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Pulmonary hypertension in children: Classification, evaluation, and diagnosis

Pulmonary hypertension in children: Classification, evaluation, and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Apr 04, 2023.

INTRODUCTION — Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure (PAP), which can result in right ventricular (RV) failure. In children, PH is most commonly associated with underlying cardiac or lung disease (eg, bronchopulmonary dysplasia). PH may also be idiopathic or familial. Other causes of PH are rare in childhood (table 1). PH can be associated with considerable risk of morbidity and mortality. Management of children with PH requires a multidisciplinary team with experience and expertise in this area.

The classification, evaluation, and diagnosis of PH in children are reviewed here. Management and prognosis of PH in children is reviewed separately. (See "Pulmonary hypertension in children: Management and prognosis".)

Persistent PH of the newborn, PH associated with bronchopulmonary dysplasia, the pathogenesis of PH, PH in adults (including adults with congenital heart disease), and Eisenmenger syndrome are reviewed in greater detail separately:

(See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

(See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)

(See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

(See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis".)

(See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis" and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

REFERRAL — The diagnostic evaluation of PH in pediatric patients should be carried out by or in close collaboration with practitioners with considerable experience and expertise in this area. Early referral is critical since treatment for many types of PH is less effective if provided at a late stage of the disease.

TERMINOLOGY — The following terms are used throughout this topic:

Pulmonary hypertension (PH) – PH refers to elevated pulmonary artery pressure (PAP; mean PAP >20 mmHg). PH can be due to a primary elevation of pressure in the pulmonary arterial system alone, increased blood flow through the pulmonary circulation (eg, systemic-to-pulmonary shunting lesions), or elevation of pressure in the pulmonary veins.

Transpulmonary gradient (TPG) – TPG is the pressure gradient across the pulmonary circulation. It is the difference between the mean PAP and the left atrial pressure (LAp).

Pulmonary vascular resistance (PVR) – PVR is a measurement of the resistance in the pulmonary circulation. It provides an estimation of whether the cross-sectional area of the pulmonary vascular bed is reduced (elevated PVR indicates reduced cross-section area). PVR is the ratio of the TPG to pulmonary blood flow (Qp): PVR = TPG/Qp (calculator 1). Normal PVR is ≤1.5 Wood units, with Qp indexed to body surface area; mean PAP of 20 mmHg corresponds to PVR of approximately 3 to 4 Wood units, depending on Qp and LAp.

Pulmonary arterial hypertension (PAH) – PAH refers to elevation of the pressure in the pulmonary arterial system (PAP >20 mmHg) and elevated PVR (PVR >3 Wood units) with normal pulmonary venous pressure (pulmonary artery wedge pressure <15 mmHg). PH occurring in the context of certain underlying diseases (eg, lung disease) is not classified as PAH. (See 'Classification' below.)

Pulmonary venous hypertension – Pulmonary venous hypertension refers to elevations of pressure in the pulmonary venous and pulmonary capillary systems (pulmonary artery wedge pressure ≥15 mmHg).

Pulmonary hypertensive vascular disease (PHVD) – PHVD (previously called pulmonary vascular obstructive disease) refers to pathologic remodeling of pulmonary small vessels that results in narrowing the vascular lumen and loss of small pulmonary vessels. PHVD is characterized by elevated PVR and/or TPG; PAP is typically elevated but may be <20 mmHg in some cases (eg, single ventricle with cavopulmonary palliation).

Although there are important distinctions between the terms PH and PAH (as noted above), for simplicity, the term PH will be generally used in this topic review, except when the distinction is important.

DEFINITION — For children and infants >3 months old, the definition of PH is the same as in adults: mean pulmonary artery pressure (PAP) >20 mmHg at sea level [1-3]. This definition is based on the 2018 6th World Symposium on Pulmonary Hypertension (WSPH) [1]. Earlier guidelines used a slightly higher cutoff of ≥25 mmHg [2,3]. However, the pressure cutoff for assigning the diagnosis of PH is somewhat arbitrary and the concept of PH as being a disease (implying the need for therapy) is useful only when it acquires nuance.

In addition to the PAP value, the following questions should be addressed:

Is the patient old enough that the elevated PAP is not simply a slower-than-normal decline in fetal pulmonary vascular resistance (PVR)?

Does the elevation in PAP reflect an abnormal pulmonary vascular bed or is it secondary to increased flow or pulmonary venous pressure?

To what degree does the PH impact right ventricle (RV) function?

Is the patient disproportionately affected by a small increase in PAP (eg, patients with Fontan circulation)?

The following sections discuss these issues in greater detail:

Neonates – PVR is high in utero and falls rapidly after birth. PAP normally reaches adult levels during the first few weeks of life. However, even if the PAP has fallen at the usual rate, the neonatal lung reacts to vasoconstrictive stimuli (eg, alveolar hypoxia) much more vigorously than does the mature lung, so stressors provoke a greater response than later in life. In addition, occasionally the neonatal transition to a low-resistance pulmonary circulation is delayed, and despite otherwise healthy lungs, the mean PAP remains elevated at ≥20 mmHg (sometimes even suprasystemic). These asymptomatic neonates require close follow-up; however, in most cases, the PH resolves over the first one to three months and they are generally not considered to have pathologic PH despite elevated PAP levels.

