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With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC]

Survival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and treatment of infections and graft-versus-host disease. Insight into the long-term patient-reported outcomes (PROs) after pediatric HSCT for nonmalignant disease is lacking but essential for optimal shared decision making, counseling, and quality of care. The purpose of this research was to determine long-term patient-reported outcomes in allogeneic pediatric HSCT for nonmalignant diseases and to compare these results with Dutch reference data. This single-center cohort study evaluated PROs (PedsQL 4.0, PROMIS item banks), self- or proxy-reported, among patients at >= 2 years after pediatric allogeneic HSCT for nonmalignant disease. Mean scores were compared with those of the Dutch general population. Of 171 eligible patients, 119 participated, for a 70% response rate. The median patient age was 15.8 years (range, 2 to 49 years), and the median duration of follow-up was 8.7 years (range, 2 to 34 years). Indications for HSCT included inborn errors of immunity (n = 41), hemoglobinopathies (n = 37), and bone marrow failure (n = 41). Compared with reference data, significantly lower scores were found in adolescents (age 13 to 17 years) on the Total, Physical Health, and School Functioning PedsQL subscales. Significantly more Sleep Disturbance was reported in children (age 8 to 18 years). On the other hand, significantly better scores were seen on PROMIS Fatigue (age 5 to 7 years) and Pain Interference (age 8 to 18 years) and, in adults (age 19 to 30 years), on Depressive Symptoms and Sleep Disturbance. This study showed better or comparable very long-term PROs in patients after pediatric HSCT for nonmalignant diseases compared with the reference population. Children and adolescents seem to be the most affected, indicating the need for supportive care to prevent impaired quality of life and, more importantly, to amplify their long-term well-being. (c) 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

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.

Background and Aims Chronic kidney disease (CKD) is an important sequela of hematopoietic stem cell transplantation (HSCT), but data regarding CKD after pediatric HSCT are limited. Method In this single center cohort study, we evaluated eGFR dynamics, proteinuria and hypertension in the first decade after HSCT and assessed risk factors for chronic kidney disease in 216 pediatric long term HSCT survivors, transplanted between 2002 and 2012. Results The eGFR decreased from median 148 to 116 ml/min/1.73m2 between pre-HSCT and ten years after HSCT. CKD, defined as an eGFR Conclusion In conclusion, a significant proportion of pediatric HSCT recipients developed chronic kidney disease within ten years after HSCT. Our data stress the importance of structural long term monitoring of eGFR, urine and blood pressure after HSCT to identify patients with beginning CKD who could benefit most from nephroprotective interventions.

Background While multiple studies have examined the cost of health care for one aspect of sickle cell disease care, few have focussed on the overall cost of comprehensive care for sickle cell disease. Methods We conducted a retrospective cohort study of children with sickle cell disease treated in a comprehensive care centre from 1 January 2015 to 31 December 2016. Health care utilisation of included patients was based upon data from two main sources. The clinical practice guideline was used to determine the expected resource use of routine comprehensive care (planned elective care), and the financial claims database was used to estimate real-world resource use associated with acute and inpatient care (additional care). Results A total of 125 children with sickle cell disease were analysed. Expenditures for these patients averaged euro5049 [standard deviation (SD) euro1634] per child per year. Total yearly costs per patient varied considerably, ranging from euro669 to euro84 010, and less than 15% of patients were responsible for 50% of the health care costs. The majority (37%) of costs was associated with inpatient hospital care, which increased by age group, 27% with diagnostics, 19% with treatment, 11% with outpatients' visits and 6% with emergency care. Conclusion We have described real-world resource use and expenditures for children with sickle cell disease in a European comprehensive care centre. It seems that costs of a comprehensive approach with effective management in the outpatient setting is favourable when compared to episodic health care.

