Peter Groneck

Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression.

Pulmonary alveolar proteinosis (PAP) is a heterogeneous disorder of genetic or acquired etiologies. In some cases congenital PAP is associated with hereditary surfactant protein (SP)-B deficiency. To date, the molecular defect in the majority of patients with PAP has not been identified. In mice, PAP has been generated by targeted deletion of the genes for either the GM-CSF/IL-3/IL-5 receptor common beta chain (beta c) or GM-CSF. Here, we describe an expression defect of beta c in three of seven pediatric patients with PAP and in one patient with severe lung disease suspected to be PAP. The patients failed to express normal levels of beta c as shown by flow cytometry. Strikingly reduced or absent function of beta c was demonstrated by ligand binding studies and progenitor clonogenic assays. Analysis of beta c DNA revealed a point mutation from proline to threonine at codon 602 in one patient. Our findings provide evidence that a defect in the expression of a hematopoietic cytokine receptor is associated with human PAP.

Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial.

BACKGROUND Surfactant is usually given to mechanically ventilated preterm infants via an endotracheal tube to treat respiratory distress syndrome. We tested a new method of surfactant application to spontaneously breathing preterm infants to avoid mechanical ventilation. METHOD In a parallel-group, randomised controlled trial, 220 preterm infants with a gestational age between 26 and 28 weeks and a birthweight less than 1·5 kg were enrolled in 12 German neonatal intensive care units. Infants were independently randomised in a 1:1 ratio with variable block sizes, to standard treatment or intervention, and randomisation was stratified according to centre and multiple birth status. Masking was not possible. Infants were stabilised with continuous positive airway pressure and received rescue intubation if necessary. In the intervention group, infants received surfactant treatment during spontaneous breathing via a thin catheter inserted into the trachea by laryngoscopy if they needed a fraction of inspired oxygen more than 0·30. The primary endpoint was need for any mechanical ventilation, or being not ventilated but having a partial pressure of carbon dioxide more than 65 mm Hg (8·6 kPa) or a fraction of inspired oxygen more than 0·60, or both, for more than 2 h between 25 h and 72 h of age. Analysis was by intention to treat. This study is registered, number ISRCTN05025922. FINDINGS 108 infants were assigned to the intervention group and 112 infants to the standard treatment group. All infants were analysed. On day 2 or 3 after birth, 30 (28%) infants in the intervention group were mechanically ventilated versus 51 (46%) in the standard treatment group (number needed to treat 6, 95% CI 3-20, absolute risk reduction 0·18, 95% CI 0·30-0·05, p=0·008). 36 (33%) infants in the intervention group were mechanically ventilated during their stay in the hospital compared with 82 (73%) in the standard treatment group (number needed to treat: 3, 95% CI 2-4, p<0·0001). The intervention group had significantly fewer median days on mechanical ventilation, (0 days. IQR 0-3 vs 2 days, 0-5) and a lower need for oxygen therapy at 28 days (30 infants [30%] vs 49 infants [45%], p=0·032) compared with the standard treatment group. We recorded no differences between groups for mortality (seven deaths in the intervention group vs five in the standard treatment group) and serious adverse events (21 vs 28). INTERPRETATION The application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving continuous positive airway pressure reduces the need for mechanical ventilation. FUNDING German Ministry of Research and Technology, University of Lübeck, and Chiesi Pharmaceuticals.

Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis.

Chorioamnionitis and funisitis are associated with preterm labor and postnatal morbidity. Activation of endothelium resulting in up-regulation of adhesion molecules seems to be a key mechanism in development of organ damage. We investigated whether chorioamnionitis with or without funisitis in preterm infants induced expression and shedding of adhesion molecules in the umbilical cord and resulted in increased concentrations of E-selectin, intercellular adhesion molecule (ICAM)-1, IL-1β, IL-6, and IL-8 in the cord blood. Data were obtained by using immunohistochemistry and ELISA. Thirty-two preterm infants were divided into three groups according to histology: chorioamnionitis with funisitis, chorioamnionitis without funisitis, and controls without signs of inflammation. ICAM-1 expression on arterial endothelium was higher with funisitis compared with chorioamnionitis alone or with the control group. Similar results for ICAM-1 expression were found in venous endothelium, vascular walls, Whartons jelly, and amnion epithelium. Endothelial E-selectin and vascular cell adhesion molecule (VCAM)-1 expression was only induced significantly with funisitis. Serum-concentrations of soluble ICAM-1 were higher with funisitis compared with chorioamnionitis alone or control group. Similarly, concentrations of soluble E-selectin, IL-1β, IL-6, and IL-8 were increased exclusively with funisitis. In conclusion, only chorioamnionitis with funisitis was associated with systemic inflammation and endothelial activation with up-regulation and shedding of umbilical cord adhesion molecules. We speculate that this activation of endothelium may not be limited to the umbilical cord but may also involve other organs resulting in neonatal morbidity. This underlines the importance of funisitis as a risk factor for adverse outcome.

Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 Are Highly Expressed in the Cerebrospinal Fluid of Premature Infants with Posthemorrhagic Hydrocephalus

The expression of specific growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) is of importance during brain development and in the pathogenesis of neurodegenerative disorders. VEGF and TGF-β1 was studied in the cerebrospinal fluid (CSF) of neonates with posthemorrhagic hydrocephalus (PHHC) and nonhemorrhagic hydrocephalus. For determining the interference of inflammatory cytokine interaction with the expression of VEGF and TGF-β1, IL-6 and IL-10 CSF concentrations were measured. Eighteen neonates who had PHHC and underwent serial reservoir puncture and nine neonates who had congenital nonhemorrhagic hydrocephalus (CHC) and underwent first shunt surgery were included in the study. CSF samples of 11 neonates with lumbar puncture for the exclusion of meningitis served as control subjects. VEGF, TGF-β1, IL-6, and IL-10 concentrations in the CSF were measured by ELISA technique. VEGF concentrations in the CSF of patients with PHHC were significantly higher (median: 377 pg/mL; range: 101–1301 pg/mL) when compared with patients with CHC (median: 66 pg/mL; range: 3–1991; p < 0.001) and control subjects (median: 2 pg/mL; range: 0–12 pg/mL; p < 0.0001). TGF-β1 CSF concentrations did not differ from control infants in all groups. Median IL-6 and IL-10 concentrations in the CSF were found to be low in all patient groups. Increased release of VEGF in the CSF of neonates with PHHC and nonhemorrhagic hydrocephalus may serve as an indicator of brain injury from progressive ventricular dilation. TGF-β1 CSF concentrations are not elevated in the phase of acute fibroproliferative reactions in patients with PHHC.

Oxygen radicals, cytokines, adhesion molecules and lung injury in neonates

Chronic lung disease of preterm infants (CLD) has a multifactorial aetiology. Pulmonary immaturity, oxygen toxicity and mechanical injury (barotrauma) as well as additional factors such as infections with Ureaplasma urealyticum and other micro-organisms may contribute to pulmonary damage. The mechanisms of acute lung injury observed during the initial stage of respiratory distress syndrome are incompletely understood. There is growing evidence, however, that an inflammatory pulmonary reaction following lung injury may be an early event in the development of CLD, finally leading to lung fibrosis. CLD is associated with a significant inflammatory response of the airways and the interstitium of the lungs; besides neutrophils, macrophages immunoreactive for tumour necrosis factor α are found in large numbers. Phagocyte influx is possibly mediated by chemotactic factors present in the alveolar secretions. Leukotriene B 4 , C5a, interleukin 8, elastin fragments and other factors may contribute to the high chemotactic activity. Intercellular adhesion molecule 1, which has been detected in bronchoalveolar secretions of infants with CLD, may promote neutrophil diapedesis. Furthermore, a number of lipid mediators including leukotrienes, prostacyclin and platelet-activating factor were found to be elevated in bronchoalveolar lavage fluid. These and other mediators which are mainly released by macrophages and pulmonary cells exert various effects on the airways and the vascular system by increasing the microvascular permeability; this increased alveolar-capillary leakage is one of the most important pathophysiological factors of early CLD. Neutrophils and macrophages attracted to the site of injured tissue can cause severe lung damage by release of potent proteases (elastase, collagenase), pro-inflammatory cytokines and by generation of toxic oxygen radicals. The presence of free elastase activity and oxidative inactivation of α 1 -proteinase inhibitor which protects the alveolar-capillary unit from autolytic proteolysis has been well documented. The protease-antiprotease imbalance as well as toxic oxygen radicals released by phagocytes or generated by tissue bound xanthine oxidase may play a central role in lung injury. In fact, increased concentrations of products of elastolytic fibre degradation and other structural components of lung tissue as well as of oxygen radical mediated lipid peroxidation were detected in infants with CLD; antioxidant activity of preterm infants seems to be insufficient to deal with free oxygen radicals. The complex interaction between mediators of inflammation and fibrosis has not been defined yet.