Cardiac shunting lesions or left heart disease – Patients with systemic-to-pulmonary cardiac shunting lesions may have PH due to increased pulmonary blood flow (Qp) rather than pulmonary vascular disease, per se. Similarly, left heart disease that is associated with elevated left atrial pressure (Lap; eg, left ventricular failure, cardiomyopathy, mitral or aortic valve stenosis or other left ventricular obstructive lesions) may cause PH due to pressure "back-up" (ie, pulmonary venous hypertension). Patients in these categories may actually have healthy pulmonary vessels or reversible pulmonary vascular abnormalities. Defining PH solely on the basis of only the PAP fails to take into account the amount of Qp or pulmonary venous pressure as a determinant of PAP. By contrast, the PVR takes these variables into consideration (PVR = [mean PAP – mean LAp]/Qp). (See 'Terminology' above.)

RV function – The RV is the primary end organ of interest in PH. Elevated PAP is mostly relevant insofar as it impacts RV systolic and diastolic function (ie, its capacity to generate blood flow) at rest and with exercise. A mean PAP considerably exceeding 20 mmHg may be well tolerated in a patient whose RV is well adapted to high pressure. Conversely, a seemingly minor increase in PVR may have critical impact on RV function in certain patients, even with mean PAP levels that are <20 mmHg. For patients with single-ventricle physiology (eg, hypoplastic left heart syndrome) and cavopulmonary palliation (eg, Fontan palliation), there is no pump to drive blood across the pulmonary circulation and a relatively minor increase in PVR can severely compromise cardiac output. (See "Management of complications in patients with Fontan circulation".)

Conditions at time of measurement – Measurements of PAP in the echocardiography or cardiac catheterization laboratory may not reflect the PAP at other times and under different conditions. For example, patients with bronchopulmonary dysplasia may have little elevation of PAP when healthy but a marked and clinically important increase in the setting of viral respiratory infection. In addition, patients with PH have relatively noncompliant pulmonary vascular beds, so a modestly elevated PAP at rest (with no appreciable impact on the patient's resting physiology) can increase substantially with exercise.

PHYSIOLOGY AND PATHOGENESIS — Increased pulmonary artery pressure (PAP) is caused by one or more of the following:

Decreased cross-sectional area of the pulmonary vascular bed

Increased pulmonary blood flow (Qp)

Increased pulmonary venous pressure (most commonly due to elevated left atrial pressure [LAp])

As previously noted, pulmonary vascular resistance (PVR) provides an estimation of whether the cross-sectional area of the pulmonary vascular bed is reduced (elevated PVR indicates reduced cross-section area). Reduced cross-sectional area is due to reduced luminal diameter of small pulmonary vessels and/or a decreased number of these vessels. In most types of PH, small pulmonary arteries are most affected, although small or large pulmonary veins may be the primary site of obstruction in some forms of PH [4-7]. Peripheral pulmonary artery stenosis involves larger pulmonary arteries and can also cause PH [8]. (See "Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis".)

The caliber of a small pulmonary arteries or pulmonary veins may be narrowed by active vasoconstriction and/or anatomic changes; often, both are present.

Vasoconstriction – Many patients with PH (eg, those with idiopathic PH, chronic lung disease, or structural congenital heart defects) have some degree of active vasoconstriction, as revealed by a fall in PAP with administration of a vasodilator (eg, inhaled nitric oxide) [9].

Anatomic changes – Pulmonary hypertensive vascular disease (PHVD; previously referred to as pulmonary vascular obstructive disease) refers to pathologic remodeling of small vessels and narrowing of the vascular lumen through medial hypertrophy, proliferation of "neointimal cells" (whose origin is unclear [10]), and deposition of connective tissue in pulmonary arteries. The number of small pulmonary arteries may also be reduced by virtue of complete occlusion of the lumen by neointimal cells or by in situ thrombi [4]. A paucity of small pulmonary arteries can also result from the failure of such vessels to develop (eg, with bronchopulmonary dysplasia, congenital diaphragmatic hernia, or, possibly, high pressure/high flow cardiac defects) [11]. Medial hypertrophy can resolve when the inciting stimulus is removed (eg, repair of a large ventricular septal defect in the first year of life). In infants with bronchopulmonary dysplasia or congenital diaphragmatic hernia, pulmonary hypertensive vascular disease usually gradually improves with growth of new pulmonary arterioles as a part of normal lung growth during the first few years of life. By contrast, pulmonary hypertensive vascular disease due to intimal proliferation and connective tissue deposition has much less potential to resolve with therapy.

A comprehensive mechanistic understanding of why and how disease occurs in pulmonary blood vessels is lacking, but a considerable amount of knowledge about the pathogenesis has been gained through translational and laboratory investigations. Factors that may contribute to the development of PHVD include:

Developmental abnormalities – Abnormal pulmonary vascular development, occurring pre- and/or postnatally, can cause increased PVR. Causes include bronchopulmonary dysplasia, congenital diaphragmatic hernia, and Down syndrome [1,12,13]. Some of the genetic variants discussed below (eg, TBX4 gene mutations) can also cause abnormal pulmonary vascular development.

External stimuli – Multiple agents and insults external to the lung itself can provoke pulmonary vasoconstriction and pathologic vascular remodeling. Examples include:

Alveolar hypoxia – Examples of extrinsic causes of alveolar hypoxia include living at a high altitude, intrinsic lung disease (without supplemental oxygen), and sleep-disordered breathing [14-16]. (See "Management of obstructive sleep apnea in children", section on 'Consequences of untreated obstructive sleep apnea' and "High-altitude disease: Unique pediatric considerations", section on 'High-altitude pulmonary hypertension'.)

