The ‘new’ bronchopulmonary dysplasia: challenges and commentary

Summary

Lung development is orchestrated by highly integrated morphogenic programs of interrelated patterns of gene and protein expression. Injury to the developing lung in the canalicular and saccular phases of lung development alters subsequent alveolar and vascular development resulting in simplified alveolar structures, dysmorphic capillary configuration, variable interstitial cellularity and fibroproliferation that are characteristic of the ‘new’ bronchopulmonary dysplasia (BPD). Fetal and neonatal infection, abnormal stretch of the developing airways and alveoli, altered expression of surfactant proteins (or genetically altered proteins), polymorphisms of genes encoding for vascular endothelial growth factors, and reactive oxygen species result in imparied gas exchange in the developing lung. However, the ‘new’ BPD represents only one form of neonatal chronic lung disease and the consistent use of both the physiologic definition and severity scale would provide greater accuracy in determining the impact of the disease currently defined by its treatment. Our present labelling of the clinical state of oxygen supplementation and/or ventilatory support at 36 weeks' postmenstrual age and the histopathologic severity of alveolar arrest and vascular ‘simplification’ may not always be predictive of the degree of altered lung development and thus longer-term pulmonary function evaluations are needed to determine the impact of this disorder in specific infants. The proposed role of novel molecular therapies, and the combined effects of currently established therapies, as well as exogenous surfactant and inhaled nitric oxide or repetitive surfactant dosing, on the severity and incidence of new BPD hold considerable promise for reducing the long-term pulmonary moribidity among infants delivered prematurely.

Introduction

Forty-two years ago Northway et al. initially described bronchopulmonary dysplasia (BPD) as an evolving radiographic pattern of lung injury among a group of moderately premature infants in the late saccular stage of lung development, who had primarily been treated with pressure-limited time-cycled ventilators and high levels of supplemental oxygen for prolonged intervals.¹ Over the past four decades, dramatic changes in maternal care, including nearly universal use of antenatal steroids for mothers <34 weeks of gestation, introduction of surfactant therapy in the late 1980s, use of a variety of ‘gentler’ ventilation strategies, and continuous monitoring of oxygen saturation have been associated with a marked increase in survival of very preterm infants predisposed to significant pulmonary morbidities including BPD. However, exogenous surfactant therapy with animal-derived surfactants and more ‘gentle’ ventilation strategies, including nasal continuous positive airway pressure (nCPAP) support for infants 25–28 weeks' gestational age, have not significantly lowered the incidence of BPD at 36 weeks' postconceptional age.

By early 2009, only vitamin A supplementation, caffeine treatment, and intratracheal instillations of a mixture of budesonide and beractant among infants in the canalicular and early saccular phases of lung development have been associated with significant reductions in BPD,2, 3, 4 while a ‘Breathsavers’ quality collaborative demonstrated a 10.2% reduction in BPD at 16 centers.⁵ However, advances in neonatal care have created a different form of BPD that generally is defined less by radiographic pattern than by requirement for ongoing ventilation or supplemental oxygen treatment at 36 or 40 weeks' corrected age (depending on gestational age at birth). This new form of BPD is associated with a disruption of lung organogenesis and impaired pulmonary function during the first years of life.

This ‘new’ form of BPD has primarily been based upon autopsy studies of 14 very preterm infants who died at various intervals after birth, and on a baboon model of lung injury that is devoid of the human intrauterine environment and frequent inflammatory changes associated with human premature birth. These histologic studies suggest that the new form of BPD represents a disruption of lung organogenesis, and specifically an arrest of alveolar septation and vascular development in the distal lung.6, 7 The ‘new’ BPD has become the most frequent chronic lung disease in infancy.⁸ However, prior to the definition of BPD suggested by the US National Institutes of Health, other forms of ‘atypical’ chronic lung disease occurring after a course of respiratory distress syndrome (RDS), or later without preceding acute lung disease, have been identified.⁹ The extent to which these atypical forms of chronic lung disease overlap has not been rigorously evaluated.

