Pediatric Sickle Cell Disease Patients Research Articles

Urinary Biomarkers for the Assessment of Acute Kidney Injury of Pediatric Sickle Cell Anemia Patients Admitted for Severe Vaso-occlusive Crises.

Sickle cell nephropathy is a progressive morbidity, beginning in childhood, which is incompletely understood partially due to insensitive measures. We performed a prospective pilot study of pediatric and young adult patients with sickle cell anemia (SCA) to assess urinary biomarkers during acute pain crises. Four biomarkers were analyzed with elevations potentially suggesting acute kidney injury: (1) neutrophil gelatinase-associated lipocalin (NGAL), (2) kidney injury molecule-1, (3) albumin, and (4) nephrin. Fourteen unique patients were admitted for severe pain crises and were found to be representative of a larger SCA population. Urine samples were collected at the time of admission, during admission, and at follow-up after discharge. Exploratory analyses compared cohort values to the best available population values; individuals were also compared against themselves at various time points. Albumin was found to be moderately elevated for an individual during admission compared with follow-up ( P = 0.006, Hedge g : 0.67). Albumin was not found to be elevated compared with population values. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephrin were not found to be significantly elevated compared with population values or comparing admission to follow-up. Though albumin was found to be minimally elevated, further research should focus on alternative markers in efforts to further understand kidney disease in patients with SCA.

The Perception of Pediatric Sickle Cell Anemia Patients’ Caregivers toward Bone Marrow Transplantation at NGHA Jeddah, Saudi Arabia

The Perception of Pediatric Sickle Cell Anemia Patients’ Caregivers toward Bone Marrow Transplantation at NGHA Jeddah, Saudi Arabia

Trends in blood transfusion, hydroxyurea use, and iron overload among children with sickle cell disease enrolled in Medicaid, 2004-2019.

There have been significant changes in clinical guidelines for sickle cell disease (SCD) over the past two decades, including updated indications for hydroxyurea, transfusions, and iron overload management. In practice however, there are few studies that examine SCD care utilization over time. We conducted a serial cross-sectional cohort study of pediatric SCD patients from 2004 to 2019 using Georgia Medicaid claims data. For each year, we reported receipt of any transfusion, chronic transfusion, or three or more filled hydroxyurea prescriptions. For children receiving chronic transfusion (six or more annual transfusions), we evaluated iron overload diagnosis, monitoring, and chelation use. Among children with sickle cell anemia (SCA), we examined rates of transfusions and hydroxyurea use. The Cochran-Armitage test was used to assess trend. There were 5316 unique children 2-18years old with SCD enrolled in Georgia Medicaid from 2004 to 2019. Children receiving any transfusion increased from 2004 to 2010, then stabilized. In SCA patients, chronic transfusions initially increased from 2004 to 2010, then stabilized from 2010 to 2019. For chronically transfused children, monitoring of iron burden and filled chelator prescriptions both increased significantly. Hydroxyurea use in SCA patients increased from 12% to 37%, with increases noted within each age group, most notably from 21% to 60% in the 13-18-year-old cohort. We demonstrated changes in SCD care utilization over time, including increased hydroxyurea use, changes in transfusion rates, and increased attention to iron overload management. While trends in clinical management do follow updates in treatment guidelines, there is still delayed and suboptimal uptake of guideline recommendations in pediatric SCD patients.

Echocardiographic Evaluation in Paediatric Sickle Cell Disease Patients: A Pilot Study

Cardiovascular involvement has a great impact on morbidity and mortality in sickle cell disease (SCD). Currently, few studies are available regarding the paediatric setting and, moreover, current guidelines for the echocardiogram screening program in the asymptomatic paediatric population are controversial. We performed a retrospective observational monocentric study on 64 SCD patients (37 male and 27 female, median age 10) at the Bambino Gesù Childrens' Hospital, who had undergone a routine transthoracic echocardiogram. In total, 46 (72%) patients had at least one cardiac abnormality. Left atrial dilatation (LAD) was present in 41 (65%) patients and left ventricular hypertrophy (LVH) was found in 29 (45%) patients. Patients with LAD showed lower median haemoglobin levels (p = 0.009), and a higher absolute reticulocyte count (p = 0.04). LVH was negatively correlated with the median haemoglobin value (p = 0.006) and positively with the reticulocyte count (p = 0.03). Moreover, we found that patients with cardiac anomalies had higher transfusion needs and a lower frequency of pain crises. In our setting, cardiac involvement has a high prevalence in the paediatric cohort and seems to be associated with specific laboratory findings, and with a specific clinical phenotype characterized by complications related to high haemodynamic load.

