Education Liaison improves implementation of school accommodations for students with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) have lower academic attainment than healthy peers. Many benefit from neuropsychological testing (NPT) and educational accommodations, including Individualized Education Programs (IEPs) and Section 504 plans (504s). Despite medical barriers to academic attainment, many children with SCD do not receive indicated NPT or accommodations. OBJECTIVE: We hypothesize that a dedicated Education Liaison (EL) embedded in the SCD team increases implementation of NPT and accommodations. STUDY DESIGN: This retrospective study included children aged 5-20 years with SCD receiving care at a single center from 2017 through 2020. Univariate analysis and multiple logistic regression were performed. RESULTS: Total 316 children with SCD were included. At baseline, 52.8% had accommodations (IEP: 24.4%, 504: 38.0%). The EL interacted with 62.0% of children. Children with EL contact were more likely to undergo NPT (odds ratio [OR]: 5.385), have an IEP (OR: 4.580), and have a 504 (OR: 2.038) (p < .001 for all). At the end of the study period, 64.6% had accommodations (IEP: 33.5%, 504: 54.4%), which increased from baseline (p < .001 for all). EL interaction was associated with overt or silent stroke history (OR: 1.911), acute chest syndrome history (OR: 2.257), hospitalizations since age 5 (OR: 3.216), and hospitalization for vaso-occlusive pain since age 5 (OR: 2.226) (p < .001 for all). CONCLUSION: EL interaction improves access to NPT and educational accommodations among children with SCD. SCD centers should incorporate ELs in comprehensive care teams to improve access to appropriate educational accommodations.

Cerebral revascularization surgery reduces cerebrovascular events in children with sickle cell disease and moyamoya syndrome: Results of the stroke in sickle cell revascularization surgery retrospective study.

BACKGROUND: Recent studies suggest that cerebral revascularization surgery may be a safe and effective therapy to reduce stroke risk in patients with sickle cell disease and moyamoya syndrome (SCD-MMS). METHODS: We performed a multicenter, retrospective study of children with SCD-MMS treated with conservative management alone (conservative group)-chronic blood transfusion and/or hydroxyurea-versus conservative management plus surgical revascularization (surgery group). We monitored cerebrovascular event (CVE) rates-a composite of strokes and transient ischemic attacks. Multivariable logistic regression was used to compare CVE occurrence and multivariable Poisson regression was used to compare incidence rates between groups. Covariates in multivariable models included age at treatment start, age at moyamoya diagnosis, antiplatelet use, CVE history, and the risk period length. RESULTS: We identified 141 patients with SCD-MMS, 78 (55.3%) in the surgery group and 63 (44.7%) in the conservative group. Compared with the conservative group, preoperatively the surgery group had a younger age at moyamoya diagnosis, worse baseline modified Rankin scale scores, and increased prevalence of CVEs. Despite more severe pretreatment disease, the surgery group had reduced odds of new CVEs after surgery (odds ratio = 0.27, 95% confidence interval [CI] = 0.08-0.94, p = .040). Furthermore, comparing surgery group patients during presurgical versus postsurgical periods, CVEs odds were significantly reduced after surgery (odds ratio = 0.22, 95% CI = 0.08-0.58, p = .002). CONCLUSIONS: When added to conservative management, cerebral revascularization surgery appears to reduce the risk of CVEs in patients with SCD-MMS. A prospective study will be needed to validate these findings.

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.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease.

Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Organ function indications and potential improvements following curative therapy for sickle cell disease.

Curative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplantation (HSCT) and gene-modified autologous stem cell transplantation. HSCT has been used for 30 years with success measured by engraftment, symptom control, graft-vs-host disease (GVHD) risk, organ toxicity, and immune reconstitution. While human leukocyte antigen-matched sibling donor (MSD) transplants have excellent outcomes, alternate donor transplants (unrelated/haploidentical) are just beginning to overcome GVHD and engraftment hurdles to match MSD. Gene therapy, a newly developed treatment, is undergoing careful evaluation in many trials with varying approaches. The risk/benefit ratio to the patient in relation to outcomes, toxicities, and mortality risk drives eligibility for curative interventions. Consequently, eligibility criteria for MSD transplants can be less stringent, especially in the young. Posttransplant outcome analysis after the "cure" with respect to organ function recovery is essential. While established damage such as stroke is irreversible, transplant can help stabilize (pulmonary function), prevent further deterioration (stroke), improve (neurocognition), and protect unaffected organs. Tracking organ functions postintervention uniformly between clinical trials and for adequate duration is essential to answer safety and efficacy questions related to curative therapies. Age-appropriate application/outcome analyses of such therapies will be the ultimate goal in overcoming this disease.

A Case Series of Kawasaki Disease in Children With Sickle Cell Disease.

