Evolution of the Classification of Pulmonary Hypertension

The first WHO World Symposium in 1973 classified PH into primary and secondary PH. In 1998, at the second World Symposium in Evian, clinical investigators from around the world proposed a new diagnostic classification; this classification categorized pulmonary vascular disease by similar clinical features, histopathology, hemodynamics, and management. PH was classified into five basic groups: PAH (group 1), left heart disease (group 2), lung disease (group 3), chronic thromboembolic PH (CTEPH; group 4), and multifactorial PH (group 5). At the 2003 Venice meeting, the term “PPH” was changed to “IPAH,” reflecting the fact that this is a diagnosis of exclusion with exact cause(s) yet unknown. Thus, in addition to IPAH (both sporadic and familial), PAH associated with congenital heart disease (CHD); connective tissue disease (CTD); portal hypertension; HIV infection; drugs and toxins (including anorexigens); and persistent pulmonary hypertension of the newborn (PPHN) were classified along with IPAH as group I PAH. In 2008 at Dana Point, the diagnostic classification system was updated further, and the term “familial pulmonary arterial hypertension” (FPAH) was abandoned in favor of heritable PAH (HPAH), defined to include all subjects with FPAH, plus any patients with an identified genetic mutation, regardless of whether there was a family history of PAH. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, which share many similarities with group I PAH but have subtle variations, was separated out to group I′. Finally, in 2013, at the fifth World Symposium held in Nice, France, although the basic framework was maintained, it was decided in conjunction with the pediatric PH task force to add elements related to pediatric PH and have a comprehensive classification common for all age groups, reflecting the understanding that many children with PH will grow up to become adults with PH ( Box 35.1 ).

Although the classification helps our understanding of the pathophysiology of PAH patients, it also has implications for the natural history. Despite the different physiologic classifications of group 1 PH, the histopathologic changes are virtually identical, so similar treatment strategies have evolved. As insight is advanced into the mechanisms responsible for the development of PAH, the introduction of novel therapeutic modalities will hopefully increase the overall efficacy of therapeutic interventions for PAH. In 2011, the members of the pediatric task force of the pediatric pulmonary vascular research institute (PVRI) proposed a functional classification of PH in children that describes assessment of functional capacity in children of different age groups, as well as a 10-category scheme of further categorizing pulmonary hypertensive vascular disease in children ( Boxes 35.2 and 35.3 ). They divided the functional classes to class I, II, IIa, IIb, and IV, and also described them separately for age groups 0–0.5 years, 0.5–1 year, 1–2 years, 2–5 years, and 5–16 years. Of particular importance is the acknowledgement of single ventricle circulation, where pulmonary vascular disease may be present without a mean PAP reaching 25 mm Hg, as these patients may benefit from targeted therapy. Thus the definition of PAH may be further expanded in single ventricle circulations to include a transpulmonary gradient of >6 mm and a PVRi >3 WU × m ² .

Gender

The gender distribution in adults is weighted toward more women with IPAH, whereas in pediatric patients, this distribution has been more variable, depending on the inclusion criteria, with female to male ratio varying from 1.09 : 1 in the French and Swiss registries to 1.7 : 1 reported by the UK group. Other studies have found a more even gender distribution, with the Dutch study reporting 55% of IPAH patients to be female. When all etiologies of PAH are included, the female to male ratio gets closer to 1 : 1 because there is no significant gender predominance for CHD with PAH. The REVEAL registry reported a 2 : 1 female to male ratio in children and a 4.1 : 1 in adults with IPAH.

Genetics of PAH

The first report of familial PPH was published as early as 1954 by Dresdale, and since then it has been increasingly evident that heritable PAH has a very strong association with germline mutations. By the1980s it was evident that FPAH had an autosomal dominant mode of inheritance, and by 1997, two independent groups localized the defect to a region on chromosome 2 Q33. Mutations of the transforming growth factor β (TGFβ) family of receptors, particularly bone morphogenetic protein receptor (BMPR2), are found in kindreds with FPAH. More than 300 germline BMPR2 mutations have been identified in FPAH patients, with the mutations being usually similar within families. These mutations are located throughout the gene. BMPR2 mutations are seen in more than 80% of patients with HPAH, while the remaining have mutations in other genes encoding the TGFβ superfamily of receptors. In addition, mutations of ACVRL 1, activin receptor–like kinase 1 (ALK 1) located on chromosome 12, and endoglin (ENG) on chromosome 9 have been described in association with hereditary hemorrhagic telangiectasia (HHT). A third locus, the SMAD8 gene identified on chromosome 13, ties in with the role of SMADs in BMP signaling.

