From Jan 31, 2008, to Feb 15, 2010, 456 patients were enrolled. Enrolment of prevalent and incident patients was stopped at one site on Feb 10 and Aug 19, of 2009, respectively, to prevent overrepresentation of that site. Enrolment of prevalent patients at all other sites was stopped on May 22, 2009, to prevent such patients accounting for more than two-thirds of the total. No further predefined restriction rules were required.
Of the 456 patients in the all-patients cohort, 362 (79%) met all enrolment criteria for confirmed pulmonary hypertension, with 357 (99%) diagnoses based on right-heart catheterisation and five (1%) based on independently reviewed echocardiography and clinical records—of these five cases, three were further confirmed by histopathological findings. Of the confirmed pulmonary hypertension cases, about 30% were incident and about 70% were prevalent (). The distribution of the all-patients cohort (456) was: Europe 157, Turkey 33, China 70, Japan 14, Australia 15, Brazil one, Mexico 21, USA 135, Canada ten. Of the 94 patients excluded from the confirmed pulmonary hypertension cohort, 11 did not meet haemodynamic criteria (six with mPAP<25 mm Hg or PVRI<3 WU/m−2; five with mPCWP>12 mm Hg), and 83 did not have sufficient data to adequately calculate PVRi. shows patient characteristics of each cohort. We recorded no apparent differences between patients in the confirmed pulmonary hypertension cohort and those excluded from that cohort.
Demographic and clinical characteristics at diagnosis in all patients and in patients with confirmed pulmonary hypertension
In those with confirmed disease, the median age at diagnostic right-heart catheterisation was 7·0 years (IQR 3–12) with 61 patients (17%) diagnosed between 3 and 24 months of age, 111 (31%) between 2 and 6 years, 89 (25%) between 7 and 11 years, and 101 (28%) between 12 and 18 years. The average time from diagnostic right-heart catheterisation to enrolment was about 34 months in prevalent cases, and less than a month in incident cases (). The mean time from onset of symptoms to diagnosis did not seem to differ between incident and prevalent cases, but tended to be longer when PAH was associated with congenital heart disease with unrepaired or residual systemic-to-pulmonary shunt and shorter in APAH not associated with congenital heart disease than in other subgroups ().
Demographic and clinical characteristics at diagnosis in patients with confirmed pulmonary hypertension (PH confirmed) diagnosis according to pulmonary hypertension groups and subgroups
PAH (group 1) and pulmonary hypertension associated with respiratory disorders or hypoxaemia (group 3) made up 88% (317) and 12% (42), respectively, of the confirmed pulmonary hypertension cohort (362). Only three patients (<1%) were in pulmonary hypertension group 4 or 5. There was an overall female preponderance (1·4 to 1) that was unchanged when stratified by incident or prevalent case, pulmonary hypertension group, PAH subgroup, or age. Of the 317 PAH patients, 57% had IPAH or FPAH and 36% had APAH associated with congenital heart disease (). Most congenital heart disease cases (106 out 115, 93%) included systemic-to-pulmonary shunts. APAH associated with disorders other than congenital heart disease was reported in 6% of PAH patients (). Bronchopulmonary dysplasia was the most frequent disorder associated with pulmonary hypertension group 3, present in 11 of 42 patients (26%). We recorded a significant association between the number of patients in each pulmonary hypertension group and age (p=0·01), with pulmonary hypertension group 3 disorders occurring more frequently in patients aged 3–24 months at diagnosis than in older age-at-diagnosis cohorts (15 aged 3–24 months, 25%; 12 aged 2–6 years, 11%; six aged 7–11 years, 7%; and nine aged 12–18 years, 9%).
We recorded comorbid disorders in 86 of 362 (24%) patients with confirmed pulmonary hypertension. Chromosomal disorder was most frequent (47, 13%) with 42 patients having trisomy 21. There was a significant association between trisomy 21 and pulmonary hypertension group (p=0·02). Trisomy 21 was present more often in patients with group 3 disorders (nine of 42, 21%) than in those with PAH (group 1, 32 of 317, 10%). Within the PAH cohort (317), trisomy 21 was present in 26 of 115 (23%) patients with APAH associated with congenital heart disease, five of 182 (3%) patients with IPAH or FPAH, and one of 20 (5%) patients with APAH not associated with congenital heart disease. In the remaining 44 patients, we recorded a spectrum of other chromosomal abnormalities, syndromes, and non-chromosomal anomalies.
