SARS-CoV-2 infection and neonates: a review of evidence and unresolved questions.

SARS-CoV-2 infection in the neonatal period poses previously unmet challenges to obstetricians and neonatologists, but several key questions are yet to be answered. Few cases of presumed in utero vertical transmission of the virus from infected mothers to fetuses have been reported, but stronger evidence is needed, from larger datasets with multiple biospecimens rigorously analyzed. Whether acquired before or after birth, SARS-CoV-2 infection in neonates can be symptomatic, but our comprehension of neonatal immune response and the subsequent clinical characteristics of COVID-19 in early life are incomplete. Finally, the pandemic challenged several dogmas regarding the management of mother-infant dyads, and again more robust data are needed to support the formulation of evidence-based guidelines. Here, we briefly summarize existing evidence and key unresolved questions about SARS-CoV-2 infection and COVID-19 in the neonatal period.

Lung UltrasouNd Guided surfactant therapy in preterm infants: an international multicenter randomized control trial (LUNG study).

BACKGROUND: The management of respiratory distress syndrome (RDS) in premature newborns is based on different types of non-invasive respiratory support and on surfactant replacement therapy (SRT) to avoid mechanical ventilation as it may eventually result in lung damage. European guidelines currently recommend SRT only when the fraction of inspired oxygen (FiO2) exceeds 0.30. The literature describes that early SRT decreases the risk of bronchopulmonary dysplasia (BPD) and mortality. Lung ultrasound score (LUS) in preterm infants affected by RDS has proven to be able to predict the need for SRT and different single-center studies have shown that LUS may increase the proportion of infants that received early SRT. Therefore, the aim of this study is to determine if the use of LUS as a decision tool for SRT in preterm infants affected by RDS allows for the reduction of the incidence of BPD or death in the study group. METHODS/DESIGN: In this study, 668 spontaneously-breathing preterm infants, born at 25+0 to 29+6 weeks' gestation, in nasal continuous positive airway pressure (nCPAP) will be randomized to receive SRT only when the FiO2 cut-off exceeds 0.3 (control group) or if the LUS score is higher than 8 or the FiO2 requirements exceed 0.3 (study group) (334 infants per arm). The primary outcome will be the difference in proportion of infants with BPD or death in the study group managed compared to the control group. DISCUSSION: Based on previous published studies, it seems that LUS may decrease the time to administer surfactant therapy. It is known that early surfactant administration decreases BPD and mortality. Therefore, there is rationale for hypothesizing a reduction in BPD or death in the group of patients in which the decision to administer exogenous surfactant is based on lung ultrasound scores. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05198375 . Registered on 20 January 2022.

Changes in respiratory mechanics at birth in preterm infants: A pilot study.

OBJECTIVE: We aimed to measure lung mechanics at birth by the forced oscillation technique (FOT) for assessment of the initial degree of lung aeration and the short-term aeration changes after applying different respiratory support strategies. METHODS: Eighteen preterm infants (gestational age = 29-36 week) were randomized to receive either continuous positive airway pressure (CPAP) at 5 cmH2 O only or combined with a sustained inflation (SI; 15 seconds at 25 cmH2 O after 5 seconds of CPAP) at birth. We assessed the respiratory system reactance at 5 Hz (X5; increases with lung volume recruitment at a given distending pressure) at 2, 40, and 150 seconds after initiation of CPAP. k-Means clustering of the initial X5 value (X5,i ) stratified newborn into either infants with lower (lowerX5,i ; X5 < -280 cmH2 O*s/L) and higher (higherX5,i ; X5 > -240 cmH2 O*s/L) initial degree of lung volume recruitment. RESULTS: Initial values were highly heterogeneous. In the LowerX5,i group, X5 increased with time, with SI-patients showing significantly higher values at 150 seconds than the non-SI group (X5 = -89 ± 27 cmH2 O vs -274 ± 58 cmH2 O). In the higherX5,i group, X5 did not improve with time, regardless of the respiratory strategy, suggesting a lack of lung recruitment. Moreover, 75% of infants receiving SI in the higherX5,i group experienced a transient loss of aeration after the maneuver. CONCLUSIONS: Preterm newborns present initially with highly heterogeneous lung aeration at birth that significantly impacts the effectiveness of the subsequent lung volume recruitment strategy. FOT may represent a valuable tool for individualizing a respiratory resuscitation at birth as it is noninvasive and may be applied simultaneously to respiratory support.

