Kirstin Faust

Risk for late-onset blood-culture proven sepsis in very-low-birth weight infants born small for gestational age: a large multicenter study from the German Neonatal Network.

Background: It was the aim of this study to assess whether very-low-birth-weight (VLBW) infants born small for gestational age (SGA; birth weight less than 10th percentile) are at increased risk for late-onset sepsis. Methods: This was a prospective, multicenter study of the German Neonatal Network including VLBW infants from 23 to < 32 weeks post menstrual age born 2009–2011. Outcomes were compared between VLBW infants born SGA (birth weight less than tenth percentile according to gestational age and gender) and non-SGA infants. The main outcome measure was at least 1 episode of late-onset sepsis defined as blood-culture–confirmed clinical sepsis occurring at ≥72 hours of age. Results: 5886 VLBW infants were included. In SGA infants (n = 692), an increased incidence of late-onset sepsis was noted compared with non-SGA infants (20.1% vs. 14.3 %, P < 0.001). This difference was only observed among infants with a gestational age of 27 to < 32 weeks and attributed to sepsis episodes with coagulase-negative staphylococci (12.8% vs. 8.3%, P < 0.001). Different treatment modalities (eg more frequent use of central venous lines) and longer duration of invasive therapies (parenteral nutrition, mechanical ventilation, hospitalization) may account for the increased sepsis risk with coagulase-negative staphylococci in our SGA cohort. In a multivariate logistic regression analysis, higher gestational age [per week; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.72–0.78, P< 0.0001], treatment with antenatal steroids (OR: 0.7, 95% CI: 0.53–0.92, P = 0.01), German descendance (OR: 0.76, 95% CI: 0.63–0.91, P = 0.003) and prophylaxis with glycopeptide antibiotics (OR: 0.64, 95% CI: 0.47–0.87, P = 0.005) were shown to be protective against late-onset sepsis. In contrast, longer duration of parenteral nutrition (per day; OR: 1.016, 95% CI: 1.011–1.021, P < 0.0001) and SGA were found to be risk factors (OR: 1.31, 95% CI: 1.02–1.68, P= 0.03). Conclusions: SGA contributes to the risk of late-onset sepsis in VLBW infants. Future studies are needed to investigate the underlying pathophysiology to guide individualized preventive measures in this vulnerable subgroup.

Short-term outcome of very-low-birthweight infants with arterial hypotension in the first 24 h of life

Objective To evaluate lowest mean arterial blood pressure during the first 24 h of life (minMAP24) in very-low-birthweight (VLBW) infants and to identify associations between hypotension and short-term outcome. Design Retrospective cohort analysis of the minMAP24 of 4907 VLBW infants with a gestational age <32 weeks in correlation with clinical data. Hypotension was defined as minMAP24 being lower than the median value of all patients of the same gestational age. Results MinMAP24 values correlated with gestational age. Median minMAP24 values of VLBW infants ≤29 weeks’ gestation were 1–2 mm Hg lower than gestational age in completed weeks. Hypotensive infants had a higher rate of intraventricular haemorrhage (IVH, 20.3% vs 15.9%, p<0.001), bronchopulmonary dysplasia (BPD, 19.2% vs 15.1%, p<0.001) and death (5.2% vs 3.0%, p<0.001). Multivariate logistic regression analyses, including potential confounders, confirmed these data. MinMAP24 was an independent risk factor for IVH (OR 0.97/mm Hg, 95% CI 0.96 to 0.99, p=0.003), BPD (OR 0.96/mm Hg, 95% CI 0.94 to 0.98, p<0.001) and mortality (OR 0.94/mm Hg, 95% CI 0.90 to 0.98, p=0.003). Conclusions Hypotension during the first 24 h of life is associated with adverse outcomes in VLBW infants. This underlines the need for randomised controlled trials on the use of vasoactive drugs in this vulnerable patient cohort.

Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

Introduction We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009–2010. Methods Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. Results In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01–55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% –6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient’s Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1–27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Discussion Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Intrauterine Growth Restriction and the Innate Immune System in Preterm Infants of ≤32 Weeks Gestation

Objective: Intrauterine growth restriction (IUGR) is a well-known cause of adverse neonatal outcomes. As it may have an impact on innate immune responses, we aimed to investigate several parameters of the innate immune response in preterm infants of ≤32 weeks gestation who were small for gestational age (SGA). Methods: We compared clinical data of SGA (n = 20) and appropriate for gestational age (AGA; n = 124) newborns with a gestational age of ≤32 weeks. We investigated full blood counts at birth and on days 3 and 7 of life and cytokine immune responses in a human whole cord blood assay. Results: SGA preterm infants had a higher risk of the combined outcome mortality or bronchopulmonary dysplasia. Numbers of white blood cells and neutrophils were diminished in SGA infants at birth and on day 3. At birth, platelet counts were also diminished while the number of nucleated red blood cells tended to be elevated in SGA infants. After stimulation of whole blood cell cultures with lipopolysaccharides, the concentrations of interleukin-6 and interleukin-10 were significantly lower in SGA preterm infants compared to AGA infants. Conclusions: SGA infants differ remarkably from AGA infants in full blood counts and in their ability to mount an immune response. Whether the quantitative deficiency in innate immunity plays a role for adverse outcomes needs to be investigated in larger future trials.

Galectin-3 in cord blood of term and preterm infants

In recent years galectin‐3 has gained attention as a signalling molecule, mainly in inflammatory diseases. Data on galectin‐3 expression in neonates, however, are limited, and expression of this lectin in cord blood has not yet been reported. The aim of this study was to determine galectin‐3 levels in cord blood of term and preterm neonates as well as galectin‐3 levels in cord blood of term neonates after stimulation with the prevalent pathogen Streptococcus agalactiae. Cord blood samples were incubated for 24 h and galectin‐3 levels were assessed by enzyme‐linked immunosorbent assay. There is a positive correlation between gestational age and galectin‐3 levels in cord blood. Expression of galectin‐3 is significantly higher in cord blood of small‐for‐gestational‐age infants compared to appropriate‐for‐gestational‐age infants. Stimulation with an invasive but not with a colonizing strain of S. agalactiae induced expression of galectin‐3. Galectin‐3 is expressed constitutively in cord blood of neonates and seems to play a role in the innate immunity of this population.

Tumor necrosis factor-α promoter -308 G/A polymorphism and susceptibility to sepsis in very-low-birth-weight infants.

Objectives:To determine whether the tumor necrosis factor-&agr; −308 G/A polymorphism is associated with blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. Design:Genetic association studies. Setting:Prospective, population-based, multicentered cohort of 1944 very-low-birth-weight infants born in 14 German study centers between 2003 and 2008 and 976 mothers, and a second prospective cohort of 926 very-low-birth-weight infants born in 2009 (German Neonatal Network). Measurements and Main Results:In cohort I, 344 of 1944 (18.2%) very-low-birth-weight infants had at least one episode of blood culture-proven sepsis develop. The sepsis incidence stratified to genotype was 19.3% for G/G, 15.8% for G/A, 10.0% for A/A genotype (Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.32; 95% confidence interval, 1.03–1.71; G/G vs. A/A: odds ratio, 1.74; 95% confidence interval, 1.06–2.91; p = .03). There was a trend for association of tumor necrosis factor-&agr; −308 A/G genotype with late-onset sepsis episodes (incidence: 17.2% for G/G, 12.5% for G/A, 10.0% for A/A genotype; Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.43; 95% confidence interval, 1.09–1.9; G/G vs. A/A: odds ratio, 2.05; 95% confidence interval, 1.19–3.56; p = .009). However, after adjustment for multiple testing, no significant associations were found. Furthermore, the genotype of the investigated 976 mothers had no impact on sepsis risk for their very-low-birth-weight infants. We additionally studied a second prospective cohort of 926 very-low-birth-weight infants and found no associations with sepsis risk. Conclusions:No association was found between the tumor necrosis factor-&agr; −308 G/A polymorphism blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. A recent meta-analysis demonstrated that the tumor necrosis factor-&agr; −308 A allele is associated with higher sepsis risk in adult cohorts. Thus, potential differences between adults and infants need to be incorporated in future study designs evaluating risk profiles for sepsis.

