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 (<25th percentile) and higher (>75th percentile) hemoglobin concentrations at study entry.
Infants were categorized by: 1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9 to12 months old: <8.0 gm/dL and >10.0gm/dL; 12 to 18 months old: <8.1 gm/dL and >9.9gm/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.
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.
Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea.
Sickle Cell Anemia; Hydroxyurea; Acute Chest Syndrome; Pain; Transcranial Doppler; Renal; Spleen
In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10-8), a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P-value=8.57x10-7), was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene (P-value=5.2x10-5). Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5’ CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.
Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.
Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.
Clinical trial setting in tertiary care centers.
Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.
Main Outcome Measure
Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).
Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7–87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.
Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
This review will focus on the strengths and limitations associated with the current standard of care for primary prevention of ischaemic strokes in children with sickle cell anaemia (SCA) - transcranial Doppler ultrasound (TCD) screening followed by regular blood transfusion therapy when TCD measurement is above a threshold defined by a randomized clinical trial (RCT). The theoretical basis for potential alternative strategies for primary prevention of neurological injury in SCA is also discussed. These strategies will include, but will not be limited to: immunizations to prevent bacterial infections, particularly in low income countries; management of elevated blood pressure; and targeted strategies to increase baseline haemoglobin levels with therapies such as hyroxycarbamide or potentially definitive haematopoietic stem cell transplant.
Sickle cell anaemia; stroke; primary prevention; treatment; child
A doctor diagnosis of asthma is associated with increased morbidity (pain and acute chest syndrome, ACS) among children with sickle cell disease (SCD). An association between IgE levels and asthma and morbidity has not been investigated in children with SCD.
We tested the hypothesis that elevated total and allergen-specific IgE levels are associated with asthma and SCD morbidity in children with SCD.
A cross-sectional study of children with SCD who participated in the Silent Cerebral Infarct Trial was conducted. Logistic regression and negative binomial regression were used to investigate potential associations of total and allergen-specific IgE levels with asthma diagnosis and SCD morbidity, both confirmed by medical record review. Elevation of total IgE was defined as age- and sex-adjusted IgE exceeding 90th percentile compared to a non-atopic reference population. IgE antibody positivity to Altermaria alternata (mold), Blatella germanica (cockroach), and Dermatophagoides pteronyssinus (dust mite) was assessed by ImmunoCAP analysis.
Children with SCD (140 asthmatics, 381 non-asthmatics) were evaluated. Elevations in total IgE (p = 0.04) and IgE antibody specific for Altermaria alternata (p = 0.0003), Blatella germanica (p = 0.008), and Dermatophagoides pteronyssinus (p = 0.01) were associated with asthma. ACS (p = 0.048) but not pain (p = 0.20) was associated with total IgE, but neither were associated with specific IgE levels.
Significantly increased levels of total and allergen-specific IgE levels are associated with asthma in SCD. High IgE levels are a risk factor for ACS and not pain rates.
Total IgE; allergen-specific IgE; asthma risk indicator; acute chest syndrome; pain; sickle cell disease; hemoglobinopathies
A 12-year-old boy with HbSS sickle cell disease (SCD) was admitted with an acute febrile illness and developed overt stroke 3 days later. Plasma glial fibrillary acidic protein levels were elevated, as compared to pediatric controls, 32 h prior to the clinical diagnosis of stroke, peaked immediately prior to the exchange transfusion, and remained elevated 1 year later despite chronic transfusion therapy. Stroke in SCD can occur in the setting of acute illness, and a biomarker that could predict the onset and triage ill children to therapeutic intervention more quickly would be useful.
Chronic transfusion; Glial fibrillary acidic protein; Sickle cell; Stroke
Children with sickle cell disease (SCD) are considered a high-risk population for complications from influenza infection, despite minimal published data characterizing the burden of influenza in this population. Our objectives were to: 1) estimate the rate of influenza-related hospitalizations (IRH) among children with SCD, 2) compare this rate to rates for children with cystic fibrosis (CF) and with neither SCD nor CF, and 3) explore mechanisms underlying these potentially preventable hospitalizations.
