Summary
Background
Limited data are available describing paediatric pulmonary arterial hypertension.
Aims
To characterize the epidemiology, management and impact on quality of life and outcome of paediatric pulmonary arterial hypertension, excluding persistent pulmonary hypertension of the newborn and pulmonary arterial hypertension caused by congenital heart disease.
Methods
In this multicentre study, children with pulmonary arterial hypertension were included and followed prospectively for two years at 21 referral centres in France. WHO functional class, 6-minute walk distance and quality of life (CHQ-PF50 questionnaire) were evaluated.
Results
Fifty children were included with a mean age of 8.9 ± 5.4 years from May 2005 until June 2006. The estimated prevalence for pulmonary arterial hypertension was 3.7 cases/million. Patients had idiopathic pulmonary arterial hypertension (60%), familial pulmonary arterial hypertension (10%), pulmonary arterial hypertension associated with, but not caused by, congenital heart disease (24%), pulmonary arterial hypertension associated with connective tissue disease (4%) or portal hypertension (2%). During follow-up, the combination of pulmonary arterial hypertension-specific therapies was increasingly prescribed (44% patients versus 22% at inclusion). Patients remained stable regarding clinical status, 6-minute walk distance and quality of life. Survival estimates after one and two years were 86% (95% CI 76, 96) and 82% (95% CI 71, 93), respectively.
Conclusions
In children, idiopathic/familial pulmonary arterial hypertension accounts for the majority of cases. A specific pulmonary arterial hypertension group in conjunction with congenital heart disease can be identified that resembles patients with idiopathic pulmonary arterial hypertension. Combined pulmonary arterial hypertension-specific therapies may have contributed to disease stability and favourable survival.
Résumé
Justification
Les données décrivant l’hypertension artérielle pulmonaire chez l’enfant sont peu nombreuses.
Objectifs
L’objectif a été de caractériser l’épidémiologie, la prise en charge, l’impact sur la qualité de vie et les conséquences de l’hypertension artérielle pulmonaire de l’enfant en excluant les patients avec une hypertension pulmonaire persistante du nouveau-né et ceux dont l’hypertension artérielle pulmonaire était causée par une cardiopathie congénitale.
Méthodes
Dans cette étude multicentrique, des enfants atteints d’hypertension artérielle pulmonaire ont été inclus et suivis prospectivement pendant deux ans dans 21 centres français. La classe fonctionnelle OMS, la distance de marche de six minutes et la qualité de vie (questionnaire CHQ-PF50) ont été évaluées.
Résultats
Cinquante enfants ont été inclus avec un âge moyen de 8,9 ± 5,4 ans de mai 2005 à juin 2006. La prévalence de l’hypertension artérielle pulmonaire a été estimée à 3,7 cas/million. Les patients avaient une hypertension artérielle pulmonaire idiopathique (60 %), familiale (10 %), associée avec une cardiopathie congénitale qui n’était pas la cause de l’hypertension artérielle pulmonaire (24 %), associée à une connectivite (4 %) ou à une hypertension portale (2 %). Pendant le suivi, le nombre d’associations de médicaments spécifiques de l’hypertension artérielle pulmonaire prescrits a augmenté (44 % patients contre 22 % à l’inclusion). Les patients sont restés stables en ce qui concerne leur état clinique, test de marche de six minutes et qualité de vie. La survie à un et deux ans a été estimée à 86 % (intervalle de confiance à 95 % : [76,96]) et 82 % (intervalle de confiance à 95 % : [71,93]).
Conclusions
Chez l’enfant, dans la majorité des cas, les hypertensions artérielles pulmonaires sont idiopathiques / familiales. Un groupe spécifique d’hypertension artérielle pulmonaire concomitante d’une cardiopathie congénitale a été identifié et ressemble à une hypertension artérielle pulmonaire idiopathique. Les associations de traitements spécifiques de l’HTAP peuvent avoir contribué à la stabilité de la maladie et à une meilleure survie.
