Definitions and Diagnostic Criteria of Bronchopulmonary Dysplasia: Clinical and Research Implications

  • Bronchopulmonary dysplasia (BPD) is a common complication of prematurity that results from abnormal lung development that leads to chronic impairment of lung function.

  • Use of standard diagnostic classifications of BPD and its severity is important in clinical trials that evaluate therapeutic strategies, in epidemiologic cohorts, and to benchmark respiratory outcomes in neonatal centers.

  • Standard criteria to diagnose BPD do not consistently predict long-term lung health. This is because postdischarge events can positively or negatively affect lung structure and function.

  • Better markers of lung injury that may predict more precisely long-term lung health in this population are needed.

Bronchopulmonary dysplasia (BPD) results from abnormal lung development after premature birth and prolonged respiratory support. BPD progresses from initial respiratory failure that evolves into more chronic forms of lung disease. The impaired lung function associated with BPD frequently persists through childhood and into adulthood. Therefore it is important that the diagnostic criteria define the severity of the pulmonary dysfunction and provide prognostic indicators of the degree of respiratory impairment after the initial hospital discharge. Standard BPD diagnostic and severity criteria are also important to compare outcomes in infants included in clinical trials, for epidemiologic identification of risk factors, and to compare outcomes between centers or within centers for quality improvement activities.

We provide a brief update of the epidemiology of BPD, describe the most frequent diagnostic criteria of BPD, and discuss their possible advantages and limitations with the changing presentation and management.

Clinical Presentation of BPD

The term “bronchopulmonary dysplasia” was introduced by Northway and collaborators to describe a clinical, radiographic, and pathologic entity that occurred in preterm infants who survived severe respiratory distress syndrome (RDS) after aggressive mechanical ventilation and exposure to high concentrations of inspired oxygen. These infants had severe respiratory failure shortly after birth and required mechanical ventilation and supplemental oxygen for long periods. The severity of the respiratory failure and the radiographic images from these infants were clear evidence of their serious lung derangement that resulted in poor short- and long-term outcomes. This presentation of BPD changed over the years with the introduction of prenatal steroid therapy, postnatal surfactant treatments, and the many advances in respiratory support. The severe forms of BPD are less common and have been replaced by milder forms that occur more frequently as the survival of extremely premature infants has markedly increased.

The underlying abnormality in the lungs of the premature infant with BPD is a disruption of the normal process of alveolar and capillary development. The more severe cases are also associated with airway and vascular remodeling, leading to airway obstruction and pulmonary hypertension that can be accompanied by interstitial edema and fibrous tissue proliferation.

Although the classic severe forms of BPD are less common today, some infants still have a severe clinical course with a prolonged need for respiratory support resulting in significant respiratory failure, pulmonary hypertension, and marked alterations in the chest radiographs. These infants offer minimal diagnostic or prognostic dilemma. The difficulty lies with the diagnosis of the less severe forms of BPD that have a mild initial respiratory course and require only low levels of respiratory support. The clinical and radiographic evidence in these infants is less conclusive than that in infants with severe BPD. The radiographs show mainly diffuse haziness, indicating loss of gas volume or fluid accumulation. Dense areas of segmental or lobar atelectasis or pneumonic infiltrates are occasionally observed but there are no areas of severe overinflation typical of the severe forms of BPD.

Lethal, severe cases of BPD were characterized by morphologic alterations, including emphysema, atelectasis, and fibrosis, and marked epithelial squamous metaplasia and smooth muscle hypertrophy in the airways and in the pulmonary vasculature. These alterations were associated with airway obstruction, pulmonary hypertension, and cor pulmonale that resulted from prolonged respiratory failure. Infants developing BPD today are considerably more immature than the earlier cases of severe BPD, and the incidence of BPD among infants born after 32 weeks’ gestation has become negligible in modern neonatal centers. Today, BPD predominantly occurs in infants of less than 29 weeks’ gestation. The incidence of BPD in infants of less than 29 weeks’ gestational age (GA) in the centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) was 42% during the years 2003 to 2007. According to a recent report from stratified samples of nearly one-fifth of U.S. hospitals, the incidence of BPD among surviving infants of birth weights below 1500 g has declined from 50% to 60% in the 1990s to nearly 40% in the years 2000 to 2006. However, in the past 10 years the incidence of BPD in infants born before 28 weeks in the centers of the NICHD-NRN has slightly increased.

