Pulmonary Hypertension in Children

Introduction

PH, regardless of age at diagnosis, is currently categorized according to the schema most recently updated by the 6^th World Symposia on Pulmonary Hypertension (WSPH), which took place early in 2018. At that conference, the definition of PH, formally determined by cardiac catheterization, was updated to a resting mean pulmonary arterial pressure (mPAP) ≥ 20 mm Hg. In addition, pre-capillary PH was formally defined to include both mPAP ≥ 20 mm Hg as well as a pulmonary vascular resistance (PVR) ⩾3 Woods Units (WU), regardless of the classified etiology of PH.¹ This is relevant due to the generally accepted view that PH-specific pulmonary vasodilator therapy should be reserved for individuals with pre-capillary PH.² While there have not been significant recent changes to the available PH-specific medications, notable advances in pediatric care approaches include enhanced understanding of PH associated with developmental lung disease and efforts to incorporate determination of the risk of clinical demise into therapeutic decision-making. Following the WSPH, PH classification remains anchored upon a 5 clinical subgroup system for children and adults: Group 1, pulmonary arterial hypertension (PAH); Group 2, PH due to left-sided heart disease; Group 3, PH due to chronic lung disease; Group 4, PH due to pulmonary artery obstructions; and Group 5, PH with unclear or multifactorial etiologies. Regardless of classification, PH in children and adults remains a complex pathophysiologic condition that may involve multiple comorbid aggravators and often associates with a high symptom burden, increased mortality, and high healthcare utilization.

Epidemiology: PH is a disease with high global burden

True estimates of the incidence of PH diagnosis per year, and current prevalence, are difficult given a high reliance upon research registries which may not capture the true breadth of diagnoses in any region or country. Deriving estimates from available publications focused upon developed western countries, most estimate the rate of new diagnoses (incidence) between 4 and 10 children per million per year, with a prevalence between 20 and 40 cases per million people.^3–5 In the developing world, replicated estimates are generally lacking, particularly in pediatric populations, and vary widely according to PH subtypes and location. The reasons for this are varied, including but not limited to: (a) reduced economic resources for clinical care and research infrastructure (even more challenging in pediatrics); (b) regional variations in human development and survival after preterm delivery; (c) variation in the prevalence of high intensity risk factors (e.g., schistosomiasis and HIV burden); (d) ancestral differences which may impact factors such as congenital heart disease; and, (e) socio-cultural factors.⁶

Classification and Hemodynamic Profile of Pulmonary Hypertension in Children

The most recent update to the classification schema for pulmonary hypertension occurred in 2018 at the 6th World Symposia on Pulmonary Hypertension (WSPH). While the schema did not separately address issues more specific to PH in children, it does incorporate subtypes with an eye toward shared subtypes with adult patients, and those separate from adult patients. As in previous classification schemes from prior WSPH, PH is divided into 5 types, which each have subtypes within them. Figure 1 shows the predominant types and subtypes of PH in the current classification, with those most often seen in children listed in purple.⁷ While children may be diagnosed with any PH condition, the majority of pediatric cases represent subtypes found in Group 1, also known as pulmonary arterial hypertension (PAH) and Group 3 (also known as PH due to lung disease and/or hypoxia). For example, in the initial 1475 patients reported by the Pediatric Pulmonary Hypertension Network (PPHNet) of 8 large PH specialty centers in North America, 602 (41%) cases were due to Group 1 and 720 (49%) were due to Group 3. Among Group 1 PH subtypes represented, congenital heart disease (CHD)-associated PAH (60%) and idiopathic PAH (23%) were the most common. Among those Group 3 PH subtypes represented, 90% classified as developmental lung disease, including preterm-associated lung disease, congenital diaphragmatic hernia, and Down Syndrome (44%, 36%, and 22% of Group 3 PH cases, respectively). Thus, preterm-associated lung disease, congenital diaphragmatic hernia, and Down Syndrome contributed three quarters of the Group 3 PH cases.⁸

Figure 1: 6^th World Symposium on PH (WSPH) Clinical Classification of PH.

