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Objective: To study the association between Ureaplasma colonization and bronchopulmonary dysplasia (BPD) with different definitions in very low birth weight (VLBW) infants., Methods: A retrospective cohort study was performed with VLBW infants admitted from January 2019 to October 2021. Neonates with a positive respiratory tract Ureaplasma culture were included in the study group. Control group infants, matched for gestational age (±1 week), birth weight (±100 g), and birth year, had a negative respiratory tract Ureaplasma culture during the same period. The primary outcomes included the incidence and severity of BPD, defined by various criteria., Results: The study included 302 neonates (151 in the study group and 151 in the control group). After adjusting for confounders, Ureaplasma colonization was not associated with BPD as defined by the National Institutes of Health (NIH) in 2001 (adjusted odds ratio [aOR]: 0.820, 95% confidence interval [CI]: 0.362-1.860, p = .635). However, it was associated with BPD as defined by the NIH in 2018 (aOR: 2.490, 95% CI: 1.128-5.497, p = .024) and the Neonatal Research Network (NRN) in 2019 (aOR: 2.352, 95% CI: 1.077-5.134, p = .032). Additionally, VLBW infants with Ureaplasma colonization had a higher risk of moderate-severe BPD according to the NIH 2001 (aOR: 2.352, 95% CI: 1.077-5.134, p = .032), NIH 2018 (aOR: 6.339, 95% CI: 1.686-23.836, p = .006), and NRN 2019 definitions (aOR: 3.542, 95% CI: 1.267-9.904, p = .016)., Conclusions: Ureaplasma colonization is not associated with BPD by the NIH 2001 definition, but is associated with an increased incidence by the NIH 2018 or NRN 2019 definitions., (© 2024 Wiley Periodicals LLC.)

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects premature infants and leads to long-term pulmonary complications. The pathogenesis of BPD has not been fully elucidated yet. In recent years, the microbiome and its metabolites, especially short-chain fatty acids (SCFAs), in the gut and lungs have been demonstrated to be involved in the development and progression of the disease. This review aims to summarize the current knowledge on the potential involvement of the microbiome and SCFAs, especially the latter, in the development and progression of BPD. First, we introduce the gut-lung axis, the production and functions of SCFAs, and the role of SCFAs in lung health and diseases. We then discuss the evidence supporting the involvement of the microbiome and SCFAs in BPD. Finally, we elaborate on the potential mechanisms of the microbiome and SCFAs in BPD, including immune modulation, epigenetic regulation, enhancement of barrier function, and modulation of surfactant production and the gut microbiome. This review could advance our understanding of the microbiome and SCFAs in the pathogenesis of BPD, which also helps identify new therapeutic targets and facilitate new drug development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Wang, Lin, Cai, Peng, He, Qi, Jin and Qian.)

Numerous studies have examined the role of the microbiome and microbiome-based therapeutics in many childhood airway and lung diseases. In this narrative review, the authors first give a brief overview of the current methods used in microbiome research. The authors then review the literature linking the microbiome with (1) early-life acute respiratory infections due to respiratory syncytial virus, (2) childhood asthma onset, (3) cystic fibrosis, and (4) bronchopulmonary dysplasia, focusing on recent studies that have used culture-independent methods to characterize the respiratory or gut microbiome in the pediatric population., Competing Interests: Disclosure Dr E.T. Zemanick reports grants and personal consulting fees from the Cystic Fibrosis Foundation, Unites States and Vertex Pharmaceuticals, Unites States. Dr C. Rosas-Salazar reports grants from the NIH, Unites States/NHLBI, Unites States, NIH/OD, and NIH/NHLBI, as well as an ongoing consultant service from Amgen, Unites States and AstraZeneca, United Kingdom., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The gut microbiota undergoes substantial development from birth, and its development in the initial years of life has a potentially lifelong effect on the health of the individual. However, various factors can disrupt the development of the gut microbiota, leading to a condition known as dysbiosis, particularly in preterm infants. Current studies involving adults have suggested that the gut microbiota not only influences the gut but also has multidimensional effects on remote organs; these pathways are often referred to as the gut-organ axis. Imbalance of the gut microbiota may lead to the development of multiple diseases. Recent studies have revealed that gut dysbiosis in preterm infants may cause several acute morbidities-such as necrotizing enterocolitis, late-onset sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity-and it may also influence long-term outcomes including neurodevelopment and somatic growth. This review mainly presents the existing evidence regarding the relationships between the gut microbiota and these morbidities in preterm infants and explores the role of the gut-organ axis in these morbidities. This paper thus offers insights into the future perspectives on microbiota interventions for promoting the health of preterm infants., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases., (© 2024. The Author(s).)

Objectives: To investigate the clinical characteristics of Ureaplasma urealyticum (UU) infection and colonization in extremely preterm infants and its impact on the incidence of bronchopulmonary dysplasia (BPD)., Methods: A retrospective analysis was conducted on 258 extremely preterm infants who were admitted to the Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, from September 2018 to September 2022. According to the results of UU nucleic acid testing and the evaluation criteria for UU infection and colonization, the subjects were divided into three groups: UU-negative group (155 infants), UU infection group (70 infants), and UU colonization group (33 infants). The three groups were compared in terms of general information and primary and secondary clinical outcomes., Results: Compared with the UU-negative group, the UU infection group had significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay ( P <0.05), while there were no significant differences in the incidence rates of BPD and moderate/severe BPD between the UU colonization group and the UU-negative group ( P >0.05)., Conclusions: The impact of UU on the incidence of BPD in extremely preterm infants is associated with the pathogenic state of UU (i.e., infection or colonization), and there are significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay in extremely preterm infants with UU infection. UU colonization is not associated with the incidence of BPD and moderate/severe BPD in extremely preterm infants.

Background: Ureaplasma species are considered commensals of the adult urogenital tract. Yet, in pregnancy, Ureaplasma parvum and Ureaplasma urealyticum have been associated with chorioamnionitis and preterm birth. In preterm infants, Ureaplasma respiratory tract colonization has been correlated with the development of bronchopulmonary dysplasia and has been implicated in the pathogenesis of other complications of prematurity. Controversies on the impact of Ureaplasma exposure on neonatal morbidity, however, remain, and recommendations for screening practices and therapeutic management in preterm infants are missing., Summary: In this review, we outline clinical and experimental evidence of Ureaplasma-driven fetal and neonatal morbidity, critically examining inconsistencies across some of the existing studies. We explore underlying mechanisms of Ureaplasma-associated neonatal morbidity and discuss gaps in the current understanding including the interplay between Ureaplasma and the maternal urogenital tract and the preterm airway microbiome. Ultimately, we highlight the importance of adequate diagnostics and review the potential efficacy of anti-infective therapies., Key Messages: There is strong evidence that perinatal Ureaplasma exposure is causally related to the development of bronchopulmonary dysplasia, and there are conclusive data of the role of Ureaplasma in the pathogenesis of neonatal central nervous system infection. Observational and experimental findings indicate immunomodulatory capacities that might promote an increased risk of secondary infections. The burden of Ureaplasma exposure is inversely related to gestational age - leaving the tiniest babies at highest risk. A better knowledge of contributing pathogen and host factors and modulating conditions remains paramount to define screening and treatment recommendations allowing early intervention in preterm infants at risk., (© 2024 S. Karger AG, Basel.)

