Early changes and later indicators

As the most common chronic lung disease in infants, bronchopulmonary dysplasia (BPD) is associated with long-term sequelae that extend into adulthood. Despite significant improvements in perinatal care, the incidence of BPD has remained unchanged or even increased among the most immature infants. The variation in incidence of BPD across perinatal centers reflects differences in both patient population and treatment modalities.

As the most common chronic lung disease in infants, bronchopulmonary dysplasia (BPD) is associated with long-term sequelae that extend into adulthood [1,2]. Despite significant improvements in perinatal care, such as prenatal treatment with steroids to achieve a maturation “spurt” of the lungs, surfactant therapy, and the development of adapted ventilation strategies, the incidence of BPD in the most immature infants has remained unchanged or even increased [3]. This is likely due to a significant reduction in mortality rates along with an increase in the total number of treated infants born significantly premature. The variation in incidence of BPD across perinatal centers reflects both differences in patient population and treatment modalities [4–7]. Publications report an incidence of BPD of up to 68% in very low birth weight infants (401-1500 g) with a gestational age less than 29 weeks’ gestation, or up to 77% in infants born at less than 32 weeks’ gestation or with a birth weight less than 1 kg [5,8,9]. These figures come mainly from countries with a high gross domestic product. With approximately 15 million children born prematurely each year worldwide, the above figures demonstrate the significant clinical and socioeconomic challenge [10].

Chronic lung disease of the newborn is classified into three severity levels as defined by Jobe and Bancalari: mild (oxygen supplementation for at least 28 days postnatally), moderate (oxygen supplementation <30% at 36 weeks postmenstrual age), and severe (oxygen supplementation 30% and/or ventilatory support at 36 weeks postmenstrual age) [1].

Large clinical trials have identified numerous risk factors for the development of BPD, including congenital and nosocomial infections, mechanical ventilation, and oxygen toxicity [11–16]. The impact of these prenatal and postnatal challenges is further determined by the presence of caloric deficiency or deficiency of vitamins and trace elements, as well as inadequate secretion of adrenal and thyroid hormones, which further increase the risk of developing pulmonary morbidity [17–19]. The vulnerability of the developing lung to the development of chronic damage is also increased 3 to 4-fold by the presence of intrauterine growth retardation [20–24], with alveolar and vascular development being critically affected by the underlying altered signal transduction [25]. Exposure to prenatal cigarette smoke – widely underestimated clinically due to lack of anamnestic information and clinical markers – has also been shown to contribute significantly to disease development, possibly beyond an impact on somatic growth [26,27].

The role of established therapies also needs to be kept under review with regard to a possible contribution to the development of chronic complications. Effects of steroid treatment and maternal antibiosis are discussed below in light of this.

** Adapted from: MRI based scoring of the diseased lung in the preterm infant with BPD. Kai Förster, Hannah Busen, Sophia Stöcklein, Olaf Dietrich, Harald Ehrhardt, Mark O. Wielpütz, Andreas W. Flemmer, Benjamin Schubert, Marcus A. Mall, Birgit Ertl-Wagner, Anne Hilgendorff. This manuscript is under submission at Thorax.

Finally, the discussion on the importance of different risk factors has to be conducted in the light of our current, constantly evolving knowledge on the importance of genetic polymorphisms, and studies report that up to 53% of the variance in BPD may be due to this [28]. Genetic abnormalities identified include mutations in genes associated with surfactant synthesis, innate immune response [29,30] and superoxide dismutase [31]. The higher risk of developing BPD and pulmonary arterial hypertension (PAH) in preterm male infants [32] has been linked to differences in hormonal regulation [33]. In contrast, further down the line, women with a history of BPD are more affected in the long term [34].

Difficulties in identifying clinically relevant genetic risk factors arise both in differentiating between variables influencing the risk of preterm birth per se [35] and in considering acute [36] and chronic complications in relation to each other. However, the fact that large genetic association studies [37] have so far not been able to follow up on the successes in other disease areas such as cystic fibrosis [38] or PAH [39,40] in terms of landmark results with clinical relevance may, in addition to the reasons mentioned above, also be an indication of the heterogeneity of BPD diagnosis. In the future, identification of underlying disease (sub)entities may allow clearer assignment of specific risk factors and genetic polymorphisms. Similarly, knowledge of key sites in signal transduction that control the interplay of different pulmonary cell populations will enable the classification of candidate genes. The following sections address various aspects of this.

