The impaired infection control related to the functional immaturity of the neonatal immune system is an important cause of infection in preterm newborns. We previously reported that constitutive Toll-like receptor (TLR) 4 expression and cytokine secretion on lipopolysaccharide (LPS) stimulation increases with gestational age. Here, we analyzed constitutive monocyte TLR2 expression and evaluated the expression profiles of the proximal downstream adapter molecule myeloid differentiation factor 88 (MyD88). We further investigated activation of protein kinases p38 and extracellular regulated kinsase (ERK) 1/2 in CD14 monocytes after ex vivo stimulation with bacterial TLR ligands (LPS and lipoteichoic acid [LTA]). The functional outcome of the stimulation was determined by cytokine secretion. Monocytes from 31 preterm newborns (<30 weeks of gestation, n=16; 30-37 weeks of gestation, n=15), 10 term newborns, and 12 adults were investigated. In contrast to TLR4 expression, TLR2 levels did not differ between age groups. However, MyD88 levels were significantly lower in preterm newborns. Activation of p38 and ERK1/2 was impaired in all newborn age groups after stimulation with TLR-specific ligands. Accordingly, after LTA stimulation, the levels of interleukin (IL)-1 beta , IL-6, and IL-8 cytokine production were substantially lower (P<.001) in preterm newborns than in adults. The reduced functional response to bacterial cell wall components appears to be part of the functional immaturity of the neonatal immune system and might predispose premature newborns to bacterial infection.

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1␤, IL-6, and tumor necrosis factor-␣ secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response. (Pediatr Res 58: 121-124, 2005) Abbreviations CB, cord blood LPS, lipopolysaccharide PAMP, pathogen-associated molecular pattern PB, peripheral blood PBMC, peripheral blood mononuclear cells TLR, Toll-like receptor TNF, tumor necrosis factor VLBWI, very low birth weight infants Bacterial infections are a major cause of neonatal morbidity (1,2), and premature newborns are highly susceptible to infections (3). This increased susceptibility appears to be related to immaturity of the immune system. Maturation of the immune system includes specific humoral and cellular responses as well as nonspecific innate immune mechanisms, such as factors of the complement system and phagocyte activity (3-5).Monocytes and macrophages play a central role in both specific and nonspecific immunity against bacterial, viral, and fungal infection. In VLBWI, a substantial decrease of fully functional phagocytes has recently been reported (6). The Toll protein has been identified as a receptor controlling dorsoventral polarization during embryonic development of Drosophila larvae and serves a defensive function (7). Structures homologous to Toll receptors were found in mammalian cells (8,9) and termed TLR. Within the last few years, 10 human TLR have been described and characterized as important sensors of the innate immune system (9,10). These TLR are phylogenetically conserved and are involved in recognition of microbial PAMP. TLR4 functions as the transmembrane component of the LPS receptor. In addition to LPS, the major glycolipid component of the outer membrane of Gram-negative bacteria, TLR4 recognizes saturated and unsaturated fatty acids such as lipoteichoic acids from Gram-positive bacteria, and heat-shock proteins (8 -10). Binding of these ...

Background: A new mode of surfactant administration without intubation - less invasive surfactant administration (LISA) - has recently been described for premature infants. Objective: We report single-center outcome data of extremely premature infants who have been managed by LISA in our department. Mortality and morbidity rates of the cohort were compared to historical controls from our own center and to data of the Vermont-Oxford Neonatal Network (VONN). Patients and Methods: All infants born at 23-27 weeks' gestational age during 01/2009 and 06/2011 (n = 224) were managed by LISA and included in the study group. Results: LISA was tolerated by 94% of all infants. 68% of infants stayed on continuous positive airway pressure on day 3. The rate of mechanical ventilation was 35% within the first week and 59% during the entire hospital stay. Compared to historical controls, we found significantly higher survival rates (75.8 vs. 64.1%) and significantly less intraventricular hemorrhage (IVH) (28.1 vs. 45.9%), severe IVH (13.1 vs. 23.9%) and cystic periventricular leukomalacia (1.2 vs. 5.6%); only persistent ductus arteriousus (PDA) (74.7 vs. 52.6%) and retinopathy of prematurity (ROP) (40.5 vs. 21.1%) occurred significantly more often. Compared to VONN data, we found significantly less chronic lung disease (20.6 vs. 46.4%), severe cerebral lesions (IVH 3/4 + cystic PVL; 9.4 vs. 16.1%) and ROP (all grades) (40.5 vs. 56.5%); only PDA (74.7 vs. 63.1%) and severe ROP (> grade 2) (24.1 vs. 14.1%) occurred significantly more often in our cohort. Conclusion: Surfactant can be effectively and safely delivered via LISA and this is associated with low rates of mechanical ventilation and various adverse outcomes in extremely premature infants.

Results from the Austrian Toxoplasmosis Register show the efficiency of the prenatal screening program. Our results are of clinical relevance for infants, healthcare systems, and policy makers to consider preventive Toxoplasma screening as a potential tool to reduce the incidence of congenital toxoplasmosis.

BackgroundPrimary infection of Toxoplasma gondii during pregnancy can be transmitted to the unborn child and may have serious consequences, including retinochoroiditis, hydrocephaly, cerebral calcifications, encephalitis, splenomegaly, hearing loss, blindness, and death. Austria, a country with moderate seroprevalence, instituted mandatory prenatal screening for toxoplasma infection to minimize the effects of congenital transmission. This work compares the societal costs of congenital toxoplasmosis under the Austrian national prenatal screening program with the societal costs that would have occurred in a No-Screening scenario.Methodology/Principal findingsWe retrospectively investigated data from the Austrian Toxoplasmosis Register for birth cohorts from 1992 to 2008, including pediatric long-term follow-up until May 2013. We constructed a decision-analytic model to compare lifetime societal costs of prenatal screening with lifetime societal costs estimated in a No-Screening scenario. We included costs of treatment, lifetime care, accommodation of injuries, loss of life, and lost earnings that would have occurred in a No-Screening scenario and compared them with the actual costs of screening, treatment, lifetime care, accommodation, loss of life, and lost earnings. We replicated that analysis excluding loss of life and lost earnings to estimate the budgetary impact alone.Our model calculated total lifetime costs of €103 per birth under prenatal screening as carried out in Austria, saving €323 per birth compared with No-Screening. Without screening and treatment, lifetime societal costs for all affected children would have been €35 million per year; the implementation costs of the Austrian program are less than €2 million per year. Calculating only the budgetary impact, the national program was still cost-saving by more than €15 million per year and saved €258 million in 17 years.Conclusions/SignificanceCost savings under a national program of prenatal screening for toxoplasma infection and treatment are outstanding. Our results are of relevance for health care providers by supplying economic data based on a unique national dataset including long-term follow-up of affected infants.