Highlights
- Infants developing moderate-to-severe bronchopulmonary dysplasia (msBPD) demonstrate poorer lung aeration and impaired oxygenation/CO2 exchange starting as early as day 10 of life.
- The pathophysiological gap between infants with and without msBPD widens over time, reaching a peak discriminatory power at 26 days of postnatal age.
- Findings remained consistent across three major BPD definitions (NIH-2001, NICHD-2018, and Jensen), suggesting a universal pathophysiological phenotype for the disease.
- Quantitative lung ultrasound (LUS) scores and transcutaneous gas monitoring provide a bedside physiological map that precedes the clinical diagnosis of BPD.
Background: The Challenge of Defining Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) remains the most common morbidity associated with extreme prematurity, affecting the long-term respiratory and neurodevelopmental outcomes of survivors. Despite decades of research, the clinical community continues to grapple with the lack of a gold-standard definition. Traditional definitions, such as the NIH-2001 consensus, the NICHD-2018 revision, and the more recent Jensen criteria, largely rely on the assessment of respiratory support and oxygen requirements at 36 weeks post-menstrual age (PMA). While these definitions are useful for prognosticating long-term outcomes, they are inherently retrospective. They describe the final state of the disease rather than the dynamic pathophysiological process leading to it.
Current clinical management is often reactive, initiated only when an infant fails to meet weaning milestones. There is a critical unmet need for objective, bedside biomarkers that can identify infants at high risk for moderate-to-severe BPD (msBPD) during the early stages of lung injury. Understanding the early evolution of lung aeration and gas exchange is essential for developing personalized, preventative strategies and identifying the optimal window for therapeutic intervention.
Study Design and Methodology
The PATH-BPD cohort study was a prospective, multicentre investigation conducted across three European neonatal intensive care units (NICUs). The study enrolled 347 preterm infants born at or before 30 weeks of gestation. The primary objective was to describe the longitudinal changes in lung physiology and identify the critical time points where the trajectories of infants who develop msBPD diverge from those who do not.
Evaluation Timepoints and Tools
Infants were systematically evaluated at five specific time points: 10, 21, and 28 days (D) of life, and at 34 and 36 weeks (W) post-menstrual age. To minimize confounding factors, researchers ensured infants received the least invasive ventilation possible during assessments. The study utilized three primary physiological markers:
- Quantitative Lung Ultrasound (LUS): A bedside, non-ionizing imaging technique used to assess lung aeration. Higher LUS scores indicate lower aeration, reflecting interstitial edema, atelectasis, or structural lung remodeling.
- SpO2/FiO2 Ratio: A non-invasive surrogate for the PaO2/FiO2 ratio, measuring oxygenation efficiency.
- PtcO2/FiO2 and Carbon Dioxide Levels: Transcutaneous blood gas measurements were used to calculate gas exchange efficiency and monitor hypercapnia.
BPD Definitions Compared
To ensure the findings were robust and not dependent on a specific diagnostic framework, msBPD was defined using three distinct criteria: the NIH-2001 consensus (based on oxygen use at 36 weeks), the NICHD-2018 revision (incorporating levels of respiratory support), and the Jensen criteria (focused primarily on the type of respiratory support at 36 weeks PMA).
Key Findings: A Consistent Phenotype of Lung Injury
Of the 347 infants studied, approximately 23-25% developed msBPD, depending on the definition applied (80 infants via NIH-2001, 79 via NICHD-2018, and 89 via Jensen). The results revealed a striking consistency in the physiological progression of the disease.
Early Divergence in Lung Aeration
The study found that lung aeration was significantly poorer in the msBPD group compared to the non-BPD group from the very first assessment at day 10. The LUS scores were consistently higher in infants who would later be diagnosed with msBPD. This difference was not static; the gap in aeration between the two groups increased progressively over the first month of life. Statistical analysis showed a β coefficient ranging from +0.009 to +0.012 (p < 0.001), indicating a steady worsening of lung aeration in the msBPD cohort relative to their peers.