Increased mechanical forces – Congenital intracardiac shunting lesions and/or left heart disease may produce increased hydrodynamic forces that can provoke PHVD. These include (listed roughly in order of potency) lesions associated with increased Qp and elevated PAP (eg, large ventricular septal defect), lesions with elevated PAP and normal Qp (eg, mitral stenosis), and lesions with increased Qp in isolation (eg, atrial septal defect) [17]. (See "Pathophysiology of left-to-right shunts", section on 'Pulmonary hypertension'.)

Toxins, drugs, and infectious agents – Examples include contaminated rapeseed oil, fenfluramine derivatives [18], methamphetamines, HIV, and schistosomiasis [19]. (See "Pulmonary arterial hypertension associated with human immunodeficiency virus" and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins'.)

Portal hypertension – Portal hypertension and portovenous shunts can cause PH, apparently by altering circulating vasoactive substance(s) in the blood [20,21].

Lung disease – Acute and chronic parenchymal pulmonary disease can lead to PH. Examples include pneumonia, bronchopulmonary dysplasia, acute respiratory distress syndrome, interstitial lung disease, and cystic fibrosis. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis" and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Consequences' and "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Pulmonary hypertension'.)

Sickle cell disease (SCD) – PH occurs in approximately 10 percent of adult patients with SCD; a similar percentage of children have an increased tricuspid regurgitant jet velocity, although this finding does not always correlate with increased PVR at cardiac catheterization. The biology of PH in SCD is not clear. The following factors may be involved: endothelial injury, chronic inflammation, hypercoagulability, intravascular hemolysis, and altered bioavailability of nitric oxide. Elevated left heart pressure from diastolic dysfunction may also contribute. (See "Pulmonary hypertension associated with sickle cell disease".)

Chronic thromboembolic disease – Physical occlusion of pulmonary blood vessels reduces the cross-sectional area of the vascular bed. Vasoconstriction and pathologic remodeling in adjacent areas of the circulation further increases PVR [22]. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Systemic disease – A number of systemic diseases are associated with PH, including rheumatologic (eg, sarcoidosis, scleroderma, mixed connective tissue disease, systemic lupus erythematosus), metabolic, endocrine, and oncologic diseases. [23]. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary vascular disease' and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Pulmonary hypertension'.)

Genetic mutations – PH may occur in families, and genetic mutations are associated with heritable PH (albeit with variable penetrance) (table 2). These include mutations in genes encoding bone morphogenetic protein receptor type II (BMPR2), endoglin (ENG), activin receptor-like kinase 1 (ALK-1), eukaryotic translation initiation factor 2-alpha kinase 4 (EIF2AK4), T-box 4 (TBX4), SOX family transcription factor 17 (SOX17), multiple SMAD genes, and others [24-29]. Additional genes and pathways implicated in PH will likely be discovered. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.)

Cellular and molecular mechanisms – A variety of cellular and molecular mechanisms have been invoked to explain this disorder: abnormalities of endothelium, imbalance of endogenous vasoconstrictors and vasodilators, clonal expansion of abnormal pulmonary vascular cells, epigenetic mechanisms, abnormal expression of proteases, endogenous growth factors and/or their receptors, and other molecules. Abnormal intracellular molecules involved with smooth muscle contraction/relaxation (eg, cyclic guanosine monophosphate) and cellular growth may also play a role. The precise role of these and other factors in causing pulmonary vascular remodeling is yet to be defined [30]. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

It is important to note, however, that many of these factors are insufficient to cause PH by themselves. PH is considered by some to be analogous to cancer and a multiple hit hypothesis has emerged.

CLASSIFICATION

Etiologic classification — The 2018 6th World Symposium on Pulmonary Hypertension (WSPH) updated clinical classification of PH includes five disease categories based upon etiology and mechanism (table 1) [31]. There is considerable overlap in some these disease categories; many aspects of PH physiology span across all categories, and some varieties of PH in one category closely resemble those in other categories. In addition, some of the groupings are quite broad and lack a consistent clinical or biologic theme (groups 1 and 5), while others are fairly tightly-themed (groups 2, 3, and 4).

It has long been appreciated that the WSPH classification is insufficient for pediatric PH, which often is related to fetal and developmental abnormalities and can have very different clinical characteristics from that seen in older patients [13].

Despite its limitations, the WSPH classification does correspond to the categories of patients included in targeted PH pharmacologic therapy trials (nearly all of which have included only adult patients), which inform treatment decisions. Most large drug trials have investigated group 1 PH (ie, pulmonary arterial hypertension [PAH], especially idiopathic PAH [including heritable PAH] and PAH associated with collagen vascular disease or congenital heart disease). By contrast, there are very few large trials involving patients with group 2 to 4 PH. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Pulmonary hypertension in children: Management and prognosis", section on 'Specific agents for targeted PH therapy'.)

Transient versus persistent/progressive — Pediatric PH can be categorized according to whether, based on the natural history of the underlying etiology, the PH typically resolves over time (transient PH) or whether it tends to persist and/or worsen over time (persistent/progressive PH):

Transient PH – Examples of transient PH include [2,32]:

Persistent PH of the newborn (see "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis")

PH associated with congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia in the neonate")

PH associated with bronchopulmonary dysplasia, which typically improves gradually but may persist (see "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis")

PH associated with acute pulmonary disease (eg, acute respiratory distress syndrome) (see "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults")

Flow-related PH associated with cardiac shunting defects that are corrected in infancy; however, in some cases, PH may persist after repair

It is important to recognize, however, that while these disorders are usually transient, they can be associated with severe and life-threatening PH in the acute setting and may require aggressive PH treatment and supportive therapy.

