Gerald M. Woods

Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial

Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S.pneumoniae in children with sickle cell anemia who were under the age of three years at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84 percent reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by four months of age to decrease the morbidity and mortality associated with pneumococcal septicemia.

Recombinant Urate Oxidase for the Prophylaxis or Treatment of Hyperuricemia in Patients With Leukemia or Lymphoma

PURPOSE To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia

BACKGROUND Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Stroke Prevention Trial in Sickle Cell Anemia

Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.

Discontinuing penicillin prophylaxis in children with sickle cell anemia

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 beta 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.

Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease

Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

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.

Alpha thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia

Purpose: Cerebrovascular complications of sickle cell disease (SCD) are common, but the risk factors remain unclear. The multicenter Stroke Prevention Trial in Sickle Cell Anemia (STOP) provided an opportunity to examine alpha thalassemia‐2 as a modifying risk factor, using abnormal transcranial Doppler ultrasonography (TCD) as a surrogate marker for cerebrovascular disease. The authors hypothesized that children with abnormal TCD are less likely to have alpha thalassemia‐2, and an increased hemoglobin level accounts for this protective effect. Methods: A retrospective study was conducted of children with SCD who had both alpha gene and TCD data from STOP: 128 with TCD of at least 200 cm/s (abnormal TCD) and 172 with TCD less than 170 cm/s (normal TCD). Results: Alpha thalassemia‐2 was more frequent in the normal TCD group compared with the abnormal TCD group. The odds ratio for normal TCD and alpha thalassemia‐2 was 4.1. Adjusting for either hemoglobin level or red cell size (mean corpuscular volume) reduced the odds ratio only slightly. Age, normal TCD, and alpha thalassemia‐2 had significant statistical interaction, so that alpha thalassemia‐2 was not related to TCD for age 10 years or older. Conclusions: The frequency of alpha thalassemia‐2 was significantly higher in children with normal TCD. Speculation on mechanisms of effect includes improved erythrocyte deformability, reduced red cell adhesion, and reduced nitric oxide scavenging in alpha thalassemia‐2. The association of alpha thalassemia‐2 and normal TCD adds to the evidence on the protective effects of alpha thalassemia‐2 in SCD and highlights the contribution of epistatic factors.

Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury

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.

Alpha–streptococcal septicemia in leukemic children treated with continuous or large dosage intermittent cytosine arabinoside

During a 2-year period after the introduction of an intensive chemotherapeutic protocol, alpha-hemolytic streptococci accounted for 75% of all episodes of sepsis among children with acute nonlymphocytic leukemia at our institution. Only one case had occurred in the previous 8 years. Fourteen of 15 episodes of streptococcal sepsis occurred after therapy with either continuous or large dosage intermittent cytosine arabinoside. Eleven episodes occurred at two specific treatment points. Septic episodes were complicated by shock (2 of 15), encephalopathy (2 of 15), pneumonia (3 of 15) and death (1 of 15). Oral mucosal lesions may provide a portal of entry for alpha-hemolytic streptococci. These data suggest that children receiving continuous or large dosage intermittent cytosine arabinoside for treatment of acute nonlymphocytic leukemia may be at increased risk for alpha-hemolytic streptococcal sepsis. Empiric antimicrobial therapy in these children when febrile and neutropenic should include antibiotics effective against alpha-hemolytic streptococci.