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.

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.

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.

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.

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.

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.

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. 2019). TOPP-2 will continue to collect data regarding this endpoint.

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.

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

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.

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.

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.