Role of Lipidomics in Respiratory Tract Infections: A Systematic Review of Emerging Evidence

Respiratory tract infections (RTIs) remain a major cause of global morbidity and mortality, yet accurate pathogen identification and risk stratification continue to pose clinical challenges. Lipidomics—the comprehensive analysis of lipid species within biological systems—has emerged as a promising tool to unravel host–pathogen interactions and reveal novel diagnostic and prognostic biomarkers. This systematic review synthesizes evidence from nine original studies applying mass spectrometry–based lipidomic profiling in human RTIs, including community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), and coronavirus disease 2019 (COVID-19). Across diverse study designs, sample types, and analytical platforms, consistent alterations in lipid metabolism were observed. Perturbations in phospholipid classes, particularly phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs), were frequently associated with disease severity and immune activation. The ratios of PC to LPC and phosphatidylethanolamine (PE) to lysophosphatidylethanolamine (LPE) emerged as markers of inflammatory remodeling. Sphingolipids—including sphingomyelins (SMs) and sphingosine-1-phosphate (S1P)—were identified as key modulators of monocyte and neutrophil activation. Fatty acid–derived lipid mediators such as oxylipins (e.g., 12,13-epoxyoctadecenoic acid and 15-hydroxyeicosatetraenoic acid) and acylcarnitines reflected pathogen-specific immune responses and mitochondrial dysfunction. Several lipid-based classifiers demonstrated superior diagnostic and prognostic performance compared to conventional clinical scores, including the CURB-65 and pneumonia severity index. However, significant heterogeneity in experimental design, lipid identification workflows, and reporting standards limits inter-study comparability. While preliminary findings support the integration of lipidomics into infectious disease research, larger multi-omic and longitudinal studies are required. This review provides the first comprehensive synthesis of lipidomic alterations in human RTIs and highlights their emerging translational relevance.