Results compared to full-term normal controls
Dynamic and passive expiratory respiratory mechanics
Tidal breathing measurements
Lower Tpef/Te in infants with BPD compared to those without BPD 
PA not different between infants with and without BPD 
Forced expiratory flow measurements
Lung volume measurement
Decreased low-frequency reactance
Older children and adults
Plethysmography maneuver being performed during infant pulmonary function testing
Tidal Breathing Measurements
Tidal breathing analysis can be performed using a mask with pneumotachometer or using respiratory inductance plethysmography (RIP). With the former method, the primary measure of interest has been the ratio of the time to peak expiratory flow over total expiratory time (Tpef/Te). Tpef/Te has been shown to be decreased in obstructive lung disease [20, 21]. In term infants, a low Tpef/Te is predictive of wheezing in the first year of life  and asthma at 10 years . Preterm infants demonstrate lower Tpef/Te, and infants with BPD have lower Tpef/Te compared to those without BPD . However, measurement of Tpef/Te does not add to the ability to predict respiratory disease in the first year of life .
RIP can be used to measure the asynchrony between thoracic and abdominal motion during tidal breathing. Healthy infants demonstrate remarkable synchrony, but in the setting of airway obstruction or decreased lung compliance, thoracoabdominal asynchrony increases. The phase angle (PA) is a quantitative measure of thoracoabdominal asynchrony that ranges from 0 (no asynchrony at all) to 180° (paradoxical breathing). Preterm infants have an elevated PA [25, 26], and PA correlates with measures of lung elastance and compliance . However, PA does not differ between infants with and without BPD .
Forced Expiratory Flows
Early studies of forced expiratory flows (FEF) in preterm infants utilized the rapid thoracoabdominal compression (RTC) technique, where expiratory flow is generated by rapidly inflating a vest around the chest and abdomen at end inspiration of the tidal breath, and the maximal flow at functional residual capacity (VmaxFRC) is measured. Studies have shown that VmaxFRC is consistently lower in preterm infants compared to healthy term infants (Table 1). In one small study of children with moderate to severe BPD, VmaxFRC at 24 months correlated with FEV1 and FEF25–75 in school-age years, indicating a lack of “catch-up” growth .
A major disadvantage of the RTC technique is that FRC is unstable in infants, leading to variability in VmaxFRC. With the raised volume RTC (RVRTC) technique, the infant’s lungs are inflated to 30 cm H2O, which is near total lung capacity. This allows generation of flows across a larger lung volume, replicating adult-type spirometry. Over time, the RVRTC technique has supplanted the RTC or partial flow-volume method, and most recent studies of preterm infants have employed this method. As with VmaxFRC, RVRTC measures such as the forced expiratory volume in 0.5 s (FEV0.5) and FEF at 75 % FVC (FEF75) are also reduced in preterm infants. Using the RVRTC technique, the degree of obstruction has been reported to be more severe in BPD compared to non-BPD infants;  however, in contrast, others have reported that BPD is not associated with decreased forced expiratory flows . Furthermore, infants with better somatic growth during the first 1–2 years of life were reported to have higher forced expiratory flows compared to those with poorer growth .
Airway function may even deteriorate during the first year of life in infants with BPD [31, 32], probably reflecting the coupled effects of an unresolved lung injury plus the developmental interferences related to prematurity itself, at a time when the infant’s respiratory system is growing rapidly . Similar airway function abnormalities have also been reported in preterm infants without BPD, underscoring the important influence of prematurity on developmental changes in the lung [34, 35].
Lung Volume Measurements
Similar to adult PFTs, infant lung volumes can be measured using gas dilution techniques or body plethysmography. The former can be done using gas washout techniques with either an inert tracer gas such as helium (He) or sulfur hexafluoride (SF6) or washing out the resident nitrogen (N2) in the lungs. With body plethysmography, the infant tidal breathes against a closed valve or balloon, generating the pressure swings needed to apply Boyle’s law. FRC is normal or even low in infants with BPD compared to healthy full-term controls during early infancy (36–42 weeks postmenstrual age), probably as a result of decreased lung compliance in the setting of a compliant chest wall . However, over time, as lung repair occurs and the chest wall becomes stiffer, FRC tends to increase, consistent with an obstructive pattern . Some studies did not detect any significant differences in FRC when comparing “healthy” term and preterm infants , or when relating results from healthy preterm infants to published reference equations for FRCHe . In contrast, Hjalmarson and Sandberg reported significantly reduced FRCN2 in healthy preterm infants compared to term neonates (data only normalized for weight at test) . In summary, in young preterm infants, FRC has been reported to be low or normal; these differences can be attributed to variations in methods and subject characteristics between these studies.
Measurements of Ventilation Homogeneity
The multiple breath washout technique assesses ventilation homogeneity. The lung clearance index (LCI) represents the number of tidal breaths needed to completely wash out either the resident N2 gas or a tracer gas to 1/40th of its original concentration. In the preterm population, LCI is not a sensitive index to discriminate disease in preterm infants compared to term infants [24, 40], as opposed to other obstructive lung diseases, such as cystic fibrosis.
