[Neonatal enterovirus meningitis: transmission via parents during rooming-in and current epidemiology in Germany]. / Neonatale Enterovirus-Meningitis: Transmission durch die Eltern beim familiären Rooming-in und derzeitige Epidemiologie der Erkrankung in Deutschland.

INTRODUCTION: Non-polio-enterovirus infections are common in children and adults and usually lead to a mild, self-limiting disease. Perinatally acquired enterovirus infections, however, may lead to a severe disease including meningitis, encephalitis, hepatitis, coagulopathy or myocarditis. The mode of transmission may be not obvious. METHODS: 2 cases of neonatal enterovirus meningitis are presented. The disease was probably transmitted by the parents after birth during rooming-in within the hospital. The frequency of neonatal enterovirus infections in Germany was determined by analysing data of the enterovirus surveillance system of the national commission for polio eradication. RESULTS: In both cases, the parents suffered from a febrile infection. In case 1, transmission by the febrile mother was suspected. In case 2, transmission of Coxsackie B5-virus by the father was confirmed by viral culture. Both neonates exhibited fever, one patient had the typical clinical signs of meningitis. Levels of inflammatory indicators in blood (CRP, IL-6) were remarkably low. From 2006 to 2009, 322 neonates were included within the voluntary, passive enterovirus surveillance system. In 81 patients (25%) an enterovirus was detected via RT-PCR. The yearly frequency of infections was between 8 and 21. In 58 of 322 specimens (18%) serotyping was possible. CONCLUSION: Infections with enterovirus are both clinically and epidemiologically relevant during the neonatal period. Predominantly in the typical season, from June to October, enteroviral infections may be an important differential diagnosis to neonatal sepsis. The infection may be transmitted via infected parents during rooming-in within the hospital.

[Pharmacological prophylaxis and treatment of bronchopulmonary dysplasia]. / Medikamentöse Prophylaxe und Therapie der bronchopulmonalen Dysplasie.

Treatment with prenatal steroids, prophylactic or early therapeutic surfactant substitution, application of early nasal CPAP, minimizing of mechanical ventilation, early treatment of PDA and avoiding nosocomial infections are the main measures to prevent the development of bronchopulmonary dysplasia (BPD) in high-risk pre-term neonates. Beside these strategies, several pharmacologic interventions to prevent or to treat BPD have been investigated. So far, clear evidence for effective prevention has only been demonstrated for the administration of vitamin A and vaccinations. The administration of oxygen is the only effective treatment modality. Unfortunately, the upper and lower limits for the dosage of oxygen are still not clear. In patients with established BPD, a transient therapeutic effect is observed following treatment with systemic diuretics, inhaled steroids, and inhaled bronchodilators. However, treatment with these drugs has no documented long-term effect on the course of the disease. Systemic steroids only play a role as rescue treatment in life-threatening situations. Treatment with inhaled or systemic pulmonary vasodilatative may have a place in the treatment of pulmonary hypertension in severely affected infants. However, long-term experience in this treatment modality is still lacking.

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 prospective 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-1beta, 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.

Procollagen I C-propeptide in the cerebrospinal fluid of neonates with posthaemorrhagic hydrocephalus.

BACKGROUND: The pathogenesis of posthaemorrhagic hydrocephalus (PHHC) following intraventricular haemorrhage (IVH) in premature infants includes a fibroproliferative reaction leading to arachnoidal fibrosis, ultimately causing malresorption of cerebrospinal fluid (CSF) at the arachnoid villi. AIMS: To determine whether an increased concentration of the carboxyterminal propeptide of type I procollagen (PICP) in the CSF of neonates after IVH reflects the activation of collagen synthesis preceding the manifestation of PHHC. METHODS: From 20 neonates with PHHC (median birth weight 740 g, median gestational age 25+1 weeks), 52 CSF samples were collected. CSF samples of four neonates (median birth weight 2170 g, median gestational age 32+4 weeks) with congenital non-haemorrhagic hydrocephalus served as controls. PICP was measured by radioimmunoassay. RESULTS: PICP in CSF taken at the start of external CSF drainage (median day 21, range 17-25 days postnatal age) was significantly increased (median 851.5, range 153.5-1944 microg/l) compared with controls (median 136.1, range 33.8-169.5 microg/l). CSF concentrations of PICP declined until permanent shunt placement (median day 70, range days 41-113). CONCLUSION: In neonates who develop PHHC, significant elevation of PICP concentration in the CSF is present 3-4 weeks after IVH. It reflects the increase of local type I collagen turnover, thereby correlating with manifestation of PHHC.

