Sickle cell disease: new opportunities and challenges in Africa.

Sickle cell disease (SCD) is one of the most common genetic causes of illness and death in the world. This is a review of SCD in Africa, which bears the highest burden of disease. The first section provides an introduction to the molecular basis of SCD and the pathophysiological mechanism of selected clinical events. The second section discusses the epidemiology of the disease (prevalence, morbidity, and mortality), at global level and within Africa. The third section discusses the laboratory diagnosis and management of SCD, emphasizing strategies that been have proven to be effective in areas with limited resources. Throughout the review, specific activities that require evidence to guide healthcare in Africa, as well as strategic areas for further research, will be highlighted.

Association of pulsatility index in the middle cerebral artery with intelligence quotient in children with sickle cell disease.

The aim of this study was to explore whether intellectual performance in children with Sickle Cell Disease and with low risk of stroke as determined with conventional transcranial Doppler ultrasonography (TCD) criteria was associated with hemodynamic parameters in imaging TCD, when controlling for hematological and socio-economical variables and presence of silent infarcts. We performed neuropsychological testing with Kaufman Brief Intelligence Test (K-BIT-IQ) and imaging TCD examinations to measure blood flow velocities and pulsatility indexes (PI) in the middle cerebral arteries (MCA) In 46 children with homozygous HbSS (mean age 108±34 months, range limits: 47-166 months; 24 females), without a history of stroke or transient ischemic attack, with no stenosis on magnetic resonance angiography and with velocities below 170 cm/s in screening conventional TCD. Mean K-BIT IQ Composite and Vocabulary scores (91±13 and 86±14 respectively) were significantly below the average scores of 100 for the age-matched population (one sample t-test=5.21, p<0.001). Using univariate and multivariate regression models, we found that lower PI in the right MCA was associated with lower K-BIT-IQ Composite and Vocabulary scores. Furthermore, we found that interhemispheric differences in PIs were even more strongly associated with neuropsychological performance, whereas flow velocities were not associated with the K-BIT-IQ score. Using a model of chronic anemia, we found that cognitive functioning was associated with cerebral hemodynamics.

Sickle cell disease in children: accuracy of imaging transcranial Doppler ultrasonography in detection of intracranial arterial stenosis.

This study aimed to determine the accuracy of imaging transcranial Doppler sonography in detection of intracranial arterial stenosis in children with sickle cell disease using three-dimensional MR angiography as a reference standard. Sixty-one children (mean age 102±39 months, 30 males), who had no history of overt stroke, and were classified as at lowest risk of stroke by mean flow velocity criterion <170 cm/s, underwent conventional and imaging transcranial Doppler ultrasonographic examinations. We employed the area under the receiver operating characteristic curve (AUC) to determine the accuracy of flow velocity measurements obtained with imaging ultrasonography with and without correction for the angle of insonation as well as with conventional ultrasonography. We also established the most efficacious velocity thresholds for detection of the stenosis. We found ten intracranial stenoses in six patients on MR angiography, but we calculated AUC only for detection of stenosis (n=6) of the left intracranial internal carotid artery. The accuracy of flow velocity with angle correction was lower than the accuracy of velocity without angle correction (AUC=0.73, 95% CI, 0.53-0.93 versus AUC=0.87, 95% CI, 0.74-1.00; p=0.017). The accuracy of flow velocity obtained with conventional ultrasonography (AUC=0.82, 95% CI, 0.67-0.97) was not different from the accuracy of flow velocities obtained with imaging ultrasonography. We found that the threshold of 165 cm/s of mean velocity without angle correction is associated with highest efficiency for imaging (92%) and conventional ultrasonography (90%). Velocity measurements without angle-correction provide good accuracy in detection of stenosis of the terminal internal carotid artery, whereas angle-corrected velocities have lower accuracy.

Sickle cell disease: reference values and interhemispheric differences of nonimaging transcranial Doppler blood flow parameters.