While a child with PH can present with any classification type, those types most prevalent in pediatrics are shown in purple. Figure created with BioRender.com

While not unique to pediatric PH, heritable and other genetic forms of PH are overrepresented in children compared to adults. For example, with recent advances in genetics and genomics, it is now appreciated that approximately 35–45% of previously diagnosed idiopathic PAH is due to mutations in established PAH risk genes, meaning that much of idiopathic PAH is actually heritable in children. In contrast, nearly 90% of idiopathic PAH in adults remains genetically unexplained (recently reviewed, ⁹). Genetic-associated PH may also be due to larger syndromic changes, such TBX4 Syndrome (due to mutations in the gene TBX4, a transcription factor), Down Syndrome, or Noonan Syndrome.¹⁰ In addition, with the rapid expansion of genomic understanding of developmental lung diseases, genes such as TBX4, SOX17, FGF10 and FOXF1 are now know to associate with varying types of developmental lung diseases, often with accompanying PH of variable severity and timing of presentation.¹¹

Clinical guidelines generally recommend that invasive cardiac catheterization by a specialty center familiar with PH diagnosis and management be performed to confirm the diagnosis of pulmonary hypertension unless the procedure is determined unsafe for the patient.¹² Cardiac catheterization allows for the confirmation of PH and assessment of severity, as well as determination of the hemodynamic profile of pulmonary hypertension (pre-capillary, post-capillary, or combined pre-capillary and post-capillary PH) (Figure 2). While cardiac catheterization-based hemodynamics may not always precisely represent the hemodynamics of a patient in all conditions (e.g., sedation is generally employed during catheterization of the young child), knowledge of the hemodynamic profile is important for PH Group determination, risk assessment, and to facilitate appropriate selection, or not, of PH-specific vasodilator medications. Patients with precapillary PH are likely to respond without detrimental setback to PH-specific vasodilator medications, which generally vasodilate the pre-capillary pulmonary arterial vasculature out of proportion to the pulmonary venous vasculature. In contrast, patients with an exclusively post-capillary condition may respond poorly to acute and/or chronic exposure to pulmonary vasodilator therapy because pre-capillary vasodilation may result in pulmonary congestion and because mechanistically pulmonary vasodilator therapies are not treating the post-capillary cause of elevated pulmonary arterial pressure. Patients with combined pre- and post-capillary PH require particular vigilance, as response to therapy may vary over time and with changing comorbid situations.¹³ In adults with PH, validated risk scores for clinical stability or decline now incorporate several key hemodynamic metrics, such as right atrial pressure and pulmonary vascular resistance (see https://www.pahinitiative.com/hcp/risk-assessment/calculators for comparison of available risk calculators for adult PH care).¹⁴ While active work is underway, a validated pediatric risk assessment and accompanying score remains an area of opportunity and need.

Figure 2: Typical Hemodynamic Profile of Pediatric PH Patients in Each WSPH Group.

By definition, Group 1 PH (PAH), is a pre-capillary condition. Group 3 PH and Group 4 PH are generally, although not always, pre-capillary conditions. Figure created with BioRender.com

Diagnostic Approach to the Child Suspected to have PH

The detrimental clinical features of PH are generally driven by right ventricular strain in the setting of elevated pulmonary vascular pressures.¹⁵ Clinical suspicion of PH should be raised in the setting of shortness of breath at rest, profound shortness of breath with activity/exercise, chest pain, syncope or pre-syncopal events. Unless presenting particularly late, features of right ventricular failure such as leg edema and ascites are typically not present in pediatric patients. For patients with Group 1 PH in particular, erroneous labels such as seizure disorder (particularly in the child with syncope or pre-syncopal events) and asthma may be used to explain PH spells or exercise intolerance, respectively.

