Pathogenesis of BPD
Part III: Long-Term Respiratory Outcomes of BPD Survivors
There is clear evidence that infants surviving with BPD have prolonged respiratory symptoms and persistent abnormalities in their lung structure and function that can persist into adulthood. While respiratory disease in adults is discussed in chapter “Sequelae of Prematurity: The Adolescent and Young Adult Patient”, and the options for diagnostic modalities are discussed in chapter “Diagnostic Modalities: Pulmonary Function Testing and Imaging”, this chapter will provide an overview of the respiratory symptomes, structural changes and functional abnormalities of patients born preterm.
Many of the premature infants with severe BPD are oxygen dependent for months prior to being discharged home, although this oxygen dependency is rarely seen after 2 years of age [35, 36]. Preterm infants are at a greater risk for being rehospitalized over the first few years of life, secondary to respiratory illnesses such as airway obstruction and respiratory tract infections [10, 37]. Early preterm infants (<32 weeks of gestation) require significantly more chronic oxygen therapy, tracheostomy, and treatment for pulmonary hypertension as compared to late-preterm (32–35 weeks of gestation) and full-term infants while being admitted to pediatric intensive care units . Throughout childhood, adolescence, and young adulthood, BPD survivors have persistent respiratory symptoms. A recent study showed that at school age, children with BPD have more respiratory symptoms including coughing, shortness of breath, wheezing, and activity restriction when compared to children born preterm without BPD and children born at term . In addition, children in the BPD group are significantly more likely to be treated with asthma medications. Some of these respiratory symptoms persist into adulthood. In a systematic review that included 14 cohort studies on the respiratory outcome in adult BPD survivors, increased respiratory symptoms were reported in this population compared with their peers . Adult BPD survivors are twice as likely to report wheezing and three times more likely to use asthma medication than preterm-born adults without BPD and term-born adult controls .
There is increasing evidence that BPD survivors have persistent lung structural abnormalities. Although the exact mechanisms contributing to these observations are not well established, early developmental disturbance and a sustained inflammatory process secondary to early insults such as oxygen toxicity and mechanical ventilation, as well as increased susceptibility to later infections or cigarette exposure are postulated as some of the underlying pathological causes.
Inflammation caused by mechanical forces, oxygen therapy and infections plays a key role in the development and progression of BPD. Some studies have indicated that the inflammatory process persists in BPD survivors. Increased levels of chemokines (interferon-gamma inducible protein-10, macrophage inflammatory protein-1α, Eotaxin, monocyte chemoattractant protein-1), growth factors (platelet-derived growth factor-bb, VEGF, fibroblast growth factor-basic, granulocyte macrophage colony-stimulating factor), T-helper cytokines 1 (Th1) (IL-12, interferon-γ), Th2 (IL-9, IL-13), Th17 (IL-6, IL-17) cytokines, and immunomodulatory mediators (IL-1RA and granulocyte colony-stimulating factor) were detected in nasopharyngeal aspirate of preterm infants at 1 year of age . Increased neutrophils and IL-8 concentrations are also found in the sputum of school children who were born before 32 weeks of gestation . These results suggest that there is a possible ongoing airway inflammatory process in infants with BPD that could contribute to long-lasting respiratory symptoms and functional disturbance.
Another marker of ongoing airway disease is increased oxidative stress that is linked to airway inflammation and remodeling. Evidence of increased oxidative stress in former preterm infants with or without BPD is also emerging. 8-isoprostane is a prostaglandin F2α isomer formed by arachidonic acid peroxidation, catalyzed by free radicals, i.e., a biomarker of lipid peroxidation and oxidative stress. In one particular study with adolescents born before 32 weeks of gestation with or without history of BPD and control subjects who were born at term, increased exhaled breath condensate 8-isoprostane concentrations were detected in the preterm groups with or without BPD . In adult lung diseases, increased oxidative stress in the airways is associated with chronic obstructive pulmonary disease (COPD) . This persistence of increased oxidative stress well into the adolescence of former premature infants may place them at a greater risk for future development of COPD.
The pathological hallmarks of BPD include decreased alveolarization and vascular growth that can lead to inhibition of alveolar–capillary membrane structural development and function (Fig. 2) . Much of our understanding of BPD pathology is from histopathological studies in lung autopsy specimens from infants who died of BPD. In the presurfactant era, generalized emphysematous changes were found in mechanically ventilated preterm infants and particularly the extremely premature infants . Studies in the postsurfactant era demonstrated similar emphysematous changes in preterm infants who died of BPD in infancy . In addition, alveolar enlargement with blunted secondary septa, thickened alveolar–capillary membrane, and poor alveolar growth were also found in lungs of mechanical ventilated preterm infants .