Study protocol: treatment with caffeine of the very preterm infant in the delivery room: a feasibility study.

INTRODUCTION: Early treatment with caffeine in the delivery room has been proposed to decrease the need for mechanical ventilation (MV) by limiting episodes of apnoea and improving respiratory mechanics in preterm infants. Thus, the purpose of this feasibility study is to verify the hypothesis that intravenous or enteral administration of caffeine can be performed in the preterm infant in the delivery room. METHODS AND ANALYSIS: In this multicentre prospective study, infants with 25+0-29+6 weeks of gestational age will be enrolled and randomised to receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth. Caffeine plasma level will be measured at 60±15 min after administration and 60±15 min before the next dose (5 mg/kg). The primary endpoint will be evaluation of the success rate of intravenous and enteral administration of caffeine in the delivery room. Secondary endpoints will be the comparison of success rate of intravenous versus oral administration and the evaluation of the need for MV in treated infants. In the absence of previous references, we arbitrarily decided to study 20 infants treated with intravenous caffeine and 20 infants treated with enteral caffeine. Primary endpoint will be evaluated measuring the success rate of intravenous and enteral caffeine administration which will be considered a success when it is followed by the achievement of the caffeine therapeutic level (8-25 µg/mL) 60±15 min before administration of the second dose. ETHICS AND DISSEMINATION: The study has been approved by the Italian Medicines Agency (AIFA: AIFA/RSC/P/32755) and by Comitato Etico Pediatrico Regione Toscana. The results will be published in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04044976; EudraCT number 2018-003626-91.

[Respiratory failure in "late preterm" infants: a retrospective cohort study]. / Insufficienza respiratoria nei neonati "late preterm": uno studio retrospettivo di coorte.

OBJECTIVE: To evaluate the incidence and characteristics of the respiratory failure in late preterm infants. STUDY DESIGN: Retrospective data analysis in years 2006-2007 in late preterm infants (GA 34(+0)-36(+6) weeks) with respiratory failure, admitted at a tertiary level NICU. RESULT: Data from 1011 late preterm infants, which accounted for 7% of all deliveries and 65% of preterm births were analyzed; 29% (292/1011) required intensive care and 13% (136/1011) presented respiratory failure (16% of all ventilated infants in the period). In late preterms with respiratory failure 23% (32/136) were treated with prenatal steroids 46% (62/136) with non -invasive ventilation (nasal continuous positive airways pressure = nCPAP) while 41% (56/136) were intubated and received exogenous surfactant. Mean days of ventilation were 5.3 +/- 6.5 (0.5-55); 3.7% (5/136) developed bronchopulmonary dysplasia defined as oxygen-dependency at 36 postconceptional age and mortality was 1.5% (2/136). CONCLUSION: Respiratory failure incidence and characteristics in late preterms suggest their peculiarity and relevance in neonatal intensive care.

Nasal high-frequency oscillatory ventilation and CO2 removal: A randomized controlled crossover trial.

OBJECTIVE: To compare short-term application of nasal high-frequency oscillatory ventilation (nHFOV) with nasal continuous positive airway pressure (nCPAP). WORKING HYPOTHESIS: nHFOV improves CO2 removal with respect to nCPAP in preterm infants needing noninvasive respiratory support and persistent oxygen supply after the first 72 h of life. STUDY DESIGN: Multicenter non-blinded prospective randomized crossover study. PATIENT SELECTION: Thirty premature infants from eight tertiary neonatal intensive care units, of mean ± SD 26.4 ± 1.8 weeks of gestational age and 921 ± 177 g of birth weight. METHODOLOGY: Infants were randomly allocated in a 1:1 ratio to receive a starting treatment mode of either nCPAP or nHFOV delivered by the ventilator CNO (Medin, Germany), using short binasal prongs of appropriate size. A crossover design with four 1-h treatment periods was used, such that each infant received both treatments twice. The primary outcome was the mean transcutaneous partial pressure of CO2 (TcCO2 ) value during the 2-h cumulative period of nHFOV compared with the 2-h cumulative period of nCPAP. RESULTS: Significantly lower TcCO2 values were observed during nHFOV compared with nCPAP: 47.5 ± 7.6 versus 49.9 ± 7.2 mmHg, respectively, P = 0.0007. A different TcCO2 behavior was found according to the random sequence: in patients starting on nCPAP, TcCO2 significantly decreased from 50.0 ± 8.0 to 46.6 ± 7.5 mmHg during nHFOV (P = 0.001). In patients starting on nHFOV, TcCO2 slightly increased from 48.5 ± 7.8 to 49.9 ± 6.7 mmHg during nCPAP (P = 0.13). CONCLUSIONS: nHFOV delivered through nasal prongs is more effective than nCPAP in improving the elimination of CO2 .

