Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants.

Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1ß and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.

Hepatitis B vaccine co-administration influences the heterologous effects of neonatal BCG vaccination in a sex-differential manner.

INTRODUCTION: Bacille Calmette-Guérin (BCG) and hepatitis B (HBV) vaccines are frequently given concomitantly at birth. Neonatal BCG vaccination induces off-target immunological effects. Whether HBV vaccine has immunomodulatory effects is unknown. As off-target effects might vary when vaccines are given simultaneously, this randomised controlled trial aimed to evaluate the influence of neonatal vaccination with BCG and/or HBV on heterologous immune responses. METHODS: A total of 185 neonates in Australia were randomised to receive either neonatal BCG-Denmark vaccine, HBV vaccine, both (BCG + HBV group), or none (No vaccine group). In-vitro responses to heterologous stimulants were assessed 7 days after vaccination. The influence of (i) randomisation group and (ii) sex on interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-α) responses was analysed using linear regression. RESULTS: Overall, BCG vaccination alone or with HBV co-administration reduced IFN-γ and MCP-1 responses to heterologous stimulants. HBV vaccination alone did not alter heterologous cytokine responses. In general, males produced more IFN-γ and TNF-α than females. We observed a sex-differential effect in relation to the influence of HBV co-administration on the effect of BCG on heterologous responses. Compared with males in the No vaccine group, males in the BCG + HBV group had lower IFN-γ and MCP-1 responses. In contrast, compared with females in the No vaccine group, females in the BCG group had higher IFN-γ response and lower MCP-1 responses. CONCLUSION: Neonatal BCG vaccination resulted in lower cytokine responses to unrelated pathogens. HBV co-administration did not have a significant impact on responses overall but influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner.

Cerebral oxygenation is stable in preterm infants transitioning to heated humidified high-flow nasal cannula therapy.

AIM: To assess cerebral oxygenation in premature infants who are transitioning from nasal continuous positive airway pressure (nCPAP) to heated humidified high-flow nasal cannula therapy (HFNC). METHODS: A prospective observational study done in a single-centre neonatal intensive care unit (NICU). Regional cerebral oxygen saturations (RcSO2 ) were measured using frequency-domain near-infrared spectroscopy (FD-NIRS) in very low birthweight (VLBW) premature infants born at <32 weeks transitioning from nCPAP to HFNC. RESULTS: Median gestational age was 27 weeks and median birthweight was 924 g. Recordings were performed at a median gestational age of 30 weeks and a median postnatal age of 10 days. Median weight at study entry was 1111 g. Cerebral oxygenation was not significantly different in infants transitioning from nCPAP to HFNC (66% vs 66%). CONCLUSION: No difference in cerebral oxygenation in premature infants transitioning from nCPAP to HFNC was observed. This finding is reassuring and further supports the use of HFNC in preterm infants.

Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants.

BACKGROUND: Treatment with nasal high-flow therapy has efficacy similar to that of nasal continuous positive airway pressure (CPAP) when used as postextubation support in neonates. The efficacy of high-flow therapy as the primary means of respiratory support for preterm infants with respiratory distress has not been proved. METHODS: In this international, multicenter, randomized, noninferiority trial, we assigned 564 preterm infants (gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. The primary outcome was treatment failure within 72 hours after randomization. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the chosen margin of noninferiority was 10 percentage points. Infants in whom high-flow therapy failed could receive rescue CPAP; infants in whom CPAP failed were intubated and mechanically ventilated. RESULTS: Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants (13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval [CI], 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events. CONCLUSIONS: When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP. (Funded by the National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12613000303741 .).

Comparison of the pharyngeal pressure provided by two heated, humidified high-flow nasal cannulae devices in premature infants.

AIMS: This study aims to determine if there is a difference in the pharyngeal pressure, measured as a surrogate for continuous positive distending airway pressure, delivered to premature infants between two commonly used heated, humidified high-flow nasal cannulae (HHHFNC) devices: Fisher & Paykel Healthcare HHHFNC and Vapotherm 2000i. METHODS: Pharyngeal pressure measurements were taken from stable premature infants receiving HHHFNC for respiratory support. Flow rates of 2-8 L/min were studied. RESULTS: Nine infants had pharyngeal pressure measurements recorded with both HHHFNC devices at flow rates of 2-8 L/min. There was no difference in pharyngeal pressures recorded between devices at flow rates of 2-6 L/min; measured pressure was linearly associated with flow (R(2) = 0.9). At flow rates of 7 L/min, Vapotherm delivered a mean (standard deviation) pharyngeal pressure of 4.7 (2.2) cmH2 O compared with 4.23 (2.2) cmH2 O by the Fisher & Paykel device (P = 0.04). At a flow of 8 L/min, the mean pharyngeal pressure via Vapotherm was 4.9 (2.2) cmH2 O compared with 4.1 (2.3) cmH2 O with the Fisher & Paykel device (P = 0.05). CONCLUSIONS: Both HHHFNC delivered similar pharyngeal pressures at flow rates of 2-6 L/min. The pressure limiter valve of the Fisher & Paykel device attenuated the pharyngeal pressures at flows of 7 and 8 L/min. Vapotherm trended towards higher delivered pharyngeal pressure at flow rates 7 and 8 L/min, but the clinical significance of the difference remains unclear.

