Evaluation, analysis, and reporting of medication adherence for clinical trials of anticoagulants in children: Guidance from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

In response to growing recognition that non-adherence prevents children, adolescents, and young adults from achieving the therapeutic benefits of anticoagulant medication, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis convened a working party on medication adherence. The primary aim of this manuscript was to synthesize recommendations from the larger adherence science literature to provide guidance regarding the classification, collection, and interpretation of anticoagulation adherence data. The secondary aim of this manuscript was to evaluate the degree to which trials published from 2013 to 2023 adhered to these guidance recommendations. As less than half of all trials reported on adherence and none included all recommended elements, the proposed ISTH SSC guidance has the potential to enhance the rigor and reproducibility of pediatric anticoagulant research.

Secondary Reporting of G6PD Deficiency on Newborn Screening.

In April 2019, the Alberta Newborn Screening Program expanded to include screening for classic galactosemia using a two-tier screening approach. This approach secondarily identifies infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The goals of this study were (i) to evaluate the performance of a two-tier galactosemia screening protocol, (ii) to explore the impact on and acceptability to families of reporting G6PD deficiency as a secondary finding, and (iii) assess the communication and follow-up process for positive G6PD deficiency screening results. The two-tiered galactosemia approach increased the positive predictive value (PPV) for galactosemia from 8% to 79%. An additional 119 positive newborn screen results were reported for G6PD deficiency with a PPV of 92%. The results show that there may be utility in reporting G6PD deficiency results. Most parents who participated in the study reported having some residual worry around the unexpected diagnosis; however, all thought it was helpful to know of their child's diagnosis of G6PD deficiency. Finally, the communication process for reporting G6PD deficiency newborn screen results was determined to result in appropriate follow up of infants.

ADaPTS "(AD)olescents (P)ath through (T)ransplant (S)ickle cell disease".

BACKGROUND: Sickle cell disease is an inherited chronic hematological disorder with an average lifespan of fifty years. The human cost of sickle cell disease includes missed school days, occupational opportunities, social isolation, stigmatization, and psychological sequelae. Hematopoietic cell transplantation (HCT) is the only curative therapy available but comes with potential morbidity and mortality. Our study explores how quality of life (QoL) is affected from the perspective of an adolescent who has undergone a nonmyeloablative matched sibling donor HCT. METHODS: We employed multiple case study methodology with purposeful sampling by selecting information-rich cases. DATA SOURCES: 1) QoL inventories 2) patient interviews 3) parent interview 4) vital support interview 5) medical record analysis. DATA ANALYSIS: Intra-case analysis by assembling evidence within a single case and then analyzing the differences within cases to create a rich case description. Next, a time series analysis was completed to track changes in patients' QoL. We used multiple sources of data to compose a timeline and changes across time. Then, we employed pattern matching as an analytical technique allowing for examination of patterns across cases. Finally, we used cross case synthesis to review results of each case. RESULTS: Quality of life was reported across the physical, social and psychological domains for 5 participants. All had sickle cell HgSS genotype, 80% were male and 80% were born outside of Canada. Physical domain: pre-transplant, 100% of patients experienced pain, and the majority suffered from fatigue, insomnia, and fevers resulting in hospitalizations. Afterwards, participants reported improved physical wellbeing. Social domain: pre-transplant, QoL was poor characterized by stigma, social isolation, and parental absenteeism. Post-HSCT adolescents gained social acceptance in areas that had stigmatized and excluded them. They were able to participate freely in activities with peers and their social life vastly improved. Psychological pre-transplant life experiences were overshadowed by psychological stress. The majority commented that their future was bleak and may lead to premature death. Afterwards adolescents described a crisis free life with positive psychological outcomes. CONCLUSIONS: Adolescents with sickle cell disease who undertook HCT demonstrated improved QoL one year post transplant with regard to physical, social and psychological well-being.

Mental health impacts of the COVID-19 pandemic on children with underlying health and disability issues, and their families and health care providers.

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.

Pediatric Benign Neutropenia: Assessing Practice Preferences in Canada.

