Lectin pathway of complement activation and relation with clinical complications in critically ill children

Abstract

Background:Critically ill children are susceptible to nosocomial infections, which contribute to adverse outcomes. Deficiencies in the innate immunity lectin pathway of complement activation are implicated in a child's vulnerability to infections in conditions such as cancer, but the role during critical illness remains unclear. We hypothesized that low on-admission levels of the pathway proteins are, in part, genetically determined and associated with susceptibility to infectious complications and adverse outcomes. Methods: We studied protein levels of mannose-binding lectin (MBL), H-ficolin and M-ficolin, three MBL-associatedserine proteases (MASPs) and MBL-associated protein (MAp44), and relation with functional genetic polymorphisms, in 130 healthy children and upon intensive care unit (ICU) admission in 700 critically ill children of a randomized study on glycemic control. results: Levels of MASP-1, MASP-2, MASP-3, and MAp-44 were lower and the levels of M-ficolin were higher in ICU patients on admission than those in matched healthy controls. Only a low on-admission MASP-3 level was independently associated with risk of new ICU infections and prolonged ICU stay, after correcting for other risk factors. On-admission MASP-3 varied with age, illness severity, and genetic variation. conclusion: Low on-admission MASP-3 levels in critically ill children were independently associated with subsequent acquisition of infection and prolonged ICU stay. The biological explanation needs further investigation.

The pattern recognition molecule collectin-L1 in critically ill children

“…A low MASP-3 concentration upon PICU admission was independently associated with a higher risk of infection in this model (OR: 0.701 (95% CI: 0.562-0.864), P = 0.001). This confirmed the association we previously observed for MASP-3, with an even lower odds ratio than in the model without CL-L1 (OR: 0.809 (95% CI: 0.675-0.959), P = 0.02) (17). The independent associations of CL-L1 and MASP-3 with infection were maintained with the addition of the interaction between both Articles protein concentrations to the model, with a P value of 0.06 for the interaction variable ( Table 2).…”

“…As for risk of infection, this association was in the opposite direction as that for MASP-3, showing a higher likelihood of earlier alive discharge at any time with a higher MASP-3 concentration (hazard ratio (HR) of 1.125 (95% CI: 1.046-1.205, P = 0.001). Again, this association was stronger than for the model without CL-L1 that was previously reported (HR: 1.088 (95% CI: 1.020-1.157), P = 0.01) (17). Addition of the interaction between both proteins had no major effect, with a P value of 0.92 for the interaction variable ( Table 3).…”

“…Moreover, several components display context specific properties, where they can act as dual function surveillance molecules, suppressing or enhancing inflammation, as, e.g., shown for the lung collectins (27,28). Therefore, we also corrected for the other lectin pathway proteins for which the concentrations upon PICU admission had been measured (17). These analyses revealed independent associations with infection and ICU stay for both CL-L1 and MASP-3.…”

“…We previously studied MBL, M-and H-ficolin, and their MBL-associated serine proteases (MASPs) in a large group of critically ill children (17). Serum concentrations of these proteins were lower in critically ill children upon admission to the pediatric intensive care unit (PICU) as compared with agematched healthy controls, except for higher concentrations of M-ficolin.…”

Mannose-Binding Lectin Levels in Critically Ill Children With Severe Infections*

“…However, other studies in adults have not found MBL to be associated with risk for sepsis (39–42) or have reported a more nuanced picture that includes a mixture of both pro-inflammatory and anti-infection effects which may be beneficial or detrimental in varying disease states. (33, 34, 43) Specifically in pediatrics, six studies have demonstrated an association between lower MBL levels, or low-MBL producing haplotypes, and increased severity of infection-related disease (4, 5, 15, 16, 44–46) while five studies showed similar findings to ours with a lack of association (12, 46–50) and two studies concluded a possible protective role for low-producing MBL genotypes or levels. (12, 51)…”