BACKGROUND AND PURPOSE: TCD screening is widely used to identify children with SCD at high risk of stroke. Those with high mean flow velocities in major brain arteries have increased risk of stroke. Thus, our aim was to establish reference values of interhemispheric differences and ratios of blood flow Doppler parameters in the tICA, MCA, and ACA as determined by conventional TCD in children with sickle cell anemia. MATERIALS AND METHODS: Reference limits of blood flow parameters were established on the basis of a consecutive cohort of 56 children (mean age, 100 ± 40 months; range, 29-180 months; 30 females) free of neurologic deficits and intracranial stenosis detectable by MRA, with blood flow velocities <170 cm/s by conventional TCD. Reference limits were estimated by using tolerance intervals, within which are included with a probability of .90 of all possible data values from 95% of a population. RESULTS: Average peak systolic velocities were significantly higher in the right hemisphere in the MCA and ACA (185 ± 28 cm/s versus 179 ± 27 and 152 ± 30 cm/s versus 143 ± 34 cm/s respectively). Reference limits for left-to-right differences in the mean flow velocities were the following: -43 to 33 cm/s for the MCA; -49 to 38 cm/s for the ACA, and -38 to 34 cm/s for the tICA, respectively. Respective reference limits for left-to-right velocity ratios were the following: 0.72 to 1.25 cm/s for the MCA; 0.62 to 1.39 cm/s for the ACA, and 0.69 to 1.27 cm/s for the tICA. Flow velocities in major arteries were inversely related to age and Hct or Hgb. CONCLUSIONS: The study provides reference intervals of TCD flow velocities and their interhemispheric differences and ratios that may be helpful in identification of intracranial arterial stenosis in children with SCD undergoing sonographic screening for stroke prevention.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

Nocturnal enuresis in pediatric sickle cell disease.

To assess the prevalence of nocturnal enuresis in children and adolescents with sickle cell disease (SCD) and associated factors, structured telephone interviews were conducted with primary caregivers of 217 children and adolescents with SCD aged 5 years or older. Prevalence, perceived causes, interventions undertaken, and emotional impact were assessed. Nocturnal enuresis was significantly higher for males (28.2% of males) than for females (11% of females), p = .002, and compared with cited population prevalence rates, nocturnal enuresis was significantly higher for children with SCD, p < .01. SCD was the most common reason given by primary caregivers for enuresis. Primary caregivers used a wide range of interventions for nocturnal enuresis, but few used empirically supported treatments for enuresis or spoke with their health care team about the enuresis. These data suggest that systematic assessment and intervention for nocturnal enuresis must be implemented in the follow-up care of children and adolescents with SCD.

Sickle cell and the brain.

Sickle cell disease affects many organ systems, but one of the major morbidities is brain disease, especially stroke. In this paper, the etiology, diagnosis, treatment, and prevention of clinical stroke, as well as so-called "silent stroke," are examined. Risk factors, diagnostic tools, and data from prevention and treatment studies as well as issues pertaining to neuropsychological function, especially in younger patients, are discussed and current best options for treatment considered.

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.

Energy expenditure and intake in children with sickle cell disease during acute illness.

BACKGROUND: Children with sickle cell disease have frequent bouts of pain and infection which may increase energy expenditure, decrease energy intake and lead to a subsequent energy deficit. METHODS: Two groups of African-American children with sickle cell disease-SS genotype were enrolled in this study upon hospital admission for a sickle cell disease related illness: a younger (<6 years, n=14, 7 M) and older group (> or =6 years, n=17, 8 M). Body composition and dietary intake were assessed, and sleeping (younger) or resting energy expenditure (older) were measured by indirect calorimetry at admission and one month later at steady state. RESULTS: Energy expenditure was not different between the two timepoints for younger children, but was slightly elevated at steady state (+50 kcal/d, P=0.049) in the older group. After controlling for gender, changes in fat-free mass and dietary intake, the significance disappeared. Energy intake in both groups was significantly depressed at admission compared to follow-up (P<0.01). CONCLUSIONS: These children and adolescents did not expend excess energy during their acute illness, however, an energy deficit was observed secondary to poor energy intake. Since 20% of patients with sickle cell disease have multiple hospitalizations per year, these results provide justification for the development and evaluation of nutrition care protocols to maintain adequate caloric intake during hospitalization and recovery.

Red blood cell folate and serum vitamin B12 status in children with sickle cell disease.

PURPOSE: To determine red blood cell (RBC) folate and serum vitamin B12 levels in children with sickle cell disease, SS-type, and to evaluate the associations of these nutrient levels with growth and hematologic parameters. PATIENTS AND METHODS: Subjects enrolled in this prospective, cross-sectional study were recruited from one tertiary care setting. Complete blood counts, measurement of red blood cell (RBC) folate and serum vitamin B12, anthropometric measures (height, weight, skinfold measurements), pubertal status, and 24-hour dietary recalls were obtained from 70 patients ages 1 to 19 years. RESULTS: Low RBC folate levels were found in 15% of the children. Fifty-seven percent of the sample had inadequate dietary folate intake. Three percent of the children had low serum vitamin B12 levels. All children and adolescents sampled had adequate dietary intake of vitamin B12. Both RBC folate (P = 0.01) and serum vitamin B12 levels (P < 0.01) decreased with increasing age. CONCLUSIONS: More than half of the subjects had inadequate intake of folate from food, and despite daily folate supplementation, 15% had low RBC folate levels. Low serum vitamin B12 levels were rare, and dietary vitamin B12 intake was adequate. Additional research is needed to explore the effects of improved folate status, the need for folate supplementation, and the relationship of folate, vitamin B12, and homocysteine levels and the risk for vascular damage and stroke in children with sickle cell disease.