Pediatric benign neutropenia is a self-limited condition with a benign clinical course. An approach to this condition is not well-defined in the literature. Our objective was to use a case-based survey to elucidate trends in the diagnosis and management of benign neutropenia among pediatric hematology/oncology practitioners in Canada. We received 46 completed surveys (response rate 66%). At initial presentation with fever and neutropenia, 67% of respondents recommended partial septic workup but 11% recommended no investigations. Nearly 70% recommended admission for empiric intravenous antibiotics, while 24% would discharge home without antibiotics. In a patient with fever and known neutropenia, respondents were more likely to pursue outpatient antibiotic therapy. For investigation of chronic neutropenia, most respondents (60%) do not use antineutrophil antibody testing. Common indications for bone marrow biopsy were severe infection, prolonged neutropenia, or before initiating granulocyte colony stimulating factor. Indications for granulocyte colony stimulating factor were based on severity and frequency of infection. Most respondents (84%) would not recommend antibiotic prophylaxis. Results demonstrate the considerable variability in management of benign neutropenia among pediatric hematology/oncology practitioners in Canada and highlight the need for prospective studies to establish diagnostic criteria for benign neutropenia and evaluate management of fever in this population.

Peripheral Nucleated Red Blood Cells and Mortality in Critically Ill Children.

The present retrospective cohort study examines whether there is an association between circulating nucleated red blood cells (nRBCs) and mortality in critically ill children. nRBCs are erythropoietic progenitor cells not found in peripheral blood of healthy adults and children beyond the neonatal period. The presence of circulating nRBCs is associated with poor prognosis in adults and neonates, though little is known about their significance in children. Admissions to both the general and cardiac pediatric intensive care unit at the Stollery Children's Hospital in Edmonton, Alberta between January 1, 2015 and December 31, 2017 were examined, and logistic regression was performed to ascertain the association between the peak absolute nRBC counts and in-hospital mortality in critically ill children. A total of 2065 admissions were included. The number of admissions with detectable nRBCs was 386 (prevalence: 13.9%), and the number of deaths was 93 (mortality: 4.5%). A statistically significant association was found between the absolute value of nRBC peak and intensive care unit mortality (odds ratio=1.37; 95% confidence interval: 1.13-1.67; P=0.002) as well as hospital mortality (odds ratio=1.38; 95% confidence interval: 1.12-1.70; P=0.003) independent of the Pediatric Index of Mortality 3 score (PIM3). This result warrants more attention to nRBC values and their potential clinical use.

The Alberta Newborn Screening Approach for Sickle Cell Disease: The Advantages of Molecular Testing.

Sickle cell disease (SCD), a group of inherited red blood cell (RBC) disorders caused by pathogenic variants in the beta-globin gene (HBB), can cause lifelong disabilities and/or early mortality. If diagnosed early, preventative measures significantly reduce adverse outcomes related to SCD. In Alberta, Canada, SCD was added to the newborn screening (NBS) panel in April 2019. The primary conditions screened for are sickle cell anemia (HbS/S), HbS/C disease, and HbS/ß thalassemia. In this study, we retrospectively analyzed the first 19 months of SCD screening performance, as well as described our approach for screening of infants that have received a red blood cell transfusion prior to collection of NBS specimen. Hemoglobins eluted from dried blood spots were analyzed using the Bio-Rad™ VARIANT nbs analyzer (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Targeted sequencing of HBB was performed concurrently in samples from all transfused infants. During the period of this study, 43 of 80,314 screened infants received a positive NBS result for SCD, and of these, 34 were confirmed by diagnostic testing, suggesting a local SCD incidence of 1:2400 births. There were 608 infants with sickle cell trait, resulting in a carrier frequency of 1:130. Over 98% of non-transfused infants received their NBS results within 10 days of age. Most of the 188 transfused infants and 2 infants who received intrauterine transfusions received their final SCD screen results within 21 ± 10 d of birth. Our SCD screening algorithm enables detection of affected newborns on the initial NBS specimen, independent of the reported blood transfusion status.

Screening and diagnosis of heparin-induced thrombocytopenia in the pediatric population: A tertiary centre experience.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a life-threatening side effect of heparin necessitating immediate heparin discontinuation. A missed diagnosis of HIT carries significant morbidity and mortality, while overdiagnosis may result in unnecessary and potentially harmful use of alternative anticoagulants in the pediatric population. We aimed to determine the proportion of HIT screening tests at our pediatric tertiary care centre ultimately leading to a diagnosis of HIT by functional assay (either lumi-aggregometry or serotonin-release assay). We hypothesized that the frequency of HIT at our centre would be lower than that reported in the literature. MATERIALS AND METHODS: We conducted a retrospective review including children aged 0 to 18 years who had HIT testing performed at our centre between 2010 and 2018 (N = 189; 51% female). A screening enzyme immunoassay, if positive, is followed by a functional assay which must be positive to establish the diagnosis of HIT. Data were analyzed to establish trends in demographic and clinical features of patients with a positive HIT screening test. Our primary outcome was the rate of HIT confirmed by functional testing amongst children screened for HIT from 2010 to 2018. RESULTS AND CONCLUSIONS: There were 233 screening tests performed on 189 distinct patients. Only one patient (0.4%) received a diagnosis of HIT based on functional assay. This patient was a 16-year-old female later found to have a JAK2 mutation. The false positive rate of the enzyme immunoassay was 9.4% (N = 22). There were no positive enzyme immunoassay tests in the neonatal age group (N = 49). These results reinforce that HIT is rare in children.

