Kwaku Ohene-Frempong

Bone marrow transplantation for sickle cell disease

BACKGROUND We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. METHODS Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. RESULTS Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively. Among patients with a history of acute chest syndrome, lung function stabilized; among patients with prior central nervous system vasculopathy who had engraftment, stabilization of cerebrovascular disease was documented by magnetic resonance imaging. CONCLUSIONS Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease.

Home management of sickle cell-related pain in children and adolescents : natural history and impact on school attendance

&NA; Some children and adolescents with sickle cell disease experience frequent painful episodes. To gain information about the natural history of the pain and its impact on sleep and school attendance, we developed a home‐based diary system. Eighteen children and adolescents completed 4756 diary days, with an average compliance of 75%. Pain was reported on 30% of days and was managed at home nine‐tenths of the time. Girls reported more days with pain than did boys, and age was positively correlated with the length of the painful episodes. The pain affected school attendance and sleep. Patients were absent from school on 21% of 3186 school days, with half of the absenteeisms on days with reported pain. Of the pain‐associated absenteeisms, two‐thirds occurred when pain was managed at home, and one‐third when patients were hospitalized. The average consecutive number of school days missed was 2.7. These findings have implications for developmentally critical activities.

5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells ,

In an attempt to find new types of anti‐sickling agents that specifically bind to intracellular sickle haemoglobin (HbS) without inhibition by plasma and tissue proteins or other undesirable consequences, we identified 5‐hydroxymethyl‐2‐furfural (5HMF), a naturally occurring aromatic aldehyde, as an agent that fulfils this criterion. Preliminary studies in vitro showed that 5HMF forms a high‐affinity Schiff‐base adduct with HbS and inhibits red cell sickling by allosterically shifting oxygen equilibrium curves towards the left. Further studies with transgenic (Tg) sickle mice showed that orally administered 5HMF was rapidly absorbed into the bloodstream from the gastrointestinal tract without being destroyed, traversed the red blood cell membrane and specifically bound with, and modified, HbS molecules at levels as high as 90%. Pretreatment of Tg sickle mice with 5HMF inhibited the formation of sickle cells and significantly prolonged survival time under severe hypoxia, compared with untreated mice, which died within 15 min because of sickling‐dependent pulmonary sequestration. These results indicate the feasibility of 5HMF as an attractive potential candidate for therapy of sickle cell disease.

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.

Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

Silent infarcts in young children with sickle cell disease

Silent infarcts have been reported most commonly in school‐aged children with homozygous sickle cell disease (SCD‐SS) and are associated with neurocognitive deficits. However, the prevalence of silent infarcts in younger children with SCD‐SS is not well defined. In this retrospective study, brain magnetic resonance imaging and angiography (MRI/A) studies performed before 6 years of age in a cohort of children with SCD‐SS were analysed and the prevalence of abnormalities was calculated. Clinical and laboratory parameters were compared between the groups with and without silent infarcts. Sixty‐eight of 96 children in the cohort had brain MRI/A performed prior to age 6 years. Of the 65 who were neurologically asymptomatic, 18 (27·7%, 95% CI 17·3–40·2%) had silent infarcts (mean age 3·7 ± 1·1 years, range 1·3–5·9 years). Factors associated with silent infarcts included cerebral vessel stensosis by magnetic resonance angiography, lower rates of vaso‐occlusive pain and acute chest syndrome and lower haemoglobin levels. The prevalence of silent infarcts in young children with SCD‐SS is similar to that of older children and anaemia and severe vasculopathy may be risk factors.

Effects of Delayed Pubertal Development, Nutritional Status, and Disease Severity on Longitudinal Patterns of Growth Failure in Children With Sickle Cell Disease

Previous studies of children with sickle cell disease (SCD) reported poor growth and delayed maturation. However, the prevalence, magnitude, and correlates of suboptimal growth remain poorly understood. A prospective longitudinal study was undertaken to determine the effects of disease severity and nutritional status on growth, an indicator of childhood well-being. Children, birth to 18 y of age, with SCD-SS were evaluated annually for 4 y. Growth, nutritional status, skeletal and sexual maturation, disease severity, dietary intake, and maternal education were assessed. In this sample of 148 children (78 females), growth in height, weight, or body mass index declined in 84% of subjects; 38% fell below the 5th percentile in one or more measures. Puberty was delayed 1 to 2 y, and median age at menarche was 13.2 y. Skeletal age was delayed by 0.7 ± 1.4 y overall and by 1.3 ± 1.5 y in children 10 to 15 y old. Height status declined over time and was positively associated with advancing puberty and hematological measures in girls, and nutritional status in girls and boys. Growth failure and maturational delay remain significant chronic problems in children with SCD-SS and are related to potentially modifiable factors such as nutritional status.

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.

Plasma zinc status, growth, and maturation in children with sickle cell disease

OBJECTIVE The objective of this study was to determine the relation of plasma zinc (Zn) status to growth and maturation in children with SS genotype sickle cell disease. STUDY DESIGN A cross-sectional study of 104 subjects who were 50% female and ranged in age from 0.4 to 18 years was performed. Measures included plasma Zn concentration (Znp), height, weight, skinfold thicknesses, elbow breadth, upper arm muscle area, and fat-free mass and fat mass by total body electrical conductivity. Skeletal maturation was assessed by hand-wrist x-ray evaluation and sexual maturation by Tanner stage. RESULTS A total of 44% of the patients had low Znp (<10.7 micromol/L [70 microg/dl]); those with low Znp had significantly lower SD scores for height (p = 0.003), weight (p = 0.003), upper arm muscle area (p = 0.045), fat-free mass (p = 0.025), and elbow breadth (p = 0.017) and greater skeletal maturation delay (p = 0.04). In older children (>9 years) low Znp was associated with decreased Tanner scores for pubic hair (p = 0.001) and breast and genital maturation (p = 0.009). No significant differences were seen in age, sex, or fat stores according to Zn status. CONCLUSIONS Decreased plasma Zn is common in children with SS genotype sickle cell disease and is associated with decreased linear growth, skeletal growth, muscle mass, and sexual and skeletal maturation.

Trial of low doses of aspirin as prophylaxis insickle cell disease

The effects of low doses of aspirin on the frequency and severity of painful vaso-occlusive crises were evaluated in children with sickle hemoglobinopathies. Aspirin was compared with placebo in 49 patients in a double-blind crossover study. Careful monitoring of patients revealed an average of 1.1 painful crises per patient year. During the 21 months of study, 70% of patients had a maximum of two painful crises, and 25% experienced four or more. The frequency and severity of crises were not affected by aspirin therapy. In view of aspirins demonstrated effect on platelet function, we suggest that platelets do not contribute to the initiation or progression of the vaso-occlusive process.