OLD BPD – NEW BPD
OLD BRONCHOPULMONARY DYSPLASIA –
NEW BRONCHOPULMONARY DYSPLASIA
Hugh O’Brodovich MD, FRCP(C)
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA,
USA 94305
Running Title: OLD BPD – NEW BPD
Address correspondence to:
Hugh O’Brodovich MD, FRCP(C)
Arline & Pete Harman Professor and Chairman
Department of Pediatrics, Stanford School of Medicine
Adalyn Jay Physician-in-Chief, Lucile Packard Children's Hospital
Department of Pediatrics
Stanford School of Medicine
300 Pasteur Drive , Room H310
Stanford , CA 94305-5208
Ph: (650) 723-5104
Fax: (650)725-7419
Hugh.OBrodovich@Stanford.edu
1
OLD BPD – NEW BPD
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of
infants and its treatment imposes considerable health care burden and costs in the
perinatal and early childhood period. Structural changes in the lung and impairment of
function persist later in life, so survivors are likely at increased risk for chronic
obstructive pulmonary disease (COPD), pulmonary hypertension, and perhaps other adult
lung diseases.
Since its first description (3), there have been remarkable changes in the clinical and
pathologic phenotype. This evolution has led clinicians and researchers to use terms
such as “Old BPD” and “New BPD” to differentiate the original from the currently most
commonly seen phenotype. To help understand the differences between “Old BPD” and
“New BPD” this brief review will utilize a “walk through history”.
Neonatal Respiratory Distress Syndrome
At one time the neonatal respiratory distress syndrome (nRDS) in the prematurely
born human infant was called “idiopathic RDS” as we did not understand the
pathophysiologic mechanisms underlying this serious disorder. Little could be done for
these infants: in 1960 infants with nRDS at The Hospital for Sick Children in Toronto
had a 50% mortality rate and nRDS was responsible for 30% of all hospital deaths. In
1959 Avery and Mead discovered that extracts from postmortem nRDS lungs had
increased air-liquid surface tension and that they were deficient in dipalmitoyl lecithin.
Although clinical trials using aerosolized lecithin followed shortly thereafter, this new
“therapy” did not benefit infants with nRDS. Two decades of research would be required
to identify the reasons for this failure, to determine the various components of surfactant
and to create a clinically efficacious exogenous surfactant that would treat the “relative
surfactant deficiency” which characterizes nRDS . During those two decades, infants
with severe nRDS began to survive as neonatal intensive care units were created and
physicians intervened with the use of continuous positive pressure ventilation and
assisted ventilation. During that era, premature infants with nRDS either died during the
few days after birth or in a comparable timeframe improved dramatically and survived
with no significant long term pulmonary sequelae.
Bronchopulmonary Dyplasia
As a result of an improved understanding of the physiology of the premature lung,
the pathophysiology of RDS and how to best utilize advances in technology, more infants
began to survive severe nRDS. Some of these new survivors, however, did not show the
marked improvement during the first week of life. In 1967, Bill Northway and
colleagues recognized this form of unresolved lung injury and gave it the name
bronchopulmonary dysplasia (BPD) (3). Although exceptions occurred, the disorder
typically occurred in infants whose gestational ages (GA) were 30 – 36 weeks. More
immature infants with severe nRDS rarely survived.
BPD evolved in characterized stages. During the first week of life, the infant had
the typical radiographic findings of nRDS (Stage I), a disorder characterized by relative
surfactant deficiency, an inability to actively clear fetal lung liquid from its airspaces and
2
OLD BPD – NEW BPD
an abnormal permeability of the alveolar capillary membrane permeability. However,
towards the latter part of the first week post-partum there was not the typical spontaneous
resolution as described above, but rather a worsening of the nRDS (Stage II). Thereafter
the “stiff small lung disease”, which is characteristic of nRDS, evolved into a severe
chronic obstructive pulmonary disorder which was frequently complicated by cor
pulmonale (Stages III and IV). Clinically these latter stages were characterized by
severe airflow limitation whilst the chest radiograph demonstrated marked over-inflation
with multiple cystic areas interspersed with fibrotic linear densities. The pathologic
findings of extensive airway and parenchymal damage in the presence of abnormal lung
structure lead to its name, bronchopulmonary dysplasia. BPD was not diagnosed until
one month of age and required the presence of 1) a respiratory disorder that began with
acute lung injury; 2) postnatal age > 28 days; 3) significant clinical and radiologic
findings consistent with the diagnosis and 4) blood gas tension abnormalities with PaO2 <
60 torr or PaCO2 > 45 torr whilst breathing room air at usual altitudes. Northway’s BPD,
now known as “Old BPD”, is reviewed in (4).
Infants who developed BPD and survived, often faced long periods of assisted
ventilation followed by months to years of supplemental oxygen therapy in hospital and
then at home during their phase of chronic hypercarbic respiratory failure. Their clinical
course was usually very complex. They suffered from numerous complications: cor
pulmonale, reactive airway disease, failure to thrive and other sequelae including
significant neurodevelopmental delay. The first years of life were characterized by
frequent hospitalizations.
From the perspective of the respiratory system, infants usually improved
significantly during the first few years of life with the vast majority of older infants and
toddlers no longer needing supplemental oxygen therapy. It is presumed that, at least in
part, this improvement occurred because alveolarization in the human lung continues
after birth; full term healthy human infants have 20- 30 million alveoli and this number
increases to approximately 300-600 million alveoli during infancy and childhood.
Although patients with BPD improved, studies in the early 1990s showed that they had
significant residual lung disease. The majority had significant airway obstruction and,
although there was bronchial hyperreactivity, most of the deficit in FEV1 was not
reversible with bronchodilators.
