American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.

BACKGROUND: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. METHODS: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. 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. RESULTS: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle- and high-income settings. CONCLUSIONS: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sß0 (HbSß0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSß0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Haemophilia A carriers experience reduced health-related quality of life.

INTRODUCTION: Haemophilia A is an X-linked recessive bleeding disorder that primarily affects males. Emerging data support evidence for increased bleeding in female haemophilia A carriers despite factor VIII activity within the normal range. AIM: Data regarding the effect of increased bleeding on health-related quality of life (HR-QOL) in haemophilia A carriers is sparse. We tested the hypothesis that haemophilia A carriers have reduced HR-QOL related to bleeding symptoms. METHODS: We conducted a cross-sectional study at Vanderbilt University. Case subjects were obligate or genetically verified haemophilia A carriers age 18-60 years. Control subjects were mothers of children with cancer who receive care at the Vanderbilt paediatric haematology-oncology clinic. Trained interviewers administered the Rand 36-Item Health Survey 1.0, a validated questionnaire evaluating eight health concepts that may affect HR-QOL, to each study participant. Mann-Whitney U-tests were used to compare median scores for the eight health domains between the case and control groups. RESULT: Forty-two haemophilia A carriers and 36 control subjects were included in analyses. Haemophilia A carriers had significantly lower median scores for the domains of 'Pain' (73.75 vs. 90; P = 0.02) and 'General health' (75 vs. 85; P = 0.01) compared to control subjects. CONCLUSION: Haemophilia A carriers in our study demonstrated significantly lower median scores on the Rand 36-item Health Survey 1.0 in the domains of 'Pain' and 'General Health' compared to women in the control group. Our findings highlight the need for further investigation of the effect of bleeding on HR-QOL in this population.

Directed blood donor program decreases donor exposure for children with sickle cell disease requiring chronic transfusion.

In children with sickle cell disease (SCD), primary and secondary prevention of strokes require indefinite regular blood transfusion therapy. The risks associated with repeated transfusions include alloimmunization and increased donor exposure. The Charles Drew Program is a directed blood donor program designed to lower donor exposure, decreasing the associated complications of transfusion; however, no evidence exists demonstrating the magnitude of the benefit to the recipient. Further, the use of extended red blood cell (RBC) antigen matching for C, E, and K has been well documented in a clinical trial setting but not extensively evaluated in a standard care setting. The goal of this study is to assess the effectiveness in reducing alloimmunization when matching for C, E, and K and the magnitude of the decrease in donor exposure in a directed blood donor program. The rate of alloimmunization and reduction of donor exposure were determined during the course of 1 year in a cohort of children with SCD who received regular directed donor blood transfusions. A total of 24 recipients were in the program, 16 females and 8 males, 4 to 20 years of age. During 2008, alloimmunization was 0 percent and donor exposure was reduced by 20 percent, compared with usual care. Extended RBC antigen matching has the same benefit as in a clinical trial setting for patients with SCD receiving blood transfusion therapy. Despite significant effort, we only achieved a modest decrease in donor exposure and cannot determine the immediate benefit of a directed blood donor program.

A pilot randomized education rehabilitation trial is feasible in sickle cell and strokes.

A randomized trial was completed to assess the feasibility of a 2-year education rehabilitation program for students with sickle cell disease and memory deficits. Eleven students were assigned to tutoring with or without memory training for 2 years. Eighty-two percent completed the program. Evidence of improvement in memory and academic achievement existed. Educational rehabilitation is a feasible strategy, but further investigation is needed to assess the benefit in a multi center trial.

The Charles Drew program in Missouri: a description of a partnership among a blood center and several hospitals to address the care of patients with sickle cell disease.

Sickle cell disease (SCD) is an inherited blood disorder which can be complicated by stroke in infancy and childhood. The primary and secondary prevention of stroke in this patient population is regular RBC transfusion therapy at least every three weeks, but there is no consensus on the ideal RBC transfusion therapy. The Charles Drew Program, a partnership among a blood center and several hospitals affiliated with academic medical centers in Missouri, provides RBCs for the care of patients with SCD. There are three basic aims: the RBC components are phenotypically matched on three minor RBC antigens, the units are less than 7 days old, and each patient has a limited number of dedicated donors, so that the donor exposure is minimized. This report describes the operational phases of this program and summarizes its performance with respect to each of these aims.