The modulatory effect of lipids and glucose on the neonatal immune response induced by Staphylococcus epidermidis

BackgroundParenteral nutrition is an important risk factor for late onset sepsis in neonates. This may be caused by the long-term need of central venous access but also through a potentially modulating effect of lipids and glucose on the immune function.ObjectiveIt was the aim of this study to characterize the effect of lipids and glucose on the neonatal immune response in an in vitro Staphylococcus epidermidis sepsis model using whole cord blood of healthy term infants and preterm infants.ResultsAt the single cell level, IL-6, IL-8 and TNF-α expression of CD14+ cells was significantly increased upon addition of 1% lipids, while the addition of clinically meaningful lipid concentrations had no remarkable effect. When glucose was added to whole cord blood cultures, a dose-dependent effect was demonstrated for IL-8 expression but not for other cytokines.ConclusionsThese in vitro data suggest that the pro-inflammatory cytokine response to S. epidermidis may be modulated by lipids and glucose. Further studies are needed to investigate whether these findings are applicable to clinical settings and to evaluate the role of cytokine monitoring in infants receiving long-term parenteral nutrition.

Differential expression of antimicrobial polypeptides in cord blood samples of preterm and term infants

To determine levels of antimicrobial polypeptides (AMP) in cord blood of term and preterm neonates and to investigate influencing factors.

Thalidomide has anti-inflammatory properties in neonatal immune cells.

Neonates demonstrate functional immaturity and dysregulation of immune responses leading to systemic inflammation and enhanced apoptosis of immune cells. Thalidomide has already been proven to differentially regulate immune responses and support anti-apoptosis in immunodeficiency syndromes. Thus, it was the aim of this study to evaluate the effects of thalidomide on the cytokine response and apoptosis of neonatal immune cells. After whole blood culture and stimulation of cord and adult blood samples, the intracytoplasmic expression and the secreted amounts of IL-2, TNF-α, IFN-γ, IL-6, IL-10 and IL-8 were assessed by flow cytometry and Cytokine Bead Array. Apoptosis was detected using Annexin-V staining. Bcl-2 expression was analysed using the Cytokine Bead Array Apoptosis Kit. Exposure to thalidomide (100 µg/ml) reduced the intracytoplasmic pro-inflammatory cytokine production of neonatal monocytes and the IFN-γ production of neonatal lymphocytes. In supernatants, the addition of thalidomide resulted in reduction of TNF-α, IL-6, IL-10 and, by trend, IFN-γ. While stimulated neonatal lymphocytes exhibited susceptibility to apoptosis, thalidomide tended to diminish apoptotic cells. Bcl-2 expression tended to be increased after addition of thalidomide. The potent anti-inflammatory effects of thalidomide and its anti-apoptotic properties in cord blood immune cells provide the basis for future strategies to optimise treatment of neonatal infections and immunodeficiency syndromes.

Successful use of recombinant factor VIIa in a preterm infant with life-threatening haematuria.

We report the case of a preterm male infant with a gestational age of 28 + 1 weeks and birth weight of 715 g who presented with life-threatening haematuria on day 28 of life. The haematuria was unresponsive to administration of platelet concentrates and fresh frozen plasma, but then successfully treated with recombinant factor VIIa. The resulting obstructive uropathy was managed by continuous bladder irrigation through suprapubic and urethral catheters. No other adverse affects were noted, and the boy was discharged from the hospital on day 108 of life.