Prompt recognition and treatment of presumed bacterial infection in febrile children with sickle cell disease is necessary due to splenic dysfunction and impaired immune response. However, fever may be a manifestation of a noninfectious process, and health care providers must consider alternative sources. We describe 2 cases of children with sickle cell disease and persistent fevers, ultimately diagnosed with Kawasaki disease. These cases provide examples of an acute febrile illness that could lead to serious consequences if differential diagnoses are not considered and treatment is delayed.

Epstein-Barr virus-induced sickle hepatopathy.

Sickle hepatopathy comprises a spectrum of disorders that vary in severity. Intravascular sickling and sinusoidal occlusion are the principal drivers of sickle hepatopathy, but infection or autoimmunity can act as triggers. We describe two cases of acute sickle hepatopathy initiated by primary Epstein-Barr virus (EBV) infection, a previously unreported association. The first case entailed a 14-year-old girl with hemoglobin SC (HbSC) disease who developed hepatic sequestration crisis that responded to a simple transfusion of erythrocytes. The second case was that of a 16-year-old boy with HbSC disease who experienced life-threatening intrahepatic cholestasis with multiorgan failure.

Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease.

We report results of a phase 1 multicenter stem cell transplantation (SCT) trial from HLA-matched (n = 7) or one-antigen-mismatched (n = 7) unrelated donors (URD) using bone marrow or cord blood as stem cell source, following reduced-intensity conditioning (RIC) in severe sickle cell disease (SCD). Conditioning included distal alemtuzumab, fludarabine, and melphalan (matched donors), with thiotepa (mismatched donors). Abatacept, a selective inhibitor of T cell costimulation, was added to tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis to offset GVHD risks, and was administered for longer duration in bone marrow recipients than in cord blood recipients because of increased incidence of chronic GVHD with bone marrow. Median age at transplant was 13 years (range, 7-21 years). The incidence of grades II to IV and grades III to IV acute GVHD at day +100 was 28.6% and 7%, respectively. One-year incidence of chronic GVHD was 57% and mild/limited in all but 1 patient who received abatacept for a longer duration. Only 1 patient developed reversible posterior encephalopathy syndrome and recovered. With a median follow-up of 1.6 years (range, 1-5.5 years), the 2-year overall and disease-free survival was 100% and 92.9%, respectively. The encouraging results from the phase 1 portion of this RIC SCT trial, despite risk factors such as older age, URD, and HLA-mismatch, support further evaluation of URD SCT in clinical trial settings. The phase 2 portion of the trial is in progress. This trial was registered at www.clinicaltrials.gov as NCT03128996.

Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease.

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non-SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3-7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ2 (1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.

Prevalence and nature of hearing loss in a cohort of children with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) may cause injury to any organ, including the auditory system. Although the association of SCD and hearing loss has been described, the nature of this complication is unknown. We sought to establish the prevalence and nature of hearing loss in a referred cohort of children with SCD and to identify correlating disease- or treatment-associated factors. PROCEDURE: We conducted a retrospective review of patients with SCD < 22 years of age who had hearing evaluations between August 1990 and December 2014. Demographics, audiograms, and disease and treatment variables were analyzed. RESULTS: Two hundred and ten audiograms among 81 patients were reviewed, and 189 were evaluable. Seventy-two children constituted the referred cohort. Fourteen (19.4%) had hearing loss documented on at least one audiogram. Seven (9.7%) patients had only conductive hearing loss, and the loss persisted for up to 10.3 years. The median age of first identification was eight years. Six (8.3%) patients had hearing loss that was at least partially sensorineural. One patient's hearing loss was ambiguous. All sensorineural hearing losses were unilateral and 4/6 patients had prior documented normal hearing, indicating acquired loss. No correlations were identified. CONCLUSIONS: Both conductive and sensorineural hearing losses are more prevalent in our study population than those observed in the general pediatric population. In children with SCD, sensorineural hearing loss appears to be acquired and unilateral. Conductive hearing loss was identified in older children and can persist. Serial screening is needed for early detection and more prompt intervention in this population.

Hematopoietic stem cell transplantation for sickle cell disease: Progress and challenges.

Sickle cell disease (SCD) presents challenges to hematopoietic stem cell transplantation (HSCT), including donor availability and morbidity with age/disease severity. However, severe SCD causes irreversible organ damage that HSCT can mitigate. This benefit must be balanced against preparative regimen toxicity, graft-versus-host disease, and mortality risk. We review efforts to balance HSCT complications with the promise of cure, and knowledge gaps that warrant further investigation. We highlight the burden of SCD, HSCT risks and benefits, and SCD families' approach to this balance. We emphasize the necessity for information exchange to ensure a joint decision-making process between providers and patients.

Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial.