Persistent/progressive PH – Examples of persistent/progressive PH include:

Idiopathic/heritable PH

PH associated with congenital cardiac shunting defects, particularly if repaired late

PH associated with chronic pulmonary disease (eg, cystic fibrosis, interstitial lung disease) (see "Classification of diffuse lung disease (interstitial lung disease) in infants and children" and "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Pulmonary hypertension')

PH associated with sickle cell disease (SCD) (see "Pulmonary hypertension associated with sickle cell disease")

Functional classification — Functional capacity in patients with PH is classified according to the World Health Organization functional classification system (table 3). However, like the etiologic classification system, this system has considerable limitations in pediatric patients in that it lacks developmentally appropriate and objective indicators of symptoms that can be used in infants and children [2]. Exercise testing is often used to determine the functional class in adults with PH; however, the lack of exercise standards for children <8 years make it difficult to place young children in the World Health Organization classification.

The proposed Panama functional classification system attempts to provide age-specific criteria for pediatric patients; however, this system requires validation [33].

EPIDEMIOLOGY — Pediatric PH is a rare condition with an estimated prevalence of approximately 3 to 20 cases per one million children [32,34,35]. The prevalence varies according to age, with the highest prevalence in infants <12 months old. Most cases of PH in infancy are secondary to lung disease (ie, bronchopulmonary dysplasia-related PH and persistent pulmonary hypertension of the newborn [PPHN]). (See "Pulmonary hypertension associated with bronchopulmonary dysplasia" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

COMMON TYPES OF PULMONARY HYPERTENSION IN CHILDREN — Virtually all types of PH included in the 2018 6th World Symposium on Pulmonary Hypertension (WSPH) classification can be observed in pediatric patients, though some categories are exceedingly uncommon in childhood (table 1). The most common types of persistent/progressive PH in children are PH associated with congenital heart disease, PH due to lung disease, and idiopathic/heritable PH [32,36,37]. Transient forms of PH, such as persistent PH of the newborn and PH related to congenital diaphragmatic hernia, are also relatively common [32]. PH is well described in children with collagen vascular disease, liver disease, and acute thromboembolism, but these diseases are rare causes of PH in children [36].

Persistent pulmonary hypertension of the newborn — Persistent PH of the newborn is usually transient in nature [32]. This is discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Congenital heart disease — Only a small minority of patients with congenital heart disease develop clinically significant PH. The two broad categories of congenital heart disease that can cause PH include shunting lesions and left heart disease associated with elevated left atrial pressure (LAp).

Systemic-to-pulmonary shunting – By definition, PH occurs in any defect that by virtue of its size and location exposes the pulmonary circulation to systemic-level arterial pressure. Large ventricular septal defects are the most common example of this. In infants with such lesions, the right ventricle (RV) is usually well adapted to high pressure and, thus, the elevated pulmonary artery pressure (PAP), per se, is of little consequence in the short term, though they may have symptoms of congestive heart failure. (See "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis".)

From the point of view of the pulmonary circulation, the greater significance of unrepaired high-pressure shunting defects is that, during the first year or two, the patient may develop high pulmonary vascular resistance (PVR) and pulmonary hypertensive vascular disease, which can be irreversible and progressive [17]. PH can persist and increase in patients after closure of intracardiac shunts, especially when closed late. If PVR increases to systemic or greater levels, unrepaired defects that are typically acyanotic (eg, ventricular septal defect, patent ductus arteriosus, atrial septal defect) may become cyanotic by virtue of shunt reversal. This is referred to as Eisenmenger syndrome. In addition to cyanosis, potential complications of Eisenmenger syndrome include stroke, renal insufficiency, hypertrophic osteoarthropathy, polycythemia, and thrombocytopenia [38]. Eisenmenger syndrome is discussed in greater detail separately. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis".)

Timely repair of high-pressure shunting defects is therefore of great importance. By contrast, atrial septal defects are associated with low-pressure shunting (at least initially) and they very infrequently lead to PH during childhood; when PH develops, it typically occurs only after the first two decades of life [17]. Unlike ventricular septal defects and patent ductus arteriosus, the timing of atrial septal defect repair (when indicated) is usually after the first year of life. (See "Isolated atrial septal defects (ASDs) in children: Management and outcome".)

Left heart disease – Conditions that increase LAp (eg, mitral valve disease, noncompliance of the left ventricle), can also cause PH; however, these are not common in childhood [39]. The magnitude of elevation of PAP is highly variable: In some patients, PAP is increased only to the same degree as the LAp but, in a substantial minority, PAP is increased to a much greater degree compared with LAp [39].

Pulmonary vein stenosis – Pulmonary vein stenosis is an uncommon cause of PH. It is a rare disease that may be idiopathic or may be associated with total or partial anomalous pulmonary venous return or prematurity [40]. This form of PH is almost entirely unique to pediatric patients, with young infants most commonly affected. It is rarely seen in adults except as a complication after catheter ablation for atrial fibrillation. (See "Total anomalous pulmonary venous connection", section on 'Outcome' and "Atrial fibrillation: Catheter ablation", section on 'Pulmonary vein stenosis' and "Partial anomalous pulmonary venous return".)

