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.

Assessment of Liver Fibrosis by Transient Elastography in Children and Young Adults With Sickle Cell Disease With and Without Iron Overload.

Transfusion-associated iron overload may cause liver fibrosis. We compared transient elastography (TE) and aspartate aminotransferase-platelet ratio index (APRI), noninvasive markers for hepatic fibrosis, to liver histology in children and young adults with sickle cell disease (SCD) who were iron overloaded (cohort 1). Age-matched subjects with SCD but without iron overload (cohort 2) were enrolled for APRI and TE assessments. Nineteen subjects ages 10 to 21 years were transfused for a mean of 9.67 years, had a mean serum ferritin of 4899±2849 ng/mL, and a liver iron concentration of 15.56±10.12 mg/g dry liver weight by R2-magnetic resonance imaging. Mean APRI was 0.33±0.13 in cohort 1 and 0.27±0.10 in cohort 2. The mean liver stiffness measures (LSM) in cohort 1, assessed by TE, was 8.46±3.95 kPa, ranging from 3.5 to 14.6 kPa (expected normal <7 kPa). Cohort 2 had a mean LSM of 5.72±1.74 kPa (4.6 to 8.7 kPa). There was a good correlation between LSM and histologic fibrosis (t value 6.94, P<0.0001). There was no significant correlation between APRI and histologic fibrosis and between APRI and LSM. A high LSM suggests liver fibrosis in children and adults with SCD with iron overload and may merit histologic confirmation especially if persistent.

Evolving Strategies in the Management of Sickle Cell Disease in the 21st Century and the Role of the Pediatrician.

Sickle cell disease (SCD) is one of the most common genetic disorders in the United States. Once a fatal disease of childhood, the majority of patients born with SCD who live in a developed country will survive to adulthood (albeit with slightly shortened life spans). Despite numerous novel therapeutic advancements in recent years that serve to mitigate the symptoms associated with SCD, the only cure for SCD is a hematopoietic stem cell transplant. The overall survival for patients with a matched sibling donor transplant is greater than 90%. However, fewer than 20% of patients with SCD in the US have a 12/12 human leukocyte antigen (HLA) matched sibling donor. In contrast, most patients have at least one HLA haploidentical first-degree relative, which expands the donor pool for patients who have diseases amenable to stem cell transplantation such as SCD. [Pediatr Ann. 2022;51(1):e34-e39.].

Stroke and stroke prevention in sickle cell anemia in developed and selected developing countries.

This comprehensive review provides an insight into the pathophysiology, epidemiology, evaluation, and treatment of sickle cell anemia (SCA)-related stroke in developed and developing countries. Vascular injury, hypercoagulability and vaso-occlusion play a role in the pathophysiology of stroke in SCA. Transcranial Doppler ultrasound (TCD) has lowered the incidence of ischemic stroke from 11% to 1% as TCD identifies children who are at risk for stroke, providing opportunities for interventions to reduce this risk. Whereas blood exchange is indicated in acute stroke, chronic transfusions (either simple or exchange on a monthly basis) are used for primary as well as secondary stroke prevention in developed countries. Children with abnormally high TCD velocities (≥ 200 cm/s) are at high risk of stroke and might benefit from hydroxyurea or hydroxycarbamide (HU) after a period of a successful transition from chronic transfusions. Hematopoietic stem cell transplant presents a cure for SCA. Gene therapy is currently investigated and may be offered to patients with SCA who had a stroke or who are at high risk of stroke if proven efficacious and safe. However, gene therapy is not likely to be implemented in low-income countries due to cost. Alternatively, HU is utilized for primary and secondary stroke prevention in developing countries. Further expansion of TCD implementation should be a priority in those settings.

Renal medullary carcinoma and sickle cell trait: A systematic review.

Sickle cell trait (SCT) carries a small risk of renal medullary carcinoma (RMC). We conducted a systematic literature review and reported new four RMC cases (total N = 217). Eighty eight percent had SCT and 8% had sickle cell disease; 50% were children. Males had 2.4× risk than females. Isolated hematuria or in combination with abdominal or flank pain was the presenting sign in 66% cases. Tumor-related mortality was 95%. Four non-metastatic patients were long-term disease-free survivors. Although risk appears to be very low, individuals with SCT should be informed about the low risk of RMC with the hope of early diagnosis. Hematuria should prompt immediate investigation.

Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload.

