Because of the low incidence of pediatric pulmonary arterial hypertension (PAH; 0.48-0.70 per million children per year), high-quality studies in this population have been scarce.1 The severity and complexity of the disease requires management by a multidisciplinary team at specialty centers, with suggested follow-up ≥3 months following diagnosis and twice annually once the patient is considered stable.1

Findings from the Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry have shown that the most common symptoms in pediatric PH are dyspnea on exertion and fatigue, and syncope affects up to 31% of patients.1 The optimal treatment approach for PAH depends upon the severity and underlying etiology of the disease. Study results point to idiopathic PAH (IPAH), heritable PAH, and PAH associated with congenital heart disease as the most common causes of PAH in children; these 3 diagnoses represented 93% of patients in the TOPP registry.1,2

However, this “may be explained by a diagnostic approach that has not excluded all possible forms of PAH and overdiagnosed IPAH,” noted the authors of a review published in Expert Review of Cardiovascular Therapy.1 PAH may also be associated with connective tissue disease, systemic disease, or infectious disease, as well as certain toxins and drugs (eg, serotonin reuptake inhibitors in persistent pulmonary hypertension of the newborn).

To learn more about the specifics of pediatric PAH, Pulmonology Advisor interviewed the following clinicians: Sharon A. McGrath-Morrow, MD, MBA, professor of pediatrics at Johns Hopkins’ Children’s Center and program director of the Pediatric Pulmonary Fellowship Program at Johns’ Hopkins Hospital in Baltimore; Catherine Avitabile, MD, an attending cardiologist in the Cardiac Center at the Children’s Hospital of Philadelphia, and assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia; and John C. Carl, MD, chair of the Center for Pediatric Pulmonary Medicine at Cleveland Clinic Children’s in Cleveland.

Pulmonology Advisor: What are some of the diagnostic and treatment challenges in pediatric PAH?

Dr McGrath-Morrow: Pediatric PH is a rare disease and most of the drug trials for PH are conducted in adults and not children, so most of the PH-specific therapies used in children have been based on adult trials. In addition, most studies performed in children with PH are not randomized controlled trials.

Since PH due to chronic lung disease is a common etiology of PH in children, recognition and correction of factors contributing to the chronic lung disease and lung injury may be instrumental in treating the underlying PH. For example, infants with chronic lung disease of prematurity may develop PH due to factors that limit lung growth, and treating conditions that limit lung growth — such as aspiration, poor nutrition, and inadequate gas exchange — may improve PH outcomes in this population.

Since PH is so rare in children, these patients should be referred to tertiary pediatric centers with expertise in the treatment of pediatric PH.

The etiology of pediatric PH in children is often different than that in adults, and diagnosis and treatment of children with PH may be delayed because of its rarity. Children may present with nonspecific symptoms such as failure to thrive, irritability, exercise intolerance, syncope, and cyanosis.

Causes of pediatric PH commonly include idiopathic PH and PH associated with congenital heart disease, congenital diaphragmatic hernias, and underlying chronic lung disease, including severe bronchopulmonary dysplasia (BPD), whereas adult patients with PH are more likely to have PH associated with connective tissue diseases, HIV, and thromboembolic diseases.

Dr Avitabile: Pediatric PH is different from adult PH in several ways. The etiologies of pediatric PH are extremely diverse. Many originate in prenatal or perinatal vascular disease. The causes of pediatric PH include, but are not limited to, developmental heart, lung, and vascular problems such congenital diaphragmatic hernia and BPD; congenital heart defects (with and without left to right shunts); PH in the setting of complex genetic syndromes; and isolated PAH, which may be idiopathic or inherited in some cases.

Infants and children may present with PH at any time in childhood, depending upon the etiology. Comprehensive diagnosis includes birth and perinatal history, family history, electrocardiogram, chest X-ray, echocardiogram, exercise testing (6-minute walk test [6MWT] and cardiopulmonary exercise testing), computed tomography (CT) angiogram, ventilation-perfusion (VQ) scan, cardiac catheterization, and cardiac magnetic resonance imaging (MRI) in some cases. These tests may be tailored based upon age at presentation and a patient’s stability.

While cardiac catheterization with acute vasoreactivity testing (AVT) is the gold standard in adult PH, we cannot always catheterize critically ill neonates such as those with congenital diaphragmatic hernia or BPD. Therefore, in many cases, drug treatments are started without catheterization data, relying instead on noninvasive data from echocardiograms.

However, cardiac catheterization is still essential to obtain hemodynamic data, rule out structural problems — such as patent ductus arteriosus, other shunts, or pulmonary vein stenosis — that may complicate PH treatment in infants and neonates and to understand the contribution of left ventricular heart disease to the PH. The role of AVT testing is not clear in all forms of pediatric PH (eg, the population with BPD) and the correct criteria for defining responders is also unclear, as these may not be the same as those used to define adult responders to calcium channel blockers.

Medical treatment of pediatric PH includes right ventricular inotropic support (with dopamine or milrinone in some cases) and pulmonary vasodilator therapies. We use inhaled nitric oxide, as well as phosphodiesterase 5 inhibitors, endothelin receptor antagonists, and prostacyclins, but few drugs are approved for pediatric indications. We need more clinical trials with innovative designs that will test drug efficacy in a rare disease with a reasonable timeline.

One surgical treatment that has promise is the Potts shunt, a central shunt originally designed to increase pulmonary blood flow in congenital heart defects in which there is pulmonary atresia or severe stenosis.3,4 In PH, a surgically placed Potts shunt can act in the reverse way, like a ductus arteriosus, and allow some blood to bypass the lungs, potentially unloading the right ventricle at the expense of lower extremity cyanosis.

Dr Carl: The incidence and pathophysiology of PH in pediatric patients is very different than in adult patients. Pediatric PH with cardiac disease affects far more children than idiopathic PH. Current definitions of BPD are based on center-specific preferences for using oxygen; there are fundamental shortcomings in defining disease by management without an association with underlying pathophysiology, disease progression, or phenotype variability.5

  • Diagnostic limitations in pediatrics include:
  • Pulmonary function limitations: younger patients are unable to perform standard pulmonary function tests, reproducible infant pulmonary function testing is difficult in more critically ill children, and the 6MWT is limited.1
  • Echocardiography, particularly in neonates, is much easier to obtain serial measures, but it is much less sensitive that catheterization data.
  • Serial measurement of pharmacologic outcomes of therapies is more difficult.

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Pulmonology Advisor: What are key differences in the screening and management of pediatric vs adult PAH patients?

Dr McGrath-Morrow: In children, screening involves identifying specific pediatric conditions that may be contributing to the development of PH, such as chronic lung disease, cardiac shunts, congenital heart disease, and congenital diaphragmatic hernias. Echocardiography is an important screening tool for PH, particularly in preterm infants with chronic lung disease.

Cardiac catheterization in pediatric PH is still the gold standard for diagnosis and risk stratification and allows for AVT. Cardiac catheterization is recommended prior to initiating vasodilator therapy. However, the risk for adverse events with cardiac catheterization in preterm infants with BPD can be high and must be weighed against the benefit of the information gained.

Unique to preterm infants is the development of PH secondary to pulmonary vein stenosis, which can be associated with poor outcomes. Biomarkers for pediatric PH are less defined than adult PH.

Management of PH in children often includes the use of targeted pharmacologic therapies including phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclin analogues, all based on studies of adults with PH. Dual therapies may also be beneficial in children with PH.

Treatment algorithms for children have been traditionally based on adult algorithms. Pediatric-specific algorithms are currently being developed to help provide a guideline approach to the management of PH in children.