Accepted Manuscript

Bronchopulmonary dysplasia: A review of pathogenesis and pathophysiology

Renjithkumar Kalikkot Thekkeveedu, Milenka Cuevas Guaman, Binoy Shivanna

PII: S0954-6111(17)30353-0
DOI: 10.1016/j.rmed.2017.10.014
Reference: YRMED 5281

To appear in: Respiratory Medicine

Received Date: 21 March 2017

Revised Date: 23 August 2017
Accepted Date: 20 October 2017

Please cite this article as: Kalikkot Thekkeveedu R, Guaman MC, Shivanna B, Bronchopulmonary
dysplasia: A review of pathogenesis and pathophysiology, Respiratory Medicine (2017), doi: 10.1016/
j.rmed.2017.10.014.

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 ACCEPTED MANUSCRIPT

1 Title Page

2 Bronchopulmonary dysplasia: A Review of Pathogenesis and Pathophysiology

3 Renjithkumar Kalikkot Thekkeveedu1, Milenka Cuevas Guaman 2, Binoy Shivanna2*

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5 Section of Neonatology, Department of Pediatrics, University of Mississippi, Jackson, MS,

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6 USA
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7 Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX,

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8 USA

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* To whom correspondence should be addressed at Division of Neonatal-Perinatal Medicine,
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11 Texas Children’s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01,

Houston, Texas 77030. Phone: 832-824-6474. Fax: 832-825-3204. E-mail: shivanna@bcm.edu

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24 Abstract

25 Bronchopulmonary dysplasia (BPD) is a chronic lung disease of primarily premature

26 infants that results from an imbalance between lung injury and repair in the developing lung.

27 BPD is the most common respiratory morbidity in preterm infants, which affects nearly 10, 000

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28 neonates each year in the United States. Over the last two decades, the incidence of BPD has

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29 largely been unchanged; however, the pathophysiology has changed with the substantial

30 improvement in the respiratory management of extremely low birth weight (ELBW) infants.

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31 Here we have attempted to comprehensively review and summarize the current literature on the

32 pathogenesis and pathophysiology of BPD. Our goal is to provide insight to help further progress

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in preventing and managing severe BPD in the ELBW infants.
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Keywords:
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36 Bronchopulmonary Dysplasia, Pathogenesis, Pathophysiology, Hyperoxia, Ventilator-Induced

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37 Lung Injury, Lung Function

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47 Abbreviations

48 BPD bronchopulmonary dysplasia

49 DLCO diffusing capacity of the lung for carbon monoxide

50 ELBW extremely low birth weight

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51 FEV1 forced expiratory volume in 1 s

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52 GA gestational age

53 IUGR intrauterine growth restriction

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54 NIH National Institutes of Health

55 PDA patent ductus arteriosus

56 PH pulmonary hypertension
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57 PMA postmenstrual age

ROS reactive oxygen species

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59 RV residual volume
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60 TLC total lung capacity

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61 VEGF vascular endothelial growth factor

62 VILI ventilator-induced lung injury

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63 V/Q ventilation-perfusion ratio

64 VT tidal volume
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70 Introduction

71 Bronchopulmonary dysplasia (BPD) is a chronic lung disease of primarily premature

72 infants that results from an imbalance between lung injury and repair in the developing immature

73 lung 1. Alveolar simplification and dysmorphic pulmonary vascularization are histopathological

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74 features of the majority of infants with current BPD 2,3. In this review, we attempted to provide a

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75 summary of the literature on pathogenesis and pathophysiology of BPD with the goal of

76 providing insight for novel therapeutic strategies to prevent and manage severe BPD and its

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77 sequelae.