Abbreviations
CI
confidence interval
CHQ-PF50
Child Health Questionnaire-Parent Form 50
IPAH
idiopathic PAH
PAH
pulmonary arterial hypertension
PAH-CHD
PAH associated with congenital heart disease
QUALIN
quality of life
WHO
World Health Organization
6MWD
6-minute walk distance
Introduction
PAH is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure . The impact on quality of life is substantial and the prognosis poor . The natural history of PAH in adults was described initially by a national registry conducted in the United States in the early 1980s, which included patients with IPAH followed for up to five years . Following subsequent significant advances in the development of PAH-specific therapies (e.g., prostacyclin, endothelin receptor antagonists, and type 5 phosphodiesterase inhibitors), a multicentre registry was initiated in France, in 2002, to collect data on adult patients with PAH treated in the modern era, and to document the evolution of PAH during a 3-year follow-up . However, no such multicentre studies have been performed in children and the current understanding of the epidemiology and natural course of paediatric PAH is consequently limited.
Adults and children with PAH present with the same histopathological lesions and the same abnormalities of vascular and endothelial homeostasis, including imbalance of prostacyclin and thromboxane A 2 and abnormal pulmonary clearance of endothelin-1 . The spectrum of associated conditions, clinical presentation, and factors influencing survival, however, may differ between adults and children. Although limited data are available on the clinical responses of paediatric PAH patients, children with severe PAH are currently treated with similar clinical strategies to those applied to adults . Treatment goals for paediatric patients with PAH may require specific adaptations of adult treatments in order to meet a different set of practical, social and therapeutic challenges . There are currently, however, insufficient data to inform treatment objectives and decisions. This prospective, multicentre, non-interventional study was therefore initiated to investigate the specific epidemiology of paediatric PAH. This study also examined the medical management of paediatric PAH in the current treatment era and the impact on quality of life and outcome during a 2-year follow-up period.
Methods
Study design
This multicentre, prospective, non-interventional study was initiated in May 2005 and was based on a previously described method . Enrolled patients either had a known diagnosis of PAH before the beginning of the study or were diagnosed during the recruitment period (cross-sectional phase), from May 2005 until June 2006. All enrolled patients were followed prospectively for two years (longitudinal phase). The protocol did not impose any procedures or therapies. Written, informed consent was obtained from patients or guardians before data collection.
Study patients
Patients aged between 28 days and 18 years were included. Patients with PAH-CHD were only included if the increase in pulmonary vascular resistance could be considered unrelated to the congenital heart defect (i.e. children with PAH related to an atrial septal defect with increased pulmonary vascular resistance from birth or a transposition of the great arteries associated with PAH after an arterial switch operation). These patients were referred to as patients with PAH in conjunction with CHD. Patients with an evolving defect, which could lead to increased pulmonary vascular resistance (either left-to-right shunt or left heart obstructive defect), were excluded. Patients with persistent pulmonary hypertension of the newborn were also excluded because their disease differs from other PAH aetiologies in terms of natural history and treatment.
Diagnosis of PAH
Diagnosis of PAH was established using either right heart catheterization or Doppler echocardiography following the European Society of Cardiology guidelines . Patients were considered responsive to vasodilator testing if inhaled nitric oxide during right heart catheterization-induced reductions in mean pulmonary arterial pressure greater than 10 mmHg, leading to a value less than 40 mmHg, with increased or unchanged cardiac output.
Patient characteristics at inclusion and study assessments
PAH history included date of first presentation, date of diagnosis and World Health Organization functional class at diagnosis. Age, height, weight and functional signs were documented at study inclusion and a complete physical and cardiac examination was performed.
WHO functional class and exercise capacity measured by the 6MWD in patients older than seven years were determined at inclusion and at six months, one year and two years. Haemodynamic parameters were collected at inclusion and at six months, one year and two years. Last assessment was defined as the latest available assessment performed at month 6, Year 1 or 2.
