Respiratory Medicine 132 (2017) 170–177

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Review article

Bronchopulmonary dysplasia: A review of pathogenesis and T

pathophysiology
Renjithkumar Kalikkot Thekkeveedua, Milenka Cuevas Guamanb, Binoy Shivannab,∗
a
Section of Neonatology, Department of Pediatrics, University of Mississippi, Jackson, MS, USA
b
Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of primarily premature infants that results from an
Bronchopulmonary dysplasia imbalance between lung injury and repair in the developing lung. BPD is the most common respiratory mor-
Pathogenesis bidity in preterm infants, which affects nearly 10, 000 neonates each year in the United States. Over the last two
Pathophysiology decades, the incidence of BPD has largely been unchanged; however, the pathophysiology has changed with the
Hyperoxia
substantial improvement in the respiratory management of extremely low birth weight (ELBW) infants. Here we
Ventilator-induced lung injury
have attempted to comprehensively review and summarize the current literature on the pathogenesis and pa-
Lung function
thophysiology of BPD. Our goal is to provide insight to help further progress in preventing and managing severe
BPD in the ELBW infants.

1. Introduction
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of
primarily premature infants that results from an imbalance between
lung injury and repair in the developing immature lung [1]. Alveolar
simplification and dysmorphic pulmonary vascularization are histo-
pathological features of the majority of infants with current BPD [2,3].
In this review, we attempted to provide a summary of the literature on
pathogenesis and pathophysiology of BPD with the goal of providing
insight for novel therapeutic strategies to prevent and manage severe
BPD and its sequelae.
2. Definition
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 age (PMA) by Shennan
and Colleagues was found to be a better predictor of long term re-
spiratory morbidity at 2 years of age [4]. A severity based definition
was proposed by National Institutes of Health (NIH) Work group
(Table 1) [5]. To further decrease the variability in BPD diagnosis,
Walsh and colleagues proposed a physiological definition at 36 wk PMA
that entails oxygen reduction test with a BPD diagnosis if infant is
unable to maintain O2 sat of > 88% in room air [6]. The use of dif-
ferent definitions in the literature resulted in wide variation in re-
porting incidence of BPD. In addition, current definitions are associated
with several limitations, including low to moderate predictive value for
long term pulmonary or neurosensory outcomes and failure to take into
account the recent changes in respiratory management such as the use
of high-flow nasal cannula, which may result in misclassification [7–9].
Therefore, there is a need for a standardized definition for BPD that will
take in account current pulmonary management strategies and would
ideally correlate with long-term outcomes.
3. Incidence
Over the last few decades there has been a significant improvement
in perinatal care with introduction of surfactant and gentle ventilation
to reduce lung injury, but on the other hand, survival of extremely
preterm infants has increased. Therefore, the incidence of BPD has not
changed and it remains the most common late morbidity of preterm
birth. It is estimated that approximately 10,000 of infants are diagnosed
with BPD each year in the United states [10]. The overall incidence of
BPD in infants born < 28 wk gestational age (GA) is estimated to be
between 48 and 68% with the incidence being inversely proportional
with the GA [11].
4. Pathology
To accomplish an effective gas exchange, it is necessary to have an
increased lung surface area i.e. increased number of alveoli and blood
vessels and a thin alveolo-capillary barrier. These changes occur during

∗
Corresponding author. Division of Neonatal-Perinatal Medicine, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030, USA.
E-mail address: shivanna@bcm.edu (B. Shivanna).

http://dx.doi.org/10.1016/j.rmed.2017.10.014
Received 21 March 2017; Received in revised form 23 August 2017; Accepted 20 October 2017
Available online 24 October 2017
0954-6111/ © 2017 Elsevier Ltd. All rights reserved.
R. Kalikkot Thekkeveedu et al. Respiratory Medicine 132 (2017) 170–177

Abbreviations PH pulmonary hypertension

PMA postmenstrual age
BPD bronchopulmonary dysplasia ROS reactive oxygen species
DLCO diffusing capacity of the lung for carbon monoxide RV residual volume
ELBW extremely low birth weight TLC total lung capacity
FEV1 forced expiratory volume in 1 s VEGF vascular endothelial growth factor
GA gestational age VILI ventilator-induced lung injury
IUGR intrauterine growth restriction V/Q ventilation-perfusion ratio
NIH National Institutes of Health VT tidal volume
PDA patent ductus arteriosus

Table 1
Definition of bronchopulmonary dysplasia: diagnostic criteria.

Gestational age < 32 wk ≥32 wk

Time point of assessment 36 wk PMA or discharge to home, whichever comes first
Treatment with oxygen > 21% for at least 28 d plus
Mild Breathing room air at 36 wk PMA or discharge, whichever comes first
Moderate Need for < 30% oxygen at 36 wk PMA or discharge, whichever comes
first
Severe Need for ≥30% oxygen and/or positive pressure, (PPV or NCPAP) at
36 wk PMA or discharge, whichever comes first
> 28 d but < 56 d postnatal age or discharge to home, whichever comes
first
Breathing room air by 56 d postnatal age or discharge, whichever comes
first
Need for < 30% oxygen at 56 d postnatal age or discharge, whichever
comes first
Need for ≥30% oxygen and/or positive pressure, (PPV or NCPAP) at 56 d
postnatal age or discharge, whichever comes first

Definition of abbreviations: BPD = bronchopulmonary dysplasia; NCPAP = nasal continuous positive airway pressure; PMA = postmenstrual age; PPV = positive-pressure ventilation.
Reprinted with permission of the American Thoracic Society. Copyright (c) 2017 American Thoracic Society. Jobe AH, Bancalari E. 2001 Bronchopulmonary dysplasia. American journal of
respiratory and critical care medicine 163(7):1723–1729. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

the later stages i.e. saccular and alveolar stages of lung development,
wherein secondary septation and distal pulmonary microvascular ma-
turation increases the surface area and minimizes the distance between
the inspired air and the blood, respectively [12]. In BPD, this critical
late lung development is interrupted, which results in ineffective gas
exchange and mandates the need for respiratory support in the form of
positive pressure ventilatory support and supplemental oxygen therapy
[13,14].
With advances in perinatal and neonatal care of preterm infants
such as antenatal steroids, postnatal surfactant and gentle ventilation,
the pathology of BPD has changed. The classic (old) form of BPD is
characterized by heterogeneity with severe airway epithelial lesions
such as squamous metaplasia, marked airway smooth muscle hyper-
plasia, extensive alveolar septal fibrosis, and hypertensive remodeling

Fig. 1. Overview of BPD pathogenesis.