Lung disease — Bronchopulmonary dysplasia is the most notable diagnostic entity in this category [41]. Maldevelopment of and acquired injury to pulmonary blood vessels underlies PH in this setting, and the vascular bed is especially prone to vasoconstriction with viral infection or other stresses [11]. Most patients with PH due to bronchopulmonary dysplasia are only mildly to moderately affected, especially when healthy, and PAP generally falls with growth and development [42,43]. However, when PH is severe and persistent in this patient population, it is associated with considerable morbidity and mortality [44]. An additional etiology for PH in formerly preterm children is pulmonary vein stenosis, which can coexist with bronchopulmonary dysplasia or develop in those with little lung disease [5]; the pathobiology of this is not understood. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)

Many other types of acute and chronic lung disease in children may be complicated by PH. These conditions are reviewed in detail separately:

Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia in the neonate")

Interstitial lung disease (see "Approach to the infant and child with diffuse lung disease (interstitial lung disease)")

Acute respiratory distress syndrome (see "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Consequences')

Pneumonia (see "Community-acquired pneumonia in children: Clinical features and diagnosis")

Cystic fibrosis (see "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Pulmonary hypertension')

Idiopathic/heritable pulmonary hypertension — Idiopathic and heritable PH are classified together since they are clinically indistinguishable. Heritable PH includes patients with a known PH genetic mutation and those with a family history of PH. Idiopathic PH refers to patients with PH in whom no underlying cause has been identified. Heritable PH is likely underdiagnosed, and some patients with idiopathic PH may actually have genetic causes of their disease. [32,35].

Syndromes — PH is associated with a large number of chromosomal abnormalities, syndromes, and complex, multiorgan diseases. In data from pediatric PH registries, 12 to 17 percent of children had underlying chromosomal or undefined syndromes [32,36,37]. Down syndrome is the most common disorder in this category; others include DiGeorge, Pierre-Robin, and Noonan syndromes [2,32,36,45]. However, the number of conditions associated with PH is growing and too numerous to comprehensively list here. In patients with these conditions, PH may develop as a result of cardiac or pulmonary disease associated with the syndrome (eg, airway abnormalities, chronic aspiration, disordered breathing, restrictive lung disease from neuromuscular weakness or scoliosis) or may be due to genetic factors resulting from chromosomal abnormalities. PH is likely multifactorial in many cases.

CLINICAL FEATURES — The presentation of PH varies considerably based upon:

Age of the patient

Presence or absence of associated medical conditions

Severity of the PH

Right ventricular (RV) function

Signs and symptoms of PH, when present, may include [35,36,46]:

Dyspnea with exertion

Fatigue

Syncope (usually with exertion)

Cyanosis (with exertion or at rest)

Failure to thrive

Cough

Chest pain

Heart failure (uncommon)

Mildly or even moderately elevated pulmonary artery pressure (PAP) may cause no or only subtle symptoms, especially in the sedentary. Symptoms may be more notable if there is a supervening infection or other stressor. In one study, the average time from onset of symptoms to diagnosis was approximately 17 months [36].

The degree of symptoms depends in large part on how well the RV adapts to the increased pressure load. Some patients (especially those with PH since birth) develop RV hypertrophy and have preserved RV contractile function. Such individuals may be relatively asymptomatic for many years despite very high PAP. In other patients with similarly elevated PAP, the RV adapts poorly, and reduced systolic and diastolic function limit cardiac output at exercise and even rest.

The physical examination may be unremarkable, especially with only modestly increased PAP. With RV dilation, there may be a left parasternal heave. The second heart sound (S2) may be narrowly split (or single), with an increased pulmonic component (movie 1), but, even with markedly elevated PAP, this may escape detection. A systolic murmur of tricuspid regurgitation or diastolic murmur of pulmonary regurgitation may be present with severely elevated RV pressure. Hepatomegaly and peripheral edema generally indicate RV dysfunction and may not be present even with severe PH.

Typical presenting symptoms and physical findings in the most common types of pediatric PH are as follows:

PH associated with congenital heart disease – The clinical features depend on the specific defect and type of repair/palliation:

Unrepaired cardiac shunting lesions – Cyanosis and polycythemia may be the presenting signs of unrepaired cardiac shunting lesions with high pulmonary vascular resistance (PVR). However, PAP and PVR can be markedly elevated, even in patients with normal oxygen saturation. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Cavopulmonary palliation – In patients with single-ventricle heart disease (eg, hypoplastic left heart disease) who have undergone cavopulmonary palliation (ie, Fontan or bidirectional Glen palliation), signs and symptoms of PH include poor exercise tolerance, peripheral edema, pleural effusions, and protein-losing enteropathy. (See "Management of complications in patients with Fontan circulation", section on 'Cardiovascular complications'.)

PH associated with lung disease — In patients with PH due to underlying lung disease, the clinical presentation is largely determined by the primary disease, and the impact of PH may be difficult to assess. Clinically significant elevations in RV pressure can result in RV systolic dysfunction (usually demonstrated by echocardiography) with consequent poor systemic perfusion and/or a tendency to retain fluid. On the other hand, difficulty with gas exchange alone does not necessarily imply a significant role for PH.

Idiopathic/heritable PH — Idiopathic/heritable PH typically presents in previously healthy ambulatory children. These patients may have no or only subtle symptoms initially. Thus, idiopathic PH tends to be diagnosed at a relatively late stage in children.

EVALUATION — The initial evaluation for PH consists of:

Electrocardiography

Brain natriuretic peptide (BNP) level

Chest radiograph

Echocardiography

Echocardiography has a high sensitivity to identify patients with clinically important PH [47]. Cardiac catheterization is the gold standard for diagnosis of PH as it affords the most accurate measure of pulmonary artery pressure (PAP) and provides additional valuable information (eg, estimates of cardiac output, atrial pressures, response to pulmonary vasodilators); however, this invasive test is not always necessary during the initial evaluation.

Additional testing is performed to evaluate functional capacity, better evaluate right ventricle (RV) size and function (if not adequately assessed with echocardiography), and identify the underlying etiology of PH if a cause is not identified in the initial evaluation. The diagnostic evaluation is guided by the clinical findings. A thorough cardiopulmonary assessment is required in all patients. For patients without a known predisposing condition (ie, idiopathic PH), a comprehensive evaluation is required.