Objective: Bronchopulmonary dysplasia (BPD) is a complex chronic lung disease that primarily affects premature or critically ill infants. This pilot study investigated early changes in gut microbiota composition in BPD patients and explored the potential risk factors associated with these changes., Study Design: Preterm infants admitted to our neonatal intensive care unit with a gestational age of 26 to 32 weeks were prospectively surveyed and eligible for stool collection on days 7 and 28 of postnatal age between February 2016 and June 2017. A 16S rRNA sequencing approach was applied to compare the gut microbiota composition between the BPD group and controls. Multiple linear regression analysis was used to identify the predictor variables., Results: Eight subjects in the BPD group and 10 subjects in the preterm group were analyzed during the observation period. Actinobacteria, Proteobacteria, Bacteroidetes, and Firmicutes were the four dominant bacteria phyla of intestinal microflora. A significantly lower diversity of gut microbiota was observed in the BPD group compared with the preterm group on day 28 (number of observed operational taxonomic units, p  = 0.034; abundance-based coverage estimator, p  = 0.022; Shannon index, p  = 0.028). Multiple linear regression analysis revealed that high Neonatal Therapeutic Intervention Scoring System score (≧19) at 24 hours was statistically significant in predicting the proportion of aerobic with facultative anaerobic bacteria on day 28 ( p  = 0.002)., Conclusion: Infants with BPD are prone to develop gut dysbiosis in early life. A higher severity of illness and treatment intensity may indicate a higher risk of disrupting an anaerobic environment in the gut during the first month of life., Key Points: · BPD patients are prone to develop gut dysbiosis.. · Lower diversity of gut microbiota.. · Higher risk of disrupting anaerobic environment.., Competing Interests: None declared., (Thieme. All rights reserved.)

Bronchopulmonary dysplasia is a chronic pulmonary disease with a high incidence in premature infants, and there is still no effective treatment. The purpose of our study was to analyze the association between the use of probiotics and BPD in premature infants. We retrospectively collected clinical data of infants with gestational age < 32 weeks admitted to the NICU of The First Hospital of Jilin University from January 1, 2019 to March 31, 2020. Demographic and clinicopathological data of the inclusion population were collected. The outcome was the incidence of BPD or death. The χ 2 tests was used to compare the categorical variables. The t test and non-parametric Wilcoxon rank-sum test were used to compare the continuous data. Univariate and multivariate logistic regression were used to analyze the association between probiotics and BPD. A total of 318 newborns met the inclusion criteria, of which 94 received probiotics and 224 received no probiotics. There were 16 deaths and 115 newborns with BPD in the included population. The results of univariate analysis showed differences in the maternal diabetes, the proportion of systemic antibiotics given to mother within 24 h before birth, the receiving rate of invasive mechanical ventilation, the prevalence of BPD/death, PDA, RDS and Ivh between newborns with and without probiotics (p < 0.05); The results of unadjusted univariate logistic regression model showed that probiotic (OR 0.034, 95% CI 0.012-0.096) was the factor affecting BPD in preterm infants (p < 0.05). Multivariate logistic regression result (OR 0.037, 95% CI 0.013-0.105) was consistent with univariate analysis (P < 0.001). Probiotics are associated with a reduced risk of BPD in preterm infants < 32 weeks of age. More prospective studies with large samples are still needed., (© 2021. The Author(s).)

Objective: The study aimed to evaluate the association between microbes in the lower respiratory tract (LRT) and the srisk for severe bronchopulmonary dysplasia (sBPD) in premature infants., Methods: We conducted a retrospective, single-center study of preterm infants who were admitted to the neonatal intensive care unit (NICU) of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, China, between January 2015 and December 2017. The microbes in the LRT were screened by using tracheobronchial aspirate fluid (TAF) culture., Results: One hundred and fifty-five infants were included in the analysis. Among 155 infants, 41 were diagnosed with sBPD, and 114 were diagnosed without sBPD. There were significant differences between infants with and without sBPD in regard to birth weight (BW), gestational age (GA), the duration of endotracheal ventilation and supplemental oxygen. The incidence of retinopathy (ROP) and sepsis was higher in the sBPD infants than in the infants without sBPD. There was a difference in the detection rate of Gram-negative bacteria (GNB) between the two groups. Stenotrophomonas maltophilia and Klebsiella pneumoniae were mainly detected in TAF., Conclusions: The LRT microbes were different between infants with and without sBPD, and GNB is more frequently detected in sBPD infants., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest in this work., (Copyright © 2020. Published by Elsevier B.V.)

Background: Chronic lung disease of prematurity (CLD), also called bronchopulmonary dysplasia, is a major consequence of preterm birth, but the role of the microbiome in its development remains unclear. Therefore, we assessed the progression of the bacterial community in ventilated preterm infants over time in the upper and lower airways, and assessed the gut-lung axis by comparing bacterial communities in the upper and lower airways with stool findings. Finally, we assessed whether the bacterial communities were associated with lung inflammation to suggest dysbiosis., Methods: We serially sampled multiple anatomical sites including the upper airway (nasopharyngeal aspirates), lower airways (tracheal aspirate fluid and bronchoalveolar lavage fluid) and the gut (stool) of ventilated preterm-born infants. Bacterial DNA load was measured in all samples and sequenced using the V3-V4 region of the 16S rRNA gene., Results: From 1102 (539 nasopharyngeal aspirates, 276 tracheal aspirate fluid, 89 bronchoalveolar lavage, 198 stool) samples from 55 preterm infants, 352 (32%) amplified suitably for 16S RNA gene sequencing. Bacterial load was low at birth and quickly increased with time, but was associated with predominant operational taxonomic units (OTUs) in all sample types. There was dissimilarity in bacterial communities between the upper and lower airways and the gut, with a separate dysbiotic inflammatory process occurring in the lower airways of infants. Individual OTUs were associated with increased inflammatory markers., Conclusions: Taken together, these findings suggest that targeted treatment of the predominant organisms, including those not routinely treated, such as Ureaplasma spp., may decrease the development of CLD in preterm-born infants., Competing Interests: Conflict of interest: D. Gallacher has nothing to disclose. Conflict of interest: E. Mitchell has nothing to disclose. Conflict of interest: D. Alber has nothing to disclose. Conflict of interest: R. Wach has nothing to disclose. Conflict of interest: N. Klein has nothing to disclose. Conflict of interest: J.R. Marchesi has nothing to disclose. Conflict of interest: S. Kotecha has nothing to disclose., (Copyright ©ERS 2020.)

