Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia?

OBJECTIVE: To assess whether breastmilk feeding is associated with a reduced risk of bronchopulmonary dysplasia (BPD). Secondary outcome measures analyzed were retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC). STUDY DESIGN: In an ongoing multicenter cohort study, the data of 1433 very low birth weight infants born before 32 weeks of gestation and discharged in 2013 were analyzed. We compared growth and neonatal complications of infants who received breastmilk exclusively (N = 223) with those who received formula feedings exclusively (N = 239). Logistic regression models were estimated for BPD, ROP, and NEC using nutrition as an independent variable. The Firth logistic regression model and Lasso were used for sensitivity analyses. RESULTS: Exclusively breastmilk-fed infants gained less weight compared with formula-fed infants. SDS for weight decreased between birth and discharge (median (Q1-Q3): formula -0.9 (-1.4 to [-0.5]) vs breastmilk -1.1 (-1.7 to [-0.6])). Exclusive formula feeding of very low birth weight infants was associated with increased risks of BPD (OR 2.6) as well as NEC (OR 12.6) and ROP (OR 1.80) after controlling for known risk factors. CONCLUSIONS: Exclusive breastmilk feeding was associated with lower growth rates and a reduced risk of BPD as well as NEC and ROP.

Preterm prelabor rupture of membranes and outcome of very-low-birth-weight infants in the German Neonatal Network.

OBJECTIVE: It was the aim of our study to evaluate the independent effect of preterm prelabor rupture of membranes (PPROM) as a cause of preterm delivery on mortality during primary hospital stay and significant morbidities in very-low-birth-weight (VLBW) infants < 32 weeks of gestation. DESIGN: Observational, epidemiological study design. SETTING: Population-based cohort, German Neonatal Network (GNN). POPULATION: 6102 VLBW infants were enrolled in GNN from 2009-2012, n=4120 fulfilled criteria for primary analysis (< 32 gestational weeks, no pre-eclampsia, HELLP (highly elevated liver enzymes and low platelets syndrome) or placental abruption as cause of preterm birth). METHODS: Multivariable logistic regression analyses included PPROM as potential risk factors for adverse outcomes and well established items such as gestational age in weeks, birth weight, antenatal steroids, center, inborn delivery, multiple birth, gender and being small-for-gestational-age. RESULTS: PPROM as cause of preterm delivery had no independent effect on the risk of early-onset sepsis, clinical sepsis and blood-culture proven sepsis, while gestational age proved to be the most important contributor to sepsis risk. The diagnosis of PPROM was associated with an increased risk for bronchopulmonary dysplasia (BPD; OR: 1.25, 95% CI: 1.02-1.55, p=0.03) but not with other major outcomes. CONCLUSIONS: The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM.

Prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics and outcome in very low birth weight infants.

OBJECTIVE: To evaluate outcome data in an observational cohort of very low birth weight infants of the German Neonatal Network stratified to prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics. STUDY DESIGN: Within the observational period (September 1, 2010, until December 31, 2012, n=5351 infants) study centers were categorized into 3 groups based on their choice of Lactobacillus acidophilus/Bifidobacterium infantis use: (1) no prophylactic use (12 centers); (2 a/b) change of strategy nonuser to user during observational period (13 centers); and (3) use before start of observation (21 centers). Primary outcome data of all eligible infants were determined according to center-specific strategy. RESULTS: The use of probiotics was associated with a reduced risk for necrotizing enterocolitis surgery (group 1 vs group 3: 4.2 vs 2.6%, P=.028; change of strategy: 6.2 vs 4.0%, P<.001), any abdominal surgery, and hospital mortality. Infants treated with probiotics had improved weight gain/day, and probiotics had no effect on the risk of blood-culture confirmed sepsis. In a multivariable logistic regression analysis, probiotics were protective for necrotizing enterocolitis surgery (OR 0.58, 95% CI 0.37-0.91; P=.017), any abdominal surgery (OR 0.7, 95% CI 0.51-0.95; P=.02), and the combined outcome abdominal surgery and/or death (OR 0.43; 95% CI 0.33-0.56; P<.001). CONCLUSIONS: Our observational data support the use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics to reduce the risk for gastrointestinal morbidity but not sepsis in very low birth weight infants.