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R. Kalikkot Thekkeveedu et al. Respiratory Medicine 132 (2017) 170–177

of the pulmonary arteries [15,16]. On the other hand, current (new) 5.1.4. Pregnancy-induced hypertensive disorders
BPD is characterized by less heterogeneity, with large simplified al- An imbalance between pro- and anti-angiogenic mediators favoring
veolar structure, reduced and dysmorphic vascular bed with rare epi- decreased angiogenesis is postulated to interrupt lung development in
thelial lesions and mild airway smooth muscle thickening [2,3]. pregnancy-induced hypertensive disorders, including gestational hy-
pertension, preeclampsia and eclampsia [40–42]. However, there is no
definitive evidence linking these hypertensive disorders in pregnant
5. Pathogenesis
women with development of BPD [23,43–47]. Recently, a prospective
population-based cohort study that included 2697 premature infants
The pathogenesis of BPD is complex and multifactorial in nature.
born before 32 wk gestation showed that the incidence of moderate to
Factors that are known to interrupt pulmonary vascular and alveolar
severe BPD was strongly associated with IUGR and pregnancy-induced
development and contribute to BPD may be antenatal, natal, or post-
hypertensive disorders with IUGR, but not with isolated pregnancy-
natal in origin (Fig. 1).
induced hypertensive disorders. Among these risk factors, IUGR was the
strongest predictor of BPD [48]. A similar observation was made by
5.1. Antenatal risk factors Bose et al. [22], wherein BPD was positively associated with maternal
preeclampsia and IUGR, but not with maternal preeclampsia alone.
5.1.1. Genetic susceptibility These studies may indicate that in the absence of IUGR, maternal hy-
Emerging evidence from twin studies [17] suggest that BPD has a pertension may not be a risk factor for the development of BPD.
strong genetic component. The incidence of moderate to severe BPD is
significantly higher in identical twins when compared with non-iden-
tical twins, whereas the incidence of mild BPD is similar in both groups 5.1.5. Maternal smoking
[18,19]. These studies indicate that genetic susceptibility may play a Maternal smoking is significantly associated with higher incidence
major role in the pathogenesis of moderate to severe disease. In addi- of preterm birth and its complications [49]. Many researchers have
tion, several candidate genes that affect BPD-associated biological investigated if there is an association between maternal smoking and
pathways have been identified by a genome wide association study BPD. Population-based cohort studies from Italy, Germany, and Canada
[20]. On the other hand, a population-based study failed to associate have shown that preterm infants born to mothers who smoke during
any genomic loci with moderate to severe BPD [21]. These findings pregnancy have an increased risk of developing BPD [50–52]. In pre-
suggest that BPD is a heterogeneous disease that results from multiple clinical studies, exposure of pregnant rodents to cigarette smoke or
genes and pathways. nicotine has also shown to cause a lung phenotype identical to that seen
in human infants with BPD [53,54]. Epigenetic changes, placental
dysfunction, altered alveolar type II cell metabolism, and dysregulated
5.1.2. Intrauterine growth restriction
angiogenesis are some of the postulated mechanisms through which
Intrauterine growth restriction (IUGR) increases the odds of devel-
cigarette smoke disrupts normal lung development and function
oping BPD [22–24]. It is postulated that the biological mechanisms such
[53–56].
as placental dysfunction and deficiency of insulin growth factor, vas-
cular endothelial growth factor (VEGF) and VEGF receptor that leads to
IUGR can also lead to restriction of fetal lung growth [22]. It is also
5.2. Natal risk factors
possible that the epigenetic alterations induced by the adverse in-
trauterine environment of these fetuses could contribute to the patho-
5.2.1. Gestational age and birth weight
genesis of BPD.
Prematurity and low birth weight represents the strongest pre-
dictors of BPD with the risk being directly proportional to both of them
5.1.3. Chorioamnionitis (Fig. 2). For example, the overall incidence of BPD in an infant born at a
Chorioamnionitis is inflammation of chorion and amnion, the GA of 23 wk is around 78%, of which 58% develop severe BPD, whereas
membranes that surround the fetus. It is usually caused by a bacterial the overall incidence of BPD in an infant born at a GA of 28 wk is just
infection. The consensus on whether chorioamnionitis increases the 23%, of which only 8% develop severe BPD [11]. In addition to the
odds of developing BPD remains disputed because studies have failed to structural and functional immaturity due to preterm birth, exposure to
consistently show an association between chorioamnionitis and BPD the routine life saving interventions such as oxygen supplementation
[25–29]. Major factors for this inconsistency are failure to adopt uni- and mechanical ventilation results in lung injury that may further in-
form diagnostic, inclusion and exclusion criteria and failure to control terrupt lung development due to impaired lung reparative responses.
for all the confounders. For example, it has been found that clinically
diagnosed chorioamnionitis correlates poorly with pathological find-
ings of chorioamnionitis, the gold standard to diagnose chor-
ioamnionitis. Therefore, studies that included patients with clinical
diagnosis without pathological confirmation of chorioamnionitis may
fail to reflect a true association between chorioamnionitis and BPD
[30]. Additionally, the placental histopathology can vary among chor-
ioamnionitis patients and the neonatal outcomes may be determined by
the site, extent and duration of the placental pathology [28,31–33].
Further, studies have shown that intrauterine inflammation is not an
independent risk factor for BPD, but it is the associated sequelae of
chorioamnionitis such as neonatal sepsis that increases the odds of
developing BPD [34,35]. In experimental models of intrauterine in-
fection, ureaplasma-mediated chronic chorioamnionitis results in a lung
pathology, which models BPD in human infants [36,37]. These pre-
clinical studies have been consistently supported by clinical studies
where colonization of the infant's respiratory tract with ureaplasma has
Fig. 2. Gestational age (GA) and BPD incidence.
been shown to be an independent risk factor for BPD [38,39].