The pathogenesis of Bronchopulmonary dysplasia (BPD) remains poorly understood. It is a multifactorial disease having a genetic-environmental basis. Although attempts have been made to identify a biomarker, none have been validated for clinical use to date. Metabolomics is a promising field of the "omics technologies" that could allow for better understanding of the pathogenesis and underlying mechanisms of BPD as well as facilitate detection of biomarkers. Identification of these biomarkers would improve diagnosis, identify patients in early disease stages and potentially target intervention. This review focuses on the evidence arising from metabolomics and its interaction with microbiomics and pharmacology with respect to pathogenesis and treatment options for this multifactorial complex disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Ureaplasma spp. is a known risk factor for bronchopulmonary dysplasia (BPD). However, little is known about the effect of different degrees of maternal Ureaplasma colonization and their adverse outcomes. Hence, the aim of this study was to determine the effects of different degrees of maternal Ureaplasma colonization on BPD., Methods: A retrospective cohort study of preterm infants delivered at <32 weeks' gestational age (GA) was performed. The infants were divided according to maternal Ureaplasma status as follows: high-colonization (≥10 4  CCU/ml, UUH), low-colonization (<10 4  CCU/ml, UUL), and noncolonization (controls). Subgroup analysis according to neonatal respiratory Ureaplasma (n-UU) was also performed to evaluate vertical transmission., Results: In total, 245 infants were included in this study (UUH = 105, UUL = 47, controls = 93). The rates of preterm labor and histological chorioamnionitis were significantly different. The rate of BPD was significantly high in UUH (P = 0.044). The transmission rate of n-UU colonization was 36% in UUH and 32% in UUL (P = 0.609). The rate of BPD was 78% in n-UU (+) of UUH but 43% in n-UU (-) of UUL (P = 0.027)., Conclusions: High-degree colonization of maternal Ureaplasma was associated with preterm labor, histological chorioamnionitis, and neonatal BPD. The incidence of BPD was significantly higher in Ureaplasma-colonized infants born to women with high-degree colonization., (Copyright © 2018. Published by Elsevier B.V.)

Our objective was to determine if broad spectrum antibiotics (BSA) are associated with multi-resistant bacterial (MRB) infections in neonatal patients. We conducted a case-control study with two groups of patients: those with and without a MRB infection. We included 43 cases and 43 controls. MRB strains were: 21 S. maltophila (49%), 11 ESBL-producing Enterobacteriae (25%), 8 P. aeruginosa (19%) and 3 MRSA (7%). Odds ratio (OR) for MRB after seven days of carbapenems was 4.25 (95% confidence interval (CI) 1.4-17.4) and OR for MRB after seven days of third generation cephalosporin was 8 (95% CI 1.1-34.9). BSA longer than seven days, increases MRB infections 22.5 times in patients with bronchopulmonary dysplasia (BPD). Our data show a clear association between the use of BSA and the development of MRB infections, especially in BPD. Although we cannot state this is a causal relationship, we can recommend avoiding prolonged treatment with these antibiotics in preterm babies at risk of BPD.

Objectives: To describe the findings, resulting changes in management, and safety profile of flexible bronchoscopy in the neonates with severe bronchopulmonary dysplasia., Study Design: This was a retrospective case series of twenty-seven neonates with severe bronchopulmonary dysplasia who underwent flexible bronchoscopy in the neonatal intensive care unit., Results: Flexible bronchoscopy revealed airway pathology in 20/27 (74%) patients. Tracheomalacia 13/27 (48%), bronchomalacia 11/27 (40.7%), and airway edema 13/27 (48%) were the most common findings. Bronchoalveolar lavage (BAL) was performed in 17 patients. BAL culture revealed a microorganism in 12/17 (70.5%) cases. Findings from bronchoscopy resulted in change in clinical management in 17/27 (63%) patients. Common interventions included initiation of antibiotics (37%) and treatment of tracheobronchomalacia with bethanechol (22.2%), atrovent (18.5%), and PEEP titration (18.5%). Bronchoscopy was performed without significant complication in 26/27 (97%) patients., Conclusion: Flexible bronchoscopy can be a safe and useful tool for the management of neonates with severe bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a major complication of preterm birth that leads to lifelong respiratory morbidity. The EPICure study has investigated the longitudinal health outcomes of infants born extremely preterm (EP; <26 weeks gestation). Our aim was to characterise the airway microbiome in young adults born extremely preterm, with and without neonatal BPD, in comparison to matched term-born controls.Induced sputum was collected from 92 young adults aged 19 years (51 EP and 41 controls). Typical respiratory pathogens were detected using quantitative PCR. 16S rRNA gene sequencing was completed on 74 samples (29 EP with BPD; 9 EP without BPD; and 36 controls).The preterm group with BPD had the least diverse bacterial communities. The relative abundance of Bacteriodetes, particularly Prevotella melaninogenica was significantly lower in the preterm group compared to controls. This decline was balanced by a nonsignificant increase in Firmicutes . Total Prevotella relative abundance correlated with forced expiratory volume in 1 s z-score (ρ=0.272; p<0.05). Typical respiratory pathogen loads and prevalence were similar between groups.In conclusion , extremely preterm birth is associated with a significant dysbiosis in airway microbiome in young adulthood regardless of neonatal BPD status. This is characterised by a shift in the community composition away from Bacteriodetes as manifested in a significant drop in Prevotella relative abundance., Competing Interests: Conflict of interest: S.A.D. Rofael reports personal fees and non-financial support from Newton Mosharafa scholarship, outside the submitted work. Conflict of interest: T.D. McHugh has nothing to disclose. Conflict of interest: R. Troughton has nothing to disclose. Conflict of interest: J. Beckmann has nothing to disclose. Conflict of interest: D. Spratt has nothing to disclose. Conflict of interest: N. Marlow reports personal fees for consultancy from Novartis and Shire, outside the submitted work. Conflict of interest: J.R. Hurst reports grants, personal fees and non-financial support for education activity and advisory board work, and support to attend meetings, from pharmaceutical companies that make medicines to treat COPD, outside the submitted work., (Copyright ©ERS 2019.)

Permall DL, Pasha AB, Chen XQ, Lu HY. The lung microbiome in neonates. Turk J Pediatr 2019; 61: 821-830. Despite the advent of culture-independent techniques to identify members of the microbiome, studies focusing on the lung microbiome of neonates are scarce. Understanding the role of the microbiome in the pathogenesis of pulmonary conditions affecting newborns could lead to the initiation of pioneering therapeutic interventions, which could potentially prevent lifelong disability. Bronchopulmonary dysplasia (BPD) has been associated with a less diverse microbiome, presence of Ureaplasma species and reduced Lactobacillus detection. Additionally, the potential role of microbial dysbiosis in the pathogenesis of asthma, cystic fibrosis and pneumonia has been described. There has also been a surge of interest in attempting to elucidate the interactions between the airway and gut microbiomes and their bearings on respiratory health and diseases to eventually broaden the scope of therapeutic interventions.

