Bronchopulmonary dysplasia with focus on early prediction and treatment: a narrative review

Introduction

Bronchopulmonary dysplasia (BPD) is a pulmonary disease seen in very preterm infants. In extremely premature infants with gestational age (GA) <26 weeks the incidence is 56% and in infants with GA ≥31 weeks the incidence decreases to four percent (1). BPD has a high mortality and morbidity as well as high treatment costs, particularly as the severity of disease increases. It may last for months and sequelae often last for years (2) and remains the most frequent complication of extreme preterm birth (3,4). BPD is multifactorial and not fully understood because several different insults both pre- and postnatal may contribute to the evolution and progression of BPD (5,6). Furthermore, some infants may be at risk because of a genetic predisposition (7). It is now accepted by most researchers that BPD is initiated by intrauterine infection either as chorioamnionitis (4,8-11) or as a silent infection where the microorganisms invade the fetal lungs (10). The same infection may initiate premature rupture of the membranes and preterm labour (4,9,10) associated with the birth of a premature infant. The low-virulence microorganisms have often been identified as mycoplasma or Ureaplasma species (12-14) causing active inflammation for weeks or months postnatally. BPD is often considered as an inflammatory disease and in addition to the initial inflammatory response, it is likely that an aberrant long lasting repair response is present in many cases (4). It is this persistent inflammation that results in abnormal development of the preterm lungs resulting in BPD.

There are no curative treatments neither in the early or late phases of BPD and further research about the epidemiology, pathobiology and pathophysiology is needed to improve the outcome through trials with early treatments. This review focuses on symptomatic treatment in the early phase of the disease which may improve outcome and, on the potential to predict the disease early with the possibility of interventions to ameliorate the course of BPD.

The article is divided in the following segments: “Introduction”, “Methods”, “Background”, “Clinical treatment in the early phases of BPD”, “Early prediction of BPD”, “Potential early therapies and prevention in at-risk babies” and “Conclusions”. Treatment of the fully developed BPD syndrome beyond day 28 and later will not be considered in this review. We present this article in according with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-21-98/rc).

Methods

The search strategy summary is described in Table 1.

The literature about prediction of BPD and early treatment of BPD were searched online via the databases PubMed and Medline. Because very early prevention of BPD in at-risk babies has not been possible before the literature were then hand searched in pediatric and pharmacologic journals to evaluate and describe the potential for very early treatment and prevention of BPD.

Background

The term “bronchopulmonary dysplasia” was used for first time in 1967 by Northway (15). He used the term for the chronic lung injury seen in infants after aggressive mechanical ventilation. This old type of BPD is seldom seen today. So called ‘new BPD’ seen nowadays is normally preceded by increased alveolar-capillary permeability in the first 1–2 weeks after birth (16) with increasing need of oxygen and lung edema as early clinical findings within 10 days after birth. Radiographically, hazy ground-glass opacity within 12–24 hours (17) is suggestive of a preceding intrauterine infection as the triggering event of BPD. New BPD is also characterized by pulmonary vasculature hypoplasia and alveolar hypoplasia in very preterm infants (5). Cystic emphysema called Wilson-Mikity syndrome (18) was previously seen often. Today this condition has largely disappeared probably due to gentler ventilation. In Japan the Wilson-Mikity syndrome is still seen in about 13–14% of babies with BPD (19) and the condition in these patients seem to be linked to high leucocyte elastase and low α1-antitrypsin (20).

Definition of BPD

The Consensus verified BPD definition from the US National Institutes of Health (NIH) (21) is currently the most used. According to this definition, moderate BPD is diagnosed in infants born <32 weeks gestation needing supplemental oxygen for 28 days and at 36 weeks postmenstrual age (PMA) or at discharge. However, the definition of BPD is still a topic of debate. A concise and clearly defined consensus BPD definition, outlining risk severity, is in all cases beneficial for both clinical purposes and for research and with such a definition, methods to accurately predict BPD severity may help individualize early treatment therapies.

Clinical treatment in the early phases of BPD

Many of the current clinical treatments of BPD such as early nasal continuous positive airway pressure (NCPAP), surfactant, caffeine and optimal nutrition are necessary early therapies together with new early therapies in at-risk babies.

