Transfusion and Treatment of severe Anaemia in African Children: a randomised controlled trial (TRACT)

In sub-Saharan Africa severe anaemia is one of the most common reasons why children end up in hospital. It can kill children directly - and also contributes indirectly to the 800,000 child malaria deaths/year. For children hospitalised with severe anaemia (defined as a haemoglobin below 6g/dl) outcomes remain poor, with 9-10% dying in-hospital and an additional 12% dying in the 6 months following admission - and a further 6% having another episode of severe anaemia requiring additional treatment and re-hospitalisation. The high 6-month case fatality and chronic ongoing health issues of children with this condition indicate that the current recommendations and/ management strategies are not working in practice. Because severe anaemia is very common, the high 'hidden' sickness and mortality occurring after the initial diagnosis is likely to contribute to overall under-five mortality. If not adequately addressed, severe anaemia may therefore be an obstacle to achievement of the Millennium Development Goal No.4 on child survival in Africa.

The investigators in this trial include specialists in child health, infectious diseases, transfusion medicine, and anaemia research. They have considerable experience in doing large clinical trials in hospitals with limited resources in Africa. Through extensive review of the available data and literature, the group have identified key areas of severe anaemia management which need to be addressed in a clinical trial, namely
1/Which children should receive a transfusion? Current WHO guidelines, designed to avoid overuse of blood, recommend transfusions only in children with a haemoglobin (Hb) <4g/dl (or <6g/dl if accompanied by complications). These specific recommendations have not been evaluated in clinical trials and thus practice varies across African countries. We don't know if giving blood to all children with Hb <6g/dl would help. 2/ How much blood should be given in a transfusion? On current recommendations a quarter of children receiving transfusions remain severely anaemic and up to one third get two or more blood transfusions during a single hospital admission. We don't know if giving larger initial volumes of blood would help - this could also reduce risks from additional transfusion (which include bad blood matching or blood infections), and the amount of time health personnel spend getting blood ready. 3/ What, if any, longer-term support should children get after hospital admission? The major factors related to poor longer term outcome are multiple vitamin and mineral deficiencies and blood infections caused by bacteria - we don't know if giving vitamin supplements or antibiotics to prevent infections would improve outcomes.

TRACT is designed to answer these questions. It is a randomised controlled trial involving 3700 children aged 2 months to 12 years admitted to hospitals with severe anaemia in Malawi and Uganda. The trial will take place over 2 years and children will be followed up for 6 months to make sure longer-term outcomes are captured. The trial will simultaneously look at three ways management of severe anaemia might be improved - with the aim of reducing early and late deaths, and anaemia recurrence or readmission to hospital. The trial will compare (i) current conservative WHO recommendations for transfusion against a more liberal approach, in terms of who gets blood and how much blood they get (iii) additional multi-vitamin multi-mineral supplements compared with the standard folate/iron recommended by WHO and (iii) an antibiotic, cotrimoxazole, to prevent new bacterial infections for 3 months compared with no antibiotic. The design is practical with broad, largely clinical inclusion criteria, so that children can be rapidly identified and recruited at hospital admission. The interventions are practical; many are already in use for other diseases so could be implemented in under-resourced paediatric health facilities across Africa at the end of the trial.

TRACT is a multicentre randomised controlled trial to identify optimal transfusion strategies and supportive treatment for 3700 African children, aged 2 months to 12 years, presenting to hospital with severe anaemia (defined as haemoglobin (Hb) <6 g/dl). Children will be enrolled at admission to hospital over 2 years in Malawi and Uganda and followed for 6 months. The trial has been designed to address the poor outcome of this condition including high rates of in-hospital mortality, 6-month case fatality and chronic morbidity. Factors associated with poor outcome include potentially treatable co-morbidities such as recurrent infection and multiple vitamin deficiencies, which are not addressed in current guidelines. TRACT is designed to probe each of these multiple contributing factors directly. TRACT will simultaneously evaluate three ways to reduce short and longer-term mortality (primary endpoint) and morbidity following severe anaemia in Sub-Saharan Africa using a factorial design:

1/ Liberal transfusion (30ml/kg) versus conservative transfusion (20ml/kg) vs no transfusion (last strategy for children with Hb>4 g/dl and uncomplicated severe anaemia only)
2/ Multi-vitamin multi-mineral (MVMM) supplementation (including folate/iron) for 3 months versus routine care (folate/iron alone)
3/ cotrimoxazole prophylaxis for 3 months versus no antibiotic prophylaxis.