[Perinatal glucocorticosteroid therapy: time for reconsideration]. / Die perinatale Therapie mit Glukokortikosteroiden: Zeit zum Umdenken1.

Glucocorticosteroids are administered antenatally and postnatally to decrease pulmonary morbidity of preterm neonates. One course of antenatal corticosteroids decreases mortality, and the frequency of respiratory distress syndrome and intraventricular hemorrhage. However, multiple courses may be associated with impaired brain development. Follow-up studies are needed to assess long-term consequences. The use of betamethasone may be of advantage compared to dexamethasone. Postnatally, steroids are given to treat or prevent bronchopulmonary dysplasia (BPD). However, recent studies have shown that treatment with dexamethasone increases the rate of cerebral palsy in preterm infants. Postnatal treatment of BPD with steroids should be restricted to life-threatening situations.

Bronchoalveolar inflammation following airway infection in preterm infants with chronic lung disease.

Chronic lung disease (CLD) of the newborn is associated with pulmonary inflammation. However, the origin of this inflammation is not known. We evaluated the impact of airway infection on bronchoalveolar inflammation in mechanically ventilated preterm infant at risk for CLD (n = 68). Mean and maximum concentrations of the inflammatory mediators (IM) interleukin-1 and interleukin-8 were assayed in the tracheobronchial aspirate fluid (TAF) of neonates with perinatal airway infection (Ureaplasma urealyticum, or bacteria), postnatal nosocomial airway infection, or respiratory disease without airway infection from days 1-10 of postnatal age. Patients with CLD (n = 23;) exhibited increased levels of IM in TAF compared to neonates without CLD. Within the three subgroups, concentrations of IM were increased in CLD patients with perinatal infection and in CLD patients with respiratory disease without airway infection, but not in CLD patients with nosocomial airway infection. Although airway colonization with Gram-negative bacteria was more frequently found in CLD patients within the first month of life, there were no differences between levels of IM in patients colonized with Gram-negative bacteria or coagulase-negative staphyloccoci. We conclude that perinatal infections with Ureaplasma urealyticum or bacteria and respiratory disease without infection, but not nosocomial airway infection, contribute to the bronchopulmonary inflammatory response in neonates with CLD.

Primary intervention for posthemorrhagic hydrocephalus in very low birthweight infants by ventriculostomy.

The objective of our study was to determine the efficacy of ventriculostomy as the primary treatment for posthemorrhagic hydrocephalus in premature infants. Within a period of 4 years, 20 very low birthweight (VLBW) infants (birthweight median 1,135 g, range 650-1,470 g) were treated for progressive posthemorrhagic hydrocephalus (PHHC) by right parietal ventriculostomy (Salmon Rickham) at a mean age of 21 days. Serial tapping of the subcutaneous reservoir was performed for temporary drainage until conversion to a permanent ventriculoperitoneal (VP) shunt or spontaneous resolution of hydrocephalus. A total of 1,402 punctures (median 71/infant, range 13-168) was performed. The results showed that only 1/20 patients developed a cerebrospinal fluid (CSF) infection, accounting for a 5% patient-related and 0.07% procedure-related infection rate. Major complications such as skin defects, subdural hygroma, or CSF leaks occurred in three patients (15%). A permanent shunt was needed in 17 patients (85%). We concluded that, as an effective alternative to serial or lumbar puncture, there should be early implantation of ventriculostomy reservoirs for serial taps to control intracranial pressure in PHHC of VLBW infants until a permanent shunt can be placed because of the low incidence of infections and technical complications.

