Alberto Valentini

Background/Objectives: Sepsis is a leading cause of hospital mortality and represents a time-sensitive medical emergency. Current diagnostic strategies rely on clinical assessment, severity scores, biomarkers, and blood cultures. However, blood cultures require 24–72 h for pathogen identification and demonstrate limited sensitivity, while biomarkers such as procalcitonin and C-reactive protein lack optimal specificity. These limitations support the widespread empirical use of broad-spectrum antibiotics and highlight the need for rapid, sensitive, and culture-independent diagnostic tools. Methods: A narrative literature review was conducted using PubMed and Google Scholar, including 28 studies published over the past 10 years, encompassing observational and preclinical investigations. Current evidence on the application of Raman spectroscopy in sepsis was summarized, with a dual focus on pathogen identification and the assessment of the host response. Results: Raman spectroscopy has demonstrated the ability to detect early molecular alterations in circulating immune cells and mitochondrial redox status, potentially preceding conventional biomarkers. For pathogen identification, Raman techniques have achieved diagnostic accuracies comparable to automated systems, but with significantly shorter turnaround times. Integration with microfluidics, optical tweezers, and deep learning algorithms has further enhanced performance, although these applications remain largely experimental. Conclusions: Despite these promising results, the lack of methodological standardization, spectral overlap among phylogenetically related species, limited large-scale validation, and challenges in interpreting certain spectral signatures remain unresolved. Most available evidence originates from preclinical, single-center, and controlled studies, underscoring the need for prospective multicenter trials and harmonized protocols.