Pediatric Sickle Cell Disease Patients on Hydroxyurea Have Higher Rates of Surgical Splenectomy

IntroductionWe sought to investigate whether hydroxyurea therapy is associated with the need for surgical splenectomy among patients with sickle cell disease (SCD). We hypothesized that as hydroxyurea gained widespread use, surgical splenectomy among pediatric patients with SCD occurred at a higher rate and older age among those taking hydroxyurea. MethodsIn this retrospective cross-sectional study, the Pediatric Health Information System was queried for all SCD International Classification of Diseases 9/10 diagnosis codes and splenectomy procedure codes from January 1, 2005, to December 31, 2020. Hydroxyurea use was defined as at least one hospital admission with hydroxyurea listed as a medication. The rates of surgical splenectomy, age at splenectomy, hospital length of stay, and incidence of blood transfusion during the splenectomy admission were compared among patients receiving hydroxyurea versus those not receiving hydroxyurea. Additional subanalysis was performed in the Hemoglobin-SS, Hemoglobin-SC, and Other cohorts separately. ResultsDuring the study period, 28,520 patients were identified. All patients with SCD receiving hydroxyurea had a significantly higher rate of surgical splenectomy compared with the nontreatment group (7.2% versus 3.2%, P = 0.01). The age at surgical splenectomy was significantly younger among Hemoglobin-SS patients receiving hydroxyurea (5.7 [5.1, 6.4] y versus 6.6 [5.8, 7.4] y; P < 0.01). There were no significant differences in length of stay or incidence of blood transfusion during the surgical splenectomy admission between treatment groups. ConclusionsHydroxyurea use in children is associated with higher rates of surgical splenectomy and occurs at a younger age in the Hemoglobin-SS population. Although these findings warrant further investigation for causality, it provides useful information to clinicians and patients alike, allowing for more informed decision-making.

Alterations in the Humoral Immunophenotype of Children with Sickle Cell Disease on Hydroxyurea