Effects of inhaled beclomethasone compared to systemic dexamethasone on lung inflammation in preterm infants at risk of chronic lung disease.

The purpose of this study was to compare the effects of daily inhaled beclomethasone (3 x 500 microg) started on day 3 of life, with that of systemic dexamethasone (0.5 mg/kg/day) started between days 11-13 on clinical variables, lung inflammation, and pulmonary microvascular permeability in preterm infants at risk for chronic lung disease (CLD). Following administration of surfactant, preterm neonates with RDS and a birth weight of less than 1,200 g were included in this comparative observational pilot study when still mechanically ventilated and with an oxygen requirement on the third day of life. The patients (gestational age 26.1+/-0.9 weeks, birth weight 826+/-140 g, mean+/-SD) were alternately allocated to prophylactic treatment with inhaled beclomethasone (n = 7), or to early systemic dexamethasone therapy after day 10 of life, if clinically indicated (n = 9). Pulmonary inflammation and lung permeability were assessed by analyzing the levels of interleukin-8, elastase alpha1 proteinase inhibitor, free elastase activity, and albumin in tracheal aspirates on days 10 and 14 of life. The secretory component of IgA served as reference protein. We observed no significant differences in the concentrations of interleukin-8, elastase alpha1 proteinase inhibitor, and albumin between the two groups on day 10 of life. On day 14, 3 (median; range, 1-3) days following initiation of dexamethasone treatment, concentrations of the inflammatory mediators and of albumin were significantly lower in the group on systemic steroid therapy than in the group treated with inhaled steroids (P < 0.01). Additionally, there was a significant difference in oxygen requirements between both groups on day 14. In the group treated with inhaled steroids, concentrations of the inflammatory mediators, albumin, and oxygen requirements did not show a difference between day 10 and 14. We conclude that, in contrast to systemic dexamethasone treatment, a 12-day course of inhaled beclomethasone does not affect lung inflammation and pulmonary microvascular permeability in preterm infants at risk for CLD within the first 2 weeks of life.

High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group.

OBJECTIVE: To investigate whether a weekly 1500 IU/kg dose of recombinant human erythropoietin (rhEPO) is more effective than a dose of 750 IU/kg/week in preventing anemia and reducing the transfusion need in infants with birth weights less than 1000 gm. STUDY DESIGN: In a randomized, double-blind, multicenter trial, 184 infants with birth weights between 500 and 999 gm were treated with either rhEPO 750 (low-dose group) or 1500 IU/kg/week (high-dose group) from day 3 of life until 37 weeks' corrected age. RESULTS: Thirty-two percent of the infants in each group did not receive any transfusion during the treatment period. The total volume of erythrocytes received was similar in each group. The success rate, defined as no transfusion needed and hematocrit value 0.30 L/L or greater, was 27.6% in the low-dose and 29.5% in the high-dose group (p = 0.96). CONCLUSION: Doubling the rhEPO dose of 750 IU/kg/week is not indicated in infants with birth weights less than 1000 gm.

Candida infection in very low birth-weight infants: outcome and nephrotoxicity of treatment with liposomal amphotericin B (AmBisome).