The relationship between advances in understanding the microbiome and the maturing hygiene hypothesis.

Expanding knowledge about an interaction of the bacterial colonization with pathogenic and non-pathogenic bacteria and the human immune system leads to speculation on potential effects on health and disease. Recent advances in sequencing technologies and new bioinformatic possibilities now allow investigating the microbes that colonize the human gut, skin and airways in more detail. In light of the hygiene hypothesis, the impact of the microbial composition of individuals with allergic sensitization and/or atopic diseases, i.e., allergic asthma or atopic eczema, were investigated in several clinical trials. Altered diversity of gut microbiota during infancy as well as colonization with specific pathogenic and apathogenic bacteria has been linked with an elevated risk for allergy. There are ongoing attempts to establish intervention strategies aimed at modifying initial colonization patterns in early life. While results from animal models, in-vitro data and epidemiological studies encourage the concept of a relationship between the microbiome and the development of allergic diseases, the transfer of these findings to intervention strategies still seems to be a major challenge.

Transient impact of omalizumab in pollen allergic patients undergoing specific immunotherapy.

BACKGROUND: Recently, we showed that combination of omalizumab with specific immunotherapy (SIT) for treatment of patients with seasonal allergic rhinitis (SAR) and comorbid seasonal allergic asthma (SAA) is safe and reduced the symptom load in a statistically significant and clinically meaningful manner during the first pollen season. OBJECTIVE: The aim of this study was to investigate long-lasting effects of an initial combination treatment with SIT+omalizumab, a monoclonal anti-IgE antibody, in a follow-up period with SIT treatment only in patients with SAR and comorbid SAA incompletely controlled by conventional pharmacotherapy. METHODS: A randomized, double-blind, placebo-controlled, multicenter trial was performed to assess the efficacy and safety of omalizumab (Xolair(®)) vs. placebo in combination with SIT (depigmented allergoid vaccine, Depigoid(®)) during the first grass pollen season. Omalizumab or placebo therapy was started 2 wk before SIT; the whole treatment lasted 18 wk. After the first pollen season, SIT was given for two subsequent years without omalizumab. Primary end-point was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use in the second and third year. RESULTS: A total of 140 patients (age 11-46 yr) were randomized; 130, 128, and 114 patients finished the study after 1, 2, and 3 yr, respectively. The main efficacy variable was the mean daily symptom load as assessed in the patients' diary. No systematic differences between both analysis groups were detected in the findings from symptom load, symptom severity score, or rescue medication score. Further subjective data did not show differences between both groups in the quality-of-life data as assessed with the ACQ, AQLQ, and the RQLQ. Investigators' assessment of treatment effectiveness in the first and second year of study extension showed more patients with favorable long-term treatment outcome ('excellent' and 'good') in the SIT plus omalizumab group than in the SIT plus placebo group. In line with these findings, FEV1 improved at the end of both years in the group which was treated with the combination therapy in the double-blind study compared with the Depigoid plus placebo group. CONCLUSION: Eighteen weeks' treatment of omalizumab in combination with SIT in patients with SAR and comorbid SAA reduced the symptom load during the treatment period but showed no prolonged effect during treatment with SIT only. A slight increase in lung function (FEV1) in patients formerly treated with the omalizumab/SIT combination therapy should encourage further evaluation of long-term effects of omalizumab.

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.

Innate immune responses to Stenotrophomonas maltophilia in immunocompromised pediatric patients and the effect of taurolidine.