Recommendations from parents, administrative staff and clinicians to improve paediatric ambulatory appointment scheduling.

BACKGROUND: Stakeholders can provide valuable input to improve scheduling paediatric ambulatory clinic appointments, a complex process that requires effective planning and communication between parents, administrative staff and clinicians. The purpose of our study was to characterize recommendations from parents, administrative staff and clinicians to improve paediatric ambulatory appointment scheduling. METHODS: Conducted between February 2018 and January 2019, this qualitative study was guided by qualitative description. Data collection was completed using focus groups with three stakeholder groups: parents, administrative staff and clinicians. Participants provided recommendations to optimize paediatric ambulatory appointment scheduling at the Stollery Children's Hospital in Edmonton, Alberta, Canada. Focus group data were transcribed verbatim and analysed using manifest inductive content analysis. RESULTS: Forty-six participants (mean age: 42.7; 87% female) participated in 12 focus groups. Parents (n = 11), administrative staff (n = 22) and clinicians (n = 13) made recommendations that were organized into two categories: appointment triaging and arranging. Triaging recommendations were related to appointment availability (e.g. providing alternatives to cancelling clinics with short notice) and waitlist management (e.g. developing clear and consistent policies regarding information flow and communication between clinics and administrative staff). Appointment arranging recommendations referred to booking (e.g. directly involving parents in the booking process), reminders (e.g. using text message reminders) and attendance (e.g. providing parents with a single point of contact who can provide the correct information about late and cancellation policies). Recommendations were similar across stakeholder groups. CONCLUSION: Our findings showed congruent recommendations across stakeholder groups to address challenges with scheduling ambulatory appointments, many of which have the potential to be modified. Experimental research and quality improvement initiatives are needed to determine the feasibility, acceptability and effectiveness of stakeholder recommendations to improve triaging and scheduling paediatric ambulatory appointments.

Measuring the impact of hemophilia on families: Development of the Hemophilia Family Impact Tool (H-FIT).

INTRODUCTION: This study aimed to assess the impact of hemophilia on families, in the context of current and emerging hemostatic therapies, and explore the need for a hemophilia-specific tool targeted at parents of boys aged <4 years. A secondary aim was to develop and validate the new tool. METHODS: Focus groups were conducted with parents of boys with hemophilia and hemophilia health care providers at Canadian hemophilia treatment centers (HTCs) to review the relevance of the Pediatric Quality of Life Family Impact Module (PedsQL-FIM); a novel questionnaire was developed by identifying core themes expressed. This questionnaire, the Hemophilia Family Impact Tool (H-FIT) was validated in a sample of parents of boys with hemophilia relative to the PedsQL-FIM. RESULTS: Seven focus groups were conducted at four HTCs, generating themes specific to hemophilia not covered by the PedsQL-FIM, suggesting that a new tool be developed (the H-FIT). In the validation phase, 54 parents completed the H-FIT and PedsQL-FIM. The H-FIT had a strong correlation with the PedsQL-FIM across all ages (r = 0.79; P < .0001) and a moderate correlation for parents of boys aged <7 years (r = 0.64; P = .0007). There was a significant difference between the mean H-FIT scores for parents of boys using extended half-life factor (68.1; standard deviation [SD]=14.2) compared to standard half-life factor (54.7; SD=18.4; P = .04). CONCLUSION: A novel, disease-specific tool, the H-FIT, has been developed to measure the impact of hemophilia on families. The H-FIT has good preliminary measurement properties and may be responsive to changes in therapy associated with a decreased burden of administration.

Updating the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) in the era of extended half-life clotting factor concentrates.

