Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Kidney failure outcomes in children and young adults with sickle cell disease in the United States Renal Data System.

BACKGROUND: Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood, with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with kidney failure (chronic kidney disease stage 5) due to SCD are not well described. This study aimed to assess the outcome of children and young adults with SCD with kidney failure compared to matched children and young adults without SCD with kidney failure in a large national database. METHODS: Utilizing the United States Renal Data System (USRDS), we retrospectively examined kidney failure outcomes in children and young adults with SCD from 1998 to 2019. RESULTS: We identified 97 patients with SCD who developed kidney failure and identified 96 matched controls with a median age of 19 years (IQR 17, 21) at the time of kidney failure diagnosis. SCD patients had significantly shorter survival (8.4 years vs. 14.0 years, p < 0.001) and had a longer waiting time for their first transplant when compared to matched non-SCD kidney failure patients (12.1 years vs. 7.3 years, p < 0.001). CONCLUSIONS: Children and young adults with SCD kidney failure have significantly higher mortality when matched to non-SCD kidney failure children and experience a longer mean time to kidney transplant.

End Stage Kidney Disease Outcomes in Children and Young Adults with Sickle Cell Disease in the United States Renal Data System.

Background: Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with end stage kidney disease (ESKD) due to SCD is not well described. This study aimed to assess the burden and outcomes of ESKD in children and young adults with SCD in a large national database. Methods: Utilizing the United States Renal Data System (USRDS) we retrospectively examined ESKD outcomes in children and young adults with SCD from 1998 - 2019. Results: We identified 97 patients with SCD that developed ESKD and identified 96 matched controls with median age of 19 years (IQR 17, 21) at time of ESKD diagnosis. SCD patients had significantly shorter survival (7.0 years vs. 12.4 years, p < 0.001) and had a longer waiting time to their first transplant when compared to matched non-SCD-ESKD patients (10.3 years vs. 5.6 years, p < 0.001). Conclusions: Children and young adults with SCD-ESKD have a significantly higher mortality when matched to non-SCD-ESKD children and experience a longer mean time to kidney transplant.

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Pediatric refractory immune thrombocytopenia: A systematic review.

Pediatric immune thrombocytopenia (ITP) is an acquired disorder associated with autoimmune destruction and impairment of platelet production in children. Some children exhibit poor or transient response to ITP-directed treatments and are referred to as having refractory ITP (rITP). There is currently no consensus on the definition of rITP, nor evidence-based treatment guidelines for patients with rITP. After a survey of pediatric ITP experts demonstrated lack of consensus on pediatric rITP, we pursued a systematic review to examine the reported clinical phenotypes and treatment outcomes in pediatric rITP. The search identified 253 relevant manuscripts; following review, 11 studies proposed a definition for pediatric rITP with no consensus amongst them. Most definitions included suboptimal response to medical management, while some outlined specific platelet thresholds to define this suboptimal response. Common attributes identified in this study should be used to propose a comprehensive definition, which will facilitate outcome comparisons of future rITP studies.

Consensus definition of essential, optimal, and suggested components of a pediatric sickle cell disease center.

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Sickle Cell Disease and the Kidney: Filters Gone Awry.

Throughout the lifespan, the kidney of a person with sickle cell disease is at increased risk of injury to the glomeruli, tubules, and renal vasculature. This injury manifests as urine concentrating defects, enuresis, albuminuria, acute kidney injury, chronic kidney disease, and end-stage kidney disease. The outcomes for patients who progress to end-stage kidney disease are poor and access to organ transplantation is limited. Therefore, identifying risk factors for progression, intervening with renoprotective agents early in life, and improving access to care are vital for sickle cell patients.

The association between sleep disturbances and neurocognitive function in pediatric sickle cell disease.