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

Hemophilic Pseudotumor: An Important Differential Diagnosis of an Intracranial Mass.

Hemophilic pseudotumor is a rare complication of hemophilia. We present the case of a male toddler with moderate hemophilia A and cranial hemophilic pseudotumor managed with factor VIII infusions. We also provide a review of the literature. Recognition of this rare manifestation of this complication of hemophilia is important to provide correct treatment and avoid unnecessary investigations, particularly biopsy, which is contraindicated in this condition.

Abnormalities in renal tubular phosphate handling in children with sickle cell disease.

BACKGROUND: The mechanisms responsible for the hyperphosphatemia in patients with sickle cell disease (SCD) and preserved glomerular filtration rate (GFR) are not fully understood. The role of fibroblast growth factor 23 (FGF23), a phosphaturic hormone has not been investigated in SCD. Hence, we evaluated parameters of renal tubular phosphorus handling and their relation to prevailing FGF23 levels in a cohort of young SCD patients. METHODS: Renal tubular phosphate handling and circulating levels of various analytes including FGF23 and parathyroid hormone (PTH) were measured in 24 children with SCD and normal estimated GFR in a cross sectional study. Correlation and regression analysis were employed to derive relationships between serum phosphorus and several variables. RESULTS: Most children showed elevated age- adjusted serum phosphorus (5.1 ± 0.7 mg/dl) levels. Tubular re-absorption of phosphorus(TRP) (96.3 ± 2.1%) and tubular maximum re-absorption of phosphorus per unit volume of GFR (TMP/GFR) (4.9 ± 0.6 mg/dl) were both elevated. Plasma intact FGF23 concentrations were elevated (81 ± 38 pg/ml) while the average PTH values were normal in most patients (50 ± 27 pg/ml). Univariate analysis showed significant correlations of serum phosphorus with TMP/GFR, alkaline phosphatase, age, lactate dehydrogenase (LDH), and log intact FGF23. TMP/GFR correlated with log intact FGF23 (r = 0.5, P< or = 0.01) but not with PTH. Multiple regression analysis yielded an independent relationship of serum phosphorus with TMP/GFR. CONCLUSION: The elevated serum phosphorus concentrations with simultaneously increased TMP/GFR and elevated FGF23 levels collectively suggest that patients with SCD display proximal tubular resistance to the action of FGF23 before any decline in GFR.

Albuminuria correlates with hemolysis and NAG and KIM-1 in patients with sickle cell anemia.

BACKGROUND: Although hyperfiltration and albuminuria are common pathological conditions, kidney injury (KI) biomarkers have been seldom studied in individuals with sickle cell anemia (SCA). METHODS: We undertook a cross-sectional assessment of urine KI biomarkers in children and adults with SCA with and without albuminuria and a normal estimated glomerular filtration rate (eGFR). Albumin, KI molecule 1 (KIM-1), N-acetyl-ß-D-glucosaminidase (NAG), endothelin-1 and transforming growth factor-ß1 (TGF-ß1) were measured. Assays were normalized by urine creatinine. Urine intracellular hemosiderin and serum lactate dehydrogenase (LDH) were assessed as markers of hemolysis. Albuminuria was associated to the biomarkers by Pearson and Spearman correlation coefficients. Differences between the albuminuria (yes, no) groups were assessed by the t test. RESULTS: Nineteen patients with albuminuria (mean urine albumin/creatinine 527.14 ± 1070 mg/g, range 38.3--190 mg/g) and 19 patients without albuminuria (mean urine albumin/creatinine 15.93 ± 5.17 mg/g, range 7.9-28.4 mg/g) were studied. The age range for the whole group was 11-48 years, and 47 % were males. Patients with albuminuria were older, had lower hematocrit, were more likely to test positive for urine hemosiderin and had a higher KIM-1 (P = 0.0035) and NAG/ creatinine ratios (P = 0.0062). Urine hemosiderin strongly correlated to a higher LDH level (P < 0.001). CONCLUSIONS: Despite a normal or increased eGFR, KI biomarkers were detected in the urine of individuals with SCA. NAG, KIM-1 and urine hemosiderin correlated with the presence of albuminuria.

Pain assessment during a vaso-occlusive crisis in the pediatric and adolescent patient: rethinking practice.

