TY - JOUR

T1 - Increase in the Complement Activation Product C4d and the Terminal Complement Complex sC5b-9 Is Associated with Disease Severity and a Fatal Outcome in Necrotizing Soft-Tissue Infection

AU - Hedetoft, Morten

AU - Madsen, M. B.

AU - Hansen, C. B.

AU - Hyldegaard, Ole

AU - Garred, Peter

N1 - Publisher Copyright: © 2021 The Author(s).

PY - 2022

Y1 - 2022

N2 - The hyperinflammatory burden is immense in necrotizing soft-tissue infection (NSTI). The complement system is a key during the innate immune response and may be a promising target to reduce the inflammatory response, potentially improving the clinical outcome. However, complement activation and its association to disease severity and survival remain unknown in NSTI. Therefore, we prospectively enrolled patients with NSTI and sampled blood at admission and once daily for the following 3 days. Plasma C4c, C4d, C3bc, and C3dg and the terminal complement complex (TCC) were evaluated using ELISA techniques. In total, 242 patients were included with a median age of 62 years, with a 60% male predominance. All-cause 30-day mortality was 17% (95% confidence interval [CI] 13-23) with a follow-up of >98%. C4c and C3dg were negatively correlated with Simplified Acute Physiology Score II (Rho -0.22, p < 0.001 and Rho -0.17, p = 0.01). Patients with septic shock (n = 114, 47%) had higher levels of baseline TCC than those in non-shock patients (18 vs. 14, p < 0.001). TCC correlated with the Sequential Organ Failure Assessment (SOFA) score (Rho 0.19, p = 0.004). In multivariate Cox regression analysis (adjusted for age, sex, comorbidity, and SOFA score), high baseline C4d (>20 ng/mL) and the combination of high C4d and TCC (>31 arbitrary units/mL) were associated with increased 30-day mortality (hazard ratio [HR] 3.26, 95% CI 1.56-6.81 and HR 5.12, 95% CI 2.15-12.23, respectively). High levels of both C4d and TCC demonstrated a negative predictive value of 0.87. In conclusion, we found that in patients with NSTI, complement activation correlated with the severity of the disease. High baseline C4d and combination of high C4d and TCC are associated with increased 30-day mortality. Low baseline C4d or TCC indicates a higher probability of survival.

AB - The hyperinflammatory burden is immense in necrotizing soft-tissue infection (NSTI). The complement system is a key during the innate immune response and may be a promising target to reduce the inflammatory response, potentially improving the clinical outcome. However, complement activation and its association to disease severity and survival remain unknown in NSTI. Therefore, we prospectively enrolled patients with NSTI and sampled blood at admission and once daily for the following 3 days. Plasma C4c, C4d, C3bc, and C3dg and the terminal complement complex (TCC) were evaluated using ELISA techniques. In total, 242 patients were included with a median age of 62 years, with a 60% male predominance. All-cause 30-day mortality was 17% (95% confidence interval [CI] 13-23) with a follow-up of >98%. C4c and C3dg were negatively correlated with Simplified Acute Physiology Score II (Rho -0.22, p < 0.001 and Rho -0.17, p = 0.01). Patients with septic shock (n = 114, 47%) had higher levels of baseline TCC than those in non-shock patients (18 vs. 14, p < 0.001). TCC correlated with the Sequential Organ Failure Assessment (SOFA) score (Rho 0.19, p = 0.004). In multivariate Cox regression analysis (adjusted for age, sex, comorbidity, and SOFA score), high baseline C4d (>20 ng/mL) and the combination of high C4d and TCC (>31 arbitrary units/mL) were associated with increased 30-day mortality (hazard ratio [HR] 3.26, 95% CI 1.56-6.81 and HR 5.12, 95% CI 2.15-12.23, respectively). High levels of both C4d and TCC demonstrated a negative predictive value of 0.87. In conclusion, we found that in patients with NSTI, complement activation correlated with the severity of the disease. High baseline C4d and combination of high C4d and TCC are associated with increased 30-day mortality. Low baseline C4d or TCC indicates a higher probability of survival.

KW - C4d

KW - Complement

KW - Necrotizing soft-tissue infection

KW - Sepsis

KW - Terminal complement complex

U2 - 10.1159/000520496

DO - 10.1159/000520496

M3 - Journal article

C2 - 34903692

AN - SCOPUS:85121452753

VL - 14

SP - 355

EP - 365

JO - Journal of Innate Immunity

JF - Journal of Innate Immunity

SN - 1662-811X

IS - 4

ER -