A novel classification of diffuse lung disease in infants and young children prepared by the Children's Interstial Lung Disease (ChILD) Research Cooperative is based on the pathologic material and clinical data from 187 infants undergoing lung biopsies in 11 centers in 2007. This system describes ‘acinar dysplasia’ characterized by lung growth arrest in the pseudoglandular or early canalicular phase, and ‘congenital alveolar dysplasia’ characterized by growth arrest in the late canalicular/early saccular phase of lung development under a general pathologic category of ‘growth abnormalities reflecting deficient alveolarization’¹⁰ (Fig. 1). It is noteworthy that the ‘new BPD’ in is not mentioned in this classification.

In the National Institute for Child Health and Human Development (NICHD) neonatal network, BPD, defined as supplemental oxygen requirement at 36 weeks' postmenstrual age, had an incidence of 52% in infants with birth weights 501–750 g, 34% among infants with birth weights of 751–1000 g, 15% among those 1001–1200 g at birth, and 7% in infants born between 1201 and 1500 g.¹¹ However, a recent longitudinal evaluation of 1656 surviving infants born at 23–29 weeks of gestation from 2001 to 2006, reported an increase in this chronic lung disease from 47.8% to 57.8% (Fig. 2). This increase may reflect increased survival of more extremely preterm infants, but the report also found that the use of surfactant during these years was decreasing as more infants were managed by non-invasive ventilation strategies.¹² Whether the ‘new’ BPD represents a specific ‘new’ disease entity of extremely preterm infants with lung injury and disrupted repair during critical phases of lung organogenesis, or whether it is a group of entities associated with complex epigenetic, environmental (especially pre- and postnatal infections), inflammatory-mediated dysregulation of lung maturation, and/or other factors within a milieu of rapidly evolving therapies within the neonatal intensive care unit (NICU) remains unresolved.

The orchestration of lung development by finely integrated and regulated networks of transcriptional factors, growth factors, matrix components, and physical factors (primarily airway stretch) results in morphologic maturation and vascular development associated with the alveolar–capillary interposition required for extrauterine gas exchange. Alveolar epithelial cells undergo marked biochemical, morphological, and functional changes in the latter at 12–14 weeks of gestation. Such alveolarization is heralded by the formation of secondary crests and alveolar formation after 36 weeks of gestation.

Early in development lung cell lineage is marked by the expression of thyroid transcription factor I (Titfl), and genetic studies have shown that Titf1 is critical for the development of distal lung progenitors.¹³ Alveolar saccules are lined with type I cells which, along with pulmonary capillaries, form an extensive and effective gas exchange area. Alveolar type II cells compose 5–10%of the alveolar surface and are critical for production of surfactant phospholipids and proteins required for lung stability and immunologic protection at birth. Transcriptional networks influence both sacculation and alveolarization by coordinating differentiation of alveolar epithelial cells critical for surfactant synthesis and secretion. Sacculation, alveolarization, and vasculogenesis of the peripheral lung are dependent on many of the transcription factors involved in lung maturation (e.g. Titfl). These same transcription factors influence the expression of factors [Foxfl, vascular endothelial growth factor (VEGF)] that orchestrate pulmonary vasculogenesis by regulating a number of genes that influence mesenchymal differentiation and blood vessel formation.14, 15, 16, 17 An interplay of these and other transcriptional factors occurs in the maturing lung, and their expression is altered during the transdifferentiation and proliferative stages of lung development when multiple forms of lung injury occur.¹⁸

This article will review mechanisms of lung injury in the preterm infant, call for greater precision regarding the diagnosis of ‘new’ BPD, a disorder defined by its treatment, and suggest that it be differentiated from other chronic lung diseases that affect preterm infants. Because nearly all diseases of the newborn have a basis in genetics, and since there is strong evidence that the new BPD is heritable, the genetics will be briefly reviewed. The role of an altered intrauterine environment, and how the neonatologist's choice of treatments at birth influences its outcome, including factors that may contribute to its severity, will also be discussed.