From cause to consequence: inflammation and oxidative stress response

The described exogenous influences acting pre- and postnatally on a structurally and functionally immature lung result in a persistent inflammatory response, remodeling of the extracellular matrix (ECM), and diffuse fibrotic changes including smooth muscle hypertrophy in the small pulmonary arteries and airways [41]. From the characteristic histopathological changes with the picture of disturbed alveolarization and vasculogenesis [1] results alveolar hypoventilation, which is expressed in the clinical picture of hypercapnia and hypoxemia and the ventilation-perfusion mismatch [42].

The acute and chronic inflammatory processes that characterize BPD are caused by both pre- and postnatal mechanisms. Infections and the corresponding ability to generate a competent immune response play an important role in the development of BPD [13,43–45]. Prenatal inflammatory processes, summarized for example by the term “fetal inflammatory response syndrome (FIRS)” or occurring in the context of manifest infectious events such as chorioamnionitis prenatally or postnatally in the context of congenital and nosocomial infections, lead to an influx of neutrophilic granulocytes into the immature lung. As a result, there is the presence of increased numbers of monocytes and macrophages as part of the so-called “second wave” of the immune response [24,46,47]. The role of innate immunity is of particular importance here, as adaptive immunity can also be variably expressed depending on gestational age [48]. Animal studies suggest that extracellular matrix remodeling and early alveolar epithelial dysfunction are not only a consequence of the inflammatory response, but also further promote it [49,50], causing lasting changes in pulmonary immune function. Prenatally, the widespread use of maternal antibiotic treatments leads to a lasting change in the bacterial flora in the child [51] and in the immune function of the offspring in a mouse model [52].

Postnatally, the induction of barotrauma and volutrauma injuries during mechanical ventilation and the consequences of moderate or severe hyperoxia are important risk factors for the initiation and maintenance of the inflammatory processes highlighted above at the local and even systemic level [53–56]. The release of cytokines such as transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-alpha, and interleukins, e.g., IL-1beta, contributes significantly to the imbalance of signal transduction of various (other) growth factors and leads to the activation of transcription factors that promote apoptosis in different cells [57–59]. Discussion of the role of recruited and resident inflammatory cells [60–64] will provide important insights into mechanistic relationships and for identifying therapeutic options. In this context, however, the presumed influence of inflammatory cells on lung development will also generate new avenues of research [65].

Acute and chronic inflammatory processes must be considered in the context of the cellular capacity to respond to persistent or recurrent postnatal challenges. Here, the relative lack of antioxidants and inhibitors of proteolytic enzymes makes the immature lung particularly vulnerable to the effects of toxic oxygen metabolites and released proteases from the extracellular matrix and resident or recruited neutrophil granulocytes and macrophages [66-69]. Several studies have demonstrated evidence for increased oxidative stress in the preterm infant. Thus, urinary malondialdehyde concentrations are elevated in the first week of life, resulting from peroxidation of lipid membranes after oxidatively mediated damage, and have been shown to correlate with risk for oxygen radical diseases, including BPD [70]. Decreased concentrations of pulmonary antioxidants have been measured in the lavage of preterm infants [71], and other studies indicate that juvenile BPD pa-tients are characterized by signs of increased oxidative stress in the airways, a sign of long-term changes in the respiratory system after preterm birth [72]. Established therapies also need to be critically reviewed for their role in pulmonary development in light of new evidence, as, for example, prenatal administration of betamethasone, despite its more widespread prenatal use to promote lung maturation and prevent respiratory distress while decreasing rates of BPD [73,74] Have been shown to increase indicators of lipid membrane peroxidation [70].

These longer-term changes in the oxidative stress response and other processes are reflected in altered responses to viral infections later in life [75]. The response of the developing lung to early damage, including long-term consequences, is specific and different from the response of the adult organism. Whereas chronic exposure to oxygen (60% for 14 days) in neonatal rat lungs increases contraction of pulmonary vessels and airway smooth muscle and reduces nitric oxide relaxation, the opposite phenomenon occurs in adult animals [76]. Long-term effects after hyperoxia exposure in the first week of life (100% for 4 days) include primarily cardiovascular complications, in which right ventricular strain developed as a consequence of pulmonary vascular disease in PAH and consecutively increased mortality in animal models [77]. Altered signal transduction by bone morphogenic protein (BMP) offers a pathomechanistic explanation. Other mechanisms explaining the increased susceptibility to acute and long-term damage in the newborn lung are demonstrated by another study of hyperoxia-induced effects. In the neonatal mouse, in contrast to the adult animal, bone marrow-derived circulating and lung endothelial progenitor cells are markedly reduced here [78], which may result in early exhaustion of repair and regenerative capacities. The impact on other key processes such as cell cycle regulation with upregulation of P21 after hyperoxia and reduced histone deacetylase activity [79] as well as the effects on DNA methylation [80] also point to the early emergence of long-term relevant accumulative effects in the context of reduced compensatory mechanisms in the immature lung.