Background: Sickle Cell Disease (SCD) is a red blood cell disorder associated with hemolysis and inflammation affecting homeostasis of the blood system. Both innate and T-cell driven adaptive immune systems are involved in SCD-linked inflammation. The involvement of B-cell compartment in etiology of SCD is much less studied. While complex interactions of ischemia-reperfusion, inflammation, and hemolysis affecting the bone marrow and immune system have been studied in adults with SCD, much less is known how their interplay affects SCD etiology in children. Objective: To determine the range of immune changes we assessed the frequency of 12 immune populations via flow cytometry, evaluated B cell related cytokines, and performed bulk RNA sequencing of the peripheral blood (PB) of pediatric patients with SCD as compared to pediatric race-matched controls as well adult patients with SCD as compared to adult race-matched controls. Method: Adult control PB was obtained from Rhode Island Blood Center. Pediatric control and pediatric and adult SCD PB were obtained from Rhode Island Hospital Hematology and Primary Care clinics. All informed consents/assents were obtained. PB samples were stained using markers identifying 12 immune populations including CD8, CD4, T Regulatory, B cells, Plasmablasts, Monocytes, Dendritic, Granulocytes, Neutrophils, Basophils, Eosinophils, and Stem Cells. Flow cytometry was performed on BDTM LSRII and analyzed using FlowJo. RNA was isolated from pediatric SCD or control PB and RNA-seq was performed by Novogene. Plasma from all patients (SCD and controls) was processed for cytokine analysis using Biolegend's LEGENDplex Human B Cell Panel. Demographics, clinical, and laboratory data were obtained from chart review. Results: Thirteen pediatric patients (ages 1-16, mean 8.7 years) and 12 adult patients (ages 8-15, mean 32.2 years) with SCD on Hydroxyurea were enrolled. HbSS genotype was found in 92.3% pediatrics and 66.7% adults. Mean Hydroxyurea dose was 23.4 mg/kg or 20.0 mg/kg for pediatric or adult SCD, respectively. Five pediatric controls (ages 9-14, mean 11.4 years) and 10 adult controls (ages 18-53, mean 31.0 years) were enrolled. Laboratory data indicated elevated hemolysis in pediatric and adult SCD with mean Absolute Reticulocyte Count (ARC) 203 ± 94.2 for pediatric SCD and 214 ± 169 for adult SCD. Flow cytometry data revealed 1.9-fold increase (p= 0.012) of CD3+CD4+ cells in Pediatric SCD versus pediatric controls, this change was not seen in adult SCD versus adult controls (Table 1). Pediatric SCD patients had 3.5-fold increase (p=0.005) in CD19+ B cells without further increase in differentiated B cells, this change was not seen in adult SCD versus adult controls (Table 1). Subsequent analysis of B cell related cytokines revealed significant increase in IL2 (p =0.013), IL4 (p=0.026), TNFβ (p= 0.039), and IL13 (p=0.034) in pediatric SCD versus pediatric controls; there was no significance for these cytokines in adult SCD versus adult controls. BAFF was elevated in both pediatric and adult SCD versus age-matched controls (p=0.041 and p=0.005, respectively). Finally, bulk RNA sequencing of pediatric SCD or control PB indicated significant changes in transcripts linked to humoral immunity. Over Representation Analysis (ORA) of cell type revealed upregulation of transcripts linked to pro-B cells (29 genes), plasma cells (37 genes) and CD34 Positive Pre-B cells (10 genes), (Figure 1). These results suggested significant alteration of the B cell maturation in pediatric SCD samples. Conclusions: Our data indicate significant changes in CD4+ and CD19+ cells in pediatric SCD patients versus controls. Increased CD4+ cell frequencies in children with SCD were previously reported (PMID 29926339). Our new finding of altered humoral immunity and differentiation of B cells noted by flow cytometry were consistent with elevated B-cell related cytokine levels in pediatric SCD versus pediatric controls. Elevated levels of pro-B cells, plasma cells, and CD34+ pre-B cell transcripts detected by RNA-seq in pediatric SCD patients versus controls further confirmed humoral alterations in pediatric SCD samples. Our findings point to previously unreported effect of SCD on the humoral immune system in children with SCD treated with Hydroxyurea, warranting further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Relationship of Sleep and Pain in Pediatric Sickle Cell Disease

Background: Pain interference and sleep problems (sleep disturbance and sleep-related impairment) are prevalent complications experienced by pediatric patients living with sickle cell disease (SCD). If sleep problems contribute to increased pain interference, sleep-directed behavioral interventions could be an additional non-opioid approach to minimizing pain in SCD patients. We hypothesized that sleep disturbance and sleep-related impairment are associated with an increase in pain interference. Second, we studied the prevalence of a later chronotype (preferred timing of sleep) and social jetlag (difference in sleep patterns during the week and weekend), which are measures of circadian sleep patterns, in pediatric patients with SCD. Methods: We performed a IRB approved cross-sectional survey of pediatric patients with SCD aged 8-17 years at a single clinic visit using PROMIS (Patient Reported Outcomes Measurement System) pain interference, sleep disturbance and sleep-related impairment item banks, which utilize T-scores to measure the severity of these parameters; greater scores in each domain signify greater severity. The µMCTQ (ultra-short Munich Chronotype Questionnaire) assessed mid-sleep time (a proxy for chronotype) and social jetlag. Analyses were performed to assess associations between PROMIS measures, sleep patterns and clinical variables using JMP Pro16 (Cary, NC). Results: One hundred and five patients (mean age: 13.1±2.6 years; 53 male, 52 female) completed the PROMIS sleep and pain measures. All participants approached completed the PROMIS evaluation for pain and sleep. The majority of patients (81.9%) were diagnosed with either HbSS or HbSβ0 -thalassemia and 61% were on hydroxyurea (alone or with an additional sickle cell modifying therapy). Pain interference was significantly associated with both sleep disturbance (r=0.49, p<0.0001) and sleep-related impairment (r=0.46, p<0.0001). In multivariate analysis for pain interference, both sleep disturbance (p=0.0007) and sleep-related impairment (p=0.006) remained in the model. Females participants reported higher T-scores for sleep-related impairment than males (females: 56.7± 10 vs males 50.2± 9.4, p=0.0009). Patients with one or more ED visits for pain in the last year reported greater sleep disturbance (55.0±8.5 vs 50.7± 10, p=0.046) and sleep-related impairment (57.1± 9.3 vs 52.1± 10.2, p=0.026) (Figure). The average mid-sleep time (clock time) was 4:14 ± 1:44 AM and the average social jetlag (hh:mm) was 2:32 ± 1:35. Conclusion: Pain interference is associated with both sleep disturbance and sleep-related impairment and our 100% acceptance rate for completing PROs highlights the clinical importance of performing formal sleep and pain assessments. A longitudinal examination of sleep and pain in pediatric SCD patients is needed to determine if sleep problems and pain have a bi-directional relationship. Furthermore, the high prevalence of later mid-sleep times and social jetlag in this sample suggests that longitudinal studies should incorporate measures of sleep timing and social jetlag impact on pain. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Understanding Caregiver Burden with Accessing Sickle Cell Care and Their Perspective on Telemedicine

