Non-Infectious Causes for Elevated Procalcitonin

<i>Background and Objectives</i>: Procalcitonin (PCT) is widely used to support the diagnosis of bacterial infection and sepsis, yet clinically relevant elevations also occur in multiple non-infectious conditions. This systematic review aimed to synthesize human evidence on non-infectious causes of elevated PCT and to summarize proposed pathophysiological mechanisms, with the goal of supporting context-based interpretation in clinical practice. <i>Materials and Methods</i>: A systematic search of PubMed/MEDLINE, Embase, Web of Science, and Scopus was performed from inception to 31 July 2025. Human studies published in English reporting quantitative PCT values in non-infectious contexts were eligible (observational studies, clinical trials, and case series with ≥5 patients). <i>Results</i>: Seventy-six unique studies were included. Evidence was organized across systemic inflammatory responses, cardiovascular pathology, nephrological disorders and renal replacement therapy, pulmonary diseases, gastrointestinal and hepatopancreatic diseases, autoimmune and rheumatologic conditions, neurologic and ophthalmologic conditions, onco-hematologic disorders, surgery, traumatology and transplanted patients. Across conditions, non-infectious PCT elevations were variable and frequently overlapped with ranges reported in bacterial infection, particularly in settings characterized by severe sterile inflammation and tissue injury (e.g., major surgery, trauma, shock, pancreatitis, and burns), as well as in selected malignancies with tumor-associated PCT production. <i>Conclusions</i>: Elevated PCT is not synonymous with bacterial infection. Interpretation should emphasize clinical context, timing, and serial trends rather than isolated thresholds, especially in high-acuity settings with strong non-infectious inflammatory stimuli. Standardized reporting of assays and sampling time points and condition-specific kinetic data are needed to refine diagnostic and stewardship algorithms.