Linking Comorbidity and Inflammation: The Role of Comorbidity Polypharmacy Score in Chronic Limb-Threatening Ischemia

Introduction: Chronic limb-threatening ischemia (CLTI) is a severe manifestation of peripheral artery disease, frequently associated with multimorbidity and polypharmacy. Chronic low-grade inflammation plays a pivotal role in atherosclerosis progression, and hematologic markers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are gaining value as prognostic tools. Aim: To investigate the relationship between the Comorbidity-Polypharmacy Score (CPPS) and inflammatory biomarkers in patients undergoing elective revascularization for CLTI. Methods: This retrospective study included 442 CLTI patients treated at the Vascular Surgery Unit, University of Siena. CPPS was calculated by summing the number of chronic diseases and long-term medications, stratifying patients into 4 groups: mild, moderate, severe, and morbid. Pre-operative bloodwork was analyzed to calculate NLR, PLR, and SII. Statistical analysis included ANOVA and linear regression. Results: CPPS distribution was mild (22.6%), moderate (54.3%), severe (21.9%), and morbid (1.2%). Inflammatory markers increased significantly with CPPS severity. Mean NLR rose from 3.1 ± 2.1 in mild to 5.8 ± 3.7 in morbid (P < 0.001), PLR from 145.0 ± 89.5 to 227.2 ± 112.9 (P < 0.001), and SII from 835.7 ± 707.6 to 1710.6 ± 944.0 (P < 0.001). Hemoglobin decreased from 13.6 ± 2.1 g/dL to 11.5 ± 1.7 g/dL (P = 0.03). Linear regression showed significant positive correlations between CPPS and NLR (R2 = 0.28), PLR (R2 = 0.35), and SII (R2 = 0.33). Conclusions: Higher CPPS is associated with elevated inflammatory markers and declining hemoglobin, suggesting that multimorbidity and polypharmacy contribute directly to systemic inflammation. CPPS, alongside NLR, PLR, and SII, may support risk stratification and personalized management in CLTI patients.