Background: Sickle cell disease (SCD) is associated with a wide range of complications. However, a multitude of barriers prevent SCD patients from receiving adequate healthcare, including difficulties with transportation and lack of provider knowledge about disease sequelae. Importantly, studies have demonstrated the benefits of telemedicine in addressing barriers to healthcare. Few studies have explored barriers which affect the pediatric SCD patient population in areas such as the Midwest, wherein the geographical landscape can prohibit healthcare access. Furthermore, few studies have established acceptability of telemedicine among caregivers and patients with SCD. The objective of this study was to increase understanding of barriers to care and perceptions of telemedicine by caregivers of pediatric SCD patients. Methods: An 88-item statewide survey was distributed to caregivers of children with SCD cared for at Riley Hospital for Children in Indianapolis, IN. Caregivers were contacted by the research team via secure text messaging or in-person. Questions for the survey were developed based on previously performed semi-structured interviews with caregivers and the validated Barriers to Care Questionnaire (BCQ). The survey included questions regarding their experience accessing care, including barriers and facilitators of care, as well as their perspective on the use of telemedicine in SCD. Responses were analyzed using t-tests or chi square tests where appropriate. Results: Of the 300 caregivers contacted, 101 completed the survey, resulting in a response rate of 34%. The majority had 1 child with SCD, with most having Hb SS genotype. Eighteen percent of families drove more than 1 hour to access comprehensive sickle cell care. Caregivers reported having a median of 2 other healthcare providers that their child regularly sees. However, nearly 10% did not have an established primary care provider. Caregivers identified a median number of 6 barriers to accessing SCD care, with other household responsibilities, childcare, lost time from work and school as the most common. About 20% of caregivers felt these barriers affected their and/or their child's well-being and/or mental health at times, yet less than half reported their healthcare team ever discussing ways to address these barriers. Approximately 40% felt having a child with sickle cell disease impacted their daily stress and/or mental health. Sixty-three percent of caregivers worried about others (e.g. school staff) caring for their child, and nearly 50% worried about the care and knowledge of medical providers other than their SCD team. Forty percent of caregivers had participated in some form of telemedicine, the majority being direct-to-consumer. Eighty-one percent were willing to participate in telemedicine visits sometimes or always. However, nearly half felt the lack of a physical exam was a negative for telemedicine, and about 25% stated it was harder to build trust via telemedicine. Willingness to participate in telemedicine was not associated with prior telemedicine use, perceived positives/negatives of telemedicine, caregiver worry about others caring for their child, or distance from SCD center. Conclusion: The experiences of caregivers accessing healthcare for their child with SCD suggests caregiver burden and barriers to care that may be unique to patients with SCD. Additionally, while the majority are willing to participate in telemedicine for future sickle cell care, the negatives of telemedicine that caregivers reported are significant. Future studies should evaluate models of telemedicine care adapted for this specific population.

