Zinc status in children and young adults with sickle cell disease

Previous studies have suggested an association of zinc deficiency and short stature in some children and adults with sickle cell disease (SCD). As a result, zinc supplementation has been recommended for these patients. The mechanism for zinc deficiency in certain patients with SCD is unknown, although renal loss of zinc has been suggested as a contributing factor. The zinc status of 29 subjects with SCD and 18 black controls was studied. No evidence of zinc deficiency in our population with SCD was found when plasma and cellular zinc levels were measured. Likewise, levels of two zinc-dependent enzymes, alkaline phosphatase and delta-aminolevulinic acid dehydratase, were normal in these subjects with SCD. Although adolescent subjects with SCD tended to be shorter than control subjects, there was no correlation between the height-forage z score and plasma zinc levels (r = -.31). It was concluded that zinc deficiency was not present in our population with SCD, and that there was no correlation between plasma zinc levels and the height-for-age z score in growing adolescent patients with SCD. These findings suggested that zinc supplementation may not be necessary in all patients with SCD.     

Emotional, social, and behavioral functioning of children with sickle cell disease and comparison peers

This research examined the emotional, social, and behavioral functioning of children with sickle cell disease (SCD) and classroom comparison peers from the perspective of primary and secondary caregivers. It was hypothesized that children with SCD would have more internalizing (emotional) and social problems and fewer externalizing (behavioral) problems than comparison peers. Caregivers of 70 children with SCD and 67 comparison peers completed the Child Behavior Checklist (CBCL) during visits to the children's homes. Relative to comparison peers, children with SCD were perceived by primary caregivers as having more total and internalizing problems and less total competence. Additionally, significantly more children with SCD exceeded clinical cutoffs on the CBCL. While caregivers of children with SCD perceive these children to be at a slightly elevated risk for problems across multiple domains, a significant number of children with SCD have problems in the clinical range. The authors recommend that vigorous screening programs for mental health problems should be included in the routine care of children with SCD, and programs of psychosocial intervention research should be implemented to ameliorate problems for the children at greatest risk.     

Growth and pubertal development in transfusion-dependent children and adolescents with thalassaemia major and sickle cell disease: a comparative study

Despite regular blood transfusion and desferrioxamine treatment, growth impairment and pubertal delay are commonly seen in children and adolescents with transfusion-dependent thalassaemia and sickle cell disease (SCD). We evaluated growth parameters and sexual maturation in a large cohort of children and adolescents with SCD (n = 110) and thalassaemia (n = 72) receiving nearly the same protocol of transfusion and chelation, and compared them with those for 200 normal age-matched children, 30 children with constitutional delay of growth (CSS), and 25 children with growth hormone deficiency (GHD). Before transfusion, haemoglobin concentration had not been less than 9 g/dl in the past 7 years; desferrioxamine was administered for 7-10 years, including by the intramuscular and subcutaneous routes, three times or more per week. The height standard deviation score (HtSDS), growth velocity (GV) (cm/yr), and growth velocity standard deviation score (GVDSD) of children and adolescents with thalassaemia and SCD were significantly decreased compared to normal children (p < 0.01). Forty-nine per cent of thalassaemic patients and 27 per cent of patients with SCD had HtSDS less than -2, and 83 per cent of thalassaemic patients and 67 per cent of SCD patients had HtSDS less than -1. Fifty-six per cent of thalassaemic children and 51 per cent of children with SCD had GVSDS less than -1. The GV of thalassaemic children was significantly slower than that for children with SCD. Children with thalassaemia and SCD had HtSDS and GVSDS comparable to those for children with CSS but higher than those for patients with GHD. Serum ferritin concentration was correlated significantly with the linear GV in all patients (r = 0.45, p < 0.001). The bone age delay did not differ among the three groups with thalassaemia, SCD and CSS, but the delay was significant in the group with GHD. The mid-arm circumference was significantly smaller in children with thalassaemia and SCD than in normal children. The triceps skin-fold thickness of patients with SCD was significantly decreased compared to thalassaemic and normal children. The upper/lower segment ratio was significantly lower in thalassaemic and SCD patients than in normal children. In thalassaemic patients between the ages of 13 and 21 years a complete lack of pubescent changes was present in 73 per cent of boys and 42 per cent of girls. Seventy-four per cent of the thalassaemic girls had primary amenorrhoea. Girls with SCD aged between 13 and 21 years had markedly delayed breast development and menarche. Twenty-five per cent of boys with SCD above the age of 14 years had absence of testicular development. Males with thalassaemia and SCD who had spontaneous testicular development had significantly smaller testicular volume than did normal controls. Short children with thalassaemia and SCD had significantly decreased serum insulin-like growth factor 1 (IGF-1) concentrations compared to children with CSS. Collectively, these data confirm the high prevalence of impaired growth and pubertal delay/failure in children and adolescents with thalassaemia and SCD. The aetiology of impaired growth includes the contributions of lack of pubertal growth spurt due to delayed/absent puberty, decreased synthesis of IGF-1 which might be secondary to a disturbed GH-IGF-1 axis and/or under nutrition, probably due to the hypermetabolic status of these children. It is suggested that newer protocols of treatment, in addition to optimization of transfusion and chelation requirements, should increase the caloric intake of these patients and properly manage their pubertal delay-failure in order to improve their adult height.     