A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants.

OBJECTIVE: To determine whether postextubation respiratory support via heated, humidified, high-flow nasal cannulae (HHHFNC) results in a greater proportion of infants younger than 32 weeks' gestation being successfully extubated after a period of endotracheal positive pressure ventilation compared with conventional nasal continuous positive airway pressure (NCPAP). STUDY DESIGN: We randomly assigned preterm ventilated infants to Vapotherm HHHFNC or NCPAP after extubation. The primary outcome, extubation failure, was defined by prespecified failure criteria in the 7 days after extubation. RESULTS: A total of 132 ventilated infants younger than 32 weeks' gestation were randomized to receive either HHHFNC (n = 67) or NCPAP (n = 65). Extubation failure occurred in 15 (22%) of the HHHFNC group compared with 22 (34%) of the NCPAP group. There was no difference in the number of infants reintubated in the first week. Treatment with HHHFNC reduced the nasal trauma score 3.1 (SD 7.2) versus NCPAP 11.8 (SD 10.7), P < .001. CONCLUSIONS: HHHFNC and NCPAP produced similar rates of extubation failure.

Deceptive simplicity: systemic oxygen delivery and pulse oximetry.

Pulse oximetry is often perceived to be a measure of the adequacy of oxygen delivery. It is, however, only a measure of oxygen bound to haemoglobin. Systemic oxygen delivery is principally determined by cardiac output, haemoglobin concentration and haemoglobin saturation. Changes to both cardiac output and haemoglobin concentration will significantly alter oxygen delivery without changing oxygen saturation. This article will describe the components of systemic oxygen delivery and the physiologic limitation of pulse oximetry and caution against over-interpretation of oximetry in the care of newborns.

Immunogenicity and immunologic memory of meningococcal C conjugate vaccine in premature infants.

BACKGROUND: Protein-polysaccharide conjugate vaccines against Neisseria meningitidis serogroup C were introduced into the U.K. routine immunization schedule in 1999. This study is the first to describe both persistence of antibody and evidence for induction of immune memory using meningococcal C conjugate (MCC) vaccine in preterm infants. METHODS: Immunogenicity and induction of immunologic memory by as MCC vaccine was assessed in premature infants; 62 preterm and 60 term controls received MCC at the accelerated schedule (2, 3 and 4 months of age). A meningococcal C polysaccharide challenge was administered at 12 months of age. RESULTS: Both groups achieved similar protective titers after primary immunization that then waned significantly by 1 year of age. Postchallenge serum bactericidal activity was significantly lower in preterm infants (P = 0.03); 73% of preterm versus 88% of term controls achieved a 4-fold rise in serum bactericidal activity (P = 0.07). CONCLUSIONS: MCC vaccine is immunogenic and primes for immunologic memory in preterm infants. The decreased memory responses in these preterm infants in conjunction with waning clinical efficacy data for all U.K. infants suggest a role for a routine booster dose of vaccine in all infants receiving MCC, especially those born preterm.

Meningococcal vaccines.

Neisseria meningitidis is one of the leading infectious causes of death in children under five years old in industrialized countries, and most cases can be attributed to five disease-causing serogroups: A, B, C, Y and W135. Meningococcal vaccine development began in the 1930s with killed whole-cell and exotoxin vaccines, but widespread use of polysaccharide vaccines did not begin until the 1970s. Serogroup A, C, Y and W135 polysaccharides are all included in vaccines for travellers, other high risk groups and control of outbreaks, but have limited immunogenicity and effficacy in childhood. Protein-polysaccharide conjugate vaccines overcome this problem and offer the possibility of protection in early childhoodfrom serogroup A, C, Y and W135. An effective serogroup B vaccine remains elusive and the greatest challengefor vaccine developers.