Complement activation in relation to capillary leakage in children with septic shock and purpura

Abstract

To assess the relationship between capillary leakage and inflammatory mediators during sepsis, blood samples were taken on hospital admission, as well as 24 and 72 h later, from 52 children (median age, 3.3 years) with severe meningococcal sepsis, of whom 38 survived and 14 died. Parameters related to cytokines (interleukin 6 [IL-6] IL-8, plasma phospholipase A2, and C-reactive protein [CRP]), to neutrophil degranulation (elastase and lactoferrin), to complement activation (C3a, C3b/c, C4b/c, and C3- and C4-CRP complexes), and to complement regulation (functional and inactivated C1 inhibitor and C4BP) were determined. The degree of capillary leakage was derived from the amount of plasma infused and the severity of disease by assessing the pediatric risk of mortality (PRISM) score. Levels of IL-6, IL-8, C3b/c, C3-CRP complexes, and C4BP on admission, adjusted for the duration of skin lesions, were significantly different in survivors and nonsurvivors (C3b/c levels were on average 2.2 times higher in nonsurvivors, and C3-CRP levels were 1.9 times higher in survivors). Mortality was independently related to the levels of C3b/c and C3-CRP complexes. In agreement with this, levels of complement activation products correlated well with the PRISM score or capillary leakage. Thus, these data show that complement activation in patients with severe meningococcal sepsis is associated with a poor outcome and a more severe disease course. Further studies should reveal whether complement activation may be a target for therapeutical intervention in this disease.

FIG. 1

C3b/c levels on admission versus the time between the onset of petechiae and the moment of blood sampling in surviving (open circles) and nonsurviving (solid circles) patients. The lines represent least-squares regression lines of the two groups (upper line, survivors; lower line, nonsurvivors). The angles of inclination of the regression lines do not differ significantly. Time-adjusted C3b/c values were on average 2.2 times higher in nonsurvivors (P = 0.004).

FIG. 2

C3-CRP complex levels versus C3b/c levels on admission in surviving (open circles) and nonsurviving (solid circles) patients show a dichotomous distribution (dotted lines represent medians). Both variables were independently related to survival.

FIG. 3

C3a levels on admission versus PRISM score in surviving (open circles) and nonsurviving (solid circles) patients. The dotted line represents the upper level of normal. The solid line represents the least-squares regression line for all data points (r = 0.69; P < 0.001).

FIG. 4

Total amount of plasma infused (in milliliters per kilogram of body weight [BW]) versus the weighted sum of the initial levels of C3a and C4BP [73.1 × (log₁₀C3a) − 1.0 × C4BP] in surviving (open circles) and nonsurviving (solid circles) patients. The line represents the least-squares regression line for all data points (r = 0.77; P < 0.001).

FIG. 5

Arterial lactate (in millimoles per liter) on admission versus the weighted sum of the initial levels of C3a, elastase, and lactoferrin [0.142 × (log₁₀C3a) + 0.280 × (log₁₀elastase) + 0.257 × (log₁₀lactoferrin)] in surviving (open circles) and nonsurviving (solid circles) patients. The line represents the least-squares regression line for all data points (r = 0.78; P < 0.001).

FIG. 6

Initial C4b/c values versus C3a levels in surviving (open circles) and nonsurviving (solid circles) patients (for all patients, r = 0.58 and P < 0.001).