Evaluation of Fecal Inflammatory Biomarkers to Identify Bacterial Diarrhea Episodes: Systematic Review and Protocol for the Enterics for Global Health Shigella Surveillance Study
Authors: Babb Courtney , Badji Henry , Bhuiyan Md Taufiqur Rahman , Cornick Jennifer , Qureshi Sonia , Sonye Catherine , Shapiama Lopez Wagner V , Adnan Mehreen , Atlas Hannah E , Begum Kehkashan , Brennhofer Stephanie A , Ceesay Bubacarr E , Ceesay Abdoulie K , Cunliffe Nigel A , Garcia Bardales Paul F , Haque Shahinur , Horne Bri’Anna , Hossain M Jahangir , Iqbal Junaid , Islam Md Taufiqul , Islam Sadia , Khanam Farhana , Kotloff Karen L , Malemia Thandizo , Manzanares Villanueva Katia , Million Gertrude Malola , Munthali Vitumbiko , Ochieng John Benjamin , Ogwel Billy , Paredes Olortegui Maribel , Omore Richard , Pavlinac Patricia B , Platts-Mills James A , Sears Khandra T , Secka Ousman , Tennant Sharon M , Peñataro Yori Pablo , Yousafzai Mohammad Tahir , Jere Khuzwayo C , Kosek Margaret N , Munga Stephen , Ikumapayi Usman N , Qadri Firdausi , Qamar Farah Naz , Rogawski McQuade Elizabeth T 
Published: March 2024

Abstract

Background
The measurement of fecal inflammatory biomarkers among individuals presenting to care with diarrhea could improve the identification of bacterial diarrheal episodes that would benefit from antibiotic therapy. We reviewed prior literature in this area and describe our proposed methods to evaluate 4 biomarkers in the Enterics for Global Health (EFGH) Shigella surveillance study.

Methods
We systematically reviewed studies since 1970 from PubMed and Embase that assessed the diagnostic characteristics of inflammatory biomarkers to identify bacterial diarrhea episodes. We extracted sensitivity and specificity and summarized the evidence by biomarker and diarrhea etiology. In EFGH, we propose using commercial enzyme-linked immunosorbent assays to test for myeloperoxidase, calprotectin, lipocalin-2, and hemoglobin in stored whole stool samples collected within 24 hours of enrollment from participants in the Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia sites. We will develop clinical prediction scores that incorporate the inflammatory biomarkers and evaluate their ability to identify Shigella and other bacterial etiologies of diarrhea as determined by quantitative polymerase chain reaction (qPCR).

Results
Forty-nine studies that assessed fecal leukocytes (n = 39), red blood cells (n = 26), lactoferrin (n = 13), calprotectin (n = 8), and myeloperoxidase (n = 1) were included in the systematic review. Sensitivities were high for identifying Shigella, moderate for identifying any bacteria, and comparable across biomarkers. Specificities varied depending on the outcomes assessed. Prior studies were generally small, identified red and white blood cells by microscopy, and used insensitive gold standard diagnostics, such as conventional bacteriological culture for pathogen detection.

Conclusions
Our evaluation of inflammatory biomarkers to distinguish diarrhea etiologies as determined by qPCR will provide an important addition to the prior literature, which was likely biased by the limited sensitivity of the gold standard diagnostics used. We will determine whether point-of-care biomarker tests could be a viable strategy to inform treatment decision making and increase appropriate targeting of antibiotic treatment to bacterial diarrhea episodes.