Cross-sectional evaluation of host biomarkers for guiding antibiotic use in bacterial and non-bacterial acute febrile illness in low- and middle-income tropical settings

ObjectivesTo evaluate the effectiveness of 18 different host biomarkers in differentiating bacterial from non-bacterial acute febrile illness (AFI) in resource-limited settings, specifically in Brazil, Malawi and Gabon.DesignMultinational, cross-sectional study.SettingThe study was carried out acros...

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Bibliographic Details
Published in:	BMJ open Vol. 15; no. 2; p. e086912
Main Authors:	Fernandez-Carballo, B Leticia, Atzeni, Michele, Escadafal, Camille, Vettoretti, Martina, Geis, Steffen, Agnandji, Selidji Todagbe, Siqueira, Andre M, Malava, Jullita Kenala, Banda, Louis, Kabwende, Anita L, Alabi, Ayodele, Ondo, Juste Christin Bie, Massinga-Loembe, Marguerite, Essone, Paulin N, Moreira, José, da Rocha Matos, Aline, Caetano, Braulia C, Siqueira, Marilda M, Bispo de Filippis, Ana Maria, dos Santos Ribeiro da Silva, Érica Aparecida, Lourenço, Maria Cristina S, Häring, Julia, Günther, Anna, Jakobi, Meike, Schneiderhan-Marra, Nicole, Hoogland, Christine, Brasil, Patrícia, Pokharel, Sunil, Ongarello, Stefano, Harris, Victoria, Macé, Aurélien, Lee, Sue J, Di Camillo, Barbara, Dittrich, Sabine
Format:	Journal Article
Language:	English
Published:	England British Medical Journal Publishing Group 13.02.2025 BMJ Publishing Group LTD BMJ Publishing Group
Subjects:	Acute Disease Adult Aged Anti-Bacterial Agents Anti-Bacterial Agents - therapeutic use Antibiotics Bacterial infections Bacterial Infections - blood Bacterial Infections - diagnosis Bacterial Infections - drug therapy Biomarkers Biomarkers - blood Brazil Child Classification Cross-Sectional Studies Diagnostic tests Diagnostics Female Fever Fever - diagnosis Fever - drug therapy Fever - microbiology Gabon Health facilities Humans Infections Laboratories Low income groups Malaria Malawi Male Middle Aged Original Research Patients Product development Proteins Public health ROC Curve Viral infections Young Adult Brazil Gabon Malawi Malaria Anti-Bacterial Agents Public health
ISSN:	2044-6055, 2044-6055
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Summary:	ObjectivesTo evaluate the effectiveness of 18 different host biomarkers in differentiating bacterial from non-bacterial acute febrile illness (AFI) in resource-limited settings, specifically in Brazil, Malawi and Gabon.DesignMultinational, cross-sectional study.SettingThe study was carried out across multiple primary healthcare facilities, including urban and rural settings, with a total of three participating centres. Recruitment took place from October 2018 to July 2019 in Brazil, May to November 2019 in Gabon and April 2017 to April 2018 in Malawi.ParticipantsA total of 1915 participants, including children and adults aged 21–65 years with a fever of≤7 days, were recruited through convenience sampling from outpatient clinics in Brazil, Gabon and Malawi. Individuals with signs of severe illness were excluded. Written consent was obtained from all participants or their guardians.InterventionThis is not applicable as the study primarily focused on biomarker evaluation without specific therapeutic interventions.Primary and secondary outcome measuresThe primary outcome measure was the ability of each host biomarker to differentiate between bacterial and non-bacterial AFI, as evaluated by area under the receiver operating characteristic (AUROC) curves. Secondary outcomes included the performance of individual biomarkers across the different study sites and in a multivariable setting.ResultsA Kruskal-Wallis test, adjusted by Benjamini-Hochberg, was performed for each biomarker to identify covariates with a significant difference in the distribution of biomarker values. The analysis revealed that country of origin (Brazil, Gabon, Malawi), age, sex and malaria status significantly impacted biomarker distribution (p≤0.001). The most widely known biomarkers, such as white blood cell (WBC) count and C-reactive protein (CRP), demonstrated the best performance in distinguishing between bacterial and non-bacterial infections, with AUROCs reaching up to 0.83 (0.77–0.88) for WBC count and 0.71 (0.59–0.82) for CRP. However, none of the evaluated novel host biomarkers exhibited high performance (AUROC<0.70 in most cases) and variations in biomarker performance were observed across the three settings. Multivariable analyses demonstrated that while the best combination of biomarkers achieved higher AUROCs, the increase was modest (1–13%), suggesting that the interaction of biomarkers contributed minimally to predictive accuracy.ConclusionsThere is a continued need for innovation in the host-biomarker space as the available markers do not meet the needs of diverse populations around the globe. This highlights the importance of targeted evaluations in non-severe patients in multiple settings to understand the true potential for real-life use. The findings highlight that not one-marker fits all settings and novel innovations remain urgently needed.Trial registration numberClinical trial number: NCT03047642.
Bibliography:	Original research ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 SD, BLFC, CE, VH, SO, CH, AM, SL are or were employed by FIND, the global alliance for diagnostic during the study period. All other authors do not declare any competing interests. CE and MV contributed equally. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. BLF-C and MA contributed equally.
ISSN:	2044-6055 2044-6055
DOI:	10.1136/bmjopen-2024-086912