Systemic fungal infection occurs in 2 to 4.5% of very low birth-weight (VLBW) infants (< 1,500 g) and may be fatal in 25 to 54%. Candida sp. is the major pathogen and amphotericin B the treatment of choice. To reduce side effects and optimize drug action, a formulation of amphotericin B encapsulated in liposomes (AmBisome) has been introduced. Data on 21 VLBW infants who received a full course of AmBisome was collected and its toxic effects with emphasis on nephrotoxicity and hypokalemia assessed. The median gestational age was 25 weeks (range 23-31) with a median birth-weight of 730 g (range 450-1,370). Antifungal therapy was started at a median age of 13 days (range 1-49). The median dose given was 2.6 mg/kg/day (range 1-5), and the median duration of therapy was 28 days (range 11-79), corresponding to a median cumulative dose of 71 mg/kg (range 12-271). Hypokalemia (< 3.0 mmol/l) was observed in 30% before, and 15% during AmBisome treatment. Twenty-one days after the termination of therapy, hypokalemia was not present in any patient. Median maximum daily potassium supplementation did not exceed doses usually recommended for VLBW infants. The median of the maximum creatinine levels before treatment was 121 mumol/l (range 71-221) and fell to 68 mumol/l (range 31-171) during treatment and 46 mumol/l (range 26-62) 21 days after the termination of therapy. All patients treated with AmBisome eradicated fungi and recovered clinically. AmBisome showed no certain nephrotoxicity in VLBW infants in this study.

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.

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

OBJECTIVE: 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 micrograms 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.

[Meconium aspiration syndrome]. / Das Mekoniumaspirationssyndrom.

Meconium aspiration syndrome (MAS) is found in 0.2-6 per 1000 lifeborn neonates. Aspiration of meconium particles may occur before, during or after delivery, associated with deep inspiratory movements due to fetal depression. Aspiration of meconium may cause mechanical obstruction of the airways, chemical pneumonitis, and surfactant inactivation. The disease is commonly associated with the development of pulmonary hypertension and severe respiratory insufficiency. MAS may be prevented, at least in some infants, by appropriate suctioning at birth. Great progress has been made in the treatment: early administration of surfactant improves gas exchange in many neonates. High frequency oscillatory ventilation, NO-inhalation and extracorporal membrane oxygenation have a role in severe respiratory failure.

Inflammatory bronchopulmonary response of preterm infants with microbial colonisation of the airways at birth.

The inflammatory indicators in the tracheobronchial aspirate (TA) of 81 ventilated preterm infants with microbial colonisation of the airways and in non-colonised neonates were analysed on the first day of life. TA was assessed for chemotactic activity, neutrophil cell count, and concentrations of leukotriene B4, C5a, interleukin-1, interleukin-8, elastase-alpha 1-proteinase inhibitor, free elastase and albumin. Concentrations of mediators were related to concentrations of the secretory component of IgA. The infants' gestational age was mean (SD) 27.9 (2.0) weeks, birthweight 945 (179) g. In 12 infants (15%) microbial colonisation of the airways was present (Ureaplasma urealyticum n = 7; bacteria n = 5). Compared with non-colonised neonates (n = 69), chemotactic activity, neutrophil count, and concentrations of interleukin-1, leukotriene B4 and elastase-alpha 1-proteinase inhibitor were significantly higher in the colonised group. The difference was most pronounced for IL-1 concentrations, both with and without correction for secretory component. There was also a trend towards increased concentrations of interleukin-8 in the latter group. There were no differences for concentrations of C5a and albumin in the TA of both groups. It is concluded that airway colonisation with U urealyticum or bacteria at birth is associated with a clinically relevant bronchopulmonary inflammatory response. Increased concentrations of interleukin-1 in TA on the first day of life may be a marker of perinatal colonisation of the airways.

[Pathogenesis of bronchopulmonary dysplasia]. / Die Pathogenese der bronchopulmonalen Dysplasie.

Bronchopulmonary dysplasia of preterm infants has a multifactorial etiology. Pulmonary immaturity, oxygen toxicity, formation of oxygen radicals and mechanical lung trauma as well as additional factors (pulmonary hyperhydration, infection a.o.) may contribute to pulmonary damage. A pulmonary inflammatory reaction is thought to play a central role in the pathogenesis of chronic lung disease. It is characterized by the presence of inflammatory cells and various inflammatory mediators including proteases, chemoattractants, cytokines, leukotrienes and others. Due to the immaturity of several protective systems (antiproteases, antioxidants, surfactant system) the inflammatory response seems to be aggravated. Moreover, the magnitude and persistence of inflammation may eventually lead to pulmonary fibrosis.

