Point-of-care C-reactive protein measurement by community health workers safely reduces antimicrobial use among children with respiratory illness in rural Uganda: A stepped wedge cluster randomized trial.

BACKGROUND: Acute respiratory illness (ARI) is one of the most common reasons children receive antibiotic treatment. Measurement of C-reaction protein (CRP) has been shown to reduce unnecessary antibiotic use among children with ARI in a range of clinical settings. In many resource-constrained contexts, patients seek care outside the formal health sector, often from lay community health workers (CHWs). This study's objective was to determine the impact of CRP measurement on antibiotic use among children presenting with febrile ARI to CHW in Uganda. METHODS AND FINDINGS: We conducted a cross-sectional, stepped wedge cluster randomized trial in 15 villages in Bugoye subcounty comparing a clinical algorithm that included CRP measurement by CHW to guide antibiotic treatment (STAR Sick Child Job Aid [SCJA]; intervention condition) with the Integrated Community Care Management (iCCM) SCJA currently in use by CHW in the region (control condition). Villages were stratified into 3 strata by altitude, distance to the clinic, and size; in each stratum, the 5 villages were randomly assigned to one of 5 treatment sequences. Children aged 2 months to 5 years presenting to CHW with fever and cough were eligible. CHW conducted follow-up assessments 7 days after the initial visit. Our primary outcome was the proportion of children who were given or prescribed an antibiotic at the initial visit. Our secondary outcomes were (1) persistent fever on day 7; (2) development of prespecified danger signs; (3) unexpected visits to the CHW; (4) hospitalizations; (5) deaths; (6) lack of perceived improvement per the child's caregiver on day 7; and (7) clinical failure, a composite outcome of persistence of fever on day 7, development of danger signs, hospitalization, or death. The 65 participating CHW enrolled 1,280 children, 1,220 (95.3%) of whom had sufficient data. Approximately 48% (587/1,220) and 52% (633/1,220) were enrolled during control (iCCM SCJA) and intervention periods (STAR SCJA), respectively. The observed percentage of children who were given or prescribed antibiotics at the initial visit was 91.8% (539/587) in the control periods as compared to 70.8% (448/633) during the intervention periods (adjusted prevalence difference -24.6%, 95% CI: -36.1%, -13.1%). The odds of antibiotic prescription by the CHW were over 80% lower in the intervention as compared to the control periods (OR 0.18, 95% CI: 0.06 to 0.49). The frequency of clinical failure (iCCM SCJA 3.9% (23/585) v. STAR SCJA 1.8% (11/630); OR 0.41, 95% CI: 0.09, 1.83) and lack of perceived improvement by the caregiver (iCCM SCJA 2.1% (12/584) v. STAR SCJA 3.5% (22/627); OR 1.49, 95% CI: 0.37, 6.52) was similar. There were no unexpected visits or deaths in either group within the follow-up period. CONCLUSIONS: Incorporating CRP measurement into iCCM algorithms for evaluation of children with febrile ARI by CHW in rural Uganda decreased antibiotic use. There is evidence that this decrease was not associated with worse clinical outcomes, although the number of adverse events was low. These findings support expanded access to simple, point-of-care diagnostics to improve antibiotic stewardship in rural, resource-constrained settings where individuals with limited medical training provide a substantial proportion of care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05294510. The study was reviewed and approved by the University of North Carolina Institutional Review Board (#18-2803), Mbarara University of Science and Technology Research Ethics Committee (14/03-19), and Uganda National Council on Science and Technology (HS 2631).

High frequency of artemisinin partial resistance mutations in the great lake region revealed through rapid pooled deep sequencing.

In Africa, the first Plasmodium falciparum Kelch13 (K13) artemisinin partial resistance mutation 561H was first detected and validated in Rwanda. Surveillance to better define the extent of the emergence in Rwanda and neighboring countries as other mutations arise in East Africa is critical. We employ a novel scheme of liquid blood drop preservation combined with pooled sequencing to provide a cost-effective rapid assessment of resistance mutation frequencies at multiple collection sites across Rwanda and neighboring countries. Malaria-positive samples (n=5,465) were collected from 39 health facilities in Rwanda, Uganda, Tanzania, and the Democratic Republic of the Congo (DRC) between May 2022 and March 2023 and sequenced in 199 pools. In Rwanda, K13 561H and 675V were detected in 90% and 65% of sites with an average frequency of 19.0% (0-54.5%) and 5.0% (0-35.5%), respectively. In Tanzania, 561H had high frequency in multiple sites while it was absent from the DRC although 675V was seen at low frequency. Conceringly candidate mutations were observed: 441L, 449A, and 469F co-occurred with validated mutations suggesting they are arising under the same pressures. Other resistance markers associated with artemether-lumefantrine are common: P. falciparum multidrug resistance protein 1 N86 at 98.0% and 184F at 47.0% (0-94.3%) and P. falciparum chloroquine resistance transporter 76T at 14.7% (0-58.6%). Additionally, sulfadoxine-pyrimethamine-associated mutations show high frequencies. Overall, K13 mutations are rapidly expanding in the region further endangering control efforts with the potential of engendering partner drug resistance.