“New BPD”
Basic, translational and clinical research during the 1970s and 1980 led to
dramatic improvements in the management of prematurely born infants with acute
respiratory disease. In addition to many improvements in general intensive care, for
example better nutrition and fluid balance, the most important interventions in relation to
the lungs might be summarized as follows:
1) an improved understanding of the hormonal regulation of fetal lung maturation leading
to the use of antenatal corticosteroids to mature the lung’s surfactant synthetic pathways
prior to preterm delivery;
2) the identification of the various component of surfactant and their properties leading to
the routine use of exogenous surfactant therapy for nRDS;
3
OLD BPD – NEW BPD
3) the recognition that the airway pressures that were “usually used” during assisted
ventilation were causing lung injury;
4) a better understanding of physiologic effects of pH, PaCO2 and PaO2.
Interventions 3) and 4) led physicians to have an “enhanced tolerance” of “abnormal”
blood gases. Together this led to less hyperoxia and “gentler” ventilation which
diminished treatment – related lung injury and led to a virtual disappearance of
“Northway’s BPD” in the infants who were born at 30 – 36 weeks GA.
The above improvements in clinical care also led to a dramatic improvement in
the survival of very low birth weight (VLBW) infants who, at birth, weighed <1,500 gm.
Physicians recognized that these markedly premature infants also frequently developed a
chronic lung disease (CLD). However, although they required long term ventilator
support and/or supplemental oxygen therapy, their CLD had a significantly different
clinical phenotype from “Northway’s BPD”. Often there was minimal or mild nRDS
during the first days post partum and the infant did not progress through the typical
Stages I, II, III and IV of BPD described above. Their chest radiograph usually did not
demonstrate the cystic areas with interspersed fibrosis and pathologic studies revealed
profound differences in the histopathology of the lungs of such infants. There were only
minor changes in the airways; the major abnormality was a marked reduction in the total
alveolar number and alveolar surface area arising from a marked impairment of alveolar
development (2). There no longer was a “B” in the “BPD” and there was minimal
evidence of fibrosis in the interstitial or alveolar airspaces. Given the significant clinical,
radiologic and pathologic differences between this new type of CLD in the prematurely
born, this CLD seen in VLBW infants is now commonly referred to as “New BPD” (see
review (1)).
Since “New BPD” occurs in VLBW infants and there is a different phenotype
there needed to be a change in diagnostic criteria from those utilized by Northway and
colleagues. The current NIH consensus diagnostic criteria for BPD in infants born less
than 32 weeks gestational age (5) is that mild BPD is diagnosed when the infant requires
supplemental oxygen at 28 days after birth but is in room air at a post menstrual age
(PMA) of 36 weeks. Moderate BPD is diagnosed when the infant reaches 36 weeks
PMA and although still requires supplemental oxygen the requirements are for an FIO2 <
0.3. Severe BPD is diagnosed when a 36 week PMA infant requires an FIO2 > 0.3 and
continuous positive airway pressure or mechanical ventilation. In contrast to the criteria
for Northway’s BPD (“Old BPD”) neither radiographic nor clinical findings are part of
the diagnostic criteria.
Although much of the clinical phenotype is different, long term follow up studies
of “New BPD” have demonstrated significantly impaired pulmonary function when
survivors are studied during their school age and adolescent years (reviewed in (1)).
Since even full term healthy infants who suffer from childhood respiratory disorders can
have a predisposition to chronic obstructive pulmonary disease (COPD) one can
speculate that “New BPD” will predispose adults to an even earlier onset of serious
morbidity and mortality from COPD.
Numerous mammal, primate and human studies have been undertaken in an
attempt to better understand the pathogenesis of “New BPD”. A crucial point is that
VLBW infants are born with lungs that are only in the canalicular and early saccular
4
OLD BPD – NEW BPD
stages of lung development. This contrasts with the infants who developed “Old BPD”;
they were typically born after 30 – 36 weeks gestation and at the time of birth their lungs
that had reached the alveolar stage of fetal lung development. The VLBW infant’s more
immature lungs are frequently exposed to different phenomena that are known to alter
lung development. For example, exposure to glucocorticosteroids can impair alveolar
septation, inflammatory mediators arising from low level or overt chorioamnionitis can
result in alveolar simplification and vascular injury and fetal growth restriction can
negatively affect lung development. A currently favored hypothesis is that a failure of
normal angiogenesis causes or contributes to the failure of normal alveolar development.
Two recent twin studies support a strong genetic contribution to the risk of new BPD and
suggest that heritability (h2) for new BPD is at least as large and probably greater than
that for systemic hypertension (h2 ~30%), cancer (~40%), and psychiatric disorders (~60).
How these various factors interact and result in failure of the distal lung unit to undergo
normal development, and result in fewer and larger “alveoli”, is largely unknown.
1. Baraldi E and Filippone M. Chronic lung disease after premature birth. N Engl J
Med 357: 1946-1955, 2007.
2. Margraf LR, Tomashefski JF, Jr., Bruce MC and Dahms BB. Morphometric
analysis of the lung in bronchopulmonary dysplasia. Am Rev Respir Dis 143: 391400, 1991.
3. Northway WHJr, Rosan RC and Porter DY. Pulmonary disease following
respiratory therapy of hyaline-membrane disease: Bronchopulmonary dysplasia. N
Engl J Med 276: 357-367, 1967.
4. O'Brodovich H and Mellins RB. Bronchopulmonary dysplasia: Unresolved
neonatal acute lung injury. Am Rev Respir Dis 132: 694-709, 1985.
5
OLD BPD – NEW BPD
5. Walsh MC, Szefler S, Davis J, Allen M, Van ML, Abman S, Blackmon L and
Jobe A. Summary proceedings from the bronchopulmonary dysplasia group.
Pediatr 117: S52-S56, 2006.
6