Guidelines for the approach to a child with suspected PH have been published, most recently by the European Pediatric Pulmonary Vascular Disease Network (2019) and the American Heart Association & American Thoracic Society (2015). While with some differences, the guidelines are similar and highlight key agreed upon approaches to the diagnosis of children with suspected PH.^12,16 As noted in Figure 3, suspicion of PH should prompt a work-up, starting with a transthoracic echocardiogram accompanied by an electrocardiogram and Chest X-ray. In particular, if the echocardiogram has features suggestive of PH, additional testing is warranted to elucidate PH etiology. For all subjects, laboratory testing and Chest CT should be pursued unless contraindications exist (while not noted in Figure 3, for individuals at risk of human immunodeficiency virus (HIV), testing for HIV should be pursued). Not all children will be able to perform pulmonary function testing (PFTs) and a Six Minute Walk Test (6MWT) but they should be performed when able. Comprehensive assessment for sleep-disordered breathing, thrombotic disease, or hepatic disease (e.g. portal hypertension or portosystemic shunt) should be considered in all patients with new PH diagnosis. Generally upon completion of the work up above, children should proceed to invasive hemodynamic testing by cardiac catheterization with acute vasodilatory testing. Given the inherent dangers of sedation with cardiac catheterization for a patient with PH, consideration is warranted as to the suitability of a child for this procedure.¹⁷

Figure 3: Simplified Approach to the Child Suspected of a PH Diagnosis.

Patients with Group 3 PH may not initially undergo cardiac catheterization if confidence in the diagnosis is established and features concerning for a post-capillary condition (e.g., pulmonary vein stenosis) are ruled out. Figure created with BioRender.com

While generally recommended for all patients, there is an unpublished trend among PH Specialty Centers to consider delay of cardiac catheterization at the time of diagnosis for formerly preterm children with PH for whom the work up is highly suggestive of no concurrent aggravating conditions, such as pulmonary vein stenosis or hemodynamically significant congenital heart disease. However, as published equipoise on this issue is lacking, it is recommended to speak with a PH Specialty Center if this approach is considered. While the general approach to diagnosis is similar across groups, neonates and young children undergoing diagnostic work up for PH may require modification of approaches in addition to careful consideration if/when cardiac catheterization would be performed; for example, sedation for a CT scan may not be appropriate under some conditions and children younger than approximately 6 years of age cannot perform adequate PFTs and 6MWT.

Acute vasoreactivity testing (AVT) in response to a vasodilator such as inhaled nitric oxide (iNO) should generally be performed in the cardiac catheterization at the time of diagnostic cardiac catheterization for any age child. While this approach does not guarantee a short- or long-term beneficial response to pulmonary vasodilator therapy, it is helpful to analyze for changes in pulmonary vascular pressures, flow and resistance in response for a variety of reasons. Criteria for a positive response have been published (though notably are based on assessment in those with primarily idiopathic or heritable PAH). A commonly utilized criteria in the pediatric population includes the modified Barst criteria, which in its simplest form states that a positive response is characterized by a 20% decrease in mPAP and indexed PVR (PVRi) to indexed systemic vascular resistance (SVR) ratio without a decrease in cardiac output.¹⁸ This is relevant because some children and adults with a positive acute response to AVT may represent a subset of individuals with significant and long-term response to treatment high-dose calcium-channel blockers alone.¹⁹ This treatment strategy in acute AVT responders may be considered for individuals with favorable functional class at the time of testing. However, a positive response is appreciated in a minority of patients—approximately 10% of idiopathic PAH patients, for example. In our experience, a low prevalence of positive AVT is generally true for most types of PH in children.

Treatment Approaches

The treatment of any adult or child with PH begins with supportive approaches for a person with a serious illness. Such measures include several key principles of management are listed in Box 1.

Box 1.

Key Supportive Approaches for a Child with Pulmonary Hypertension (PH)

Avoid hypoxemia when awake, exercising/active, and asleep.

Avoid anemia, which may be common depending on the developmental stage of a child (e.g., infant with iron-deficiency; menstruating adolescent female).

Maintain a euvolemic state to both avoid dehydration and avoid excessive vascular engorgement—excessive vascular hydration may be particularly important for the child with Group 3 PH for whom balanced diuretic therapy may be necessary.

