Pharmacometabolomics of Respiratory Phenotypic Response to Dexamethasone in Preterm Infants at Risk for Bronchopulmonary Dysplasia

Abstract

A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate‐aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post‐treatment (P value < 0.05). In regression analyses, 6 serum and 28 urine metabolites were significantly associated with change in RSS. Urine gluconic acid lactone was the most significantly correlated with clinical response (correlational coefficient 0.915). Pharmacometabolomic discovery of drug response biomarkers in preterm infants may allow precision therapeutics in BPD treatment.

Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant

“…There is one previous report addressing untargeted pharmacometabolomics effects of corticosteroid treatment of premature infants. 7 Serum samples were collected before and after systemic dexamethasone given to ten infants for respiratory failure. Of the 17 identified metabolites where levels changed with treatment, 13 were also detected in our study.…”

“…One approach is metabolomics, and currently there is limited information on metabolic responses to glucocorticoids in infants. 7 …”

Phenotypes of Bronchopulmonary Dysplasia

“…Pharmacometabolomics may be a helpful tool to identify patients who might benefit from specific drug therapy [ 18 ]. Lewis et al [ 19 ] performed the first pharmacometabolomic study in systemic-dexamethasone-treated BPD infants. They found that 11 metabolites in the blood and 15 in the urine differed significantly before and after steroid treatment.…”

“…Another pilot study by Fattuoni et al [ 177 ] also revealed that the only metabolite significantly upregulated in the cord blood of neonates born to mothers with chorioamnionitis was gluconic acid. Besides urine gluconic acid, the levels of uridine and mannitol also have a negative correlation with the degree of steroid response [ 19 ]. Conclusively, the changes in serum and urine metabolites indicate that dexamethasone therapy does have effects on the major metabolic pathways involved in the inflammatory cascade and oxidative stress [ 19 ].…”

“…However, there are debates about the right kind of steroid, and the right dosage with the right route at the right timing to get the most effective result and simultaneously attenuate the negative impact. Using steroids in preterm infants is challenging because of the variability in clinical effects and the inability to target the possible responders prior to the treatment [ 19 ]. Pharmacometabolomics may provide a solution to this clinical dilemma.…”