Lung-Gut Microbiota and Tryptophan Metabolites Changes in Neonatal Acute Respiratory Distress Syndrome.

Purpose: Neonatal Acute Respiratory Distress Syndrome (NARDS) is a severe respiratory crisis threatening neonatal life. We aim to identify changes in the lung-gut microbiota and lung-plasma tryptophan metabolites in NARDS neonates to provide a differentiated tool and aid in finding potential therapeutic targets. Patients and Methods: Lower respiratory secretions, faeces and plasma were collected from 50 neonates including 25 NARDS patients (10 patients with mild NARDS in the NARDS_M group and 15 patients with moderate-to-severe NARDS in the NARDS_S group) and 25 control patients screened based on gestational age, postnatal age and birth weight. Lower airway secretions and feces underwent 16S rRNA gene sequencing to understand the microbial communities in the lung and gut, while lower airway secretions and plasma underwent LC-MS analysis to understand tryptophan metabolites in the lung and blood. Correlation analyses were performed by comparing differences in microbiota and tryptophan metabolites between NARDS and control, NARDS_S and NARDS_M groups. Results: Significant changes in lung and gut microbiota as well as lung and plasma tryptophan metabolites were observed in NARDS neonates compared to controls. Proteobacteria and Bacteroidota were increased in the lungs of NARDS neonates, whereas Firmicutes, Streptococcus, and Rothia were reduced. Lactobacillus in the lungs decreased in NARDS_S neonates. Indole-3-carboxaldehyde decreased in the lungs of NARDS neonates, whereas levels of 3-hydroxykynurenine, indoleacetic acid, indolelactic acid, 3-indole propionic acid, indoxyl sulfate, kynurenine, and tryptophan decreased in the lungs of the NARDS_S neonates. Altered microbiota was significantly related to tryptophan metabolites, with changes in lung microbiota and tryptophan metabolites having better differentiated ability for NARDS diagnosis and grading compared to gut and plasma. Conclusion: Significant changes occurred in the lung-gut microbiota and lung-plasma tryptophan metabolites of NARDS neonates. Alterations in lung microbiota and tryptophan metabolites were better discriminatory for the diagnosis and grading of NARDS.

Clinical characteristics and outcomes in neonates with perinatal acute respiratory distress syndrome in China: A national, multicentre, cross-sectional study.

Background: Neonatal acute respiratory distress syndrome (NARDS) was defined in 2017 and the epidemiological data remain unknown. Our objective was to explore aetiological factors, clinical characteristics and outcomes in patients with perinatal NARDS. Methods: A multicentre, prospective, cross-sectional study was performed in 58 tertiary neonatal intensive care units in China from Jan 1, 2018 to June 30, 2019. Neonates diagnosed with NARDS were included. Primary outcomes were aetiological factors, clinical characteristics and outcomes. Binary logistic regression and multivariate cox proportional regression were performed to identify independent predictors for bronchopulmonary dysplasia (BPD) and/or death or single death. This study was registered with ClinicalTrials.Gov, NCT03311165. Findings: Among 70,013 admitted neonates, the incidence of NARDS was 1.44% (1005). The cumulative incidences were 65.6%, 86.7%, 94.1% within one, two and three days after birth. The median gestational age and birth weight were 36.4 weeks and 2700 g. Three main aetiological triggers included pneumonia (58.1%), asphyxia (24.3%) and early-onset sepsis (EOS) (21.3%). BPD and/or death was observed in 213 (21.2%) infants, consisting 104 (10.3%) BPD and 126 (12.6%) deaths. The numbers of mild, moderate and severe NARDS were 537 (53.4%), 286 (28.4%) and 182 (18.2%). Two or more doses of surfactant was associated with increased mortality as compared with one or less doses of surfactant (odds ratio [OR] 1.93, 95% confidence interval [CI] 1.20-3.10, P = 0.006). Similarity also appeared in the comparison between EOS and non-EOS triggers (OR 1.57, 95% CI 1.06-2.33, P = 0.023). Interpretation: NARDS incidence was 1.44% and the three main aetiologies were pneumonia, asphyxia and EOS. The cumulative incidences were 65.6%, 86.7%, and 94.1% within one, two and three days after birth. Our results suggested that two or more doses of surfactant increased mortality compared with one or less doses of surfactant. Funding: The National Clinical Research Center of China and Clinical Medical Study Program of Children's Hospital of Chongqing Medical University (NCRC-2019-GP-13) and Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0197).