Randomised clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome.

AIMS: To compare treatment regimens of two widely used natural surfactant preparations Curosurf and Survanta in respiratory distress syndrome (RDS). METHODS: The effects of the two treatment regimens on gas exchange, ventilatory requirements, and 28 day outcome in infants with RDS were compared. Seventy five preterm infants (birth weight 700-1500 g) with RDS requiring artificial ventilation with an FIO2 of > or = 0.4, were randomly selected at 1-24 hours of age. One group received an initial dose of Curosurf (200 mg/kg); the other group Survanta (100 mg/kg). Patients who remained dependent on artificial ventilation with an FIO2 of > or = 0.3 received up to two additional doses of Curosurf (each of 100 mg/kg) after 12 and 24 hours or up to three additional doses of Survanta (each of 100 mg/kg) between six and 48 hours after the initial dose. RESULTS: There was a rapid improvement in oxygenation and ventilatory requirements were reduced in both groups. However, infants treated with Curosurf had a higher arterial:alveolar oxygen tension ratio and required a lower peak inspiratory pressure and mean airway pressure at several time points within 24 hours of randomisation (p < 0.05-0.001). The incidences of pneumothorax in the Curosurf and Survanta groups were 6% and 12.5%, respectively; the corresponding figures for grades 3-4 intracerebral haemorrhage were 3% and 12.5%, respectively. Mortality was 3% in the Curosurf group and 12.5% in the Survanta group. However, these differences did not reach significance. CONCLUSION: The Curosurf treatment regimen resulted in a more rapid improvement in oxygenation than Survanta and reduced ventilatory requirements up to 24 hours after start of treatment. This was associated with a trend towards reduced incidence of serious pulmonary and non-pulmonary complications.

Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) of preterm neonates is associated with an increased recruitment of inflammatory cells into the airways. To evaluate further the role of inflammation in the pathogenesis of BPD, tracheobronchial aspirate fluid of neonates with birth weight < 1200 g (n = 59) was sequentially analyzed in a prospective study. METHODS: Tracheobronchial aspirate fluid was assessed for chemotactic activity, neutrophil cell count, concentrations of elastase-alpha 1-proteinase inhibitor and activity of free elastase, concentrations of chemoattractants (complement component C5-derived anaphylatoxin, leukotriene B4, interleukin-8), and albumin concentrations as well as alpha 1-proteinase inhibitor activity. The secretory component for immunoglobulin A was used as reference protein. Only specimens without evidence of microbiological colonization were studied. RESULTS: In neonates with prolonged respiratory disease (BPD-risk neonates, n = 24, fraction of inspired oxygen > or = 0.3 and/or peak inspiratory pressure > or = 16 cm H2O at day 10 postnatal age, birth weight 892 +/- 36 g, gestational age 27.2 +/- 0.3 weeks) chemotactic activity, cell count, concentrations of the chemoattractants complement component C5-derived anaphylatoxin, leukotriene B4, interleukin-8, as well as levels of elastase-alpha 1-proteinase inhibitor were significantly higher at day 10 and/or day 15 of postnatal age compared with neonates without chronic pulmonary disease (total n = 35; day 10, n = 11; day 15, n = 8). There was no difference in free elastolytic activity. Concentrations of albumin as well as alpha 1-proteinase inhibitor activity were higher in BPD-risk patients on day 15, indicating an increased pulmonary leak. CONCLUSION: We conclude that preterm neonates at risk for the development of BPD show an enhanced inflammatory reaction in the lungs and an associated increase in pulmonary microvascular permeability. We speculate that inflammation may play an important role in the pathogenesis of BPD.