BACKGROUND AND OBJECTIVE: Youth with sickle cell disease (SCD) without neurological complications continue to be at increased risk of neurocognitive difficulties. Nocturnal hypoxemia is associated with neurocognitive outcomes and has been identified as a chronic complication in youth with SCD. The objective of this study was to assess the relationship between sleep disturbances and neurocognitive functioning in youth with SCD, while taking into account demographic and socioeconomic factors. METHODS: Youth with SCD were identified through retrospective chart review who underwent a standardized polysomnography (PSG) and completed a neuropsychological testing battery to assess cognitive skills, including verbal comprehension, working memory, processing speed, and cognitive flexibility. Questionnaires were also collected to assess parent-reported concerns with their youth's executive and adaptive skills. RESULTS: Twenty-seven youth with SCD, ages 6-17, were identified who completed both a PSG and neuropsychological testing. Results demonstrated that verbal comprehension decreased by 2.37 standard points for every unit decrease in mean nocturnal oxygen saturation (SpO2) (p = 0.031). Working memory was also found to decrease by 1.46 standard points for each 1% increase in time spent under 90% oxygen saturation (pTST SpO2 < 90%) (p = 0.030). Sleep parameters did not significantly predict other cognitive scores or parent-reported executive or behavioral ratings. CONCLUSION: Our study found that sleep disturbance, mean nocturnal SpO2 and pTST SpO2 < 90%, significantly affected verbal comprehension and working memory performance, respectively. Overall, these findings have the potential to identify sleep needs in youth with SCD to promote sleep-targeted interventions as a modifiable factor to reduce neurocognitive deficits.

Enuresis and Hyperfiltration in Children With Sickle Cell Disease.

Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSß 0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.

The influence of perceived racial bias and health-related stigma on quality of life among children with sickle cell disease.

Objectives: Individuals with sickle cell disease (SCD) experience significant health problems that may result in unpredictable pain episodes and frequent healthcare utilization. Disparities in clinical care may contribute to health-related stigma and racial bias for this majority African-American/Black population. There is less known about the influence of health-related stigma and racial bias on the health-related quality of life (HRQOL) of children with SCD. In the present study, we assessed these relationships and identified differences across demographic factors (i.e. age, gender).Design: Data was collected from African American children with SCD aged 8-16 years (57% male, 63% HbSS). Children completed the Childhood Stigma Scale (adapted for SCD), the Child Perceptions of Racism in Children and Youth scale, and the Pediatric Quality of Life Inventory Sickle Cell Disease Module. Caregivers provided demographic information.Results: In the first regression model, health-related stigma (p = .007) predicted HRQOL, but neither age nor gender were significant predictors. In the second regression model, age (p = .03) predicted HRQOL, but neither gender nor racial bias were significant predictors. Of interest, there was a significant interaction between age, gender, and racial bias (p = .02). Specifically, older girls who reported high levels of perceived racial bias had poorer HRQOL.Conclusions: Our study highlights the need for increased awareness about the effects of health-related stigma and racial bias on HRQOL for children with SCD, particularly for older girls who endorse racial bias. Our findings will guide future stigma and bias reduction interventions that may meet the needs of older girls with SCD.

Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease.

OBJECTIVE: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. CONCLUSIONS: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.

American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease.

BACKGROUND: Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. METHODS: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed. CONCLUSIONS: Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management.

Hyperfiltration predicts long-term renal outcomes in humanized sickle cell mice.

We previously reported that humanized sickle cell (HbSS) mice develop spontaneous nephropathy, a major cause of morbidity and mortality in sickle cell disease (SCD). Because sex-dependent protective mechanisms in SCD have been reported, we examined the course of nephropathy in male and female HbSS mice to determine contributors and/or predictors of disease severity. In male HbSS mice, glomerular filtration rate was characterized by a rapid onset of hyperfiltration and subsequent progressive decline of renal function over 20 weeks. Early tubular injury presented with increased excretion of kidney injury marker 1 (KIM-1), progressive loss of tubular brush border, and interstitial fibrosis that preceded the onset of glomerular damage, suggesting a tubuloglomerular mechanism of kidney injury in these mice. Additionally, we observed a strong association between the magnitude of hyperfiltration and the degree of long-term kidney injury in male HbSS mice. Unlike males, female HbSS mice did not demonstrate a significant loss of renal function or severe kidney damage during the time course of the study. These results suggest that magnitude of hyperfiltration predicts the onset of chronic kidney damage in male HbSS mice, whereas protective mechanisms in female HbSS mice delay the onset of SCD nephropathy.

Effect of Sickle Cell Anemia Therapies on the Natural History of Growth and Puberty Patterns.