Diagnose and manage sleep-disordered breathing such as obstructive sleep apnea.

Diagnose and manage forms of airway aspiration such as related to swallow dysfunction and gastroesophageal reflux disease

To address these and other supportive approaches, oxygen supplementation is a frequent mechanism of support for children with PH, often with activity but also during times of rest and sleep as needed. Careful determination of pulse oximetry readings during different phases of the day is helpful to evaluate as the family is able, often with a diary during the early days of a diagnosis. Blood-based laboratory tests including for anemia, as well as thyroid dysfunction, are employed regardless of therapeutic approach and as needed when on therapy (noted below). If there is any form of concern by history, physical exam, or nighttime oximetry of sleep-disordered breathing, a formal sleep study should be pursued at the time of diagnosis and as needed over time thereafter. For any infant diagnosis in particular, vigilance regarding aspiration, airway irregularities (consider airway evaluation by pulmonary and/or otolaryngology services), and nutrition are paramount. Nutritional decline or plateau may be an important early sign of concern even in the absence of other concerning PH features.²⁰

For older children, judicious attention to cardiopulmonary capacity, and efforts to maintain fitness without excessive exercise stress and/or maneuvers such as the Valsalva Maneuver are important to maintain cardiovascular fitness as high as possible for a given patient. Such efforts may pay particular dividends during times of acute strain, such as a serious viral respiratory infection or other form of acute illness. While studies in children are less numerous, formal cardiopulmonary exercise programs, and less formal programs such as via remote monitoring devices, have demonstrated beneficial results.^21–25 Growing data suggest that children who maintain skeletal strength in accordance with interest in maintaining activity have better outcomes, as well.²⁶ This is not surprising, given evidence that adults who are less active are more likely to experience serious setbacks including acute need for hospitalization.²⁷ Other features of basic pediatric care are crucial, including recommended vaccines.

As with adults with PH, recommended treatment algorithms designed to guide medicinal therapy have emerged over the past decade for children with PH.^12,16 While they differ slightly, the guidelines are similar and rely on the same current classes of pharmacologic agents; these medication classes have been in existence now for nearly 20 years, and strongly associate with improved survival and quality of life for adults and children with PH. Each class functions in a beneficial manner predominantly via action as a pulmonary vascular vasodilator of the distal pulmonary arterial circulation. However, each agent may contribute to vasodilation of the systemic vasculature which should not be overlooked, particularly but not limited to times of treatment initiation and acute illness. As noted in Figure 4, current PH-specific vasodilators target three distinct pathways for vasodilation, each of which molecularly initiates in the endothelial cell layer but impacts vascular smooth muscle of the smallest pulmonary arteries: (a) the Endothelin-1 Pathway; (b) the Prostacyclin (PGI₂) Pathway; and, (c) the Nitric Oxide (NO) Pathway. Table 1 lists the medications available in the United States for each class, although most are not approved for pediatric use by the Food and Drug Administration (FDA).

Figure 4:

The 3 Pulmonary Vasodilator Pathways Targeted by Current PH-Specific Medications. Figure created with BioRender.com

Table 1.

Molecular Pathway Addressed

	Representative PH-Specific Medications (delivery)
Endothelin-1 Pathway, blocked by Endothelin Receptor Antagonists (ERAs)	Bosentan, Ambrisentan, Macitentan (all enteral)
Prostacyclin (PGI2) Pathway augmented by prostacyclin, prostacyclin derivatives, and IP agonists	Prostacylin (iv), Treprostinil (iv, sq, inhaled), Iloprost (inhaled), Selexipag (enteral), Orenitram (enteral)
Nitric Oxide (NO) Pathway, augmented by exogenous NO, phosphodiesterase 5 inhibitors (PDE5is), and soluble guanylate cyclase (sGC)	NO (inhaled), Sildenafil (enteral, iv), Treprostinil (enteral), Riociguat (enteral)