The diffusion capacity of the lung to carbon monoxide (DLCO) can be measured in infants; however, the methodology is technically challenging, not commercially available, and requires analysis of C18O with a mass spectrometer, which makes the measurements expensive. The two components of DLCO, the pulmonary membrane-diffusing capacity (DM) and the pulmonary capillary blood volume (VC), can be determined by measuring DLCO under conditions of room air and high inspired oxygen . Infants with BPD demonstrate decreased DLCO but normal alveolar volume (VA) when compared to full-term controls, adjusting for race, gender, body length, and corrected age . In addition, both DM and VC are lower in infants with BPD compared with infants born at term . These in vivo physiological findings are consistent with pathological autopsy reports with impaired alveolar development with larger, but fewer alveoli and decreased pulmonary capillary density [44–47]. In contrast with infants with BPD, infants born prematurely without BPD had higher DLCO than full-term subjects, after adjusting for body length, gender, and race, suggesting that prematurity per se does not impair lung parenchymal development .
Lung Function in Preschool Aged Preterm Children
Recommendations for conducting preschool lung function testing have been endorsed by the American Thoracic Society and European Respiratory Society . Obtaining PFT data from the preschool population (i.e., ages 3–5 years) presents a special challenge. They are too old for the RVRTC technique, but performing the voluntary breathing maneuvers needed for spirometry, body plethysmography, or DLCO requires cooperation, which proves challenging in this age group. There are some preschool PFT methods that require less cooperation (tidal breathing techniques) than spirometry that have been used to study lung function in preschool preterm children.
With the interrupter technique, children breathe through a mouthpiece or mask, and passive expiratory flow is briefly occluded with a balloon or shutter for 100 ms. By measuring flow just prior to the occlusion (V′) and the resultant pressure plateau (Pplat), the interrupter resistance (Rint) can be calculated using the equation Rint = Pplat/V′. Rint reflects airway resistance, although it is not a direct measure. Rint is elevated in preterm children compared to full-term ones, and children with a history of severe BPD have higher Rint than other preterm children [49–51].
Another PFT technique that has been used in studies of preschool children is forced oscillometry (FO), which measures the total respiratory system impedance (Zrs) across a spectrum of oscillation frequencies . Zrs is composed of resistance (R) and reactance (X). At lower frequencies, the latter reflects the viscoelastic forces of the lung. Several studies using FO have shown that preschool preterm children have elevated R and decreased low-frequency X, therefore demonstrating that lung function is worse in children with a history of BPD [51, 53].
Lung Function in Older Children and Adults Born Prematurely
Many studies of lung function have been conducted in older children and adults born prematurely. Most of the information on long-term lung function in survivors of BPD has been derived from preterm infants born before surfactant treatment was available, or studies are limited to selected populations of children who had severe pulmonary disease as neonates. Study results often reflect the outcome for children with “old” BPD and may not reflect physiological findings in children who received modern neonatal care or who have “new” BPD .
Spirometric values reflecting airflow are consistently lower in survivors of BPD at any age compared to controls born at term; those with BPD have substantial airway obstruction and alveolar hyperinflation [2, 55–58]. In most studies [2, 57, 59, 60], the mean forced expiratory volume in 1 s (FEV1) values in those with BPD range from normal to values indicative of significant airflow limitation, reflecting the heterogeneity in the functional expression of the disease. These data should be interpreted with caution, however, since they are not generally applicable to the whole population of survivors, and especially not to those with new BPD or mild neonatal pulmonary disease. Patients who were born prematurely but did not have BPD usually fare better , but they too may have airflow limitation at school age [2, 58, 59, 62] and into adolescence and adulthood [3, 63, 64].
Lung Volume Measurements
Air trapping has been reported in premature children with BPD [65–67] secondary to obstructive airway disease, impaired alveolarization, and/or abnormal lung growth or injury. In contrast, normal FRC has also been reported in former preterm adolescents with BPD . The presence of residual lung function abnormalities, mainly airflow obstruction and progressive static hyperinflation, raise the question as to whether chronic lung disease of infancy may ultimately affect pulmonary aging, leading to the development of chronic obstructive pulmonary disease (COPD) .
DLCO in school-age children born prematurely has been noted to be impaired in several studies [64, 65]. The decrease of DLCO/Va may reflect a deficit in the alveolar number leading to increased airspace and a reduction in the gas exchange-surface area . Due to the challenges to performing DLCO during infancy, there are no longitudinal studies tracking DLCO from infancy into childhood and adulthood.
Evolution of Lung Function Over Time in Preterm Children and Adults
The degree of airflow limitation in the first years of life also predicts later pulmonary function. In a small group of infants with severe BPD who were followed from birth, VmaxFRC at 2 years of age was closely related to FEV1 at 8 years, suggesting tracking of lung function with time and negligible “catch-up” growth of the lung . This finding highlights an irreversible early airway-remodeling process.