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R. Kalikkot Thekkeveedu et al.
5.3. Postnatal risk factors
5.3.1. Oxidative stress and hyperoxia
Oxidative stress, an imbalance favoring a pro-oxidant over an anti-
oxidant state, is one of the major risk factors implicated in the devel-
opment of BPD. It is important to recognize that hyperoxia is not the
only factor that causes oxidative stress. Premature infants are at high
risk of developing oxidative stress due to their immature antioxidant
defenses, increased susceptibility to infection and inflammation, and
exposure to free iron [57]. Oxidative stress leads to interrupted lung
development by mechanisms entailing disruption of growth factor sig-
naling, extracellular matrix assembly, cell proliferation, apoptosis, and
vasculogenesis [14].
Hyperoxia implies that the tissue oxygen supply exceeds its demand,
which in turn increases tissue oxygen levels that causes production of
toxic levels of ROS. Importantly, the levels of oxygen that determine
normoxia, hypoxia, or hyperoxia may be context dependent. For ex-
ample, brain and muscle tissues require different levels of oxygen for
their normal function; whether a given oxygen level constitutes nor-
moxia, hypoxia, or hyperoxia in these tissues are determined by their
underlying physiologic or pathologic processes [58]. Similarly, ex-
posure of newly born human premature neonates to normal atmo-
spheric oxygen (21% O2) may result in hyperoxia since they are
adapted to a hypoxic environment (4% O2) as a fetus [59]. The ROS
generated by hyperoxia exposure are potent oxidizing agents that di-
rectly damage the cellular constituents. These ROS are mostly free ra-
dicals and thereby are highly reactive and capable of oxidizing mem-
brane lipids, structural proteins, enzymes, and nucleic acids, which
leads to cell death and tissue damage [58]. Additionally, hyperoxia
increases the influx of inflammatory cells such as neutrophils and
macrophages into the lungs by mechanisms that entail increased gen-
eration and expression of chemotactic factors. Upon exposure to hy-
peroxia, the alveolar and interstitial macrophages secrete early-re-
sponse cytokines, which in turn activate the lung endothelial cells,
epithelial cells, and fibroblasts to produce additional chemokines that
attract neutrophils into the lungs [60]. Pathologically, exposure to
acute hyperoxia initially results in endothelial cell injury and death,
followed by epithelial cell damage and disruption of the alveolar-ca-
pillary membrane causing alveolar edema and impairment of gas ex-
change [61–63].
Although supplemental oxygen is frequently used as a life-saving
therapy in human preterm infants with hypoxic respiratory failure,
excessive or prolonged oxygen exposure results in increased ROS gen-
eration and the expression of proinflammatory cytokines [64]. Hyper-
oxia-induced ROS generation and inflammation causes injury and dis-
rupts the reparative processes in the developing lungs that ultimately
leads to the development of BPD [60]. Moreover, the antioxidant de-
fense system develops late in gestation, making preterm neonates
highly susceptible to hyperoxia-induced lung injury [65,66].
5.3.2. Mechanical ventilation
The pathogenesis of ventilator-induced lung injury (VILI) is complex
and is determined by the interactions between the ventilator settings
and the patient-related factors.
Barotrauma, volutrauma, atelectrauma and biotrauma are the major
ventilator determinants of VILI. Barotrauma is lung injury caused by
excessive airway pressure, whereas volutrauma is lung injury caused by
excessive lung volume and distension. Animal studies have clearly de-
monstrated that the degree of lung inflation is a more important med-
iator of lung injury than airway pressure [67–69]. For example, high
airway pressure causes severe lung injury in animals who have un-
restricted lung expansion, whereas the same airway pressure does not
cause lung injury in animals whose lung expansion is restricted by
strapping their chest and abdomen. The lung expansion is determined
by the transpulmonary pressure, which is the difference between al-
veolar and pleural pressure. Therefore, the peak airway pressure may
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Respiratory Medicine 132 (2017) 170–177
not always be directly proportional to the lung distending or trans-
pulmonary pressure. The lung physiology of trumpet players provides a
prime example of this concept. Trumpet players while playing a note
can generate alveolar pressures as high as 150 cm H2O; however, they
also generate pleural pressures as high as 140 cm H2O and therefore,
their lung distending pressure (150–140 = 10 cm H2O) is normal and
they have no lung injury [70]. These findings clearly indicate volu-
trauma is a more important determinant of VILI. Therefore, it is im-
portant to avoid excessive tidal volumes (VT) in mechanically ventilated
preterm infants to prevent lung injury. However, both volutrauma and
barotrauma can be inter-related because of the complex interactions
between the patient and the ventilator [71]. Atelectrauma refers to lung
injury caused by ventilating the lungs that are inadequately recruited
[72,73]. Ventilation at low lung volumes increases shear stress from
repeated alveolar collapse and expansion and causes surfactant dys-
function and regional hypoxia [72,74,75]. The stretching forces at the
margins between aerated and atelectatic lungs can be five times higher
than those in other regions [76]. Based of Laplace's law, the delivered
VT takes the path of least resistance and preferentially enters the aer-
ated lungs rather than the atelectatic lungs because the critical opening
pressure is lower in the former compared with the latter regions of the
lungs. This heterogeneous distribution of VT leads to regional volu-
trauma of the relatively healthy lungs despite the delivered VT being in
the normal range [77,78]. Therefore, use of adequate positive end ex-
piratory pressure to recruit lungs or prevent the collapse of the less
compliant alveoli at end expiration can prevent atelectrauma and its
associated sequelae such as regional volutrauma. Biotrauma is lung
injury caused by inflammatory response mediators such as chemokines
and cytokines [79]. Volutrauma, barotrauma, oxygen toxicity and
sepsis are the predominant causes of biotrauma [80], which leads to
uninhibited inflammation and interrupted lung development. It is im-
portant to recognize that these inflammatory responses need not be
compartmentalized to the lungs; severe lung inflammation can result in
systemic inflammatory response syndrome and multiorgan dysfunction
[81]. This pathological process can be mistaken for neonatal sepsis
resulting in exposure of these patients to unnecessary antibiotics, which
in fact may alter the respiratory microbiome and paradoxically worsen
their lung injury.
The patient determinants of VILI include preexisting lung injury,
lung inflammation, and surfactant abnormalities, and prematurity.
Premature infants are prone to develop lung atelectasis because of
anatomic and functional immaturity of the respiratory system
[77,82,83]. Further, these infants have lower lung tissue resilience due
