Neonatal Gram Negative and Candida Sepsis Survival and Neurodevelopmental Outcome at the Corrected Age of 24 Months

Objectives

To evaluate the long term neurodevelopmental outcome of premature infants exposed to either gram- negative sepsis (GNS) or neonatal Candida sepsis (NCS), and to compare their outcome with premature infants without sepsis.

Methods

Historical cohort study in a population of infants born at <30 weeks gestation and admitted to the Neonatal Intensive Care Unit (NICU) of the Academic Medical Center in Amsterdam during the period 1997–2007. Outcome of infants exposed to GNS or NCS and 120 randomly chosen uncomplicated controls (UC) from the same NICU were compared. Clinical data during hospitalization and neurodevelopmental outcome data (clinical neurological status; Bayley –test results and vision/hearing test results) at the corrected age of 24 months were collected. An association model with sepsis as the central determinant of either good or adverse outcome (death or severe developmental delay) was made, corrected for confounders using multiple logistic regression analysis.

Results

Of 1362 patients, 55 suffered from GNS and 29 suffered from NCS; cumulative incidence 4.2% and 2.2%, respectively. During the follow-up period the mortality rate was 34% for both GNS and NCS and 5% for UC. The adjusted Odds Ratio (OR) [95% CI] for adverse outcome in the GNS group compared to the NCS group was 1.4 [0.4–4.9]. The adjusted ORs [95% CI] for adverse outcome in the GNS and NCS groups compared to the UC group were 4.8 [1.5–15.9] and 3.2 [0.7–14.7], respectively.

Conclusions

We found no statistically significant difference in outcome at the corrected age of 24 months between neonatal GNS and NCS cases. Suffering from either gram –negative or Candida sepsis increased the odds for adverse outcome compared with an uncomplicated neonatal period.     

Proinflammatory effects of IL-10 during human endotoxemia

IL-10 is considered a potent antiinflammatory cytokine that strongly inhibits the production of proinflammatory cytokines. Recent studies have suggested that IL-10 also has immunostimulatory properties on CD4+, CD8+ T cells, and/or NK cells, resulting in increased IFN-gamma production. To determine the effect of IL-10 on IFN-gamma production and related inflammatory responses in humans, 16 healthy subjects received a bolus i.v. injection of LPS (4 ng/kg) in combination with either placebo or recombinant human IL-10 (25 microg/kg), administered just before or 1 h after LPS. IL-10 treatment, particularly when administered after LPS, enhanced LPS-induced IFN-gamma release, as well as the release of the IFN-gamma-dependent chemokines IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma, while inhibiting or not influencing the production of IFN-gamma-inducing cytokines. In addition, IL-10 treatment enhanced activation of CTLs and NK cells after LPS injection, as reflected by increased levels of soluble granzymes. These data indicate that high-dose IL-10 treatment in patients with inflammatory disorders can be associated with undesired proinflammatory effects.     

Alterations in lipoprotein homeostasis during human experimental endotoxemia and clinical sepsis

Cell wall constituents of bacteria are potent endotoxins initiating inflammatory responses which may cause dramatic changes in lipid metabolism during the acute phase response. In this study, the sequential changes in lipoprotein composition and lipid transfer and binding proteins during clinical sepsis and during low-dose experimental endotoxemia were followed. In addition, the effect on (phospho)lipid homeostasis by administration of reconstituted HDL (rHDL) prior to low-dose LPS administration was investigated. Changes in (apo)lipoprotein concentrations typical of the acute phase response were observed during clinical sepsis and experimental endotoxemia with and without the rHDL intervention. During clinical sepsis negative correlations between the acute phase marker C-reactive protein (CRP) and lecithin:cholesterol acyltransferase (LCAT) and cholesterylester transfer protein (CETP) activities were seen, whereas positive correlations between plasma phospholipid transfer protein (PLTP) activity and acute phase markers such as CRP and LPS binding protein were observed. Plasma lipid changes upon rHDL/LPS infusion were comparable with the control group (low-dose LPS only). PLTP activity decreased upon LPS infusion and transiently increased during rHDL infusion, whereas LCAT activity slightly decreased upon both LPS infusion and LPS/rHDL infusion. However, long-lasting increases of circulating HDL cholesterol, apo A-I and a high initial processing of both phosphatidylcholine (PC) and lyso-PC, were indicative for extensive rHDL and LDL remodelling. Both sepsis and experimental endotoxemia lead to a disbalance of lipid homeostasis. Depending on the magnitude of the inflammatory stimulus, LCAT and PLTP activities reacted in divergent ways. rHDL infusion did not prevent the lipid alterations seen during the acute phase response. However profound changes in both HDL and LDL phospholipid composition occurred upon rHDL infusion. This may be explained, at least in part, by the fact that PLTP as a positive acute phase protein, can accelerate the alterations in (phospho)lipid homeostasis thereby playing a role in the attenuation of the acute phase response.