Objectives: To summarize evidence regarding microbial dysbiosis of the airway associated with bronchopulmonary dysplasia (BPD) and to explore heterogeneity among studies., Study Design: We included studies that evaluated the airway microbiome in preterm infants who developed BPD using culture-independent molecular techniques and reported alpha- and beta-diversity metrics and microbial profiles., Results: The 6 included studies had substantial clinical and methodological heterogeneity. Most studies reported the presence of an airway microbiome early after birth and an evolution in the first weeks of life with increasing bacterial loads. The early airway microbiome was dominated by Staphylococcus and Ureaplasma spp. Two studies reported differences in alpha- and beta- diversity indices in preterm infants with BPD compared with those who did not develop BPD. Increased microbial community turnover, changes in the relative abundance of Proteobacteria and Firmicutes, and decreased Lactobacilli were reported with BPD progression. Most included infants were born by cesarean delivery, and a majority were exposed to postnatal antibiotics. No data regarding feeding human milk or correlations with the development of gut microbiota (gut-lung axis) were available., Conclusions: Microbial dysbiosis may be associated with BPD progression and severity, and further study of microbiome optimization in preterm infants at risk for BPD is warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The pathogenesis of bronchopulmonary dysplasia (BPD) is not well understood. We previously identified differences in the airway microbiome at birth between preterm infants who were BPD predisposed versus those who were BPD resistant. In this study, we attempted to identify mechanisms by which the airway microbiome could modify the risk for BPD. We used a software-based method to predict the metagenome of the tracheal aspirate (TA) microbiome from 16S rRNA sequencing data in preterm infants and to identify functional ortholog genes that were differentially abundant in BPD-predisposed and BPD-resistant infants. We also identified metabolites that were differentially enriched in these samples by use of untargeted mass spectrometry and mummichog to identify the metabolic pathways involved. Microbial metagenome analysis identified specific pathways that were less abundant in the functional metagenome of the microbiota of BPD-predisposed infants compared with BPD-resistant infants. The airway metabolome of BPD-predisposed infants was enriched for metabolites involved in fatty acid activation and androgen and estrogen biosynthesis compared with BPD-resistant infants. These findings suggest that in extremely preterm infants the early airway microbiome may alter the metabolome, thereby modifying the risk of BPD. The differential enrichment of sex steroid metabolic pathways supports previous studies suggesting a role for sexual dimorphism in BPD risk. This study also suggests a role for metabolomic and metagenomic profiles to serve as early biomarkers of BPD risk.

Staphylococcus epidermidis accounts for the majority of cases of neonatal sepsis. Moreover, it has been demonstrated to be associated with neonatal morbidities, such as bronchopulmonary dysplasia (BPD), white matter injury (WMI), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP), which affect short-term and long-term neonatal outcome. Imbalanced inflammation has been considered to be a major underlying mechanism of each entity. Conventionally regarded as a harmless commensal on human skin, S. epidermidis has received less attention than its more virulent relative Staphylococcus aureus. Particularities of neonatal innate immunity and nosocomial environmental factors, however, may contribute to the emergence of S. epidermidis as a significant nosocomial pathogen. Neonatal host response to S. epidermidis sepsis has not been fully elucidated. Evidence is emerging regarding the implication of S. epidermidis sepsis in the pathogenesis of neonatal inflammatory diseases. This review focuses on the interplay among S. epidermidis, neonatal innate immunity and inflammation-driven organ injury.

The pathogenesis of Bronchopulmonary Dysplasia (BPD) is multifactorial and the clinical phenotype of BPD is extremely variable. Predicting BPD is difficult, as it is a disease with a clinical operational definition but many clinical phenotypes and endotypes. Most biomarkers studied over the years have low predictive accuracy, and none are currently used in routine clinical care or shown to be useful for predicting longer-term respiratory outcome. Targeted cellular and humoral biomarkers and novel systems biology 'omic' based approaches including genomic and microbiomic analyses are described in this review., (Copyright © 2016. Published by Elsevier B.V.)

Preterm birth exposes the developing lung to an environment with direct exposure to bacteria, often facilitated by endotracheal intubation. Despite evidence linking bacterial infections to the pathogenesis of bronchopulmonary dysplasia (BPD), systematic studies of airway microbiota are limited. The objective was to identify specific patterns of the early respiratory tract microbiome from tracheal aspirates of mechanically ventilated preterm infants that are associated with the development and severity of BPD. Infants with gestational age ≤34 weeks, and birth weight 500-1250g were prospectively enrolled. Mechanically ventilated infants had tracheal aspirate samples collected at enrollment, 7, 14, and 21 days of age. BPD was determined by modified NIH criteria with oxygen reduction tests; infants without BPD were excluded due to low numbers. Aspirates were processed for bacterial identification by 16S rRNA sequencing, and bacterial load by qPCR. Cross-sectional analysis was performed using 7 day samples and longitudinal analysis was performed from subjects with at least 2 aspirates. Microbiome analysis was performed on tracheal aspirates from 152 infants (51, 49, and 52 with mild, moderate, and severe BPD, respectively). Seventy-nine of the infants were included in the cross-sectional analysis and 94 in the longitudinal. Shannon Diversity, bacterial load, and relative abundance of individual taxa were not strongly associated with BPD status. Longitudinal analysis revealed that preterm infants who eventually developed severe BPD exhibited greater bacterial community turnover with age, acquired less Staphylococcus in the first days after birth, and had higher initial relative abundance of Ureaplasma. In conclusion, longitudinal changes in the airway microbial communities of mechanically ventilated preterm infants may be associated with BPD severity, whereas cross-sectional analysis of airway ecology at 7 days of age did not reveal an association with BPD severity. Further evaluation is necessary to determine whether the observed longitudinal changes are causal or in response to clinical management or other factors that lead to BPD., Competing Interests: The authors have declared that no competing interests exist.

Aim  We determined whether the bacteria in the lower respiratory tract (LRT) in extremely premature infants with severe bronchopulmonary dysplasia (BPD) are different from those with nonsevere BPD. Study Design  We conducted a retrospective study of extremely premature infants who were admitted to the neonatal intensive care unit of Fukushima Medical University Hospital, Japan between April 2005 and March 2014. We screened for the bacterial colonization of the LRT using tracheobronchial aspirate fluid. Results  A total of 169 extremely premature infants were included. Overall, 102 did not experience severe BPD, whereas the remaining 67 experienced severe BPD. Corynebacterium species (Cs) were more frequently detected in the severe BPD than nonsevere BPD infants ( p  = 0.03). There were significant differences between infants with and without severe BPD in the duration of endotracheal ventilation ( p  = 0.00, odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.06), the duration of supplemental oxygen ( p  = 0.00, OR, 1.02; 95% CI, 1.01-1.03) before 36 weeks of postmenstrual age, and the frequency of sepsis after 7 postnatal days ( p  = 0.01, OR, 1.73; 95% CI, 1.18-2.54). Conclusion  Cs are more likely to be present in the severe BPD infants with longer duration of endotracheal ventilation., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Both histologic chorioamnionitis (HCAM) and Ureaplasma infection are considered important contributors to perinatal lung injury. We tested the hypothesis that coexistence of maternal HCAM and perinatal Ureaplasma exposure increases the risk of prolonged mechanical ventilation in extremely low-birthweight (ELBW) infants., Methods: A retrospective cohort study was carried out of all ELBW infants born between January 2008 and December 2013 at a single academic center. Placental pathology and gastric fluid Ureaplasma data were available for all infants. Culture and polymerase chain reaction were used to detect Ureaplasma in gastric fluid. Prolonged mechanical ventilation was defined as mechanical ventilation that began within 28 days after birth and continued., Results: Of 111 ELBW infants enrolled, 84 survived beyond 36 weeks of postmenstrual age (PMA) and were included in the analysis. Eighteen infants (21.4%) had both HCAM and Ureaplasma exposure. Seven infants (8.3%) required mechanical ventilation beyond 36 weeks of PMA. Coexistence of HCAM and Ureaplasma in gastric fluid was significantly associated with prolonged mechanical ventilation after adjustment for gestational age, sex, mode of delivery, and use of macrolide antibiotics (OR, 8.7; 95%CI: 1.1-67.2)., Conclusions: Coexistence of maternal HCAM and perinatal Ureaplasma exposure significantly increases the risk of prolonged mechanical ventilation in ELBW infants., (© 2016 Japan Pediatric Society.)