to deficiency of the following: mature collagen and elastin elements,
surfactant and anti-oxidants in their lungs [71]. Therefore, premature
infants have a higher incidence of biophysical and biochemical lung
injury when subjected to an insult such as mechanical ventilation. In
summary, VILI results in an inflammatory cascade that disrupts sig-
naling pathways involved in lung development and repair and con-
tributes to the development of BPD [84]. Therefore, the best strategy to
prevent VILI is to avoid mechanical ventilation if possible. Strategies to
decrease VILI and facilitate lung growth and repair include avoiding
excessive VT, providing adequate PEEP to prevent atelectrauma, mini-
mizing excessive oxygen administration, preventing nosocomial infec-
tion, and providing good nutrition. BPD is a multifactorial disease with
a complex pathophysiology; therefore, it is important to avoid “one-
size-fits-all” approach to manage BPD patients.
5.3.3. Sepsis
Multiple studies indicate that postnatal sepsis independently in-
creases the incidence of BPD [35,85,86]. In fact, studies suggest that
postnatal infection is a more important predictor of BPD than antenatal
inflammation. Sepsis interrupts lung development and leads to BPD by
mechanisms that entail inflammation, oxidative stress, and endothelial
injury in the lungs [87].
R. Kalikkot Thekkeveedu et al.
5.3.4. Patent ductus arteriosus
By necessity, ductus arteriosus is normally present in a fetus where
it functions to shunt blood from pulmonary artery to ascending aorta,
bypassing the high-resistance nonfunctioning lungs [88]. The absence
or closure of ductus arteriosus in fetus impedes decompression of right
ventricle resulting in pulmonary hypertension and right heart failure
[89–91]. Several biophysical and biochemical changes that occur
physiologically in pulmonary and systemic blood vessels following birth
leads to the closure of ductus arteriosus within a few days of birth [92].
Patent ductus arteriosus (PDA) is a condition where ductus arteriosus
fails to close after birth. It is almost universally present in extremely
low birth weight infants. Because the pulmonary vascular resistance
decreases and systemic vascular resistance increases after birth, the
direction of blood flow changes from right-to-left seen in the fetus to
left-to-right after birth. Theoretically these changes can initiate or
worsen lung injury and predispose preterm infants to develop BPD for
several reasons. The increase in pulmonary blood flow can elevate the
vascular hydrostatic pressure and cause lung edema and a decrease in
lung compliance [93] necessitating an increase in the degree and
duration of ventilatory support, which can lead to VILI. Additionally,
the increased pulmonary blood flow can cause neutrophil margination
and activation and thereby increase lung inflammation [94], which is a
well known risk factor for BPD. The answer to whether hemodynami-
cally significant PDA is a risk factor for BPD continues to be ambiguous.
However, it is clear that closure of PDA does not necessarily decrease
the incidence of BPD raising doubts that the relationship between PDA
and BPD is more of an association rather than causation [95,96]. In fact,
some studies indicate that PDA closure by medical or surgical therapies
is associated with worsening BPD [97,98]. It is possible that PDA
therapy-associated complications such as lung fluid retention and lung
inflammation may have contributed to worsening of BPD in PDA-
treated patients. Significant practice variations, including patient
Fig. 3. Pulmonary function testing in BPD.
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Respiratory Medicine 132 (2017) 170–177
selection, PDA severity classification, presence of comorbid conditions,
and disease stage and the age at which the patients were treated may be
some of the factors responsible for the inconsistent study results. There
may be sub groups of BPD patients with PDA who might benefit or are
at risk from PDA closure. Therefore, future studies should factor in
several variables in their study design to identify these sub groups of
BPD patients.
5.3.5. Respiratory microbial dysbiosis
Dysbiosis, an imbalance in the structure of complex microbial
communities on or inside the body, is known to contribute to several
diseases where inflammation plays a major pathogenic role [99].
Contrary to the traditional belief that the human neonatal respiratory
tract is sterile at birth, current studies indicate that the human re-
spiratory tract microbial colonization begins in utero [100,101] or
shortly after birth [102,103]. A recent study demonstrated that the lung
microbiome, including the relative abundance of bacterial phyla and
diversity index of the preterm and term neonates were similar at birth
irrespective of the gestational age and the mode of delivery. Firmicutes
and Proteobacteria were the predominant microbes at birth [103].
Factors such as chorioamnionitis, antibiotic exposure, mode of delivery,
method of feeding, and bowel colonization can decrease bacterial di-
versity and increase pathogenic microbial colonization in the lungs
[104], which may potentially lead to an inflammatory lung phenotype
that ultimately contributes to the development of BPD.
6. Pathophysiology and BPD phenotypes
The pathophysiology of BPD has changed significantly in the past
two decades [105]. However, similar to infants with old BPD, new BPD
patients continue to have lung function abnormalities in later life.
Hence understanding the pathophysiology of BPD is pivotal to improve
R. Kalikkot Thekkeveedu et al.
the outcomes of preterm infants with BPD. The pathophysiology of new
BPD (Fig. 3) is characterized by alveolar and pulmonary vascular sim-
plification, and persistent abnormalities in gas exchange, airway func-
tion, respiratory system mechanics, and lung volumes [105,106].
Therefore, BPD patients can have varied clinical manifestations or
phenotypes, including lung parenchymal disease, pulmonary vascular
disease, and airway disease. However, majority of the BPD patients
have a substantial overlap of these three phenotypes.
6.1. Lung parenchymal disease
Alveolar simplification and reduced dysmorphic pulmonary vas-
cular bed leads to decreased and inefficient alveolar-capillary mem-
branes causing suboptimal pulmonary gas exchange [107–109]
(Fig. 3A). Management strategies include avoiding or minimizing ven-
tilator- or hyperoxia-induced lung injury, preventing infection, and
providing optimal nutrition. A subgroup of patients can also have het-
erogeneous parenchymal disease characterized by areas of atelectasis,
hyperinflation, and fibrosis. These pathological changes causes in-
creased lung dead space, multifocal abnormalities in lung resistance
and compliance, ventilation-perfusion (V/Q) mismatch, and increased
intrapulmonary shunts [110–114]. Further, the time constants in lung
regions with increased resistance are prolonged because they are di-
rectly proportional to lung resistance. Ventilator strategies that in-
corporate higher VT, longer inspiratory time, and lower rate to account
for the dead space, to completely deliver the VT to the alveoli, and to
allow for increased exhalation time, respectively, are therefore in-