Of the 362 patients with confirmed pulmonary hypertension, 21 (6%) had lived at an altitude greater than 2000 m for more than 6 months, 47 (13%) were premature (gestation <37 weeks), and eight (2%) had a history of persistent pulmonary hypertension of the newborn. In five of these eight, pulmonary hypertension seemed to persist and was confirmed by right-heart catheterisation (done at >3 months of age), whereas in the other three, the disorder was thought to have resolved during the neonatal period with PAH subsequently diagnosed by right-heart catheterisation. A history of bronchopulmonary dysplasia was reported in 17 of 362 patients (5%) and was regarded as the cause of the pulmonary hypertension by the treating physician in 11. Of the 362 patients, 34 (9%) had reactive airway disease, 23 (6%) had sleep disordered breathing or obstructive apnoeas (with obstructive sleep apnoea judged causative for the pulmonary hypertension in five), and 168 (46%) had a history of congenital heart disease, which was deemed causative for pulmonary hypertension in 115.
Family history was available in 320 of 362 patients with confirmed pulmonary hypertension. Family history for PAH was present in 21 of 182 patients with PAH without an associated disorder (12% FPAH) and in two of 20 patients with APAH not associated with congenital heart disease (10%). Genetic testing was done for 56 of the 317 patients with PAH, eight of whom (14%) had abnormal results—ie, four of the 29 IPAH (14%), two of the nine FPAH (22%), and two of the 18 APAH (11%) patients. Because of patient-privacy regulations, the abnormality cannot be disclosed in the registry.
The most frequently reported symptoms at presentation were dyspnoea on exertion and fatigue (). Syncope was reported in 73 of 298 (25%) patients without shunt defined as either no history of a congenital systemic-to-pulmonary shunt, or a repaired congenital systemic-to-pulmonary shunt without a residual shunt (in about 30% with IPAH or FPAH and in roughly 20% without shunt), but was not reported in any child with an unrepaired or residual congenital systemic-to-pulmonary shunt. A history of syncope was less frequent in the youngest age group at diagnosis (two aged 3–24 months; 3%) than in older age groups at diagnosis: 24 aged 2–6 years, 22%; 24 aged 7–11 years, 27%; and 23 aged 12–18 years, 23% (p=0·0006).
Clinical symptoms at diagnosis, reported for 5% or more of all patients with confirmed pulmonary hypertension (PH confirmed), according to pulmonary hypertension groups and subgroups
We recorded functional class at diagnosis for all patients. Irrespective of pulmonary hypertension group, most (230 [64%] of 362 patients with confirmed pulmonary hypertension) were in functional class I or II at diagnosis. The 6 min-walk test was reported in about 150 patients with confirmed pulmonary hypertension with a mean distance of roughly 420 m (). This test was not done in children in the youngest age group (3–24 months), but was done in 23% (25) of children aged 2–6 years, 58% (52) of those aged 7–11 years, and 75% (76) of those aged 12–18 years at diagnosis.
shows haemodynamic indices at diagnosis. Of 362 patients with confirmed pulmonary hypertension, 76 (21%) had cardiac index (ie, systemic blood flow) <2·5 L/min per m2 (normal 2·5–4·0 L/min per m2); 34 (9%) had mean right atrial pressure >12 mm Hg. Haemodynamics differed significantly between patients with PAH (group 1) and patients with pulmonary hypertension associated with respiratory disorders or hypoxaemia (group 3). mPAP, mean systemic arterial pressure (mSAP), mPAP to mSAP ratio, PVRi, systemic vascular resistance index (SVRi), PVRi to SVRi ratio, and resting systemic arterial oxygen saturation were all lower in patients in group 3 than in those with IPAH, FPAH, or APAH associated with congenital heart disease (). Cardiac index was lower in patients with IPAH or FPAH than in those in group 3 (). For PAH, systemic arterial oxygen saturation was lower for APAH associated with congenital heart disease than for IPAH or FPAH, but we recorded no other differences between these subgroups () nor clinically relevant differences in haemodynamics between IPAH and FPAH at diagnosis.
Haemodynamic characteristics at diagnosis in patients with confirmed pulmonary hypertension (PH confirmed), according to pulmonary hypertension groups and subgroups