Jürgen Seidenberg

Mutations of Genes Involved in the Innate Immune System as Predictors of Sepsis in Very Low Birth Weight Infants

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the −159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture–proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture–proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7–6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0–3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0–10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5%versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial

BACKGROUND Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING Deutsche Forschungsgemeinschaft.

Hypoxaemia after nebulised salbutamol in wheezy infants: the importance of aerosol acidity.

The effect of nebulised iso-osmolar, preservative free, but acidic salbutamol solution was studied in 34 acutely wheezing infants aged 1-17 months. Transcutaneous oxygen pressure (TcPO2) and oxygen saturation (SO2) fell significantly during the first five minutes after nebulisation with further deterioration at 15-20 minutes. Ten of these infants were followed up for another two hours and showed slight improvement. Even after the second hour TcPO2 had not reached baseline values. Three months later the response to salbutamol and a placebo of equal acidity (pH 3.9) was studied in 11 infants from the same group, now free of symptoms. Lung function tests were included and showed no significant changes in specific conductance and volume corrected maximum expiratory flows (Vmax at functional residual capacity/thoracic gas volume). However, hypoxaemia occurred after the acidic placebo with a significant drop of TcPO2 (mean 0.9 kPa); SO2 decreased similarly but this did not reach significance. After salbutamol there was a further significant deterioration of mean TcPO2 (1.4 kPa) and of SO2. These results show that beside a possible pharmacological effect of salbutamol the acidity of the aerosol also induces hypoxaemia in infants.

Inhaled frusemide against cold air induced bronchoconstriction in asthmatic children.

Inhaled frusemide prevents bronchoconstriction in asthmatic adults induced by various triggers. To determine if frusemide provides similar protection in children, whether this is age dependent and equally effective for central and peripheral airways, we performed a double blind, placebo controlled, randomised, crossover study on the effect of inhaled frusemide on lung function changes induced by cold air challenge in 21 asthmatic children. In addition, we measured diuresis before and after inhalation. Bronchodilatation after frusemide was not observed. However, deterioration in lung function after frusemide, compared with placebo, was significantly diminished: forced expiratory volume in one second (FEV1) was -5.7% v -11.5%, peak expiratory flow (PEF) -7.7% v -23.3%, maximum expiratory flow at 50% of vital capacity (MEF50VC) -16.0% v -35.2%, and at 60% of total lung capacity (MEF60TLC) -32.4% v -61.6%, and specific airways conduction -42.0% v -57.7%, respectively. This effect was not age dependent. Diuresis was significantly increased from a mean (SEM) of 198 (34) ml/3 hours before inhaled frusemide to 379 (62) ml/3 hours after nebulisation. We conclude that inhaled frusemide prevents cold air induced bronchoconstriction in asthmatic children and that increased diuresis can be expected with a dose as low as 28 mg of frusemide given by nebuliser.

Assessment of Tidal Breathing Patterns for Monitoring of Bronchial Obstruction in Infants

ABSTRACT: Two parameters of tidal breathing, the ratio of time to reach peak tidal expiratory flow to the total expiratory time (Tme/TE) and the ratio of volume exhaled at peak tidal expiratory flow to the total exhaled volume (dV/VT) were used to assess lung function in 21 sedated infants (aged 6–14 mo) with different degrees of airway obstruction. These parameters were compared with airway resistance as percentage predicted (Raw%) and maximum expiratory flow at functional residual capacity corrected for lung volume (VmaxFRC/TGV) VmaxFRC/TGV values correlated significantly with Tme/TE (r = 0.630, p = 0.002) as well as with dV/VT (r = 0.728. p - 0.001). Raw% values showed only a weak correlation with dV/VT (r - - 0.435, p - 0.048). We conclude that Tme/Te and dV/VT are both able to detect airway obstruction in infants and that these parameters corrclate much better with the forced expiratory flow values obtained by the rapid thoracic compression method than with airway resistance, determined by body plethysmography.

Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.Food allergy is an increasing public health problem. In a genome-wide scan of children diagnosed by oral food challenge, Marenholz et al. find new genetic associations underlying food allergy, implicating the immune system and the epithelial barrier.

Comparison of Heliox and Oxygen as Washing Gases for the Nitrogen Washout Technique in Preterm Infants

The nitrogen washout technique usually involves exposure of the patient to 100% oxygen for several minutes. This may be dangerous in preterm infants who are at risk of retinopathy of prematurity (ROP). We wanted to know whether heliox (79% He, 21% O2) can be used instead of oxygen when determining functional residual capacity (FRC). FRC measurements were made in 14 preterm infants [median (range) gestational age at birth 34 wk (27-37 wk), and at time of study 36 wk (33-40 wk)] who were breathing room air. FRC was measured using a computerized infant pulmonary function system, beginning in random order with either 100% O2 followed by heliox or vice versa. There was no systematic difference between the two methods with regard to lung volume measurements: mean (SD) FRC values, corrected for body weight, were 22.9 (7.1) mL/kg for O2 and 23.4 (7.0) mL/kg for heliox. We did not observe a systematic influence of the type of washing gas used (heliox or oxygen) on FRC in these infants. Our results suggest that the use of heliox instead of pure oxygen may be a suitable and safer alternative for FRC measurements with the nitrogen washout technique in preterm infants who are breathing low concentrations of inspired oxygen and are still at risk of ROP.

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study

Background Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. Methods Infants (n=359) between 400 and 1000 g birth weight and 23 0/7–28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). Results There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60–96, high target) and 84 (58–96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57–100) and 84 (65–96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. Conclusions A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. Trial registration number ISRCTN56143743.

Evaluation of food allergy candidate loci in the Genetics of Food Allergy study

A recent genome-wide association study suggested novel candidate loci for food allergy. Apart from the established locus at 11q13, these revealed no association with food allergy in the Genetics Of Food Allergy Study.

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants

Background: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. Objectives: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. Methods: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. Results: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). Conclusions: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.