dicated for BPD patients with a heterogeneous lung parenchymal dis-
ease. The diffusing capacity of the lung for carbon monoxide (DLCO),
which is the most commonly used lung function test to measure pul-
monary gas exchange in infants indicate that BPD patients have sub-
optimal alveolar-capillary gas transfer that persists into later life
[109,115,116].
6.2. Pulmonary vascular disease
Decreased growth and altered vasoreactivity and extracellular ma-
trix of the lung endothelial cells and endothelial cell dysfunction-
mediated inflammation are the major pulmonary vascular abnormal-
ities seen in BPD patients [117–120]. These abnormalities causes sub-
optimal pulmonary gas exchange. Pulmonary hypertension (PH) is the
most severe form of this phenotype and regular screening for PH is
needed in BPD patients. Effective management strategies in this group
of BPD patients include avoidance of hypoxemia, respiratory and me-
tabolic acidosis, and prevention of lung overinflation and atelectasis.
Majority of the PH patients will also need specific pulmonary vasodi-
lator therapy.
6.3. Airway disease
Premature infants in general and those with moderate to severe BPD
in particular have increased airway obstruction on lung function tests as
demonstrated by reduced forced expiratory volume in 1 s (FEV1) and
decreased FEV1/forced vital capacity. Airway remodeling, decreased
airway and alveolar growth, and mechanical ventilation-associated
complications such as tracheomalacia, bronchomalacia, and stenosis of
glottis, subglottis and trachea contribute to these persistent airway
abnormalities in BPD patients [105,121–124] (Fig. 3B). Although the
total lung capacity (TLC) in these infants are normal, the underlying
airflow obstruction leads to air trapping and abnormal lung volumes
such as increased residual volume (RV) and RV/TLC [105,113,125]
(Fig. 3B). In addition to increased airflow obstruction and abnormal
lung volumes, preterm infants with BPD have abnormal respiratory
system mechanics. The interrupted lung growth in BPD infants de-
creases the lung parenchymal elastic network, which in turn reduces
airway tethering and causes airway instability, increased airway closure
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Respiratory Medicine 132 (2017) 170–177
and collapse of alveolar units [126,127]. These abnormal respiratory
system mechanics decreases lung compliance and reactance and in-
creases pulmonary resistance in BPD infants [128,129] (Fig. 3C). BPD
patients with airway disease are best managed with increased PEEP
levels that are titrated to prevent premature closure or collapse of the
larger airways prior to completion of the expiratory phase [130,131].
Further, the high airway resistance in these patients increases the lung
time constants mandating the need for a prolonged expiratory time to
facilitate complete exhalation of their inspired gas volume. Failure to
incorporate these strategies can cause gas trapping, lung hyperexpan-
sion, and worsening V/Q mismatch. In chronically ventilated BPD pa-
tients, it is important to be aware of this pathophysiology and not al-
ways attribute hyperexpanded lungs to overventilation because
decreasing the mean airway pressure may in fact worsen oxygenation
and ventilation in these patients.
7. Conclusions
BPD continues to be a significant short- and long-term morbidity of
ELBW infants. There is a need for a standardized definition for BPD that
should ideally include more currently used therapies such as HFNC,
define severity, and predict long term morbidity. Trying to understand
the three most common pathophysiological components of BPD and
applying them to the individualized patient may be helpful in guiding
therapies and designing clinical trials.
Disclosure
The authors report no conflicts of interest in this work.
Acknowledgements
This work was supported by grants from the National Institutes of
Health (NIH) HD-073323, American Heart Association BGIA-20190008,
and American Lung Association RG-349917 to B.S.
References
[1] A.H. Jobe, Animal models, learning lessons to prevent and treat neonatal chronic
lung disease, Front. Med. 2 (2015) 49.
[2] A.N. Husain, N.H. Siddiqui, J.T. Stocker, Pathology of arrested acinar development
in postsurfactant bronchopulmonary dysplasia, Hum. Pathol. 29 (7) (Jul 1998)
710–717.
[3] J.J. Coalson, Pathology of new bronchopulmonary dysplasia, Seminars Neonatol.
SN. 8 (1) (Feb 2003) 73–81.
[4] A.T. Shennan, M.S. Dunn, A. Ohlsson, K. Lennox, E.M. Hoskins, Abnormal pul-
monary outcomes in premature infants: prediction from oxygen requirement in the
neonatal period, Pediatrics 82 (4) (Oct 1988) 527–532.
[5] A.H. Jobe, E. Bancalari, Bronchopulmonary dysplasia, Am. J. Respir. Crit. care
Med. 163 (7) (Jun 2001) 1723–1729.
[6] M.C. Walsh, D. Wilson-Costello, A. Zadell, N. Newman, A. Fanaroff, Safety, re-
liability, and validity of a physiologic definition of bronchopulmonary dysplasia,
J. Perinatol. Official J. Calif. Perinat. Assoc. 23 (6) (Sep 2003) 451–456.
[7] D. Hines, N. Modi, S.K. Lee, et al., Scoping review shows wide variation in the
definitions of bronchopulmonary dysplasia in preterm infants and calls for a
consensus, Acta Paediatr. (Oslo, Nor. 1992) 106 (3) (Mar 2017) 366–374.
[8] B.B. Poindexter, R. Feng, B. Schmidt, et al., Comparisons and limitations of current
definitions of bronchopulmonary dysplasia for the prematurity and respiratory
outcomes program, Ann. Am. Thorac. Soc. 12 (12) (Dec 2015) 1822–1830.
[9] S.H. Abman, J.M. Collaco, E.G. Shepherd, et al., Interdisciplinary care of children
with severe bronchopulmonary dysplasia, J. Pediatr. 181 (Feb 2017) 12–28 e11.
[10] C.T. McEvoy, L. Jain, B. Schmidt, S. Abman, E. Bancalari, J.L. Aschner,
Bronchopulmonary dysplasia: NHLBI workshop on the primary prevention of
chronic lung diseases, Ann. Am. Thorac. Soc. 11 (Suppl 3) (Apr 2014) S146–S153.
[11] B.J. Stoll, N.I. Hansen, E.F. Bell, et al., Neonatal outcomes of extremely preterm
infants from the NICHD Neonatal Research Network, Pediatrics 126 (3) (Sep 2010)
443–456.
[12] P.H. Burri, Structural aspects of postnatal lung development - alveolar formation
and growth, Biol. Neonate. 89 (4) (2006) 313–322.
[13] C.D. Baker, C.M. Alvira, Disrupted lung development and bronchopulmonary
dysplasia: opportunities for lung repair and regeneration, Curr. Opin. Pediatr. 26
(3) (Jun 2014) 306–314.
[14] A. Madurga, I. Mizikova, J. Ruiz-Camp, R.E. Morty, Recent advances in late lung
development and the pathogenesis of bronchopulmonary dysplasia, Am. J.
R. Kalikkot Thekkeveedu et al.
Physiol. Lung Cell. Mol. Physiol. 305 (12) (Dec 2013) L893–L905.
[15] W.H. Northway Jr., R.C. Rosan, D.Y. Porter, Pulmonary disease following re-
spirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia, N.
Engl. J. Med. 276 (7) (Feb 16 1967) 357–368.
[16] D.S. Bonikos, K.G. Bensch, W.H. Northway Jr., D.K. Edwards, Bronchopulmonary
dysplasia: the pulmonary pathologic sequel of necrotizing bronchiolitis and pul-
monary fibrosis, Hum. Pathol. 7 (6) (Nov 1976) 643–666.
[17] G.M. Shaw, H.M. O'Brodovich, Progress in understanding the genetics of
bronchopulmonary dysplasia, Seminars Perinatol. 37 (2) (Apr 2013) 85–93.
[18] V. Bhandari, M.J. Bizzarro, A. Shetty, et al., Familial and genetic susceptibility to
