Bronchopulmonary dysplasia: The earliest and perhaps the longest lasting obstructive lung disease in humans

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Abstract

Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term-born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients.

Introduction

Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy, an umbrella term for a number of different diseases that evolve as a consequence of a neonatal respiratory disorder. BPD is defined as the need for supplemental oxygen for at least 28 days after birth, and its severity is graded according to the respiratory support required at 36 post-menstrual weeks [1].

BPD was initially described as a chronic respiratory disease occurring in premature infants exposed to mechanical ventilation and oxygen supplementation [2]. This respiratory disease (later named “old BPD”) occurred in relatively large premature newborn and, from a pathological standpoint, it was characterized by intense airway inflammation, disruption of normal pulmonary structures and lung fibrosis [3].

Since 1990, this “old” type of BPD has been supplanted by a “new BPD” that occurs mostly in very low birth weight (VLBW) or extremely low birth weight (ELBW) infants, whose chances of survival were hugely improved by the introduction of more gentle ventilation modalities and the use of antenatal steroids, and once surfactant replacement had become routine in the management of premature newborns.

VLBW and ELBW babies are delivered several weeks before alveolarization begins and the complex process of their lungs' development has to be completed after birth. During this extremely awkward developmental process, the lung is particularly susceptible to the harmful effects of numerous noxae, including lung inflammation, oxygen, ventilation modalities, comorbidities (e.g. neonatal sepsis), drugs, maternal smoking, and so on [4]. The effects of such injuries on the developing lung give rise to a pathological picture characterized by fewer, larger alveoli, abnormal vascular growth and less prominent inflammation than in the case of “old BPD” [3], [5]. Interestingly, recent data suggest that, although the alveolar simplification existing at premature birth persists during infancy, alveolarization might catch up to some degree during childhood [6].

Eventually, among the pathogenetic mechanisms of BPD, recent studies have suggested that stem cell depletion in the developing lung may have a role and various types of stem cells have proved beneficial in experimental models of neonatal lung injury [7].

The clinical picture of infants with BPD is characterized by a complex pattern of respiratory problems. During the first 2 years of life, the main problem is represented by respiratory exacerbations, caused mainly by viral infections [8]. Infants with BPD who still need oxygen supplementation on discharge from neonatal intensive care unit (NICU) have a particularly severe course, with more frequent hospitalizations, than those who are no longer oxygen-dependent when they leave the NICU [9]. It is worth emphasizing, nonetheless, that prematurity is per se associated with more respiratory symptoms in infancy, even in late-preterm infants (born at a gestational age between 32 and 37 weeks) [10].

Upper airway problems resulting from prolonged or reiterated intubation (laryngo-tracheal stenosis, laryngomalacia, tracheomalacia, unilateral vocal cord paralysis) can worsen the respiratory course of infants with BPD, although the incidence of the more severe forms of stenosis requiring tracheostomy has fortunately declined in the last decade [11].

The respiratory condition of extremely preterm infants with BPD can also be complicated by concomitant pulmonary arterial hypertension (PAH), which has a prevalence in the range of 17% to 43% according to available retrospective studies [12]. PAH has been associated with a higher mortality rate in BPD infants [11].

Beyond infancy, the clinical condition of BPD survivors generally improves and their symptoms become less severe, although respiratory symptoms (coughing, wheezing) remain very common during their preschool years.

In school age, children with BPD still experience more chronic cough and asthma-like symptoms than their peers, and they need to use asthma medication more often than term-born controls [13].

More frequent asthma-like respiratory symptoms are also reported in adolescents born preterm by comparison with their peers born at term [14], [15]. Such symptoms gradually become less severe during the course of adolescence, however, and most BPD subjects lead apparently normal lives [3], [16]. Data available on the respiratory health of preterm-born adults are limited and refer mainly to cases of “old BPD”, but still suggest that adult BPD survivors tend to have more respiratory symptoms than their peers [17]. Airway hyper-responsiveness and impaired exercise tolerance has been reported in adult BPD subjects, too [18].

BPD is frequently associated with other conditions related to preterm birth (including growth retardation, pulmonary hypertension, neurodevelopmental delay, hearing defects, and retinopathy of prematurity), so it requires a multidisciplinary approach. Such issues, as well as the general health of BPD survivors, including their psychological, physical and social functioning, should be considered not only in the early stages of the disease but also in the long-term follow-up of these subjects [18].

