Child Health and Infection with Low Density (CHILD) Malaria, a randomized controlled trial to assess the long-term health and socioeconomic impact of interventions targeting low-density malaria infection (LMI) among children in Tanzania

As malaria transmission declines, an increasing proportion of infections persist in the body at low levels. Low-density malaria infection (LMI) are often chronic and represent a high proportion of infections among children in the community and children presenting with fever, but they have been largely ignored because standard point-of-care diagnostics have limited sensitivity to detect them, and they are considered incidental or beneficial in that they may provide protective immunity again future malaria illness. There is a growing body evidence to suggest that LMI are associated with recurrent malaria, chronic anemia, poor growth, co-infection with invasive bacterial disease, and cognitive impairment. The ob jective of the proposed project is to determine the long-term health and socioeconomic effects of detecting and treating LMI in children. We hypothesize that compared to a standard of care where malaria detection is passive and based on standard diagnostics (PCD), detecting and treating LMI through use molecular detection methods in active case detection (ACDm) and passive case detection (PCDm) in children will improve all-cause morbidity and have cognitive and socioeconomic benefits. To test this hypothesis, we propose to conduct an open-label randomized controlled trial in children 6 months to 10 years of age at an established trial site in Bagamoyo, Tanzania, where transmission is low and we have found that a high proportion of infections are low-density. The effects of treating Plasmodium falciparum LMI through active or passive case detection may differ. As such, we will study these as separate interventions and compare each to the standard of care. A population representative sample of 600 children total will be recruited and randomized into one of three study arms: 1) standard of care PCD (Control) whereby children presenting with fever will receive artemether lumefantrine (AL) based on positive rapid diagnostic test (RDT) result, 2) ACDm (Arm 2) whereby children will receive testing for malaria (using RDT and qPCR) three times annually, with AL administered for RDT or qPCR-positivity, and 3) PCDm (Arm 3), in which children, when they have fever, will receive testing for malaria (using RDT and qPCR) with AL administered for RDT or qPCR-positivity. Standard PCD will be conducted in Arm 2 and no ACD will be conducted in Arm 3. To capture subacute or chronic effects, follow-up will occur over 2 years. Specific aims are: (1) To assess the impact of standard PCD plus ACDm vs standard PCD alone on long-term child health. (2) To assess the impact of PCDm vs standard PCD on long-term child health. (3) To evaluate the cost-effectiveness of ACDm and PCDm. Findings have potential to change recommendations and practices regarding active and passive case detection in low transmission settings. The potential long-term impact is improved health, cognitive, and socioeconomic potential for millions of children living in areas afflicted by malaria worldwide.

Jebiwott S, Gutapaka N, Sumari D, Loss G, Athuman T, Nyandele J.P, Cummins H, Chemba M, Benjamin-Chung J, Gangar P, Wu X, Smith J, Chen I, Dorsey G, Fink G, Olotu A, Hsiang M. Child health and infection with low density (CHILD) malaria: a protocol for a randomised controlled trial to assess the long-term health and socioeconomic impacts of testing and treating low-density malaria infection among children in Tanzania. BMJ Open. 2024;14(3):e082227. DOI: 10.1136/bmjopen-2023-082227