NCPAP and surfactant to avoid barotrauma and oxytrauma

Treatment with NCPAP early after birth vs. invasive mechanical ventilation (IMV) has a positive effect on respiratory distress syndrome (RDS) (22,23) and because of this also on BPD (24). The combined use of NCPAP and early, rescue surfactant with less invasive surfactant administration (LISA) technique (25,26) and the INSURE (INtubate SURfactant Extubation) method (27,28) are ideal in this context (29,30). However, only 80–85% of the infants with BPD had a diagnosis of RDS (31) reflecting that BPD is not a continuum of RDS but representing a different entity (31,32). Therefore, these treatments are not the only ideal early treatments for BPD prevention. It is also important to know that prophylactic surfactant treatment at birth of tiny infants increases the combined outcome of BPD and mortality (33), possibly due to unnecessary ventilation of some very premature infants with relatively more mature lungs. Targeted surfactant for infants with RDS is a better approach. Recently it has been possible to measure lung surfactant in gastric aspirate at birth (34,35) and clinical trials with targeted surfactant treatment based on surfactant measurements at birth compared to the standard surfactant treatment of RDS in Europe (36) are underway in Denmark. In this trial data on BPD will also be monitored.

When mechanical ventilation is needed

If necessary, nasal intermittent positive pressure ventilation (NIPPV) can often be used with success prior to IMV (37). If mechanical ventilation is required, volume targeted ventilation has been shown to decrease the combined outcome of death or BPD compared to pressure-limited ventilation (38).

Caffeine

Caffeine is recommended prophylactically in very preterm infants (36) and has been shown to reduce the risk of BPD (39) by decreasing the duration of IMV. Caffeine is a competitive adenosine receptor antagonist that stimulates the respiratory center in medulla indirectly by reducing the inhibitory effect of adenosine, and in this way decreases the frequency of apnea and the need for mechanical ventilation. In addition, caffeine increases the likelihood of successful extubation reducing the duration of mechanical ventilation.

Corticosteroids

Antenatal corticosteroid has been shown to decrease the incidence of RDS, but it has not been shown to reduce the incidence of BPD (40).

Early (<8 days of age) systemic corticosteroid treatment reduces the incidence of BPD but has more adverse effects such as hypertension, gastrointestinal bleeding and cerebral palsy (41). A systematic review and network meta-analysis evaluating fourteen different corticosteroid regimens to prevent BPD found that moderately early (8–14 days), medium cumulative dose (2–4 mg/kg), short course (<8 days), systemic dexamethasone might be the most appropriate regimen for BPD prevention and or early treatment of exudative or evolving BPD (42).

Nitric oxide (NO)

NO is produced in the nose and the concentration is around 4 parts per billion (ppb) in newborns. It influences the vascular tone in the lungs and has anti-inflammatory effects. In intubated infants auto-inhalation of endogenously produced NO is lost. In a few cases inhaled NO (iNO) has led to a reduction in death and BPD (43) and one study (44) of infants less than 34 weeks gestation who were mechanically ventilated found reduced BPD in the subgroup of infants with birth weight 1,000–1,250 g. Also, postnatal iNO in a fetal baboon model of BPD has reduced the incidence of BPD (45). However, the observed effects in randomized trials in humans have been inconsistent (46) and at present there is insufficient evidence to support the routine use of iNO in preterm babies either for prevention or treatment of BPD (47).

Oxygen saturation targeting

Though oxidant injury markers in tracheal aspirates have been linked to increased risk of BPD (48). Askie et al. in a meta-analysis (49) found no important differences in the composite outcome of death and BPD between low saturations (85–89%) vs. high saturations (91–95%). But there was a significant difference in the rates of moderate BPD (supplemental oxygen at 36 weeks PMA) favoring lower oxygen saturations (49).

Infections

Intrauterine colonization of the lungs with Ureaplasma urealyticum has been associated with increased incidence of BPD (14). Erythromycin in ventilated infants has not prevented development of BPD (50). However, other macrolides, such as azithromycin (51) and clarithromycin (52) treatment have been associated with a lower incidence of BPD. Further larger prospective studies are needed to evaluate the effect on BPD from treatment of Ureaplasma infections before this can be recommended as routine treatment.

Infections with coagulase negative staphylococci (53) and cytomegalovirus (54) have also been associated with development of BPD, but studies on prophylactic treatment and risk/ benefit analysis have not, to our knowledge been undertaken.

Optimal nutrition from birth

Decreased caloric intake and especially low protein intake decreased alveolar numbers significantly in premature rabbits (55). In preterm infants, BPD is associated with lower caloric intake and fat during the first month of life (56). Therefore, early nutritional optimization through total parenteral nutrition in addition to early enteral feeding are important in the very tiny babies to diminish BPD. Exclusive human milk-based nutrition has been shown to impact lung microbiome and decrease BPD risk. However, probiotic supplementation does not seem to affect the risk of BPD (57).

Early prediction of BPD

The literature about BPD prediction is extensive. Early prediction and intervention of BPD ideally may allow to stop or slow the progression of the disease before development of permanent sequelae.