INTRODUCTION: The purpose of this study was to review and update the content of the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool version 2.0 (CHO-KLAT), in the context of extended half-life (EHL) factor concentrates (FCs) and to establish the validity and reliability of the updated CHO-KLAT. METHODS: Focus groups were conducted with boys with hemophilia, their parents, and health care providers across Canada to review the CHO-KLAT v2.0 and determine if any modifications were required. The validity of the revised CHO-KLAT (version 3.0) was then determined in a sample of boys with hemophilia and their parents by calculating its correlation with the Pediatric Quality of Life Core Module (PedsQL-Core). Test-retest reliability was assessed using an intraclass correlation coefficient (ICC). RESULTS: Thirteen focus groups at 5 pediatric hemophilia treatment centers (HTCs) (n = 71) resulted in 19 changes to the CHO-KLAT v2.0, generating a revised 40-item CHO-KLAT, the CHO-KLAT v3.0. Thirty-five boys with hemophilia (median age, 14; range, 7-17 years) and 47 parents participated in the validation of the CHO-KLAT v3.0. There was a moderate correlation between the CHO-KLAT v3.0 child self-report and PedsQL-Core (r = 0.56, P = .01), and a strong correlation between the CHO-KLAT v3.0 parent-proxy and PedsQL-Core (r = .79, P = .0007). The test-retest reliability ICC was 0.90 for the child self-report CHO-KLAT v3.0 and 0.68 for the parent-proxy CHO-KLAT v3.0. CONCLUSION: The CHO-KLAT v3.0 is a reliable and valid child-centric tool that effectively measures health-related quality of life in boys with hemophilia who are receiving standard half-life or EHL FCs.

Pediatric ambulatory appointment scheduling: a qualitative study of stakeholders' perceptions and experiences.

OBJECTIVE: Scheduling ambulatory clinic appointments includes a complex set of factors and diverse stakeholders. Families, administrative staff and clinicians may have varied experiences with scheduling clinic appointments. The objective of our study was to understand stakeholders' perceptions and experiences with scheduling pediatric ambulatory clinic appointments. DESIGN: Guided methodologically by qualitative description, focus groups were conducted separately with three stakeholder groups and analyzed using qualitative content analysis. SETTING: This qualitative study was completed at a children's hospital in Alberta, Canada. PARTICIPANTS: Parents, administrative professionals and clinicians who used the pediatric ambulatory scheduling system regularly to elicit perceptions and experiences about issues and areas where improvements could be made. RESULTS: Across 12 focus groups, parents (n = 11), administrative professionals (n = 23) and clinicians (n = 13) discussed areas for improvement related to the pediatric ambulatory scheduling system. The perceived areas for improvement were grouped into three categories regarding levels of influence: (i) 'intrapersonal': knowledge, skills and behaviors (e.g. insufficient training of administrative professionals); (ii) 'interpersonal': communication processes (e.g. parents not receiving confirmation letters); and (iii) 'institutional': structures and processes (e.g. varying practices and processes across clinics). CONCLUSIONS: Stakeholders provided a rich description of the interrelated factors and processes that influenced the scheduling of pediatric ambulatory clinic appointments. Multilevel, experimental interventions are needed to test whether the findings described herein can enhance the structure and function of pediatric ambulatory appointment scheduling.

Fludarabine, Campath, and Low-Dose Cyclophosphamide (FCClow) with or without TBI Conditioning Results in Excellent Transplant Outcomes in Children with Severe Aplastic Anemia.

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCClow) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCClow (± TBI) conditioned transplantation in children with SAA.

Stable renal function in children and adolescents with sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation.

BACKGROUND: Sickle cell disease (SCD) is associated with renal complications starting as early as infancy. Allogeneic hematopoietic stem cell transplant (HSCT) treatments using newer nonmyeloablative (NMA) conditioning regimens show promising results in treating SCD in the pediatric population, but renal outcome parameters after transplantation have not been described. AIM: To describe baseline renal parameters as well as short- and long-term renal outcomes in pediatric patients with SCD who underwent NMA-HSCT. METHODS: A retrospective chart review of pediatric patients who received NMA-HSCT in Alberta, Canada. Short-term renal outcomes evaluated were: (1) acute kidney injury (AKI), (2) fluid overload (FO), and (3) hypertension. Long-term outcomes evaluated were: (1) estimated glomerular filtration rate (eGFR) development and at last follow-up with hyperfiltration defined as eGFR ≥ 150 mL/min/1.73 m2 , (2) proteinuria, and (3) hypertension. RESULTS: The mean follow-up time was 128.6 weeks (standard deviations, 69.3). No posttransplant AKI events or FO were observed. eGFR remained > 90 mL/min/1.73 m2 at last follow-up in all patients, whereas hyperfiltration was present in eight (44.4%) and four (22.2%) patients pre- and post-HSCT, respectively, which are significantly different (P < 0.0001). Consequently, median GFR was significantly higher pre-HSCT compared with 24 months HSCT (P < 0.009). Long-term hypertension post-HSCT was present in six patients (33.3%). CONCLUSION: This study describes stable kidney function in children with SCD after NMA-HSCT without evidence of AKI or FO episodes. Rates of hyperfiltration decreased post-HSCT, which signifies that NMA-HSCT could potentially preserve long-term renal function in this population at risk of progressive chronic kidney disease. Further prospective studies are needed to confirm these novel findings.