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79 Definition
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80 Definition of BPD continues to be very challenging and different definitions have been

used in the literature. Defining BPD by the use of O2 at 36 wk (rather than 28 d) postmenstrual
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82 age (PMA) by Shennan and Colleagues was found to be a better predictor of long term
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83 respiratory morbidity at 2 years of age 4. A severity based definition was proposed by National
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84 Institutes of Health (NIH) Work group (Table 1) 5. To further decrease the variability in BPD

85 diagnosis, Walsh and colleagues proposed a physiological definition at 36 wk PMA that entails
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86 oxygen reduction test with a BPD diagnosis if infant is unable to maintain O2 sat of > 88% in

87 room air 6. The use of different definitions in the literature resulted in wide variation in reporting
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88 incidence of BPD. In addition, current definitions are associated with several limitations,
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89 including low to moderate predictive value for long term pulmonary or neurosensory outcomes

90 and failure to take into account the recent changes in respiratory management such as the use of

91 high-flow nasal cannula, which may result in misclassification 7-9. Therefore, there is a need for a

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92 standardized definition for BPD that will take in account current pulmonary management

93 strategies and would ideally correlate with long-term outcomes.

94 Incidence

95 Over the last few decades there has been a significant improvement in perinatal care with

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96 introduction of surfactant and gentle ventilation to reduce lung injury, but on the other hand,

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97 survival of extremely preterm infants has increased. Therefore, the incidence of BPD has not

98 changed and it remains the most common late morbidity of preterm birth. It is estimated that

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99 approximately 10,000 of infants are diagnosed with BPD each year in the United states . The

100 overall incidence of BPD in infants born < 28 wk gestational age (GA) is estimated to be

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between 48-68% with the incidence being inversely proportional with the GA 11.
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Pathology
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104 To accomplish an effective gas exchange, it is necessary to have an increased lung

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105 surface area i.e. increased number of alveoli and blood vessels and a thin alveolo-capillary
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106 barrier. These changes occur during the later stages i.e. saccular and alveolar stages of lung

107 development, wherein secondary septation and distal pulmonary microvascular maturation
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108 increases the surface area and minimizes the distance between the inspired air and the blood,
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109 respectively . In BPD, this critical late lung development is interrupted, which results in
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110 ineffective gas exchange and mandates the need for respiratory support in the form of positive
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111 pressure ventilatory support and supplemental oxygen therapy 13,14.

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113 With advances in perinatal and neonatal care of preterm infants such as antenatal steroids,

114 postnatal surfactant and gentle ventilation, the pathology of BPD has changed. The classic (old)

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115 form of BPD is characterized by heterogeneity with severe airway epithelial lesions such as

116 squamous metaplasia, marked airway smooth muscle hyperplasia, extensive alveolar septal
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117 fibrosis, and hypertensive remodeling of the pulmonary arteries . On the other hand, current

118 (new) BPD is characterized by less heterogeneity, with large simplified alveolar structure,

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119 reduced and dysmorphic vascular bed with rare epithelial lesions and mild airway smooth muscle

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120 thickening 2,3.

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122 Pathogenesis

123 The pathogenesis of BPD is complex and multifactorial in nature. Factors that are known

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to interrupt pulmonary vascular and alveolar development and contribute to BPD may be
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125 antenatal, natal, or postnatal in origin (Fig. 1).
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127 Antenatal risk factors:

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128 Genetic Susceptibility

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129 Emerging evidence from twin studies suggest that BPD has a strong genetic

130 component. The incidence of moderate to severe BPD is significantly higher in identical twins
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131 when compared with non-identical twins, whereas the incidence of mild BPD is similar in both
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132 groups . These studies indicate that genetic susceptibility may play a major role in the
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133 pathogenesis of moderate to severe disease. In addition, several candidate genes that affect BPD-
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134 associated biological pathways have been identified by a genome wide association study 20. On

135 the other hand, a population-based study failed to associate any genomic loci with moderate to
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136 severe BPD . These findings suggest that BPD is a heterogeneous disease that results from

137 multiple genes and pathways.

