Sally C. Davies

Bone marrow transplantation for sickle cell disease

BACKGROUND We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. METHODS Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. RESULTS Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively. Among patients with a history of acute chest syndrome, lung function stabilized; among patients with prior central nervous system vasculopathy who had engraftment, stabilization of cerebrovascular disease was documented by magnetic resonance imaging. CONCLUSIONS Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease.

ACUTE CHEST SYNDROME IN SICKLE-CELL DISEASE

25 consecutive episodes of acute chest syndrome in 13 adult patients with sickle-cell disease were studied retrospectively. Chest symptoms were present on admission in 23 of 25 episodes. Abnormal chest signs and an abnormal chest X-ray were present on admission in only 11 and 9 episodes, respectively, but developed later in the remainder. The 9 episodes with bilateral radiological changes were associated with higher pulse rates, longer-lasting fever, more profound arterial hypoxaemia, and greater falls in haemoglobin than the 16 unilateral episodes. 2 patients with bilateral disease died; both had platelet counts less than 100 X 10(9)/litre. In 12 episodes (6 bilateral, 6 unilateral) exchange transfusion was required and produced striking improvement in 11. Despite intensive microbiological investigation, infection was found in only 2 episodes--1 mycoplasma and 1 evidence of Escherichia coli. Pulmonary intravascular sickling may account for much of the clinical picture.

The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial

BACKGROUND No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. METHODS We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sβ(0)thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. FINDINGS 67 (96%) of 70 enrolled patients-33 no preoperative transfusion and 34 preoperative transfusion-were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0.023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3.8 (95% CI 1.2-12.2, p=0.027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. INTERPRETATION Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. FUNDING NHS Blood and Transplant.

Red cell alloimmunization in sickle cell disease

Summary. Alloimmunization to red cell antigens contributes to morbidity in transfused patients. It has been recommended that blood for sickle cell patients need not be matched for antigens other than ABO and Rh(D), as there is no greater incidence of antibody production than in other multitransfused patient populations. Post transfusion alloimmunization was studied in a group of 34 sickle cell disease patients attending a U.K. haemoglobinopathy clinic. Red cell antibodies were formed in 17‐6% of the transfused patients and Rhesus and Kell antibodies accounted for 66% of this total. In order to reduce alloimmunization, a policy of performing extended red cell phenotyping on the patients, and providing blood matched for Kell, and in certain circumstances the Rhesus antigens other than Rh(D), is recommened.

Provision of social norm feedback to high prescribers of antibiotics in general practice: a pragmatic national randomised controlled trial

Summary Background Unnecessary antibiotic prescribing contributes to antimicrobial resistance. In this trial, we aimed to reduce unnecessary prescriptions of antibiotics by general practitioners (GPs) in England. Methods In this randomised, 2 × 2 factorial trial, publicly available databases were used to identify GP practices whose prescribing rate for antibiotics was in the top 20% for their National Health Service (NHS) Local Area Team. Eligible practices were randomly assigned (1:1) into two groups by computer-generated allocation sequence, stratified by NHS Local Area Team. Participants, but not investigators, were blinded to group assignment. On Sept 29, 2014, every GP in the feedback intervention group was sent a letter from Englands Chief Medical Officer and a leaflet on antibiotics for use with patients. The letter stated that the practice was prescribing antibiotics at a higher rate than 80% of practices in its NHS Local Area Team. GPs in the control group received no communication. The sample was re-randomised into two groups, and in December, 2014, GP practices were either sent patient-focused information that promoted reduced use of antibiotics or received no communication. The primary outcome measure was the rate of antibiotic items dispensed per 1000 weighted population, controlling for past prescribing. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN32349954, and has been completed. Findings Between Sept 8 and Sept 26, 2014, we recruited and assigned 1581 GP practices to feedback intervention (n=791) or control (n=790) groups. Letters were sent to 3227 GPs in the intervention group. Between October, 2014, and March, 2015, the rate of antibiotic items dispensed per 1000 population was 126·98 (95% CI 125·68–128·27) in the feedback intervention group and 131·25 (130·33–132·16) in the control group, a difference of 4·27 (3·3%; incidence rate ratio [IRR] 0·967 [95% CI 0·957–0·977]; p<0·0001), representing an estimated 73 406 fewer antibiotic items dispensed. In December, 2014, GP practices were re-assigned to patient-focused intervention (n=777) or control (n=804) groups. The patient-focused intervention did not significantly affect the primary outcome measure between December, 2014, and March, 2015 (antibiotic items dispensed per 1000 population: 135·00 [95% CI 133·77–136·22] in the patient-focused intervention group and 133·98 [133·06–134·90] in the control group; IRR for difference between groups 1·01, 95% CI 1·00–1·02; p=0·105). Interpretation Social norm feedback from a high-profile messenger can substantially reduce antibiotic prescribing at low cost and at national scale; this outcome makes it a worthwhile addition to antimicrobial stewardship programmes. Funding Public Health England.