Many authors have reported data on various biomarkers to predict BPD as early as possible before day 28. A biomarker is defined as “a characteristic that is, measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. Biomarkers are any clinical features, radiological findings, or laboratory-based tests, that characterize disease severity, or useful to monitor disease processes and response to therapy (48). Biomarkers for prediction of BPD include genomics, microbiomics, proteomics and metabolomics (48). Several predictive risk scores for BPD have been developed based on various biomarkers, diseases and symptoms using different techniques including ‘big data’ based on artificial intelligence (AI) (31). El Faleh et al. (58) from the Swiss neonatal network primarily looked at different clinical parameters and biomarkers in 1,488 liveborn preterm infants. Using logistic regression, the authors selected the following seven variables for their predictive risk score: Antenatal steroids, median GA, median birth weight, surfactant therapy, mechanical ventilation in median days, proven infections, and patent ductus arteriosus (PDA). They evaluated their results by area under the receiver operating characteristic curves (AUCs) and found an AUC value of 0.90 for BPD day 28. Zhang et al. (59) studied 435 preterm infants from a single Chinese center. Fourteen variables that may predict BPD were analysed with Lasso regression (60) and the three most potentially useful predictors, GA, duration of mechanical ventilation, and the serum concentration of the N-terminal-pro-brain natriuretic peptide (NT-proBNP) in the first week of life were screened for the training set. The data were used to develop a nomogram to assess the risk of BPD at day 7 of life and found an AUC value of 0.85. Ding et al. (61) also from a single Chinese center studied 44 preterm infants and developed a risk score including clinical data, caloric intake and biochemical data and evaluated the score on day 40. Gursoy et al. (62) studied 652 preterm infants from a single Turkish center. They included several clinical data points including GA, birth weight, RDS, intraventricular haemorrhage, hypotension and PDA and were able to predict BPD by 72 hours after birth. Clinical complications are likely related to RDS and to the severity of RDS at this early time after birth. Concerning the scoring systems in these four studies it is obvious that the variables, namely, surfactant therapy, mechanical ventilation, infections, and PDA are not available until many days after birth and therefore are not ideal predictors. Other diagnostic tests for BPD have focused on markers linked to infections like sphingolipid metabolites (63), ceramides in tracheal aspirates (64), and changes in plasma proteome concentrations related to infections and to BPD (65). However, these metabolites need to be measured in special labs and are therefore less useful as clinical diagnostic tests. Also, neutrophil-to-lymphocyte ratio in cord blood (sensitivity 52%) and in blood at 72 hours after birth (sensitivity 61%) has been described as predictors of BPD (66). These data showed that the ratio is more reliable for neonatal infections than for prenatal infections. Larger reviews for known biomarkers of BPD are available including Cerny et al. (67) and Rivera et al. (68).

Prediction at birth

Recently it has been possible to predict BPD at birth (31) using Fourier transform mid-infrared spectroscopy (FTIR) (69) as dry transmission on gastric aspirate combined with clinical data and analysed by AI. This technology which is very rapid (results are obtained within 10–15 minutes) is reagent free and low cost. It has been pervasive in the process industry and thus well suited for deployment in acute point of care settings where speed is critical. The FTIR spectroscopy is pro tempo the only method which can produce predictive results from analyses of many molecules immediately after birth. Other methods such as mass spectroscopy are lab methods, and the results are earliest available in days (in best cases many hours) after birth. Gastric aspirate in the newborn is a fluid produced mainly in the fetal lungs (70) with contributions from the fetal kidneys and cells of the amniotic sac and therefore may include biomarkers linked to infection in cases with chorioamnionitis and correlated with intrauterine pneumonia. The sensitivity was 88% and the specificity 91% of the BPD model in a clinical study of preterm infants. An example of a FTIR spectrum of gastric aspirate from an infant born in gestational week 31 is shown in Figure 1. The clinical predictors on the day of birth were surfactant treatment, birth weight, GA, Apgar score at 5 minutes, type of delivery, need of mechanical ventilation, antenatal steroid, maternal diabetes, pre-eclampsia, intrauterine growth retardation, clinical chorioamnionitis verified by rupture of the membranes, fever, and whether there was pus in the amniotic fluid. By using Lasso regression (31,60) need for surfactant treatment was found to be the most important variable linked to BPD followed by birth weight and GA. The other clinical data did not improve the model and were not useful as predictors. The FTIR measurements of gastric aspirates were performed on a concentrate of lamellar bodies as previously described for prediction of lung maturity and RDS at birth (34). We propose that the lamellar body concentration in addition to biomarkers for lung maturity may also contain biomarkers produced in connection with feto-placental infections and other intrauterine conditions. As mentioned, the FTIR method is very fast, and the method may also be used to measure lung maturity bed-side at birth (34).

