Metabolic Biomarkers Associated with Neutrophils in SARS-CoV-2 Infected Individuals: A Systematic Review

Background Neutrophils play a central role in the progression of COVID-19, contributing to inflammation, immunothrombosis, and organ dysfunction through mechanisms such as neutrophil extracellular trap (NET) formation and the release of metabolic mediators. Several metabolic biomarkers related to neutrophil activity have been investigated as predictors of disease severity, but findings across studies remain fragmented. Objective This systematic review aimed to synthesize current evidence on metabolic biomarkers associated with neutrophil activation in COVID-19 patients and evaluate their clinical and therapeutic implications. Methods A systematic search was conducted across seven databases (PubMed, Scopus, Web of Science, Google Scholar, AJOL, Embase, and ScienceDirect) for studies published between December 2019 and November 2024. Keywords related to COVID-19, neutrophils, and metabolic biomarkers were combined using Boolean operators. Eligible studies were observational designs assessing metabolic biomarkers linked to neutrophil activation and COVID-19 severity. Dual screening, data extraction, and quality appraisal were performed using Rayyan software and the Newcastle-Ottawa Scale. A narrative synthesis was conducted due to study heterogeneity. Results Fifteen studies were included, highlighting consistent associations between elevated biomarkers such as myeloperoxidase (MPO), neutrophil extracellular traps (NETs), calprotectin, interleukins (IL-6, IL-8), D-dimer, neutrophil elastase, resistin (RETN), lipocalin-2 (LCN2), and neutrophil gelatinase-associated lipocalin (uNGAL) and worse clinical outcomes, including respiratory failure, organ dysfunction, and mortality. Emerging biomarkers like RETN, DEFA3, and LCN2 showed potential for improving risk stratification but require further validation. Despite promising findings, heterogeneity in study designs, assay methods, and patient populations limited comparability. Conclusion Metabolic biomarkers related to neutrophil activation hold significant promise for early risk stratification and therapeutic targeting in COVID-19. However, inconsistencies across studies, a lack of standardization, and limited data from low-resource settings underscore the need for further multicenter, longitudinal research. Implementation of biomarker-based approaches must prioritize affordability and accessibility, particularly for low- and middle-income countries.