Unmet needs

There has been considerable progress made in the prognosis of pediatric PH over the last decades. This has coincided with advancements in diagnosis and general management of the disease, as well as the application of adult-specific treatment strategies to children due to the sparsity of data concerning the pediatric population.

Efforts to increase the understanding of pediatric PH led to the initiation of the TOPP-1 registry in 2007. In 2013, at the World Symposium of Pulmonary Hypertension (WSPH) in Nice, the first assembly of the pediatric PH task force took place. Recommendations concerning the classification, diagnosis, risk assessment and treatment goals of PH, specifically in children, were published as a result, also considering results from the TOPP-1 registry.

Despite these great achievements in pediatric PH, unmet needs remain to be addressed in this field. Below we present some of these important open questions and how the PePH, with the valued support of the pediatric community, aims to tackle these issues via the continued analysis of TOPP-1 data, the completion of the newly launched TOPP-2 registry, and other innovative initiatives.

Open questions

Classification and etiology of pediatric PH

Do disease demographics and outcome differ by clinical classification of CHD according to the ABCD classification?

The proposed ABCD classification for children in clinical practice:

  1. Eisenmenger syndrome
  2. PAH associated with systemic-to-pulmonary shunts
  3. PAH with small defects
  4. PAH after corrective cardiac surgery

A TOPP-1 analysis is currently being performed to address the question if disease demographics and outcome differ with the presence of CHD or by clinical classification of CHD. This manuscript will also investigate the validity of ABCD classification in children. Further information will follow on this webpage when the results have been published.

Furthermore, TOPP-2 will continue to collect the ABCD classification of enrolled patients and further insights are expected from the successor registry on this topic.

What is the prevalence of PAH gene mutations? Is there a correlation between genotype, phenotype and disease outcome?

TOPP-2 takes into account the question of genetics in idiopathic and heritable forms of pediatric PH by collecting information of mutation type at diagnosis including the known mutations of BMPR2, ALK-1, TBX4 and others. Information on consanguinity and familial PH are also assessed, enabling a deeper dive into the genetic catalysts of hereditary PH.

Is neonatal history a contributor to the development of future pediatric PH?

As part of the patient’s medical history, TOPP-2 routinely collects for all enrolled patients incidences of neonatal disorder and respective conditions such as persistent PH of the newborn, respiratory distress syndrome and continued oxygen past the gestational age of 37 weeks. With this information, the PePH Association is confident to be able to enlarge the knowledge base of the influences of neonatal history on the development of PH in children.

Is neonatal history a contributor to the development of future pediatric PH?

As part of the patient’s medical history, TOPP-2 routinely collects for all enrolled patients incidences of neonatal disorder and respective conditions such as persistent PH of the newborn, respiratory distress syndrome and continued oxygen past the gestational age of 37 weeks. With this information, the PePH Association is confident to be able to enlarge the knowledge base of the influences of neonatal history on the development of PH in children.

Do correlations with long-term risk and successful treatment exist in patients with PH associated with BPD?

PH is a common complication of bronchopulmonary dysplasia (BPD) in children. Also for BPD, TOPP-2 assesses the occurrence of BPD as well as connected disorders (pulmonary vascular stenosis, pulmonary vein stenosis, left ventricular diastolic dysfunction and with systemic to pulmonary shunt). From these data, we might be able to conclude the influence of BPD on the long-term outcome of patients with PH.

Diagnostics

What effect do the Nice 2013 recommendations have on the diagnostic and follow-up aspects of patient care?

TOPP-1 registry data has shown that diagnosis and follow-up investigations can often vary between countries and centers. Comparing TOPP-1 and TOPP-2 data might reveal if the recent achievements in collecting clinical data and translating them into recommendations for patient care were able to positively affect the outcome for patients in clinical practice across the world.

Prognostication and therapeutic strategies

What are the predictive prognostic values of the individual components that make up TTCW in pediatric PH?

Time to clinical worsening (TTCW) is frequently used as a (secondary) endpoint in PH trials (Humbert et al. 2014). TTCW has been identified as an appropriate and meaningful outcome in pediatric PH following statistical analyses of the TOPP-1 registry (Beghetti et al., abstract presented at AEPC 2016; manuscript in preparation). TOPP-2 will continue to collect data regarding this endpoint.

Can we adapt the updated adult treatment strategies in the pediatric population?

In adult PAH treatment goals have been raised to encourage improved disease management and therefore outcomes in patients. The use of initial combination therapy, rather than sequential therapy is one example of this; the use of upfront triple combination therapy has been investigated in a pilot clinical study among adults with PAH FC III/IV. The success of this study and potential of upfront triple therapy to be beneficial in even lower risk adult patients, has also led to the commencement of the TRITON study. This clinical study aims to compare the efficacy and safety of an initial triple oral treatment regimen (macitentan, tadalafil and selexipag) versus an initial dual oral treatment regimen (macitentan, tadalafil and placebo) in newly diagnosed, treatment-naïve adult patients with PAH.
Similarly, there are plans by the PePH to investigate upfront triple combination therapy in children initiated on triple therapy following a diagnostic right heart catheterization.

What are the current clinical drivers of treatment escalation and strategy, and how do these effect children’s clinical outcomes?

The TOPP-2 registry is specifically designed to capture the initialization and change in therapy in connection with adverse events or other outcomes to identify the drivers for therapy adaption

Can biomarkers be used as a measure for vascular and ventricular function?

A research group from Colorado, USA, has shown that in pediatric PAH, B-type natriuretic peptide (BNP) and the amino-terminal fragment (NT-proBNP), are strongly correlated and predict changes in clinical variables and hemodynamics.

Currently conducted analyses on TOPP-1 data aim to assess correlations between change in NT-proBNP and specific outcomes such as change in functional class, whether NT-proBNP at diagnosis is predictive of overall survival and whether fold change in NT-proBNP during follow-up is predictive of overall survival. Further information will follow on this webpage when the results have been published.

In addition, BNP/NT-proBNP values are collected in TOPP-2 and are expected to reveal further insights into the value of these biomarkers for pediatric PH.

What patients will benefit from surgical palliative treatment such as Pott’s shunt, and what is the evidence supporting its efficacy?

Children with severe PH have limited therapeutic options. Pott’s shunts have been proposed as a surgical, palliative treatment in children with severe PH. Case studies (Kim et al. 2015; Blanc et al. 2004) of children who have received this intervention show improved right ventricular function, and syncope and sudden death are potentially avoided. However, skepticism concerning this therapeutic option remains due to a lack of data on its use in pediatric PH. The PePH Association proposes further research in children with PH, who have received a Pott’s shunt, in order to answer these open questions.

What are the treatment recommendations regarding pediatric patients with PH-LHD?

There are many outstanding questions regarding PH due to left heart disease (PH-LHD) in pediatrics. In the TOPP registries children with pediatric PH due to left heart disease were excluded, because they presented clinically in a different way to other patient groups with PH. This meant assessing these patients using different clinical parameters than other PH subtypes. The PePH Association proposes further clinical research to collect important and necessary data regarding the current therapeutic strategies and therapies used in PH-LHD and their effectiveness and safety. These data collection may provide important information, such as the incidence of PH-LHD in children, the hemodynamic characteristics of this population, and the current diagnostic work-up done in these patients.