Hyperoxia-Induced miR-195 Causes Bronchopulmonary Dysplasia in Neonatal Mice.

Background: Exposure to hyperoxia is an important factor in the development of bronchopulmonary dysplasia (BPD) in preterm newborns. MicroRNAs (miRs) have been implicated in the pathogenesis of BPD and provide a potential therapeutic target. Methods: This study was conducted utilizing a postnatal animal model of experimental hyperoxia-induced murine BPD to investigate the expression and function of miR-195 as well as its molecular signaling targets within developing mouse lung tissue. Results: miR-195 expression levels increased in response to hyperoxia in male and female lungs, with the most significant elevation occurring in 40% O2 (mild) and 60% O2 (moderate) BPD. The inhibition of miR-195 improved pulmonary morphology in the hyperoxia-induced BPD model in male and female mice with females showing more resistance to injury and better recovery of alveolar chord length, septal thickness, and radial alveolar count. Additionally, we reveal miR-195-dependent signaling pathways involved in BPD and identify PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) as a novel specific target protein of miR-195. Conclusions: Our data demonstrate that high levels of miR-195 in neonatal lungs cause the exacerbation of hyperoxia-induced experimental BPD while its inhibition results in amelioration. This finding suggests a therapeutic potential of miR-195 inhibition in preventing BPD.

Iron Deficiency Prior to Discharge in Very Low Birth Weight Infants: Screening with Reticulocyte Hemoglobin Content.

OBJECTIVE: This study aimed to assess the iron status prior to discharge in very low birth weight (VLBW) infants utilizing reticulocyte hemoglobin content (CHr) and evaluate the impact of delayed cord clamping (DCC) on iron status. STUDY DESIGN: This is a retrospective analysis of VLBW infants from two tertiary level of care Neonatal Intensive Care Units. The primary outcome was the proportion of VLBW infants with low CHr (<29 pg) prior to discharge. Hematologic parameters were also compared between infants who received or did not receive DCC. Infants with a positive newborn screen for hemoglobin Bart's were excluded. RESULTS: Among the 315 infants included, 99 infants (31.4%) had low CHr prior to discharge. The median (interquartile range) CHr prior to discharge was 30.8 pg (28.4-39 pg). DCC was performed in 46.7% of infants. Hemoglobin at birth, discharge, and CHr prior to discharge were higher and the need for blood transfusion and the number of infants with low CHr prior to discharge were lower in the DCC group. CONCLUSION: Approximately 31.4% of VLBW infants had low CHr near the time of discharge suggesting they were iron deficient. DCC improved hematological parameters prior to discharge in VLBW infants. CHr content can be used to guide iron supplementation in VLBW infants to potentially improve their iron status and long-term neurocognitive outcomes. KEY POINTS: · DCC was associated with an improved hemoglobin and iron status at discharge in VLBW infants.. · CHr is an early and reliable marker for iron deficiency.. · Approximately one in three VLBW infants can be iron deficient at the time of discharge..

COVID-19 Infection During Pregnancy Induces Differential Gene Expression in Human Cord Blood Cells From Term Neonates.

Background: The COVID-19 pandemic continues worldwide with fluctuating case numbers in the United States. This pandemic has affected every segment of the population with more recent hospitalizations in the pediatric population. Vertical transmission of COVID-19 is uncommon, but reports show that there are thrombotic, vascular, and inflammatory changes in the placenta to which neonates are prenatally exposed. Individuals exposed in utero to influenza during the 1918 pandemic had increased risk for heart disease, kidney disease, diabetes, stomach disease and hypertension. Early exposure of COVID-19 during fetal life may lead to altered gene expression with potential long-term consequences. Objective: To determine if gene expression is altered in cord blood cells from term neonates who were exposed to COVID-19 during pregnancy and to identify potential gene pathways impacted by maternal COVID-19. Methods: Cord blood was collected from 16 term neonates (8 exposed to COVID-19 during pregnancy and 8 controls without exposure to COVID-19). Genome-wide gene expression screening was performed using Human Clariom S gene chips on total RNA extracted from cord blood cells. Results: We identified 510 differentially expressed genes (374 genes up-regulated, 136 genes down-regulated, fold change ≥1.5, p-value ≤ 0.05) in cord blood cells associated with exposure to COVID-19 during pregnancy. Ingenuity Pathway Analysis identified important canonical pathways associated with diseases such as cardiovascular disease, hematological disease, embryonic cancer and cellular development. Tox functions related to cardiotoxicity, hepatotoxicity and nephrotoxicity were also altered after exposure to COVID-19 during pregnancy. Conclusions: Exposure to COVID-19 during pregnancy induces differential gene expression in cord blood cells. The differentially expressed genes may potentially contribute to cardiac, hepatic, renal and immunological disorders in offspring exposed to COVID-19 during pregnancy. These findings lead to a further understanding of the effects of COVID-19 exposure at an early stage of life and its potential long-term consequences as well as therapeutic targets.

