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Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6-4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA.

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

Background Overt stroke in sickle cell anemia (SCA) is associated with intracranial stenosis and thrombus formation. Platelet activation is critical for thrombus formation. Procedure Platelet activation studies were performed in 50 subjects: 18 SCA patients with history of stroke or abnormal transcranial Doppler (TCD) and intracranial stenosis seen by magnetic resonance angiogram (MRA), 7 SCA patients with history of stroke or abnormal TCD but no intracranial stenosis, 13 SCA patients with no history of stroke or abnormal TCD, and 12 healthy African-Americans. Results Of the 18 patients with intracranial stenosis, 11 (61%) had evidence of the moyo-moya phenomenon on MRA. SCA children with intracranial stenosis had a significantly greater total white cell count compared to both healthy African-American controls and SCA patients in the steady-state (P

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Background Clinical complications of sickle cell anemia begin in infancy. BABY HUG (ClinicalTrials.gov, NCT00006400) was a NHLBI-NICHD supported randomized phase III placebo-controlled trial of hydroxyurea (HU) in infants (recruited at 9–18 months) unselected for clinical severity with sickle cell anemia. This secondary analysis of data from BABY HUG examines the influence of anemia on the incidence of sickle cell related complications, and the impact of hydroxyurea therapy in altering these events by comparing children with lower ( 75th percentile) hemoglobin concentrations at study entry. Procedure Infants were categorized by: (1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9–12 months old: 10.0 gm/dL; 12–18 months old: 9.9 gm/dL) and (2) treatment arm (hydroxyurea or placebo). Four subgroups were created: placebo (PL) LoHb (n = 25), PL HiHb (n = 27), hydroxyurea (HU) LoHb (n = 21), and HU HiHb (n = 18). The primary and secondary endpoints of BABY HUG were analyzed by subgroup. Results Infants with lower hemoglobin at baseline were more likely to have a higher incidence of clinical events (acute chest syndrome, pain crisis, fever) as well as higher TCD velocities and lower neuropsychological scores at study exit. Hydroxyurea reduced the incidence of these findings. Conclusion Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea. Pediatr Blood Cancer 2012;59:675–678. © 2011 Wiley Periodicals, Inc.

Background Stroke occurs in 5–10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload.

We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by 99mTc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of ≤ 1.2% or HJB ≤ 55/106 red blood cells and absent function by PIT ≥ 4.5% or HJB ≥ 665/106. HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400.

Background Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years. Procedure TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7–17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n = 192). Results No patient had an abnormal TCD as defined in the older child (time averaged maximum mean TAMM velocity ≥200 cm/sec) and only four subjects (2%) had velocities in the conditional range (170–199 cm/sec). TCD velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age. Conclusion Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD's and long-term follow-up, which is ongoing (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:256–259. © 2009 Wiley-Liss, Inc.

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9–17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:250–255. © 2009 Wiley-Liss, Inc.

Background A urine concentrating defect is quite common in sickle cell anemia, has its onset in early childhood, and may be reversible with transfusion. The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) is a double-blind, placebo-controlled trial to assess efficacy of hydroxyurea in preventing organ damage in young children with sickle cell anemia. Procedures Enrolled infants were subjected to parent-supervised fluid deprivation, and urine and serum osmolality were determined. Results Of 185 infants age 7.5–17.9 months (mean 13.0 ± 2.7) and fluid-deprived 7.4 ± 2.4 hr (range 4–13), 178 had concurrent determinations of urine and serum osmolality. Mean serum osmolality was 286 ± 6 mOsm/kg H2O (range 275–312) and independent of age, height, weight, or duration of fluid deprivation. Urine osmolality (mean 407 ± 151, range 58–794 mOsm/kg H2O) was greater than serum (P 500 mOsm/kg H2O. Urine osmolality correlated with 99mTc-DTPA clearance (P = 0.02) and serum urea nitrogen (P 500 mOsm/kg H2O had higher mean fetal hemoglobin concentrations than did those who could not (P = 0.014). Conclusions Even with often limited fluid deprivation, 77.2% of young infants with sickle cell anemia were able to concentrate urine. Preservation of concentrating ability was associated with higher fetal hemoglobin concentration. Assessment will be repeated after 2 years of hydroxyurea or placebo treatment (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:265–268. © 2009 Wiley-Liss, Inc.

This study evaluated the initial psychometric properties of the Self Care Inventory-Sickle Cell (SCI-SC), a brief measure of adherence to health behaviors for pediatric sickle cell patients. Ninety-nine parents completed the measure regarding their child's behavior. Factor analysis of the measure yielded three meaningful factors accounting for 64% of the variance in the measure, including General Health Behavior, Sickle Cell Management, and Pain Management. Internal consistency of the SCI-SC was very good at .88. With further validation, the SCI-SC could be a method of evaluating baseline adherence and changes in adherence following an intervention.

Though the impact of disease knowledge on adherence to medical recommendations has long been the focus of research, little of this research has focussed on sickle cell compliance in the child and adolescent population. The present study examined the relationship of caregiver knowledge of sickle cell disease (SCD) and children's adherence to prescribed behaviors. Though caregivers with high levels of knowledge of SCD were more likely to report higher levels of adherence, knowledge test score did not predict adherence for the majority of participants (72%). The effect of caregiver knowledge on reported adherence was greater among preadolescents (age ≤ 11) than adolescents (age ≥12). The relationship between knowledge and adherence may not be as strong or direct as is assumed in many theories of health behavior change.

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.

Before the mid-1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV-seropositive patients, age 13-88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross-sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV-1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV-1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV-1-positive participants had > or = 200 CD4+ cells microL(-1), only 59% were on HAART. HIV-1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti-HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV-1-positive than HIV-1-negative participants (85% vs. 70%, P < 0.0001). HIV-1-positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV-negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self-reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non-Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV-1, HCV or both.