Impaired Gas Exchange and Hypercapnia
Oxygenation and carbon dioxide exchange followed a similar downward trajectory. Infants developing msBPD exhibited lower SpO2/FiO2 ratios and higher transcutaneous CO2 levels starting at day 10. The impairment in CO2 clearance was particularly noteworthy, with β values ranging from +0.01 to +0.014 (p < 0.001). This suggests that the underlying pathology of msBPD involves not only a loss of alveolar surface area for oxygenation but also a significant increase in dead space or ventilation-perfusion mismatch that hinders CO2 elimination.
The Critical Window: Day 26 of Life
One of the most significant findings of the PATH-BPD study was the identification of the peak discriminatory moment. Using a longitudinal model, researchers determined that the maximum difference in lung aeration evolution between msBPD and non-BPD infants occurred at 26 days of life (β(t) = 0.227, 95% CI: 0.152, 0.302, p < 0.001). This suggests that the fourth week of life represents a physiological "tipping point" where the lung injury phenotype becomes most distinct, potentially offering the best window for starting targeted therapies like postnatal corticosteroids.
Expert Commentary and Clinical Implications
The findings from the PATH-BPD cohort provide a powerful argument for the integration of physiological monitoring into routine neonatal care. Historically, BPD has been treated as a “black box” until the 36-week mark. This study illuminates the path, showing that the disease has a clear, measurable signature long before the clinical diagnosis is formalized.
The Utility of Quantitative Lung Ultrasound
Lung ultrasound has emerged as a superior tool compared to traditional chest X-rays in the NICU. It is more sensitive to subtle changes in aeration and avoids ionizing radiation. The fact that LUS scores at day 10 can differentiate future msBPD cases suggests that ultrasound could be used to risk-stratify infants for enrollment in clinical trials or for the early implementation of lung-protective strategies.
Universal Pathophysiology Across Definitions
A major strength of this study is the consistency of results across the three BPD definitions. While clinicians and researchers often debate which definition is “best,” these data suggest that they are all capturing the same underlying biological process. Whether one uses the Jensen criteria or the NIH-2001 definition, the physiological impairment in aeration and gas exchange remains the core driver of the clinical state.
Study Strengths and Limitations
The multicentre, prospective design of the study enhances the generalizability of the results. However, it is important to note that while the study identifies a peak divergence at 26 days, the trajectory begins much earlier. Future research should investigate whether interventions initiated even earlier—prior to day 10—could flatten this trajectory. Additionally, while LUS is highly effective, it requires specialized training to ensure inter-operator consistency across different clinical settings.
Conclusion: Moving Beyond Retrospective Diagnosis
The PATH-BPD study demonstrates that moderate-to-severe BPD is a progressive physiological failure that begins in the first days of life. By day 10, the “die is cast” for many infants, and by day 26, the pathophysiological phenotype is fully established. These findings challenge the current reliance on 36-week PMA definitions for clinical decision-making. By utilizing bedside tools like lung ultrasound and transcutaneous gas monitoring, neonatologists can move toward a more proactive, precision-medicine approach, intervening during the critical windows where lung development can still be redirected toward a healthier path.
Funding and References
This study was supported by institutional funding provided to the authors for their research time. No external commercial funding was used.
Reference:
De Luca D, Bonadies L, Neri C, Loi B, Silva-Garcia TM, Noguera GR, Vivalda L, Res G, Cidoncha-Fuertes MLN, Baena-Palomino C, Zanetto L, Vedovelli L, Gregori D, Baraldi E, Alonso-Ojembarrena A. Lung aeration and gas exchange in preterm infants developing moderate-to-severe bronchopulmonary dysplasia: a multicentre prospective study from the PATH-BPD cohort. Lancet Reg Health Eur. 2026 Jan 10;63:101584. doi: 10.1016/j.lanepe.2025.101584. PMID: 41567169; PMCID: PMC12818268.