Paul Telfer

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.).

Guidelines for the management of the acute painful crisis in sickle cell disease

Severe acute pain is the commonest manifestation of sickle cell disease (SCD) requiring hospital admission in Europe and the USA. Although the pain itself is not directly lifethreatening, inappropriate treatment leads to unnecessary suffering and potentially fatal complications, related both to the disease and the treatment, and repeated admissions with pain are associated with a higher mortality rate (Platt et al, 1994). There are thought to be more than 10 000 patients with SCD in the UK (Streetly et al, 1997), the majority of these live in London. Whereas some hospitals see large numbers of patients with SCD and have established protocols and experienced staff, most hospitals will see only a few patients each year. These guidelines aim to provide advice on a basic, minimum standard of care for patients with acute painful crises and SCD, and pay particular attention to adequate analgesia and monitoring for life-threatening complications.

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.

Hyperhemolytic transfusion reaction in sickle cell disease

BACKGROUND: An atypical form of life‐threatening hemolytic transfusion reaction (HTR) in patients with sickle cell disease (SCD) has been well described in the literature. Continuation of blood transfusion may be lethal, as it can further exacerbate hemolysis. The pathophysiologic mechanism of HTR is not well understood.

Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone

Life expectancy in thalassemia major (TM) is reduced, mainly as a result of deaths from transfusion iron-overload and cardiac dysfunction. Early deaths are preventable by effective long-term iron chelation therapy, but 50% are unable to adhere adequately to standard treatment consisting of sub-

Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

Using the eosin‐5‐maleimide binding test in the differential diagnosis of hereditary spherocytosis and hereditary pyropoikilocytosis

Flow cytometric analysis of eosin‐5‐maleimide (EMA)‐labeled red blood cells (RBCs) has been used as a screening test for the diagnosis of patients with hereditary spherocytosis (HS). We assessed the fluorescence profiles for patients having HS and hereditary pyropoikilocytosis (HPP) together with their red cell indices.

Detecting white matter injury in sickle cell disease using voxel-based morphometry.

Sickle cell disease (SCD) is associated with cerebrovascular disease, cerebral infarction, and cognitive dysfunction. This study aimed to detect the presence and extent of white matter abnormalities in individuals with SCD using voxel‐based morphometry (VBM).

UPDATE ON SURVIVAL IN THALASSEMIA MAJOR

Long-term follow-up of cohorts of patients treated in high-income countries has shown a progressive improvement in life expectancy. Myocardial toxicity from iron overload has been the major cause of mortality; however, there has been a substantial decline in cardiac deaths in recent years, related to switching high-risk patients from subcutaneous desferrioxamine to chelation regimes which include the oral chelator deferiprone. The role of deferasirox in enhancing life expectancy is yet to be determined, but it is reasonable to expect an improvement compared with past experience with desferrioxamine. Other causes of mortality will become an increasingly important issue for older thalassemic patients: Surveillance, prophylaxis, and prompt treatment of infection remains essential, and chronic hepatitis virus infection should be managed with best available current therapies. More data on follow-up of thalassemic patients in middle income countries are needed to demonstrate a similar trend in improved survival. The life expectancy for those in low-income countries is similar to the situation 50 years ago in Europe and the United States. The global thalassemia and public health community should consider how to respond to this disparity.

An exploratory study of physiological correlates of neurodevelopmental delay in infants with sickle cell anaemia

This study aimed to investigate whether infants with sickle cell anaemia (SCA) are at risk of neurodevelopmental delay, and whether any delay is associated with SCA pathology. Twenty‐eight infants (14 SCA; 14 age‐ and ethnic‐similar controls) were assessed longitudinally with the Bayley Infant Neurodevelopmental Screener (BINS) at 3, 9 and 12 months. Transcranial Doppler (TCD) and pulse oximetry (SpO2) measures were recorded longitudinally in SCA infants, and a subgroup of controls. Haemoglobin values were obtained from SCA infants. At each age, SCA infants obtained BINS scores indicative of greater risk of neurodevelopmental delay compared with controls. The number of moderate–high BINS risk scores increased significantly between 3 and 9 months. At 9 months BINS raw scores correlated negatively with TCD velocity and positively with haemoglobin. This exploratory study suggests that SCA infants may be at greater risk of neurodevelopmental delay than previously considered, and may provide the impetus for further research into the very early precursors of cognitive impairment.