We explored whether cognitive development level (CDL) and chronological age were related to sickle-cell disease (SCD) knowledge and pain conceptualization in young children with SCD. We found that CDL was not significantly related to either disease knowledge or pain conceptualization. In contrast, chronological age was significantly related to disease knowledge, but not pain conceptualization. Overall, children had limited knowledge regarding SCD, and pain conceptualizations were consistent with the "transitional" stage of cognitive development. However, several children reported maladaptive thinking patterns regarding SCD-related pain that need to be addressed in future studies.

We conducted two separate experiments designed to increase parents' question-asking at pediatric diabetes and sickle cell appointments using a brief intervention. Sixty-two parent-child dyads attending pediatric diabetes appointments and ninety-two parent-child dyads attending sickle cell appointments were included in the study. In experiment 1, parents of pediatric diabetes patients were randomly assigned to either an oral instruction or written instruction condition. Participants in the oral instruction condition were asked by a psychology resident if they had any questions that they planned to ask the pediatrician and encouraged to ask all questions. Participants in the written instruction condition were treated identically to the oral instruction condition participants except that their questions were recorded on 3 × 5 index cards and given to them as reminders. Results showed that parents in the written instruction condition asked more questions than parents in the oral instruction condition. A secon...

PURPOSE To evaluate the consequences of prolonged prophylactic penicillin use on the rates of nasopharyngeal colonization with Streptococcus pneumoniae and the prevalence of resistant pneumococcal strains in children with sickle cell anemia. METHODS Nasopharyngeal specimens were obtained from children with sickle cell anemia (Hb SS or Hb S beta degrees thalassemia) at 10 teaching hospitals throughout the United States. These patients were participating in a prospective, randomized, placebo-controlled trial in which they were prescribed prophylactic penicillin before their fifth birthday and were randomized to prophylactic penicillin or placebo after their fifth birthday (PROPS II). The specimens were cultured for S. pneumoniae, and isolates were analyzed for antimicrobial susceptibility to nine commonly prescribed antimicrobial agents. RESULTS Of the 226 patients observed, an average of 8.4 specimens were collected per patient. From 1,896 individual culture specimens, 5.5% of the specimens were positive for S. pneumoniae; 27% of patients had at least one positive culture. Nine percent of the study patients had at least one isolate of penicillin intermediate or resistant pneumococci. There was no significant difference in the percent of positive cultures for S. pneumoniae in those patients given penicillin prophylaxis after 5 years of age (4.1%) compared with those patients given placebo after 5 years of age (6.4%). Likewise, there was no significant difference (p = 0.298) in the percent of patients with at least one positive culture for S. pneumoniae in the group given prophylactic penicillin after 5 years of age (21.8%) compared with the group given placebo after 5 years of age (28.3%). There was no difference between the penicillin and placebo groups in the proportion of patients with penicillin intermediate or resistant pneumococci, but there was a trend toward increased carriage of multiply drug-resistant pneumococci in children > 5 years of age receiving prophylactic penicillin compared to children > 5 years of age receiving placebo. The increased colonization rate with multiply drug-resistant organisms of children > 5 years of age receiving penicillin prophylaxis is not statistically significant. CONCLUSIONS The potential for continued penicillin prophylaxis to contribute to the development of multiply resistant pneumococci should be considered before continuing penicillin prophylaxis in children with sickle cell anemia who are older than 5 years of age. Added to the published data from PROPS II, which demonstrated no apparent advantage to continue prophylaxis, the data support the conclusion that, for children with no history of invasive pneumococcal disease, consideration should be given to discontinue prophylactic penicillin after their fifth birthday.

Summary Stroke is a traumatic complication in sickle cell anaemia (SCA) that is associated with significant morbidity and a risk of recurrent overt stroke of 2·2–6·4 events per 100 patient-years. A retrospective study was performed on all paediatric SCA patients diagnosed with a history of overt stroke between 1997 and 2010. A total of 31 children with SCA had new onset overt stroke. The mean age of the active patients (n = 27) was 17·9 years (range 6·8–27·6 years) with a total period of observation of 305 patient-years. Twenty-two of 27 (81%) were receiving long term red blood cell transfusions and 16 (59%) were taking the anti-platelet agent, aspirin, since diagnosis of the stroke. Two of 27 (7%) patients had a second overt stroke with an overall risk of recurrent stroke of 0·66/100 patient-years (one stroke was ischaemic and the other haemorrhagic). In patients taking aspirin with 180 patient-years of follow up, the recurrence rate of haemorrhagic stroke was 0·58/100 patient-years. We have an excellent outcome for overt stroke in paediatric SCA patients with a low rate of recurrent stroke. Further studies are needed to determine the risk-benefit ratio of aspirin therapy in the prevention of recurrent stroke in paediatric SCA.

OBJECTIVES: (1) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and (2) to determine whether continued penicillin prophylaxis had any adverse effects on these responses. STUDY DESIGN: Children with sickle cell anemia, who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday, were randomly selected at age 5 years to continue penicillin prophylaxis or to receive placebotreatment. These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of randomization. RESULTS: Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor; the poorest response was to serotype 6B. The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment, and in subjects who received one or two pneumococcal vaccinations before reimmunization. The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype. CONCLUSIONS: Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies, regardless of previous pneumococcal vaccine history. Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization. (J Pediatr 1996;129:828-35)

