The TOPP-1 registry closed in July 2015 after including 699 patients and has already generated several very important publications for the understanding of pediatric pulmonary hypertension:

Clinical features of pediatric pulmonary hypertension: a registry study, was published in the Lancet in 2012 (Pubmed).

The major aim of this manuscript was to report the clinical features of pediatric pulmonary hypertension (PH) and in particular its epidemiology.

Consecutive patients ≤ 18 years of age at diagnosis with PH and increased pulmonary vascular resistance (PVR) were enrolled in the registry at 31 centers in 19 countries from 2008 to 2010. All of the included participants required a confirmatory cardiac catheterization for inclusion. Of 362 subjects with “PH-confirmed” (defined as mean pulmonary artery pressure [mPAP] ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and PVR-index [PVRI] ≥ 3 WU·m2), the majority (88%) had PH-group 1 pulmonary arterial hypertension ([PAH]: 57% idiopathic or familial PAH [iPAH/FPAH] and 43% associated PAH [APAH] of which 85% were PAH associated with congenital heart disease [CHD]). The remaining 12% had PH-group 3 – PH associated with respiratory disease and/or hypoxemia, with bronchopulmonary dysplasia being most frequent.

Chromosomal anomalies, primarily trisomy 21, were reported in 13% of all PH-confirmed subjects. Median age at diagnosis was 7 years; 59% were female. Although dyspnea and fatigue were the most frequent symptoms, syncope occurred in 31% of iPAH/FPAH and in 18% of repaired CHD; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope reported. Despite severe PH, i.e. mPAP 58±19 mmHg and PVRI 16±10 WU·m2, functional class was I/II in 64% of subjects consistent with preserved right heart function.

These results identify important information that is specifically relevant to the care of pediatric PH. These findings highlight the need for discrete pediatric data, rather than extrapolation and application of data from adult studies to children.

Diagnostic evaluation of pediatric pulmonary hypertension in current clinical practice, was published in the European Respiratory Journal in 2013 (Pubmed).

Current diagnostic algorithms for pediatric pulmonary hypertension (PH) include some pediatric-specific tests but it is unclear if the tests are used in clinical practice. This manuscript describes the current diagnostic work-up of the TOPP registry for suspected PH.

We investigated 456 patients enrolled until February 2010. The majority had electrocardiograms (94%), echocardiograms (96%) and/or chest radiographs (89%) performed and these were the non-invasive tests most frequently used for evaluation of suspected PH. There were no patients in which all three tests were considered normal. This suggests that there may be diagnostic potential for the combined three tests in ruling out PH.

For evaluation of complications associated with heart catheterization (HC) we analyzed a total of 908 HCs reported until February 2012. Of these, 554 were performed at diagnosis and 354 during follow-up. Complications were reported in 5.9% of patients with 5 deaths that were considered to be related to HC. This suggests that there may be a higher rate of HC complications in the pediatric population compared to the adult population. However, current recommendations support HC in pediatric PH. A proper application of the risk/benefit ratio for HC requires further data. Most children did not undergo the diagnostic work up currently recommended for adults, which highlights either incomplete awareness of current guidelines and/or challenges regarding their appropriateness for children.

This manuscript highlights the need of a complete diagnostic process in pediatric patients.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: insights from the global TOPP registry (tracking outcomes and practice in paediatric pulmonary hypertension), was published in the International Journal of Cardiology in 2016 (Pubmed).

This manuscript describes important characteristics of the hemodynamic profile at diagnosis and HC complications of pediatric patients presenting with PH. HC datasets underwent blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥25 mmHg, pulmonary capillary wedge pressure ≤12 mmHg and PVRI of >3 WU·m2). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analyzed. A total of 908 diagnostic and follow-up HC were performed and complications occurred in 5.9% of all HC including five (0.6%) deaths. General anesthesia (GA) was used in 53% and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analyzed for the entire group (3.7 L/min/m2; 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU·m2, 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI <2.5 L/min/m2 at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001).

In this registry the hemodynamic assessment was remarkable as the CI was preserved in the majority of patients despite severely elevated PVRI. HC-related complications incidence was 5.9%, and were associated with GA and higher functional class.

Acute vasodilator response in pediatric pulmonary arterial hypertension: current clinical practice from the TOPP registry, was published in the Journal of the American College of Cardiology in 2016 (Pubmed).

