Project Summary/Abstract 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. However, much of this data comes for high transmission settings and results are mixed. Also data from lower transmission settings suggests negative health consequences. 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. Data from trials of intermittent preventative therapy (IPT) and mass drug administration (MDA) also suggest benefits of treating LMI. However, these presumptive treatment strategies can also promote drug resistance and are not practical in low transmission settings. More sensitive detection methods including molecular approaches are increasingly available, but evidence of their effectiveness to reduce disease burden is lacking. To inform policy and practice, there is an urgent need for evidence on the impact and safety of detecting and treating LMI in children. The objective 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 (n=200 per arm, inclusive of 15% loss to follow-up) enabling at least 85% power (two-sided a=0.05) to detect a 20% effect size for each of the interventions compared to control. Children will be 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 (usi...