What is BPD today and in the next 50 years?

WHAT IS BPD TODAY

After more than 50 years from its original description, bronchopulmonary dysplasia (BPD) continues to be one of the most common and devastating consequences of extreme preterm birth. Although the clinical presentation today is quite different and milder from that described originally by Northway and collaborators (1), it still occurs in ∼40% of the infants born under 28 wk of gestation, and it is associated with longer hospitalization and increased medical costs. It is also associated with increased mortality and other comorbidities such as pulmonary hypertension and abnormal neurodevelopmental outcome (2, 3). Although the original form of BPD occurred in more mature infants who had severe respiratory distress syndrome (RDS) requiring aggressive respiratory support with high oxygen, which caused severe disruption of lung morphology and function, today BPD occurs in more immature infants who because of antenatal steroids and surfactant use have only mild initial respiratory failure and receive noninvasive or less aggressive respiratory support. The disruption in lung architecture and function in most of these infants is much less striking and is characterized by decreased alveolarization and abnormal vascular development and by milder respiratory failure. This milder phenotype has made obsolete many of the original diagnostic criteria that applied mainly to severe cases and has created confusion among clinicians and researchers who have difficulty classifying these milder forms of BPD. It has also frustrated researchers who are now faced with a much more complex task of preserving normal lung development rather than just preventing lung injury. The abnormal lung development may be an inevitable consequence of prematurity, and quite independent of BPD (4). Today, it is not a question of whether an extremely premature infant has BPD or not, but what is the degree of alteration of their lung development that will define their long-term pulmonary outcome. Dichotomizing infants in those with and without BPD is clearly not the best approach but we need to understand the multiple variables contributing to abnormal lung development, and how they interact during fetal life and postnatal care resulting in different degrees of lung disruption and poor long-term outcomes. There is clear evidence in the literature that many ex-preterm infants without the diagnosis of BPD still have abnormal lung function later in life (5). Identifying these infants early will require new, more precise tools to determine the degree of abnormality in their lung morphology and function (6–9).

HOW MUCH IS RESPIRATORY CONTROL INSTABILITY CONTRIBUTING TO THE DIAGNOSIS OF BPD?

Apnea of prematurity and the need for cardiorespiratory monitoring have been well recognized as integral to neonatal intensive care as we know it today over the past half-century (10). Such respiratory pauses were widely considered a self-resolving problem, unlikely to be of great clinical significance. Early studies in preterm infants had clearly documented diminished ventilatory responses to CO₂ and hypoxia-induced ventilatory depression in this population (11). The challenge from those studies, which persists to this day, is to differentiate immature respiratory control from impaired lung mechanics as the primary mechanism compromising ventilation in both the healthy and injured preterm lung.

The advent of universal noninvasive measurement of oxygenation provided previously unsuspected data that even short respiratory pauses of 10 s or less could result in hypoxemia in premies. This has redirected the focus to intermittent hypoxemic (IH) episodes, which have also become a subject of considerable interest to pediatric and adult pulmonary subspecialists. The very high frequency of these episodes, which seems to peak beyond the first postnatal week, has attracted increasing attention for neonatology investigators (12). As indicated above, they variably reflect a mixture of immature respiratory control and a vulnerable low lung volume reserve, which may be aggravated by an unstable breathing pattern comprising active expiratory muscle contraction (13). Are there potential consequences to such episodic desaturations in this high-risk population?

Characterization of hypoxemic episodes in the Canadian Oxygen Trial provided evidence that an increased time with an $\text{S}{\text{a}}_{{\text{O}}_2}$ less than 80% was associated with a variety of adverse outcomes (14). Three subsequent studies have now shown that IH episodes in the first weeks of postnatal life precede a subsequent diagnosis of BPD (15–17). Whether this is an associative or causal relationship of course remains to be determined. For example, do both IH events and later BPD simply reflects an adverse prenatal environment or is it the enhanced ventilatory or supplemental O₂ used to treat the IH events that contribute to later diagnosis of BPD (18). There is minimal available information in the neonatal period regarding the role of cellular or biochemical markers of oxidant stress on adverse outcomes such as BPD (19). Both IH episodes resulting from respiratory control instability and the relative hyperoxic recovery from such events may be important players. The increasing availability of automated supplemental oxygen titration allows $\text{S}{\text{a}}_{{\text{O}}_2}$ to largely stay within an optimal range (20). This makes it all the more important to identify which component of IH events (e.g., magnitude, duration, frequency) has pathophysiological consequences. That challenge is being addressed by the ongoing multicenter National Heart, Lung, and Blood Institute (NHLBI)-sponsored Prematurity-Related Ventilatory Control study (21).