New Insights on Early Patterns of Respiratory Disease among Extremely Low Gestational Age Newborns.

BACKGROUND: The analysis of early patterns of lung disease among preterm infants may help to identify predictors of pulmonary deterioration. OBJECTIVES: To analyze FIO2 requirement in the first 14 days of life among preterm infants and to find predictors of bronchopulmonary dysplasia (BPD). METHODS: Retrospective cohort study. SETTING: 3 Italian level III NICUs. POPULATION: infants born between 240/7 and 276/7 weeks' gestational age (GA) who survived to 14 days. A consecutive sample of 588 infants was analyzed. Daily mode FIO2 in the first 2 weeks of life were analyzed according to the criteria defined by Laughon et al. [Pediatrics 2009;123:1124-1131], who found 3 early respiratory patterns: consistently low FIO2 (LowFIO2), pulmonary deterioration (PD), and early persistent pulmonary deterioration (EPPD). Factors associated with pulmonary deterioration were studied by univariate and multivariate analysis. RESULTS: Forty percent of infants had low FIO2, 18% had pulmonary deterioation, 21% had early persistent pulmonary deterioration, and 21% had a previously unreported pattern (pulmonary improvement, PI). The prevalence of BPD was 7% in the LowFIO2 group, 28% in the PI group, 44% in the PD group, and 62% in the EPPD group (p = 0.000). Infants with lung deterioration were more frequently males (OR = 2.019, CI: 1.319-3.090, p = 0.001), had lower GA (OR = 0.945, CI: 0.915-0.975, p = 0.000), higher incidence of severe respiratory distress syndrome (OR = 2.956, CI: 1.430-6.112, p = 0.003), and lack of postnatal caffeine (OR = 0.167, CI: 0.052-0.541, p = 0.003). CONCLUSIONS: We report 4 distinct patterns of early respiratory disease associated with significantly different prevalence of BPD and discuss risk factors for lung deterioration.

Oxygen administration at birth in preterm infants: a retrospective analysis.

OBJECTIVE: The aim of the study was to retrospectively investigate the association between initial oxygen concentration in delivery room and short-term outcomes in preterm infants. METHODS: Data from infants needing neonatal resuscitation, born at our department between January 2008 and December 2011, were analyzed. Patients were divided into three groups based on gestational age: between 32 and 36 weeks, between 31 and 28 weeks, and below 28 weeks. RESULTS: The administration of each additional unit of oxygen up to 50% showed an association with a 5% increased need for mechanical ventilation (MV) in the neonatal intensive care unit in infants between 32 and 36 weeks [adjusted odds ratio 1.1, 95% confidence interval (CI) 1.04-1.1] and infants between 28 and 31 weeks (adjusted odds ratio 1.12, 95% CI 1.08-1.44). On the contrary, in infants below 28 weeks, increasing initial concentration of supplementary oxygen did not show any association with MV. CONCLUSIONS: Initial oxygen concentration seems to be associated with increased MV in the NICU. Our observations further stress the need for randomized controlled studies in order to obtain definitive recommendations for the optimal initial oxygen concentration during neonatal resuscitation of preterm infants.

Calcium signaling-related proteins are associated with broncho-pulmonary dysplasia progression.