In pulmonary arterial hypertension (PAH) acute pulmonary vasodilator testing (AVT) is considered important to identify patients with favorable prognosis using calcium channel blocker (CCB) therapy. However, in pediatric PAH, the criteria used to identify acute responders, the prevalence of responders and the use of CCB are insufficiently studied. This manuscript describes current clinical practice of AVT and subsequent treatment decisions in pediatric PAH.

From January 2008 to May 2013, 529 consecutive PH-confirmed children were enrolled in the registry, of which 382 with evaluable AVT were analyzed.

Of the 382 included patients, 212 had idiopathic/familial PAH (iPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide (± oxygen supplementation), a variety of other agents were used in the remaining patients. In iPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL-pediatric criteria and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%) and 7 (7%) respectively. Correlation between AVT-responder status as judged by the treating physician and by published response criteria was poor. Of the iPAH/FPAH patients judged by the treating physician to be acute responders only 37% were treated with CCB without additional PAH-targeted therapy, which could not be explained by WHO-FC or age. The Sitbon criteria selected patients with better prognosis that had excellent outcome when treated with CCB.

The current practice of identifying responders to AVT and subsequent treatment with CCB therapy in centers treating children with iPAH/FPAH shows large discrepancies with current international guidelines. This study suggests that, also in pediatric iPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.

Treatment initiation in pediatric pulmonary hypertension – insights from a multinational registry, was published in Cardiology in the Young in 2016 (Pubmed).

Different treatment options for pulmonary hypertension (PH) have emerged in recent years and evidence–based management strategies have improved quality of life and survival in adults. In children with pulmonary vascular disease, therapeutic algorithms are not so clearly defined. This manuscript aims to determine the current treatment initiation in children with PH in participating centers of a registry.

Through the multinational TOPP Registry (Tracking Outcomes and Practice in Pediatric PH) patient demographics, diagnosis and treatment as judged and executed by the local physician were collected. Inclusion criteria were >3 months and <18 years of age; diagnostic cardiac catheterization consistent with PH (mean pulmonary arterial pressure ≥25 mmHg, pulmonary vascular resistance index ≥3 Wood Units.m2, mean pulmonary capillary wedge pressure ≤12 mmHg).

At diagnostic catheterization, 217/244 patients (88.9%) were treatment naïve for PH targeted therapy. Targeted therapy was initiated after catheterization in 170 (78.3%) treatment naïve patients. Nineteen patients received supportive therapy, 28 patients were not started on therapy. Twenty-six patients (10.7%) were on targeted treatment prior to catheterization. Among treatment naïve subjects, treatment was initiated with one targeted drug (n=112, 51.6%), dual therapy (n=39, 18%) or triple-therapy (n=5, 2.3%), calcium channel blocker with one targeted medication in 1 patient (0.5%). Phosphodiesterase inhibitors type 5 were used frequently; some patients with PH related to lung disease received targeted therapy.

This study shows that there is a diverse therapeutic approach for children with PH with a need of better defined treatment algorithms based on pediatric consensus for different etiologies including the best possible diagnostic work-up.

Meaningful and feasible composite clinical worsening definitions in paediatric pulmonary arterial hypertension: An analysis of the TOPP registry, was published in the International Journal of Cardiology in 2019 (Pubmed).

Composite clinical worsening (cCW) outcomes might allow measurement of disease progression in paediatric pulmonary arterial hypertension (PAH). This analysis investigated three cCW outcomes and their predictive strength for lung transplantation/death.

Patients ≤17 years with idiopathic/familial PAH or PAH-associated congenital heart disease diagnosed ≤3 months before enrolment were included. cCW outcomes included the following variables at enrolment and/or follow-up: all-cause death, PAH-related hospitalisation, lung transplantation, atrial septostomy (cCW1, 2 and 3), WHO FC deterioration, intravenous/subcutaneous prostanoids initiation, syncope (cCW2,3) and occurrence/worsening of ≥2 PAH symptoms (cCW3). The predictive value of CW (excluding transplantation and death) to transplantation or death was assessed. Predictive values of each cCW for lung transplantation/death were analysed by Cox proportional hazards models. From 255 patients, first-event rate/100 person-years (95% CI) were cCW1: 23.1 (19.3, 27.6), cCW2: 43.6 (37.6, 50.6), and cCW3: 46.3 (40.0, 53.7) with PAH-related hospitalisation as the most frequent first event in each. The cCW definitions comprised from endpoints (excluding transplantation and death), were associated with higher risk [hazard ratio (95% CI)] for lung transplantation/death [4.23 (2.27, 7.91), 3.25 (1.65, 6.39), 2.74 (1.41, 5.34), respectively]; individual parameters with higher risks were WHO FC deterioration [3.49 (1.47, 8.29)], PAH-related hospitalisation [2.62 (1.32, 5.20)] and occurrence/worsening of ≥2 PAH symptoms [2.13 (1.02, 4.45)].

