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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.)

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.)

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.)

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.

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.

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.

There is controversy regarding the role of mycoplasmas (MP) colonizing the neonatal respiratory tract in the development of bronchopulmonary dysplasia (BPD). To determine the association of respiratory MP colonization and BPD. Retrospective analysis of neonates (26-32 weeks of gestation) intubated for respiratory insufficiency. Tracheal aspirate cultures were obtained for MP if the lung disease was not improving by 7-10 days or there were radiographic changes suggestive of inflammation. Of 63 infants who had tracheal aspirates sent, 17 had positive MP cultures. We found no significant difference in the gestational ages (27.6 +/- 0.4 vs 27.8 +/- 0.2 weeks) or birth weights (1097 +/- 86 vs 997 +/- 42 grams) in MP positive vs negative infants. No differences were noted in antenatal or postnatal steroid use, gender, race, sepsis, RDS, PDA, air leaks, NEC, GER, days on positive pressure ventilation or days on oxygen. There were significantly (p = 0.04) more infants with severe BPD (defined as oxygen requirement at 36 weeks corrected post menstrual age) among MP positive (n = 14; 82%) versus MP negative (n = 25; 54%) infants. Presence of MP in the tracheal aspirates is associated with an increased likelihood of developing severe BPD.

Background: Airway colonization with Gram-negative bacilli (GNB) and Gram-positive cocci (GPC) is common in mechanically ventilated neonates. Whether GNB are related to nosocomial bloodstream infection (BSI) and/or to the severity of bronchopulmonary dysplasia (BPD) is unknown., Methods: We prospectively examine this relationship using a cohort design. Data from 260 < or = 1250-g birth weight inborn infants (1991 to 1995) intubated > or = 2 weeks included 917 serial tracheal cultures and 583 blood cultures. The severity of BPD was assessed by duration of mechanical ventilation, oxygen dependency at 36 weeks of postconceptional age and the use of home oxygen supplementation., Results: After 2 weeks of ventilation, 80% of the infants were colonized with GPC (Staphylococus epidermidis and Staphylococcus haemolyticus in 90% of the cases). Superimposed on 36% of these infants was GNB airway colonization with Klebsiella pneumoniae (25%), Enterobacter cloacae (25%), Escherichia coli (25%), Pseudomonas aeruginosa (10%), Serratia marcescen (10%), Acinetobacter baumannii and Haemophilus influenzae (5%). Comparison between 174 GPC- and 86 GNB-colonized infants showed that demographics, birth weight, gestational age, perinatal risk factors and mortality were similar. Fifteen percent of GNB-colonized infants developed BSI caused by GNB and 14% developed BSI caused by GPC. No significant temporal relationship between airway colonization and BSI was noted. GNB infants were ventilated longer and required oxygen at 36 weeks of postconceptional age and home oxygen supplementation twice as often as infants colonized only with GPC. GNB colonization was a predictor of severe BPD after controlling for ventilation. Ureaplasma colonization occurred in 28% of GNB-colonized and 33% of noncolonized infants and was not a predictor of BPD severity., Conclusion: GNB airway colonization creates a moderate risk for BSI. Antibiotic treatment does not regularly eradicate GNB. GNB airway colonization is associated with severe BPD, but further studies will be necessary before therapeutic efforts to eradicate GNB from the airways should be undertaken.