False-positive malaria rapid diagnostic tests and antimalarial overuse among children under 5 in Uganda

Malaria is the leading cause of morbidity in Uganda and accounts for roughly 13% of mortality among children under five years of age (under-5s). The introduction of malaria rapid diagnostic tests (mRDTs), into care-seeking settings has improved access to high-quality malaria diagnostics. However, mRDTs have limitations; they detect antigen produced by the malaria parasite which persists after treatment, producing false-positive results. Still, mRDTs are widely used in point-of-care malaria management across Uganda. While malaria is a substantial cause of febrile illness among under-5s, acute respiratory illnesses (ARI) also contribute to febrile illnesses and care seeking. Because false-positives may be frequent in high transmission settings, the routine use of mRDTs in children presenting with ARI likely contributes to malaria overdiagnosis and antimalarial overuse. This overuse accelerates antimicrobial resistance, which threatens current and future malaria control efforts. In Aim 1, using data from 7,754 under-5s enrolled in the 2018-2019 Uganda Malaria Indicator Survey (MIS), the prevalence of false-positive mRDTs among microscopy-negative under-5s in Uganda was 10.7% (8.8%, 12.6%). We determined that recent fever and recent antimalarial use were associated with an increased probability of a false-positive mRDT. Recent antibiotic use was associated with a decreased probability of a false-positive mRDT. Lastly, we developed a lasso regression model that modestly predicted false-positive mRDTs among under-5s with recent fever. In Aim 2, we used data from 1,218 children enrolled in the STAR study between November 2021 and May 2022 who sought care for ARI in Bugoye, Uganda. The uncorrected malaria prevalence in the study was 51.6% (48.7%, 54.4%). Using the MIS as external validation data, the corrected malaria prevalence in the STAR study was 46.1% (33.1%, 59.1%). Since antimalarial prescription was based on mRDT results in the STAR study, we estimated that 5.5% (-7.0%, 18.0%) of children in the cohort received antimalarials unnecessarily. False-positive mRDT results due to antigen persistence are common among under-5s in Uganda and can be predicted with demographic, clinical, and environmental covariates. Further, antimalarial overuse due to false-positive mRDTs occurred in a cohort of under-5s seeking care for ARI. These findings highlight the need to improve malaria testing and treatment algorithms.