The BMPR2 mutations are germ line mutations and are potentially heritable, regardless of whether they appear de novo in an index case or have been inherited. Because of reduced penetrance, only approximately 20% of people with a BMPR2 mutation develop the disease. Females have a greater incidence and prevalence of HPAH, suggesting either that the male fetuses with the disease die in utero or there are hitherto undetected risk factors increasing the predilection for developing the disease in women. The clinical expression of PAH is variable, even within families having the same mutation. Genetic anticipation has been described with HPAH (i.e., affected individuals in successive generations in a family pedigree express the disease earlier with earlier age of death); however, this has been recently been questioned. BMPR2 mutations are seen in 80% of subjects with FPAH and are also seen in approximately 10%–25% of patients with no family history of PAH, suggesting that these represent de novo mutations. Individuals with BMPR2 mutation have more severe disease phenotype associated with earlier disease manifestation, worse hemodynamics, less vasoreactivity, and earlier mortality. This is also seen with the ACVRL 1 mutation. Male carriers of the BMPR2 mutations tend to have a worse prognosis. It has been suggested that genetic testing for BMPR2 mutations be performed in children with PAH and healthy siblings. Because of the large number of potential mutations in the gene, and the fact that mutations within a given pedigree are constant, testing should start with the proband and then the family members of the affected individual.

Whole exome sequencing (WES) techniques have shown a rare mutation in the caveolin 1 (CAV1) gene in members of a family with PAH. More recently, a novel channelopathy has been described in the potassium channel (KCNK3), which may have implications for finding a therapeutic pathway.

Persistent Pulmonary Hypertension of the Newborn

PPHN is a unique form of PAH, which usually resolves completely with appropriate intervention. PPHN is a syndrome characterized by increased PVR, right to left shunting (at the atrial and/or ductal level), and severe hypoxemia. It is frequently associated with pulmonary parenchymal abnormalities (e.g., meconium aspiration, pneumonia, or sepsis) or may occur when there is pulmonary hypoplasia, maladaptation of the pulmonary vascular bed postnatally as a result of perinatal stress, or maladaptation of the pulmonary vascular bed in utero from unknown causes. In some instances, there is no evidence of pulmonary parenchymal disease and the cause of PAH is unknown. Although some children die during the neonatal period despite maximal cardiopulmonary therapeutic interventions, PPHN is almost always transient, with infants recovering completely without requiring long-term medical therapy. In contrast to these infants, patients with IPAH, as well as PAH related to the other conditions discussed previously, appear to require treatment indefinitely. It is possible that in some neonates the PVR does not fall normally after birth and goes unrecognized during the neonatal period; the patient is then diagnosed with PAH at a later date as the pulmonary vascular disease progresses. Pathologic studies examining the elastic pattern of the main pulmonary artery suggest that IPAH is present from birth in some patients, although it is acquired later in life in others. The histopathologic changes have illustrated increased muscularity of the peripheral pulmonary arterioles, similar to IPAH.

Bronchopulmonary Dysplasia and Pulmonary Hypertension

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy that occurs in premature infants after oxygen and ventilator therapy for acute respiratory failure at birth. When first characterized nearly 50 years ago, BPD was originally described as severe chronic respiratory disease with very high morbidity and high mortality in relatively late-gestation preterm infants, because infants below 28 weeks gestation rarely survived in that era. With improved care in very premature infants in modern neonatal units, including gentle ventilation techniques, appropriate oxygenation and acid-base balance, nutrition, and other interventions, survival of infants beyond 23 weeks has dramatically improved. However, these successes have not led to a reduction in persistence of BPD, which remains a major problem, occurring in an estimated 10,000–15,000 infants per year in the United States alone, or in 68% of infants born at less than 29 weeks gestation and weighing less than 1500 g. In the previous era, BPD was related to airway injury, inflammation, and fibrosis due to ventilator damage and oxygen toxicity. The “new BPD” in the current era is characterized by impaired angiogenesis and alveolarization, with decreased vascular branching and persistent precapillary arteriovenous anastomotic vessels. Despite the differences in the pathology and epidemiology of BPD over time, PH continues to contribute significantly to high morbidity and mortality and is present early in the course of disease. Even the original descriptions of BPD noted striking pulmonary hypertensive vascular remodeling in severe cases and that the presence of PH beyond 3 months of age was associated with high mortality. Now in the “postsurfactant era” or the “new BPD,” late PH continues to be strongly linked with poor survival, with reports suggesting mortality rates of greater than 50% for infants with severe PH. Furthermore, the chronic lung disease can persist after infancy, with frequent hospitalizations due to respiratory problems in childhood and exercise limitations extending into adulthood.

