When inflammation meets lung development-an update on the pathogenesis of bronchopulmonary dysplasia.

Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD.

Statistical inference for ordinal predictors in generalized additive models with application to Bronchopulmonary Dysplasia.

OBJECTIVE: Discrete but ordered covariates are quite common in applied statistics, and some regularized fitting procedures have been proposed for proper handling of ordinal predictors in statistical models. Motivated by a study from neonatal medicine on Bronchopulmonary Dysplasia (BPD), we show how quadratic penalties on adjacent dummy coefficients of ordinal factors proposed in the literature can be incorporated in the framework of generalized additive models, making tools for statistical inference developed there available for ordinal predictors as well. RESULTS: The approach presented allows to exploit the scale level of ordinally scaled factors in a sound statistical framework. Furthermore, several ordinal factors can be considered jointly without the need to collapse levels even if the number of observations per level is small. By doing so, results obtained earlier on the BPD data analyzed could be confirmed.

Correlation of Early Nutritional Supply and Development of Bronchopulmonary Dysplasia in Preterm Infants <1,000 g.

Background: Bronchopulmonary dysplasia (BPD) has multifactorial origins and is characterized by distorted physiological lung development. The impact of nutrition on the incidence of BPD is less studied so far. Methods: A retrospective single center analysis was performed on n = 207 preterm infants <1,000 g and <32 weeks of gestation without severe gastrointestinal complications to assess the impact of variations in nutritional supply during the first 2 weeks of life on the pulmonary outcome. Infants were grouped into no/mild and moderate/severe BPD to separate minor and major limitations in lung function. Results: After risk adjustment for gestational age, birth weight, sex, multiples, and antenatal steroids, a reduced total caloric intake and carbohydrate supply as the dominant energy source during the first 2 weeks of life prevailed statistically significant in infants developing moderate/severe BPD (p < 0.05). Enteral nutritional supply was increased at a slower rate with prolonged need for parenteral nutrition in the moderate/severe BPD group while breast milk provision and objective criteria of feeding intolerance were equally distributed in both groups. Conclusion: Early high caloric intake is correlated with a better pulmonary outcome in preterm infants <1,000 g. Our results are in line with the known strong impact of nutrient supply on somatic growth and psychomotor development. Our data encourage paying special attention to further decipher the ideal nutritional requirements for unrestricted lung development and promoting progressive enteral nutrition in the absence of objective criteria of feeding intolerance.

Oxygen Toxicity to the Immature Lung-Part II: The Unmet Clinical Need for Causal Therapy.

Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures.

Bacterial Colonization within the First Six Weeks of Life and Pulmonary Outcome in Preterm Infants <1000 g.

Bronchopulmonary dysplasia (BPD) is a multifactorial disease mainly provoked by pre- and postnatal infections, mechanical ventilation, and oxygen toxicity. In severely affected premature infants requiring mechanical ventilation, association of bacterial colonization of the lung and BPD was recently disclosed. To analyze the impact of bacterial colonization of the upper airway and gastrointestinal tract on moderate/severe BPD, we retrospectively analyzed nasopharyngeal and anal swabs taken weekly during the first 6 weeks of life at a single center in n = 102 preterm infants <1000 g. Colonization mostly occurred between weeks 2 and 6 and displayed a high diversity requiring categorization. Analyses of deviance considering all relevant confounders revealed statistical significance solely for upper airway colonization with bacteria with pathogenic potential and moderate/severe BPD (p = 0.0043) while no link could be established to the Gram response or the gastrointestinal tract. Our data highlight that specific colonization of the upper airway poses a risk to the immature lung. These data are not surprising taking into account the tremendous impact of microbial axes on health and disease across ages. We suggest that studies on upper airway colonization using predefined categories represent a feasible approach to investigate the impact on the pulmonary outcome in ventilated and non-ventilated preterm infants.

The Microbiome and Preterm Birth: A Change in Paradigm with Profound Implications for Pathophysiologic Concepts and Novel Therapeutic Strategies.

Preterm birth poses a global challenge with a continuously increasing disease burden during the last decades. Advances in understanding the etiopathogenesis did not lead to a reduction of prematurely born infants so far. A balanced development of the host microbiome in early life is key for the maturation of the immune system and many other physiological functions. With the tremendous progress in new diagnostic possibilities, the contribution of microbiota changes to preterm birth and the acute and long-term sequelae of prematurity have come into the research focus. This review summarizes the latest advances in the understanding of microbiomes in the amniotic cavity and the female lower genital tract and how changes in microbiota structures contribute to preterm delivery. The exhibition of these highly vulnerable infants to the hostile environment in the neonatal intensive care unit necessarily entails the rapid colonization with a nonbalanced microbiome in a situation where the organism is still very prone and at an early stage of development. The global research efforts to decipher pathologic changes will pave the way to new pre- and postnatal therapeutic concepts.