Environmental exposure and cancer in children. A conceptual framework for the pediatrician.

Ultimately, after gathering and assessing all available evidence, pediatricians and health care policymakers must make informed decisions on whether exposure to a specific agent has the potential to cause cancer in children. In the case of DES, for which the results were clear, there was no question that the drug should be taken off the market; however, most cases of suspected carcinogens lack such clear evidence documenting cause and effect. An example of a murky topic is the suspected relationship between residential electromagnetic fields (EMFs) and childhood cancer. Epidemiologic and biologic researchers have tried for more than 2 decades to determine whether exposure to relatively high levels of EMFs poses health hazards, especially cancer in children. Although the preponderance of evidence favors a judgment that this ubiquitous environmental exposure is harmless, concerns remain in many public circles and some scientific ones. Any proposed intervention to remove a potentially carcinogenic agent must be weighed against the cost and inconvenience to the affected community. Pediatricians are placed in a vulnerable position when faced with questions of a carcinogenic potential because of the frequency of claims in the popular literature stating that exposure to a certain product or food is associated with an increased risk for cancer in adults and possibly children. When such studies are published or, more often, released to the press, the strength of the evidence for a causal association with cancer, coupled with the context of the study, should be considered as a reasonable starting point. Better communication models of disseminating cancer-risk information are needed so that the public understands the difference between a weak study that appeared on the local news with little evidence to support a cause-and-effect relationship versus a well-designed study that was published in a peer-reviewed journal and indicates a likely cause-and-effect association.

Clinical parameters associated with low bacteremia risk in 1100 pediatric oncology patients with fever and neutropenia.

BACKGROUND: Traditionally, children with malignant disease who present with fever and neutropenia are hospitalized for parenteral antibiotics. More recently, outpatient strategies have been proposed for lower risk cohorts of such patients. The authors sought to identify clinical and laboratory parameters that are associated with a low risk of bacteremia in children with malignant disease who presented with febrile neutropenia. METHODS: A multicenter, retrospective cohort of children with malignant disease and fever with neutropenia was established in three pediatric oncology centers over a 5-year period. A total of 1171 episodes of febrile neutropenia (absolute neutrophil count [ANC] < 500 cells per mm(3)) were identified in children with malignant disease age > 1 year. The endpoints examined were 1) bacteremia and 2) intensive care unit admission or death related to bacteremia. The odds ratio was used to determine which of the following admission parameters and cut-off values were associated with the lowest risk for bacteremia: ANC, absolute phagocyte count (APC), absolute monocyte count (AMC), platelet count, and admission temperature. RESULTS: A total of 189 episodes of bacteremia were identified among the 1171 episodes of febrile neutropenia (14% bacteremia). Only 11 of 1171 episodes (0.9%) resulted in intensive care unit admission, and 3 of these patients died. All 11 patients had an AMC < 30 cells per mm(3). The lowest frequency of bacteremia (6.1%) occurred in the children with an admission AMC of > or = 155 cells per mm(3). None of the patients identified as low risk by AMC required an intensive care unit admission or died. No level of ANC, APC, temperature, or platelet count was associated with a statistically significant decrease in the risk for bacteremia in the patient population. CONCLUSIONS: Adverse outcomes due to bacteremia are infrequent in pediatric oncology patients who present with fever and neutropenia are treated with parental antibiotics. Patients with fever and neutropenia and an AMC value of > or = 155 cells per mm(3) have the lowest risk for bacteremia and may be potential candidates for outpatient management.

Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease.

OBJECTIVE: To determine whether children with homozygous sickle cell anemia (SCD) who have silent infarcts on magnetic resonance imaging (MRI) of the brain are at increased risk for overt stroke. METHODS: We selected patients with homozygous SCD who (1) enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) before age 6 months, (2) had at least 1 study-mandated brain MRI at age 6 years or older, and (3) had no overt stroke before a first MRI. MRI results and clinical and laboratory parameters were tested as predictors of stroke. RESULTS: Among 248 eligible patients, mean age at first MRI was 8.3 +/- 1.9 years, and mean follow-up after baseline MRI was 5.2 +/- 2.2 years. Five (8.1%) of 62 patients with silent infarct had strokes compared with 1 (0.5%) of 186 patients without prior silent infarct; incidence per 100 patient-years of follow-up was increased 14-fold (1.45 per 100 patient-years vs 0.11 per 100 patient-years, P =.006). Of several clinical and laboratory parameters examined, silent infarct was the strongest independent predictor of stroke (hazard ratio = 7.2, P =.027). CONCLUSIONS: Silent infarct identified at age 6 years or older is associated with increased stroke risk.

Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model.

BACKGROUND: We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated. PROCEDURES: We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival. RESULTS: Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (< $50,000 per life year saved). CONCLUSIONS: Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy for a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice.

Outcome of early hepatic portoenterostomy for biliary atresia.

BACKGROUND: The outcome of the hepatic portoenterostomy (Kasai) procedure for biliary atresia is improved when it is performed before 90 days of age. However, it is not known whether intervention before 30 days is better than intervention between 30 and 90 days. METHODS: The authors reviewed the records of all patients seen by the Pediatric Gastroenterology Service at St. Louis Children's Hospital from 1984-1999 to ascertain the outcome of patients who underwent Kasai procedure before or after 30 days of age. RESULTS: Of 92 patients with biliary atresia treated at St. Louis Children's Hospital over 15 years, 9 underwent the Kasai procedure before 30 days of age. Liver transplantation was necessary in 77.8% of these patients at a mean age of 11.0 +/- 4.26 months, as compared with 53.4% at 32.14 +/- 7.14 months for the remainder of the patients who underwent the procedure after 30 days of age. CONCLUSIONS: Although these data suggest that outcomes are worse for patients who undergo the procedure before 30 days of age, they may reflect a difference in the pathogenesis of biliary atresia that brings it to clinical attention earlier and may provide further evidence that biliary atresia is a phenotype for a number of distinct underlying disease processes.

Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition.

Simpson Golabi Behmel syndrome (SGBS) is a complex congenital overgrowth syndrome with features that include macroglossia, macrosomia, and renal and skeletal abnormalities as well as an increased risk of embryonal cancers. Most cases of SGBS appear to arise as a result of either deletions or point mutations within the glypican-3 (GPC3) gene at Xq26, one member of a multigene family encoding for at least six distinct glycosylphophatidylinositol-linked cell surface heparan sulfate proteoglycans. As a class of molecules, heparan sulfate proteoglycans have been found to play essential roles in development by modulating cellular responses to growth factors and morphogens. Specifically, mutations in both the murine GPC3 gene and the Drosophila glypican, dally, have been found to modify cellular responses to bone morphogenetic proteins, providing important clues to the molecular basis of SGBS in humans. Despite these advances, there remains a paucity of information about the natural history of SGBS and optimal medical management strategies, and whether select mutations influence the SGBS phenotype and risk of cancer. To this end, an International SGBS Registry has been created and is being maintained to improve the clinical care and understanding of the pathogenesis of SGBS. Using an integrated approach employing epidemiology, molecular genetic characterization of specific GPC3 mutations, and the use of model organisms should rapidly expand the understanding of this complex disorder.

Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease.

The authors evaluated education attainment and neuropsychological deficits in children with sickle cell disease (SCD) and silent cerebral infarcts. Children with silent infarcts had twice the rate of school difficulties as children without infarcts. Eighty percent of silent infarct cases had clinically significant cognitive deficits, whereas 35% had deficits in academic skills. Children with silent cerebral infarcts show high rates of poor educational attainment, cognitive deficits, and frontal lobe injury. Poor school performance in SCD is one indicator of silent infarcts.

Posttransplant lymphoproliferative disease in children: correlation of histology to clinical behavior.

PURPOSE: To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. PATIENTS AND METHODS: We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. RESULTS: Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. CONCLUSIONS: We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.

A lesion analysis of visual orienting performance in children with cerebral vascular injury.

Anterior brain insults during development have been shown to result in visual orienting deficits; however, the type of orienting deficit has varied across studies. Performance on an orienting task was examined in relation to the location and volume of injury on magnetic resonance exams in 15 children with cerebral infarction and 32 control children. Contralateral lesions including the parietal lobe were associated with larger validity effects, suggesting difficulties disengaging attention. A similar trend was found for the middle-frontal gyrus. Basal ganglia injury contralateral to a given hemifield was associated with less facilitation of attention. Lesion volume in each hemisphere did not show a significant relation with contralateral validity effects. The data suggest that variability in the type of visual orienting deficits shown in prior studies of children with anterior brain insults may be related in part to the specific location of lesions within the frontal lobe.