Introduction Sickle cell disease (SCD) is an autosomally, recessive inherited hemoglobinopathy and multisystem disorder characterized by ongoing hemolytic anemia, episodes of vaso-occlusion and progressive organ failure with ultimately a shortened life expectancy. Despite intensive comprehensive care and improved rates of morbidity and mortality, SCD care is still marked by high utilization of medical resources. Until now, most cost-of care studies have focused on one or two care categories, such as hospitalizations and physician visits [1-4]. Also, few studies have evaluated healthcare expenditures exclusively in children. Estimating cost-of care is important as it can ensure sufficient allocation of resources. In addition, SCD expenditures can be used to raise awareness of disease severity and serve as an incentive for prevention and management of disease complications. Primary aims of this study were to (a) investigate the overall cost of healthcare for pediatric SCD patients and to (b) estimate major cost drivers. Methods All pediatric SCD patients visiting the Erasmus University Medical Center-Sophia Children's Hospital for routine or emergency care from January 1st to December 31st 2017 with a diagnosis of SCD were included. Retrospective data of this cohort were analyzed for 24 months during January 1st 2015 to December 1st 2016. Patients were grouped into four age categories; (A) 0-12 months, (B) 1-5 years, (C) 5-13 years and (D) 13-19 years. For patients born before January 1st 2015, each individual contributed two years of follow-up time. As some children were born during one of the two years during the study time period, the weighted average was calculated based on the time patients were potentially able to make costs. Healthcare utilization of included patients was based upon data from two main sources. The clinical SCD standard treatment guideline was used to determine the expected resource use of routine comprehensive care (planned elective care) and the Erasmus University Medical Center financial claims database was used to estimate real-world resource use associated with acute and inpatient care (additional care). The included items for the SCD guideline and financial claims database per cost category are summarized in Table 1. Results A total of 125 patients were analyzed. The mean age was 8.1 years (SD: 5 years) on December 31st 2015 and 9.9 year (SD: 5 years) on December 31st 2016. Expenditures for the 125 children with SCD averaged €4285.09 (SD: €820.36) per child per year. The majority (49%) of costs was associated with standard treatment (i.e. prophylactic antibiotics); 23% with diagnostics; 19% with inpatient hospital care and 9% with outpatients visits. Annual average costs per patient per age group are depicted in Figure 1. Total expenditures for children with SCD increased per age group, ranging from €2962 (category A), €3726 (category B), and €4087 (category C) to €5890 (category D). This was mostly explained by increases in admission costs. Discussion Although healthcare utilization and costs of pediatric SCD patients have been studied previously [5-7], studies from Europe comprehensive care centers are scarce and have been mostly based on only one aspect of care such as hospitalizations costs [2]. To our knowledge, this is the first study combining standard treatment costs with real world resource use. The total annual coast of healthcare for children with SCD, including inpatient care, outpatient care, diagnostics and treatment averaged €4285.09 per patient per year. This is much lower when compared to costs of healthcare for pediatric patients with SCD reported in other studies. Kauf et al. calculated total costs of healthcare for SCD patients aged 0-9 years to be $10.704 [7]. In addition, inpatient care accounts for a relatively small part of total costs in our study. This finding has been inline with previous research where comprehensive care has been suggested as a means of reducing costs associated with SCD care [8]. A comprehensive, multidisciplinary approach is necessary to address the physical, mental and social needs of each child and their family. Comprehensive care, with effective management in the outpatient setting is able to prevent hospital admission, and is essential for delivery of high quality cost-effective care in SCD. Disclosures Cnossen: Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Sobi: Research Funding; Baxter: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Takeda: Other: Travel Grants, Research Funding; Roche: Other: Travel Grants; NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018.