Association of histologic chorioamnionitis, increased levels of cord blood cytokines, and intracerebral hemorrhage in preterm neonates

The objective of this study was to investigate in a prospectie study whether histological chorioamnionitis (ChA) is a risk factor predisposing for intracerebral hemorrhage (ICH), and whether ICH is associated with a systemic fetal inflammation in preterm neonates with a gestational age <32 weeks. 106 neonates were studied; 20 (18.9%) suffered from ICH. ChA occurred significantly more often in neonates with ICH compared to neonates without ICH (70.0 vs. 36.0%, p = 0.006). Neonates with ICH had significantly higher median levels of proinflammatory cytokines (IL-1β, IL-6 and IL-8) compared to neonates without ICH (p < 0.001 for all comparisons). We conclude that the development of ICH in preterm infants is associated with both ChA and high levels of proinflammatory cytokines at birth.

Detection of bocavirus DNA in nasopharyngeal aspirates of a child with bronchiolitis

Summary We describe a case of bronchiolitis associated with the newly detected human bocavirus (hBoV) in a child with a suspected Noonan syndrome. This is the first report of a bronchiolitis probably linked to hBoV that required intensive care while being accompanied by a congenital heart disease and a history of several episodes of severe respiratory symptoms.

Improvement of oxygenation induced by aerosolized prostacyclin in a preterm infant with persistent pulmonary hypertension of the newborn

AbstractObjective: Case report on the effect of inhaled prostacyclin in a preterm infant (28 weeks gestational age) with respiratory distress syndrome complicated by marked hypoxemia due to persistent pulmonary hypertension of the newborn. Treatment with surfactant, hyperventilation, and elevation of systemic blood pressure had failed to improve oxygenation. Measures: A solution containing 10 ng PGI2/ml was aerosolized by the SPAG-2 aerosol-generator and then introduced into the afferent loop of the ventilatory circuit. Results: Oxygenation improved dramatically and worsened when aerosolization was withdrawn. Intravenous prostacyclin had no additional effect on oxygenation. We observed no side effects on blood pressure and no bleeding complications. Inhalation was stopped after 40 hours and the baby was successfully weaned from the ventilator after 108 hours. Conclusion: Inhaled PGI2 had a beneficial effect on the oxygenation of a preterm neonate with persistent pulmonary hypertension of the newborn.

Less invasive surfactant administration is associated with improved pulmonary outcomes in spontaneously breathing preterm infants

Providing less invasive surfactant administration (LISA) to spontaneously breathing preterm infants has been reported to reduce mechanical ventilation and bronchopulmonary dysplasia (BPD) in randomised controlled trials. This large cohort study compared these outcome measures between LISA‐treated infants and controls.

Blood Transfusion in Anemic Infants with Apnea of Prematurity

We found recently that blood transfusions had no effect on bradycardia and hypoxemia, the clinically important components of apnea of prematurity, in mildly anemic infants. Here, we wanted to know whether this also holds true for more severely anemic patients. Nineteen preterm infants, median gestational age at birth 25 (range 22–30) weeks, age at the time of study 5.5 (range 1–13) weeks, for whom a blood transfusion was ordered because of recurrent episodes of bradycardia and/or hypoxemia in conjunction with anemia (median hemoglobin level 78 g/l, range 63–98 g/l) were investigated. One infant received two transfusions and was thus studied twice. 4-hour recordings of pulse oximeter saturation (SpO2), pulse waveforms, electrocardiogram, breathing movements, and nasal airflow were performed immediately before transfusion of 20 ml/kg packed red blood cells and again 24 h later. The recordings were analyzed for baseline heart and respiratory rates and SpO2, all measured during regular breathing, as well as for apnea (≧20 s), bradycardia (heart rate <2/3 of baseline for ≧4 s), and episodic desaturation (SpO2 ≤80% for ≧4 s). There was no significant change in the combined frequency of bradycardia and desaturation, the primary study end point – median 6.4/h (range 3.0–13.5/h) before versus 4.6/h (range 0.6–15.7/h) after transfusion –, although there was slightly less bradycardia – 0.8/h (range 0.0–8.8/h) versus 0.7/h (range 0.0–5.1/h; p < 0.05). Baseline heart and respiratory rates decreased, respectively, from 163/min (range 140–182/min) and 58/min (range 34–98/min) to 152/min (range 134–172/min) and 55/min (range 36–82/min; p < 0.01). We conclude that blood transfusions significantly reduced heart and respiratory rates in these anemic infants, but had little effect on apnea of prematurity.