These data support the use of cCW outcomes in paediatric PAH research. WHO FC deterioration, PAH-related hospitalisation, occurrence/worsening of ≥2 PAH symptoms may be important for risk assessment during clinical management.

Hemodynamic and prognostic impact of the diastolic pulmonary arterial pressure in children with pulmonary arterial hypertension—a registry-based analysis, was published in Cardiovascular Diagnosis and Therapy in 2021 (full text).

Diastolic pulmonary arterial pressure (dPAP) is regarded to be less sensitive to flow metrics as compared to mean PAP (mPAP), and was therefore proposed for the assessment of a precapillary component in patients with postcapillary pulmonary hypertension (PH). To analyze the diagnostic and prognostic impact of dPAP in patients with pure precapillary PH, we purposed to compare the correlation between dPAP and mPAP, as well as hemodynamically-derived calculations [ratio of PAP to systemic arterial pressure (PAP/SAP), pulmonary vascular resistance index (PVRI), transpulmonary gradient (TPG)], using both dPAP and mPAP, at rest and during acute vasoreactivity testing (AVT) in children with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH). Furthermore, we aimed to assess the association of these metrics (at baseline and changes after AVT) with transplant-free survival.

We conducted a retrospective analysis of the TOPP (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) registry including 246 IPAH/HPAH patients. Of these, 45 children (18.3%) died, and 13 (5.3%) received lung transplantation during the observation period. dPAP and mPAP-derived variables showed almost linear relationship. Higher mPAP/mSAP, and dPAP-/mPAP-derived PVRI at rest was associated with time to death/transplantation. At maximum AVT-response, the decrease of dPAP and mPAP, diastolic pulmonary gradient (DPG) and TPG, as well as dPAP/dSAP and mPAP/mSAP was associated with time to death/transplantation, showing higher significance than corresponding baseline values. Remarkably, no predictive value was found for PVRI-reduction during AVT, neither dPAP- nor mPAP-derived.

There is a strong relationship between dPAP and mPAP-derived variables. According to our results, hemodynamics during AVT (irrespectively of dPAP- or mPAP-derived) may have more prognostic implications than resting hemodynamics in children with IPAH/HPAH, except for PVRI.

Long-term outcome of children with newly diagnosed pulmonary arterial hypertension: results from the global TOPP registry, was published in in 2023 (full text).

The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global network established to gain insights into the disease course and long-term outcomes of paediatric pulmonary arterial hypertension (PAH). Previously published cohorts in paediatric PAH are obscured by survival bias due to the inclusion of both prevalent (previously diagnosed) and incident (newly diagnosed) patients. The current study aims to describe long-term outcome and its predictors in paediatric PAH, exclusively of newly diagnosed patients.

Five hundred thirty-one children with confirmed pulmonary hypertension, aged ≥3 months and <18 years, were enrolled in the real-world TOPP registry at 33 centres in 20 countries, from 2008 to 2015. Of these, 242 children with newly diagnosed PAH with at least one follow-up visit were included in the current outcome analyses. During long-term follow-up, 42 (17.4%) children died, 9 (3.7%) underwent lung transplantation, 3 (1.2%) atrial septostomy, and 9 (3.7%) Potts shunt palliation (event rates: 6.2, 1.3, 0.4, and 1.4 events per 100 person-years, respectively). One-, three-, and five-year survival free from adverse outcome was 83.9%, 75.2%, and 71.8%, respectively.

Overall, children with open (unrepaired or residual) cardiac shunts had the best survival rates. Younger age, worse World Health Organization functional class, and higher pulmonary vascular resistance index were identified as independent predictors of long-term adverse outcome. Younger age, higher mean right atrial pressure, and lower systemic venous oxygen saturation were specifically identified as independent predictors of early adverse outcome (within 12 months after enrolment).

This comprehensive analysis of survival from time of diagnosis in a large exclusive cohort of children newly diagnosed with PAH describes current-era outcome and its predictors.