The initial presentation of the infants who develop BPD, even when they are more premature, is more heterogeneous than in earlier years. Most infants who had BPD in earlier years had severe RDS, and it is likely that the incidence of BPD would have been even higher absent the relatively high early mortality resulting from severe respiratory failure in those years. At present, many premature infants who develop BPD present with no or only mild RDS after birth. Based on autopsy and animal models the BPD cases today probably have a reduction in alveolar septation and vascular development, suggesting that the underlying lung immaturity contributes to the pathogenesis and the clinical presentation of BPD.

BPD Diagnosis

Clinicians are confident with a diagnosis of severe BPD because there are not diagnostic ambiguities. These infants have persistent severe respiratory failure and require supplemental oxygen and respiratory support for prolonged periods, which indicates severe chronic lung injury and conveys a poor long-term prognosis. In contrast, most infants who develop BPD today have mild or transient initial respiratory distress. Although these infants receive prolonged respiratory support, they do not require high levels of assistance and the support is not always continuous, which results in inconsistencies in the diagnosis of BPD based on the levels of respiratory support.

Because diagnostic criteria for BPD are intended not only for use by clinicians to diagnose individual infants but also for benchmarking clinical outcomes and as endpoints for clinical and epidemiologic studies, such criteria are expected to fulfill several requirements:

  • 1.

    They should capture the severity of lung damage. This is particularly important because the lung dysfunction associated with BPD is a continuum from mild to severe disease rather than a categorical presence or absence of disease.

  • 2.

    They must provide meaningful information to clinicians, serve as a reliable outcome to researchers, and, ideally, predict long-term lung function and health.

  • 3.

    They must be based on objective and verifiable data that can be easily obtained from the medical record. This is necessary for standardization purposes for benchmarking clinical outcomes within and between neonatal centers and in epidemiologic or interventional studies.

  • 4.

    They should not be affected by confounding pathologies that can produce respiratory failure or by therapies that may acutely but transiently improve lung function at the time of assessment.

While some of the current diagnostic criteria of BPD fulfill most of these requirements, none fulfills all of them. This is in part because current criteria rely on treatments for the respiratory failure rather than on assessments of lung structure or function. Until now, the diagnostic criteria have been primarily based on the need for supplemental oxygen as the marker of respiratory failure with the duration of supplemental oxygen and the fraction of inspired oxygen (F io 2 ) needed for adequate arterial oxygen levels used as surrogates of the severity of BPD. There are some important caveats in using oxygen supplementation as the main criterion to diagnose BPD. Although the need for oxygen is a simple variable to assess, oxygen is also linked to the pathogenesis of BPD and is the main therapy used to maintain adequate oxygenation in respiratory failure from any cause.

The indications for supplemental oxygen can vary from center to center because there is no consensus among clinicians on the optimal arterial oxygen level for these infants. In addition, there are interventions, such as steroids, diuretics, and respiratory stimulants, that can change oxygen requirement. The use of different forms of respiratory support can also influence the need for supplemental oxygen and the diagnosis of BPD. Application of positive airway pressure in any form can improve gas exchange and oxygenation, thereby reducing the need for oxygen. For this reason, most diagnostic criteria of BPD must also include the use of positive airway pressure.

Diagnosis Based on Various Supplemental Oxygen Criteria

Continuous Oxygen Use for the First 28 Days

A workshop sponsored by the National Institutes of Health in 1979 proposed the diagnosis of BPD based on a continued use of supplemental oxygen during the first 28 days plus clinical and radiographic findings compatible with chronic lung disease. These criteria are not suitable for today’s preterm infants who develop chronic lung disease because many of them do not receive continuous supplemental oxygen for the first month after birth. Fig. 6.1 illustrates a declining proportion of premature infants who require supplemental oxygen during the first week after birth. As shown in Fig. 6.2 this results in a small proportion of premature infants who require continuous supplemental oxygen during the first 28 days after birth. Nevertheless, many infants who initially need oxygen for only a few days will subsequently have prolonged oxygen dependency and chronic respiratory failure. This is also illustrated in the increasing proportion of infants who require oxygen after the first and second week shown in Fig. 6.1 . These infants present a diagnostic dilemma because they have an early relatively mild but persistent respiratory insufficiency that cannot be directly attributed to their initial RDS but they do have persistent chronic lung changes.

Fig. 6.1

The figure shows the proportion of infants who require supplemental oxygen during the first 16 weeks for each stratum of gestational age (GA). Varying proportions of infants require oxygen supplementation at different time points during the first 4 weeks after birth with increasing proportions at lower gestations. Most infants have an initial decline in the need for supplemental oxygen, but the proportion of infants requiring supplemental oxygen increases after the first week, peaks between weeks 2 and 4, and remains elevated for several weeks. This is more evident among infants of lower GA. Dashed lines show the proportion of infants classified as having bronchopulmonary dysplasia (BPD) based on their need for oxygen at 36 weeks PMA for each 2-week GA stratum.