As pediatric patients with sickle cell anemia (SCA) have impaired growth and puberty patterns, we studied the effect of disease-modifying therapies on growth and puberty patterns for patients with SCA receiving hydroxyurea (HU), transfusions, or no therapy. We performed a retrospective study of children with SCA in whom anthropometric measurements and therapy type were recorded. Penalized smoothing splines were fitted to estimate growth curves and growth velocity, and linear mixed models were used to examine differences across treatment groups. Across group analyses were divided into early childhood (4.0 to 7.9 y) and peripubertal (8.0 to 12.0 y). We analyzed growth data on 157 SCA patients. From 8.0 to 12.0 years, girls on transfusion therapy were significantly taller than girls on HU (range, 5.7 to 7.2 cm; P-value range 0.002 to 0.01). From 10.0 to 12.0 years, boys on transfusion therapy were significantly taller than boys on HU (range, 4.1 to 9.4 cm; P-value range <0.0001 to 0.04). In addition, boys on transfusion therapy had an earlier peak height velocity as compared with boys on either HU or no therapy. In conclusion, children receiving transfusions tended to be taller than children on HU or no therapy. Children on HU did not demonstrate superior growth pattern when compared with children on no therapy in the peripubertal years.

Hyperfiltration during early childhood precedes albuminuria in pediatric sickle cell nephropathy.

BACKGROUND: In patients with diabetes mellitus, hyperfiltration precedes the development of albuminuria. Pediatric sickle cell anemia (SCA) patients have a high prevalence of hyperfiltration and albuminuria during early childhood and adolescence. We tested the hypothesis that hyperfiltration precedes the development of albuminuria in a longitudinal pediatric SCA cohort. METHODS: We identified 91 participants with HbSS or SB0 thalassemia 5-21 years of age enrolled in a longitudinal sickle cell nephropathy cohort study who had a cystatin C measured during early childhood (4-10 years of age). Early hyperfiltration was defined as a mean eGFR >180 mL/min/1.73m2 using cystatin C obtained from 4 to 10 years of age. Persistent albuminuria was defined as an albumin to creatinine ratio > 30 mg/g on two of three untimed urine specimens. Time to event analysis estimated survival curves for participants with and without hyperfiltration using Kaplan-Meier curves and used logrank test for categorical variables to assess the association with time to development of the first episode persistent albuminuria. RESULTS: Persistent albuminuria occurred more often and at an earlier age in participants with early hyperfiltration compared to those without early hyperfiltration (log-rank, P = .004). Participants who developed albuminuria have a significant increase in their eGFR during childhood (P = .003) as compared to participants who have not yet progressed to albuminuria (P = .26). For every 1 g/dL increase in hemoglobin, the hazard ratio for developing persistent proteinuria decreased by 0.56 (95% CI: 0.3, 1.06, P = .07). CONCLUSION: Hyperfiltration precedes the development of persistent proteinuria in pediatric SCA patients. Intervention strategies should target lowering eGFR during early childhood.

Outcomes of febrile events in pediatric patients with sickle cell anemia.

BACKGROUND: Limited evidence exists to create institutional admission criteria guidelines for febrile sickle cell patients. In addition, evidence is lacking to understand readmission rates for febrile sickle cell patients discharged from the emergency department (ED) or hospital. PROCEDURES: We conducted a 16-year retrospective study of bacteremia outcomes for febrile sickle cell patients. Risk variables analyzed included fever (either ≥ 39.5°C or ≥40°C), abnormal white blood cell (WBC) (>30,000 or <5,000/mcL), tachycardia and hypotension, or "ill appearing." Fourteen-day readmission rates were analyzed to determine outcomes for febrile sickle cell patients discharged from the ED or discharged within 72 h. RESULTS: Bacteremia was identified in 17 (2.6%) of 653 febrile events that are presented to the ED. "Ill-appearing" patients had an 8.5-fold increased odds of being diagnosed with bacteremia. Models using WBC count, "ill appearing," and hypotension have the highest sensitivity and specificity (AUC > 0.75). Among 427 patients discharged from the ED or within 72 h of hospitalization, only 10 (2.3%) were readmitted for a new sickle cell complication. CONCLUSIONS: Institutions can develop admission criteria based on WBC count, hypotension, and "ill appearance." Persistently febrile, well-appearing patient can be discharged at 48 h with minimal risk for new complications.