Pulmonary immune cell transcriptome changes in double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia.

BACKGROUND: Preterm infants with bronchopulmonary dysplasia (BPD) have lifelong increased risk of respiratory morbidities associated with environmental pathogen exposure and underlying mechanisms are poorly understood. The resident immune cells of the lung play vital roles in host defense. However, the effect of perinatal events associated with BPD on pulmonary-specific immune cells is not well understood. METHODS: We used a double-hit model of BPD induced by prenatal chorioamnionitis followed by postnatal hyperoxia, and performed a global transcriptome analysis of all resident pulmonary immune cells. RESULTS: We show significant up-regulation of genes involved in chemokine-mediated signaling and immune cell chemotaxis, and down-regulation of genes involved in multiple T lymphocyte functions. Multiple genes involved in T cell receptor signaling are downregulated and Cd8a gene expression remains downregulated at 2 months of age in spite of recovery in normoxia for 6 weeks. Furthermore, the proportion of CD8a+CD3+ pulmonary immune cells is decreased. CONCLUSIONS: Our study has highlighted that perinatal lung inflammation in a double-hit model of BPD results in short- and long-term dysregulation of genes associated with the pulmonary T cell receptor signaling pathway, which may contribute to increased environmental pathogen-associated respiratory morbidities seen in children and adults with BPD. IMPACT: In a translationally relevant double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia, we identified pulmonary immune cell-specific transcriptomic changes and showed that T cell receptor signaling genes are downregulated in short term and long term. This is the first comprehensive report delineating transcriptomic changes in resident immune cells of the lung in a translationally relevant double-hit model of BPD. Our study identifies novel resident pulmonary immune cell-specific targets for potential therapeutic modulation to improve short- and long-term respiratory health of preterm infants with BPD.

Hyperoxia causes miR199a-5p-mediated injury in the developing lung.

BACKGROUND: Hyperoxia-induced acute lung injury (HALI) is characterized by increased permeability and infiltration of inflammatory cells, impairment of alveolar development, and compromised lung function. Recent evidence has determined that microRNAs (miRs) are implicated in hyperoxia-induced lung injury, including bronchopulmonary dysplasia (BPD). However, the expression profile and functional role of miR199a-5p in developing lungs have not been reported. METHODS: The present study was undertaken to explore the role of miR199a-5p in developing mice lungs and human neonates. We exposed neonatal mice for 7 days, mouse lung epithelial cells (MLE12), mouse lung endothelial cells (MLECs), and macrophages (RAW246.7), to hyperoxia at different time points. RESULTS: Our results demonstrated enhanced miR199a-5p expression in hyperoxia-exposed mice lungs and cells, as well as in tracheal aspirates of infants developing BPD, with significant reduction in the expression of its target, caveolin-1. Next, we observed that miR199a-5p-mimic worsens HALI as evidenced by increased inflammatory cells, cytokines, and lung vascular markers. Conversely, miR199a-5p-inhibitor treatment attenuated HALI. CONCLUSION: Thus, our findings suggest that miR199a-5p is a potential target for attenuating HALI pathophysiology in the developing lung. Moreover, miR199a-5p-inhibitor could be part of a novel therapeutic strategy for improving BPD in preterm neonates.

Hypertensive disorders during pregnancy are associated with reduced severe intraventricular hemorrhage in very-low-birth-weight infants.