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.     

Co-occurrence of Chiari malformations and sickle cell disease-a diagnostic dilemma: a report of 4 cases and review of literature

The co-occurrence of sickle cell disease (SCD) and Chiari malformation (CM) poses clinical and diagnostic challenge since symptoms of both conditions may overlap. Although SCD and CM do not have a causal relationship, the overlapping neurologic symptoms may pose a diagnostic dilemma. To the best of our knowledge, the clinical manifestations and long-term consequence of CM in children with SCD has hitherto not been reported in the literature. We describe clinical manifestations of co-occurrence of SCD and CM in a case series of 4 African American children.     

Spondylocostal dysostosis with tetralogy of Fallot and herniation of the spleen through the diaphragm

Spondylocostal dysostosis (SCD) is a very rare syndrome characterized by vertebral malformation and rib deformity. Some of the patients with SCD have other birth defects in the central nervous system, the genitourinary tract, diaphragm or heart and so forth. There have been reported SCD with complex congenital heart disease, such as pulmonary atresia, double outlet right ventricle, and d‐transposition of great arteries. However, there have been no reported SCD patients with confirmed tetralogy of Fallot (TOF). Here, a patient with SCD having a very rare combination of rib defects on the right side and left‐sided scoliosis, tetralogy of Fallot, and diaphragmatic spleen herniation, which had not been reported before, was described.     

Demands and challenges for patients with sickle‐cell disease requiring hematopoietic stem cell transplantation in Saudi Arabia

Allogeneic HSCT is the only curative treatment for SCD. In this study, we estimated the number of Saudi patients with SCD who are candidates for HSCT. We used the presence of overt stroke, recurrent ACS, and frequent severe pain crisis as indications for HSCT. We calculated the frequencies of these complications among a Saudi SCD cohort of 376 patients with SCD, 250 from SW and 126 from Eastern (E) provinces. We found that 59 (23.6%) of SW patients were transplant candidates compared to 22 (17.4%) from E province. It is estimated that about 61 000 patients with SCD live in Saudi Arabia. Thus, the projected number of Saudi patients with SCD who are candidates for HSCT is 10 536 patients. Of those, 2148 are children. The burden of SCD on HSCT centers in Saudi Arabia is substantial and is difficult currently to meet the demand. We recommend recruiting/training more transplant physicians and nurses, expand current capacity of centers if feasible, and open new transplant centers to make HSCT a practical therapeutic option for patients with severe SCD in Saudi Arabia.     

Nocturnal enuresis and psychosocial problems in pediatric sickle cell disease and sibling controls

To evaluate current and lifetime prevalence rates of nocturnal enuresis and psychosocial problems among children with sickle cell disease (SCD) in comparison with sibling controls, a structured interview and the Pediatric Symptom Checklist were administered to primary caretakers regarding 126 of their children aged 5 to 17 with SCD and 47 sibling controls. Lifetime rates of enuresis among children with SCD were comparable to similar studies, and exceeded population prevalence and sibling control rates. In addition, enuretic children had higher levels of total psychosocial problems on the Pediatric Symptom Checklist regardless of group status, although patterns of subscale differences varied by group and enuresis history after controlling for child age. These findings replicate and extend previous findings and provide further evidence to support a need for monitoring of hydration levels and screening for psychosocial problems among children with SCD and enuresis, as well as evaluation of the psychometric properties of psychosocial screening measures and identification of efficacious treatments for enuresis in children with SCD.     

Infections and sickle cell disease in Eastern Saudi Arabian children

The rate and pattern of infections in 144 Saudi Arabian children with sickle cell disease (SCD) and matched normal control subjects are reported. All diagnoses of SCD were made at birth by means of screening blood from the umbilical cord. The children were prospectively followed up from birth to 4 years of age. Severe bacterial infections occurred in none of the children with SCD; one of the control children developed pneumococcal meningitis. Acute gastroenteritis was significantly more common among patients with SCD. For the first year of life, patients with SCD had significantly more infections than did the control children; but the reverse was true in the group that was 37 to 48 months of age. Considering all types of infections for all age groups, no difference was noted between patients with SCD and control subjects in terms of infection rate or related hospital admission. There were no deaths caused by infection in this series. We conclude that Saudi Arabian infants and young children of oasis origin with SCD are not at increased risk of infections compared with healthy children of the same age.     