Data from 1735 infants of 23–30 weeks GA admitted to the neonatal intensive care unit of Holtz Children’s Hospital of the Jackson Health System/University of Miami during the years 2005–2015. The proportion of infants receiving supplemental oxygen is calculated from the infants alive at each postnatal age.

Fig. 6.2

The figure shows the incidence of bronchopulmonary dysplasia (BPD) according to each diagnostic criteria of BPD across different gestational ages. A small proportion of infants require oxygen continuously during the first 28 days. A considerably greater proportion of infants need oxygen at day 28 or longer than 28 days. This is particularly evident in the lower GA groups. Nearly two-thirds of those infants remain oxygen-dependent at 36 weeks postmenstrual age (PMA) and about one-third of them need an oxygen concentration of 30% or higher.

Data from 1735 infants of 23–30 weeks GA admitted to the neonatal intensive care unit of Holtz Children’s Hospital of the Jackson Health System/University of Miami during the years 2005–2015 who were alive at 36 weeks postmenstrual age.

Supplemental Oxygen at Day 28

To simplify the diagnosis of BPD some clinicians and investigators have classified as BPD infants who require supplemental oxygen at day 28. This approach simplifies the diagnosis of BPD by eliminating the need to count days of oxygen supplementation. However, this single time point criterion lacks specificity and has important limitations. Some infants may require supplemental oxygen around day 28 because of a transient deterioration and not because of chronic lung damage. On the other hand, in the smaller infants the 4-week postnatal age assessment time may be too early to be a reliable indicator of chronic lung disease, whereas in the older infants it may be too late (see Fig. 6.1 ).

Oxygen at 36 Weeks Postmenstrual Corrected Age

The use of supplemental oxygen at 36 weeks postmenstrual age (PMA) has become the most frequent criterion to diagnose BPD. This criterion was introduced to define the abnormal respiratory status at near-term corrected age and to better predict poor long-term outcome.

By adjusting for GA oxygen use at 36 weeks requires longer times of supplemental oxygen for the more immature infants. An infant born at 24 weeks of gestation must be receiving oxygen at 12 weeks after birth to meet criteria, whereas one born at 30 weeks is labeled as having BPD if receiving supplemental oxygen at 6 weeks of age. Fig. 6.1 illustrates the relatively longer oxygen supplementation in infants in the lower GA stratum who are still oxygen dependent at 36 weeks PMA. A serious limitation of BPD diagnosed only by the need for oxygen at a specific time point is that it will capture infants without chronic lung disease who may be receiving oxygen only briefly for other reasons.

Cumulative Oxygen Supplementation Combined With Oxygen Requirement at 36 Weeks PMA

The diagnostic classification of BPD based on the cumulative need for oxygen longer than 28 days and at 36 weeks PMA as recommended by the NIH workshop in 2001 addressed the limitations of using oxygen requirement at a single time point or the duration of oxygen dependency as the only indicators of BPD. The recommendations included a cumulative duration of oxygen supplementation of at least 28 days to indicate the chronicity of the lung damage plus the concentration of inspired oxygen at 36 weeks PMA to define the severity of the chronic lung damage at near-term corrected age before discharge. These criteria classify BPD as mild, moderate, and severe based on the F io 2 or the need for positive pressure support at 36 weeks PMA ( Table 6.1 ).

Table 6.1

National Institutes of Health Workshop Definition of Bronchopulmonary Dysplasia

Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Adapted from Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–1729. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Gestational Age <32 Weeks ≥32 Weeks
Time point of assessment 36 Weeks PMA or discharge to home, whichever comes first >28 days but <56 days postnatal age or discharge to home, whichever comes first
Treatment With Oxygen Concentration >21% for At Least 28 Days Plus
Mild BPD Breathing room air at 36 weeks PMA or discharge, whichever comes first Breathing room air by 56 days postnatal age or discharge, whichever comes first
Moderate BPD Need for <30% oxygen at 36 weeks PMA or discharge, whichever comes first Need for <30% oxygen at 56 days postnatal age or discharge, whichever comes first
Severe BPD Need for ≥30% oxygen and/or positive pressure (PPV or NCPAP) at 36 weeks PMA or discharge, whichever comes first Need for ≥30% oxygen and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge, whichever comes first

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Dec 29, 2019 | Posted by in PEDIATRICS | Comments Off on Definitions and Diagnostic Criteria of Bronchopulmonary Dysplasia: Clinical and Research Implications
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