The findings on echocardiography, cardiac catheterization, and other tests are integrated with assessment of functional class (table 3) and degree of symptoms to determine the severity of illness (table 4).

History and physical examination — A complete history and physical examination should be performed with particular attention to the following:

Associated disease(s)

Symptoms referable to the cardiovascular system (eg, easy fatigability, syncope, and chest pain)

Birth and neonatal history

Family history of PH or of early death possibly due to cardiovascular disease

History of residence at high altitude

Signs of congenital cardiac disease or RV dilation and/or dysfunction – Left parasternal heave, pathologic second heart sound (S2) (movie 1), systolic or diastolic murmurs, and hepatomegaly and peripheral edema

Airway anomalies, chest wall deformity, or other signs of pulmonary disease

Signs of other systemic disease (eg, telangiectasia)

Electrocardiography — The electrocardiogram is abnormal in most, but not all, patients with moderate to severe PH [48]. Characteristic findings include RV hypertrophy (waveform 1) and/or RV strain (eg, ST-T wave abnormalities in the inferior leads); less commonly, right atrial enlargement may be noted (waveform 1). However, these findings are somewhat nonspecific and the electrocardiogram alone is insufficiently sensitive to serve as a screen for PH.

BNP and NT-proBNP — Trending BNP levels can be a useful component of globally assessing the patient's clinical course and monitoring response to treatment. BNP and N-terminal pro-BNP (NT-proBNP) are biomarkers that are commonly used to assess severity and monitor response to therapy in children and adults with heart failure. BNP is elevated in patients with PH and may have prognostic value; however, data in pediatric patients are limited [49-52]. In addition, an elevated BNP level does not distinguish between left and RV failure. (See "Natriuretic peptide measurement in non-heart failure settings", section on 'Pulmonary hypertension'.)

Chest radiograph — Dilation of the main and proximal branch pulmonary arteries is a common finding in patients with severe PH. Cardiomegaly suggests RV dysfunction and dilation. Pulmonary edema may be present with heart failure (even if the RV is the failing chamber) but also raises the possibility of pulmonary venous obstruction. If present, pulmonary parenchymal disease is often apparent on the chest radiograph; this finding should prompt consideration of chest computed tomography (CT). (See 'Additional testing' below.)

Echocardiography — Echocardiography is the most helpful test in the initial assessment and follow-up of patients with PH. It provides the following information [53]:

Identification of structural cardiac lesions.

Estimation of RV pressure – The most accurate echocardiographic method for measuring RV (and hence pulmonary artery) systolic pressure is to determine the velocity of the tricuspid regurgitant jet. However, not all patients have appreciable tricuspid regurgitant and, even for those who do, careful interrogation of the jet is required. Lacking an adequate tricuspid regurgitant jet, the position of the interventricular septum at end systole may be helpful. The septal position provides only a rough estimate of RV systolic pressure, and accurate quantification is not possible without a tricuspid regurgitant jet [54]. High RV pressure is also suggested if right-to-left shunting is seen across communications that normally shunt left-to-right (eg, ventricular septal defect, patent ductus arteriosus, atrial septal defect). (See "Echocardiographic assessment of the right heart", section on 'Pulmonary artery pressure'.)

Assessment of RV systolic function – RV systolic function can be qualitatively assessed with echocardiogram, as can RV free wall thickness and cavity size (although magnetic resonance imaging [MRI] more accurately measures the variables) [55].

Assessment of valve regurgitation – Tricuspid (and less commonly, pulmonary valve) regurgitation may be revealed.

Cardiac catheterization — Cardiac catheterization is the gold standard for diagnosis of PH; however, it is not always necessary during the initial evaluation. Because it is an invasive procedure that carries risks, cardiac catheterization is sometimes deferred until initiation of targeted PH therapy is under consideration. (See "Pulmonary hypertension in children: Management and prognosis", section on 'Targeted pulmonary hypertension therapy'.)

Indications – Cardiac catheterization should generally be performed prior to initiation of targeted PH therapy, with certain exceptions (eg, critically ill children who require immediate empiric therapy) [2,56]. In addition, cardiac catheterization may be performed in the following settings:

When noninvasive testing is inadequate or nondiagnostic

Follow-up of patients on targeted therapy

In patients with systemic-to-pulmonary shunts to assess operability (although this is infrequently required, especially in the first year of life)

In patients undergoing evaluation for heart or heart-lung transplantation to assess suitability for transplantation

Information provided by catheterization – Compared with echocardiography, cardiac catheterization:

Provides a more accurate measurement of PAP

Provides additional hemodynamic measurements (eg, cardiac output, atrial pressures, pulmonary capillary wedge pressure)

Allows vasoreactivity testing (ie, measurement of the response to vasodilators, such as inhaled nitric oxide)

Allows measurement of flow through shunt lesions

In some cases, interventions can be performed to close shunting lesions (eg, device closure of atrial septal defect, coiling of aortopulmonary collaterals)

Can demonstrate abnormally shaped and distributed pulmonary arteries or stenosis of large pulmonary arteries; however, the morphology of the small pulmonary arteries has not proven to be a robust prognostic indicator [57]

Acute vasoreactivity testing (AVT) – AVT is a particularly important component of the cardiac catheterization in children with PH as it informs prognosis and can guide therapy (eg, reactive patients are often treated with calcium channel blockers) [56,58,59]. (See "Pulmonary hypertension in children: Management and prognosis", section on 'Reactive acute vasoreactivity testing'.)