Sickle cell disease and implementation science: A partnership to accelerate advances

Sickle cell disease (SCD) results in end organ damage and a shortened lifespan. Both the pathophysiology of the disease and the social determinants of health affect patient outcomes. Randomized controlled trials have been completed among this population and resulted in medical advances; however, the gestation of these advances and the lack of penetrance into clinical practice have limited advancements in clinical improvements for many people with SCD. We discuss the role of implementation science in SCD and highlight the need for this science to shorten the length of time to implement evidence‐based care for more people with SCD.     

Hemoglobin A1c and fructosamine correlate in a patient with sickle cell disease and diabetes on chronic transfusion therapy

In patients with sickle cell disease (SCD) and diabetes mellitus (DM), hemoglobin A_1c (HbA_1c) is unreliable and the American Diabetes Association recommends monitoring long‐term glycemia by measuring serum glucose, but use of serum fructosamine (SF), a measurement independent of red cell lifespan, has been reported. SF as a screen for DM in SCD, however, is not standardized and its relationship to serum glucose has not been validated. Further, screening for DM was not adequately addressed in the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines for SCD management. Blood transfusions, an important treatment for some patients with SCD, can also impact HbA_1c. We present a case of a patient with SCD and cystic fibrosis‐related diabetes on monthly chronic transfusions therapy (CTT) who had well‐correlated “steady state” HbA_1c and SF levels over time, suggesting for the first time these markers may actually be useful when following long‐term glycemic control in patients with SCD on CTT programs.     

Growing up with sickle cell disease: a pilot study of a transition program for adolescents with sickle cell disease

We implemented the Duke Sickle Cell Disease (SCD) Transition Program for adolescents with SCD and investigated the knowledge about SCD; concerns and emotions about transitioning; and the initial impact of the Transition Program. Thirty-three adolescents participated in the initial study. Gaps in knowledge included ethnicities affected by SCD and inheritance of SCD. Adolescents were primarily concerned about transferring to a new medical team. There was a mix of both positive and negative emotions that varied over time. Overall, we have identified educational gaps and concerns and emotions about transitioning, which we will address through the Duke SCD Transition Program.     

Complete resolution of sickle cell chronic pain with high dose vitamin D therapy: a case report and review of the literature

With age, individuals with sickle cell disease (SCD) experience daily chronic pain. Vitamin D deficiency (VDD) can result in chronic pain, osteoporosis, fractures, and muscle weakness. Several studies report a high prevalence of VDD in SCD; however, the clinical correlates have not been well described. We describe a case of SCD chronic pain associated with profound VDD, osteoporosis, and osteonecrosis. Treatment with high-dose vitamin D resulted in complete resolution of chronic pain symptoms and improvement in bone density. Randomized studies of vitamin D in SCD may help elucidate its role in the management of chronic pain and bone disease.     

Sudden cardiac death in infants, children, and adolescents

Although SCD is relatively uncommon, its psychosocial impact is devastating. This article has reviewed the potential causes of SCD in infants, children, and adolescents. Many patients who die from SCD have identifiable cardiac disease and are known to have been at risk; however, the existence of other cardiac abnormalities, such as hypertrophic cardiomyopathy or long QT syndrome, may not be known, and SCD may be the first symptom. The authors' contention is that many of the patients in this latter group (e.g., patients who have hypertrophic cardiomyopathy or LQLTS but who have no symptoms) can be screened with a careful, accurate, and detailed history, including family history and review of systems, and physical examination. Any patient with a positive family history, positive review of systems, or positive physical examination should receive further in-depth evaluation, such as an ECG and echocardiogram. These studies permit the detection of most, if not all, of the entities potentially associated with SCD in the pediatric population.     

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.     