Preterm children show a significant airflow limitation during the first years of life, with reduced flows [19], and there is even the chance of their lung function deteriorating in their first year of life [20].

Although some authors report an improvement in airway obstruction during childhood [21], lung function of BPD subjects seems tracking over time with a negligible catch-up of the spirometric parameters. Longitudinal studies following up premature-born subjects into adolescence and early adulthood demonstrate that BPD subjects have a persistently reduced lung function [22], [23], [24], with no significant change in the parameters reflecting airflow limitation, and with a trend towards a progressive deterioration in the lung function of those who had a more severe airflow obstruction during infancy as they grow older [23]. An accelerated decline in FEV1/FVC during adolescence has been described in an Australian cohort of preterm-born individuals, which could mean an earlier deterioration in their respiratory health [24]. These findings emphasize the need to follow up BPD survivors into adulthood, and to minimize their exposure to risk factors associated with a faster decline in lung function, such as cigarette smoking.

Patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations in their school years and later on [23]. A recent meta-analysis demonstrated that individuals born preterm, with and without BPD, have a significantly reduced FEV1 later in life, and this deficit is more severe in survivors of BPD [25].

It is worth noting that recent cohort studies on children born extremely prematurely in the post-surfactant era who did not develop BPD report that airflow limitation persists throughout their years of schooling. These studies seem to indicate that premature birth coincides per se with an impaired lung maturity and growth, with life-long detrimental effects on pulmonary function [13], [26], [27], [28].

Other functional anomalies reported in BPD subjects during childhood and adolescence include a higher residual volume and a higher ratio of residual volume to total lung capacity, probably due to air trapping [26]. In addition, it has been reported that BPD subjects have an impaired gas diffusion capacity, and an increased airway responsiveness [3], [29]. BPD subjects' exercise performance may suffer too, although most authors report that they tolerate maximal exercise workloads and have a normal or only slightly reduced aerobic capacity [30], [31], [32], [33].

As for imaging findings, abnormal structural features on high-resolution computed tomography (HRCT) have been described in up to 80% of extremely premature-born subjects, a diagnosis of BPD and prolonged oxygen therapy after birth being major risk factors for HRCT abnormalities during childhood and adolescence [34]. In 10- to 19-year-olds born extremely preterm, the most common radiological anomalies apparent on HRCT were linear and triangular opacities, air trapping and mosaic perfusion [35]. In studies conducted on adults the main radiographic findings in BPD survivors were emphysema, triangular and linear opacities and gas trapping [36], [37].

A still-debated issue concerns whether such radiographic and functional anomalies are the expression of a stabilized damage that occurred in early infancy or correlate with an active underlying pathogenic process. For the time being, we have a limited understanding of the presence and nature of pathological mechanisms in the lung of BPD survivors. The possible role of asthma-like inflammation has been investigated because BPD subjects often present with recurrent wheezing and other symptoms resembling asthma during their childhood and adolescence. But BPD subjects have normal or lower than normal exhaled nitric oxide levels and exhaled air temperatures, whereas they are higher than normal in asthmatic patients [38], [39]. On the other hand, recent reports suggest that prematurity may be associated with neutrophilic airway inflammation and oxidative stress later in life [40], [41].

Some authors have hypothesized a link between BPD and the onset of COPD, and suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD [42]. This hypothesis is doubtless intriguing, but more lung pathology data will be needed to confirm it because, although we know what histological anomalies occur in the lung of BPD subjects in the early stages of their disease (in their first few months of life), we do not know how this picture evolves over time [43].

Section snippets

Conclusion

Of all obstructive lung diseases in humans, BPD has the earliest onset and is possibly the longest lasting. Given its frequent association with other conditions related to preterm birth (e.g. growth retardation, pulmonary hypertension, neurodevelopmental delay, hearing defects, and retinopathy of prematurity), it often warrants a multidisciplinary management.

In the early stages, BPD is characterized by a severe burden of respiratory disease, with a significant impact on the affected children's

Conflict of interest statement

The authors have no conflict of interest to disclose.

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    This article is published on behalf of the Italian Paediatric Respiratory Society (SIMRI) as part of a themed issue series on paediatric respiratory diseases.

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