Assessment of quality of life was collected at inclusion, one year and two years, using parent-administered versions of the most appropriate questionnaires for each age group. For children aged less than five years, analyses from the QUALIN and Autoquestionnaire Enfant Image (AUQUEI) instruments planned per protocol were not presented due to the small number of patients. For children over five years, results from the Child Health Questionnaire – Parent. Form 50 (CHQ-PF50) questionnaire at inclusion were compared with those of standard ( n = 73; age range 5–7 years) and asthmatic ( n = 74; age range 5–12 years) paediatric reference cohorts.
Statistical analysis
Quantitative variables are described as mean ± SD or median (range), when appropriate. For analytical comparisons between two groups of normally distributed quantitative data, Student’s t -test was performed; in case of small samples of patients or not normally distributed variables, the non-parametric Wilcoxon’s test was used. For multiple comparisons of quantitative data, analysis-of-variance or non-parametric tests were used. Qualitative variables are described using frequencies and percentages. For analytical comparisons between two groups of matched qualitative data, the Mc Nemar’s test was performed. A p value less than 0.05 was considered significant. Statistical analyses were performed using SAS software (version 8; SAS Institute, Cary, NC).
Patient height and weight were compared with average values for French children of the same age. Delayed growth was defined as height or weight at least twice the standard deviation below the mean.
Prevalence of PAH was calculated as the ratio between the number of enrolled patients and the number of persons aged between 28 days and 18 years in the French population (excluding overseas territories) in 2006, derived from public data provided by the Institut national d’études démographiques population census .
Survival, assessed from study inclusion until death/data cut-off date, was summarized using Kaplan-Meier estimates and 95% confidence interval (CI) of the event-free survival at relevant time points.
Results
Fifty patients (35 with a diagnosis established before study initiation) were included from 21 referral centres with a widespread geographical distribution in France . Five participating centres did not recruit patients. Patients were followed for a median duration of 23.4 months (range 0.1–31).
Diagnosis of PAH
Diagnosis of PAH was confirmed using right heart catheterization in 43 of 50 patients (86%) and was performed a median 2.7 years before study initiation (range 0–15 years). The mean pulmonary artery pressure was 59 ± 18 mmHg and the cardiac index was 3.9 ± 1.8 Ll/min/m 2 . Four of 35 patients evaluated (11%) were responsive to nitric oxide. The remaining seven patients had the diagnosis confirmed by Doppler echocardiography; their mean calculated systolic pulmonary arterial pressure using maximum velocity of tricuspid regurgitation was 87 ± 18 mmHg.
Prevalence of PAH
The overall prevalence of PAH (excluding persistent pulmonary hypertension of the newborn and PAH caused by CHD) in paediatric patients in 2005 was estimated to be at least 3.7 cases per million. The prevalence of idiopathic IPAH in paediatric patients was estimated to be at least 2.2 cases per million.
Patient demographics and disease characteristics at inclusion
The characteristics at inclusion of the 50 patients are summarized in Table 1 . The male to female ratio was 1.1:1.0. Patients were 4.4 ± 4.5 years at first symptoms and 5.1 ± 4.8 at diagnosis. They most frequently had IPAH (60%). PAH associated with but not caused by CHD was encountered in 24% of the patients ( Table 2 ).
| Characteristic | |
|---|---|
| Boys / girls | 26 (52) / 24 (48) |
| Age, years | 8.9 ± 5.4 (0.4–18) |
| Weight, kg | 28.3 ± 17.9 (4–70) |
| Aetiology of pulmonary arterial hypertension | |
| Idiopathic | 30 (60) |
| In conjunction with CHD | 12 (24) |
| Familial | 5 (10) |
| Connective tissue disease | 2 (4) |
| Portal hypertension | 1 (2) |
| Haemodynamics | |
| Mean pulmonary artery pressure, mmHg ( n = 43) | 59 ± 18 |
| Cardiac index, L/min/m 2 ( n = 30) | 3.8 ± 1.8 |
| Indexed pulmonary vascular resistance, Wood units.m 2 ( n = 29) | 20 ± 19 |
| Acute vasoreactivity | 4 (11) |
| WHO FC I, II, III, IV ( n = 46) a | 8, 25, 12, 1 (17, 54, 26, 2) |
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