BACKGROUND: Stenotrophomonas maltophilia is an emerging pathogen causing invasive infections in immunocompromised pediatric patients, including neonates and pediatric oncology patients. Information on innate immune responses to S. maltophilia and its potential modulation are scarce. METHODS: We established an in vitro S. maltophilia whole blood sepsis model and studied the proinflammatory cytokine production of CD14-positive cells by flow cytometry. We compared the cytokine expression of term newborns (n = 13) and healthy adults (n = 10) and investigated in vitro responses of pediatric oncology patients after recovery from neutropenia (n = 10) with healthy adults (n = 10). We further evaluated the immunomodulatory role of the amino-acid derivative taurolidine in our in vitro sepsis model. RESULTS: Proinflammatory cytokine responses to S. maltophilia were largely diminished in the neonatal population. No remarkable differences were noted for cytokine responses between pediatric oncology patients and healthy controls. Taurolidine inhibited immunoglobulin (IL)-6, IL-8 and tumor necrosis factor-alpha expression in a dose dependent-fashion in both, pediatric oncology patients and healthy controls. CONCLUSION: Deficient immune responses to S. maltophilia require optimized prevention strategies against infection in immunocompromised patients, including neonates. Taurolidine may be an effective immunomodulatory agent in a clinical setting.

Intrapartum colonization with Streptococcus pneumoniae, early-onset sepsis and deficient specific neonatal immune responses.

BACKGROUND: Intrapartum colonization with Streptococcus pneumoniae (S. pneumoniae) is a rare but important risk factor for severe courses of early-onset sepsis (EOS) in the newborn, as underlined in the case of a preterm infant born after 32 weeks of gestation described here. One potential explanation could be an immature immune response of the neonate to S. pneumoniae, however, immunological data in term and preterm infants are scarce. METHODS: To determine the neonatal immune responses to S. pneumoniae, flow-cytometry analysis of the cytokine production by CD14+ cells was performed after full pathogen stimulation with S. pneumoniae (serotype 18C, derived from an EOS case described here) of cord blood of 10 term (37-41 gestational weeks) and 6 preterm (31-32 gestational weeks) neonates, compared to peripheral venous blood samples of 10 healthy adults in vitro. RESULTS: Neonatal cytokine responses of term and preterm infants to S. pneumoniae are diminished compared to adults. The quantities of cytokine expression were comparable to immune responses induced by other important gram-positive pathogens of EOS such as Streptococcus agalacticae. CONCLUSION: Severe courses of EOS with S. pneumoniae may be attributed to remarkable deficiencies of the specific neonatal immune response. To protect the neonate from invasive pneumococcal disease, maternal immunization may be an important prevention strategy, as protective antibodies can be transferred through the placenta and vaccination of pregnant women may reduce colonization.

Influence of different intravenous lipid emulsions on hepatobiliary dysfunction in a rabbit model.

OBJECTIVES: Long-term total parenteral nutrition (TPN) in children is often complicated by the development of cholestasis, liver fibrosis, and liver failure. High doses of intravenous lipids may be involved in the pathogenesis of hepatobiliary dysfunction. The purpose of this study was to determine whether the use of 2 newly developed lipid emulsions could reduce liver damage. MATERIALS AND METHODS: Three groups of prepubescent rabbits received TPN including a lipid emulsion either based on soybean oil, olive oil, or soybean oil with n-3 fatty acids added. Enterally fed animals served as controls. After 21 d the animals were killed. Serum samples were obtained at the beginning and end of the study period. Specimens were processed for histological evaluation using a specific score to assess the severity of liver damage. RESULTS: Biochemical parameters did not predict the extent of liver damage. Hydropic degeneration as an indicator of toxic liver injury was the predominant histological alteration regardless of the type of lipids infused. The extent of fibrosis did not significantly differ among treatment groups except for animals infused with n-3 fatty acids exhibiting increased fibrotic transformation as compared with controls. CONCLUSION: In our animal model, the use of a lipid emulsion with a reduced amount of polyunsaturated fatty acids was not superior to a lipid emulsion based on soybean oil. Long-term application of n-3 fatty acids was associated with more extensive fibrosis. Therefore, intravenous n-3 fatty acids containing lipid preparations (fish oil) should not be used in patients for long-term TPN.