There are limited longitudinal outcome data in preterm children born in the postsurfactant era. Most studies demonstrate that lung function deficits persist into adulthood and do not worsen over time. This finding has been reported even in those with severe BPD requiring home ventilation . Two small studies reported some improvement in airway obstruction  or lung hyperinflation  in adolescents with BPD. According to a meta-analysis and follow-up study, the adverse effects of prematurity on pulmonary function were still detectable in school-aged children prematurely born in comparison to sex-matched controls born at term . On the other hand, Doyle et al.  reported that survivors of BPD may have a substantial decline in pulmonary function over time, on the basis of data from a large cohort with a birth weight of < 1500 g who were followed from 8 to 18 years of age . Overall, most studies suggest that airway growth in preterm infants is maintained with somatic growth, but does not “catch up.”
In summary, prematurity has a profound impact on lung development and growth, thereby leading to lung function deficits. Early in life, respiratory compliance is low. For some infants born prematurely, especially those with BPD, substantial airway obstruction persists into adolescence and young adulthood. This pulmonary derangement remains latent in many, but a reduced respiratory reserve could increase the risk of a COPD-like phenotype later in life. Studies suggest that airway growth in preterm infants is maintained with somatic growth, but does not “catch up.”
Structural defects have been noted in infants and children born preterm; these structural defects have been assessed using a number of modalities including chest radiographs, chest computed tomography (CT), ultrashort echo time magnetic resonance imaging (UTE MRI), and hyperpolarized gas MRI.
The chest radiograph (CXR) is the simplest and most widely available method for imaging preterm children. The original case description of BPD included CXR abnormalities such as linear fibrotic opacities and hyperexpanded regions of lung parenchyma , thereby leading to the bronchopulmonary dysplasia terminology describing radiological changes . Several scoring systems were subsequently developed . These severe changes on CXR are rarely seen in today’s “new” BPD, and in general, CXRs in contemporary preterm cohorts demonstrate minimal abnormalities. The modern clinical diagnosis of BPD does not incorporate a radiological component and instead focuses on the clinically assessed need for supplemental oxygen. Although chest radiographs have the advantages of accessibility and simplicity, the modality is considered only marginally useful for diagnosis. While chest films may only provide limited information to guide care, this modality is performed routinely to assess progression of disease.
Chest Computed Tomography
Chest computed tomography (CT) provides more detailed imaging of the lung parenchyma and airways compared to CXR. CT images can be obtained during quiet breathing or at full inspiration. Expiratory images are useful when identifying air trapping. This includes the interpretation of mixed attenuation, where either the area of high attenuation can represent a parenchymal abnormality or a low attenuation can be due to air trapping. There are often indications of air trapping on inspiratory images, but expiratory images may identify air trapping not seen on inspiratory images in the same patient. Young or uncooperative children may need to be sedated due to the difficulty with interpreting images due to motion artifact, which can further be decreased using a controlled ventilation technique [76, 77].
Chest CT is considered the most sensitive imaging modality to detect structural abnormalities in patients with BPD . Chest CT may provide insight into BPD pathophysiology; the early neonatal course may be predictive of later impairment noted on imaging . Several CT protocols and scoring methods have been described over the last 30 years to characterize and quantify the structural abnormalities of preterm patients with BPD. Most of them assessed the clinical severity of BPD (mild, moderate, severe) and reported an increase in CT abnormalities within those with more severe BPD [79–85]. CT findings of BPD patients have been compared with control patients, which were either healthy term-born  or preterm without BPD [79, 86, 87]. These studies report higher or worse CT scores in those with BPD. In CTs of survivors of old BPD, persistent radiological abnormalities have been reported in a majority of patients . Respiratory mechanical measurements and functional residual capacity during infancy have been reported to be associated with structural disease on chest CT; [85, 89] however, diffusing capacity and forced expiratory flows were reported to not correlate with the structural disease . Furthermore, chest CT has been reported to be more sensitive to identifying disease during infancy in those with chronic lung disease of infancy compared to diffusing capacity and forced flows . Wong et al.  described a definitive appearance of emphysema in a group of young adults with a history of moderate to severe old BPD, and the extent of emphysema on CT was inversely related to their FEV1 z-scores. Aukland et al.  studied two cohorts of BPD survivors, one from 1982–1985 and the other from 1991–1992, using inspiratory and expiratory high-resolution CT images. Participants were evaluated at a mean age of 10 and 18 years. Abnormalities were reported on chest CT scans in 86 % of the participants; the majority of the findings were linear/triangular opacities. Although the CT scores were higher or worse in the older cohort, the difference between the two groups was not statistically significant. A higher or worse HRCT score was associated with worse lung function as assessed through spirometric variables as well as the ratio of residual volume (RV) and total lung capacity (TLC). It is important to note that, to date, there are no validated and universally accepted CT scoring systems for quantifying structural changes . Given the wide variations in the visual appearance of lung parenchyma observed in this population, the potential for imaging-based phenotyping is a possibility. These quantitative imaging biomarkers could be further refined to phenotype BPD and inform clinical care (Fig. 2) .
WordPress theme by UFO themes