major neonatal morbidities in preterm twins, Pediatrics 117 (6) (Jun 2006)
1901–1906.
[19] P.M. Lavoie, C. Pham, K.L. Jang, Heritability of bronchopulmonary dysplasia,
defined according to the consensus statement of the national institutes of health,
Pediatrics 122 (3) (Sep 2008) 479–485.
[20] N. Ambalavanan, C.M. Cotten, G.P. Page, et al., Integrated genomic analyses in
bronchopulmonary dysplasia, J. Pediatr. 166 (3) (Mar 2015) 531–537 e513.
[21] H. Wang, K.R. St Julien, D.K. Stevenson, et al., A genome-wide association study
(GWAS) for bronchopulmonary dysplasia, Pediatrics 132 (2) (Aug 2013) 290–297.
[22] C. Bose, L.J. Van Marter, M. Laughon, et al., Fetal growth restriction and chronic
lung disease among infants born before the 28th week of gestation, Pediatrics 124
(3) (Sep 2009) e450–458.
[23] G. Klinger, N. Sokolover, V. Boyko, L. Sirota, L. Lerner-Geva, B. Reichman,
Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-
low-birthweight infants, Am. J. Obstet. Gynecol. 208(2) (115) (Feb 2013)
e111–119.
[24] I. Reiss, E. Landmann, M. Heckmann, B. Misselwitz, L. Gortner, Increased risk of
bronchopulmonary dysplasia and increased mortality in very preterm infants
being small for gestational age, Arch. Gynecol. Obstet. 269 (1) (Nov 2003) 40–44.
[25] L.J. Van Marter, O. Dammann, E.N. Allred, et al., Chorioamnionitis, mechanical
ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm
infants, J. Pediatr. 140 (2) (Feb 2002) 171–176.
[26] B.W. Kramer, S. Kallapur, J. Newnham, A.H. Jobe, Prenatal inflammation and lung
development, Seminars fetal & neonatal Med. 14 (1) (Feb 2009) 2–7.
[27] K.L. Watterberg, L.M. Demers, S.M. Scott, S. Murphy, Chorioamnionitis and early
lung inflammation in infants in whom bronchopulmonary dysplasia develops,
Pediatrics 97 (2) (Feb 1996) 210–215.
[28] N. Plakkal, A.S. Soraisham, C. Trevenen, E.A. Freiheit, R. Sauve, Histological
chorioamnionitis and bronchopulmonary dysplasia: a retrospective cohort study,
J. Perinatol. Official J. Calif. Perinat. Assoc. 33 (6) (Jun 2013) 441–445.
[29] W.W. Andrews, R.L. Goldenberg, O. Faye-Petersen, S. Cliver, A.R. Goepfert,
J.C. Hauth, The Alabama Preterm Birth study: polymorphonuclear and mono-
nuclear cell placental infiltrations, other markers of inflammation, and outcomes
in 23- to 32-week preterm newborn infants, Am. J. Obstet. Gynecol. 195 (3) (Sep
2006) 803–808.
[30] L. Hartling, Y. Liang, T. Lacaze-Masmonteil, Chorioamnionitis as a risk factor for
bronchopulmonary dysplasia: a systematic review and meta-analysis, Arch. Dis.
Child. Fetal neonatal Ed. 97 (1) (Jan 2012) F8–F17.
[31] Z. Liu, Z. Tang, J. Li, Y. Yang, Effects of placental inflammation on neonatal
outcome in preterm infants, Pediatr. Neonatol. 55 (1) (Feb 2014) 35–40.
[32] R.W. Redline, Inflammatory response in acute chorioamnionitis, Seminars
fetal & neonatal Med. 17 (1) (Feb 2012) 20–25.
[33] S.Y. Kim, C.W. Choi, E. Jung, et al., Neonatal morbidities associated with histo-
logic chorioamnionitis defined based on the site and extent of inflammation in
very low birth weight infants, J. Korean Med. Sci. 30 (10) (Oct 2015) 1476–1482.
[34] A.R. Ballard, L.H. Mallett, J.E. Pruszynski, J.B. Cantey, Chorioamnionitis and
subsequent bronchopulmonary dysplasia in very-low-birth weight infants: a 25-
year cohort, J. Perinatol. Official J. Calif. Perinat. Assoc. 36 (12) (Dec 2016)
1045–1048.
[35] M.M. Lahra, P.J. Beeby, H.E. Jeffery, Intrauterine inflammation, neonatal sepsis,
and chronic lung disease: a 13-year hospital cohort study, Pediatrics 123 (5) (May
2009) 1314–1319.
[36] J.J. Collins, S.G. Kallapur, C.L. Knox, et al., Inflammation in fetal sheep from intra-
amniotic injection of Ureaplasma parvum, Am. J. Physiol. Lung Cell. Mol. Physiol.
299 (6) (Dec 2010) L852–L860.
[37] R.M. Viscardi, S.P. Atamas, I.G. Luzina, et al., Antenatal Ureaplasma urealyticum
respiratory tract infection stimulates proinflammatory, profibrotic responses in the
preterm baboon lung, Pediatr. Res. 60 (2) (Aug 2006) 141–146.
[38] J. Lowe, W.J. Watkins, M.O. Edwards, et al., Association between pulmonary ur-
eaplasma colonization and bronchopulmonary dysplasia in preterm infants: up-
dated systematic review and meta-analysis, Pediatr. Infect. Dis. J. 33 (7) (Jul
2014) 697–702.
[39] R.L. Schelonka, B. Katz, K.B. Waites, D.K. Benjamin Jr., Critical appraisal of the
role of Ureaplasma in the development of bronchopulmonary dysplasia with me-
taanalytic techniques, Pediatr. Infect. Dis. J. 24 (12) (Dec 2005) 1033–1039.
[40] A.J. Bhatt, G.S. Pryhuber, H. Huyck, R.H. Watkins, L.A. Metlay, W.M. Maniscalco,
Disrupted pulmonary vasculature and decreased vascular endothelial growth
factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia,
Am. J. Respir. Crit. care Med. 164 (10 Pt 1) (Nov 15 2001) 1971–1980.
[41] E. Shibata, A. Rajakumar, R.W. Powers, et al., Soluble fms-like tyrosine kinase 1 is
increased in preeclampsia but not in normotensive pregnancies with small-for-
gestational-age neonates: relationship to circulating placental growth factor, J.
Clin. Endocrinol. Metabol. 90 (8) (Aug 2005) 4895–4903.
[42] J.R. Tang, S.A. Karumanchi, G. Seedorf, N. Markham, S.H. Abman, Excess soluble
vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung
growth in rats: linking preeclampsia with bronchopulmonary dysplasia. American
176
Respiratory Medicine 132 (2017) 170–177
journal of physiology, Lung Cell. Mol. Physiol. 302 (1) (Jan 01 2012) L36–L46.
[43] A.R. Hansen, C.M. Barnes, J. Folkman, T.F. McElrath, Maternal preeclampsia
predicts the development of bronchopulmonary dysplasia, J. Pediatr. 156 (4) (Apr
2010) 532–536.
[44] H. Ozkan, M. Cetinkaya, N. Koksal, Increased incidence of bronchopulmonary
dysplasia in preterm infants exposed to preeclampsia, J. Maternal-fetal neonatal
Med. Official J. Eur. Assoc. Perinat. Med. Fed. Asia Ocean. Perinat. Soc. Int. Soc.
Perinat. Obstet. 25 (12) (Dec 2012) 2681–2685.
[45] D.J. Henderson-Smart, J.L. Hutchinson, D.A. Donoghue, N.J. Evans, J.M. Simpson,
I. Wright, Prenatal predictors of chronic lung disease in very preterm infants, Arch.
Dis. Child. Fetal neonatal Ed. 91 (1) (Jan 2006) F40–F45.
[46] J.E. O'Shea, P.G. Davis, L.W. Doyle, Maternal preeclampsia and risk of broncho-
pulmonary dysplasia in preterm infants, Pediatr. Res. 71 (2) (Feb 2012) 210–214.
[47] T.A. Yen, H.I. Yang, W.S. Hsieh, et al., Preeclampsia and the risk of broncho-
pulmonary dysplasia in VLBW infants: a population based study, PLoS One. 8 (9)
(2013) e75168.
[48] H. Torchin, P.Y. Ancel, F. Goffinet, et al., Placental complications and broncho-
pulmonary dysplasia: EPIPAGE-2 cohort study, Pediatrics 137 (3) (Mar 2016)
e20152163.
[49] M.A. Wagijo, A. Sheikh, L. Duijts, J.V. Been, Reducing tobacco smoking and smoke
exposure to prevent preterm birth and its complications, Paediatr. Respir. Rev. 22
(Sep 21 2015) 3–10.
[50] R. Antonucci, P. Contu, A. Porcella, C. Atzeni, S. Chiappe, Intrauterine smoke
exposure: a new risk factor for bronchopulmonary dysplasia? J. Perinat. Med. 32
(3) (2004) 272–277.
[51] T. Isayama, P.S. Shah, X.Y. Ye, et al., Adverse impact of maternal cigarette
smoking on preterm infants: a population-based cohort study, Am. J. Perinatol. 32
(12) (Oct 2015) 1105–1111.
[52] J. Spiegler, R. Jensen, H. Segerer, et al., Influence of smoking and alcohol during
