Complement Activation Is Associated With Mortality in Patients With Necrotizing Soft-Tissue Infections-A Prospective Observational Study

Markus Korsholm Kristensen, Marco Bo Hansen, Martin Bruun Madsen, Cecilie Bo Hansen, Katrine Pilely, Ole Hyldegaard, Peter Garred, Markus Korsholm Kristensen, Marco Bo Hansen, Martin Bruun Madsen, Cecilie Bo Hansen, Katrine Pilely, Ole Hyldegaard, Peter Garred

Abstract

Aim: We assessed whether different complement factors and complement activation products were associated with poor outcome in patients with necrotizing soft-tissue infection (NSTI). Methods: We conducted a prospective, observational study in an intensive care unit where treatment of NSTI is centralized at a national level. In 135 NSTI patients and 65 control patients, admission levels of MASP-1, MASP-2, MASP-3, C4, C3, complement activation products C4c, C3bc, and terminal complement complex (TCC) were assessed. Results: The 90-day mortality was 23%. In a Cox regression model adjusted for sex, and SAPS II, a higher than median MASP-1 (HR 0.378, CI 95% [0.164-0.872], p = 0.0226) and C4 (HR 0.162, 95% CI [0.060-0.438], p = 0.0003), C4c/C4 ratio (HR 2.290 95% CI [1.078-4.867], p = 0.0312), C3bc (HR 2.664 95% CI [1.195-5.938], p = 0.0166), and C3bc/C3 ratio (HR 4.041 95% CI [1.673-9.758], p = 0.0019) were associated with 90-day mortality, while MASP-2, C4c, C3, and TCC were not. C4 had the highest ROC-AUC (0.748, [95% CI 0.649-0.847]), which was comparable to the AUC for SOFA score (0.753, [95% CI 0.649-0.857]), and SAPS II (0.862 [95% CI 0.795-0.929]). Conclusion: In adjusted analyses, high admission levels of the C4c/C4 ratio, C3bc, and the C3bc/C3 ratio were significantly associated with a higher risk of death after 90 days while high admission levels of MASP-1 and C4 were associated with lower risk. In this cohort, these variables are better predictors of mortality in NSTI than C-reactive protein and Procalcitonin. C4's ability to predict mortality was comparable to the well-established scoring systems SAPS score II and SOFA on day 1.

Trial registration: ClinicalTrials.gov NCT02180906.

Keywords: amputation; immune system; necrotizing fasciitis; sepsis; soft tissue infection; survival complement activation.

Copyright © 2020 Kristensen, Hansen, Madsen, Hansen, Pilely, Hyldegaard and Garred.

Figures

Figure 1
Figure 1
Flowchart of patient inclusion. NSTI, necrotizing soft-tissue infection. The figure is adapted from Figure 1 in Hansen et al. (19).
Figure 2
Figure 2
Receiver operating characteristic curves for predicting the 90-day mortality in necrotizing soft-tissue infection patients for (A) MASP-1, MASP-2, and MASP-3. (B) C4, C4c, and C4c/C4. (C) C3, C3bc, and C3bc/C3. (D) Sequential Organ Failure Assessment and score day 1 (SOFA), Simplified Acute Physiology Score II (SAPS II), and the terminal complement complex (TCC). (E) Arterial pH, base excess, and lactate.

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