(a) Lung autopsy from a 12-year-old with BPD who was born at 26 weeks shows abnormally large air spaces (asterisk) with simplified alveoli. A small bronchiole (BR) shows mild, chronic peribronchitis. (b) Lung section from an age-matched control shows normal alveolarization with numerous alveoli and a normal small bronchiole (BR) 
Given the limited availability of such lung autopsy specimens in later BPD survivors, it is unclear whether these structural abnormalities of alveolar–capillary membrane persist into childhood, adolescence, and adulthood. However, studies assessing pulmonary gas exchange strongly support that there is a decreased alveolar–capillary membrane function in older BPD survivors. Multiple studies have used carbon monoxide diffusing capacity (DLco) to assess alveolar–capillary membrane function in preterm survivors at childhood, adolescence, and adulthood [48–52]. These studies consistently demonstrated a lower diffusing capacity in the subjects with a history of BPD. Furthermore, in the EPICure study with 11-year pulmonary outcomes, it was found that children with a history of BPD not only had a decreased DLco but they also had a reduced exercise capacity, even though these children were clinically well . Taken together, these evidence highlight the complexity and persistence of lung structural abnormalities that last well into the later life of preterm infants, particularly those survivors who had BPD. Furthermore, these structural alterations provide a pathological basis for the persistent respiratory symptoms and functional disturbance observed in this population.
Persistent radiographic abnormalities including multifocal hypoattenuated areas, linear and subpleural opacities, bronchial wall thickening, bullae, and bronchiectasis are commonly reported in BPD survivors [50, 54–57]. High-resolution computed tomography (HRCT) of the chest is a sensitive tool for assessing lung parenchyma abnormalities in survivors of preterm infants [50, 54, 55]. A population-based study showed that linear opacities and triangular subpleural opacities are the two most common chest CT abnormalities in BPD survivors at 10 and 18 years of age . The hypoattenuated areas may reflect “obstructive emphysema,” whereas the well-defined linear densities may reflect areas of atelectasis, all of which are radiographic abnormalities that correlate with the pathological hallmarks of the “Old” BPD. These results further support that there is persistent lung structural damage in the survivors of BPD. The clinical relevance of these chest CT abnormalities was investigated in several studies. A retrospective study reported that the presence of areas of decreased attenuation significantly correlated with the BPD severity . Chest CT abnormalities are also associated with decreased lung function in long-term survivors of BPD. The increased subpleural opacities and limited linear opacities are associated with low functional residual capacity (FRC) and longer duration of oxygen therapy . The linear/triangular opacities and hypoattenuated areas were significantly associated with decreased forced expiratory volume at 1 s (FEV1) in BPD survivors at a mean age of 10–18 years . In adult BPD survivors, the presence of emphysema on chest CT is inversely related to the FEV1 z-score .
Abnormal Pulmonary Function
Children, adolescents, and adults born extremely or very preterm, with or without BPD tend to have persistent lung function abnormalities. Measurements of forced flows and volumes, respiratory system mechanics, lung volumes and ventilation homogeneity, and pulmonary gas exchange studies have been performed in these subjects. Common findings are airway obstruction, increased resistance and decreased compliance of the respiratory system, decreased alveolar–capillary diffusion capacity, and decreased exercise capacity.
Persistent airway obstruction is one of the most common pulmonary function abnormalities associated with preterm birth at various ages. In early childhood, studies have uniformly demonstrated that BPD survivors have decreased airflow [60–62]. A longitudinal study assessing pulmonary function in infants with BPD up to 3 years of age demonstrated significant airflow obstruction and modest restriction that tends to persist with time . These abnormal findings were detected by spirometry using the raised volume rapid thoracoabdominal compression technique and by assessment of lung volume using plethysmography. Spirometry showed significant reductions in FEV in 0.5 s (FEV0.5), FEV at 75 % of expired FVC (FEV75), and FEV25–75. Lung volume measurements demonstrated a mild elevation of residual volume (RV)/total lung capacity (TLC). These lung function abnormalities persisted at a mean postnatal age of almost 2 years. Other studies have also showed similar findings in infants with history of BPD [59–61]. In addition, infants with the most severe obstruction also demonstrate increased bronchodilator responsiveness . These abnormal findings may be attributed to persistent airway injury and remodeling resulting from a combination of lung immaturity and injury caused by mechanical ventilation, oxygen therapy, and infection. Multiple studies have assessed pulmonary function at early infancy in healthy premature infants born at 30–34 weeks of gestation without neonatal respiratory complications and found persistently reduced airflow in the presence of normal lung volumes [64, 65]. These data suggest that prematurity alone could result in persistent airway obstruction in early infancy.