Iron status of children with sickle cell disease.

BACKGROUND: Dietary iron requirements are unclear in children with SS-type sickle cell disease. METHODS: Iron status was assessed in 104 nontransfused African American children (aged 0.5 to 17.6 years) with sickle cell disease who receive no iron supplement. Dietary iron intake was not measured at the time of this study. RESULTS: Serum ferritin was normal or high in all children. Other hematologic and biochemical indicators of iron deficiency were in the normal range in most children. CONCLUSIONS: Unlike previous studies, this sample of children and adolescents did not show signs of iron deficiency.

Indications for red cell transfusion in sickle cell disease.

Transfusion of red blood cells is an important therapeutic method employed in the care of people with sickle cell disease (SCD). There are several clinical situations in which patients with SCD clearly need red cell transfusion (RCT). In other situations, the indication for RCT is doubtful, controversial, or III-advised. RCT is used on either an episodic or chronic basis in the management of SCD. Episodic transfusions are usually applied in a patient who has already developed a serious complication of SCD or are used to reduce the chances for the development of a complication. Chronic transfusion therapy is often used to prevent the recurrence of a major complication such as a stroke. Recently, chronic transfusion has been applied to patients with evidence of cerebrovascular disease to prevent the first occurrence of stroke.

Effect of hydroxyurea therapy on resting energy expenditure in children with sickle cell disease.

Effects of hydroxyurea therapy on resting energy expenditure (REE) in children with sickle cell disease have not been evaluated. Eight children with sickle cell disease were examined before hydroxyurea therapy and again 6.9 +/- 3.5 months after hydroxyurea initiation. Resting energy expenditure, dietary intake, and growth were assessed. In six children, baseline REE was elevated, and REE decreased an average of 17% with hydroxyurea. This was associated with a significant increase in fetal hemoglobin. These pilot data suggest that hydroxyurea may curtail the hypermetabolic state observed in children with sickle cell disease and may offer a clinically important secondary benefit.

Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease.

Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)

Impact of acute illness on nutritional status of infants and young children with sickle cell disease.

OBJECTIVE: To evaluate changes in growth, nutritional status, body composition, and energy and nutrient intakes during illness and usual state of health in infants and young children with sickle cell disease. DESIGN: Sixteen children, aged 0.4 to 5.6 years, with SS type sickle cell disease (SCD-SS) were assessed at the time of hospital admission for an acute illness episode and during an 18-hour overnight follow-up visit 2 to 6 weeks after the acute illness episode when in a state of usual health. Main outcome measures included growth in height and weight compared with reference standards, body composition determined by the skinfold thickness technique and total body electrical conductivity, and dietary intake determined by 24-hour recall during hospital admission and at follow-up. RESULTS: Height, weight, and weight-for-height z scores did not differ from national reference data; triceps skinfold thickness and arm fat area z scores were less. Mean +/- standard error body fat was 15.6 +/- 2.1% at the time of hospital admission, as measured by total body electrical conductivity, and was not significantly different from the follow-up value (16.2 +/- 2.2%). Mean energy intake was 44 +/- 9% of Recommended Dietary Allowances at the time of admission and differed significantly from the follow-up value of 90 +/- 9% (P < .05). APPLICATIONS: Infants and children with sickle cell disease appear to be at nutritional risk during an acute illness episode, as indicated by body fat measures and inadequate intakes of energy and macronutrients. Energy intake may be suboptimal for several days surrounding an admission for an acute illness in children with sickle cell disease. Physicians and other health practitioners should be alert to inadequate nutrient intakes of their patients during this time period and may consider supplemental energy to avoid a potential net negative energy balance.

Total and resting energy expenditure in children with sickle cell disease.

OBJECTIVE: To investigate energy balance in children with sickle cell disease (SCD) as the possible cause of impaired growth and undernutrition. STUDY DESIGN: Growth, resting (REE), total (TEE), and activity-related (AEE) energy expenditure and dietary intake were examined in 36 African American children with SCD (20 girls and 16 boys) and 30 control subjects (15 girls and 15 boys) of similar age (mean, 11.2 years) and ethnicity. TEE was measured by means of the doubly labeled water technique and REE by indirect calorimetry. AEE was calculated as TEE minus REE. Fat free mass (FFM) was calculated from skinfold prediction equations. RESULTS: REE was significantly increased (131 kcal/d) in children with SCD (P =.001), after adjusting for sex and FFM. Children with SCD tended to have lower TEE (214 kcal/d) than control subjects, but there was no difference after adjusting for FFM and sex (P =.57). Children with SCD had significantly (P =.025) lower AEE (268 kcal/d) but only marginally (P =.08) lower AEE after adjusting for FFM and sex. CONCLUSIONS: The elevated REE and lower AEE, in combination with poor growth status, indicate chronic energy deficiency in children with SCD. Further studies are needed to determine the best approaches to the treatment and prevention of undernutrition in children with SCD.

Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group.

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted.

Silent cerebral infarcts in sickle cell anemia: a risk factor analysis. The Cooperative Study of Sickle Cell Disease.

BACKGROUND: Silent infarcts have been reported in 17% of young patients with sickle cell disease and are associated with impaired performance on standardized psychometric tests. Risk factors for the development of these lesions have not been identified. METHODS: Investigators in the Cooperative Study of Sickle Cell Disease performed a brain magnetic resonance imaging scan on sickle cell anemia patients age 5.9 years and older who had been followed according to the protocols of the Cooperative Study since birth. Individuals with a known history of cerebrovascular accident were excluded from this analysis. Patients with and without silent infarctions were compared with regard to clinical and laboratory parameters. RESULTS: The study sample included 42 patients (18.3%) with silent infarcts. Patients who had silent infarcts were significantly more likely to have a clinical history of seizure and a lower painful event rate. Lower hemoglobin level, increased leukocyte count, elevated pocked red blood cell count, and SEN betaS globin gene haplotype were associated also with the presence of silent infarcts. There was no relationship between silent infarcts and platelet count, fetal hemoglobin level, reticulocyte percentage, serum aspartate aminotransferase level, total bilirubin concentration, blood pressure, growth parameters, or presence of alpha-thalassemia. A multivariate model for silent infarction identified the following as risk factors: low pain event rate, history of seizure, leukocyte count >/=11.8 x 10(9)/L, and the SEN betaS globin gene haplotype. CONCLUSIONS: Patients with risk factors for silent infarcts should be evaluated for cerebrovascular disease. If evidence of infarction is found, consideration must be given to therapeutic intervention. At present, the appropriate treatment has not been determined.

Psychological adjustment of adolescents with sickle cell disease: relations with demographic, medical, and family competence variables.

OBJECTIVE: Investigate the hypothesis that family competence in addressing challenges associated with sickle cell disease (SCD) contributes to adolescents' adjustment. METHOD: During routine clinic appointments, 80 adolescents (M age = 14.4 years) and their parents independently completed the Self-Report Family Inventory (SFI), which assesses family competence, and measures of adolescent adjustment problems. Information related to disease severity was obtained from clinic files. RESULTS: Regression analyses controlling for demographic and medical variables revealed that higher family competence was associated with fewer internalizing and externalizing behaviors by the adolescent; these relations were particularly true for younger adolescents and for girls. Parental reports of somatic complaints in girls were predicted by parental ratings of family competence. DISCUSSION: Interventions for adolescents with SCD should be family-centered and should focus on strengthening the family's ability to manage stressors associated with parenting an adolescent with a chronic illness.

Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis.

As a mediator of neurogenic inflammation and pain, we hypothesized that levels of the neuropeptide Substance P (SP) would be elevated in patients with sickle cell disease (SCD) with vaso-occlusive pain crisis. SP is a known stimulator of tumor necrosis factor-alpha (TNF-alpha) release and a promoter of interleukin-8 (IL-8), which are reported to be increased in SCD. These cytokines enhance adhesion of leukocytes to endothelium and may play a role in vaso-occlusive events. Serum levels of IL-8, TNFalpha, and SP were studied in three groups of children aged 2 to 18 years: 30 well children with SCD, 21 with SCD in pain crisis, and 20 healthy age-matched controls. Serum levels of SP were elevated in all SCD patients and were highest in patients in pain crisis. The percentage of sera with detectable levels of IL-8 (>5.0 pmol/L) was increased in SCD patients as compared with the control group. IL-8 levels were similar for well SCD patients and those with pain. TNFalpha levels were not significantly different among the three groups. In three children with SCD, SP was measured at baseline and again during pain crisis. In each case, serum levels during pain crisis were higher than they were when the patient was well. We conclude that levels of SP are high in patients with SCD and increase during pain crisis. These results imply that SP plays a prominent role in the pain and inflammation of SCD and may be a measurable laboratory marker of vaso-occlusive crisis. We speculate that neurokinin receptor antagonists may have a therapeutic potential in the treatment of crisis pain.