Objective : To evaluate the consequences of discontinuing penicillin prophylaxis at 5 years of age in children with sickle cell anemia who had received prophylactic penicillin for much of their lives. Design : Randomized, double-blind, placebo-controlled trial. Setting : Eighteen teaching hospitals throughout the United States. Patients : Children with sickle cell anemia (hemoglobin SS or hemoglobin S β 0 -thalassemia) who had received prophylactic penicillin therapy for at least 2 years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between 2 and 3 years of age and again at the time of randomization. Of 599 potential candidates, 400 were randomly selected and followed for an average of 3.2 years. Interventions : After randomization, patients received the study medication twice daily-either penicillin V potassium, 250 mg, or an identical placebo tablet. Patients were either seen in the clinic or contacted every 3 months thereafter for an interval history and dispensing of the study drug. A physical examination was scheduled every 6 months. Main outcome measures : The primary end point was a comparison of the incidence of bacteremia or meningitis caused by Streptococcus pneumoniae in children continuing penicillin prophylaxis versus those receiving the placebo. Results : Six children had a systemic infection caused by S. pneumoniae , four in the placebo group (2.0%; 95% confidence interval 0.5%, 5.0%) and two in the continued penicillin prophylaxis group (1.0%; 95% confidence interval 0.1%, 3.6%), with a relative risk of 0.5 (95% confidence interval 0.1, 2.7). All invasive isolates were either serotype 6(A or B) or serotype 23F. Four of the isolates were penicillin susceptible, and two (one from each treatment group) were penicillin and multiply antibiotic resistant. Adverse effects of the study drug were reported for three patients (nausea, vomiting, or both), one of whom was in the placebo group. Conclusion : Children with sickle cell anemia who have not had a prior severe pneumococcal infection or a splenectomy and are receiving comprehensive care may safely stop prophylactic penicillin therapy at 5 years of age. Parents must be aggressively counseled to seek medical attention for all febrile events in children with sickle cell anemia. (J PEDIATR 1995;127:685-90)

Background Preoperative transfusions are frequently given to prevent perioperative morbidity in patients with sickle cell anemia. There is no consensus, however, on the best regimen of transfusions for this purpose. Methods We conducted a multicenter study to compare the rates of perioperative complications among patients randomly assigned to receive either an aggressive transfusion regimen designed to decrease the hemoglobin S level to less than 30 percent (group 1) or a conservative regimen designed to increase the hemoglobin level to 10 g per deciliter (group 2). Results Patients undergoing a total of 604 operations were randomly assigned to group 1 or group 2. The severity of the disease, compliance with the protocol, and the types of operations were similar in the two groups. The preoperative hemoglobin level was 11 g per deciliter in group 1 and 10.6 g per deciliter in group 2. The preoperative value for hemoglobin S was 31 percent in group 1 and 59 percent in group 2. The most frequent operations w...

Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.

Background Children with sickle cell anemia (SCA) often develop hyposthenuria and renal hyperfiltration at an early age, possibly contributing to the glomerular injury and renal insufficiency commonly seen later in life. The Phase III randomized double-blinded Clinical Trial of Hydroxyurea in Infants with SCA (BABY HUG) tested the hypothesis that hydroxyurea can prevent kidney dysfunction by reducing hyperfiltration. Procedure 193 infants with SCA (mean age 13.8 months) received hydroxyurea 20 mg/kg/day or placebo for 24 months. 99mTc diethylenetriaminepentaacetic acid (DTPA) clearance, serum creatinine, serum cystatin C, urinalysis, serum and urine osmolality after parent-supervised fluid deprivation, and renal ultrasonography were obtained at baseline and at exit to measure treatment effects on renal function. Results At exit children treated with hydroxyurea had significantly higher urine osmolality (mean 495 mOsm/kg H2O compared to 452 in the placebo group, P = 0.007) and a larger percentage of subjects taking hydroxyurea achieved urine osmolality >500 mOsm/kg H2O. Moreover, children treated with hydroxyurea had smaller renal volumes (P = 0.007). DTPA-derived glomerular filtration rate (GFR) was not significantly different between the two treatment groups, but was significantly higher than published norms. GFR estimated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula was the best non-invasive method to estimate GFR in these children, as it was the closest to the DTPA-derived GFR. Conclusion Treatment with hydroxyurea for 24 months did not influence GFR in young children with SCA. However, hydroxyurea was associated with better urine concentrating ability and less renal enlargement, suggesting some benefit to renal function. (ClinicalTrials.gov number NCT00006400) Pediatr Blood Cancer 2012;59:668–674. © 2012 Wiley Periodicals, Inc.

Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects.This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400.96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia.On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia.The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

Stroke occurs in 5-10% of children with sickle cell anemia (SCA) and has a high (50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long-term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload.Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH is to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload.SWiTCH has several distinctive study features including novel methodological and design components: (1) composite primary endpoint including both stroke recurrence rate and iron burden; (2) non-inferiority design with an "acceptable" increased stroke risk; (3) transfusion goals based on current academic community practices; (4) special oversight for the enrollment and randomization process; (5) overlap treatment period within the alternative treatment arm; (6) masking of the overall trial Principal Investigator to treatment results; (7) inclusive independent stroke adjudication process for all suspected new neurological events; and (8) periodic therapeutic phlebotomy program to alleviate iron overload.Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA, stroke, and iron overload.

The state of Mississippi has consistently been ranked as the state with most number of obese people in the United States with prevalence rates of >30%. Our aims in this study were to estimate the prevalence of overweight and obesity in children and adults diagnosed with haemophilia in Mississippi, and to assess whether race/ethnicity and the severity of haemophilia are important risk factors. A retrospective chart review was performed for all haemophilic patients seen at the Mississippi Hemophilia Treatment Center. Patients were classified into two major age groups: age 2-19.9 years and > or =20 years. Body mass index (BMI) was calculated from the height and weight in kg m(-2) from the last clinic visit. Out of a total of 132 haemophilic patients, 61% were white and 37% were African American. Overall, 51% of the haemophilic patients were either obese or overweight. The prevalence of obesity in the adult (> or =20 years old) haemophilic patients was 36% and an additional 32% were overweight. A significantly greater proportion of patients >20 years old were overweight or obese as compared with the patients in the 2-19.9 year age range (P < 0.002). However, race/ethnicity and severity of haemophilia were not significant risk factors for overweight and obesity. There is a very high prevalence of obesity in the Mississippi haemophilic population, especially in adults. Particular attention at clinic visits should be paid to the BMI in order to identify patients that are overweight or obese to allow for early and appropriate intervention.

Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years.TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7-17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n = 192).No patient had an abnormal TCD as defined in the older child (time averaged maximum mean TAMM velocityor =200 cm/sec) and only four subjects (2%) had velocities in the conditional range (170-199 cm/sec). TCD velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age.Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD's and long-term follow-up, which is ongoing (ClinicalTrials.gov number, NCT00006400).

Multicenter trials have shown that hematopoietic cell transplantation (HCT) has an excellent outcome for children with sickle cell disease (SCD). As a single center, we performed a total of 11 transplants in 10 patients (6 male, 4 female) with SCD between 1997 to 2005. Eight patients had hemoglobin SS disease and 2 patients had HbSβ0 thalassemia. The median age of HCT was 10.1 (range 2.8–16.3) years. The indications were cerebrovascular accident (6 patients), abnormal transcranial Doppler (2 patients), acute chest syndrome (1 patient) and recurrent vasoocclusive disease with hypertension (1 patient). The median number of packed red blood cell units transfused prior to transplant was 9 (range 1 to 99). Only one patient developed red cell alloantibodies prior to transplant and this patient’s post-transplant period was complicated by transplant related immune hemolysis. Three patients had gallstones and four patients had high ferritin levels (median 3550 and range 1110 to 4380 ng/ml) prior to transplant. All donors were HLA-identical siblings; 6 patients received bone marrow (BM), 2 patients received mobilized peripheral blood, 1 patient received umbilical cord blood (UCB) and 1 patient received both UCB and BM from the same donor. Myeloablative conditioning regimen consisted of busulfan, horse antithymocyte globulin and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A (CSP). All patients received G-CSF until neutrophil engraftment and received seizure prophylaxis with phenytoin during busulfan and CSP therapy; 3 patients had a seizure at days 15, 44 and 345 respectively with MRI changes of posterior leukoencephalopathy secondary to CSP. None of these patients had any sequelae. The patient with hypertension received mycophenolate mofetil for GVHD and had normalization of blood pressure after transplant. The median number of days to neutrophil engraftment (ANC>500) and platelet engraftment (>50000/μL) was 14.5 days (range 11 to 44 days) and 19.5 days (range 13 to 101 days) respectively. Nine of 10 patients had acute grade I GVHD and but none had acute grade II–IV GVHD. Five patients had limited chronic grade I GVHD and none had grades II–IV chronic GVHD. Currently, three females are >14 years, and 2/3 females have premature ovarian failure. One of the 10 patients had a gradual decrease in donor chimerism to 15% and increase in HbS to 57.7% and subsequently had a second BMT using a reduced intensity conditioning regimen consisting of alemtuzumab, fludarabine and melphalan. Follow-up at day +420 shows stable engraftment. Patient had grade I skin GVHD and no chronic GVHD. Currently, 9 of 10 patients are alive with a median follow-up of 4.3 (range 1.9 to 9.9) years. Five year overall and event-free survival probabilities with our relatively small number of patients were 90% and 77% respectively. One patient at day +28 had extensive new CVA with neurologic devastation and subsequently died at day +270 from multi-organ failure secondary to sepsis. All patients alive have a Karnofsky/Lansky of 100%. As one of the largest single institution’s experience with HCT in children with SCD, we are reporting an excellent outcome with tolerable toxicities and suggest HCT be considered early for a broader range of indications in this population.

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9-17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400).

Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% ± 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% ± 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% ± 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% ± 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients.We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors.Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P=0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups.These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies.

Subject retention and adherence are essential to maintain the power and validity of the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). We designed a study to assess adherence with study medication administration and study visits and to evaluate socioeconomic factors (SES) that may influence these measurements of adherence. These data are important for assessing impact of adherence on BABY HUG trial outcome and defining impact of SES on adherence.Each subject's median study medication (MedAd) and mean visit adherence (VAd) were evaluated. We examined associations of adherence with SES of participating families.MedAd data were available on 153 of the 191 subjects who started randomized study medication. MedAd was 101.7% of volume prescribed, with 88.9% of subjects taking at least 80% of doses. VAd data were available on 185 of the 191 subjects who started randomized study medication. VAd was 97.3%, with 82.2% of subjects having no missed visits. During dose titration, subjects had on average 12.9% higher medication adherence than subjects who were on a stable dose and had less frequent study visits. MedAd and VAd were not significantly associated with SES.Subjects in the BABY HUG trial have had excellent adherence. SES was not associated with adherence, suggesting that SES should not be used as a criterion for enrolment in clinical trials. Additional efforts are needed to maintain medication adherence, particularly when the interval between scheduled visits increases. (ClinicalTrials.gov number, NCT00006400).

PURPOSE Few studies address the association of Chlamydia pneumoniae infection with pulmonary disease and outcome in patients with underlying pathology such as sickle cell disease (SCD). SCD patients are susceptible to the pulmonary disorder known as acute chest syndrome (ACS), where the etiology remains ill defined. The purpose of this study was to analyze the clinical course and outcome of C. pneumoniae-associated ACS among SCD patients as part of the National Acute Chest Syndrome Study.This was a longitudinal study of SCD patients presenting with ACS to multiple U.S. medical centers. Two hundred ninety-six SCD patients who developed ACS were tested by PCR for C. pneumoniae and by standard techniques for other respiratory pathogens. These infections were evaluated for association with ACS, clinical course, and complications.Forty-one (14%) patients with first episodes of ACS were PCR positive for C. pneumoniae. Compared with other infections, C. pneumoniae-infected patients were older, were more likely to present with chest pain, and had higher hemoglobin levels at diagnosis. Both groups had similar rates of respiratory failure and prolonged hospitalization. Of the 89 patients with single-pathogen infections, 27 (30%) were due to C. pneumoniae, 21% to Mycoplasma pneumoniae, 10% to RSV, 4% to Staphylococcus aureus, and 3% to Streptococcus pneumoniae.C. pneumoniae was the most prevalent pathogen in this study of ACS and was responsible for significant morbidity. Additional research is required to develop effective treatment guidelines for ACS.

