T-cells. Given the association of HHV6 reactivation and aGvHD, these T-cells may be alloreactive.
Healthcare grapples with staff shortages and rising burnout rates for medical students, residents and specialists. To prioritise both their well-being and the delivery of high-quality patient care, it becomes imperative to deepen our understanding of physicians' developmental aims and needs. Our first aim is, therefore, to gain comprehensive insights into the specific developmental aims physicians prioritise by examining the coaching goals they set at the beginning of coaching. Since physicians face distinct roles as they advance in their careers, our second aim is to highlight similarities and differences in developmental aims and needs among individuals at various medical career stages.
Abstract Background Little is known about health‐related quality of life (HRQoL) in young children with sickle cell disease living in a European country. Methods A retrospective cross‐sectional evaluation of TNO‐AZL Preschool Children Quality of Life questionnaire (TAPQOL, 0–1 year) and Pediatric Quality of Life Inventory (PedsQL, 2–7 years) data was conducted. Study participants included caregivers of children with sickle cell disease aged 0–7 years attending the sickle cell centre at the Erasmus Medical Center or the Amsterdam University Medical Centers between April 2012 and October 2020. Comparisons were made with normative data on HRQoL in the general paediatric population. Results The study enrolled 136 caregivers of 136 children. In children aged 0–5 years, no significant differences emerged between children with sickle cell disease and the general population. However, in children aged 5–7 years, children with sickle cell disease scored significantly lower on all subscales except for emotional functioning. Multiple regression models showed a negative association between age and HRQoL. No association was found between HRQoL and disease severity or sociodemographic characteristics. Conclusions This study demonstrates that HRQoL is negatively correlated with age in young children with sickle cell disease with a significantly lower HRQoL in 5‐ to 7‐year‐olds when compared to the general population. Our study underlines the importance of measuring HRQoL in young children to identify patients with impaired HRQoL early in life in order to be able to intervene accordingly. Future research should focus on deepening the knowledge of factors influencing HRQoL in children with sickle cell disease.
In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors, compared to 115 healthy controls. CH was detected in 16% of HCT survivors, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older stem cell age and the HCT procedure independently increased the risk of CH (odds ratios 1.07 per year increase (p<0.001) and 2.61 for HCT (p=0.02)), indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival.