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138

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140 Intrauterine growth restriction

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141 Intrauterine growth restriction (IUGR) increases the odds of developing BPD . It is

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142 postulated that the biological mechanisms such as placental dysfunction and deficiency of insulin

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143 growth factor, vascular endothelial growth factor (VEGF) and VEGF receptor that leads to IUGR
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144 can also lead to restriction of fetal lung growth . It is also possible that the epigenetic

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145 alterations induced by the adverse intrauterine environment of these fetuses could contribute to

146 the pathogenesis of BPD.

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148 Chorioamnionitis

Chorioamnionitis is inflammation of chorion and amnion, the membranes that surround

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150 the fetus. It is usually caused by a bacterial infection. The consensus on whether
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151 chorioamnionitis increases the odds of developing BPD remains disputed because studies have
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152 failed to consistently show an association between chorioamnionitis and BPD 25-29. Major factors

153 for this inconsistency are failure to adopt uniform diagnostic, inclusion and exclusion criteria and
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154 failure to control for all the confounders. For example, it has been found that clinically diagnosed

155 chorioamnionitis correlates poorly with pathological findings of chorioamnionitis, the gold
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156 standard to diagnose chorioamnionitis. Therefore, studies that included patients with clinical
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157 diagnosis without pathological confirmation of chorioamnionitis may fail to reflect a true

158 association between chorioamnionitis and BPD 30. Additionally, the placental histopathology can

159 vary among chorioamnionitis patients and the neonatal outcomes may be determined by the site,
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160 extent and duration of the placental pathology . Further, studies have shown that

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161 intrauterine inflammation is not an independent risk factor for BPD, but it is the associated

162 sequelae of chorioamnionitis such as neonatal sepsis that increases the odds of developing BPD
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163 . In experimental models of intrauterine infection, ureaplasma-mediated chronic
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164 chorioamnionitis results in a lung pathology, which models BPD in human infants . These

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165 preclinical studies have been consistently supported by clinical studies where colonization of the

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166 infant’s respiratory tract with ureaplasma has been shown to be an independent risk factor for

167 BPD 38,39.

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169 Pregnancy-induced hypertensive disorders

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An imbalance between pro- and anti-angiogenic mediators favoring decreased
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171 angiogenesis is postulated to interrupt lung development in pregnancy-induced hypertensive
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disorders, including gestational hypertension, preeclampsia and eclampsia . However, there
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173 is no definitive evidence linking these hypertensive disorders in pregnant women with
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174 development of BPD 23,43-47. Recently, a prospective population-based cohort study that included
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175 2697 premature infants born before 32 wk gestation showed that the incidence of moderate to

176 severe BPD was strongly associated with IUGR and pregnancy-induced hypertensive disorders
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177 with IUGR, but not with isolated pregnancy-induced hypertensive disorders. Among these risk

178 factors, IUGR was the strongest predictor of BPD 48. A similar observation was made by Bose et.
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179 al.22, wherein BPD was positively associated with maternal preeclampsia and IUGR, but not with
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180 maternal preeclampsia alone. These studies may indicate that in the absence of IUGR, maternal

181 hypertension may not be a risk factor for the development of BPD.

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183 Maternal smoking

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184 Maternal smoking is significantly associated with higher incidence of preterm birth and
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185 its complications . Many researchers have investigated if there is an association between

186 maternal smoking and BPD. Population-based cohort studies from Italy, Germany, and Canada

187 have shown that preterm infants born to mothers who smoke during pregnancy have an increased

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188 risk of developing BPD . In preclinical studies, exposure of pregnant rodents to cigarette

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189 smoke or nicotine has also shown to cause a lung phenotype identical to that seen in human
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190 infants with BPD . Epigenetic changes, placental dysfunction, altered alveolar type II cell

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191 metabolism, and dysregulated angiogenesis are some of the postulated mechanisms through

192 which cigarette smoke disrupts normal lung development and function 53-56.

