Ciccone, Emily J., Hu, Di, Preisser, John S., Cassidy, Caitlin A., Kabugho, Lydiah, Emmanuel, Baguma, Kibaba, Georget, Mwebembezi, Fred, Juliano, Jonathan J., Mulogo, Edgar M., and Boyce, Ross M.
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.govNCT05294510. 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). Emily J. Ciccone and colleagues investigate if measuring C-reactive protein levels can lead to decreased antibiotic use in rural Uganda's children with fever and respiratory illness. Author summary: Why was this study done?: Globally, antibiotics are frequently used to treat children with fever and respiratory symptoms. However, most of these illnesses are likely viral and/or self-resolving and therefore do not require antibiotics. This overuse can lead to the development and spread of antimicrobial resistance (AMR). Measurement of C-reactive protein (CRP) levels in blood can decrease antibiotic use in children with fever and respiratory illness in health care facilities in low- and middle-income countries (LMICs). Many children in sub-Saharan Africa, when ill, present first to lay community health workers, outside of the formal health care system. What did the researchers do and find?: We conducted a stepped wedge cluster randomized trial involving 65 community health workers (CHW) in 15 villages in rural western Uganda that compared the Integrated Community Care Management (iCCM) algorithm currently in use by CHW in the region with an amended study algorithm (STAR Sick Child Job Aid [SCJA]) that included semiquantitative CRP measurement by CHW to guide antibiotic treatment decisions among children presenting with fever and respiratory symptoms. We enrolled 1,280 children, 1,220 of whom were included in the analyses. Our primary outcome of interest was antibiotics given or prescribed at the initial visit. As secondary outcomes, we assessed for adverse effects at 7 days after initial visit to the CHW, including clinical failure (a composite outcome that included persistent fever, development of danger signs, hospitalization, or death) and perceived improvement by the child's caregiver. We observed a decrease in antibiotic use of 24.6% (95% CI: −36.1%, −13.1%) in the SCJA (intervention) group compared to the iCCM (control) group. There was no statistical difference in rates of clinical failure, perceived improvement by the caregiver, or other safety outcomes at day 7, although the number of these events in both groups was small, and therefore, our estimates are imprecise. What do these findings mean?: This study shows that point-of-care CRP testing by CHW with limited clinical training outside of the formal healthcare system is feasible and has the potential to decrease unnecessary antibiotic use. We did not observe a concomitant increased risk of adverse effects in the SCJA group, although our study was not specifically designed to detect a difference in these outcomes. The results provide rationale for larger-scale studies of clinical algorithms for CHW including CRP that focus on safety outcomes, implementation, and cost-effectiveness. This research supports the use of simple, point-of-care diagnostics in rural, resource-constrained settings to improve antibiotic stewardship. [ABSTRACT FROM AUTHOR]