To compare the results of the nonduplex ultrasonography (US) Stroke Prevention Trial in Sickle Cell Anemia (STOP) with those of transcranial duplex power Doppler US by using the STOP protocol and to correlate abnormal transcranial Doppler findings with magnetic resonance (MR) imaging and MR angiographic findings.One hundred twenty-five asymptomatic patients aged 2-16 years with sickle cell anemia or sickle cell-beta thalassemia were examined by using transcranial duplex power Doppler US with a 2.5-MHz transducer and classified according to STOP criteria. The results were compared with those obtained in the nonduplex STOP study. Eight of 10 patients with abnormal results, as well as one who had normal results and a subsequent stroke, were examined with MR imaging and MR angiography.Ten (8.0%) patients were judged to have abnormal findings by using the duplex Doppler US and STOP criteria compared with 9.4% of patients in the nonduplex US STOP study. Of the eight patients with abnormal transcranial Doppler US results who underwent MR imaging and MR angiography, six had abnormal MR imaging findings and all eight had abnormal MR angiographic findings.The STOP protocol can be reproduced by using duplex power Doppler US. Abnormal results with the STOP criteria strongly suggest vascular abnormality.

We reviewed the clinical courses of children < or = 16 years of age with hereditary hemolytic anemias who were admitted to the University of Mississippi Medical Center for aplastic crisis. Constitutional signs, gastrointestinal complaints, and headache were the most frequent findings. Statistically significant decreases in hemoglobin levels, hematocrit, and reticulocyte counts, but not total white blood cell or platelet counts, were found on admission when compared to other times of determination. For 27 of 49 patients, IgM antibody determinations to human parvovirus (B19) were available, and 15 (56%) had positive values. We conclude that erythroid (but not other) blood cell lines are helpful in establishing a clinical diagnosis, and that both acute and convalescent titers are necessary to assess the immune response to the infection. Physicians should continue to search for agents other than B19 parvovirus in patients in whom B19 antibodies cannot be found.

Abstract 2134 BABY HUG randomly assigned children with sickle cell anemia ages 9 to 18 months at entry to a two-year double-masked treatment course of 20 mg/kg/d of hydroxyurea (HU) or placebo (PBO). The primary goal of this clinical trial was to determine if treatment with HU could reduce organ damage or dysfunction (spleen function assessed by 99mTc-sulfur colloid and renal function by 99mTc-DTPA clearance) by 50%. Children were seen at least monthly for blood and clinical evaluations. [Lancet 2011; 377(9778):1663–1672.] Between March 23, 2006 and June 1, 2006, the BABY HUG study was placed on “clinical hold” due to the omission of an expiration date on the treatment label for one lot of the study treatments. During the clinical hold, there were 94 children on active study treatment (47 HU, 47 PBO); four and six children, respectively, had finished their two-year follow up. Subjects continued regular visits and clinical event monitoring but received no study medication. To examine the impact of the clinical hold on toxicity and clinical events, the BABY HUG study period was divided into three intervals: Before, During, and After the clinical hold. Each period was offset by a one-month delay from the actual onset and end date to allow for wash-out and wash-in periods surrounding the clinical hold. The clinical hold produced both hold effects (effects produced by the hold that were consistent in the two treatment groups) and treatment-hold interaction effects (hold effects that were different by treatment). The interaction effects are presented below. The table presents the rate or prevalence of selected clinical events during each interval. The rate of pain, one of the clinical events shown to benefit from treatment with HU, was comparable to the PBO rate during the clinical hold but was significantly lower in the pre- and post-hold intervals. The prevalence of splenomegaly (defined by palpation ≥2 cm below the costal margin), which was slightly greater in the HU group than in the PBO group during the pre- and post-hold intervals, increased to a four-fold difference during the clinical hold. There was no difference between the groups in the rate of splenic sequestration in any interval.Clinical Events Before, During and After Clinical Hold+Before HoldDuring HoldAfter HoldHU 55.1*PBO 50.3*HU 8.3*PBO 7.8*HU 125.1*PBO 126.8*AENo.RateNo.RateNo.RateNo.RateNo.RateNo.RateDactylitis59.13467.6112.0338.51814.48667.8Pain3461.772143.114168.715192.3129103.1288227.1Splenomegaly^3054.42039.814168.7338.58366.36551.6Lab ResultsMeanMeanMeanMeanMeanMeanRetic Ct (k/mm3)191.5329.4300.5327.3237.0335.4Hgb (gm/dL)10.078.699.098.739.288.69MCV (fL)86.8481.9082.8279.8585.0080.00+Rates in bold are significantly different at p < 0.05 within each time period*Person Years of Exposure^Prevalence Hematologic changes showing a treatment-period interaction included a significantly larger difference in absolute reticulocyte count between the HU and placebo group During the Hold as compared to Before and After. The HU-induced increase in Hb and MCV was significantly diminished During the Hold. All measurements moved back towards their pre-hold differences after the hold was lifted. The clinical hold in BABY HUG provided an unforeseen opportunity to study the clinical and laboratory impact of cessation of HU therapy for a brief time period. No serious clinical effects or toxicities occurred during the clinical hold, perhaps due to its limited time span. Parents and physicians should be aware that stopping HU therapy may result in increased episodes of pain or splenic enlargement. Disclosures: Off Label Use: Hydroxyurea which is not approved for use in children with sickle cell disease. Casella:Adventrix: Honoraria.