Tilt-table Echocardiography Unmasks Early Diastolic Dysfunction in Patients With Hemoglobinopathies.

Individuals with hemoglobinopathy (sickle cell anemia and thalassemia major) are at risk for cardiac complications such as heart failure and cardiomyopathy. Diastolic dysfunction is known to precede systolic dysfunction in many cardiac diseases. This study sought to determine whether changes in left atrial (LA) function during manipulation of cardiac preload by tilt-table echocardiography can unmask subclinical diastolic dysfunction in pediatric patients with hemoglobinopathies. Eleven sickle cell anemia, 9 transfusion-dependent thalassemia major, and 10 control subjects underwent tilt-table echocardiogram in the supine (loading) and 30-degree upright (unloading) positions and cardiac magnetic resonance imaging (MRI). Echocardiography assessed LA and left ventricular (LV) strain, strain rate, mitral inflow, and annular velocities. MRI assessed LV function, myocardial T1 and T2* for iron deposition. Both thalassemia major and sickle cell anemia patients had normal LV function and no evidence of cardiac iron deposition on MRI T2* measurements. During cardiac loading, controls appropriately increased LA conduit (P=0.002) and reservoir strain (P=0.002), mitral e' velocity (P<0.0001) and medial e' velocity (P=0.002), while the hemoglobinopathy patients showed no change in these parameters. In pediatric sickle cell anemia and thalassemia, tilt-table echocardiography unmasked a failure to augment LA function in response to loading, suggesting altered myocardial relaxation is present, before evidence of iron overload or systolic dysfunction.

Cold External Temperatures and Sickle Cell Morbidity in Children: A Retrospective Analysis.

BACKGROUND: Genetic and environmental factors affect the occurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). Research provides inconsistent evidence on how environmental temperature affects SCD. Edmonton, Alberta, has an increasing SCD population and is the northern-most city in North America with a population of over a million. OBJECTIVE: The objective of this study was to identify whether pediatric patients with SCD experience increased morbidity in cold external temperatures. MATERIALS AND METHODS: This study was a retrospective case series. Emergency visits, phone calls, and admission data for VOC in children were recorded from July 2011 to June 2016. Temperatures were recorded and statistically analyzed using descriptive statistics, to determine the relation to VOC. RESULTS: A total of 118 patients with 257 VOC events were reviewed. When analyzing the mean, minimum, and change in temperatures at presentation, the largest percentage of VOC events occurred at mild to moderate temperatures. Temperature data at 24 and 48 hours before the presentation had similar results. When accounting for the relative frequency of extreme weather days, there are increased VOC events with temperature fluctuations >20°C. CONCLUSIONS: There was no correlation between mean and minimum temperature change. Fluctuation in temperature of >20°C was associated with increased relative VOC frequency, suggesting that large temperature variability should be avoided in SCD, but a prospective study is required to determine causality.

Supplemental oxygen therapy recommendations in patients with sickle cell disease during air travel: A cross-sectional survey of North American health care providers.

INTRODUCTION: Air travel may expose patients with sickle cell disease (SCD) to an increased risk of disease-related complications. Several factors are felt to contribute including prolonged hypoxia, dehydration, temperature changes, and stress. The Canadian Paediatric Society (CPS) position statement, published in 2007, recommends that SCD patients use supplemental oxygen on flights. While the National Heart, Lung and Blood Institute (NHLBI) recommend that SCD patients dress warmly, stay hydrated, and move about the cabin. Other guidelines do not make specific recommendations. METHODS: A cross-sectional online survey was circulated through the Canadian Hemoglobinopathy Association (CanHaem) and American Society of Pediatric Hematology and Oncology (ASPHO) listservs to North American health care practitioners (HCPs). Participants were asked to share their air travel recommendations for patients with SCD. Similarly, a patient survey regarding experiences with air travel was circulated through the Sickle Cell Disease Association of Canada (SCDAC) and the Sickle Cell Foundation of Alberta (SCFOA) listservs and discussion boards. RESULTS: Although air travel is perceived to be a risk factor for sickling complications, only 18% of HCPs recommend supplemental oxygen. Most HCPs advise patients to increase hydration, carry analgesics, and wear warm clothes to prevent sickling complications. The patient survey was limited by a low response rate. CONCLUSION: The majority of HCPs are not routinely recommending prophylactic oxygen to patients with SCD during air travel.