Figure 1 Fourier transform mid-infrared spectrum of a gastric aspirate developed in the lungs from an infant born in week 31. The figure is from Verder et al. (31). The fingerprint region is the most informative region in the spectrum for analysis of biological material. Each peak denotes a composition of chemical bonds. The spectrum can be further differentiated to obtain underlying signals. To diagnose BPD, calculations as described in the manuscript are needed. Dipalmitoyl-phosphatidylcholine the most surface-active part of surfactant is expressed in the peak at 1,740 cm⁻¹ together with other phospholipids and therefore, the infant may have mature lungs. BPD, bronchopulmonary dysplasia.

Potential early therapies and prevention in at-risk babies

More authors have published reviews of current and prospective pharmacologic therapies of BPD (5,6,67,71,72). With new methods to predict development of BPD at birth (31) the prospect of creating and testing new and more effective treatments within 24–48 hours after birth may result in prevention or less severe BPD.

Surfactant with added budesonide

Two studies have recently suggested beneficial effects of adding inhaled budesonide to surfactant for BPD prevention (73,74), and further studies are underway to confirm these findings. Focusing on selected populations at higher risk of BPD would make such studies more meaningful. Very early treatment with systemic corticosteroids has more adverse effects (41).

Surfactant with other additives

New synthetic surfactants with surfactant protein (SP) analogues of SP-B and SP-C have been shown to be clinically effective in RDS treatment. SP-D is a naturally occurring protein of the surfactant system with anti-inflammatory properties (75). Recombinant SP-D is now available and will soon be evaluated for safety in phase 1 clinical trials in preterm infants at high risk of developing BPD.

Inositol

Inositol is an important component of surfactant and trials in the 1980’s and 1990’s suggested that inositol supplementation could potentially have a role in BPD prevention (76). Recently this therapy re-emerged as a potential means of disease modification in BPD and phase-II trials have confirmed the safety and tolerability of inositol in preparation for planned efficacy studies (77).

Retinol (vitamin A), tocopherol (vitamin E), and superoxide dismutase (SOD)

Antioxidants such as retinol and tocopherol and SOD have been administered to babies in an attempt to reduce oxygen free radical induced lung damage. Of these, retinol has shown the most promise with a modest reduction in BPD found in babies treated with retinol compared with controls (78). This may be because retinol has a role in promoting alveolar septation which is reduced in “new BPD”. In animal studies topical SOD was effective at reducing lung injury, but human studies were disappointing, perhaps because of low BPD rates in the populations studied (79).

Recombinant human Clara cell 10 protein (rhCC10)

Clara cell protein developed in the respiratory epithelium was found in low concentrations in premature infants and results in reduced inflammation (80) but has not proven successful in reducing the incidence of BPD (81).

Azithromycin and macrolide therapy

Macrolide therapy has previously been used as a potential strategy for infants at risk of BPD with Ureaplasma colonisation. Azithromycin has anti-inflammatory properties in addition to antimicrobial effects and is currently being tested in a large double blind placebo controlled trial in preterm babies as a means to prevent BPD (82).

Estradiol and progesterone

Estrogen and progesterone are important in lung development and alveolar formation (83) but no significant differences between treatment groups could be identified in a randomised trial (84).

Stem cell therapy

Mesenchymal stem cell (MSC) dysfunction is thought to prevent the self-repair of immature lungs and dysfunction of MSCs increases the risk of BPD (85). Many clinical trials with MSC are currently ongoing. Very important before clinical use will be to perform safety trials and trials to determine optimal timing.

Pulmonary vasodilators, diuretics and bronchodilators

These treatments are late treatments and will not be discussed in this review.

Conclusions

BPD continues to have a high mortality and morbidity but improved understanding of the pathogenesis and the new possibility of predicting the disease at birth increases the possibility of improving the prognosis by investigation of early targeted treatment with different pharmaceuticals.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-21-98/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-21-98/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-21-98/coif). The study was part of a public-private partnership between the department of Pediatrics, Holbaek Hospital, Region Zealand, Denmark and SIME Diagnostics Ltd. (trading as SIME clinical AI), a private company focused on developing preventative, data-driven medicine in neonatology. HV holds part of a patent for spectroscopic analysis of biological samples. PS, NS, PV and HV hold part of a patent for prediction of bronchopulmonary dysplasia and are option holders of SIME Diagnostics Ltd. PV is CEO of SIME Diagnostics Ltd. HC is a director of Trimonocor Ltd., which is a company developing novel surfactant protein therapy. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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