Respiratory tract colonization with the genital mycoplasma species Ureaplasma parvum and Ureaplasma urealyticum in preterm infants is a significant risk factor for bronchopulmonary dysplasia (BPD). Recent studies of the ureaplasmal genome, animal infection models, and human infants have provided a better understanding of specific virulence factors, pathogen-host interactions, and variability in genetic susceptibility that contribute to chronic infection, inflammation, and altered lung development. This review provides an update on the current evidence supporting a causal role of ureaplasma infection in BPD pathogenesis. The current status of antibiotic trials to prevent BPD in Ureaplasma-infected preterm infants is also reviewed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: The aim of this study was to compare the incidence of bronchopulmonary dysplasia (BPD) in symptomatic ureaplasma-positive treated preterm infants and asymptomatic preterm infants not tested or treated for ureaplasma., Methods: A retrospective matched cohort study was conducted in a tertiary, neonatal unit between January 2007 and December 2012. Infants ≤29 completed weeks with signs and symptoms suggesting ureaplasma pneumonia who received macrolides comprised the study group. Infants ≤29 weeks without signs and symptoms not tested or treated with macrolides were the controls. Infants were mandatorily matched for gestational age ± one week or birthweight ± 100 grams., Results: There were 31 infants in the study group and 62 in the control group. The baseline demographic data of both groups were similar on the whole. The incidence of moderate and severe BPD, defined by oxygen dependency or the need for continuous positive airway pressure at 36 weeks of postconceptual age, was 45.2% in the study group and 40.3% in the controls (p = 0.65). There was no significant difference in morbidities or mortality between the groups., Conclusion: A selective approach of treating symptomatic ureaplasma-positive preterm infants with macrolides did not affect the incidence of moderate and severe BPD., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Bronchopulmonary dysplasia (BPD) is associated with perinatal inflammatory triggers. Methods targeting bacterial rRNA may improve detection of microbial colonization in premature infants. We hypothesize that respiratory microbiota differs between preterm infants who develop BPD and those unaffected and correlates with inflammatory mediator concentrations., Methods: Twenty-five infants, born at ≤32 wk of gestation and intubated in the first 24 h, were enrolled. Tracheal aspirates were obtained at intubation and on days 3, 7, and 28. Bacterial DNA was extracted, and 16S rRNA genes were amplified and sequenced. Concentrations of interleukins (IL-1β, IL-6, IL-8, IL-10, and IL-12), tumor necrosis factor-α, interferon-γ, lipopolysaccharide (LPS), and lipoteichoic acid (LTA) were measured. Chorioamnionitis was diagnosed by histology. BPD was defined as an oxygen requirement at 36 wk postmenstrual age., Results: Acinetobacter was the predominant genus in the airways of all infants at birth. Ten infants developed BPD and showed reduced bacterial diversity at birth. No differences were detected in bacterial diversity, cytokines, LPS, and LTA from infants with and without exposure to chorioamnionitis., Conclusion: The airways of premature infants are not sterile at birth. Reduced diversity of the microbiome may be an important factor in the development of BPD and is not associated with differences in inflammatory mediators.

There is controversy regarding the roles of Ureaplasma urealyticum (U. urealyticum) colonization in the development of bronchopulmonary dysplasia (BPD). This study explored the association between U. urealyticum and bronchopulmonary dysplasia at 36 weeks post-menstrual age (BPD36). Studies published before December 31, 2013 were searched from Medline, Embase, Ovid, Web of Science, and Cochrane databases, with the terms "Ureaplasma urealyticum", "chronic lung disease", or "BPD36" used, and English language as a limit. The association between U. urealyticum colonization and BPD36 was analyzed with RevMan 4.2.10 software, using the odds ratio (OR) and relative risk (RR) for dichotomous variables. Out of the enrolled 81 studies, 11 investigated the BPD36 in total 1193 infants. Pooled studies showed no association between U. urealyticum colonization and subsequent development of BPD36, with the OR and RR being 1.03 (95% CI=0.78-1.37; P=0.84) and 1.01 (95% CI= 0.88-1.16, P=0.84), respectively. These findings indicated no association between U. urealyticum colonization and the development of BPD36.

Background: Ureaplasma spp. respiratory tract colonization is a risk factor for bronchopulmonary dysplasia (BPD) in preterm infants, but differences in host susceptibility have not been elucidated. We hypothesized that variants in genes regulating the innate immune response are associated with altered risk for Ureaplasma spp. respiratory colonization and BPD in preterm infants., Methods: Twenty-four tag single nucleotide polymorphisms (SNPs) from Toll-like receptor (TLR)1, TLR2, TLR4 and TLR6 were assayed in 298 infants <33 weeks gestation who had serial respiratory cultures for Ureaplasma spp. and were evaluated for BPD., Results: The majority of subjects (N = 205 [70%]) were African-American. One hundred ten (37%) were Ureaplasma positive. Four SNPs in TLR2 and TLR6 were significantly associated with Ureaplasma respiratory tract colonization. Single SNPs in TLR2, TLR4 and TLR6 were associated with BPD. TLR6 SNP rs5743827 was associated with both a decreased risk for Ureaplasma respiratory tract colonization and decreased risk for BPD (odds ratio: 0.54 [0.34-0.86] and odds ratio: 0.54 [0.31-0.95], respectively). There was a significant additive interaction between Ureaplasma colonization and genotype at TLR6 SNP rs5743827 (Padditive = 0.023), with an attributable proportion due to interaction of 0.542., Conclusions: Polymorphisms in host defense genes may alter susceptibility to Ureaplasma infection and severity of the inflammatory response contributing to BPD. These observations implicate host genetic susceptibility as a major factor in BPD pathogenesis in Ureaplasma-infected preterms.

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Ureaplasma is an organism with low virulence and is a commensal of the lower genito-urinary tract in females. From here, it can gain entry in the amniotic fluid to cause inflammation in the amniotic compartment during pregnancy. Ureaplasma spp. are the most common organisms isolated from women with chorioamnionitis. Ureaplasma spp. are associated with increased risk for preterm labor and morbidity in the preterm neonate. However, there is some controversy regarding the importance of Ureaplasma in the pathogenesis of bronchopulmonary dysplasia (BPD). This article will review the microbiology of Ureaplasma, host innate immune responses, and the pathology of lung injury in animal models of Ureaplasma chorioamnionitis. We will review epidemiological studies of Ureaplasma and BPD in preterm infants and efficacy of antibiotics in preventing preterm labor and BPD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Chronic lung disease of prematurity (CLD) remains a major cause of morbidity and mortality in preterm infants. Ureaplasma has received intermittent attention over the last two decades as a possible contributory factor. In addition, pulmonary inflammation is associated with the development of CLD. The macrolide azithromycin provides an attractive option to determine if it can decrease the development of CLD as it has both anti-inflammatory and anti-infective properties. In this article, the authors review the evidence for the role of Ureaplasma in the development of CLD and the obstacles faced in the development of a drug before it reaches clinical practice.