The primary outcome is cumulative mortality to 4 weeks (transfusion comparisons) and to 6 months for the nutritional support/antibiotic prophylaxis comparison. Secondary outcomes include mortality at 48 hours, 4 weeks, 3 months and 6 months (cumulative) (where not the primary outcome); development of new profound anaemia (Hb<4g/dl) during acute admission or development of severe anaemia (Hb<6g/dl) post discharge; readmission to hospital; proportion achieving correction of anaemia (defined by WHO as Hb>9g/dl); adverse events relating to transfusion.

Children with severe anaemia (SA) in Africa will be key beneficiaries. SA is a leading cause of morbidity, hospital admission and death in Sub-Saharan Africa, contributing to ~800,000 malaria deaths/year. Incomplete response to SA treatment results in relapse, readmission and death occurring soon after diagnosis. Current policies guiding clinical management are fragmented, based on weak evidence and often impractical. Since SA is so common the poor outcome and high 'hidden' chronic morbidity, if not adequately addressed, may be a key obstacle to achievement of Millennium Development Goal No.4 on child survival in Africa. The proposed trial will evaluate key elements of an integrated management strategy, including transfusion, in African hospitals on the basis of clinical effectiveness and costs.
In order for benefits to be realised, we plan to engage with (1) national policymakers (Ministry of Health, blood transfusion services, child health services); (2) international policymakers (WHO, UNICEF); (3) healthcare workers, nursing and paediatric associations, and NGOs involved in providing treatment or advocacy for children with severe anaemia in order to disseminate the outputs from the trial.
These stakeholders will benefit from our research, which aims to provide clear evidence on optimal treatment of children with severe anaemia, which is currently lacking. If the trial interventions reduce rates of re-admission to hospital, and are efficient and cost-effective for transfusion services, this could greatly improve overstretched acute child health and transfusion services.
In order to influence relevant policymakers and practitioners, we will also need to engage with academic audiences (who influence WHO policy), and those training health workers. Trainers of healthcare workers may benefit from new evidence from a controlled trial of what works and what does not work. Results from the trial may spur further research and academic debate, helping to catalyse further research on (cost-)effective interventions and improvement of care for children with severe anaemia in low-income settings.
Since the trial is large and pragmatic, incorporating children with both acute and acute-on-chronic anaemia, with few exclusion criteria, it will enable development of new guidelines and policy that cut across multiple 'syndromic' presentations - adopting a horizontal integrated rather than a vertical approach to management. Key enrolees will include children admitted to hospital with anaemia and malaria, sepsis, malnutrition, HIV, sickle cell disease and other conditions (eg lower respiratory tract infection). The pragmatic design is critical to translation of results to clinical practice; in malaria-endemic Africa, distinguishing between different underlying comorbidities, eg malaria and sepsis, in a severely ill child is often impossible at presentation to hospital. Since most treatment decisions are made on clinical criteria alone (or with limited diagnostic information eg malaria film and haemoglobin test), the trial results will have relevance to clinical practice and be immediately generalisable. There may be variation in response to the trial interventions and therefore the analysis plan will ensure that key syndromic groups, age groups and susceptibility (HIV or genetic factors) are considered. Whilst a single guideline is anticipated, refinement of this will be possible for particular sub-groups where response is not uniform.
The proposal will address whether the interventions represent value-for-money through a cost-effectiveness analysis (CEA) for each strategy investigated in the trial, which will draw upon existing knowledge and generate new costing data. Particular attention will be paid to blood transfusion service needs; ways in which blood can be delivered most efficiently to the benefit of the largest number of individuals (children in particular), will be explored during the trial and incorporated with trial results.