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194 Natal risk factors:

Gestational age and birth weight

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196 Prematurity and low birth weight represents the strongest predictors of BPD with the risk being
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197 directly proportional to both of them (Fig. 2). For example, the overall incidence of BPD in an
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198 infant born at a GA of 23 wk is around 78%, of which 58% develop severe BPD, whereas the

199 overall incidence of BPD in an infant born at a GA of 28 wk is just 23%, of which only 8%
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200 develop severe BPD . In addition to the structural and functional immaturity due to preterm

201 birth, exposure to the routine life saving interventions such as oxygen supplementation and
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202 mechanical ventilation results in lung injury that may further interrupt lung development due to
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203 impaired lung reparative responses.

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205 Postnatal risk factors:

206 Oxidative stress and hyperoxia

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207 Oxidative stress, an imbalance favoring a pro-oxidant over an anti-oxidant state, is one of

208 the major risk factors implicated in the development of BPD. It is important to recognize that

209 hyperoxia is not the only factor that causes oxidative stress. Premature infants are at high risk of

210 developing oxidative stress due to their immature antioxidant defenses, increased susceptibility

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211 to infection and inflammation, and exposure to free iron 57. Oxidative stress leads to interrupted

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212 lung development by mechanisms entailing disruption of growth factor signaling, extracellular

213 matrix assembly, cell proliferation, apoptosis, and vasculogenesis 14.

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215 Hyperoxia implies that the tissue oxygen supply exceeds its demand, which in turn

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increases tissue oxygen levels that causes production of toxic levels of ROS. Importantly, the
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217 levels of oxygen that determine normoxia, hypoxia, or hyperoxia may be context dependent. For

example, brain and muscle tissues require different levels of oxygen for their normal function;
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219 whether a given oxygen level constitutes normoxia, hypoxia, or hyperoxia in these tissues are
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220 determined by their underlying physiologic or pathologic processes . Similarly, exposure of
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221 newly born human premature neonates to normal atmospheric oxygen (21% O2) may result in
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222 hyperoxia since they are adapted to a hypoxic environment (4% O2) as a fetus . The ROS
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223 generated by hyperoxia exposure are potent oxidizing agents that directly damage the cellular

224 constituents. These ROS are mostly free radicals and thereby are highly reactive and capable of
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225 oxidizing membrane lipids, structural proteins, enzymes, and nucleic acids, which leads to cell
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226 death and tissue damage . Additionally, hyperoxia increases the influx of inflammatory cells

227 such as neutrophils and macrophages into the lungs by mechanisms that entail increased

228 generation and expression of chemotactic factors. Upon exposure to hyperoxia, the alveolar and

229 interstitial macrophages secrete early-response cytokines, which in turn activate the lung

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230 endothelial cells, epithelial cells, and fibroblasts to produce additional chemokines that attract
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231 neutrophils into the lungs . Pathologically, exposure to acute hyperoxia initially results in

232 endothelial cell injury and death, followed by epithelial cell damage and disruption of the

233 alveolar-capillary membrane causing alveolar edema and impairment of gas exchange 61-63.

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235 Although supplemental oxygen is frequently used as a life-saving therapy in human

236 preterm infants with hypoxic respiratory failure, excessive or prolonged oxygen exposure results

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237 in increased ROS generation and the expression of proinflammatory cytokines . Hyperoxia-

238 induced ROS generation and inflammation causes injury and disrupts the reparative processes in

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the developing lungs that ultimately leads to the development of BPD 60
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240 antioxidant defense system develops late in gestation, making preterm neonates highly

susceptible to hyperoxia-induced lung injury 65,66.