At school age, preterm-born infants, particularly those who had history of BPD, continue to have airway obstruction on pulmonary function tests [38, 53, 66–71]. The EPICure study assessed children’s lung function at 11 years after extremely preterm birth (<25 weeks of gestation) and compared them to their full-term born classmates . Even after correction for height, age, and sex using standardized z-scores, the premature born children have significantly worse baseline lung function, including FEV1, FVC, FEV1/FVC, and FEV25–75. These differences are most prevalent in those with history of BPD. Children who were born with very low birth weight (≤1500 g) and without history of BPD also have lower FEV1, high residual volume to TLC, high flow resistance, and higher rate of bronchial hyperreactivity as compared to the cohort of term controls [51, 66, 67]. These abnormalities are associated with low birth weight, long duration of oxygen therapy, low socioeconomic status, and exposure to animal dander . In addition, prematurely born children also have a more frequent response to bronchodilator and lower post bronchodilator FEV1, indicating some degree of fixed airway obstruction [38, 69, 70]. It is important to note that airway obstruction persists into adulthood in those born preterm as well . A recent controlled population-based study assessed lung function from mid-childhood to adulthood after extreme preterm birth . Two cohorts that represent the presurfactant era (born at 1982–1985) and the postsurfactant era (born at 1991–1992) were included in this study. It was found that preterm-born cohorts, particularly those with history of BPD, have significantly lower FEV1 and FEV25–75 at 10 and 18 and at 18 and 25 years of age, respectively. In addition, in subjects with moderate/severe BPD, the predicted FEV1 barely exceeded 80 % that is considered a cut-off level required for the diagnosis of COPD (Fig. 3).
Besides airway obstruction and increased respiratory system resistance, preterm infants have decreased respiratory system compliance, particularly in those with moderate/severe BPD [73, 74]. This low compliance tends to normalize at 2 years of age, which may be related to increased alveolar formation. As discussed in the lung structural abnormalities section, children with history of BPD have reduced alveolar–capillary gas exchange as assessed by DLco and DLco to alveolar volume (DLco/VA). At 11 months of age, preterm infants with BPD exhibit lower DLco and DLco/VA, despite unchanged VA . In older children, around 8 years of age, those born very preterm (≤32 weeks of gestation) also have lower DLco and DLco/VA compared to age-matched controls born at term . Increasing length of oxygen therapy, but not gestational age or birth weight, is the strongest risk factor correlating negatively with the z-DLco/VA measurement .
Both normal and abnormal exercise capacities, reflected by oxygen uptake at maximal exercise (VO2max) and 6-min walking distance, were reported in children, adolescents, and young adults born preterm [39, 71, 76–83]. Studies showed that adults who were born extremely premature in 1980s had reduced peak VO2 [78, 84], while adolescents who were born in 1991–1992 had modestly reduced peak VO2 and treadmill distance compared to a term-born control group . However, the values were within normal range in most subjects. Children with history of BPD have a reduced 6-min walking distance as compared to preterm children without BPD and term controls . However, this difference was not significant after adjusting for confounding factors including gender, body height, and weight. A study reported that at 10 years of age, children who were born extreme preterm have significantly lower peak VO2 but normal 6 min walking distance when compared to full-term born subjects . A systematic review and meta-analysis concluded that preterm-born subjects with or without BPD have lower exercise capacity than term-born control subjects . The differences are small, and the BPD subjects are able to achieve near normal exercise capacity, but this may be at the expense of using more of their ventilatory reserve.
Taken together, the evidence is that long-term survivors of prematurity, particularly those born very premature and those with BPD, have chronic pulmonary function impairment, particularly airway obstruction and gas trapping in childhood, adolescence, and young adulthood. Those who had BPD have more compromised lung function, alveolar–capillary gas exchange, and excise capacity than those who did not have BPD early in life. The long-term functional impairment may be related to persistent structural abnormalities in the small airways and alveoli. These findings support the hypothesis that adults born preterm may be at increased risk for premature onset COPD.
Long-Term Respiratory Outcomes in Late-Preterm-Born Infants
Most of the studies of long-term respiratory outcomes have been conducted in extremely and very preterm-born infants. Late-preterm infants born between 34 and 36 weeks of gestation account for over 70 % of all preterm births and about 8 % of all birth in the United States [86, 87]. These infants were previously referred to as near-term infants, and until recently, they have been considered mature enough to be treated as term infants. The lungs of late-preterm infants are at the late saccular and beginning of alveolar stage. The surfactant production may still be relatively insufficient, and the antioxidant systems are not optimal. The alveolar structures are also immature with fewer alveoli and thicker alveolar septa. Delivery at this period can interrupt the critical developmental processes of alveolar formation and maturation and contribute to both short-term and long-term respiratory morbidities.