Fetal haemoglobin augmentation in E/β0 thalassaemia: clinical and haematological outcome

Patients with E/β0 thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long‐term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18–20 mg/kg) for 24 ± 9 months, hydroxyurea with sodium phenyl butyrate (n = 8) and hydroxyurea with erythropoietin (n = 9), each for ∼6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1·3 g/dl steady‐state increase in haemoglobin in 40% of patients, and a milder response (≤1 g/dl) in the others. Baseline haemoglobin F was significantly associated with an increase in haemoglobin (P < 0·001). Combined treatment with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate had no effect. Of the 27/45 patients who discontinued regular transfusions before the study, 13 remained transfusion independent during long‐term follow‐up, 6/13 continued hydroxyurea. Hydroxyurea moderately increased steady‐state haemoglobin in a sub‐group of E/β0 thalassaemia patients and can be considered for patients with intermediate severity disease, thus delaying or avoiding the need for life‐long transfusions. Continuous monitoring of toxicity and growth is required.

Blood transfusion in sickle cell disease

Blood transfusion can be life-saving in sickle cell disease. There is an increasing body of literature available to help define its place in this patient population. In this review, we have brought together the reported trials, case reports and our experience to discuss the role of transfusion now and in the future for sickle cell disease. Advances are continually being made in all fields and we have in addition. considered the relevant ones from immunohaematology, virology and clinical medicine so that their impact on the subject is taken into consideration.

Neonatal screening for haemoglobinopathies : the results of a 10-year programme in an English Health Region

Neonatal identification of sickle cell disease can significantly reduce mortality and morbidity during the first 5 years of life. During a 10‐year period, 414 801 neonates were screened by isoelectric focusing. The most common variants detected were haemoglobins S, C, D and E. Two hundred and fifty of the samples tested were homozygotes or compound heterozygotes, and 6554 samples were heterozygotes for the common variants. The gene frequencies in the population tested were calculated from this data for the most common variants. They were: S, 0·0057; C, 0·0014; DPunjab(Los Angeles), 0·0007; E, 0·0005. Additionally, 16 babies had beta thalassaemia major and 405 had rarer variants, of which six had never previously been described. Knowledge of the distribution of these inherited diseases is useful in healthcare planning and appropriate allocation of resources, while counselling targeted at appropriate couples enables informed parental choice and may prevent disease.

Therapeutic challenges in childhood sickle cell disease. Part 1: current and future treatment options.

Sickle cell disease (SCD) is one of the commonest inherited diseases in the UK, affecting approximately 1 in 4000 live births every year. For the majority of patients, the mainstays of treatment are preventative and supportive. For those children with severe SCD, three major therapeutic options are currently available: blood transfusion, hydroxyurea and bone marrow transplantation. This review focuses on the relative roles of these therapeutic modalities in severe paediatric SCD and assesses the prospects for new treatment modalities, including non-myeloablative stem cell transplantation, short chain fatty acids, membrane active drugs and gene therapy.

Our children deserve better: prevention pays

The Chief Medical Offi cer for England’s Annual Report is designed to highlight the evidence underpinning current health issues, stimulate debate, and galvanise momentum for improvement. On Oct 24, 2013, the Annual Report of the Chief Medical Offi cer 2012, Our Children Deserve Better: Prevention Pays was published focusing on child health. Child health and building the resilience of children was chosen as a focus because of the powerful story to be found in the data: high mortality, poor outcomes, (particularly for chronic disorders), and health in equality. With respect to high mortality, data recently published by Wolfe and colleagues show that compared with Sweden (the best performing country in 15 pre-2004 countries of the European Union), every day in England fi ve extra children younger than 14 years die: an equivalent of 132 874 excess person years of life lost per year in the UK. The management of non-communicable diseases in England is similarly poor. Fewer people younger than 25 years with type 1 diabetes in England and Wales have good diabetes control compared with their peers in other countries—only 16% achieved glycated haemo globin A1c under 7·5%, whereas in Germany and Austria 34% of young people achieved this standard. Finally, there are growing inequalities in health both between sexes and social classes. The proportion of young people who meet recommended physical exercise levels is low, and is worst among girls, particularly those older than 15 years. In addition, diff erences in social class account for a substantial proportion of health diff erences among children. As an example, there would be a 59% potential reduction in psychological and behavioural problems in children and young people with conduct disorders if all children had the same risk as the most socially advantaged. These data matter to us all because poor health in childhood has health, social, and economic consequences in adulthood. The life course approach proposed in Fair Society, Healthy Lives emphasised the need to focus improvement eff orts early in life, and it is becoming increasingly clear that the times of rapid brain development during the fi rst 2 years of life and in adolescence provide key opportunities for improving life chances and interventions. This year the Annual Report of the Chief Medical Offi cer 2012 examines costs related to children’s current poor health outcomes by focusing on four high-cost issues: pre-term birth, injury, obesity, and mental health disorders (panel 1). The costs are huge and our analysis points to the potential savings that could be made should these outcomes improve even slightly. There is also an increasing evidence base showing that in children prevention pays, with an expected return on 6–10% from investing in interventions early in life. The case for early intervention and prevention is increasingly clear both biologically and economically. Yet the UK‘s National Audit Offi ce estimates that only 6% of current government spending is on early action and within health, and only 4% is spent directly on preventive measures. There is also evidence that children are disproportionately disadvantaged. In the UK, 26·9% of children and young people (aged 0–19 years) are living in, or at risk of, poverty or social exclusion, compared with an overall population rate of 22·6%; these fi gures compare poorly with the Netherlands, the best performing country in Europe, which has a corresponding rate of 15·7%. The recommendations of the Chief Medical Offi cer in the Annual Report should catalyse action across