Children of all ages are treated by PH Specialty Centers with these medications, provided there is confidence that the hemodynamic profile of the type of PH is pre-capillary in nature (Figure 2). In the rare instance of a patient with a positive AVT (discussed above) in the setting of a pre-capillary profile, the use of a calcium channel blocker alone or in combination with an additional PH-specific medication may be employed. For children with an exclusively post-capillary profile, such as those with Group 2 PH, PH-specific medications should not be used. Some children may have a combined pre- and post-capillary profile; in those children, the use of PH-specific medications should generally be avoided unless directed by an experienced PH specialist at a PH Specialty Care Center given the risk of pulmonary edema and other complications.

For those with a pre-capillary hemodynamic profile (classically those with Group 1 PH (PAH) and often those with certain Group 3 subtypes such as preterm-associated PH and Down Syndrome), the use of an more aggressive approach with early use of combination therapy to target two of the pathways is increasingly common for those patients with moderate-to-severe PH features. This approach derives from several adult studies, including most prominently the randomized, controlled AMBITION trial in adult PAH patients, which demonstrated a significant reduction in time to clinical worsening in those treated with upfront dual (ambrisentan, an endothelin receptor antagonoist (ERA) + tadalafil, a phosphodiesterase 5 inhibitor (PDE5i)) versus upfront single agent therapy.²⁸ While no formal randomized trials are completed and published to investigate this in children, it is a strategy increasingly employed by PH Specialty Centers, particularly for children with idiopathic and heritable PAH. A current randomized clinical trial is underway by the Pediatric Pulmonary Hypertension Network (PPHNet), funded by the NIH (NCT04039464).²⁹ While not appropriate for all patients depending on disease severity and toleration, PGI₂ and PGI₂ analogues may be utilized off-label in pediatric patients with severe hemodynamic phenotypes or high-risk disease features (e.g. syncope, low functional class). Similar to adult populations, pediatric patients may have significant hemodynamic, functional, and survival benefits when treated with prostacyclin analogues, which is typically employed in combination with other medication classes.³⁰

Determination about the approach to PH-specific medications is best made by experienced PH providers. Such providers should be knowledgeable about the features most suggestive of lower and higher risk of clinical decline when making decisions on medication approach. While determinants of low and high risk have not been validated in pediatric PH, extrapolation of features from both experience and adult studies has resulted in a number of components widely accepted. These include but are not limited to data acquired from the history and physical exam (progression of PH symptoms such as syncope; evidence of right ventricular failure; 6MWT data; growth parameters; functional class), laboratory values (BNP or NT-proBNP values), imaging features of severity by echocardiography, and data from invasive hemodynamic assessments.^12,16 In general, children with a lower risk profile will start with single or dual enteral therapy targeting the Endothelin-1 and/or Nitric Oxide (NO) Pathways, either in combination or sequentially provided over time. In contrast, those children with substantial burden of high risk determinants will typically be treated with upfront Prostacyclin Pathway (PGI₂) therapy, often with associated early dual combination therapy adding enteral therapy from the Endothelin-1 and Nitric Oxide (NO) Pathways.

Management Over Time

A key component of PH care is judicious reassessment over time, as features may change over time. For example, children with Group 3 PH due to developmental lung disease may experience progression of the diffuse lung disease, development of pulmonary venous disease, or other features over time. Most often, reassessment occurs via repeated clinic visits with associated history, physical examination, echocardiography, and laboratory studies. BNP or NT-proBNP is a helpful laboratory tool, for example, to follow cardiac strain (although not specific to the right heart). In addition, children on ERAs require intermittent CBC and CMP studies, depending on the agent. For children on Prostacyclin (PGI₂) Pathway medications, we check thyroid studies annually.³¹ Decisions on timing of repeat cardiac MRI assessment to evaluate ventricular function, as well as repeat hemodynamic assessment by cardiac catheterization and/or cardiac MRI assessment to evaluate ventricular function, are made on a per patient basis, but should be considered with major clinical changes and/or if not evaluated in multiple years. It is notable that while most forms of PH in children do not resolve, some children with Group 3 PH subtype preterm-associated lung disease PH may resolve detectable PH with growth, development and avoidance of interval clinical setbacks; in addition, chronic thromboembolic PH (CTEPH), a form of Group 4 PH, may be cured with adequate clot resolution and prevention of future clotting events (although full resolution is not always the case).³²

