Inflammation and adrenocortical development as potential biomarkers for bronchopulmonary dysplasia
Authors:   , Romijn Michelle 
Published: June 2024

Bronchopulmonary dysplasia is the most common complication of preterm birth. It is a chronic lung disease with long-term consequences on both pulmonary and neurocognitive development, and affects approximately 30% of the infants born extremely preterm. Although its pathophysiology is multifactorial, inflammation seems to play a key role. At the same time, the adrenal cortex of preterm infants fails to mount an appropriate cortisol (i.e., the most important anti-inflammatory hormone) response to stress or illness. This thesis is centered around the hypothesis that the development of BPD is caused by an imbalance between inflammation and anti-inflammation. The aim was to investigate whether the prediction of BPD development in preterm infants could be improved by quantifying this imbalance. We first performed a systematic review and meta-analysis including, appraising and summarizing all previously developed and/or externally validated multivariable prediction models for BPD development in the first two weeks of life. We assessed the risk of bias and accuracy following the PROBAST guideline in the 158 identified development and 108 externally validated studies. The discriminative performances were satisfactory, but all studies had a high risk of bias or applicability concerns. Therefore, the results of all these prediction models should be interpreted with caution. Due to shortcomings, clinicians are reluctant to implement these multivariable BPD prediction models in clinical practice. The development of an accurate BPD prediction model is of utmost importance, since the balance between benefits and harms of dexamethasone treatment is strongly associated with the baseline risk to develop BPD. Next, we investigated the effects of inflammation associated with BPD development. We showed that the need for, and duration of mechanical ventilation during a late onset sepsis were the only risk factors independently associated with BPD. Furthermore, we showed that volatile organic compounds (VOCs) measured in exhaled breath samples improve the prediction of BPD in the first week of life in preterm infants receiving non-invasive respiratory support, in addition to clinical predictors. Next, we investigated the adrenocortical development in preterm infants, and its association with BPD development. We showed that higher levels of cortisol precursors and cortisone, relative to cortisol, were measured in the first week of life in infants with developing BPD compared to infants without developing BPD. The glucocorticoid hormone levels were measured by an LC-MS/MS steroid based analysis. We showed that LC-MS/MS analysis should be the preferred method to measure glucocorticoid hormone levels in this specific population, since immunoassays are prone to cross-reactivity resulting in severely overestimated hormone levels. At last we showed that addition of these glucocorticoid hormone levels to a BPD prediction models including clinical predictors and VOCs in exhaled breath might have the potential to further improve the prediction of BPD development and thereby the identification of preterm infants at high risk for developing BPD.