Broncho-pulmonary dysplasia (BPD) is a chronic pulmonary disorder that follows premature birth. It is preceded by respiratory distress syndrome (RDS), characterized by acute respiratory failure due to deficiency of surfactant at birth. Clinical characteristics of infants affected by BPD have widely changed in the last decades: they are extraordinarly immature, with impaired alveolar and vascular lung development. To build up new therapeutic strategies for BPD babies, it is necessary to understand the pathogenic mechanisms, which are complicated by environmental risk factors and genetic predisposition. Therefore, the aim of this study was to highlight protein changes in the broncho-alveolar lavage fluid (BALF), thus providing an appropriate picture on what is happening in the locus of injury. We analyzed BALF samples from preterm babies, born at different stages of lung development. We confirmed that gestational age is relevant for BPD progression, but we also detected few de-regulated proteins in the younger babies; we discovered less abundant calcium signaling-related proteins, consistent with BPD severity, comparing severe to mild BPD babies with matched gestational age. In conclusion, this study suggests a subset of proteins to be investigated to better treat BPD babies and facilitate the definition of potential drug targets for novel therapies. BIOLOGICAL SIGNIFICANCE: Pulmonary biomarkers are needed to predict the clinical course of lung disease, status, progression and response to treatment. A key aspect in biomarker discovery is uncovering molecules that appear early during disease initiation, when the natural history of the disease can be modified. Using a proteomic-based approach we compared broncho-alveolar lavage fluid (BALF) protein profile from preterm neonates at different postmenstrual ages, to have a molecular description of broncho-pulmonary dysplasia (BPD) progression. BALF provided a snapshot of local molecular changes, which are relevant for early diagnosis, assessment and characterization of lung disorders. We showed that even if the studied patients had similar clinical phenotype (they all developed severe BPD and they were all cured in the same way in terms of mechanical ventilation, surfactant administration, antenatal steroid treatment and ibuprofen treatment for patent ductus arteriosus), however their BALF protein profiling displayed significant differences in a subset of proteins, which could be exploited to facilitate the development of novel effective therapies, distinct for age and severity of the disease.

Nasal continuous positive airway pressure with heliox in preterm infants with respiratory distress syndrome.

OBJECTIVE: To assess the therapeutic effects of breathing a low-density helium and oxygen mixture (heliox, 80% helium and 20% oxygen) in premature infants with respiratory distress syndrome (RDS) treated with nasal continuous positive airway pressure (NCPAP). METHODS: Infants born between 28 and 32 weeks of gestational age with radiologic findings and clinical symptoms of RDS and requiring respiratory support with NCPAP within the first hour of life were included. These infants were randomly assigned to receive either standard medical air (control group) or a 4:1 helium and oxygen mixture (heliox group) during the first 12 hours of enrollment, followed by medical air until NCPAP was no longer needed. RESULTS: From February 2008 to September 2010, 51 newborn infants were randomly assigned to two groups, 24 in the control group and 27 in the heliox group. NCPAP with heliox significantly decreased the risk of mechanical ventilation in comparison with NCPAP with medical air (14.8% vs 45.8%). CONCLUSIONS: Heliox increases the effectiveness of NCPAP in the treatment of RDS in premature infants.

Uptake of KRAS mutation testing in patients with metastatic colorectal cancer in Europe, Latin America and Asia.

The mutation status of the KRAS gene in the tumors of patients with metastatic colorectal cancer (mCRC) is a predictive biomarker for the efficacy of epidermal growth factor receptor monoclonal antibody therapy. The establishment of KRAS mutation testing in this setting represents a significant change to standard diagnostic procedures and a major advance in the personalization of cancer care. Against a changing regulatory background, three cross-sectional surveys of physicians in 14 countries in Europe, Latin America and Asia were conducted in 2008, 2009, and 2010 to investigate the uptake and outcome of KRAS testing for patients with mCRC. Physicians in each year answered questions on four patients (last patient seen and last seen in first-, second- and third-line settings). Fieldwork was carried out February-May 2008, January-April 2009, and January-April 2010. Data from 3,819, 3,740 and 3,820 anonymized, uncoded patient records were collated. The frequency of KRAS testing in patients with mCRC increased from 3% in 2008 to 47% in 2009 and 69% in 2010. The 2010 survey revealed that test results were available within 15 days for 82%, 51% and 98% of the 1679, 679, and 261 tested patients in the European, Latin American and Asian regions, respectively. Cetuximab was the most commonly administered targeted agent in tested patients with KRAS wild-type mCRC (798/1607 patients; 50%) and bevacizumab was the most commonly administered targeted agent in tested patients with KRAS mutant tumors (396/893; 44% overall). In conclusion, KRAS testing is now widely established as a routine diagnostic procedure for patients with mCRC and is used increasingly to guide treatment selection.