HMGB1 and Kallistatin: Novel Serological Markers for Differentiating Peritonsillar Cellulitis and Abscess

<b>Background/Objectives</b>: Peritonsillar abscess (PTA) and cellulitis (PTC) often present with similar clinical features, making differentiation challenging despite imaging. This study evaluates the diagnostic performance of serum HMGB1 and kallistatin levels as potential independent biomarkers to distinguish PTA from PTC. <b>Methods</b>: In this single-center prospective cohort study, 97 patients aged 18 to 65 years who met the inclusion criteria and presented with peritonsillar infection (39 PTA; 58 PTC) between February and July 2025 were enrolled. Serum levels of HMGB1, kallistatin, and routine inflammatory markers were measured and compared. Univariate and multivariate logistic regression analyses identified independent predictors for distinguishing PTA from PTC. Receiver operating characteristic (ROC) curve analysis assessed the diagnostic accuracy of biomarkers. Decision curve analysis (DCA) was performed to evaluate the clinical net benefit of individual biomarkers and their combinations across a range of threshold probabilities. <b>Results</b>: Compared to controls, patients with peritonsillar infection had significantly higher WBC, neutrophil, CRP, procalcitonin, and HMGB1 levels and significantly lower kallistatin levels (all <i>p</i> < 0.05). Within the infection group, PTA patients showed significantly higher CRP (<i>p</i> = 0.036) and HMGB1 (<i>p</i> = 0.003) levels and lower kallistatin (<i>p</i> < 0.001) levels compared to PTC patients. In univariate analysis, CRP, HMGB1, and kallistatin were significantly associated with PTA; however, in multivariate analysis, only elevated HMGB1 (OR: 1.21; 95% CI: 1.09-1.35; <i>p</i> < 0.001) and reduced kallistatin (OR: 0.395; 95% CI: 0.24-0.648; <i>p</i> < 0.001) remained independent predictors. ROC analysis showed that both HMGB1 and kallistatin demonstrated good discriminative ability in distinguishing PTA from PTC. DCA revealed that the three-biomarker combination (kallistatin + HMGB1 + CRP) achieved the highest mean net benefit (0.183) across all threshold probabilities, outperforming individual biomarkers (kallistatin: 0.131, HMGB1: 0.111, CRP: 0.099) and the two-biomarker model (0.176). The combined model maintained superior net benefit across threshold probabilities of 25-75%, indicating optimal clinical utility within this decision range. <b>Conclusions</b>: Serum HMGB1 and kallistatin may be effective adjunctive biomarkers for differentiating PTA from PTC.