Histopathological characteristics – clock and “memory” function

The interaction of the epithelial, mesenchymal, and endothelial cell compartments in their interplay to develop the gas exchange area is largely orchestrated by the regulation of various growth factors. These include Notch and Wingless Int-1 (Wnt), fibroblast and platelet derived growth factor (FGF and PDGF), and BMP and vascular endothelial growth factor (VEGF) [81–87]. Early interference with these transcription factors disrupts normal lung morphogenesis [88] resulting in a lack of differentiation of alveolar structures [89]. Similarly, regulation of key transcription factors such as nuclear factor kappa B (NF-kB) plays a role and contributes to the maldevelopment of the gas exchange surface [88,90,91]. The characteristic association of impaired alveolarization with the presence of dysmorphic capillaries is driven by altered angiogenic growth factor expression, which includes reduced pulmonary expression of vascular endothelial growth factor (VEGF) and VEGF receptors [92–94] as well as decreased endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) in pulmonary blood vessels and airways include. [95,96]. The changes are similar to those in the aging organism and contribute – also due to the reduced plasticity of capillaries and small vessels – to the risk of PAH and impaired development of the lymphatic system in the lungs in the further course [97–100].

The impaired signal transduction together with direct effects of, for example, the stretch stimulus from mechanical ventilation and oxygen toxicity contribute to severe changes in the lung scaffold [101,102]. Increased remodeling of the extracellular matrix is indicated, for example, by increased urinary excretion of desmosine, which is preceded by increased elastase activity [103–105] and is similar to findings in patients with acute respiratory distress syndrome (ARDS) [106]. However, physiological lung development also depends on the presence of pulmonary elastases and metalloproteinases, as complete matrix metalloproteinase deficiency promotes BPD-type lung remodeling [107].

As a result of remodeling, BPD is characterized by pathological arrangement of elastin and qualitative and quantitative changes in the collagen skeleton. [108–110] characterized, which influence the structuring function of the matrix as a scaffold for the formation of new alveoli and capillaries and define the fate of the cells that populate the developing organ [111,112] (Fig. 2). The irreversible reorganization of the extracellular matrix will thus lead to long-term changes that will manifest themselves at various levels.

The histopathological alterations and the clinically heterogeneous development and appearance of BPD suggest the existence of disease (sub)entities or at least an individually different influence of various structural alterations on the clinical appearance and long-term course. The presence of primary emphysematous or interstitial remodeling processes, vascular changes and/or pathologies of the respiratory tract are presumably directional “variables” of BPD, which can also be depicted image-morphologically in premature infants by means of clinically feasible imaging strategies in initial studies [113–117]. With the replication of successful studies from other disease areas, the use of additional imaging strategies [118–121] could further improve patient stratification in the future.

Lung function in BPD – Early changes and long-term consequences.

Despite sustained efforts in perinatal care to prevent long-term complications [122,123], manifestation of respiratory symptoms in adulthood is common and often misinterpreted as asthma or COPD, especially when early life events are not known or inquired about [124,125].

Clinically, pulmonary dysfunction is characterized by decreased pulmonary compliance, tachypnea, and increased minute ventilation reflected by increased work of breathing with and without oxygen dependence. This clinical picture may be accompanied by an increase in microvascular pressure in the lungs, which contributes to the development of interstitial pulmonary edema. The increased pulmonary vascular resistance, typically associated with decreased responsiveness to inhaled nitric oxide and other vasodilators, may progress to reversible or persistent PAH and right heart failure [99,100]. Knowledge of early changes in lung function is critical because more severe lung disease after birth is more likely to develop into moderate/severe BPD on the calculated date of delivery [126] and lung function is a good predictor of subsequent morbidity and mortality [127]. BPD is characterized in lung function by increased airway resistance and hyperreactive airways [128]which manifests clinically – in association with or independent of pulmonary infections – by episodic bronchoconstriction and cyanosis (Fig. 3). The proportion of vascular-mediated pathology involved in this beyond the Euler-Liljestrand effect often remains unclear because sensitive indicators are lacking. Affected infants may remain oxygen dependent for months or years, with only a minority actually dependent on oxygen beyond the age of two years [129,130]. Oxygen dependence distinguishes the particular severity of lung disease, and these infants are twice as likely to be readmitted to the hospital compared with nonoxygen-dependent infants. However, even after cessation of oxygen therapy, patients with moderate or severe in up to 70% require repeat hospitalizations, especially in the first two years of life [126,131,132]. Overall, however, lower respiratory tract infections caused by respiratory syncytial virus (RS) remain the leading cause of hospital readmission in preterm infants regardless of BPD status [133].