Multiplex, real-time PCR for the identification of Ureaplasma urealyticum and Ureaplasma parvum was performed on nucleic acids extracted from sequential endotracheal aspirates obtained from preterm neonates born at <29 weeks of gestation and ventilated for more than 48 h admitted to two level 3 neonatal intensive care units. Specimens were obtained shortly after birth and sequentially up until extubation. One hundred fifty-two specimens (93.8%) contained material suitable for analysis. Ureaplasma spp. were identified in 5 of 13 neonates studied. In most cases, the DNA load of the detected Ureaplasma species was low and decreased over time. In addition, changes in detectable Ureaplasma species DNA did not relate to changes in the inflammatory marker C-reactive protein (CRP) or respiratory status. All but two blood samples obtained at times of suspected sepsis were culture positive for other microorganisms; the species cultured were typically coagulase-negative staphylococci and were associated with increased levels of CRP (>10 mg/liter). This study was limited by the small number of patients examined and does not have the power to support or contradict the hypothesis that postnatal lung infection with Ureaplasma parvum is causally related to bronchopulmonary dysplasia (BPD) or adverse respiratory outcomes after preterm birth. However, in this study, increases in CRP levels were not associated with patients in whom Ureaplasma parvum was detected, in contrast to the detection of other bacterial species.

Bronchopulmonary dysplasia (BPD) remains the major morbidity of extreme preterm birth. The incidence of BPD has remained stable despite recent efforts to reduce postnatal exposures to volutrauma and hyperoxia. This review will focus on recent clinical and experimental insights that provide support for the concept that the 'new BPD' is the result of inflammation-mediated injury and altered lung development during a window of vulnerability in genetically susceptible infants that is modified by maternal and postnatal exposures., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To determine the prevalence of Ureaplasma urealyticum and Ureaplasma parvum bacteremia in very low birth weight (VLBW) infants and to evaluate the associated factors., Materials and Methods: Ninety-five VLBW newborns with gestational age ≤32 weeks were included in the study conducted between March 2009 and July 2010. DNA was extracted from the blood samples collected during the first 72 hours of life, and U. urealyticum and/or U. parvum were identified by polymerase chain reaction. The newborns were followed up until hospital discharge., Results: The prevalence of U. urealyticum and/or U. parvum bacteremia was 12.6% (12 cases): 5 (5.2%) for U. urealyticum, 5 (5.2%) for U. parvum, and 2 (2.1%) for both. Based on the univariate analysis, the presence of Ureaplasma was associated with clinical chorioamnionitis and spontaneous preterm labor. Preeclampsia and small for gestational age were associated with lower incidence of Ureaplasma. When spontaneous preterm labor was present, the prevalence of Ureaplasma bacteremia was 25%. Only spontaneous preterm labor was a statistically significant factor after step-by-step logistic regression analysis (P = 0.006), with 9-fold increase in chance of neonatal Ureaplasma bacteremia., Conclusions: Ureaplasma bacteremia is common in VLBW infants, especially among those born after preterm labor.

Objective: Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Whether the 4 Ureaplasma parvum and 10 Ureaplasma urealyticum serovars differ in virulence is unknown. This study was conducted to determine the distribution of Ureaplasma serovars in respiratory secretions of a prospective cohort of preterm infants and to assess whether any of the serovars are associated with BPD., Methods: Serial endotracheal and/or nasopharyngeal aspirates were obtained for Ureaplasma culture and PCR from 136 infants of gestational age <33 weeks. All positive samples were speciated and serovars were determined by real-time PCR., Results: A total of 51 (37.5%) infants were Ureaplasma-positive one or more times during the first month of life. Respiratory colonization was inversely related to gestational age. Sixty-five percent of infants <26 weeks compared with 31% infants ≥ 26 weeks were culture or PCR positive. U. parvum was more common (N = 32, 63%) than U. urealyticum (N = 17, 33%); both species were present in 2 samples. Serovars 3 and 6 alone and in combination accounted for 96% U. parvum isolates. U. urealyticum isolates were commonly a mixture of multiple serovars, with serovar 11 alone or combined with other serovars (10/17, 59%) being the most common serovar. No individual species or serovars or serovar mixtures were associated with moderate-to-severe BPD., Conclusions: U. parvum serovars 3 and 6 and U. urealyticum serovar 11 were the most common serovars detected in respiratory samples from a prospective cohort of preterm infants.

Aims: We determined the association between short-term neonatal morbidities, such as bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH), and Ureaplasma spp. in amniotic fluid, placental and amniotic membrane of preterm infants., Methods: This study enrolled 257 patients who were born by cesarean section at <34 weeks' gestation. Patients were divided into two groups according to detection of Ureaplasma spp. by culture-based and/or polymerase chain reaction (PCR) techniques., Results: Significant differences were observed between both groups for all IVH (P=0.032) and IVH grades III or IV (P=0.013), as wells as for BPD [odds ratio (OR) 5.46, 95% confidence interval (CI) 2.02-14.77], oxygen requirement at 28 days postnatal age (OR 1.93, 95% CI 1.00-3.70), and for death between 28 days and 36 postmenstrual weeks or BPD (OR 4.20, 95% CI 1.77-9.96). Ureaplasma spp. was a significant predictor (P<0.001) of BPD after correcting for birth weight (P=0.003) and positive pressure ventilation (P=0.001)., Conclusions: In our study population Ureaplasma spp. was associated with BPD and IVH in preterm infants even after adjustment for multiple risk factors.

Background: Despite strong evidence linking infections to the pathogenesis of bronchopulmonary dysplasia (BPD), limitations of bacterial culture methods have precluded systematic studies of airway organisms relative to disease outcomes. Application of molecular bacterial identification strategies may provide new insight into the role of bacterial acquisition in the airways of preterm infants at risk for BPD., Methods: Serial (within 72 hours, 7, 14, and 21 days of life) tracheal aspirate samples were collected from 10 preterm infants with gestational age ≤34 weeks at birth, and birth weight of 500-1250 g who required mechanical ventilation for at least 21 days. Samples were analyzed by quantitative real time PCR assays for total bacterial load and by pyrosequencing for bacterial identification., Results: Subjects were diagnosed with mild (1), moderate (3), or severe (5) BPD. One patient died prior to determination of disease severity. 107,487 sequences were analyzed, with mean of 3,359 (range 1,724-4,915) per sample. 2 of 10 samples collected <72 hours of life contained adequate bacterial DNA for successful sequence analysis, one of which was from a subject exposed to chorioamnionitis. All other samples exhibited bacterial loads >70copies/reaction. 72 organisms were observed in total. Seven organisms represented the dominant organism (>50% of total sequences) in 31/32 samples with positive sequences. A dominant organism represented>90% of total sequences in 13 samples. Staphylococcus, Ureaplasmaparvum, and Ureaplasmaurealyticum were the most frequently identified dominant organisms, but Pseudomonas, Enterococcus, and Escherichia were also identified., Conclusions: Early bacterial colonization with diverse species occursafter the first 3 days of life in the airways of intubated preterm infants, and can be characterized by bacterial load and marked species diversity. Molecular identification of bacteria in the lower airways of preterm infants has the potential to yield further insight into the pathogenesis of BPD.