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243 Mechanical ventilation

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244 The pathogenesis of ventilator-induced lung injury (VILI) is complex and is determined

245 by the interactions between the ventilator settings and the patient-related factors.
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247 Barotrauma, volutrauma, atelectrauma and biotrauma are the major ventilator
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248 determinants of VILI. Barotrauma is lung injury caused by excessive airway pressure, whereas
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249 volutrauma is lung injury caused by excessive lung volume and distension. Animal studies have

250 clearly demonstrated that the degree of lung inflation is a more important mediator of lung injury
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251 than airway pressure . For example, high airway pressure causes severe lung injury in

252 animals who have unrestricted lung expansion, whereas the same airway pressure does not cause

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253 lung injury in animals whose lung expansion is restricted by strapping their chest and abdomen.

254 The lung expansion is determined by the transpulmonary pressure, which is the difference

255 between alveolar and pleural pressure. Therefore, the peak airway pressure may not always be

256 directly proportional to the lung distending or transpulmonary pressure. The lung physiology of

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257 trumpet players provides a prime example of this concept. Trumpet players while playing a note

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258 can generate alveolar pressures as high as 150 cm H2O; however, they also generate pleural

259 pressures as high as 140 cm H2O and therefore, their lung distending pressure (150-140 = 10 cm

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260 H2O) is normal and they have no lung injury 70. These findings clearly indicate volutrauma is a

261 more important determinant of VILI. Therefore, it is important to avoid excessive tidal volumes

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(VT) in mechanically ventilated preterm infants to prevent lung injury. However, both
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263 volutrauma and barotrauma can be inter-related because of the complex interactions between the
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patient and the ventilator . Atelectrauma refers to lung injury caused by ventilating the lungs
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265 that are inadequately recruited . Ventilation at low lung volumes increases shear stress from
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266 repeated alveolar collapse and expansion and causes surfactant dysfunction and regional hypoxia
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267 . The stretching forces at the margins between aerated and atelectatic lungs can be five
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268 times higher than those in other regions . Based of Laplace’s law, the delivered VT takes the
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269 path of least resistance and preferentially enters the aerated lungs rather than the atelectatic lungs

270 because the critical opening pressure is lower in the former compared with the latter regions of
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271 the lungs. This heterogeneous distribution of VT leads to regional volutrauma of the relatively
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272 healthy lungs despite the delivered VT being in the normal range 77,78. Therefore, use of adequate

273 positive end expiratory pressure to recruit lungs or prevent the collapse of the less compliant

274 alveoli at end expiration can prevent atelectrauma and its associated sequelae such as regional

275 volutrauma. Biotrauma is lung injury caused by inflammatory response mediators such as

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276 chemokines and cytokines . Volutrauma, barotrauma, oxygen toxicity and sepsis are the
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277 predominant causes of biotrauma , which leads to uninhibited inflammation and interrupted

278 lung development. It is important to recognize that these inflammatory responses need not be

279 compartmentalized to the lungs; severe lung inflammation can result in systemic inflammatory

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280 response syndrome and multiorgan dysfunction 81. This pathological process can be mistaken for

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281 neonatal sepsis resulting in exposure of these patients to unnecessary antibiotics, which in fact

282 may alter the respiratory microbiome and paradoxically worsen their lung injury.

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284 The patient determinants of VILI include preexisting lung injury, lung inflammation, and

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surfactant abnormalities, and prematurity. Premature infants are prone to develop lung atelectasis
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286 because of anatomic and functional immaturity of the respiratory system . Further, these

infants have lower lung tissue resilience due to deficiency of the following: mature collagen and
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288 elastin elements, surfactant and anti-oxidants in their lungs 71. Therefore, premature infants have
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289 a higher incidence of biophysical and biochemical lung injury when subjected to an insult such
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290 as mechanical ventilation. In summary, VILI results in an inflammatory cascade that disrupts

291 signaling pathways involved in lung development and repair and contributes to the development
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292 of BPD . Therefore, the best strategy to prevent VILI is to avoid mechanical ventilation if

293 possible. Strategies to decrease VILI and facilitate lung growth and repair include avoiding
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294 excessive VT, providing adequate PEEP to prevent atelectrauma, minimizing excessive oxygen
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295 administration, preventing nosocomial infection, and providing good nutrition. BPD is a

296 multifactorial disease with a complex pathophysiology; therefore, it is important to avoid “one-

297 size-fits-all” approach to manage BPD patients.