Abstract 7 BABY HUG [Clinical Trials #NCT00006400], an NIH-NICHD sponsored randomized placebo-controlled trial showed that hydroxyurea (HU) administered to 9–18 month old children with sickle cell anemia (SCA) provides substantial clinical benefit. Benefits include a decrease in pain crises, acute chest syndrome events, need for transfusion and hospital admission; hematologic improvement include higher total and fetal hemoglobin concentration, larger red cell size, and lower WBC counts with toxicity limited to transient reduction in absolute neutrophil count (ANC) [Lancet 2011; 377:1663–72]. The parent or guardian of all 176 children who completed at least 18 months of randomized treatment were offered participation in an initial observational BABY HUG Follow-Up Study and 163 (93%) consented to participate. Clinical and laboratory data were collected every 6 months by structured abstraction of the medical record regarding use of clinically prescribed HU (dose escalation recommended), blood counts, clinical imaging, and sickle cell-related events. At the time of enrollment the family did not know their child's randomized study treatment assignment; 133 (82%) initially chose clinical prescription of open-label HU. Acceptance of HU has remained high through 36 months of follow-up; during each 6 month data collection period 68–75% of participants reported having taken HU. Only 2 patients have left the study (due to relocation) and more than 93% of expected data have been collected. Preliminary analyses as of May 2011, including 417 patient years (pt-yrs) of follow up, demonstrate that in comparison to participants not taking HU, children who continue to take HU have statistically lower rates of pain crises requiring emergency department (ED) visits, episodic transfusions, and hospital admissions for any reason, including acute chest syndrome or febrile illness (see table). The substantial decrease in acute chest syndrome episodes is similar to the effect demonstrated with HU use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of HU therapy in older children and adults. The decrease in the rate of admission for febrile events in HU-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain. There was no difference in hospitalization rates for painful events including dactylitis. Two patients in the non-HU group had a stroke. There were no differences between groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up children taking HU had persistently higher hemoglobin and MCV, and lower WBC and ANC than those not taking HU. Results of these analyses including growth and development assessments will enhance our understanding of the impact of HU use in children with SCA starting at a very young age. The accruing data from the BABY HUG Follow-Up Study demonstrate a continuation of the substantial benefits of early HU therapy with no discernable additional toxicities. Ongoing follow up of this cohort is essential to fully define these benefits as children grow, and to observe for late toxicity.Event Rate per 100 pt-yrsHUNo HUp valueED visit for Pain Crisis28.853.60.004Episodic Transfusion18.334.00.010Hospital Admission (any cause)74.9133.20.001Acute Chest Syndrome (admission)9.522.30.0001Febrile Illness (admission)30.764.3 Disclosures: Off Label Use: Hydroxyurea is not indicated for treatment of children with sickle cell disease. Use of this medication was for clinical indications and not mandated by this observational study.

Abstract 846 Elevation of the serum level of secretory phospholipase A2 (sPLA2) has previously been reported to predict impending acute chest syndrome (ACS) in sickle cell disease (SCD) patients admitted with pain. The Sickle Cell Disease Clinical Research Network initiated the PROACTIVE Feasibility Study to 1) assess the feasibility of screening, randomizing and treating with simple transfusion eligible patients and 2) assess the predictive utility of sPLA2 in screening for imminent ACS, characterize the distribution of sPLA2 values in sickle cell patients hospitalized with pain, and define a cut-off point for predicting ACS to optimize its reliability, sensitivity and specificity in predicting ACS. All SCD patients (hemoglobin SS, SC and SBeta-thalassemia) admitted for pain at a participating center were to be screened for eligibility; patients with a diagnosis of ACS at entry were not eligible. sPLA2 levels were drawn daily on consenting patients for up to three days during the admission. All patients had at least one CXR (mandated at 72 hr if not done for clinical indications) during the course of their hospital stay to determine if they had developed a new infiltrate, considered diagnostic for ACS. Patients who developed T>38°C, a sPLA2 level > 100ng/ml and had a normal CXR were eligible for randomization to observation or simple transfusion; the remaining patients were followed in an Observation arm. Of 421 patients potentially eligible for screening, 238 were enrolled in the study with 10 of these patients randomized (4 to transfusion 6 to standard care). Of these, 203 patients had from one to three sPLA2 levels drawn prior to an ACS diagnosis or did not develop ACS; if transfused, they received blood only after a diagnosis of ACS was made. Twenty-two of these patients (11%) developed ACS. Analysis of the maximum sPLA2 levels prior to ACS diagnosis revealed that a threshold of 45 ng/ml was the most accurate level to predict ACS (accuracy: 73%, sensitivity: 73%, specificity: 73%). The positive predictive value (PPV: 25%) was low due to the relative infrequency of ACS events. When sPLA2 levels were analyzed in children versus adults, sPLA2 was more accurate for adults in predicting ACS with a level of 65ng/ml having accuracy: 88%, sensitivity: 44%, specificity: 95%, PPV: 57%. The addition of a requirement for fever did not improve the accuracy of sPLA2 in either adults or children. Further analysis of sPLA2 levels with various clinical and laboratory data is ongoing to improve the PPV of sPLA2. These results indicate that sPLA2 can predict ACS with good sensitivity, but may require additional parameters to be useful in clinical management of SCD patients admitted with pain and at risk for ACS. Supported by the NHLBI. Disclosures: Labotka: HemaQuest Pharmaceuticals, Inc: Research Funding.