Survival in APAH-CHD

Barst et al. compared patients with IPAH or HPAH ( n = 1,626) to those with CHD-associated PAH ( n = 353) who were enrolled in the REVEAL registry. Of patients with CHD-associated PAH, 151 had ES. They showed that there was no significant survival rate at 4 and 7 years in patients with APAH-CHD (regardless of presence of a shunt) versus IPAH. Analysis of 240 patients with APAH-CHD enrolled in the Spanish registry (REHAP) revealed that within the group, patients with ES had better survival than postoperative PAH (which had outcomes similar to IPAH). Among ES, a pretricuspid shunt predicted worse survival. Data from the German national register revealed 1-, 5-, and 10-year survival rates of 92, 75, and 57%, respectively, in the entire cohort of ES patients, with treatment-naïve patients having survival rates of 86, 60, and 34%, respectively.

Idiopathic/Heritable Pulmonary Arterial Hypertension

IPAH and HPAH, subtypes of PH group 1 PAH, are characterized by progressive pulmonary arterial vascular obliteration and subsequent right heart failure if untreated. A PAH patient is subclassified as having IPAH when a patient meets the hemodynamic criteria of PAH and all other associated forms of PAH (APAH) have been ruled out. HPAH previously referred to as FPAH occurs when there is a family history of PAH or identification of one of the genetic mutations associated with PAH, regardless of whether there is a family history or not. Although HPAH may represent a different clinical phenotype, both IPAH and HPAH likely represent overlapping diagnostic subgroups of PAH and are classified with other forms of PH group 1 PAH because of similar characteristics, histopathologic changes, and treatment responses.

Epidemiology

The exact incidence and prevalence of IPAH/HPAH in children worldwide is unknown. Adult studies have reported an overall incidence of approximately 1–2 new IPAH cases per million in industrialized countries. In the French and Scottish registries, the prevalence of group I PAH was reported as 15–50 PAH cases per million adults and included cases of APAH. With respect to children, a national cohort study of IPAH children in the United Kingdom followed over 7 years reported a lower incidence and prevalence compared with adults. The incidence of childhood IPAH was 0.48 cases per million children per year, and the prevalence was 2.1 cases per million. Of these patients, 7.8% had HPAH similar to reports in adults. The difference between the prevalence in the French registry and the UK childhood registry may be in part attributable to cases of PAH (including anorexigen related and CTD) included in the adult French registry that are not seen in children. A French pediatric registry reported a 4.4 per million prevalence of pediatric IPAH/HPAH. However, this prevalence does not include APAH-CHD, a subgroup of PAH that is considered to make up at least 50% of pediatric PAH. Thus the “best” estimate for pediatric PAH prevalence is approximately 10 per million.

Although the disease is rare, with improved diagnostics and increased awareness, it appears that more patients (both children and adults) have PAH than was previously recognized. On occasion, infants who died with the presumed diagnosis of sudden infant death syndrome had IPAH diagnosed at postmortem examination. The female preponderance in adult patients with IPAH previously reported as approximately 1.7 : 1 females:males is similar to earlier reports in children with IPAH (i.e., 1.8 : 1), with no significant difference in younger children compared with older children. More recent reports from the United States have reported a higher female preponderance in adults with PAH (i.e., approximately 4 : 1), with the gender ratio in the pediatric patients more similar to previous reports (i.e., approximately 2 : 1).

Natural History

Historically, untreated IPAH exhibited a course of progressive right heart failure and early death. In contrast, patients with unrepaired CHD with shunts often lived for at least several decades without targeted treatment. Several large survival studies of primarily adult patients with IPAH were conducted in the 1980s prior to the current treatment era. These retrospective and prospective studies yielded quite uniform results: adult patients with IPAH who did not have lung or heart/lung transplantation had actuarial survival rates at 1, 3, and 5 years of 68%–77%, 40%–56%, and 22%–38%, respectively. In the era before the use of continuous intravenous epoprostenol (approved in 1995), in children who were nonresponders to acute vasodilator testing and therefore not candidates for oral calcium channel blockade, the 1-, 3-, and 5-year survival rates were 66%, 52%, and 35%, respectively In more recent times, with the use of epoprostenol treatment for nonresponders, and calcium channel blockade for responders, the 10-year survival for children was reported by Yung et al. at 78%. However, there is significant biological variability in the natural history of the disease in both adults and children, with some patients having a rapidly progressive downhill course resulting in death within several weeks after diagnosis and others surviving for at least several decades.

Pathogenesis and Pathobiology of Pediatric Pulmonary Arterial Hypertension

Although the exact mechanism of PAH development has not been completely elucidated, endothelial cell dysfunction with smooth muscle cell (SMC) proliferation, dysfunction, and altered apoptosis secondary to imbalance of vasoactive mediators is the most consistent common factor ( Fig. 35.1 ). A thorough understanding of the factors underlying the pathogenesis is the mainstay for developing targeted treatment modalities. As more and more factors involved in this complex process are uncovered, molecules targeting these individual pathways are concomitantly undergoing testing on animal and cellular models, giving rise to a whole new generation of medications recently added to the armamentarium available to clinicians.

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