Malignant peripheral nerve sheath tumors in neurofibromatosis 1.

One of the most clinically aggressive cancers associated with neurofibromatosis 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST). To determine the incidence and relative risk (RR) of MPNSTs in individuals with NF1, 1,475 individuals with NF1 were included from a cohort of patients examined by a single experienced geneticist from 1977 to 1996. The end points were incidence of MPNST, relative risk of MPNST, and relative risk associated with specific NF1 physical findings. Thirty-four individuals were identified with MPNST (2%). The relative risk of MPNST was higher than expected with an RR value of 113 (95% confidence interval [CI] = 78-158). The average 10-year annual incidence of MPNST between the second and fifth decade of life was roughly the same with a range of 0.0013 and 0.0068 MPNST per patient year. Most lesions occurred in the limbs (n = 18; 53%), and those with limb lesions survived longer than those with nonlimb MPNSTs. Pain associated with a mass was the greatest risk factor associated with MPNST development (RR = 31.4; 95% CI = 13.2-75.1). Further biological and epidemiological studies are needed to determine other factors that influence the risk of MPNST development in individuals affected with NF1. Am. J. Med. Genet. 93:388-392, 2000. Published 2000 Wiley-Liss, Inc.

Hypoglycemia in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macrosomia, macroglossia, abdominal wall defects, hypoglycemia in the neonatal period and embryonal cancers of infancy and early childhood. The frequency of hypoglycemia in this population is between 30% and 50%. The majority of infants with hypoglycemia will be asymptomatic and have resolution of the hypoglycemia within the first 3 days of life. Less than 5% will have hypoglycemia beyond the neonatal period requiring either continuous feeding or a partial pancreatectomy. The cause of hypoglycemia is unclear, but direct and indirect evidence supports a hyperinsulinemia as the major factor. Recent identification of the majority of genes associated with BWS in the 11p15 region and the genotype of persistent hyperinsulinemia hypoglycemia of childhood also in the 11p15 region may provide a molecular basis for hypoglycemia in BWS, particularly for the occasional patients with hypoglycemia requiring a partial pancreatectomy. Detailed genotype phenotype evaluations are needed and should provide an insight as to why patients with BWS have hypoglycemia.

Preliminary study of working memory in children with stroke related to sickle cell disease.

The verbal working memory abilities of children with stroke related to sickle cell disease (SCD) (n = 20) were compared to those of control children with SCD who had no history of stroke (n = 11). Memory span for one-, two-, and three-syllable words was assessed. For children with anterior infarcts, overall span was comparable to that of controls, but the typical effect of word length on span was reduced. For children with diffuse infarcts, overall span was reduced in comparison to that of controls, but the typical effect of word length on span was observed. For children with posterior infarcts, overall span was comparable to that of controls and the typical effect of word length on span was observed. These results provide preliminary evidence that patterns of working memory performance may vary across children with infarcts affecting different regions of the brain.

High incidence of posttransplant lymphoproliferative disease in pediatric patients with cystic fibrosis.

A major cause of morbidity and mortality following lung transplantation is posttransplant lymphoproliferative disease (PTLD). In a retrospective cohort analysis of pediatric patients, we evaluated the risk factors associated with PTLD in 128 first-time lung transplant recipients from 1990 to 1997. The greatest risk factor for PTLD was a diagnosis of cystic fibrosis (CF). Of the 16 patients in our analysis who had PTLD, 13 had a diagnosis of CF (odds ratio [OR]: 5.8; confidence interval 95% [CI]: 1.6 to 21.4). Because of the high frequency of PTLD in patients with CF (13 of 61; 23%), we performed a retrospective cohort analysis in which patients with CF and PTLD were designated as cases and patients with CF and without PTLD served as controls. In patients with CF, the only risk factor associated with PTLD was two or more episodes of acute rejection within 3 mo after transplantation (OR: 11.0; 95% CI: 2.7 to 55.7). Age, recipient Epstein-Barr virus or cytomegalovirus status, induction with antilymphocyte globulin or antithymocyte globulin (ATG), or use of ATG or OKT3 for acute rejection episodes were not risk factors for PTLD. The high frequency of PTLD in the subgroup of patients with two or more episodes of graft rejection within 2 mo after lung transplantation was unexpected, and warrants further investigation in prospective clinical studies and basic laboratories.