OBJECTIVE: To determine differences in severe intraventricular hemorrhage (IVH) between very-low-birth-weight (≤1500 g, VLBW) infants born to mothers with and without hypertensive disorders (HD). DESIGN/METHODS: Retrospective analysis from the Optum Neonatal Database. The primary outcome of interest was severe IVH (grade 3 or 4). Secondary outcomes included other neonatal morbidities, mortality, and length of hospitalization. Outcomes were compared between VLBW infants born to mothers with and without HD. RESULTS: A total of 5456 infants met inclusion criteria. After multivariable regression analysis, risks of severe IVH and bronchopulmonary dysplasia (BPD) were lower ([OR 0.42, 95% CI 0.33-0.89, p = 0.01] and [OR 0.75, 95% CI 0.58-0.97, p = 0.03], respectively) and median length of hospitalization was decreased in the HD group (49 versus 61 days, p < 0.001). CONCLUSIONS: VLBW infants born to mothers with HD have a decreased risk of severe IVH, BPD, and a shorter duration of hospitalization.

Identification of new biomarkers of bronchopulmonary dysplasia using metabolomics.

OBJECTIVE: To identify new biomarkers of bronchopulmonary dysplasia (BPD) in preterm neonates. STUDY DESIGN: Metabolomic study of prospectively collected tracheal aspirate (TA) samples from preterm neonates admitted in 2 neonatal intensive care units measured by a mass spectroscopy-based assay and analysed using partial least squares-discriminant analysis. RESULTS: We evaluated 160 TA samples from 68 neonates, 44 with BPD and 24 without BPD in the first week of life. A cluster of 53 metabolites was identified as characteristic of BPD, with 18 select metabolites being highly significant in the separation of BPD versus No BPD. To control for the gestational age (GA) differences, we did a sub-group analyses, and noted that the amino acids histidine, glutamic acid, citrulline, glycine and isoleucine levels were higher in neonates with BPD. In addition, acylcarnitines C16-OH and C18:1-OH were also higher in neonates who developed BPD, but especially in the most preterm infants (neonates with GA < 27 weeks). CONCLUSION: Metabolomics is a promising approach to identify novel specific biomarkers for BPD.

Adverse effects of small for gestational age differ by gestational week among very preterm infants.

OBJECTIVE: To characterise the excess risk for death, grade 3-4 intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) and stage 3-5 retinopathy of prematurity independently associated with birth small for gestational age (SGA) among very preterm infants, stratified by completed weeks of gestation. METHODS: Retrospective cohort study using the Optum Neonatal Database. Study infants were born <32 weeks gestation without severe congenital anomalies. SGA was defined as a birth weight <10th percentile. The excess outcome risk independently associated with SGA birth among SGA babies was assessed using adjusted risk differences (aRDs). RESULTS: Of 6708 infants sampled from 717 US hospitals, 743 (11.1%) were SGA. SGA compared with non-SGA infants experienced higher unadjusted rates of each study outcome except grade 3-4 IVH among survivors. The excess risk independently associated with SGA birth varied by outcome and gestational age. The highest aRD for death (0.27; 95% CI 0.13 to 0.40) occurred among infants born at 24 weeks gestation and declined as gestational age increased. In contrast, the peak aRDs for BPD among survivors (0.32; 95% CI 0.20 to 0.44) and the composites of death or BPD (0.35; 95% CI 0.24 to 0.46) and death or major morbidity (0.35; 95% CI 0.24 to 0.45) occurred at 27 weeks gestation. The risk-adjusted probability of dying or developing one or more of the evaluated morbidities among SGA infants was similar to that of non-SGA infants born approximately 2-3 weeks less mature. CONCLUSION: The excess risk for neonatal morbidity and mortality associated with being born SGA varies by adverse outcome and gestational age.

Do infants in the neonatal intensive care unit diagnosed with urinary tract infection need a routine voiding cystourethrogram?

OBJECTIVE: To determine if infants diagnosed with urinary tract infection (UTI) in the neonatal intensive care unit (NICU) require a routine voiding cystourethrogram (VCUG). STUDY DESIGN: Retrospective data analysis from three centers for infants admitted to the NICU born between 2000 and 2013 and diagnosed with UTI. RESULTS: One hundred twenty-six infants from three centers were diagnosed with UTI during their hospitalization. Renal ultrasound (RUS) was performed in 115 infants (91.2%), of which 69 (60%) were abnormal. Mild to moderate hydronephrosis or pelviectasis were the most common abnormalities identified (n = 34, 30%). There were 14 infants (12%) with severe abnormalities on RUS. VCUG was performed in 71 infants (56%), of which 3 (4%) were interpreted as abnormal with grade 2 vesicoureteral reflux (VUR) or less (two infants were with normal RUS and one infant was with abnormal RUS). CONCLUSIONS: More than 50% of infants with a UTI had an abnormal RUS but severe abnormalities were found only in 11% of infants. Only 4% of infants with UTI had VUR; none of these infants had severe VUR on VCUG. A routine VCUG after UTI in the NICU has a low yield and may be reserved for infants with severe or persistent abnormalities on RUS.

