Neonatal and Pediatric Medicine
Open Access

Pediatric pulmonary hypertension (PH) is a potentially life-threatening condition characterized by increased pulmonary arterial pressure. It can affect children of any age and stems from a wide range of causes, including idiopathic and hereditary factors as well as underlying pulmonary, cardiac, and systemic disorders. In contrast to adults, where left-sided heart disease and chronic lung conditions are predominant causes, pediatric PH is often associated with developmental lung diseases and various forms of pulmonary arterial hypertension (PAH) [1]. The relative rarity and complexity of pediatric PH limit large-scale studies, leading to a reliance on adult data and expert consensus for treatment strategies. This article reviews the latest understanding of pediatric PH causes and classifications, current therapies, and future research directions.

Genetic Factors

Pediatric-onset PH can arise from genetic mutations leading to primary pulmonary vascular disease or occur as part of broader genetic syndromes. Similar to adult PH, mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are frequently identified in pediatric PAH. However, pediatric cohorts also show higher frequencies of mutations in the T-box 4-containing protein (TBX4) and SRY-related HMG box transcription factor 17 (SOX17) genes. TBX4 mutations often present with a constellation of features including newborn PH, lung disease, skeletal abnormalities, and congenital heart defects [2-5]. SOX17 mutations have been linked to PAH associated with congenital heart disease as well as idiopathic and heritable PAH. Genetic studies indicate that 17% to 55% of pediatric PH cases involve identifiable genetic abnormalities, ranging from chromosomal and single-gene disorders to uncertain copy number variants. This genetic complexity often correlates with multisystem involvement, including congenital heart disease and lung disease, which is less common in adult PH.

Prenatal and Perinatal Factors

Prenatal and perinatal factors significantly contribute to the development of PH due to abnormal pulmonary vascular development. Vascular endothelial growth factor (VEGF) plays a crucial role in vascular development, and its abnormal signaling is associated with conditions like preeclampsia and intrauterine growth restriction (IUGR), both of which can negatively affect pulmonary vascular development. Persistent pulmonary hypertension of the newborn (PPHN) results from inadequate transition from fetal to neonatal physiology, leading to high pulmonary vascular resistance (PVR) and hypoxemia. Contributing factors include maternal conditions such as hypertension, smoking, and medication use, as well as perinatal insults like asphyxia, pneumonia, sepsis, and meconium aspiration. Management of PPHN involves supportive care including mechanical ventilation, supplemental oxygen, inhaled nitric oxide, and surfactant therapy [6]. Long-term effects of abnormal vascular development may include bronchopulmonary dysplasia and increased risk of pulmonary vascular disease in later life.

Advances in Diagnostic Techniques

 Imaging technologies

Recent innovations in imaging technologies have improved the accuracy of PH diagnosis in pediatric patients. Techniques such as high-resolution echocardiography, cardiac magnetic resonance imaging (MRI), and advanced Doppler studies offer enhanced visualization of the pulmonary vasculature and cardiac function. For instance:

• High-Resolution Echocardiography: Allows detailed assessment of right ventricular function and pressure estimates.
• Cardiac MRI: Provides comprehensive evaluation of cardiac structure and function, helping to differentiate between various types of PH and assess response to therapy.
• Advanced Doppler Ultrasound: Enhances the measurement of pulmonary artery pressures and flow dynamics.

Biomarkers

The identification and validation of biomarkers are crucial for diagnosing PH and monitoring disease progression. Emerging biomarkers such as N-terminal pro b-type natriuretic peptide (NT-proBNP) and soluble guanylate cyclase (sGC) levels are being studied for their role in:

• Early Detection: Biomarkers can signal the presence of PH before significant clinical symptoms develop.
• Disease Monitoring: Levels of specific biomarkers can indicate treatment efficacy and disease progression.

Genetic Testing

Advances in genetic testing have improved our understanding of hereditary forms of pediatric PH [7]. Whole exome sequencing (WES) and targeted gene panels are now used to identify mutations associated with PAH, such as those in the BMPR2, TBX4, and SOX17 genes. Genetic testing helps:

• Diagnose Heritable PH: Identifying specific mutations allows for more accurate diagnosis and personalized treatment plans.
• Predict Disease Course: Understanding genetic variants can provide insights into disease severity and progression.

Innovative Treatment Strategies

Pharmacotherapy : Recent developments in pharmacotherapy for pediatric PH include:

• Endothelin Receptor Antagonists (ERAs): Medications such as bosentan and ambrisentan have shown efficacy in reducing pulmonary pressures and improving functional capacity.
• Phosphodiesterase-5 Inhibitors (PDE-5Is): Drugs like sildenafil and tadalafil help to dilate pulmonary vessels and improve exercise capacity.
• Prostacyclin Analogues: Agents such as epoprostenol and treprostinil are used to manage severe cases, providing potent vasodilation and improved survival.

Novel Therapies

Emerging treatments are being explored to provide new options for managing pediatric PH:

• Guanylate Cyclase Stimulators: These agents, such as riociguat, are being studied for their ability to enhance nitric oxide signaling and reduce pulmonary arterial pressure.
• Gene Therapy: Experimental approaches aiming to correct genetic defects associated with PH are showing promise in preclinical models.

Multidisciplinary Care

A multidisciplinary approach is increasingly recognized as essential for managing pediatric PH. This involves collaboration between cardiologists, pulmonologists, geneticists, and specialized nursing teams to provide comprehensive care that addresses the complex needs of these patients.

 Future Directions and Research Needs

Ongoing research is critical for further advancements in pediatric PH:

• Long-Term Outcomes: Studies are needed to assess the long-term effects of new treatments and interventions.
• Personalized Medicine: Research into individualized treatment plans based on genetic, molecular, and clinical factors will improve patient outcomes.
• Health Disparities: Addressing disparities in access to care and treatment efficacy across different populations is essential for equitable management of pediatric PH.

Developmental and Congenital Factors

Developmental lung diseases, congenital heart disease (CHD), and other anomalies significantly impact the development and progression of pediatric PH. Key areas of focus include bronchopulmonary dysplasia, congenital diaphragmatic hernia (CDH), and trisomy 21 [8-10]. These conditions often involve complex interactions between lung development and PH. Advances in understanding these subphenotypes have important implications for clinical management, providing insights into how developmental and congenital factors contribute to pediatric PH and informing treatment approaches.

Conclusion

The field of pediatric pulmonary hypertension is undergoing significant transformation, driven by advances in diagnostic techniques and therapeutic strategies. State-of-the-art imaging technologies, novel biomarkers, and innovative treatments are enhancing our ability to diagnose and manage this challenging condition. As research continues to evolve, these advancements hold promise for improving outcomes and quality of life for children with PH.

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