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299 Sepsis

300 Multiple studies indicate that postnatal sepsis independently increases the incidence of

301 BPD 35,85,86. In fact, studies suggest that postnatal infection is a more important predictor of BPD

302 than antenatal inflammation. Sepsis interrupts lung development and leads to BPD by

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303 mechanisms that entail inflammation, oxidative stress, and endothelial injury in the lungs 87.

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305 Patent ductus arteriosus

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306 By necessity, ductus arteriosus is normally present in a fetus where it functions to shunt

307 blood from pulmonary artery to ascending aorta, bypassing the high-resistance nonfunctioning

308 lungs 88

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309 ventricle resulting in pulmonary hypertension and right heart failure . Several biophysical

and biochemical changes that occur physiologically in pulmonary and systemic blood vessels
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311 following birth leads to the closure of ductus arteriosus within a few days of birth . Patent
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312 ductus arteriosus (PDA) is a condition where ductus arteriosus fails to close after birth. It is
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313 almost universally present in extremely low birth weight infants. Because the pulmonary

314 vascular resistance decreases and systemic vascular resistance increases after birth, the direction
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315 of blood flow changes from right-to-left seen in the fetus to left-to-right after birth. Theoretically

316 these changes can initiate or worsen lung injury and predispose preterm infants to develop BPD
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317 for several reasons. The increase in pulmonary blood flow can elevate the vascular hydrostatic
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318 pressure and cause lung edema and a decrease in lung compliance 93 necessitating an increase in

319 the degree and duration of ventilatory support, which can lead to VILI. Additionally, the

320 increased pulmonary blood flow can cause neutrophil margination and activation and thereby

321 increase lung inflammation 94, which is a well known risk factor for BPD. The answer to whether

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322 hemodynamically significant PDA is a risk factor for BPD continues to be ambiguous. However,

323 it is clear that closure of PDA does not necessarily decrease the incidence of BPD raising doubts

324 that the relationship between PDA and BPD is more of an association rather than causation 95,96.

325 In fact, some studies indicate that PDA closure by medical or surgical therapies is associated

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326 with worsening BPD 97,98. It is possible that PDA therapy-associated complications such as lung

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327 fluid retention and lung inflammation may have contributed to worsening of BPD in PDA-

328 treated patients. Significant practice variations, including patient selection, PDA severity

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329 classification, presence of comorbid conditions, and disease stage and the age at which the

330 patients were treated may be some of the factors responsible for the inconsistent study results.

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There may be sub groups of BPD patients with PDA who might benefit or are at risk from PDA
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332 closure. Therefore, future studies should factor in several variables in their study design to

identify these sub groups of BPD patients.

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335 Respiratory microbial dysbiosis

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336 Dysbiosis, an imbalance in the structure of complex microbial communities on or inside

337 the body, is known to contribute to several diseases where inflammation plays a major
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338 pathogenic role . Contrary to the traditional belief that the human neonatal respiratory tract is

339 sterile at birth, current studies indicate that the human respiratory tract microbial colonization
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340 begins in utero or shortly after birth . A recent study demonstrated that the lung
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341 microbiome, including the relative abundance of bacterial phyla and diversity index of the

342 preterm and term neonates were similar at birth irrespective of the gestational age and the mode
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343 of delivery. Firmicutes and Proteobacteria were the predominant microbes at birth . Factors

344 such as chorioamnionitis, antibiotic exposure, mode of delivery, method of feeding, and bowel

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345 colonization can decrease bacterial diversity and increase pathogenic microbial colonization in
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346 the lungs , which may potentially lead to an inflammatory lung phenotype that ultimately

347 contributes to the development of BPD.

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349 Pathophysiology and BPD phenotypes

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350 The pathophysiology of BPD has changed significantly in the past two decades .