HFOV vs CMV for neonates with moderate-to-severe perinatal onset acute respiratory distress syndrome (NARDS): a propensity score analysis.

This study aimed to evaluate whether high-frequency oscillatory ventilation (HFOV) could reduce mortality and the incidence of bronchopulmonary dysplasia (BPD) of perinatal-onset neonatal acute respiratory distress syndrome (NARDS) compared with conventional mechanical ventilation (CMV). Medical records were collected and retrospectively analyzed. Among the 700 neonates with NARDS who needed invasive ventilation, 501 (71.6%) received CMV, while 199 (28.4%) received HFOV. One-to-one propensity score matching (127:127) was used to match the baseline characteristics of patients who received CMV and HFOV. The results showed that birth weight and oxygenation index (OI) were independently associated with mortality in the multivariate logistic regression. No significant differences were observed in mortality or the incidence of BPD between the two groups. The incidence of intraventricular hemorrhage (IVH) and ventilation-free days were significantly lower in the HFOV group than in the CMV group (3.9 vs 11.80%, p=0.02; 15.226 vs 20.967 days, p=0.01). There were no significant differences between the two groups regarding other secondary outcomes.Conclusion: HFOV was associated with a decreased incidence of IVH in infants with NARDS compared with CMV. However, there were significantly more VFDs in the CMV group than in the HFOV group, and HFOV did not appear to be superior to CMV in decreasing the mortality and incidence of BPD in infants with NARDS. What is Known: • The diagnostic criteria of neonatal acute respiratory distress syndrome (Montreux criteria) were established in 2017. • To date, studies comparing high-frequency oscillatory ventilation and conventional mechanical ventilation in the treatment of neonatal acute respiratory distress syndrome are insufficient. What is New: • High-frequency oscillatory ventilation did not appear to be superior to conventional mechanical ventilation in decreasing the mortality and incidence of bronchopulmonary dysplasia in infants with moderate-to-severe perinatal-onset neonatal acute respiratory distress syndrome. • High-frequency oscillatory ventilation was associated with a decreased incidence of intraventricular hemorrhage in infants with moderate-to-severe perinatal-onset acute respiratory distress syndrome compared with conventional mechanical ventilation.

Surfactant therapies for pediatric and neonatal ARDS: ESPNIC expert consensus opinion for future research steps.

Pediatric (PARDS) and neonatal (NARDS) acute respiratory distress syndrome have different age-specific characteristics and definitions. Trials on surfactant for ARDS in children and neonates have been performed well before the PARDS and NARDS definitions and yielded conflicting results. This is mainly due to heterogeneity in study design reflecting historic lack of pathobiology knowledge. We reviewed the available clinical and preclinical data to create an expert consensus aiming to inform future research steps and advance the knowledge in this area. Eight trials investigated the use of surfactant for ARDS in children and ten in neonates, respectively. There were improvements in oxygenation (7/8 trials in children, 7/10 in neonates) and mortality (3/8 trials in children, 1/10 in neonates) improved. Trials were heterogeneous for patients' characteristics, surfactant type and administration strategy. Key pathobiological concepts were missed in study design. Consensus with strong agreement was reached on four statements: 1. There are sufficient preclinical and clinical data to support targeted research on surfactant therapies for PARDS and NARDS. Studies should be performed according to the currently available definitions and considering recent pathobiology knowledge. 2. PARDS and NARDS should be considered as syndromes and should be pre-clinically studied according to key characteristics, such as direct or indirect (primary or secondary) nature, clinical severity, infectious or non-infectious origin or patients' age. 3. Explanatory should be preferred over pragmatic design for future trials on PARDS and NARDS. 4. Different clinical outcomes need to be chosen for PARDS and NARDS, according to the trial phase and design, trigger type, severity class and/or surfactant treatment policy. We advocate for further well-designed preclinical and clinical studies to investigate the use of surfactant for PARDS and NARDS following these principles.