Hematopoietic stem cell transplantation from HLA-matched sibling donors results in disease-free survival of >90% in patients with sickle cell disease (SCD); however, only approximately 18% of these patients have suitable donors available. Unrelated cord blood transplantation (UCBT) is one way to expand donor options for patients with severe SCD, but historically has been associated with high graft rejection rates (50% to 62%). We hypothesized that the addition of thiotepa to a previously tested reduced-intensity conditioning (RIC) regimen would support engraftment after UCBT in patients with SCD. Nine children (age 3 to 10 years) with cerebrovascular complications of SCD underwent 5-6/6 HLA-matched (A, B, and DRB1 loci) UCBT after conditioning with hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. A calcineurin inhibitor and mycophenolate mofetil were used for graft-versus-host-disease (GVHD) prophylaxis. With median follow up of 2.1 years (range, 1 to 4.2 years), 7 patients had sustained donor cell engraftment and are free of SCD, and 2 patients had autologous recovery. Acute GVHD (grade II-IV) and mild and moderate chronic GVHD developed in 3 patients, 2 patients, and 1 patient, respectively. At >2 years post-UCBT, 4 of 5 patients discontinued systemic immunosuppression. Seven patients had viral infections (cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, or adenovirus) and recovered. The 1-year overall survival and disease-free survival rates were 100% and 78%, respectively. Thus, this RIC regimen was able to achieve donor engraftment in the majority of patients. Future efforts will focus on further reducing rates of acute GVHD and viral infection.

Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease.

BACKGROUND: Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions. METHODS: This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated. RESULTS: Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals. CONCLUSION: aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD.

Large-Vessel Vasculopathy in Children With Sickle Cell Disease: A Magnetic Resonance Imaging Study of Infarct Topography and Focal Atrophy.

BACKGROUND: Large-vessel vasculopathy (LVV) increases stroke risk in pediatric sickle cell disease beyond the baseline elevated stroke risk in this vulnerable population. The mechanisms underlying this added risk and its unique impact on the developing brain are not established. METHODS: We analyzed magnetic resonance imaging and angiography scans of 66 children with sickle cell disease and infarcts by infarct density heatmaps and Jacobian determinants, a metric utilized to delineate focal volume change, to investigate if infarct location, volume, frequency, and cerebral atrophy differed among hemispheres with and without LVV. RESULTS: Infarct density heatmaps demonstrated infarct "hot spots" within the deep white matter internal border zone region in both LVV and non-LVV hemispheres, but with greater infarct density and larger infarct volumes in LVV hemispheres (2.2 mL versus 0.25 mL, P < 0.001). Additional scattered cortical infarcts in the internal carotid artery territory occurred in LVV hemispheres, but were rare in non-LVV hemispheres. Jacobian determinants revealed greater atrophy in gray and white matter of the parietal lobes of LVV compared with non-LVV hemispheres. CONCLUSION: Large-vessel vasculopathy in sickle cell disease appears to increase ischemic vulnerability in the borderzone region, as demonstrated by the increased frequency and extent of infarction within deep white matter, and increased risk of focal atrophy. Scattered infarctions across the LVV-affected hemispheres suggest additional stroke etiologies of vasculopathy (i.e., thromboembolism) in addition to chronic hypoxia-ischemia.

The tip of the thrombos-is-berg.

A high risk of venous thromboembolic events is just one of the challenges faced by people with malignant brain tumors.

Reduction in Overt and Silent Stroke Recurrence Rate Following Cerebral Revascularization Surgery in Children with Sickle Cell Disease and Severe Cerebral Vasculopathy.

BACKGROUND: Children with sickle cell disease (SCD) and moyamoya may benefit from indirect cerebral revascularization surgery in addition to chronic blood transfusion therapy for infarct prevention. We sought to compare overt and silent infarct recurrence rates in children with SCD undergoing revascularization. METHODS: This was a retrospective cohort study of all children with SCD and moyamoya treated at two children's hospitals. Clinical events and imaging studies were reviewed. RESULTS: Twenty-seven children with SCD and confirmed moyamoya receiving chronic transfusion therapy were identified, of whom 12 underwent indirect cerebral revascularization. Two subjects had postoperative transient ischemic attacks and another had a subarachnoid blood collection, none of which caused permanent consequences. Two subjects had surgical wound infections. Among these 12 children, the rate of overt and silent infarct recurrence decreased from 13.4 infarcts/100 patient-years before revascularization to 0 infarcts/100 patient-years after revascularization (P = 0.0057); the postrevascularization infarct recurrence rate was also significantly lower than the overall infarct recurrence of 8.87 infarcts/100 patient-years in 15 children without cerebral revascularization (P = 0.025). CONCLUSIONS: The rate of overt and silent infarct recurrence was significantly lower following indirect cerebral revascularization. A prospective study of cerebral revascularization in children with SCD is needed.