| Severe malarial anaemia is a major cause of in-hospital childhood mortality in Africa. Recent studies conducted by us in Malawi and by others in Kenya indicate that transfused children also have unacceptably high rates of rebound severe anaemia (8.8%) and post-discharge mortality (additional 7.5%), despite initial clinical improvement during the in-hospital period following blood transfusions and antimalarials. They represent a selected group at high risk of rebound severe anaemia and death due to a combination of factors that may include parasite (e.g. drug resistance), host (genetic factors, such as sickle cell disease) and environmental and socio-behavioural factors affecting exposure to subsequent malaria. Rebound severe anaemia was associated with malaria parasitaemia due to partially effective antimalarial treatment (recrudescence of drug-resistant infection) or a new malaria infection resulting in delayed or no haematological recovery. The relative contribution of each needs to be determined and is likely to vary with the level of drug resistance and environmental (e.g. transmission season) and behavioural factors determining the risk of new infections during the recovery period. Currently, the standard treatment for severe malarial anaemia in many parts of Africa includes a blood transfusion and parental quinine followed by a single dose of oral ulfadoxine pyrimethamine (SP). The efficacy of the combination of IV quinine and oral SP is perceived to be good. Resistance to SP, however, is emerging rapidly and failure rates to SP as monotherapy now exceed 10% by day 14 in many areas of East and southern Africa. Artemisinin based combination therapy (ACT), such as the fixed-combination lumefantrine-artemether (Coartem®, Co-artemether), offers great promise in the treatment of malaria and maximises the potential to obtain radical cure and haematological recovery. Targeted chemo-prophylaxis prevents malaria morbidity but is no longer advocated in endemic areas. Recently, the use of Intermittent Preventive Therapy in infants (IPTi) has been successfully used in Tanzania, (SP or amodiaquine) to halve the incidence of moderate-severe anaemia in areas with intense malaria transmission. IPT consists of effective antimalarial treatment doses delivered at predefined intervals to clear parasites and induces prolonged periods of aparasitaemia. More recently 3 monthly doses of IPT with SP-artesunate during the rainy season reduced clinical attacks of malaria in children aged <5 years by more than 80% in an area with highly seasonal transmission. We hypothesize that by creating a prophylactic-time-window post transfusion the bone marrow gets time to recover, resulting in a further rise in haemoglobin in the post-discharge period. Preliminary data from Malawi show that this process takes 2-3 months in children with severe anaemia and will result in a haemoglobin rise from 6-7 mg/dl post transfusion to >11 mg/dl after 2 months. This will take the child out of the haemoglobin danger zone with a much smaller chance that a new malaria infection will result into a rebound severe anaemia or deaths. We propose to conduct a randomized controlled trial that aims to define the role of effective initial antimalarial treatment and the additional benefits of monthly Intermittent Preventive Therapy post-discharge (IPTpd) in the post-discharge management of children with severe malarial anaemia. Rationale and Capacity development: The high risk of post-discharge morbidity and mortality has received little attention thus far as most research on severe malaria has focused on interventions that reduce in-hospital malaria mortality. IPTpd is an innovative and potentially cost-effective strategy to reduce post-hospitalization morbidity and possibly mortality in this high risk group. The study will be among the first large ICH-GCP compliant intervention studies conducted in Malawi. It will therefore have an important capacity development component by providing on the job training in the conduct of clinical trials according to the new EU-directive for clinical trials. It will also be the core study for a PhD training of one of the clinical Malawian investigators. |
