Pulmonary hypertension in the premature infant population: Analysis of echocardiographic findings and biomarkers

O'Connor, M.G.; Suthar, Divya; Vera, Kimberly; Slaughter, James C.; Maitre, Nathalie L.; Steele, Steven; Beller, Amy B.; Fike, Candice D.; Aschner, Judy L.; Moore, Paul; Austin, Eric D.

doi:10.1002/ppul.23913

Cited by 17 publications

(7 citation statements)

References 31 publications

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“…There are a multitude of candidate biomarkers that have been identified through pre‐clinical and clinical studies as directly involved in the pathophysiology of PH by disrupting pulmonary endothelium, including nitric oxide, prostaglandins and endothelins, while some biomarker candidates target inflammation and/or cardiac function . Nitric oxide (NO) metabolites in urine at day of life 3 and decreased citrulline at day of life 7, both have been reported as significant predictors of PH severity at 36 weeks corrected gestational age . Also, in a small cohort of extremely low birth weight infants with BPD‐PH, B‐type natriuretic peptide (BNP) levels were lower in infants that survived, demonstrating potential as a biomarker for mortality in this patient population .…”

Section: Discussionmentioning

confidence: 99%

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

et al. 2018

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Aim: Pulmonary hypertension significantly increases morbidity and mortality in infants with bronchopulmonary dysplasia. The frequency of single nucleotide polymorphisms in arginase-1 (ARG1 rs2781666) and dimethylarginine dimethylaminohydrolase-1 (DDAH1 rs480414) genes have been found to differ in a cohort of bronchopulmonary dysplasia patients with pulmonary hypertension (cases) and without pulmonary hypertension (controls). Therefore, we tested the hypothesis that combining these genotypes with phenotypic data would better predict pulmonary hypertension in bronchopulmonary dysplasia patients. Methods: Bronchopulmonary dysplasia patients (n=79) born at <35 weeks gestation were studied. Pulmonary hypertension was diagnosed by echocardiographic criteria (n=20). ROC curves to predict pulmonary hypertension in bronchopulmonary dysplasia were generated from genotype and/or clinical data. Results: Cases were born at an earlier gestation and weighed less at birth than did controls. ROC curves for rs2781666 had an AUC of 0.61, while rs480414 had an AUC of 0.66. Together, the AUC was 0.70. When clinical data was added to the genetic model, AUC was 0.73. Conclusion: These findings demonstrate that ROC predictive modeling of pulmonary hypertension in bronchopulmonary dysplasia improves with inclusion of both genotypic and phenotypic data. Further refinement of these types of models could facilitate the implementation of precision medicine approaches to pulmonary hypertension in bronchopulmonary dysplasia.

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Section: Discussionmentioning

confidence: 99%

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

et al. 2018

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“…Various biomarkers have been studied in association with BPD but have yet to be validated as predictors of important long-term outcomes (see TABLE 2 for a non-exhaustive list of BPD biomarkers). Ideal biomarkers for BPD will target causal pathways that have been implicated in BPD pathogenesis 120,121 , such as biomarkers of endothelial injury and dysfunction 124,125 ; growth factors and biomarkers of altered angiogenesis 6,[126][127][128][129][130][131] ; biomarkers of epithelial injury and fibrosis [132][133][134][135] ; biomarkers of nitric oxide deficiency or insufficiency 120,[136][137][138][139][140] ; biomarkers of oxidative stress, oxidant and antioxidant capacity, and redox status [141][142][143] ; oxyradical biomarkers [141][142][143][144] ; biomarkers of inflammation and host immune responses 129,145,146 ; genomic, epigenomic, metabolomic 147 , microbiomic 148 , methylomic and transcriptomic biomarkers 119,149 ; lung function measures 119,150 ; MRI of the lungs for measurement of perfusion, blood flow, ventilation, gas exchange, mechanics and early changes in alveolar structure 119 ; and biochemical 151 and physiological biomarkers of vascular injury and pulmonary hypertension 80,82,123,140,…”

