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

Abstract

Citation: Kristensen MK, Hansen MB, Madsen MB, Hansen CB, Pilely K, Hyldegaard O and Garred P (2020) Complement Activation Is Associated With Mortality in Patients With Necrotizing Soft-Tissue Infections-A Prospective Observational Study. 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.

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

“…We evaluated different complement activation products at the C4, C3, and terminal levels. Earlier, in a smaller part of the present cohort, we have demonstrated that consumption of molecules, particularly from the lectin pathway and other downstream molecules, were associated with increased risk of death, contrasting to patients capable of maintaining high circulating levels of complement molecules [19, 20]. Of particular relevance, we have previously reported high C4 to be associated with improved survival [20], and in that context, we demonstrated in the present and larger cohort a high C4d to be associated with increased mortality.…”

“…Earlier, in a smaller part of the present cohort, we have demonstrated that consumption of molecules, particularly from the lectin pathway and other downstream molecules, were associated with increased risk of death, contrasting to patients capable of maintaining high circulating levels of complement molecules [19, 20]. Of particular relevance, we have previously reported high C4 to be associated with improved survival [20], and in that context, we demonstrated in the present and larger cohort a high C4d to be associated with increased mortality. Interestingly, we have earlier found a high level of C3bc at admission to be associated with increased mortality, but this was not mirrored in the present analyses, showing no statistical association to death.…”

“…Of these, 50 were monomicrobial infections. Patients with Group A Streptococcus NSTI had significantly higher baseline TCC than in other type of microbiological NSTIs (19 AU [IQR [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] 41 (17,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) Continuous data are presented as medians (IQR) and categorical data as absolute n (percentage, %). Blood samples were obtained at arrival to a specialized hospital.…”

Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections

“…The development of rapid diagnostic tools for NSTI, such as levels of disease-associated biomarkers, to support clinical decisions could increase the accuracy of early diagnosis, leading to swifter surgical exploration and treatment only when clinically indicated. However, to date, there are only a few studies of molecular biomarkers in NSTIs (22,(28)(29)(30)(31)(32), and these are limited to analyses of only a few markers. The comprehensive multiplex analysis of 36 analytes conducted here revealed, as expected, a greater systemic inflammatory response in NSTI patients than in noninfected patients (surgical controls).…”

Complement in sepsis—when science meets clinics

“…The anaphylatoxin production in particular seems to be associated with a bad outcome [55][56][57][58][59][60][61][62]. In patients suffering from necrotizing soft tissue infections with or without septic shock, complement activation was evident and high levels of the C4c/C4 ratio, C3bc, and the C3bc/C3 ratio were associated with an enhanced long-term mortality [63]. Patients with severe tissue trauma also exhibited enhanced C3a and C5a plasma levels especially when they developed septic complications [64,65].…”