Introduction The most common neurological finding in children and adults with sickle cell disease (SCD) is the presence of silent cerebral infarcts (SCIs). SCIs are, by definition, undetectable by neurologic examination and are recognized on magnetic resonance imaging (MRI) as increased signal intensity in multiple T2-weighted images (1). SCIs are associated with a decline in full-scale IQ (2, 3) and increased risk for future strokes (4). In this paper, we provide an overview of studies that have used magnetic resonance imaging (MRI) to detect SCIs in patients with SCD. We systematically review evidence on SCI prevalence, incidence and associated risk factors. Methods A comprehensive systematic search was performed of Embase, MEDLINE, Cochrane, Web of Science and Google Scholar. Publications through June 1st, 2019 were included. Search terms included synonyms for 'SCIs' and 'SCD' in various combinations. All references listed in identified papers, or noted in footnotes of data tables, were reviewed for additional articles missed by computerized database search. After removal of duplicates, 651 studies were screened on potential eligibility. Studies were included if they concerned patients of all ages with either homozygous or compound heterozygous SCD and assessed for and specifically reported MRI-detected SCIs (Figure 1). We present a weighted prevalence by study size. When multiple articles reported on a single or overlapping population sample, prevalence estimates were obtained from the article with the largest sample size to prevent duplications. Results We included 61 original papers describing results in a total of 3740 individual SCD patients. Most studies were performed in HbSS or HbSβ0thal SCD patients (n=2122). However, five studies separately reported SCI prevalence in other SCD genotypes i.e. HbSC, HbSβ+thal (n=254) and healthy controls (n=52). The pooled prevalence of SCI among all included patients with SCD (n=3740) was 28.4% (95% CI: 4.0;32.9). Data from included studies showed a statistically significant correlation (P Conclusions SCIs are common in patients with SCD with a weighted prevalence of 28.4%. Despite advancing neuroimaging technologies and therefore potentially enhanced detection of SCIs, there has been no apparent rise in SCI prevalence over the years. SCIs occur much more frequently in individuals with HbSS or HbSβ0thal than in other SCD genotypes. Analyses of risk- and protective factors showing varying results. The absence of robust findings is probably due to a combination of small sample sizes and weak associations. We believe SCIs are a poorly understood entity in patients with SCD. Despite substantial research efforts into risk- and protective factors, too little attention has been given to underlying pathophysiological mechanisms. Further research should focus on both SCI etiology in SCD as well as on clinical management of patients with evidence of these MRI lesions. Disclosures Cnossen: Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Sobi: Research Funding; Baxter: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Takeda: Other: Travel Grants, Research Funding; Roche: Other: Travel Grants; NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018.

Introduction Sickle cell disease (SCD) is a hereditary red blood cell disorder characterized by severe anemia, acute and painful vaso-occlusive crises and progressive organ failure. Success of health management of children with SCD is highly contingent on caregivers' capabilities. Caregivers of SCD affected children must perform a variety of tasks including communication with healthcare providers, reading and understanding of health information, interpretation of acute symptoms and administration of medication and complex decision making with regard to treatment options. A construct which describes the knowledge and competences of persons to meet the complex demands of health is 'health literacy' (HL) (1, 2). The measurement and assessment of HL is of growing importance due to expected and reported relationships between inadequate HL and health outcomes (3-5). In addition, caregivers with higher HL levels feel more confident in their ability to perform caregiving tasks, e.g. have a higher self-efficacy, often associated with higher quality of life (6, 7). Information on literacy levels and the relationship between HL, disease knowledge and self-efficacy may guide interventions in comprehensive SCD care. The aims of this study were to: (a) gain insight into levels of HL in caregivers of children with SCD using objective and subjective measures and to (b) assess the relationship between HL, caregivers self-efficacy' in communication with healthcare professionals and knowledge of SCD on different topics related to the illness. This abstract reports preliminary results. Methods In this cross-sectional, observational study, we included caregivers of children with SCD who attended the outpatient clinic of the Sickle Cell Comprehensive Care Center in the Erasmus Medical Center for a routine follow-up visit. Caregivers included in the study had to be able to communicate verbally in Dutch with professionals. HL was measured using the Short Assessment of Health Literacy in Dutch (SAHL-D) (8, 9); self-reported HL was evaluated by the Set of Brief Screening Questions (SBSQ) (10, 11). Self-efficacy was measured using the Perceived Self-Efficacy in Caregiver-Patient Interactions (PECPI) scale (12). Knowledge of SCD was assessed using a structured 13-item questionnaire (SCD-K) based on information and education provided in our clinic. Since data were not-normally distributed, they were analyzed using non-parametric statistics. Results To date, a total of 42 caregivers were included. Study inclusion will continue until at least 75 caregivers have been included. Demographics are presented in Table 1. Caregivers were mainly the child's mother (81.0%) often the single head of household (66.7%). The mean age of caregivers was 34.4 years. Educational level ranged from never attended school to post college Almost a quarter (23.8%) of caregivers was born in the Netherlands, others the rest were non-western migrants (76.2%). 78.6% of caregivers had low HL according to the SAHL-D. Caregivers with lower HL were more likely to have lower education (p=0.012) and to have been born outside the Netherlands (p=0.002). Only four caregivers (9.5%) reported having difficulties in understanding and applying health information (measured by SBSQ). The correlation between the SAHL-D and the SBSQ scores was weak (r=0.39). Mean scores on the SBSQ and PECPI were high, indicating that caregivers perceived their abilities for self-efficacy and their ability to read and understand medical information as quite high. Responses to individual SCD-K items however suggest large knowledge deficits: only 64.3% of caregivers knew which temperature is considered as fever [>38.0 °C or >38.5 °C] and only 14.3% was aware which risk factors are able to provoke sickle cell crises. The relationship between literacy status and item responses on SCD-K assessment scale was also examined. Caregivers with low literacy scored significantly lower on almost every individual item. Discussion Inadequate HL is highly prevalent in caregivers of children with SCD. Not being born in the Netherlands and lower education levels are strong predictors of low HL. Our study suggests that healthcare professionals should be attentive to possible low HL. In addition, these results underline that health information should be tailored to the HL skills and specific context of patients and their families. Disclosures Cnossen: NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018; Roche: Other: Travel Grants; Takeda: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Baxter: Other: Travel Grants, Research Funding; Sobi: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding.