Children with sickle cell disease and human immunodeficiency virus-1 infection: use of inpatient care services in the United States

BACKGROUND: The purpose of this study was to describe hospital use patterns of children with sickle cell disease (SCD) and human immunodeficiency virus type-1 (HIV) infection in the United States. METHODS: Hospital discharges of children with 1 or both of the 2 conditions (SCD and HIV infection) were analyzed using nationally weighted data from the 1994 to 2003 Nationwide Inpatient Databases of the Healthcare Cost and Utilization Project. Demographic and hospital characteristics, length of stay, charges and the most frequent diagnoses and procedures performed during the hospitalization were compared. Multivariate logistic regression was used to analyze the effects of age, sex and HIV infection on number of hospitalizations for selected conditions. RESULTS: There were an estimated 686 hospitalizations of children with SCD and HIV infection in the United States in the 10-year period 1994-2003; these hospitalizations aggregated in the South (78.2%) and their expected payer was mostly Medicaid/Medicare (82.0%). Their average length of stay was longer than that of children with SCD alone (8.0 days vs. 4.3 days, respectively), and the mean charges associated with the hospitalization were also higher ($18,291 vs. $9584). Compared with patients with SCD without HIV, HIV infection conferred a higher risk for hospitalizations for bacterial infections and sepsis (odds ratio 2.75; 95% CI, 1.66-4.6), but less of a risk for vaso-occlusive crises (odds ratio 0.32; 95% CI, 0.22-0.48). Inpatient case-fatality rate of children with SCD and HIV was no different from that of children with SCD alone, but lower than that of the rest of children with HIV infection. CONCLUSIONS: Hospitalized children with SCD and HIV infection have higher odds of infection than those with SCD alone. Their inpatient case-fatality rate is lower than that of children with HIV infection alone. These findings should be considered in designing appropriate interventions for this population.     

Interactions of biomedical and environmental risk factors for cognitive development: a preliminary study of sickle cell disease

Sickle cell disease (SCD) is associated with a number of biopsychosocial risk factors for cognitive development. Understanding how these risk factors may interact is important for developing interventions for cognitive functioning. The authors assessed the cognitive abilities of children with SCD (n = 50) and related their performance to anemia severity, socioeconomic status (SES), and their interaction. Demographically matched peers without SCD (n = 36) served as a comparison group. Four areas of cognitive weakness were identified among children with SCD: general cognitive ability, crystallized ability, short-term memory, and processing speed. Anemia severity predicted general cognitive ability, crystallized ability, and processing speed. Interactions between anemia severity and SES were found for general cognitive ability and short-term memory. Disease effects in SCD appear to vary depending on the child's level of socioenvironmental risk. Biomedical interventions to benefit cognitive functioning may have different effects depending on whether additional socioenvironmental risk factors are present.     

A global perspective on sickle cell disease

The global burden of sickle cell disease (SCD) is now being increasingly realized. SCD poses a significant public health problem in sub-Saharan Africa, the Middle East, some regions of India, the Caribbean, and Brazil. In many of these regions, progress in the management of SCD has been slow. Long-term North-South and South-South partnerships between SCD professionals, funding agencies, governments, and industry are needed to help reduce the high disease burden in developing countries, through widespread SCD education, relevant research and implementation of evidence-based cost-effective interventions. A group of SCD professionals have responded with action by forming a global network.     

Patterns of arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive crisis and acute chest syndrome

PURPOSE: Our objective was to evaluate L-arginine and nitric oxide metabolite (NOx) levels in children with sickle cell disease (SCD) at steady-state and during vaso-occlusive crisis (VOC). Because alterations in nitric oxide production may have an important role in the pathophysiology of SCD, our second aim was to determine if a relationship exists between these levels and vaso-occlusive crisis (VOC). PATIENTS AND METHODS: Plasma L-arginine and serum NOx levels were examined in 36 patients with SCD with 39 episodes of VOC and 10 children with SCD at steady-state. Daily levels were obtained in children requiring hospitalization. RESULTS: Steady-state L-arginine levels were normal in children with SCD. L-arginine levels were low, however, in children with VOC (37.4 +/- 2.7 vs. 53.6 +/- 4.6 micromol/L; P = 0.008) but returned to baseline during hospitalization. In contrast, NOx levels were normal at presentation but decreased during hospitalization for both patients with VOC and patients with acute chest syndrome (ACS) (21.1 +/- 2.0, 17.4 +/- 2.4, and 12.3 +/- 1.6 micromol/L, respectively; P < 0.05). In the patients with VOC who had ACS develop, L-arginine decreased to the lowest levels at the time of the ACS diagnosis, correlating with decreasing NOx levels. CONCLUSION: These data suggest that there may be a relationship between the L-arginine-nitric oxide pathway and vaso-occlusion in SCD. Low arginine levels during VOC could reflect a state of acute substrate depletion that results in a decrease in nitric oxide production.     

Sudden death in children and adolescents

This article focuses on sudden unexpected cardiac death (SCD) in children and adolescents. The authors discuss the epidemiology of SCD in children and adolescents, its incidence and etiologies, and strategies for prevention. Because most of the episodes of SCD or sudden cardiac arrest in children and adolescents occur in asymptomatic individuals unknown to have an underlying abnormality before their "event," the issues in this article primarily focus on this group of individuals.