Association of Promis Pediatric Profile Parent Proxy 25 with Clinical and Functional Outcomes in Pediatric Sickle Cell Disease Patients

Background: Patient reported outcomes (PROs) can be critical in allowing the clinical team to understand patients' perspectives on their quality of life (QoL) and functioning. PROs can serve as a basis for fostering shared decision making and individualized care. Patients with sickle cell disease (SCD) often experience a high symptom burden and PROs can be an important tool for improving patients' health. In the case of pediatric patients, guardian proxy reports may give additional insight since children may be too young to complete assessments themselves. Additionally, guardian perceptions can influence healthcare-related decision making. Understanding the relationships between guardian-reported PROs with clinical outcomes, such as healthcare utilization, and functional impairment may provide a valuable tool for shaping clinical decisions. Here, we examine the relationships between the six domains of QoL using the parent proxy version of the Patient Reported Outcome Measurement System (PROMIS), healthcare utilization and functional limitations in children with SCD. Methods: Pediatric patients and their guardians between the ages of 5 and 18 were approached while attending outpatient appointments at Children's Hospital of Richmond Comprehensive Sickle Cell Clinic. Children who were ill or in pain were excluded from enrollment during that visit. Consented guardians (n=43) completed a demographic questionnaire that included questions on recent healthcare utilization followed by the PROMIS Parent Proxy Pediatric Profile-25 with short forms assessing depression and sadness, pain interference, fatigue, anxiety and fear, mobility, and peer relations during the prior seven days. Outcome variables of interest included emergency department (ED) utilization and hospitalizations in the previous six months; acute SCD-related events in the prior year (acute chest syndrome, right upper quadrant syndrome, skeletal and joint issues, hand/foot issues, CNS involvement, acute anemia, sepsis, priapism), missed school days/planned activities due to SCD pain in the prior 30 days as well as academic performance. Counts and percentages were used to describe characteristics of children and guardians; t-tests were used to examine the relationship between domains of the PROMIS and outcome variables of interest. Specifically, we dichotomized all outcomes of interest, and then examined the means and 95% confidence intervals of the dichotomized groups for each of the PROMIS domains. Results: Demographic characteristics of both guardians and children are described in Table 1. Thirty five percent of participants had a hospitalization and 44% had an ED visit in the previous six months, 33% had an acute SCD event in the prior year, 62% reported one or more missed days of school/activities and 38% reported grades lower than a B. Healthcare utilization (ED visit and hospitalization) and acute medical events were all significantly associated with higher levels of proxy-reported pain interference, fatigue, and anxiety/fear; ED visits was also associated with higher levels of proxy-reported depression and sadness (Table 2). Missed days of school were associated with greater proxy-reported pain interference and decreased mobility while none of the domains were associated with grades achieved. Conclusions: Despite being administered during non-sick visits, multiple PROMIS Parent Proxy Pediatric Profile-25 domains that assessed QoL in the past seven days were associated with previous healthcare utilization in the past six months, acute medical events in the past year and missed school days in the past month. PROs can provide valuable information to clinicians, suggesting both the importance of addressing QoL outcomes for patients with recent healthcare events and the usefulness of guardian responses. The association of these PROs with clinical outcomes suggests that the PROMIS may be used prospectively to help identify and prevent further disease-related impairment and healthcare use. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Surveillance for Sickle Cell Disease - Sickle Cell Data Collection Program, Two States, 2004-2018.

Surveillance for Sickle Cell Disease - Sickle Cell Data Collection Program, Two States, 2004-2018.

Satisfaction and access to care for adults and adolescents with sickle cell disease: ASCQ‐Me quality of care and the SHIP‐HU study