Introduction Sickle cell disease (SCD) is a severe inherited red blood cell disorder with high morbidity requiring integrated comprehensive care. There are not many chronic diseases that primarily affect those from an often impoverished, minority background. Care delivery is complicated by disparities in healthcare regarding access. Cultural mismatches between providers and families also play a role. Healthcare access can be defined as the degree of fit between patients and the healthcare system (1, 2), and is described by four overlapping dimensions: physical accessibility, affordability, information accessibility and non-discrimination (3, 4). This qualitative study focuses on the challenges regarding the right to healthcare for children and adolescents with SCD and their families. The aims of this study were to (a) map the various perspectives and initiatives of SCD healthcare professionals, while focusing on existing best practices and lessons learned and (b) to provide practical recommendations relevant for high-income countries to improve accessibility of healthcare in SCD. Methods This qualitative study consisted of semi-structured, in-depth interviews which were conducted from February 1st to May 1st 2019 with SCD healthcare professionals, including (pediatric) hematologists, nurses, and psychosocial staff. Participants were affiliated with the SCORE (Sickle Cell Outcome REsearch) consortium which includes all SCD comprehensive care centers in the Netherlands (Fig 1). We identified eligible participants within SCORE and recruited participants using a combination of maximum variation and snowball sampling. Interviews occurred privately and were audio-recorded. The audio-recordings were transcribed verbatim and analyzed using the NVivoâ qualitative analysis software. Results Twenty-four healthcare professionals from different clinical sites participated in the study (Fig 1). Transcripts were coded into the four dimensions of health care access. Content analyses of the four dimensions in turn, revealed seven themes associated with best practices on topics related to improving accessibility of health care for children and adolescent SCD patients and their families (Fig 2). These themes included: 1) Cutting invisible costs: addressing the financial burden of a child with SCD; 2) Same-day appointments: reducing the amount of hospital visits; 3) Specialized and shared care: bridging the gap; 4) Optimizing methods of verbal and written communication: enabling mutual understanding between patients and healthcare professionals; 5) Building strong digital connections: improving the use of e-health while watching out for pitfalls; 6) Tools for patient empowerment and resilience: being aware of (self) stigmatization; and 7) Changing society: towards compassion and public awareness. Discussion The United Nations Convention on The Rights of the Child is the most widely signed and ratified human rights treaty and safeguards the right of the child to the enjoyment of the highest attainable standard of health. This right must be interpreted broadly, paying attention to all factors that may affect the realization of this right (5). Equity of access to healthcare for all patient populations requires the appreciation of intersecting vulnerabilities. This qualitative study provides best practices and solution-based recommendations from a grassroots-level to improve access to healthcare for children and adolescents with SCD and their families. Healthcare professionals experience a unique combination of intersecting vulnerabilities that characterize SCD patients and hampers their overall access to necessary healthcare. The seven key recommendations address these obstacles across all four dimensions of accessibility. Holistic implementation would positively impact the access to the highest attainable standard of healthcare for pediatric SCD patients and their families. These recommendations are built on local best practices that deserve wider implementation. They are especially relevant in the organization of SCD care, but all physicians will recognize these experiences with regard to healthcare in vulnerable patient populations in general. Disclosures Cnossen: Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Sobi: Research Funding; Baxter: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Takeda: Other: Travel Grants, Research Funding; Roche: Other: Travel Grants; NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018.