pregnancy on outcome of VLBW infants, Z. fur Geburtshilfe Neonatol. 217 (6) (Dec
2013) 215–219.
[53] S.P. Singh, S. Gundavarapu, K.R. Smith, et al., Gestational exposure of mice to
secondhand cigarette smoke causes bronchopulmonary dysplasia blocked by the
nicotinic receptor antagonist mecamylamine, Environ. health Perspect. 121 (8)
(Aug 2013) 957–964.
[54] G.S. Maritz, H. Dennis, Maternal nicotine exposure during gestation and lactation
interferes with alveolar development in the neonatal lung, Reprod., Fertil. Dev. 10
(3) (1998) 255–261.
[55] L. Duijts, I.K. Reiss, G. Brusselle, J.C. de Jongste, Early origins of chronic ob-
structive lung diseases across the life course, Eur. J. Epidemiol. 29 (12) (Dec 2014)
871–885.
[56] D.S. Lambers, K.E. Clark, The maternal and fetal physiologic effects of nicotine,
Seminars Perinatol. 20 (2) (Apr 1996) 115–126.
[57] S. Perrone, M.L. Tataranno, G. Buonocore, Oxidative stress and bronchopulmonary
dysplasia, J. Clin. Neonatol. 1 (3) (Jul 2012) 109–114.
[58] A.C. Kulkarni, P. Kuppusamy, N. Parinandi, Oxygen, the lead actor in the patho-
physiologic drama: enactment of the trinity of normoxia, hypoxia, and hyperoxia
in disease and therapy, Antioxidants redox Signal. 9 (10) (Oct 2007) 1717–1730.
[59] E. Maltepe, O.D. Saugstad, Oxygen in health and disease: regulation of oxygen
homeostasis–clinical implications, Pediatr. Res. 65 (3) (Mar 2009) 261–268.
[60] V. Bhandari, J.A. Elias, Cytokines in tolerance to hyperoxia-induced injury in the
developing and adult lung, Free Radic. Biol. Med. 41 (1) (Jul 1 2006) 4–18.
[61] S. Horowitz, Pathways to cell death in hyperoxia, Chest 116 (1 Suppl) (Jul 1999)
64S–67S.
[62] J.D. Crapo, Morphologic changes in pulmonary oxygen toxicity, Annu. Rev.
Physiol. 48 (1986) 721–731.
[63] P.J. Fracica, M.J. Knapp, C.A. Piantadosi, et al., Responses of baboons to pro-
longed hyperoxia: physiology and qualitative pathology, J. Appl. Physiol.
(Bethesda, Md. 1985) 71 (6) (Dec 1991) 2352–2362.
[64] A.H. Jobe, N. Hillman, G. Polglase, B.W. Kramer, S. Kallapur, J. Pillow, Injury and
inflammation from resuscitation of the preterm infant, Neonatology 94 (3) (2008)
190–196.
[65] J. Vina, M. Vento, F. Garcia-Sala, et al., L-cysteine and glutathione metabolism are
impaired in premature infants due to cystathionase deficiency, Am. J. Clin. Nutr.
61 (5) (May 1995) 1067–1069.
[66] T.M. Asikainen, C.W. White, Antioxidant defenses in the preterm lung: role for
hypoxia-inducible factors in BPD? Toxicol. Appl. Pharmacol. 203 (2) (Mar 1 2005)
177–188.
[67] D. Dreyfuss, P. Soler, G. Basset, G. Saumon, High inflation pressure pulmonary
edema. Respective effects of high airway pressure, high tidal volume, and positive
end-expiratory pressure, Am. Rev. Respir. Dis. 137 (5) (May 1988) 1159–1164.
[68] L.A. Hernandez, K.J. Peevy, A.A. Moise, J.C. Parker, Chest wall restriction limits
high airway pressure-induced lung injury in young rabbits, J. Appl. Physiol.
(Bethesda, Md. 1985). 66 (5) (May 1989) 2364–2368.
[69] D.P. Carlton, J.J. Cummings, R.G. Scheerer, F.R. Poulain, R.D. Bland, Lung over-
expansion increases pulmonary microvascular protein permeability in young
lambs, J. Appl. Physiol. (Bethesda, Md. 1985). 69 (2) (Aug 1990) 577–583.
[70] A. Bouhuys, Physiology and musical instruments, Nature 221 (5187) (Mar 29
1969) 1199–1204.
[71] T. Whitehead, A.S. Slutsky, The pulmonary physician in critical care * 7: ventilator
induced lung injury, Thorax 57 (7) (Jul 2002) 635–642.
[72] A.S. Slutsky, Lung injury caused by mechanical ventilation, Chest 116 (1 Suppl)
(Jul 1999) 9S–15S.
[73] G. Mols, H.J. Priebe, J. Guttmann, Alveolar recruitment in acute lung injury, Br. J.
Anaesth. 96 (2) (Feb 2006) 156–166.
[74] A.M. Bilek, K.C. Dee, D.P. Gaver 3rd, Mechanisms of surface-tension-induced
R. Kalikkot Thekkeveedu et al.
epithelial cell damage in a model of pulmonary airway reopening, J. Appl. Physiol.
(Bethesda, Md. 1985) 94 (2) (Feb 2003) 770–783.
[75] R.K. Albert, The role of ventilation-induced surfactant dysfunction and atelectasis
in causing acute respiratory distress syndrome, Am. J. Respir. Crit. care Med. 185
(7) (Apr 01 2012) 702–708.
[76] J. Mead, T. Takishima, D. Leith, Stress distribution in lungs: a model of pulmonary
elasticity, J. Appl. Physiol. 28 (5) (May 1970) 596–608.
[77] M. Keszler, G. Sant'Anna, Mechanical ventilation and bronchopulmonary dys-
plasia, Clin. Perinatol. 42 (4) (Dec 2015) 781–796.
[78] S. Tsuchida, D. Engelberts, V. Peltekova, et al., Atelectasis causes alveolar injury in
nonatelectatic lung regions, Am. J. Respir. Crit. care Med. 174 (3) (Aug 01 2006)
279–289.
[79] L.N. Tremblay, A.S. Slutsky, Ventilator-induced injury: from barotrauma to bio-
trauma, Proc. Assoc. Am. Phys. 110 (6) (Nov-Dec 1998) 482–488.
[80] A.S. Slutsky, V.M. Ranieri, Ventilator-induced lung injury, N. Engl. J. Med. 369
(22) (Nov 28 2013) 2126–2136.
[81] A.S. Slutsky, L.N. Tremblay, Multiple system organ failure. Is mechanical venti-
lation a contributing factor? Am. J. Respir. Crit. care Med. 157 (6 Pt 1) (Jun 1998)
1721–1725.
[82] A.H. Jobe, M. Ikegami, Lung development and function in preterm infants in the
surfactant treatment era, Annu. Rev. Physiol. 62 (2000) 825–846.
[83] C. Morley, Continuous distending pressure, Arch. Dis. Child. Fetal neonatal Ed. 81
(2) (Sep 1999) F152–F156.
[84] J. Balany, V. Bhandari, Understanding the impact of infection, inflammation, and
their persistence in the pathogenesis of bronchopulmonary dysplasia, Front. Med.
2 (2015) 90.
[85] D.D. Marshall, M. Kotelchuck, T.E. Young, C.L. Bose, L. Kruyer, T.M. O'Shea, Risk
factors for chronic lung disease in the surfactant era: a North Carolina population-
based study of very low birth weight infants. North Carolina Neonatologists
Association, Pediatrics 104 (6) (Dec 1999) 1345–1350.
[86] G. Klinger, I. Levy, L. Sirota, V. Boyko, L. Lerner-Geva, B. Reichman, Outcome of
early-onset sepsis in a national cohort of very low birth weight infants, Pediatrics
125 (4) (Apr 2010) e736–740.
[87] E.A. Jensen, B. Schmidt, Epidemiology of bronchopulmonary dysplasia, Birth
Defects Res. Part A, Clin. Mol. Teratol. 100 (3) (Mar 2014) 145–157.
[88] S. Lakshminrusimha, The pulmonary circulation in neonatal respiratory failure,
Clin. Perinatol. 39 (3) (Sep 2012) 655–683.
[89] G. Mielke, E. Steil, J. Breuer, R. Goelz, Circulatory changes following intrauterine
closure of the ductus arteriosus in the human fetus and newborn, Prenat. Diagn. 18
(2) (Feb 1998) 139–145.
[90] M. Gewillig, S.C. Brown, L. De Catte, et al., Premature foetal closure of the arterial
duct: clinical presentations and outcome, Eur. heart J. 30 (12) (Jun 2009)
1530–1536.
[91] H. Ishida, Y. Kawazu, F. Kayatani, N. Inamura, Prognostic factors of premature
closure of the ductus arteriosus in utero: a systematic literature review, Cardiol.
Young (Jun 20 2016) 1–5.
[92] S.E. Hamrick, G. Hansmann, Patent ductus arteriosus of the preterm infant,
Pediatrics 125 (5) (May 2010) 1020–1030.
[93] T. Gerhardt, E. Bancalari, Lung compliance in newborns with patent ductus ar-
teriosus before and after surgical ligation, Biol. Neonate. 38 (1–2) (1980) 96–105.
[94] E. Varsila, M. Hallman, P. Venge, S. Andersson, Closure of patent ductus arteriosus