A lack of adult sickle cell providers has long been blamed for poor satisfaction and access to specialty care for adults with sickle cell disease (SCD). We were interested in comparing how adolescent and adult patients already in established SCD centers perceived access and quality of care. Hydroxyurea-eligible patients aged 15 years and older were enrolled in the Start Healing in Patients with Hydroxyurea trial, which required them to be affiliated with a SCD specialist. Patients were seen in one of three adult-oriented specialty clinic sites or one of three pediatric-oriented sites. At baseline, patients completed the Adult Sickle Cell Quality of Life Measurement Information System measure as part of a survey battery. Patients treated at adult clinic sites reported being less able to get timely ambulatory appointments (p=.004). They reported emergency department (ED) wait times of >1h far more often (47.7 vs. 19.3%, p=.0048). They reported less overall satisfaction with care (7.47 vs. 8.77, p<.0001), and less satisfaction with care in the ED (2.88 vs. 3.4, p=.0068. Ambulatory satisfaction was no different between pediatric site versus adult site patients. Poorer systems of care appeared to underlie reported differences, rather than differences in biopsychosocial determinants. Even among specialty-care-affiliated SCD patients, those seen in adult clinics reported worse access to care and lower satisfaction with care than patients seen in pediatric clinics. In addition to increasing the number of adult SCD providers and better preparing pediatric SCD patients to transfer to adult programs, SCD clinical caregivers must also improve aspects of adult care quality to meet reasonable patient expectations of timeliness and interpersonal aspects of care quality.

Genetic modulation of anemia severity, hemolysis level, and hospitalization rate in Angolan children with Sickle Cell Anemia.

Sickle Cell Anemia (SCA) is a genetic disease caused by the c.20A > T mutation in HBB gene, generally characterized by sickle erythrocytes, chronic hemolytic anemia, and vaso-occlusive events. This study aimed to investigate genetic modulators of anemia severity, chronic hemolytic rate, and clinical manifestations in pediatric SCA patients from Angola, where the disease is a severe public health problem. The study was conducted on 200 SCA children living in Luanda or Caxito province. Their clinical phenotype was collected from patients' hospital records. Hematological and biochemical phenotypes were characterized in steady state condition. Twelve polymorphic regions in VCAM1, CD36 and NOS3 genes were genotyped using PCR, RFLP, and Sanger sequencing. CD36 gene promoter variants showed a significant impact on anemia severity. Particularly, the rs1413661_C allele was associated with lower hemoglobin levels, and increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA phenotypic heterogeneity. Moreover, the rs1041163_C allele in VCAM1 was associated with lower LDH levels; inversely the rs2070744_C allele in NOS3 was related with higher LDH levels and number of hospitalizations, being a risk factor for increased hemolytic rate. This study highlights, for the first time in the Angolan population, the importance of the genetic modifiers of vascular cell adhesion and nitric oxide metabolism in SCA pediatric phenotypic variability.

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease.

One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD.

Recent advances in "sickle and niche" research - Tribute to Dr. Paul S Frenette.

SummaryIn this retrospective, we review the two research topics that formed the basis of the outstanding career of Dr. Paul S. Frenette. In the first part, we focus on sickle cell disease (SCD). The defining feature of SCD is polymerization of the deoxygenated mutant hemoglobin, which leads to a vicious cycle of hemolysis and vaso-occlusion. We survey important discoveries in SCD pathophysiology that have led to recent advances in treatment of SCD. The second part focuses on the hematopoietic stem cell (HSC) niche, the complex microenvironment within the bone marrow that controls HSC function and homeostasis. We detail the cells that constitute this niche, and the factors that these cells use to exert control over hematopoiesis. Here, we trace the scientific paths of Dr. Frenette, highlight key aspects of his research, and identify his most important scientific contributions in both fields.

In-Depth Immunological Typization of Children with Sickle Cell Disease: A Preliminary Insight into Its Plausible Correlation with Clinical Course and Hydroxyurea Therapy.

Sickle cell disease (SCD) is a condition of functional hypo-/a-splenism in which predisposition to bacterial infections is only a facet of a wide spectrum of immune-dysregulation disorders forming the clinical expression of a peculiar immunophenotype. The objective of this study was to perform an in-depth immunophenotypical characterization of SCD pediatric patients, looking for plausible correlations between immunological biomarkers, the impact of hydroxyurea (HU) treatment and clinical course. This was an observational case–control study including 43 patients. The cohort was divided into two main groups, SCD subjects (19/43) and controls (24/43), differing in the presence/absence of an SCD diagnosis. The SCD group was split up into HU+ (12/19) and HU− (7/19) subgroups, respectively receiving or not a concomitant HU treatment. The principal outcomes measured were differences in the immunophenotyping between SCD patients and controls through chi-squared tests, t-tests, and Pearson’s correlation analysis between clinical and immunological parameters. Leukocyte and neutrophil increase, T-cell depletion with prevalence of memory T-cell compartment, NK and B-naïve subset elevation with memory and CD21low B subset reduction, and IgG expansion, significantly distinguished the SCD HU− subgroup from controls, with naïve T cells, switched-memory B cells and IgG maintaining differences between the SCD HU+ group and controls (p-value of <0.05). The mean CD4+ central-memory T-cell% count was the single independent variable showing a positive correlation with vaso-occlusive crisis score in the SCD group (Pearson’s R = 0.039). We report preliminary data assessing plausible clinical implications of baseline and HU-related SCD immunophenotypical alterations, which need to be validated in larger samples, but potentially affecting hypo-/a-splenism immuno-chemoprophylactic recommendations.