Section: Screening and Preventionmentioning

confidence: 99%

Bronchopulmonary dysplasia

Thébaud

Goss

Laughon

et al. 2019

Nat Rev Dis Primers

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The strongest risk factors for BPD are prematurity and low birth weight 19-25. Almost 80% of infants who are born at 22-24 weeks of gestation are diagnosed with BPD 26 , whereas only 20% of infants born at 28 weeks of gestation develop BPD. Among infants with BPD, 95% are VLBW 27. Other perinatal risk factors include intrauterine growth restriction (IUGR) 13 , male sex 13,20,23 and, inconsistently, chorioamnionitis 28 , race or ethnicity 13,20,23 , and smoking 29,30. Genetic risk factors may also contribute to the development of BPD, as indicated by twin studies 31,32 , and there is an ongoing search for genetic markers for BPD 33-37. Early respiratory patterns of premature infants provide insight into risk factors for BPD. An early study suggested that peak inspiratory ventilator pressure and requirement for assisted ventilation on day 4 of life are early predictors of BPD 38. Subsequent studies found that three patterns of lung disease generally emerge in the first 2 weeks of life 39-45 (FIG. 2). In the first pattern, infants have fairly minimal lung disease and progressively recover. In the second pattern, early persistent pulmonary deterioration (EPPD), substantial and prolonged respiratory support is required from birth. In the third pattern, an initial improvement in lung disease in the first week of life is followed by a respiratory decompensation termed pulmonary deterioration, which often requires mechanical ventilation and an increase in supplemental oxygen. Risk factors that may be associated with pulmonary deterioration include late surfactant deficiency 46 , sepsis, increased levels of inflammatory proteins (such as RANTES) 47 and patent ductus arteriosus 40,43. Almost 50% of infants with pulmonary deterioration and almost 70% of infants with EPPD develop BPD 48. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network developed an online, publicly available risk estimator (https:// neonatal.rti.org/index.cfm) that accurately estimates the risk of developing BPD by postnatal day 49. Investigators identified risk factors for BPD, and the competing outcome of death, among gestational age, birth weight, ethnicity and sex, ventilatory support (ranging from no support (breathing room air without positive airway pressure) to high frequency ventilation) and fraction of inspired oxygen (FiO 2), on postnatal days 1, 3, 7, 14, 21 and 28 in 3,636 infants born at 23-30 weeks of gestation. The BPD prediction tool is internally and externally validated. The models predict the correct level of BPD or the occurrence of death in >80% of cases and have the highest area under the curve (AUC) among current BPD risk predictors 50. This tool is used to provide counselling to families and to quantify risk for determining patient inclusion in early phase therapeutic trials. Interestingly, systemic inflammation occurs early in the neonatal period and precedes clinical symptoms in infants with BPD 51. This finding suggests that a therapeutic window of opportunity exists during the early p...

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“…PH is widely recognized as a serious complication of BPD and may present—at least according to echocardiographic criteria—early in the course of intensive care. In order to explore the mechanisms that may underlie this late complication, O'Connor et al correlated urine nitric oxide (NOX) metabolites and plasma citrulline concentrations in patients born very preterm with the later development of PH in a subset, diagnosed by echocardiography obtained at 36 weeks for clinical indications . NOX metabolites were elevated in PH‐diagnosed subjects, but it is not clear whether this increase was due to higher NO production or increased NO oxidation.…”

Section: Pulmonary Vasculaturementioning

confidence: 99%

2018 year in review: Part 2 of 4: Neonatal lung disease

Auten

2019

Pediatric Pulmonology

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Pulmonary hypertension in the premature infant population: Analysis of echocardiographic findings and biomarkers

Abstract: Respiratory morbidity may not always associate with PH at 36 weeks among ELGANs. However, components of nitric oxide metabolism are potential biologic markers of PH in need of further study.

Cited by 17 publications

References 31 publications

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

Bronchopulmonary dysplasia

2018 year in review: Part 2 of 4: Neonatal lung disease

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