decreases pulmonary myeloperoxidase in premature infants with respiratory dis-
tress syndrome, Biol. Neonate. 67 (3) (1995) 167–171.
[95] J.L. Slaughter, P.B. Reagan, T.B. Newman, M.A. Klebanoff, Comparative effec-
tiveness of nonsteroidal anti-inflammatory drug treatment vs No treatment for
patent ductus arteriosus in preterm infants, JAMA Pediatr. 171 (3) (Mar 06 2017)
e164354.
[96] V.Y. Chock, R. Punn, A. Oza, et al., Predictors of bronchopulmonary dysplasia or
death in premature infants with a patent ductus arteriosus, Pediatr. Res. 75 (4)
(Apr 2014) 570–575.
[97] A.K. Edstedt Bonamy, A. Gudmundsdottir, R.F. Maier, et al., Patent ductus arter-
iosus treatment in very preterm infants: a european population-based cohort study
(EPICE) on variation and outcomes, Neonatology 111 (4) (Jan 26 2017) 367–375.
[98] S.I. Sung, Y.S. Chang, J.Y. Chun, et al., Mandatory closure versus nonintervention
for patent ductus arteriosus in very preterm infants, J. Pediatr. 177 (Oct 2016)
66–71 e61.
[99] C. Petersen, J.L. Round, Defining dysbiosis and its influence on host immunity and
disease, Cell. Microbiol. 16 (7) (Jul 2014) 1024–1033.
[100] R. Hansen, K.P. Scott, S. Khan, et al., First-pass meconium samples from healthy
term vaginally-delivered neonates: an analysis of the microbiota, PLoS One. 10 (7)
(2015) e0133320.
[101] E. Jimenez, L. Fernandez, M.L. Marin, et al., Isolation of commensal bacteria from
umbilical cord blood of healthy neonates born by cesarean section, Curr.
Microbiol. 51 (4) (Oct 2005) 270–274.
[102] P. Lohmann, R.A. Luna, E.B. Hollister, et al., The airway microbiome of intubated
premature infants: characteristics and changes that predict the development of
bronchopulmonary dysplasia, Pediatr. Res. 76 (3) (Sep 2014) 294–301.
[103] C.V. Lal, C. Travers, Z.H. Aghai, et al., The airway microbiome at birth, Sci. Rep. 6
(Aug 04 2016) 31023.
177
Respiratory Medicine 132 (2017) 170–177
[104] D.J. Gallacher, S. Kotecha, Respiratory microbiome of new-born infants, Front.
Pediatr. 4 (2016) 10.
[105] S.J. Simpson, G.L. Hall, A.C. Wilson, Lung function following very preterm birth in
the era of 'new' bronchopulmonary dysplasia, Respirol. Carlt. Vic. . 20 (4) (May
2015) 535–540.
[106] J.Y. Islam, R.L. Keller, J.L. Aschner, T.V. Hartert, P.E. Moore, Understanding the
short- and long-term respiratory outcomes of prematurity and bronchopulmonary
dysplasia, Am. J. Respir. Crit. care Med. 192 (2) (Jul 15 2015) 134–156.
[107] S.K. Ahlfeld, Y. Gao, S.J. Conway, R.S. Tepper, Relationship of structural to
functional impairment during alveolar-capillary membrane development, Am. J.
Pathol. 185 (4) (Apr 2015) 913–919.
[108] C. May, C. Kennedy, A.D. Milner, G.F. Rafferty, J.L. Peacock, A. Greenough, Lung
function abnormalities in infants developing bronchopulmonary dysplasia, Arch.
Dis. Child. 96 (11) (Nov 2011) 1014–1019.
[109] S. Cazzato, L. Ridolfi, F. Bernardi, G. Faldella, L. Bertelli, Lung function outcome at
school age in very low birth weight children, Pediatr. Pulmonol. 48 (8) (Aug 2013)
830–837.
[110] N. Bamat, S. Ghavam, Y. Liu, et al., Reliability of a noninvasive measure of V./Q.
Mismatch for bronchopulmonary dysplasia, Ann. Am. Thorac. Soc. 12 (5) (May
2015) 727–733.
[111] P. Thunqvist, P. Gustafsson, M. Norman, M. Wickman, J. Hallberg, Lung function
at 6 and 18 months after preterm birth in relation to severity of bronchopulmonary
dysplasia, Pediatr. Pulmonol. 50 (10) (Oct 2015) 978–986.
[112] M. Filippone, M. Sartor, F. Zacchello, E. Baraldi, Flow limitation in infants with
bronchopulmonary dysplasia and respiratory function at school age, Lancet
(London, Engl.) 361 (9359) (Mar 01 2003) 753–754.
[113] B. Robin, Y.J. Kim, J. Huth, et al., Pulmonary function in bronchopulmonary
dysplasia, Pediatr. Pulmonol. 37 (3) (Mar 2004) 236–242.
[114] M. Keszler, S. Nassabeh-Montazami, K. Abubakar, Evolution of tidal volume re-
quirement during the first 3 weeks of life in infants < 800 g ventilated with
Volume Guarantee, Arch. Dis. Child. Fetal neonatal Ed. 94 (4) (Jul 2009)
F279–F282.
[115] J.E. Balinotti, V.C. Chakr, C. Tiller, et al., Growth of lung parenchyma in infants
and toddlers with chronic lung disease of infancy, Am. J. Respir. Crit. care Med.
181 (10) (May 15 2010) 1093–1097.
[116] S. Lum, J. Kirkby, L. Welsh, N. Marlow, E. Hennessy, J. Stocks, Nature and severity
of lung function abnormalities in extremely pre-term children at 11 years of age,
Eur. Respir. J. 37 (5) (May 2011) 1199–1207.
[117] V.H. Kumar, R.M. Ryan, Growth factors in the fetal and neonatal lung, Front.
Biosci. a J. virtual Libr. 9 (Jan 01 2004) 464–480.
[118] B. Thebaud, S.H. Abman, Bronchopulmonary dysplasia: where have all the vessels
gone? Roles of angiogenic growth factors in chronic lung disease, Am. J. Respir.
Crit. care Med. 175 (10) (May 15 2007) 978–985.
[119] W.M. Maniscalco, R.H. Watkins, G.S. Pryhuber, A. Bhatt, C. Shea, H. Huyck,
Angiogenic factors and alveolar vasculature: development and alterations by in-
jury in very premature baboons, Am. J. Physiol. Lung Cell. Mol. Physiol. 282 (4)
(Apr 2002) L811–L823.
[120] D.N. Cornfield, Developmental regulation of oxygen sensing and ion channels in
the pulmonary vasculature, Adv. Exp. Med. Biol. 661 (2010) 201–220.
[121] M. Vollsaeter, O.D. Roksund, G.E. Eide, T. Markestad, T. Halvorsen, Lung function
after preterm birth: development from mid-childhood to adulthood, Thorax 68 (8)
(Aug 2013) 767–776.
[122] J. Fawke, S. Lum, J. Kirkby, et al., Lung function and respiratory symptoms at 11
years in children born extremely preterm: the EPICure study, Am. J. Respir. Crit.
care Med. 182 (2) (Jul 15 2010) 237–245.
[123] I.J. Doull, Q. Mok, R.C. Tasker, Tracheobronchomalacia in preterm infants with
chronic lung disease, Arch. Dis. Child. Fetal neonatal Ed. 76 (3) (May 1997)
F203–F205.
[124] G.J. Downing, H.W. Kilbride, Evaluation of airway complications in high-risk
preterm infants: application of flexible fiberoptic airway endoscopy, Pediatric 95
(4) (Apr 1995) 567–572.
[125] A.G. Filbrun, A.P. Popova, M.J. Linn, N.A. McIntosh, M.B. Hershenson,
Longitudinal measures of lung function in infants with bronchopulmonary dys-
plasia, Pediatr. Pulmonol. 46 (4) (Apr 2011) 369–375.
[126] C.G. Plopper, S.J. Nishio, E.S. Schelegle, Tethering tracheobronchial airways
within the lungs, Am. J. Respir. Crit. care Med. 167 (1) (Jan 1 2003) 2–3.
[127] M. Henschen, J. Stocks, I. Brookes, U. Frey, New aspects of airway mechanics in
pre-term infants, Eur. Respir. J. 27 (5) (May 2006) 913–920.
[128] E.J. Vrijlandt, H.M. Boezen, J. Gerritsen, E.F. Stremmelaar, E.J. Duiverman,
Respiratory health in prematurely born preschool children with and without
bronchopulmonary dysplasia, J. Pediatr. 150 (3) (Mar 2007) 256–261.
[129] E.B. Brostrom, P. Thunqvist, G. Adenfelt, E. Borling, M. Katz-Salamon, Obstructive
lung disease in children with mild to severe BPD, Respir. Med. 104 (3) (Mar 2010)
362–370.
[130] A. Greenough, V. Chan, M.F. Hird, Positive end expiratory pressure in acute and
chronic respiratory distress, Arch. Dis. Child. 67 (3) (Mar 1992) 320–323.
[131] H.B. Panitch, J.L. Allen, B.E. Alpert, D.V. Schidlow, Effects of CPAP on lung me-
chanics in infants with acquired tracheobronchomalacia, Am. J. Respir. Crit. care
Med. 150 (5 Pt 1) (Nov 1994) 1341–1346.