Moyamoya syndrome and stroke among pediatric sickle cell disease patients in Sudan: A cross-sectional study

BackgroundSickle cell disease (SCD) is autosomal recessive hemolytic anemia due to hemoglobinopathy commonly in Sub-Saharan Africa, and particularly in Sudan. The disease induces a pro-inflammatory cascade in the intimal layer that leads to hyperplasia and progressive stenosis in the major vessel of the circle of Willis. This is associated with the development of Moyamoya collaterals. The aim of this study is to highlight the frequency of Moyamoya syndrome in Sudanese pediatric patients with sickle cell disease presenting with stroke. Materials and methodsA descriptive cross-sectional hospital-based study was conducted in the Department of Hematology at Gaafar Ibnauf Pediatric Tertiary Hospital in Khartoum state in Sudan, in the period between March 2021 and August 2021. Secondary data has been collected from the medical record after ethical approval and informed consent. ResultsA total of 104 patients were included in the study. The males were the majority, about 60 (57.7) compared to 44 (42.3%) females. More than half of our study population was in the school-age 54 compared to 42 adolescents and only 8 patients of preschool age. Only 50 out of 104 patients had diagnostic MRA which revealed features of Moyamoya syndrome in 48 (96%) patients. Motor weakness (100%), aphasia (52.9%), and facial palsy (35%) were the major stroke presentations. The left anterior circulation territory was the most common site of moyamoya features involvement in 31 patients out of 48. ConclusionStroke is a common problem in Sudanese pediatric patients with sickle cell disease, with a very high frequency of Moyamoya vasculopathy among patients with stroke presentation. The burden of Moyamoya syndrome in Sudanese pediatric patients with sickle cell disease is underestimated due to the cost of the available screening and diagnostic tools.

Regional anesthesia for sickle cell disease vaso-occlusive crisis: A single-center case series.

Pain management is challenging for patients with sickle cell disease (SCD) who present in vaso-occlusive crisis (VOC). Opioid therapy is highly effective, nevertheless undesirable side effects can hinder their effectiveness. Regional anesthesia with deposition of perineural anesthetic offers nociceptive blockade, local vasodilatation, and reduces the inflammatory response. Among pediatric patients, continuous peripheral nerve block (CPNB) for perioperative adjunctive analgesia is safe. Herein, we describe the trajectory of a cohort of pediatric SCD patients with opioid-refractory upper-extremity VOC following placement of CPNBs for analgesia; highlighting reduced opioid consumption, improved pain scores, and decreased length of hospitalization.

Peroxiredoxin-2 recycling is slower in denser and pediatric sickle cell red cells.