Abstract 1631 Introduction: Infants with sickle cell anemia (SCA) are at risk for organ damage and clinical events. Risk may vary depending on steady state hemoglobin level. BABY HUG (ClinicalTrials.org, NCT00006400), a NHLBI-NICHD supported phase III randomized placebo-controlled trial, examined the ability of hydroxyurea (HU) to reduce end organ damage to the kidneys and spleen and attenuate other complications of SCA in infants. In this secondary study, we investigated whether placebo-treated subgroups defined by extremes of baseline hemoglobin level differed from one another in frequency of sickle cell-related complications and other laboratory findings, and then compared these data to the entire group of infants treated with HU. Methods: BABY HUG subjects randomized at ages 9 – 18 mo were treated with hydroxyurea (20 mg/kg/d) (N=96) or with placebo (N=97) for 2 years. Those randomized to placebo were classified according to their age-adjusted baseline hemoglobin level and subgroups in the lowest (n=24) and highest (n=24) quartiles compared. (Demarcating Hb values were: age 9 to 10.2gm/dL; age12 – 18 mo, 9.9gm/dL.) Results: BABY HUG primary endpoints of spleen (splenic uptake of 99mTc sulfur colloid on liver-spleen scan) and kidney (GFR by DTPA clearance) function did not differ in placebo group subjects who were in the lowest and highest quartile hemoglobin levels. However, those in the lowest hemoglobin quartile had a higher incidence of acute chest syndrome (ACS) than those in the highest quartile (0.31 vs. 0.02 events/person-year, RR 14.4, p=0.01) and this difference was significantly attenuated by HU (0.05 events/person-year). The relative risk for developing a pain crisis did not differ between the two placebo subgroups (2.2 vs. 2.1 events/person-year), but HU significantly reduced pain frequency compared to either subgroup (0.94 events/person-year, p Conclusions: Severe anemia in very young patients with SCA was associated with elevated WBC and platelet counts and higher TCD velocities. Interestingly, severe anemia also was associated with increased frequency of ACS, in contrast to the association of ACS with higher hemoglobin levels in older patients. Future studies will need to confirm this relationship and clarify to what extent associated findings (e.g., hyposplenia, elevated WBC or platelet count) contribute to this susceptibility. Severe anemia in young SCA patients is a negative prognostic factor that is significantly impacted by early hydroxyurea therapy. Disclosures: Off Label Use: Hydroxyurea is not approved by FDA for infants with sickle cell disease. Miller:NIH/NHLBI; Emmaus Med Inc, Novartis Pharmaceutical; St Jude Childrens Hospital: Research Funding.

BABY HUG is an NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled clinical trial (NCT00006400) to test the hypothesis that hydroxyurea can prevent chronic organ damage in very young children with sickle cell anemia (SCA). Renal and splenic function measures are the co-primary endpoints. Renal disease in SCA begins early in life with impaired urine concentration and acidification, along with glomerular hyperfiltration; some patients will progress to microalbuminuria, glomerulosclerosis, macroalbuminuria, and even renal failure. In BABY HUG, glomerular filtration rate (GFR) elevation was selected as a primary endpoint, to be measured quantitatively by plasma clearance of injected 99mTc-DTPA and also estimated by the Schwartz equation where GFR = (height × 0.55)/(serum creatinine), with creatinine measured by HPLC to .01 mg/dL precision. Of 233 enrolled subjects, 193 completed screening and were randomized to study treatment. Quantitative GFR measurement was successful in most cases: 176 of 182 (97%) of DTPA clearance studies were adequate and 157 subjects had both baseline DTPA and Schwartz GFR values available for analysis. The average age at GFR measurement was 13.7 ± 2.6 months (range 9–19 months) and 59% of subjects were female. Baseline mean (± 1SD) hematological parameters included hemoglobin = 9.0 ± 1.4 gm/dL, absolute reticulocytes = 295.3 ± 137.4 × 109/L, WBC = 14.3 ± 5.8 × 109/L, and fetal hemoglobin (HbF) = 25.6 ± 8.8%. Baseline past medical history included dactylitis (34%), splenic sequestration (7%), and acute chest syndrome (5%). The average baseline quantitative GFR measurement determined by DTPA clearance was elevated at 125.4 ± 34.4 mL/min/1.73m2, (range 40.2 – 300.9 mL/min/1.73m2, normal value 100 ± 20 mL/min/1.73m2). The average baseline GFR estimate by Schwartz equation was substantially higher at 193.9 ± 53.8 mL/min/1.73m2, range 65.8 – 350.0 mL/min/1.73m2. In univariate analysis, the DTPA GFR value was positively correlated with the Schwartz GFR estimate (r=0.22, p=0.0059, slope=0.145) as well as age, weight, height (all p≤.001) but not with hemoglobin, HbF, WBC, reticulocytes, previous sickle cell-related events, or measures of splenic function including liver-spleen scan and quantitation of pitted erythrocytes and micronuclei. The Schwartz GFR estimate was positively correlated with age, height, WBC, and splenic function, and negatively correlated with hemoglobin and HbF. Using a quantitative GFR threshold of 120 mL/min/1.73m2 and an age threshold of 15 months, higher GFR values were observed in older infants, p=0.026. These data indicate that renal dysfunction measured by GFR elevation may begin early in life in SCA; quantitative GFR measurement is feasible but highly variable in this very young patient population; (3) the Schwartz and DTPA GFR values are strongly correlated, but the Schwartz estimate is usually greater and only modestly agrees with the quantitative DTPA GFR value. These baseline GFR measurements in BABY HUG support the hypothesis of age- and disease-related glomerular hyperfiltration in SCA. BABY HUG should yield important information regarding the ability of hydroxyurea to prevent renal damage among infants with SCA.

