Anaemia, either due to insufficient numbers of red blood cells or an impaired ability of these cells to carry oxygen, can result in weakness, fatigue, and dizziness, and in its most severe form can be fatal. According to the World Health Organization the highest proportion of affected individuals are in Africa. Preschool age children were found to be especially at risk, with approximately two thirds of preschoolers affected. Childhood anaemia therefore presents a major public health burden in this region. Severe anaemia, which requires blood transfusion for treatment, is of particular concern. Limited blood supplies have led to guidelines for the rational use of blood transfusions in severe anaemia. However, the effectiveness of these guidelines on clinical outcomes is unclear. Kathyrn Maitland from Imperial College London, UK, and colleagues conducted a phase II clinical trial to investigate the safety and efficacy of transfusing a higher volume of blood in Ugandan children with severe anaemia, as published in their recent study in BMC Medicine (with an associated Commentary by Thomas Brick and Mark Peters from Great Ormond Street Hospital, UK). Maitland explains the extent of the severe anaemia problem faced in sub-Saharan Africa and the implications of their results.
What is severe anaemia, and what is its health burden in sub-Saharan Africa?
In sub-Saharan Africa severe anaemia (SA) in children is a leading cause of hospital admission, a major cause of direct mortality and a key factor in the 800,000 malaria deaths per year. The definition of severe anaemia varies with some researchers and guidelines defining it as either a haemoglobin level of less the 5g/dl and others using less than 6g/dl as the definition. As SA includes a very heterogeneous group of children other studies have addressed this by classifying children into subgroups based on both clinical severity and haemoglobin levels.
Why is severe anaemia such a big problem for paediatric patients in Africa and what are its main causes?
The causes of anaemia are multi-factorial with several co-factors causally related to mortality risk. Malaria still plays an important role in the development of severe anaemia (SA) in many parts of Africa. However, in the only comprehensive case-control study of children hospitalised with SA in Africa, undertaken in Malawi, the key associations with SA were bacteraemia (OR=5.3; 95% CI 2.6-10.9), malaria (2.3; 1.6-3.3), hookworm (4.8; 2.0-11.8), HIV infection (2.0; 1.0-3.8), vitamin A deficiency (2.8; 1.3-5.8) and vitamin B12 deficiency (2.2; 1.4-3.6). Neither iron nor folate deficiencies (which are currently recommended as treatments for severe anaemia) were associated with mortality, and were less prevalent among cases than controls.
What are the current recommendations for management of severe anaemia?
The World Health Organization management guideline includes conservative use of transfusion, iron and folate and antihelminths. Current recommendations are to give 20ml/kg whole blood (or 10ml/kg packed cells) only to children with profound anaemia (haemoglobin less than 4g/dl) or children with haemoglobin less than 6g/dl with signs of severity. Outcomes remain poor with an inpatient mortality 9-10 percent, and following initial transfusion with about 25 percent remaining severely anaemic (haemoglobin less than 5g/dl) leading to frequent use of multiple, low volume (20ml/kg) transfusions, which is wasteful, inefficient and exposes children to additional risks (such as reaction and infection).
What were the main findings of your study?
In a clinical trial we evaluated the safety and efficacy of a higher initial volume of whole blood (30ml/kg) against standard volume (20ml/kg) in 160 Ugandan children for 24 hour anemia correction (haemoglobin more than 6g/dl: primary outcome) and 28-day survival. We found that the higher initial transfusion volume prescribed at hospital admission was safe and resulted in an accelerated haematological recovery. By 24 hours 70 (90 percent) children in 30ml/kg arm had corrected severe anaemia compared to 61 (74 percent) in 20ml/kg arm. From admission to day 28 there was a greater hemoglobin increase from enrollment in the 30ml/kg arm (global p<0.0001) with only 1 death in 30ml/kg arm versus 6 deaths in 20ml/kg arm (p=0.12).
What impact do you think your findings will have on public health, policy and clinical practice?
Current transfusion guidelines, were developed to protect scarce resources, avert overuse, and reduce the risk of transfusion-transmissible infections but are conservative not only in terms of criteria applied for administering a transfusion at all, but also in terms of the volume of blood transfused. The evidence base for the paediatric guidelines is weak and consequently adherence is poor. A poor or incomplete response to recommended treatment in children with severe anaemia results in relapse, readmission and death. Because severe anaemia is very common, the high ‘hidden’ morbidity and mortality occurring within the first few weeks after initial diagnosis is likely to contribute importantly to overall under-five mortality. If not adequately addressed, severe anaemia may thus be an obstacle to the achievement of Millennium Development Goal No.4 on child survival in Africa. A Phase II trial demonstrating the safety and efficacy of a higher volume of blood is an essential step to the justification of a large Phase III trial.
What are the barriers to optimal severe anaemia management in sub-Saharan Africa?
The evidence base informing managements guidelines for children with severe anaemia is weak, and have not been revised despite new evidence suggesting that key correlates with poor outcome – inadequate response to transfusion, bacterial co-infection and vitamin deficiencies – are not covered within current guidelines. Combining different strategic approaches within a new management ‘bundle of care’, including more liberal and larger-volume transfusion, may reduce immediate mortality, subsequent transfusion requirements and additionally address nutritional deficiencies by using multi-vitamins and preventing further infections by anti-infective prophylaxis post-discharge that might have their greatest impact after the effects of transfusion have waned (by 2-3 months).
How do you think these barriers can be overcome to implement changes to increase transfusion volume?
More liberal transfusion policies may in fact be associated with both economic and indirect benefits for blood transfusion resources. In the short term, benefits may arise from averting the need for re-transfusion, with associated costs and cumulative person-hours per patient of health staff, prolongation of admission and inherent biological risks of multiple transfusions. Future research is needed to investigate ways in which blood can be delivered most efficiently to the benefit of the largest number of individuals.
What further research is required?
The TRansfusion and TReatment of severe Anaemia in African Children: a randomised controlled Trial (TRACT) was designed to address these barriers in optimal management and will evaluate three components that could form an integrated treatment package for severe anaemia: transfusion, micro-nutrient supplementation to address underlying nutrient deficiencies, and short-term antimicrobial prophylaxis to prevent recurrent infections. Each targets a different mechanism for reducing mortality and morbidity and targets both early and late outcomes: effects are thus expected to be additive. It will be conducted over the next 3 years in 3954 Ugandan and Malawian children.