Later in the course of the disease, BPD is a significant risk factor for persistent “wheezing” and for the need for inhalation therapy (odds ratios 2.7 and 2.4, respectively), which affects approximately 20-30% of infants with BPD at six and 12 months of age [134,135]. Respiratory symptoms, especially in children with a history of wheezing, often persist through preschool and school age [129,136] and up to 80% of preterm infants present with frequently symptomatic airway obstruction in early childhood and adolescence [137–139]. Important data on long-term outcome after preterm birth were obtained in the EPICure study [140]. Preterm infants with extreme immaturity suffer significantly lower peak oxygen consumption (“PEOC”) at school age as a direct assessment of cardiorespiratory fitness, lower forced expiratory volume at one second (FEV1), and impaired gas transfer. Here, significantly lower peak loads and higher respiratory rates combined with lower tidal volumes during peak loading and increased residual capacity may reflect the effect of hyperinflation on airway obstruction and/or changes in pulmonary chemoreceptor function and indicate the presence of persistent limitations in airway function and reduction in alveolar area. The non-physiological lung growth based changes with impaired FEV1 and FEV1/forced vital capacity in the context of BPD have been confirmed by several studies in children and young adults [141–144].

The course of the disease into adulthood varies. In some patients, particularly those with severe BPD, symptoms persist into adulthood [145]. Other courses indicate a transient (subjective) improvement with a subsequent recurrence of disease symptoms that are the result of (further) limitation of lung function below a clinical (or individual) threshold. This reduction may appear due to aging processes or an emerging mismatch in lung-to-body mass ratio and/or energy expenditure. While one group reported a divergent course of lung growth during adolescence according to spirometric measurements [141], the EPICure study showed no catch-up of suboptimal lung growth from 11-19 years in adolescents after extreme prematurity regardless of BPD status and even demonstrated significant impairment of all lung function parameters in 19-year-old extremely premature patients [144]. Meanwhile, Vollsaeter and colleagues reported parallel courses of lung function in early adulthood [146].

To better understand features and effects of premature pulmonary aging after prematurity. [147,148] and to clarify the characterization of the effects of secondary injury, e.g., from smoking, from exacerbations in the setting of viral infections, and from broader environmental influences on the course of lung function [149,150] will also be critical for early counseling of families with an eye toward long-term outcome and agreement on control strategies.

Another field is defined by the occurrence of comorbidities for which BPD is a risk factor in its own right [151]. This concerns neurological and cardiovascular diseases and includes consideration of therapy-associated complications. Here dexamethasone treatment, in particular, takes on a special role with adverse effects on cardiac function, life expectancy and neurological development [152,153].

Summary

The response of the immature lung to pre- and postnatal damage mechanisms that manifests as a sustained inflammatory response, an oxidative stress response, and altered growth factor signal transduction, leading to severe alterations in alveolar and vascular development including remodeling of the extracellular matrix, is associated with significant long-term consequences. Abnormalities of lung function (and immunity) in infancy and early childhood predispose to reduced lung function in adult survivors of preterm birth and alteration of the physiologic aging process through a pulmonary “memory effect” in response to early injury. Iterative knowledge exchange between pediatricians, family physicians, and adult pulmonologists is needed to generate a better understanding of these long-term outcomes, including the characteristics and effects of premature aging, and translate them into adapted treatment strategies and lifestyle recommendations for this patient population. In the context of the age at which BPD was diagnosed, interpretation of the pulmonary function findings should also take into account the original underlying BPD definition and the standards of perinatal care applied.

Take-Home Messages

BPD is a chronic respiratory disease of infancy characterized by alveolar rarefaction, small airway affection, and pulmonary vascular changes. During follow-up observations of pulmonary function, one second capacity may be decreased in children and adults with a history of BPD, among others.
The characteristic association of impaired alveolarization with the presence of dysmorphic capillaries is driven by altered expression of angiogenic growth factors. Some changes resemble those in the aging organism and contribute to the risk of PAH and impaired development of the lymphatic system in the lungs as the disease progresses.
As a result of remodeling, BPD is characterized by a pathological arrangement of elastin and qualitative and quantitative changes in the collagen scaffold, which affect the structure-giving function of the matrix as a scaffold for the formation of new alveoli and capillaries and define the fate of the cells that populate the developing organ.
Early damage to the lung results in a sustained inflammatory response, an oxidative stress response, and altered signal transduction of important growth factors.
Iterative knowledge exchange between pediatricians, primary care physicians, and adult pulmonologists is necessary to achieve a better understanding of long-term outcomes, including the characteristics and effects of premature aging.
The impact of early chronic lung disease on the development of comorbidities must be considered when designing monitoring and treatment strategies and making lifestyle recommendations for this patient population.

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