The weanling pig model was used to determine the long-term local effects, if any, on tibial bone marrow after intraosseous (IO) infusion of resuscitation fluid and drugs at standard dosages. One of six IO treatments (two normal saline boluses [20 mL/kg]; bolus sodium bicarbonate [1 mEq/kg]; 10% sodium bicarbonate infusion at a maintenance rate for 1 hour; bolus 1:10,000 epinephrine [0.01 mg/kg]; 1:10,000 epinephrine solution infusion, 1 microgram/kg/min for 1 hour; or dopamine infusion, 10 micrograms/kg/min for 1 hour) was randomly administered via the left tibia to 18 pigs at 4 weeks of age. The animals were subsequently followed for 3 months, after which marrow from the same space and peripheral blood were examined. Marrow from the right tibia of each animal served as control; untreated historic controls were also used for comparison. Examination of the marrow revealed normal cell differentials in all limbs in all groups. Overall cellularity was somewhat decreased in the experimental limbs of the normal saline bolus group when compared with same-animal control limbs, perhaps due to the pressure effect from rapid injection. Peripheral blood counts and differentials in these and all other animals were normal. The authors conclude that IO administration of commonly used resuscitative medications does not result in significant adverse effects in the tibial bone marrow in this model.

Abstract 1301 Poster Board I-323 Background Neutralizing factor VIII (FVIII) alloantibodies (“inhibitors”) develop in about 15% of all patients with hemophilia A following replacement therapy. The pathogenesis of this important treatment-related alloimmune complication is complex and involves both genetic and environmental factors, and likely their interactions. The type of hemophilia-causing FVIII gene (F8) mutation influences the risk of developing inhibitors with large deletions conferring the greatest risk and subtypes of single-base substitution mutations the lowest. Additional genetic factors that include possible transcription-modulating polymorphisms in the promoter regions of the structural loci encoding tumor necrosis factor a (TNFA), interleukin 10 (IL10), and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) were recently found to be associated with alloimmunization risk in the Malmo International Brother Study (MIBS). We recently demonstrated that mismatched FVIII replacement therapy due to the presence of common F8 nonsynonymous-single-nucleotide polymorphisms (ns-SNPs), which result in single amino acid changes in FVIII but do not cause hemophilia, may represent a novel genetic determinant of risk and contribute to the greater frequency of inhibitor development in black compared to white patients with hemophilia A (Viel et al. N Engl J Med. 360:1618-27, 2009). Because the implicated immune response gene variants described above were not controlled for in our initial study, however, we are now evaluating their influence on inhibitor development in this sample of black Americans with hemophilia A. Methods We used PCR and genomic DNA from 78 black hemophilia A patients to genotype a SNP in the TNFA promoter (-308 G>A) and a CA-dinucleotide repeat polymorphism in the IL10 promoter (IL10G) by direct sequencing and fragment-length analysis, respectively. The inhibitor status, baseline severity, age at enrollment, and biologic relationships of these study subjects were already known as was their hemophilic F8 mutations and the background haplotypes on which they reside. Analyses for genotype-specific associations with inhibitor status were performed with and without controlling for background F8 haplotype. Results Although we found the frequency of the 134bp IL10 risk allele (102bp in our modified assay) to be 20.3%, which is similar to that observed previously in the largely Euro-Caucasian MIBS cohort (26.8%), no obvious association between inhibitor risk and genotypes containing this allele was identified in the black hemophilia A patients studied, even after controlling for the background F8 ns-SNP haplotype. The frequency we identified for the -308A TNFA risk allele (8.8%) was similar to that observed previously in non-hemophilic African Americans (12%), but was far less frequent than observed in the MIBS (32.9%). Analogous to the IL10 results, we identified no association between inhibitor development and TNFA genotypes containing the risk allele (which was only G/A heterozygotes since no homozygous A/A individuals were identified) in this black patient cohort, even after controlling for their ns-SNP haplotypes. Conclusions We found no association between inhibitor development in black Americans with hemohilia A and promoter variants in two immune response genes recently implicated as risk genotypes in the MIBS. While we did not replicate the prior findings, the small sample size of our present study could explain these results if a true functional variant in one of these genes either has a small effect or is in poor linkage disequilibrium with the typed variant in this black patient population. Our findings therefore require confirmation in a larger study, which is currently under way. Disclosures Howard: Haplomics, Inc.: Equity Ownership, Patents & Royalties. Kempton:Biomeasure Inc: Consultancy; CSL Behring Foundation: Research Funding.

Abstract 262 Introduction: The most common cause of neurological injury in sickle cell anemia is silent cerebral infarcts (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) cohort, we sought to identify risk factors associated with SCI. Patients and Methods: In this cross-sectional study, we evaluated the clinical history, baseline laboratory values and performed magnetic resonance imaging of the brain. For those children with SCI-like lesions, a pediatric neurologist examined the child and neuroradiology and neurology committees adjudicated the presence of SCI. Children between the ages of 5 and 15 years with hemoglobin SS or S-beta° thalassemia and no history of overt strokes or seizure were evaluated. Results: A total of 542 children were evaluated; 173 (31.9%) had SCI. The mean age of the children was 9.3 years, with 280 males (51.7%). In a multivariate logistic analysis, two covariates were significant: a single systolic blood pressure (SBP) obtained during a baseline well-visit, p = 0.015 and hemoglobin F (Hgb F) level obtained after three years of age, p = 0.038. Higher values of SBP and lower values of Hgb F increased the odds of SCI; Figure. Baseline values of white blood cell count, hemoglobin level, oxygen saturation, reticulocytes, pain, or ACS event rates were not associated with SCI. Conclusion: SBP and Hgb F level are two previously unidentified risk factors for SCI in children with sickle cell disease. Modulation of SBP and Hgb F levels might decrease the risk of SCI. Disclosures: No relevant conflicts of interest to declare.