For the child with PH with features of enhanced severity and/or progression of disease despite appropriate therapeutic management, invasive options should be considered in consultation with an experienced PH provider. For example, atrial septostomy may be employed for patients with recurrent syncope or pre-syncopal events, right ventricular failure due to severe pulmonary vascular pressure elevation, or a symptomatic condition of reduce heart function.³³ The past decade has seen increased use of palliative surgical shunts, most prominently in the form of a modified Potts Shunt, typically as an artificial connection between the left pulmonary artery and the descending aorta, often modified to include a one-way valve that only allows right to left blood to flow. This allows for a post-tricuspid “pop-off” to allow for reduction in right ventricular strain. This procedure is typically considered for those with severe, unrelenting elevations in pulmonary artery pressure despite therapy but generally preserved right ventricular function. This pulmonary-to-systemic shunt appears to provide durable clinical improvement, sometimes often facilitating reduction in medication therapy burden, with five year survival similar to lung transplantation for PH.³⁴ However, prospective studies are need to confirm its utility, optimize the approach and selection of patient, and other key features. Finally, lung transplantation remains a surgical option for patients refractory to therapeutic approaches and with limited options. While lung transplant volumes have decreased over the past decade with the rise in therapeutic approaches and surgical palliation, outcomes remain similar to previous eras as well as to other indications for lung transplantation.³⁵

Conclusions

A heterogeneous group of PH types and subtypes comprise the different forms of PH found in children. Children with PH present at any age with a variety of comorbid conditions and disease severity. The diagnostic approach to PH is fairly uniform regardless of age at presentation, and should at a minimum determine the PH Classification and hemodynamic profile. While not uniformly employed in all cases, strong justification to omit cardiac catheterization should be provided for any pediatric PH case. Fortunately, largely based upon experience and application of adult trial data, short- and long-term outcomes have improved over the past 30 years since the advent of modern PH-specific medications. Despite progress, however, well-funded clinical studies of pediatric PH remain of high need to determine best therapeutic approaches, features of risk and resilience to clinical decline, and nuanced treatment choices according to PH classification.

Clinical Care Points:

• Regardless of PH classification, it is imperative to determine the hemodynamic condition (pre-capillary, post-capillary, or combined) of the PH form prior to starting PH-specific medications.

• The PH condition is not a static condition. The child with PH may alter over time, which is one of multiple reasons for vigilance about the overall clinical condition over time.

• PH-specific medications approved for adults and used (often off-label) in children have led to substantial improvement including heightened survival and quality of life.

Key Points:

• All forms of pulmonary hypertension (PH) present in adults are found in children, as well.

• The prevalence of certain PH types (and subtypes) is different in children than adults. For example, Pediatric PH is predominantly Group 1 PH (pulmonary arterial hypertension, PAH) and Group 3 PH (PH Due to Lung Diseases and Hypoxia). Within Group 3, Developmental Lung Disorders are most common.

• For any patient with PH, control of concurrent aggravating conditions, such as hypoxemia due to diffuse lung disease or sleep-disordered breathing, is paramount.

Synopsis:

Pulmonary hypertension (PH) may manifest at any age, including during childhood. While pediatric PH frequently associates with early life alterations that cause occult or overt pulmonary vascular disease, all forms of PH seen in adults are also found in children, although with different degrees of prevalence according to PH subtype. The goal of every child, family, and PH specialist is to see the child with PH one day become an adult with PH—this unfortunately is not always possible. While not uniformly the case in the current era, PH-specific medications, rapid implementation of therapeutic advances, multidisciplinary teams for improved child and family support, and programs to facilitate successful transition to adult care have contributed to substantial improvement in survival to adulthood.