AVT involves the administration of a short-acting vasodilator (typically inhaled nitric oxide) followed by measurement of the hemodynamic response. The criteria used to identify "reactivity" on AVT in pediatrics have differed somewhat between centers and among published studies [1,2,9,59]. The Pediatric Task Force of the 2018 6th World Symposium on Pulmonary Hypertension (WSPH) suggested that "reactivity" be defined by a decrease in mean PAP by at least 10 mmHg to a value of <40 mmHg with no decrease in cardiac output [1]. Alternative criteria define reactivity as a ≥20 percent decrease in mean PAP with a decreased ratio of systemic to pulmonary vascular resistance (PVR) and unchanged or increased cardiac index [60]. An international registry study found that the Pediatric Task Force definition more accurately identified patients who could be successfully treated with calcium channel blockers compared with other AVT criteria or the judgement of the treating clinician [59].

Other specific details of AVT are beyond the scope of this topic review and are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization'.)

Procedural risks – The main disadvantages of cardiac catheterization are the invasive nature of the procedure, its inherent risks, and the need for general anesthesia or sedation. Cardiac catheterizations in children with PH should be performed in centers with experience and expertise in management of PH patients. In this setting, the risks associated with the procedure are low, except for the most compromised patients [61,62]. The risk of cardiac arrest is 0.8 to 2 percent, and the risk of pulmonary hypertensive crisis is approximately 5 percent [2,61,63]. (See "Complications of diagnostic cardiac catheterization".)

Additional testing — Additional testing is performed to better evaluate cardiac and pulmonary function, assess the patient's functional capacity, and identify the underlying etiology of PH if a cause is not identified in the initial evaluation. The diagnostic evaluation is guided by the initial clinical findings.

Cardiac MRI – Cardiac MRI more accurately quantifies RV size and ejection fraction than does echocardiography. Some cardiac structural abnormalities (eg, abnormally connected pulmonary veins) are also better defined on MRI than on echocardiography. Also, pulmonary blood flow and cardiac output can be measured using this modality. The need for sedation or even general anesthesia limits the use of this modality in younger children.

Six-minute walk test – This test of functional capacity, when applied according to strict protocol, provides a useful estimate of cardiopulmonary capacity [64]. It is routinely used by many practitioners for longitudinal follow-up of patients who are approximately seven years of age and older. In younger children, testing is generally not feasible, because of inability to cooperate with testing and lack of normative reference values. Cardiopulmonary exercise testing is used less often in children with PH, is more expensive, and requires more expertise in interpretation. (See "Exercise testing in children and adolescents: Principles and clinical application", section on 'Idiopathic pulmonary arterial hypertension'.)

Pulmonary function tests – Pulmonary function tests are performed to identify and characterize underlying lung disease that may be contributing to PH. (See "Overview of pulmonary function testing in children".)

Chest CT scan – For children with clinical and/or radiographic findings suggestive of parenchymal lung disease, chest CT with contrast can be helpful in the diagnostic evaluation. Chest CT with contrast can also reveal large and small airways disease, pulmonary emboli, and pulmonary vein stenosis. If pulmonary embolus is suspected, formal CT pulmonary angiography should be performed (rather than a simple contrast study). Chest CT can also suggest (but not confirm) the diagnosis of pulmonary veno-occlusive disease [65]. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Computed tomography' and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Computed tomography'.)

Polysomnography – For patients with clinical suspicion for upper airway obstruction or sleep-disordered breathing, polysomnography may be warranted [66]. (See "Evaluation of suspected obstructive sleep apnea in children".)

Pulmonary perfusion scan – Nuclear lung scintigraphy or pulmonary ventilation/perfusion scanning is routinely used in many centers for initial evaluation of patients with PH. The primary reason for this testing is to detect evidence of chronic pulmonary thromboemboli, although perfusion abnormalities are also seen with pulmonary vein stenosis and multiple large pulmonary arterial stenoses. Ventilation/perfusion scan may be performed if the suspected etiology for PH is multiple pulmonary emboli. Since this is an exceedingly uncommon cause of PH in pediatric patients, the ventilation/perfusion scan is a low-yield test in the pediatric population. It has a high sensitivity but low specificity due to variable perfusion in hypertensive lungs and/or pulmonary vein obstruction. CT angiography is the preferred imaging modality for detecting acute pulmonary thromboembolism.

Genetic testing – For children with idiopathic PH or a suggestive family history, genetic testing for mutations associated with PH (table 2) should be discussed with the patient and parents during the diagnostic work up [2,52]. Initially, studies to identify causative mutations in the affected child are undertaken by analyzing a panel of selected candidate genes. Subsequent testing can be offered to family members if a definitive mutation is identified. Given rapid progress in molecular diagnostics, follow-up genetic counseling for PH patients and relatives is suggested during ongoing care.

Mutations in the gene encoding the transforming growth factor B cell surface receptor (BMPR2) are noted in 70 percent of patients with heritable PH and 10 to 40 percent of those with idiopathic PH [52,67-69]. These genes display autosomal dominant inheritance with variable penetrance. Other mutations have been identified in patients with PH associated with hereditary hemorrhagic telangiectasia and other forms of pulmonary arterial hypertension (PAH) (table 2) [70-73]. Genetic mutations are more commonly identified in patients with childhood-onset idiopathic PAH compared with adult-onset (35 percent versus 11 percent, respectively) [74].

Lung biopsy – Lung biopsy is not a routine part of PH evaluation, partly due to its invasive nature and associated morbidity but more importantly because it seldom informs prognosis and therapy. Certain forms of diffuse lung disease may be associated with PH and require diagnosis through lung biopsy. These are discussed in greater detail separately. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Lung biopsy'.)