Pain assessment of the child and adolescent with sickle cell disease is complex and challenging. We present a paradigm of pain assessment during a vaso-occlusive crisis in children and adolescents based on the Pain Assessment as a Social Transaction model. Using this model, the assessment of pain severity in sickle cell disease is uniquely highlighted as comprising at least 4 key factors: the limitations of current pain assessment tools, the existence of acute pain of various origins and the emergence and coexistence of chronic pain, the prevalence of cognitive deficits, and the sociocultural dynamics in America. Improved tools for pain assessment and targeted practitioner education are warranted.

Sickle cell disease related mortality in the United States (1999-2009).

BACKGROUND: Little is known about the national outcome of children and adults with sickle cell disease (SCD) given contemporary care. PROCEDURE: We investigated the number of deaths, standardized crude and age-adjusted mortality rates, and causes of death among individuals with SCD across the United States during 1999-2009 according to death certificates by using a publicly available website (http://wonder.cdc.gov/). Data were compared to mortality during 1979-1998. RESULTS: When compared to 1979-1998, mortality significantly decreased by 61% in infants <1 year of age, by 67% in children aged 1-4 years, and by 22-35% in children aged 5-19 years. After 19 years of age, mortality rates increased from 0.6 in the 15-19 year group to 1.4/100,000 in the 20-24 year group, corresponding to the transition period from pediatric to adult medical care, and this increase was similar during 1979-1998. Although the age groups with the highest mortality were 35-44 years for males and 45-54 years for females, there was a tendency for longer survival because there were more deaths among those individuals 55-74 years of age compared to previous years. For all individuals, the causes of deaths were cardiac disease (31.6%), respiratory (28.1%), renal (16.4%), infectious (14.4%), neurologic (11.9%), and gastrointestinal and hepatobiliary (9.2%) in nature. Cancer was the cause of death in <1%. CONCLUSION: Mortality during childhood has decreased significantly. However, the transition period from pediatric to adult care is critical. Risk-reduction, monitoring, and early treatment intervention of cardiovascular disease in adults is warranted.

Impact of hydroxyurea on clinical events in the BABY HUG trial.

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).

Durable immune response to inactivated H1N1 vaccine is less likely in children with sickle cell anemia receiving chronic transfusions.

BACKGROUND: Defects in the immune system may affect vaccine responsiveness. Because of the splenic hypofunction and abnormal opsonic activity, it was unknown whether patients with sickle cell disease (SCD) would respond appropriately to H1N1 vaccination. The objective of this study was to assess seroprotective post-vaccine H1N1 antibody response in children with SCD. PROCEDURE: Serum antibody titers were measured by hemagglutination inhibition and microneutralization (MN) assays. Correlations were established between clinical and treatment parameters and immune response. RESULTS: Twenty-nine of 38 (76.3%) subjects (mean age 11 ± 5.4 years) had durable protective antibody titers 8 ± 1.6 months (range 5-12 months) post-vaccination. Lessened immune response was not associated with time interval from vaccination, splenectomy, or hydroxyurea treatment. Lack of antibody response was associated with age less than 3 years and treatment with chronic transfusions. Of the nine non-responders, seven were on chronic transfusions (39% unresponsiveness rate in the transfused group). The difference in the number of patients with seropositivity between the non-transfused and the transfused groups was statistically significant (P = 0.039). CONCLUSIONS: Most subjects were able to mount an influenza-specific antibody response against the inactivated H1N1 vaccine. Similar to the general population, children less than 3 years were less likely to respond. In addition, patients on chronic transfusions were less likely to respond when compared to non-transfused children. Clinicians should be aware of the possibility of decreased vaccine response in patients with SCD on chronic transfusions. We postulate that transfusion-related immunomodulation (TRIM) may be related to decreased response.

Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia.