We analyzed hospitalizations from 4 states (California, Florida, Maryland, New York) across 2 influenza seasons (2003/4 and 2004/5) from the Healthcare Cost and Utilization Project State Inpatient Databases. We included hospitalizations with a discharge diagnosis code for influenza in a child less than 18 years of age. Using census data and disease prevalence estimates to calculate denominators, we compared rates of IRH among children with SCD, CF, and neither.
There were 7,896 pediatric influenza-related hospitalizations during the 2 influenza seasons. Of these, 159 (2.0%) included a co-occurring diagnosis of SCD. Annual rates of IRH were 112 and 2.0 per 10,000 children with and without SCD, respectively, across both seasons. Children with SCD were hospitalized with influenza at 56 times the rate of children without SCD (95% CI: 48–65). Children with SCD had approximately double the risk of IRH compared to children with CF (RR = 2.1 [1.5 – 2.9]). IRH among children with SCD were not longer, more costly or more severe than IRH among children without SCD, were rarely nosocomial, and co-occurred with a diagnosis of asthma in 14% of cases.
Influenza-related hospitalizations are substantially more common among children with SCD than those without, supporting the potential importance of vigorous influenza vaccination efforts targeting children with SCD.
Sickle cell disease; influenza; surveillance; hospitalization
Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined.
Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks.
Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia.
Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA.
A child with homozygous protein C deficiency was treated at age 20 months by orthotopic hepatic transplantation. Postoperatively there was complete reconstitution of protein C activity and resolution of the thrombotic condition.
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 to 17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for two 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 two hundred. 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)
hydroxyurea; clinical trial; infants; sickle cell
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 velocity ≥ 200cm/sec) and only 4 subjects (2%) had velocities in the conditional range (170–199cm/sec). TCD velocities were inversely related to hemoglobin 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)
Transcranial Doppler Ultrasonography; TCD; sickle cell anemia; stroke; infant
To compare the relative rates and risk factors associated with stroke in adults vs. children with sickle cell disease (SCD) in the U.S. over the last decade.
We identified incident strokes in patients with SCD using ICD-9 codes for acute stroke and SCD and the California Patient Discharge Databases. We estimated SCD prevalence by using the incidence of SCD at birth with adjustment for early mortality from SCD.
We identified 255 acute strokes (70 primary hemorrhagic and 185 ischemic) among 69,586 hospitalizations for SCD-related complications from 1998–2007. The rate of stroke in children [<18 years old (310/100,000 person-years)] was similar to young adults [18 to 34 years old (360/100,000 person-years)], but much higher in middle-aged [35 to 64 years old (1160/100,000 person-years)] and elderly adults [≥65 years old (4700/100,000 person-years)]. Stroke was associated with hypertension in children and hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and renal disease in adults. Most acute strokes (75%) and in-hospital deaths from stroke (91%) occurred in adults.
Our results suggest that the rate of stroke in SCD peaks in older adults and is 3-fold higher than rates previously reported in African-Americans of similar age (35 to 64 years) without SCD. Stroke in SCD is associated with several known adult risk factors for ischemic and hemorrhagic stroke. Studies for the primary and secondary prevention of stroke in adults with SCD are urgently needed.
Stroke; sickle cell disease; epidemiology; transfusion
The Silent Cerebral Infarct Multicenter Transfusion (SIT) Trial is a multi-institutional intervention trial in which children with silent cerebral infarcts are randomized to receive either blood transfusion therapy or observation (standard care) for 36 months. The SIT Trial is scheduled to enroll approximately 1,880 children with sickle cell disease from 29 clinical sites in the United States, Canada, UK, and France. Each child undergoes a screening magnetic resonance imaging (MRI) of the brain to detect the presence of silent cerebral infarct-like lesions, a pre-randomization (baseline) MRI and exit MRI to determine if there are new or enlarged cerebral infarcts, using a designated, prospective imaging protocol. The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging. Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers. Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infarct-like lesions. Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center. The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days. This novel strategy was designed to maximize efficiency and minimize cost of a complex large multicenter trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures. The technology, process, and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements.
Clinical trial imaging; PHI; case report forms; central review
Acute chest syndrome (ACS) is a frequent cause of hospitalization and mortality in children with sickle cell disease. Transfusion is often required to prevent respiratory failure and treatment with dexamethasone may reduce the length of admission and the need for transfusions. We performed a retrospective cohort study to evaluate risk factors for readmission and prolonged hospitalization after different treatments for ACS.