Other tests – Other tests may be warranted based upon individual clinical findings or if the etiology of PH remains uncertain after the initial evaluation (eg, patients with apparently idiopathic PH). These include:

Liver function tests and hepatic ultrasound to identify portal vein abnormalities (portal atresia or porto-systemic shunts)

HIV testing (although PH with HIV is rare in pediatric patients [1])

Screening for autoimmune/inflammatory disorders (eg, erythrocyte sedimentation rate and/or C-reactive protein, antinuclear antibodies, rheumatoid factor)

Thyroid function tests

Coagulation studies and thrombophilia evaluation

DIAGNOSIS — A presumptive diagnosis of PH can be established on the basis of echocardiography showing quantitatively or qualitatively elevated right ventricular [RV] pressure. Definitive diagnosis of PH requires cardiac catheterization; however, because this test is invasive, it is sometimes deferred until initiation of targeted PH therapy is under consideration. The diagnosis of PH is confirmed if mean pulmonary artery pressure (PAP) is >20 mmHg. (See 'Definition' above and 'Echocardiography' above and 'Cardiac catheterization' above.)

Specific diagnostic criteria for the different 2018 6th World Symposium on Pulmonary Hypertension (WSPH) classes of PH are reviewed in detail separately. However, it is important to note that the WSPH classification system has limitations in pediatric patients, as previously discussed. (See 'Classification' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PH is broad, given the variable presenting signs and symptoms. Other causes of undue dyspnea with exertion (which is the most common presenting symptom in older children with PH) include structural heart disease, cardiomyopathy, myocarditis, pericarditis, endocarditis, endocrine disorders (eg, hypothyroidism), postural orthostatic tachycardia syndrome, lung disease (eg, asthma), malignancy, renal disease, liver disease, viral syndrome, anemia, and psychiatric disorders (eg, depression, anxiety). The clinical history and physical examination can distinguish some of these conditions from PH; however, a formal cardiac evaluation including echocardiography is ultimately required to make the diagnosis.

The differential diagnosis of dyspnea in children is described in greater detail separately. (See "Causes of acute respiratory distress in children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

Basics topic (see "Patient education: Pulmonary hypertension (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure (PAP), which may result in right ventricular (RV) failure. For children and infants >3 months old, the definition of PH is the same as in adults: mean PAP >20 mmHg at sea level. (See 'Definition' above.)

This definition has several limitations:

It does not address infants ≤3 months old

It fails to account for the impact PAP has on the RV

It does not reflect whether the high PAP is due to an abnormal pulmonary vascular bed, increased pulmonary blood flow, or increased pulmonary venous pressure

It fails to account for the fact that pulmonary hypertensive vascular disease (PHVD) can occur with PAP <20 mmHg

It may not reflect the PAP during conditions other than those at the time of PAP measurement.

Causes and classification – Causes of PH are summarized in the table (table 1). In children, PH is usually associated with underlying cardiac or lung disease (eg, congenital heart disease, bronchopulmonary dysplasia). PH may also be idiopathic or familial. Other causes of PH are rare in childhood. (See 'Common types of pulmonary hypertension in children' above.)

PH is classified according to etiology/mechanism (table 1) and functional capacity (table 3); however, these classification systems have important limitations in pediatric patients, as discussed above. (See 'Classification' above.)

Evaluation

Referral – The diagnostic evaluation of PH in pediatric patients should be carried out by or in close collaboration with practitioners with considerable experience and expertise in this area. Early referral is critical since treatment for many types of PH is less effective if provided at a late stage of the disease. (See 'Referral' above.)

Initial testing – The initial evaluation for PH consists of (see 'Evaluation' above):

-A complete history and physical examination (see 'History and physical examination' above)

-Electrocardiography (see 'Electrocardiography' above)

-Brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) level (see 'BNP and NT-proBNP' above)

-Chest radiograph (see 'Chest radiograph' above)

-Cardiac echocardiography(see 'Echocardiography' above)

This testing has a high sensitivity to identify patients with clinically important PH.

Cardiac catheterization – Cardiac catheterization is the gold standard for diagnosis of PH as it affords the most accurate measure of PAP and provides additional valuable information; however, it is not always necessary during the initial evaluation. Because it is an invasive procedure that carries risks, cardiac catheterization is sometimes deferred until initiation of targeted PH therapy is under consideration. (See 'Cardiac catheterization' above.)

Additional testing – Additional testing is performed to evaluate functional capacity, better evaluate RV size and function (if not adequately assessed with echocardiography), and identify the underlying etiology of PH if a cause is not identified in the initial evaluation. The diagnostic evaluation is guided by the clinical findings. A thorough cardiopulmonary assessment is required in all patients. For patients without a known predisposing condition, a comprehensive evaluation is required. (See 'Additional testing' above.)

Diagnosis – A presumptive diagnosis of PH can be established with echocardiography showing quantitatively or qualitatively elevated RV pressure. Definitive diagnosis of PH requires cardiac catheterization; mean PAP >20 mmHg confirms the diagnosis. (See 'Diagnosis' above.)

The findings on echocardiography, cardiac catheterization, and other tests are integrated with assessment of functional class (table 3) and degree of symptoms to determine the severity of illness (table 4). (See 'Evaluation' above.)

Differential diagnosis – The differential diagnosis of PH is broad, given the variable presenting signs and symptoms. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas Kulik, MD, now deceased, who contributed to an earlier version of this topic review.

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Topic 17234 Version 15.0

References

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