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.

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.

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.

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.

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.

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.

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.

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.

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.

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease.

Sickle cell disease is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT) with a matched sibling donor. The National Institutes of Health nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated granulocyte colony stimulating factor mobilized peripheral blood stem cells. All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date. Two patients have donor myeloid chimerism in the range of 30% to 40%. No sickling crises post-HCT have been observed. Event-free and overall survival rates are 100% with median follow-up of 19.5 months. No cases of GVHD have been observed. Sirolimus weaning was possible in all but one eligible patient to date. Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen in children.

"A complex interface: Exploring sickle cell disease from a parent's perspective, after moving from Sub-Saharan Africa to North America".

INTRODUCTION: Sickle cell disease (SCD) is an inherited, multi-system, chronic disease with the highest prevalence affecting people of Sub-Saharan African descent. While major advances in SCD care have occurred over the last few decades in many African countries these advances are not readily available. Prior literature from Ghana and Kenya describe stigma, despair, and economic burden as well as hope when a child has SCD. When people migrate to North America with a child with SCD it is unknown whether their perception of the disease changes. We asked, "How do immigrant parents of children with SCD from Sub-Saharan Africa perceive, and manage the disease in the context of western medical care?" METHODS: The research question was explored with qualitative methodology, specifically focused ethnography. Semi-structured interviews were conducted with parent(s). The interviews were audio recorded, transcribed, and open coded. Rigor was determined through methodological coherence, appropriate and sufficient sampling, and iterative data collection and analysis. RESULTS: Twelve interviews were conducted. Identified themes are as follows: memories of SCD in Africa, the emotional journey towards acceptance, and parental approach to care for their child. CONCLUSIONS: Healthcare providers should be responsive to an immigrant families' needs and not expect linear progression of emotional acceptance to the diagnosis. Healthcare providers patience with the process helps establish trust, works to facilitate and encourage hope and acknowledges the strength of the families, and their dedication to their family member. Healthcare providers should acknowledge parents' sources of support (religion/family) and ensure parents are aware of medical advances.

Coagulopathy in Children With Liver Disease.

It was thought that a high international normalized ratio predicted bleeding in patients with chronic liver disease (CLD) and patients were "autoanticoagulated." Contrary to this belief, while patients with CLD experienced bleeding, they also developed thromboses. In the last decade, the prevailing literature challenged the idea that an elevated international normalized ratio increased bleeding risk. The global assays of coagulation such as thromboelastography (TEG)/rotational thromboelastometry and thrombin generation assays provide additional insight into coagulation processes. It has become apparent that a parallel reduction of procoagulant and anticoagulant factors leave patients in a new "balanced" state, albeit a fragile one, where the balance can be easily disrupted. The inherent differences in coagulation between children and adults such as differences in levels of procoagulant and anticoagulant factors, underlying liver disease, and the paucity of studies in children make extrapolation of these findings to the pediatric population problematic. Ultimately, this is an area that requires further investigation to avoid inappropriate use of blood products and medication.

Immunizations in Children Requiring Warfarin Therapy.

Children with conditions requiring chronic warfarin therapy have increased. The importance of receiving immunizations in this population is magnified due to potential weakness in their immune response. There is concern about immunizing on therapeutic anticoagulation due to risk of hematomas and the influence of vaccine on warfarin metabolism. This study evaluated the influence of vaccines on warfarin effect as measured by the International Normalized Ratio and the clinically relevant hematomas or bruising postimmunization. There were no clinically relevant negative outcomes postimmunizations. This study demonstrates that immunizations may be safely administered to children receiving therapeutic warfarin therapy.

Refractory cardiogenic shock in a patient with ß-thalassemia major requiring mechanical circulatory support: Case report and literature review.

Iron overload cardiomyopathy secondary to ß-thalassemia major is a potentially reversible condition managed with chelation and medical hemodynamic support, as bridge-to-recovery or transplant. We describe our experience, and challenges faced, in a pediatric patient with iron overload cardiomyopathy secondary to ß-thalassemia major, requiring biventricular MCS.

The Changing Epidemiology of Pediatric Hemoglobinopathy Patients in Northern Alberta, Canada.

BACKGROUND: Hemoglobinopathies are associated with significant morbidity and mortality. Accurate epidemiologic data reflecting the number of hemoglobinopathy patients are lacking in Canada. Immigration patterns are shifting such that regions where these diseases were rare are seeing a rapid population expansion, revealing a gap in the health care system and the need for a public health response. METHODS: To understand the epidemiology of pediatric hemoglobinopathy patients given the provincial population growth and immigration patterns, a retrospective chart review was conducted at the Stollery Children's Hospital from January 2004 to July 2014. RESULTS: A total of 88% of patients had sickle cell disease; 55% of patients were Canadian born and 63% of families originated from Africa. There was a 3.5-fold increase in patient numbers with acceleration in patient accrual over the study period and a delay in diagnosis in 70% of patients. There was a significant increase in the number of hospitalizations over the study period. Thirteen percent required at least 1 exchange transfusion, 16% received chronic transfusions, and 30% of patients developed at least 1 severe complication related to their diagnosis. CONCLUSIONS: It is imperative to demonstrate the growing hemoglobinopathy population and changing health care requirements to advocate for appropriate resources, educate health care providers, and increase awareness.

Bedside to bench: The risk of bleeding with parenteral omega-3 lipid emulsion therapy.

Our clinical experience led us to reassess the effect of sole omega-3 lipid therapy on hemostasis. We compared thromboelastography platelet mapping in neonatal piglets given sole omega-3 lipid. We identified abnormalities in reaction time (P = .025) and the arachidonic acid pathway (P = .025). The potential for bleeding complications from parenteral omega-3 lipid emulsion therapy in high-risk infants with liver disease has been dismissed but, on the basis of this data, should be reconsidered.