We identified patients <22 years of age hospitalized with ACS at Johns Hopkins Hospital from January 1998 to April 2004 using the hospitals discharge database and by reviewing dictated summaries.
We identified 65 patients with 129 episodes of ACS (mean age 12.5 years, range 1.2–21.9 years). Thirty-nine episodes were treated with corticosteroids and 51 with transfusions. Patients were readmitted within 14 days after 23 episodes (18%). Readmission was strongly associated with report of an inhaler or nebulizer at home [odds ratio (OR) 6.0, P < 0.05], diastolic BP at 48 hr (OR 1.8 per 10 mm increase, P<0.01), corticosteroids (OR 20, P < 0.005), or transfusion (OR 0.03, P < 0.05). Treatment with corticosteroids alone (P < 0.05) and older age (P < 0.001) were associated with longer hospitalization.
These results demonstrate a greatly elevated independent risk of readmission after ACS in children with asthma and after treatment with corticosteroids and a protective effect of transfusion. Although dexamethasone has documented efficacy for reducing the duration of ACS, the substantial risk of readmission for pain should limit its use.
acute chest syndrome; cohort study; corticosteroids; sickle cell disease; transfusions
An investigation of malaria in a US patient without recent travel established Plasmodium falciparum molecular genotype identity in 2 patients who shared a hospital room. P. falciparum can be transmitted in a hospital environment from patient to patient by blood inoculum if standard precautions are breached.
molecular epidemiology; infection; case report; Malaria; nosocomial; microsatellite; plasmodium falciparum; transmission; blood-borne; mass spectrometric
Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC).
To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care.
Design, Setting and Participants
Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home.
Inhaled NO gas versus inhaled nitrogen placebo.
There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite.
Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution.
Nitric oxide; sickle cell disease; vaso-occlusive pain crisis; acute chest syndrome
Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5×10−8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10−25). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15×10−4). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.
Incidental findings identified by MRI of the brain have been reported in up to18% of healthy adults, with clinically significant neuropathology in 0.5-2%. There are two smaller series of incidental findings on MRI of the brain in children. We describe the prevalence and range of incidental intracranial abnormalities identified by MRI of the brain in a large group of children screened for a clinical trial.
We included 953 children between 5 and 14 years of age screened with MRI of the brain for the Silent Infarct Transfusion Trial. All have sickle cell anemia or sickle β-null thalassemia. MRIs were interpreted by 3 neuroradiologists. MRIs reported to have any abnormality were re-reviewed by 2 study neuroradiologists. Incidental findings were classified into 4 categories: no referral, routine, urgent, and immediate referral recommended. Cerebral infarcts and vascular lesions were not considered incidental and were excluded.
We identified 63 children (6.6%, 95% CI: 5.1 to 8.4%) with 68 incidental intracranial MRI findings. Findings were classified as urgent in 6 children (0.6%), routine in 25 children (2.6%), and no referral required in 32 children (3.4%). No children required immediate referral. Two children with urgent findings underwent surgery in the next 6 months.
In this large cohort of children, incidental intracranial findings were identified in 6.6%, with potentially serious or urgent findings in 0.6%. These data should assist pediatricians and researchers in planning for and counseling families when unexpected, incidental findings are encountered on MRI of the brain.
Incidental Findings; MRI-Magnetic resonance imaging; Brain imaging; Children; Sickle Cell Disease
The Silent Cerebral Infarct Multi Center Transfusion (SIT) Trial is a multi-institutional intervention trial in which children with silent cerebral infarcts are randomized to receive either blood transfusion therapy or observation (standard care) for 36 months. The SIT Trial is scheduled to enroll approximately 1880 children with sickle cell disease from 29 clinical sites in the United States, Canada, England and France. Each child undergoes a screening MRI of the brain to detect the presence of silent cerebral infarct-like lesions, a pre-randomization (baseline) MRI and exit MRI to determine if there are new or enlarged cerebral infarcts, using a designated, prospective imaging protocol. The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging. Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers. Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infarct-like lesions. Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center. The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days. This novel strategy was designed to maximize efficiency and minimize cost of a complex large multi-center trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures. The technology, process and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements.
Clinical Trial Imaging; PHI; Case Report Forms; Central Review