351 However, similar to infants with old BPD, new BPD patients continue to have lung function

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352 abnormalities in later life. Hence understanding the pathophysiology of BPD is pivotal to

353 improve the outcomes of preterm infants with BPD. The pathophysiology of new BPD (Fig. 3) is

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characterized by alveolar and pulmonary vascular simplification, and persistent abnormalities in
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355 gas exchange, airway function, respiratory system mechanics, and lung volumes .

Therefore, BPD patients can have varied clinical manifestations or phenotypes, including lung
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357 parenchymal disease, pulmonary vascular disease, and airway disease. However, majority of the
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358 BPD patients have a substantial overlap of these three phenotypes.

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360 Lung parenchymal disease

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361 Alveolar simplification and reduced dysmorphic pulmonary vascular bed leads to

362 decreased and inefficient alveolar-capillary membranes causing suboptimal pulmonary gas
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363 exchange (Fig. 3A). Management strategies include avoiding or minimizing ventilator- or
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364 hyperoxia-induced lung injury, preventing infection, and providing optimal nutrition. A

365 subgroup of patients can also have heterogeneous parenchymal disease characterized by areas of

366 atelectasis, hyperinflation, and fibrosis. These pathological changes causes increased lung dead

367 space, multifocal abnormalities in lung resistance and compliance, ventilation-perfusion (V/Q)

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368 mismatch, and increased intrapulmonary shunts 110-114. Further, the time constants in lung regions

369 with increased resistance are prolonged because they are directly proportional to lung resistance.

370 Ventilator strategies that incorporate higher VT, longer inspiratory time, and lower rate to

371 account for the dead space, to completely deliver the VT to the alveoli, and to allow for increased

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372 exhalation time, respectively, are therefore indicated for BPD patients with a heterogeneous lung

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373 parenchymal disease. The diffusing capacity of the lung for carbon monoxide (DLCO), which is

374 the most commonly used lung function test to measure pulmonary gas exchange in infants

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375 indicate that BPD patients have suboptimal alveolar-capillary gas transfer that persists into later

376 life 109,115,116.

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378 Pulmonary vascular disease

Decreased growth and altered vasoreactivity and extracellular matrix of the lung
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380 endothelial cells and endothelial cell dysfunction-mediated inflammation are the major
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381 pulmonary vascular abnormalities seen in BPD patients . These abnormalities causes
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382 suboptimal pulmonary gas exchange. Pulmonary hypertension (PH) is the most severe form of

383 this phenotype and regular screening for PH is needed in BPD patients. Effective management
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384 strategies in this group of BPD patients include avoidance of hypoxemia, respiratory and

385 metabolic acidosis, and prevention of lung overinflation and atelectasis. Majority of the PH
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386 patients will also need specific pulmonary vasodilator therapy.

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388 Airway disease

389 Premature infants in general and those with moderate to severe BPD in particular have

390 increased airway obstruction on lung function tests as demonstrated by reduced forced expiratory

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391 volume in 1 s (FEV1) and decreased FEV1/forced vital capacity. Airway remodeling, decreased

392 airway and alveolar growth, and mechanical ventilation-associated complications such as

393 tracheomalacia, bronchomalacia, and stenosis of glottis, subglottis and trachea contribute to these
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394 persistent airway abnormalities in BPD patients (Fig. 3B). Although the total lung

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395 capacity (TLC) in these infants are normal, the underlying airflow obstruction leads to air

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396 trapping and abnormal lung volumes such as increased residual volume (RV) and RV/TLC
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397 (Fig. 3B). In addition to increased airflow obstruction and abnormal lung volumes,

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398 preterm infants with BPD have abnormal respiratory system mechanics. The interrupted lung

399 growth in BPD infants decreases the lung parenchymal elastic network, which in turn reduces

