Do tertiary paediatric hospitals deal with the same spectrum of paediatric pulmonary hypertension as multicentre registries?

To the Editor:

Although national [1–5] and international paediatric registries for pulmonary hypertension (PH) [6, 7] have been published recently, inclusion criteria and, therefore, the distribution of aetiologies and severity of cases have not always been comparable [8].

In order to determine possible differences between registries, we have compared the aetiologies of confirmed PH of prevalent versus incident cases of PH in our own large database (in a tertiary paediatric hospital), and compared these to recently reported large multinational registries.

According to pre-specified protocols, any children with clinical symptoms or at risk of PH at our centre were referred for echocardiography. If tricuspid regurgitation velocity was >2.8 m·s⁻¹, right heart catheterisation was performed and the diagnosis of PH was confirmed if mean pulmonary artery pressure was ≥25 mmHg. The Dana Point classification was used [1, 9]. A standardised diagnostic work-up was used in PH cases: thoracic computed tomography scan, hepatic echography, lung function tests, genetic screening, screening for systemic diseases, and HIV serology were used when appropriate.

At the beginning of our study, our database included 86 prevalent PH patients. Over the next 3 yrs, 126 incident PH patients were referred. Median age at inclusion was 2.4 yrs (range 0.5–15 yrs); there were 120 (56%) females and 92 males. Mean pulmonary artery pressure was 55±16 mmHg, pulmonary vascular resistance was 16±7 Wood units and cardiac index was 3.6±1.2 L·min·m⁻². Distribution of PH causes for the 212 patients are shown in the table 1.

First, the proportion of pulmonary arterial hypertension (PAH) in our series (75%) is lower than in the recently published TOPP (Tracking Outcomes and Practice in Paediatric Pulmonary hypertension; 82%) or REVEAL (Registry to EValuate Early And Long term PAH disease; 92%) registries [6, 7]. In addition, the distribution within the subgroups of PAH is also different; idiopathic PAH (iPAH) was present in 16% versus 53% in TOPP and 56% in REVEAL [6, 7]. Our results more closely match those observed in the Netherlands national registry (23% iPAH and 72% PAH associated with congenital heart disease) [4]. The higher proportion of iPAH observed in multinational registries is most likely due to the fact that these patients are referred to expert centres to be treated with advanced therapies whereas congenital heart disease associated with PAH patients aggregate in paediatric cardiac centres such as ours.

Secondly, we observed a four-fold larger proportion of incident patients in Group 3 (PH due to lung disease and/or hypoxia). This emerging problem was also pointed out in the TOPP registry [7]. The apparent increase in incidence of these patients is probably due to enhanced screening strategies in infants with lung disease and to closer collaborations between paediatric cardiologists and pulmonologists. Survival of congenital diaphragmatic hernia has increased considerably over the last few years, reaching 60% in reference centres but PH is a common complication and its severity predicts the outcome [10]. Within this group, 30% of patients had congenital diaphragmatic hernia and 33% had bronchopulmonary dysplasia. This proportion may still be an underestimate as bronchopulmonary dysplasia is more frequent in developing countries which do not generally participate in large registries. Similarly, the proportion of PH due to PAH associated with congenital heart disease is probably different in different regions of the world.

Furthermore, paediatric PH patients may have multiple contributing pathologies and therefore the Dana Point classification can be imprecise. In our series, for example, 22 patients could have been classified in another Dana Point group because of co-existing pathologies (lung disease but without hypoxia and/or small cardiac defects, genetic, metabolic or other associated diseases). Indeed those patients would have been classified according to the Panama classification [11] in category 6 (multifactorial pulmonary hypertensive vascular disease in congenital malformation syndromes) or 10 (paediatric pulmonary vascular disease associated with other system disorders). Finally the number of patients in Group 3 is somewhat limited by the fact that advanced PH therapies are not approved in this group and they are therefore often not referred to “expert centres”. This may change in the future as dedicated trials will be developed to evaluate efficacy and safety of PH drugs in these patients, usually in larger referral centres.

We also observed a four-fold higher proportion in Group 5 patients, in the incidence compared to the prevalence group (PH with unclear and/or multifactorial mechanisms). This proportion of 7.5% is different to TOPP (1%) or REVEAL (<1%) and the Dutch registry (0%). This increase in Group 5 may have several explanations: incorrect classification elsewhere because of limitation of available diagnostic data or a truly new emerging group related to our local screening strategy for PH in rare paediatric diseases (such as cancer, immune defects and inborn errors of metabolism). This screening strategy is related to our multidisciplinary approach across 32 nationally designated reference centres for rare paediatric diseases. Also, for the same reason as in Group 3, these patients may be underdiagnosed, not referred to expert centres and therefore do not appear in registries.

Our data clearly show that the full picture of the aetiologies of paediatric PH cannot be described through large registries outlining incidences in selected participating centres. Information from national centralised registries (Dutch and UK), multicentre registries and tertiary expert paediatric PH centres are complementary for this purpose. Thus, the aetiology and consequently epidemiology of paediatric PH probably varies according to countries involved in registries (particularly the proportion of participating centres from developing countries) and further according to the health system involved (for example, if it has expert PH referral centres or not, or planned screening programmes in certain associated disease states).

Finally it appears obvious that the distribution of aetiologies described in different registries is related, at least in part, to the availability of PH specific treatments, for some but not all possible indications. Such treatments have allowed major progress in the management of children with PAH; however, different availability patterns introduce inevitable biases into the types of patients reported in different types of registries.

It is clear that a new paediatric PH population is emerging. Building dedicated international registries that attempt to solve some of the issues raised in this letter is an important challenge for the future.

• ©ERS 2013