It is quite clear that infants born late preterm have increased short-term respiratory complications compared to term-born infants [88–90]. Late-preterm infants have an increased need for resuscitation at birth due to respiratory insufficiency . A systematic review in 2011 demonstrated that they are more likely to need mechanical ventilation (RR, 4.9; 95 % CI, 2.8–8.6), nasal continuous positive airway pressure (RR, 9.8; 95 % CI, 5.1–18.8), and oxygen therapy (RR, 24.4; 95 % CI, 5.1–116.1) . They also have a significant increase in respiratory distress syndrome (RR, 17.3; 95 % CI, 3.3–17.3), transient tachypnea of the newborn (RR, 7.5; 95 % CI, 5.0–11.2), and pneumonia (RR, 3.5; 95 % CI, 1.4–8.9). These respiratory complications are inversely associated with gestational age [90, 92]. Given that mechanical ventilation and oxygen therapy are important risk factors for lung injury in preterm infants, the increased need for these methods of support in the late-preterm infants may also put their relative immature lungs at a great risk for short-term injury and perhaps long-term injury. Furthermore, respiratory infections, whether acquired prenatally or postnatally, are recognized to be a risk factor in the pathogenesis of BPD. The increased rate of pneumonia in late-preterm infants not only highlights the risk for early lung disease but also indicates a risk factor for long-term lung injury.
Persistent respiratory symptoms are being recognized in children born late preterm. During infancy and early childhood, these children are at an increased risk for respiratory tract infections, particularly from respiratory syncytial virus (RSV) [93–97]. A retrospective study showed that infants <6 months of age who were born at 33–35 weeks of gestation have increased rates of hospitalization due to RSV infection compared to term-born infants . The late-preterm infants with proven or probable RSV infection also have significant increases in all hospital utilization parameters and a mortality rate of 8.1 % compared to 1.6 % in the control cohort . Exposure to smoke is recognized to be an important risk factor for severe RSV infection requiring hospitalization in late-preterm infants from smoking families . In addition, outpatient RSV respiratory tract infection is higher, ranging from 183.3 to 245.7/1000 among late-preterm infants than in full-term infants (128.8 to 171.3/1000) . There are also reports that infants and children who were born at 34–36 weeks of gestation, may be at increased risk for developing wheezing and asthma compared to those born at term [100, 101]. Persistent asthma and corticosteroids usage were found to be associated with late-preterm birth by 18 months of age . At near school age, late-preterm-born children also experienced more wheezing and nocturnal cough, and received more inhaled steroids than term-born children . A recent study reported that children at 3–5 years of age who were born late preterm have increased risks for asthma (18.4 %) and bronchitis (10.2 %) as compared to those born at term (asthma, 12.8 %; bronchitis, 8.3 %) . It also found that needing oxygen therapy or mechanical ventilation during the neonatal period, or RSV infection, was associated with higher rates of asthma and bronchitis. There is little information on respiratory complications in adults who were born late preterm. A Swedish national cohort study reported no association between late-preterm birth and using asthma medication in young adults, age 25–35 years .
Some studies have assessed pulmonary function by spirometry in children born late preterm and found increased incidence of airway obstruction. One of the these studies showed that at around 11 years of age, children who were born at 34–36 weeks of gestation had a significantly higher increased residual volume and residual volume/TLC as compared to their siblings who were born at term . In the Avon Longitudinal Study, reduced FEV1/FVC and FEV25–75 were found at 8–9 years of age in children who were born at 33–34 weeks of gestation compared to term-born controls . However, in follow-up studies at 14–17 years of age, measures of airway function were similar between late-preterm-born subjects and term-born subjects with the exception of FEV25–75, suggesting that there are improvements in lung function during this period. Data are lacking in regard to whether late-preterm infants have other pulmonary function abnormalities, such as airway hyper responsiveness and decreased alveolar–capillary gas diffusion that are frequently observed in very preterm infants.
Significant progress has been made in the understanding of basic lung developmental processes, mechanisms of injury, and repair of the immature lung, as well as in the pathogenesis of BPD. In contrast, long-term respiratory outcomes in preterm infant survivors, particularly those with a history of BPD, who are now well into their adulthood, are less clear. There are still many unanswered questions as to why early injury to an immature lung has long-lasting negative impact on its structure and function. It is also unknown what the impact of early lung injury on lung function and overall health will be as these BPD survivors age to late adulthood. Thus, additional studies of these BPD survivors are needed to better understand the mechanisms contributing to the prolonged disruption of lung structure and respiratory dysfunction seen in these patients. It is also important that long-term follow-up and care by pulmonary specialists are provided to enhance the overall lung health of these survivors.