BACKGROUND: Children with sickle cell anemia (SCA) often develop hyposthenuria and renal hyperfiltration at an early age, possibly contributing to the glomerular injury and renal insufficiency commonly seen later in life. The Phase III randomized double-blinded Clinical Trial of Hydroxyurea in Infants with SCA (BABY HUG) tested the hypothesis that hydroxyurea can prevent kidney dysfunction by reducing hyperfiltration. PROCEDURE: 193 infants with SCA (mean age 13.8 months) received hydroxyurea 20 mg/kg/day or placebo for 24 months. (99m) Tc diethylenetriaminepentaacetic acid (DTPA) clearance, serum creatinine, serum cystatin C, urinalysis, serum and urine osmolality after parent-supervised fluid deprivation, and renal ultrasonography were obtained at baseline and at exit to measure treatment effects on renal function. RESULTS: At exit children treated with hydroxyurea had significantly higher urine osmolality (mean 495 mOsm/kg H(2) O compared to 452 in the placebo group, P = 0.007) and a larger percentage of subjects taking hydroxyurea achieved urine osmolality >500 mOsm/kg H(2) O. Moreover, children treated with hydroxyurea had smaller renal volumes (P = 0.007). DTPA-derived glomerular filtration rate (GFR) was not significantly different between the two treatment groups, but was significantly higher than published norms. GFR estimated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula was the best non-invasive method to estimate GFR in these children, as it was the closest to the DTPA-derived GFR. CONCLUSION: Treatment with hydroxyurea for 24 months did not influence GFR in young children with SCA. However, hydroxyurea was associated with better urine concentrating ability and less renal enlargement, suggesting some benefit to renal function.

Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention.

Chronic transfusion reduces the risk of recurrent stroke in children with sickle cell anemia (SCA) but leads to iron loading. Management of transfusional iron overload in SCA has been reported as suboptimal [1], but studies characterizing monitoring and treatment practices for iron overload in children with SCA, particularly in recent years with the expansion of chelator options, are lacking. We investigated the degree of iron loading and treatment practices of 161 children with SCA receiving transfusions for a history of stroke who participated in the Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) trial. Data obtained during screening, including past and entry liver iron concentration (LIC) measurements, ferritin values, and chelation were analyzed. The mean age at enrollment was 12.9 ± 4 years and the mean duration of transfusion was 7 ± 3.8 years. Baseline LIC (median 12.94 mg/g dw) and serum ferritin (median 3,164 ng/mL) were elevated. Chelation therapy was initiated after a mean of 2.6 years of transfusions. At study entry, 137 were receiving chelation, most of whom (90%) were receiving deferasirox. This study underscores the need for better monitoring of iron burden with timely treatment adjustments in chronically transfused children with SCA.

Stroke With Transfusions Changing to Hydroxyurea (SWiTCH): a phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload.

BACKGROUND: Stroke occurs in 5-10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long-term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload. METHODS: Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH is to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload. DISCUSSION: SWiTCH has several distinctive study features including novel methodological and design components: (1) composite primary endpoint including both stroke recurrence rate and iron burden; (2) non-inferiority design with an "acceptable" increased stroke risk; (3) transfusion goals based on current academic community practices; (4) special oversight for the enrollment and randomization process; (5) overlap treatment period within the alternative treatment arm; (6) masking of the overall trial Principal Investigator to treatment results; (7) inclusive independent stroke adjudication process for all suspected new neurological events; and (8) periodic therapeutic phlebotomy program to alleviate iron overload. CONCLUSION: Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA, stroke, and iron overload.

Increased prevalence of false positive hemoglobinopathy newborn screening in premature infants.

BACKGROUND: The objective was to investigate the specificity of the hemoglobinopathy newborn screening in premature neonates as compared to term neonates. PROCEDURE: The screening results from infants suspected to have hemoglobinopathy disease identified by the Florida Newborn Screening Program for years 2002-2007 were compared to the corresponding confirmatory testing. The risks for false positives for preterm and full term newborns were calculated by Chi-square or the Cochran-Armitage test for trend. Isoelectric focusing and HPLC were the methods of hemoglobin screening. RESULTS: Over 2,300 neonates (1/576 neonates born in Florida) were suspected to have hemoglobinopathy. The most common abnormal pattern in term and preterm infants (gestational age 22-36 weeks) suggesting disease at screening was FS. Overall, 93% of the children who screened positive for FCA and 64% of infants identified with FSA were later confirmed with trait. FSC was confirmed in 96% of the cases in both preterm and term infants. Compared to term newborns, preterm newborns were more likely to have a false positive result for FS or FC at screening. Twenty-three percent of preterms with FS and 59% of preterms with FC were diagnosed as traits by confirmatory testing, compared to only 2% and 6% for term infants (P < 0.001). CONCLUSIONS: As compared to term newborns, more preterm newborns with trait were misidentified as having sickle cell anemia or hemoglobin C at screening. We speculate that abnormal hemoglobins may precede the development of hemoglobin A during fetal life.

Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury.

Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% +/- 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% +/- 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% +/- 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% +/- 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.