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airway tethering and causes airway instability, increased airway closure and collapse of alveolar
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401 units . These abnormal respiratory system mechanics decreases lung compliance and

reactance and increases pulmonary resistance in BPD infants 128,129 (Fig. 3C). BPD patients with
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403 airway disease are best managed with increased PEEP levels that are titrated to prevent
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404 premature closure or collapse of the larger airways prior to completion of the expiratory phase
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405 . Further, the high airway resistance in these patients increases the lung time constants

406 mandating the need for a prolonged expiratory time to facilitate complete exhalation of their
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407 inspired gas volume. Failure to incorporate these strategies can cause gas trapping, lung

408 hyperexpansion, and worsening V/Q mismatch. In chronically ventilated BPD patients, it is
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409 important to be aware of this pathophysiology and not always attribute hyperexpanded lungs to
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410 overventilation because decreasing the mean airway pressure may in fact worsen oxygenation

411 and ventilation in these patients.

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413 Conclusions

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414 BPD continues to be a significant short- and long-term morbidity of ELBW infants.

415 There is a need for a standardized definition for BPD that should ideally include more currently

416 used therapies such as HFNC, define severity, and predict long term morbidity. Trying to

417 understand the three most common pathophysiological components of BPD and applying them to

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435 Acknowledgements

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436 This work was supported by grants from the National Institutes of Health (NIH) HD-

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437 073323, American Heart Association BGIA-20190008, and American Lung Association RG-

438 349917 to B.S.

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771 Archives of disease in childhood. Fetal and neonatal edition. May 1997;76(3):F203-205.
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775 function in infants with bronchopulmonary dysplasia. Pediatric pulmonology. Apr
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788 131. Panitch HB, Allen JL, Alpert BE, Schidlow DV. Effects of CPAP on lung mechanics in infants with
789 acquired tracheobronchomalacia. American journal of respiratory and critical care medicine. Nov
790 1994;150(5 Pt 1):1341-1346.
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819 Table 1: DEFINITION OF BRONCHOPULMONARY DYSPLASIA:

820 DIAGNOSTIC CRITERIA

Gestational age < 32 wk ≥ 32 wk

Time point of assessment 36 wk PMA or discharge to >28 d but <56 d postnatal

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home, whichever comes first age or discharge to home,
whichever comes first
Treatment with oxygen >21% for at least 28 d plus

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Mild Breathing room air at 36 wk Breathing room air by 56
PMA or discharge, whichever d postnatal age or

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comes first
Moderate Need for <30% oxygen at 36 wk Need for <30% oxygen at

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PMA or discharge, whichever 56 d postnatal age or
comes first discharge, whichever
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Severe Need for >30% oxygen and/or Need for >30% oxygen
positive pressure, (PPV or and/or positive pressure,
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NCPAP) at 36 wk PMA or (PPV or NCPAP) at 56 d

discharge, whichever comes postnatal age or
first discharge, whichever
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821

822 Definition of abbreviations: BPD = bronchopulmonary dysplasia; NCPAP = nasal continuous

823 positive airway pressure; PMA = postmenstrual age; PPV = positive-pressure ventilation.
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824 Reprinted with permission of the American Thoracic Society. Copyright (c) 2017 American
825 Thoracic Society. Jobe AH, Bancalari E. 2001 Bronchopulmonary dysplasia. American journal
826 of respiratory and critical care medicine 163(7):1723-1729. The American Journal of
827 Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
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835 Figure legends

836 Figure 1: Overview of BPD pathogenesis
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838 Figure 2: Gestational age (GA) and BPD incidence

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840 Figure 3: Pulmonary function testing in BPD

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• BPD remains the most common chronic lung disease of premature infants
• Definition of BPD needs to be standardized
• Maternal smoking and IUGR are significant antenatal risk factors for BPD
• Hyperoxia and mechanical ventilation are significant postnatal risk factors for BPD
• New BPD patients continue to have long-term cardiopulmonary morbidities

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Disclosure

The authors report no conflicts of interest in this work.

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