Peroxiredoxin-2 (Prx-2) is a critical antioxidant protein in red blood cells (RBC). Prx-2 is oxidized to a disulfide covalently-bound dimer by H2 O2 , and then reduced back by the NADPH-dependent thioredoxin-thioredoxin reductase system. The reduction of oxidized Prx-2 is relatively slow in RBCs. Since Prx-2 is highly abundant, Prx-2s' peroxidase catalytic cycle is not considered to be limiting under normal conditions. However, whether Prx-2 recycling becomes limiting when RBCs are exposed to stress is not known. Using three different model systems characterized by increased oxidative damage to RBCs spanning the physiologic (endogenous RBCs of different ages), therapeutic (cold-stored RBCs in blood banks) and pathologic (RBCs from sickle cell disease (SCD) patients and humanized SCD mice) spectrum, basal levels of Prx-2 oxidation and Prx-2 recycling kinetics after addition of H2 O2 were determined. The reduction of oxidized Prx-2 was significantly slower in older versuin older versus younger RBCs, in RBCs stored for 4-5weeks compared to 1week, and in RBC from pediatric SCD patients compared to RBCs from control non-SCD patients. Similarly, the rate of Prx-2 recycling was slower in humanized SCD mice compared to WT mice. Treatment of RBC with carbon monoxide (CO) to limit heme-peroxidase activity had no effect on Prx-2 recycling kinetics. Treatment with glucose attenuated slowed Prx-2 recycling in older RBCs and SCD RBCs, but not stored RBCs. In conclusion, the reduction of oxidized Prx-2 can be further slowed in RBCs, which may limit the protection afforded by this antioxidant protein in settings associated with erythrocyte stress.

Health-Related Quality of Life Assessments by Children and Adolescents with Sickle Cell Disease and Their Parents in Portugal.

Health-Related Quality of Life (HRQL) can be used to measure the impact of Sickle Cell Disease (SCD) on the child and their family and is generally reduced. No research has yet measured HRQL in Portuguese pediatric SCD patients. Objectives: (1) Describe and compare HRQL of children with SCD reported by them and their parents; (2) Compare with a pediatric population with no SCD; (3) Find predictive factors of HRQL in SCD children. Methods: Descriptive, case-control study that included sixty-eight children and adolescents with SCD (aged 3 to 18 years) and their parents. Control group—children with no SCD, matched by age, gender and ethnic background. HRQL was assessed using the multidimensional self-report PedsQL® 4.0 Generic Scales. Summary scores for overall HRQL and subscale scores for physical, emotional, social and school functioning were compared within groups (children-parents) and with the control group. Clinical and socio-demographic variables were analyzed to find predictive factors of HRQL in pediatric SCD patients. Results: Children with SCD and their parents had significantly lower overall and all subdomains of HRQL, compared with the control group. Children with SCD also rated lower when compared with their parents (only significant for social functioning), with low to moderate correlations. Children and parent reports declined with increasing age. Higher pain frequency was associated with worse total and psychosocial domains of HRQL. The number of hospitalizations was a predictor of worse school score, and female gender was a predictor of worse emotional score. Conclusions: SCD significantly affects children’s HRQL. Parents can provide a good proxy report, although both evaluations are beneficial. Disease status, like number of hospitalizations and frequency of pain, influences HRQL. Interventions in SCD should consider improvements in HRQL as an important outcome.

Hematopoietic Stem Cell Transplantation Stabilizes Cerebral Vasculopathy in High-Risk Pediatric Sickle Cell Disease Patients: Evidence From a Referral Transplant Center.

BackgroundSevere sickle cell disease (SCD) can present with different vaso-occlusive manifestations with cerebral vasculopathy (CV) as one of the most serious complications. Hematopoietic stem cell transplant (HSCT) is the ultimate therapy for this complication. The aim of this study was to assess the outcome and impact of HSCT on severe SCD patients with CV complications.MethodsTwenty-five consecutive transplants-naive pediatric SCD patients with CV complications underwent HSCT at our institution between 1993 and 2015, using bone marrow as stem cells source from fully match related donors were included. Neurologic evaluation was done both clinically and radiologically before transplantation and regularly following the HSCT.ResultsWith a median follow-up of 52.2 ± 5.8 months, the cumulative probability of overall survival (OS) at 3 years was 92.0% and event-free survival (EFS) was 88%. Significant neurologic improvements were observed in most of the patients clinically. Different neurologic complications were assessed. The neurologic manifestations before and after HSCT were hemiparesis (11, 1), seizures (13, 8), focal neurologic deficit (4, 2), loss of conscious (2, 1) headache (6, 1), and psychological symptoms (5, 2). Post-HSCT radiological imaging was done in 15 patients, which showed stabilization of CV among all.ConclusionsAllogeneic HSCT in patients with severe SCD presenting with CV complications including moyamoya vasculopathy showed favorable outcome with significant clinical neurologic improvement and stabilization of the disease. None of the patients with severe vasculopathy underwent neurological vascular by-pass surgery prior to HSCT.