Association between early antibiotic exposure and bronchopulmonary dysplasia or death.

OBJECTIVE: To characterize the independent association between antibiotic exposure in the first week of life and the risk of bronchopulmonary dysplasia (BPD) or death among very preterm infants without culture-confirmed sepsis. METHODS: Retrospective cohort study using the Optum Neonatal Database. Infants without culture-confirmed sepsis born less than 1500 g and less than 32 weeks gestation between 1/2010 and 11/2016 were included. The independent association between antibiotic therapy during the first week of life and BPD or death prior to 36 weeks postmenstrual age (PMA) was assessed by multivariable logistic regression. RESULTS: Of 4950 infants, 3946 (79.7%) received antibiotics during the first week of life. Rates of BPD or death (41.5% vs. 31.1%, p < 0.001) and the two individual outcomes were significantly higher among antibiotic treated infants. After adjusting for potential confounding variables, antibiotic use in the first week of life was not associated with increased risk of BPD or death (OR 0.96, 95% CI [0.76,1.21]) or BPD among survivors (OR 0.86, 95% CI [0.67,1.09]). Antibiotic use was associated with increased risk of death prior to 36 weeks PMA (OR 3.01, 95% CI [1.59,5.71]), however, secondary analyses suggested this association may be confounded by unmeasured illness severity. CONCLUSIONS: Antibiotic exposure in the first week of life among preterm infants without culture-confirmed sepsis was not independently associated with increased risk of BPD or death.

Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes.

OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap.

Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs.

Hyperoxia-induced acute lung injury (HALI) is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in neonates, for which no specific preventive or therapeutic agent is available. Here we show that lung micro-RNA (miR)-34a levels are significantly increased in lungs of neonatal mice exposed to hyperoxia. Deletion or inhibition of miR-34a improves the pulmonary phenotype and BPD-associated pulmonary arterial hypertension (PAH) in BPD mouse models, which, conversely, is worsened by miR-34a overexpression. Administration of angiopoietin-1, which is one of the downstream targets of miR34a, is able to ameliorate the BPD pulmonary and PAH phenotypes. Using three independent cohorts of human samples, we show that miR-34a expression is increased in type 2 alveolar epithelial cells in neonates with respiratory distress syndrome and BPD. Our data suggest that pharmacologic miR-34a inhibition may be a therapeutic option to prevent or ameliorate HALI/BPD in neonates.

The Airway Microbiome at Birth.

Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease.

Continuous Positive Airway Pressure versus Mechanical Ventilation on the First Day of Life in Very Low-Birth-Weight Infants.

Objective The objective of this study was to determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in very low-birth-weight (VLBW) infants managed successfully on continuous positive airway pressure (CPAP) versus mechanical ventilation on the first day of life (DOL). Study Design This is a retrospective analysis of the Alere neonatal database for infants born between January 2009 and December 2014, weighing ≤ 1,500 g. Baseline demographics, clinical characteristics, and outcomes were compared between the two groups. Multivariable regression analysis was performed to control the variables that differ in bivariate analysis. Results In this study, 4,629 infants (birth weight 1,034 ± 290 g, gestational age 28.1 ± 2.5 weeks) met the inclusion criteria. The successful use of early CPAP was associated with a significant reduction in BPD or death (p < 0.001), as well as days to room air, decreased oxygen use at discharge, lower risk for severe intraventricular hemorrhage, and patent ductus arteriosus requiring surgical ligation (p < 0.001 for all outcomes). Conclusion Successful use of early CPAP on the first DOL in VLBW infants is associated with a reduced risk of BPD or death.

High Flow Nasal Cannula Use Is Associated with Increased Morbidity and Length of Hospitalization in Extremely Low Birth Weight Infants.