Although premature infants are increasingly surviving the neonatal period, up to one-third develop bronchopulmonary dysplasia (BPD). Despite evidence that bacterial colonization of the neonatal respiratory tract by certain bacteria may be a risk factor in BPD development, little is known about the role these bacteria play. The aim of this study was to investigate the use of culture-independent molecular profiling methodologies to identify potential etiological agents in neonatal airway secretions. This study used terminal restriction fragment length polymorphism (T-RFLP) and clone sequence analyses to characterize bacterial species in endo-tracheal (ET) aspirates from eight intubated pre-term infants. A wide range of different bacteria was identified in the samples. Forty-seven T-RF band lengths were resolved in the sample set, with a range of 0-15 separate species in each patient. Clone sequence analyses confirmed the identity of individual species detected by T-RFLP. We speculate that the identification of known opportunistic pathogens including S. aureus, Enterobacter sp., Moraxella catarrhalis, Pseudomonas aeruginosa and Streptococcus sp., within the airways of pre-term infants, might be causally related to the subsequent development of BPD. Further, we suggest that culture-independent techniques, such as T-RFLP, hold important potential for the characterization of neonatal conditions, such as BPD.

The role of infection in bronchopulmonary dysplasia (BPD) is unknown. We present an observational study of 55 premature infants born weighing less than 1.3 kg within two level III neonatal intensive care units. Endotracheal aspirates (ETA) and nasogastric aspirates (NGA) were studied with denaturing gradient gel electrophoresis (DGGE) profiling to elucidate the total bacterial community, and species-specific PCR was used to detect the presence of Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum. DGGE identified bacterial species in 59% of NGA and ETA samples combined. A diverse range of species were identified including several implicated in preterm labor. Species-specific PCR identified M. hominis in 25% of NGA and 11% of ETA samples. Among the 48 infants surviving up to 36 wk-postconceptual age, ordinal logistic regression showed the odds ratio for BPD or death where Ureaplasma was present/absent as 4.80 (95% CI 1.15-20.13). After adjusting for number of days ventilated, this was reduced to 2.04 (0.41-10.25). These data demonstrate how the combined use of DGGE and species-specific PCR identifies a high exposure in utero and around the time of birth to bacteria that might be causally related to preterm delivery and subsequent lung injury.

Background: A proteolytic imbalance has been implicated in the development of "classical" chronic lung disease of prematurity (CLD). However, in "new" CLD this pattern has changed. This study examines the longitudinal relationship between neutrophil proteinases and their inhibitors in ventilated preterm infants and their relationship to microbial colonisation., Methods: Serial bronchoalveolar lavage fluid was obtained from ventilated newborn preterm infants. Neutrophil elastase (NE) activity, cell counts, metalloproteinase (MMP)-9, MMP-9/TIMP-1 complex, SerpinB1 concentration and percentage of SerpinB1 and alpha(1)-antitrypsin (AAT) in complex with elastase were measured. The presence of microbial genes was examined using PCR for 16S rRNA genes., Results: Statistically more infants who developed CLD had NE activity in at least one sample (10/20) compared with infants with resolved respiratory distress syndrome (RDS) (2/17). However, NE activity was present in a minority of samples, occurring as episodic peaks. Peak levels of MMP-9, MMP-9/TIMP-1 complex, percentage of AAT and SerpinB1 in complex and cell counts were all statistically greater in infants developing CLD than in infants with resolved RDS. Peak values frequently occurred as episodic spikes and strong temporal relationships were noted between all markers. The peak values for all variables were significantly correlated to each other. The presence of bacterial 16S rRNA genes was associated with the development of CLD and with elevated elastase and MMP-9., Conclusion: NE activity and MMP-9 appear to be important in the development of "new" CLD with both proteinase and inhibitor concentrations increasing episodically, possibly in response to postnatal infection.

Chorioamnionitis is associated with increased lung and brain injury in premature infants. Ureaplasma is the microorganisms most frequently associated with preterm birth. Whether Ureaplasma-induced antenatal inflammation worsens lung and brain injury is unknown. We developed a mouse model combining antenatal Ureaplasma infection and postnatal oxygen exposure. Intraamniotic Ureaplasma Parvum (UP) increased proinflammatory cytokines in placenta and fetal lungs. Antenatal exposure to UP or broth caused mild postnatal inflammation and worsened oxygen-induced lung injury. Antenatal UP exposure induced central microgliosis and disrupted brain development as detected by decreased number of calbindin-positive and calretinin-positive neurons in the neocortex. Postnatal oxygen decreased calretinin-positive neurons in the neocortex but combined with antenatal UP exposure did not worsen brain injury. Antenatal inflammation exacerbates the deleterious effects of oxygen on lung development, but the broth effects prohibit concluding that UP by itself is a compounding risk factor for bronchopulmonary dysplasia. In contrast, antenatal UP-induced inflammation alone is sufficient to disturb brain development. This model may be helpful in exploring the pathophysiology of perinatal lung and brain injury to develop new protective strategies.

Objective: Gastric fluid microbes were examined in preterm infants at birth to assess their influence on the postnatal outcome., Study Design: Prospective cohort study., Setting: Level III neonatal intensive care unit., Patients: A total of 103 premature neonates with a gestational age of less than 32 weeks., Main Outcome Measure: Gastric fluid microbes were identified by analysis of bacterial 16S ribosomal RNA gene. Additionally, the urease gene of Ureaplasma species was detected by polymerase chain reaction of gastric fluid obtained at birth and/or tracheal aspirate from ventilated preterm infants. The association between detection of microbes and bronchopulmonary dysplasia was investigated through assessment from clinical features and by a lung injury marker (KL-6)., Results: Forty-two of 103 gastric fluid specimens were positive for microbes. Ureaplasma species were detected in 23 of the 42 (55%) gastric fluid specimens. All infants with Ureaplasma species in tracheal aspirate fluid also had positive gastric fluid specimens. Compared to infants negative for gastric fluid microbes, infants positive for microbes had higher rates of maternal chorioamnionitis (18% vs 78%), premature rupture of membranes (11% vs 55%), severe bronchopulmonary dysplasia (1.6% vs 14%) and showed higher plasma KL-6 levels during the initial 4 weeks of life., Conclusion: Detection of gastric fluid microbes was correlated well with antenatal infection and severe bronchopulmonary dysplasia. Detection of Ureaplasma species in gastric fluid was associated with subsequent respiratory colonisation. These results suggest that antenatal exposure of the immature fetus to microbes may cause lung injury and promote the onset of bronchopulmonary dysplasia.