WHAT IS THE OUTLOOK FOR RESPIRATORY MORBIDITY IN FORMER PRETERM INFANTS?

Despite the well-recognized challenges in defining BPD, prior focus has been primarily on the respiratory morbidity, both short and longer term, of this group of preemies. The earliest follow-up was that of the original Northway cohort, which demonstrated primarily airway obstruction and airway hyperreactivity in adolescence and young adulthood (22). Also 30 years ago, Barker et al. (23) recognized that low birth weight associated with impaired adult lung function manifest as chronic obstructive airways disease. Over the subsequent 3 decades, it has become increasingly apparent that the odds of childhood wheezing are increased approximately threefold in low-birth-weight infants of less than 32 wk gestation, a majority of whom will not be diagnosed with BPD (24).

Follow-up of respiratory function in preterm survivors continues to focus on airway-related parameters such an FEV₁. In a large Australian preemie cohort studied at 8 yr of age, FEV₁ values were only at 85% of predicted values despite increasing use of noninvasive ventilation strategies (25). In a large UK cohort of extremely preterm survivors at age 19 yr, FEV₁ z-scores were at −2 and −1 (corresponding to 2 and 1 SD below mean) for those diagnosed with and without BPD, respectively (26). Airway function did not appear to improve when 18-yr-old former preterm infants reached 25 yr of age (27).

It is well recognized that alveolar simplification and impaired pulmonary vasculature are key components of the developmental stages of neonatal lung injury (4). Unfortunately, human population-based measures of alveolar and pulmonary vascular structures are largely invasive and longer-term outcome data are scant, although new imaging approaches for the developing lung are moving forward (9). This challenge probably has contributed to outcome studies being focused on airway function. What is the pathogenesis of both structural and functional impairments in the airways of former preemies? For example, is it secondary to impaired tethering of airways by simplified alveoli, so reducing airway caliber (28)? Is there an increase in airway smooth muscle mass after neonatal interventions, as has been well demonstrated in neonatal rodent models (29, 30)? Regardless of etiology, there is increasing concern regarding the vulnerability of airway function as preemies mature into advanced adulthood (5). Given that lung function peaks in early adulthood before a slow but steady decline, we need to warn this already vulnerable population of former preemies, and their caregivers, that they are at very high risk if exposed to adverse respiratory stimuli such as smoking exposure. It seems as if the challenge of BPD will not just be one for neonatologists and pediatric pulmonologists to tackle.

WHAT WILL HAPPEN WITH BPD IN THE NEXT 50 YEARS?

Although the progress in the prevention of the more severe forms of BPD associated with preventable factors like volutrauma, oxygen toxicity, and infection is likely to continue, the challenge of preserving normal lung development in infants born extremely premature will be much more difficult to resolve. There is a long list of antenatal and postnatal factors that can disrupt the delicate balance that orchestrates lung development, including airway development, alveolar septation, and capillary formation (Fig. 1). These alterations in development are associated with abnormal lung structure and function that are likely to persist, at least in part, throughout the life of these infants (31, 32). Because of the complexities of the mechanisms involved in normal lung development and growth, and the multiple factors that can disrupt this process, finding drugs or interventions that may modulate the molecular mechanisms of normal and abnormal lung development is likely to offer a substantial challenge and be much more complex than looking for a “magic bullet.” This challenge has already been suggested by recent data from the Neonatal Research Network showing that the incidence of BPD in the smaller infants has not decreased in recent years but in fact may be increasing (33). Although efforts to reduce BPD will continue and hopefully some will be successful, it is likely that as long as infants are supported at earlier gestations they will have increasing challenges not only with their lung function but also with other organ systems that may share similar developmental pathways such as the heart and the kidney (34).

Figure 1.

The effects of preterm birth and postnatal therapeutic interventions on short-term and long-term respiratory outcomes.

The challenge for the next 50 years should be to take a deep dive into the developmental biology of the lung to identify the pathways and signaling molecules that might be possible targets for new and innovative treatments, which go beyond the current considerations of the inflammation/injury associated with BPD.

GRANTS

This work was supported in part by the National Heart, Lung, and Blood Institute of the National Institutes of Health Grants R01 HL56470 (to R.M.) and U01HL133643 (to R.M. and E.B.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

R.J.M., A.H.J., and E.B. prepared figure; drafted manuscript; edited and revised manuscript; and approved final version of manuscript.