Circulating HMGB1 in Acute Respiratory Distress Syndrome: A Critical Review of Measurement Validity and Biosensor Evidence

Biological plausibility has outpaced the measurement and clinical validation of the role of circulating high-mobility group box 1 (HMGB1) in linking tissue injury to inflammation in acute respiratory distress syndrome (ARDS). This is a critical narrative review to determine whether the evidence concerning HMGB1 biology, circulating assays, and emerging biosensors can support the same clinical assertions. Focused appraisal of 33 clinical, biosensor, and analytical reports was facilitated by PubMed, Scopus, and Google Scholar searching and reference-list checking. Investigational trials reveal linkage to injury or poor outcomes, as well as negative results and significant selection criteria, sampling, assays, and endpoints. Reported prognostic thresholds are not applicable across matrices or platforms, and an enhanced panel AUC does not separate the contribution of HMGB1. There were six quantitative biosensor reports that showed detection of the analytes in controlled solutions, cell-derived material, or experimental disease states; however, human ARDS cohort validation was not reported in accessible biosensor reports. Thus, low detection limits cannot determine the accuracy or clinical utility of ARDS diagnosis. Central Gap is the information missing between an analytically created measurement and a prospectively validated clinical choice. There is need for matrix-specific assay verification, evaluation in an independent ARDS cohort, and, then, for testing to determine whether an HMGB1-informed strategy improves decision-making or outcomes.