Objective: As Ureaplasmas may be pathogens in preterm infants, this study was conducted to determine the incidence of invasive disease with Ureaplasma parvum and Ureaplasma urealyticum and the relationship with adverse outcomes in a prospective cohort of very low birth weight (VLBW) infants., Study Design: DNA was extracted from the cord or venous blood and cerebrospinal fluid (CSF) samples obtained from 313 VLBW infants. PCR was performed using primers for the mba gene to detect all 14 serovars and then repeated for all positive samples using species-specific primers., Result: Ureaplasma species were detected in serum and/or CSF samples from 74 of 313 (23.6%) infants. U. parvum was the predominant species (70%). Presence of Ureaplasma was significantly associated with elevated interleukin-1beta in cord blood (odds ratio (OR) 2.6, 1.05 to 6.45, P=0.039). Ureaplasma serum-positive infants had a 2.3-fold increased risk of intraventicular hemorrhage > or =grade 3 (OR 2.50; 1.06 to 5.89, P=0.036)., Conclusion: Invasive Ureaplasma occurs commonly in VLBW infants and may increase the risk for severe intraventricular hemorrhage.

Microorganisms are hypothesized to contribute to the pathogenesis of bronchopulmonary dysplasia (BPD) in very low birth weight (VLBW) infants. This hypothesis remains controversial. We sought to determine whether endotracheal colonization with Ureaplasma sp., adenovirus, or Chlamydia sp. increases the risk of BPD. Intubated VLBW infants were included. Polymerase chain reaction (PCR) analysis was used to detect Ureaplasma sp., adenovirus, and Chlamydia sp. The outcome measure was BPD or death due to lung disease. Detection of microorganisms was compared between subjects with and without BPD. Logistic regression was used to control for covariates. Of 139 subjects, 33 (25%) screened positive for Ureaplasma sp., 22 of 136 (16%) were positive for adenovirus; eight of 133 (6%) were positive for Chlamydia sp. At 36 wk postmenstrual age, 14 patients had died, 68 (57%) had BPD. Detection of Ureaplasma sp. was associated with BPD or death (p < 0.001); adenovirus (p = 0.52) and Chlamydia sp. (p = 0.33) were not. Controlling confounding factors, the odds ratio for Ureaplasma sp. and BPD or death was 4.2 (95% CI 1.03, 17). In our population, detection of Ureaplasma sp., but not adenovirus or Chlamydia sp. was associated with BPD or death due to lung disease.

We investigated the relation between perinatal endotracheal colonization, the associated cytokine response and respiratory outcome in ventilated preterm neonates. Between September 1999 and March 2002, a cohort of 141 neonates with a gestational age <31 weeks requiring ventilation directly after birth, were followed prospectively. All were admitted to the Neonatal Intensive Care Unit, University Hospital of Antwerp, Belgium. A tracheal aspirate (TA) sample was collected soon after birth and was processed for microbiological examination, leukocyte count, and cytokine analysis (interleukins [IL] IL-1beta, IL-6, CXCL8 (formerly called IL-8), IL-10, IL-12p70 and tumor necrosis factor alpha [TNF-alpha]). Together with the prospectively registered patient's comorbidities and severity of disease, these inflammatory parameters were analyzed in a multivariate Cox proportional hazards model with time of extubation and duration of oxygen therapy as main outcome measures. Of the 141 patients included, 31 (22%) died before discharge from the unit and 37 (26%) had a positive TA culture. Independent predictors of duration of mechanical ventilation were: gestational age <28 weeks, degree of respiratory distress syndrome (RDS) at birth, significant patent ductus arteriosus (PDA), the SNAP-score, and high levels of CXCL8 (>4,153 pg/ml) in TA only in neonates with a gestational age <28 weeks. Variables associated with extended duration of oxygen therapy were gestational age <28 weeks, birth weight <1,000 g, degree of RDS at birth, and duration of mechanical ventilation., (2007 Wiley-Liss, Inc.)

Candidal infections are one of the common causes of late-onset sepsis (LOS) among very low birthweight (VLBW) infants, and are associated with substantial morbidity and mortality. The aim of this study was to evaluate the perinatal and neonatal risk factors for fungal LOS compared with bacterial LOS in VLBW infants. This was a population-based observational study of VLBW infants in 28 neonatal intensive care units across Israel, with information on 11,830 infants born between 1995 and 2002 from the Israeli National VLBW infant database. The study population comprised 3054 infants with one or more episodes of LOS. Univariate analysis and logistic regression models were used to compare perinatal and neonatal risk factors between infants with fungal sepsis only (N=179) and those with bacterial sepsis only (N=2630). The mean birthweight and gestational age of infants with candidal LOS were significantly lower (940 g; 27.1 weeks) than those in the bacterial LOS group (1027 g; 28.3 weeks) (P<0.001). Logistic regression analysis showed that candidal sepsis, in contrast to bacterial sepsis, was independently associated with decreasing gestational age and bronchopulmonary dysplasia (BPD). In addition, BPD only [odds ratio (OR) 1.84; 95% confidence intervals (CI) 1.03-3.23] and BPD with postnatal steroid therapy (OR 2.66; 95% CI 1.59-4.46) were independently associated with an increased risk for candidal sepsis.

Unlabelled: The aim of this study was the analysis of the clinical state of newborns infected with various species of ureaplasma., Methods: 50 prematurely born patients with respiratory disturbances and confirmed presence of ureaplasma in the respiratory tract were analyzed. Endotracheal aspirates were collected for examination. Presence of ureaplasma was confirmed by culture and a commercial test (Biomerieux), the ureaplasma species were identified using PCR., Results: In 40 examined newborns Ureaplasma parvum (U.p.) was found, in 10 Ureaplasma urealyticum (U.u.). Newborns infected with U.u. were subject to more frequent and longer therapeutic procedures supporting respiration (respirator, nCPAP), needed more frequent surfactant and antibiotic administration. In the mentioned group the mortality rate was 33%, while in newborns infected with U.p. it was 15%., Conclusions: Initial results suggest worse clinical status and higher mortality of prematurely born infected with Ureaplasma urealyticum.

Background: Controversy exists over whether or not Ureaplasma colonization or infection of the respiratory tract contributes to the development of bronchopulmonary dysplasia (BPD). Because BPD is a major cause of morbidity and mortality in preterm infants and a potential therapeutic intervention with antimicrobials is possible, we sought to evaluate and critique the current medical literature and to document the reported association between Ureaplasma and BPD., Methods: We analyzed all peer-reviewed articles and previous reviews including cross-references that reported Ureaplasma respiratory tract colonization or infection and development of BPD in neonates published from January 1966 to December 2004. Inclusion criteria included a cohort limited to all neonatal intensive care unit admissions or all colonized infants, articles that did not define a numerator and a denominator for BPD and Ureaplasma or that included patients from other reports were excluded from the analysis. We evaluated BPD at 28 postnatal days (BPD28) or 36 weeks post-menstrual age (BPD36)., Results: Twenty-three studies with an aggregate of 2216 infants reported BPD28, and 8 studies with 751 infants reported BPD36. Although there was significant association between Ureaplasma colonization and both BPD28 and BPD36, there was substantial heterogeneity (Q test statistic, P < 0.01). We therefore focused on describing the study characteristics associated with an increased relative proportion of BPD. The greatest contribution to effect was from the studies enrolling fewer than 100 infants., Conclusion: Ureaplasma colonization is associated with higher reported rates of BPD, but the greatest reported effect is seen in small studies; reporting bias may be partially responsible for this effect.