OBJECTIVE: To determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in extremely low birth weight infants managed on high flow nasal cannula (HFNC) vs continuous positive airway pressure (CPAP). STUDY DESIGN: This is a retrospective data analysis from the Alere Neonatal Database for infants born between January 2008 and July 2013, weighing ≤1000 g at birth, and received HFNC or CPAP. Baseline demographics, clinical characteristics, and neonatal outcomes were compared between the infants who received CPAP and HFNC, or HFNC ± CPAP. Multivariable regression analysis was performed to control for the variables that differ in bivariate analysis. RESULTS: A total of 2487 infants met the inclusion criteria (941 CPAP group, 333 HFNC group, and 1546 HFNC ± CPAP group). The primary outcome of BPD or death was significantly higher in the HFNC group (56.8%) compared with the CPAP group (50.4%, P < .05). Similarly, adjusted odds of developing BPD or death was greater in the HFNC ± CPAP group compared with the CPAP group (OR 1.085, 95% CI 1.035-1.137, P = .001). The number of ventilator days, postnatal steroid use, days to room air, days to initiate or reach full oral feeds, and length of hospitalization were significantly higher in the HFNC and HFNC ± CPAP groups compared with the CPAP group. CONCLUSIONS: In this retrospective study, use of HFNC in extremely low birth weight infants is associated with a higher risk of death or BPD, increased respiratory morbidities, delayed oral feeding, and prolonged hospitalization. A large clinical trial is needed to evaluate long-term safety and efficacy of HFNC in preterm infants.

Effects of Multiple Ventilation Courses and Duration of Mechanical Ventilation on Respiratory Outcomes in Extremely Low-Birth-Weight Infants.

IMPORTANCE: Extubation failure is common in extremely preterm infants. The current paucity of data on the adverse long-term respiratory outcomes associated with reinitiation of mechanical ventilation prevents assessment of the risks and benefits of a trial of extubation in this population. OBJECTIVE: To evaluate whether exposure to multiple courses of mechanical ventilation increases the risk of adverse respiratory outcomes before and after adjustment for the cumulative duration of mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of extremely low-birth-weight (ELBW; birth weight <1000 g) infants born from January 1, 2006, through December 31, 2012, who were receiving mechanical ventilation. Analysis was conducted between November 2014 and February 2015. Data were obtained from the Alere Neonatal Database. EXPOSURES: The primary study exposures were the cumulative duration of mechanical ventilation and the number of ventilation courses. MAIN OUTCOMES AND MEASURES: The primary outcome was bronchopulmonary dysplasia (BPD) among survivors. Secondary outcomes were death, use of supplemental oxygen at discharge, and tracheostomy. RESULTS: We identified 3343 ELBW infants, of whom 2867 (85.8%) survived to discharge. Among the survivors, 1695 (59.1%) were diagnosed as having BPD, 856 (29.9%) received supplemental oxygen at discharge, and 31 (1.1%) underwent tracheostomy. Exposure to a greater number of mechanical ventilation courses was associated with a progressive increase in the risk of BPD and use of supplemental oxygen at discharge. Compared with a single ventilation course, the adjusted odds ratios for BPD ranged from 1.88 (95% CI, 1.54-2.31) among infants with 2 ventilation courses to 3.81 (95% CI, 2.88-5.04) among those with 4 or more courses. After adjustment for the cumulative duration of mechanical ventilation, the odds of BPD were only increased among infants exposed to 4 or more ventilation courses (adjusted odds ratio, 1.44; 95% CI, 1.04-2.01). The number of ventilation courses was not associated with increased risk of supplemental oxygen use at discharge after adjustment for the length of ventilation. A greater number of ventilation courses did not increase the risk of tracheostomy. CONCLUSIONS AND RELEVANCE: Among ELBW infants, a longer cumulative duration of mechanical ventilation largely accounts for the increased risk of chronic respiratory morbidity associated with reinitiation of mechanical ventilation. These results support attempts of extubation in ELBW infants receiving mechanical ventilation on low ventilator settings, even when success is not guaranteed.

Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: To determine if an early commencement of caffeine is associated with improved survival without bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Retrospective data analysis from the Alere Neonatal Database for infants weighing ≤1250 g, and treated with caffeine within the first 10 days of life. The neonatal outcomes were compared between the infants who received early caffeine (0-2 days) with the infants who received delayed caffeine (3-10 days). RESULTS: A total of 2951 infants met the inclusion criteria (early caffeine 1986, late caffeine 965). The early use of caffeine was associated with reduction in BPD (OR 0.69, 95% CI 0.58-0.82, p < 0.001) and BPD or death (OR 0.77, 95% CI 0.63-0.94, p = 0.01). Other respiratory outcomes also improved with the early commencement of caffeine. The frequency of severe intraventricular hemorrhage and patent ductus arteriosus was lower and the length of hospitalization was shorter in infants receiving early caffeine therapy. However, early use of caffeine was associated with an increase in the risk of nectrotizing enterocolits (NEC) (OR 1.41, 95% CI 1.04-1.91, p = 0.027). CONCLUSION: Early commencement of caffeine was associated with improvement in survival without BPD in preterm infants. The risk of NEC with early caffeine use requires further investigation.

IFN-γ and IP-10 in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia.

BACKGROUND: Interferon-gamma (IFN-γ) and interferon-inducible protein of 10 kDa (IP-10) are potent inflammatory mediators and contribute to acute lung injury in adults. Recently, a potential role for IFN-γ and IP-10 in the pathogenesis of bronchopulmonary dysplasia (BPD) has been reported in animal models. OBJECTIVE: To study the association between IFN-γ and IP-10 in tracheal aspirate (TA) and the development of BPD in premature infants. DESIGN/METHODS: TA samples collected within 48 hr after birth from 79 mechanically ventilated premature neonates [gestational age (GA) <30 weeks (w), birth weight (BW) <1,250 g (g)] were analyzed. IFN-γ was measured in a subgroup of 38 infants by using a biochip multi-analyte immunoassay. The level of IP-10 was determined using a commercially available ELISA kit. Total protein in TA was measured by Bradford assay to correct for sampling related dilution. BPD was defined as the need of supplemental oxygen at 36 weeks postmenstrual age (PMA). RESULTS: Twenty infants (GA 26.4 ± 1.9w, BW 860 ± 201 g) survived without BPD at 36 weeks PMA and 59 infants (GA 25.5 ± 1.5w, BW 751 ± 163 g) died before 36 weeks PMA or developed BPD. The mean IFN-γ level was higher in infants who died or developed BPD (9.7 ± 2.8 vs. 3.1 ± 1.1 pg/ml, P = 0.03). Similarly, the mean IP-10 level was higher in infants who died or developed BPD (63.4 ± 17.5 pg/ml) compared to those who survived without BPD (18.5 ± 7.5 pg/ml, P = 0.02). CONCLUSIONS: Higher IFN-γ and IP-10 levels in TA samples are associated with the development of BPD or death in premature infants.

Impact of histological chorioamnionitis on tracheal aspirate cytokines in premature infants.

BACKGROUND: Histological chorioamnionitis (CHORIO) may increase inflammatory mediators in the lungs of preterm infants. OBJECTIVE: To study the impact of CHORIO on tracheal aspirate (TA) cytokines in ventilated infants. DESIGN/METHODS: TA samples collected within 48 hours after birth from 40 ventilated neonates (gestational age [GA] <30 weeks, body weight [BW] <1250 g) were analyzed. Levels of 12 cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, epidermal growth factor [EGF], interferon-γ [IFN-γ], monocyte chemotactic protein-1 [MCP-1], tumor necrosis factor-α [TNF-α], vascular endothelial growth factor [VEGF]) were measured using a biochip multianalyte immunoassay (Randox Laboratories, Antrim, UK). Total protein was measured by the Bradford assay. CHORIO assessment was done by a blinded pathologist. RESULTS: Twenty-six infants (GA 26.6 ± 1.4 weeks, BW 852 ± 162 g) had no CHORIO and 14 (GA 25.1 ± 1.0 weeks, BW 776 ± 164 g) had CHORIO. IL-1α, IL-1ß, IL-8, and VEGF were significantly higher in TA of infants with CHORIO. After correction for dilution, IL-1α, IL-1ß, and IL-8 were significantly elevated. Increased TA total cell count correlated with CHORIO, VEGF, EGF, MCP-1, IL-8, and IL-6 TA levels (all p ≤ 0.02). Ventilator, oxygen supplementation, and hospital days correlated with TA IFN-γ levels (all p ≤ 0.01). CONCLUSION: CHORIO is associated with increased specific proinflammatory mediators in TA samples of preterm infants.