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ORIGINAL ARTICLE
Assessing Pulmonary Hypertensive Vascular Disease in Childhood Data from the Spanish Registry 1 M. J. del Cerro Marı´n1, A. Sabate´ Rotes ´ 2, A. Rodriguez Ogando3, A. Mendoza Soto4, M. Quero Jimenez ´ , 5 6 7 8 J. L. Gavilan ´ Camacho , I. Raposo Sonnenfeld , A. Moya Bonora , D. C. Albert Brotons , and A. Moreno Galdo´ 9, on behalf of the REHIPED Investigators* 1 Department of Pediatric Cardiology, Hospital Universitario Ramon ´ y Cajal, Madrid, Spain; 2Universitat Autonoma ` de Barcelona, Barcelona, Spain; 3Department of Pediatric Cardiology, Hospital Gregorio Maran˜on, ´ Madrid, Spain; 4Department of Pediatric Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain; 5Department of Pediatric Cardiology, Complejo Hospitalario Virgen del Roc´ıo, Sevilla, Spain; 6Department of Pediatric Cardiology, Complejo Hospitalario Universitario Juan Canalejo, Corun˜a, Spain; 7Department of Pediatric Cardiology, Hospital Infantil Universitario la Fe, Valencia, Spain; and 8Department of Pediatric Cardiology, and 9 Pediatric Pulmonology Unit, Hospital Vall d’Hebron, Universitat Autonoma ` de Barcelona, Barcelona, Spain
Abstract
Of the patients studied, 31% had multifactorial pulmonary hypertension.
Rationale: There is a lack of knowledge regarding the epidemiology, clinical characterization, and survival in pediatric pulmonary hypertension. Objectives: To describe the epidemiology, outcomes, and risk factors for mortality in pediatric pulmonary hypertension in Spain. Methods: We analyzed data from the Spanish Registry for Pediatric Pulmonary Hypertension. From January 2009 to June 2012, a total of 225 patients diagnosed with pulmonary hypertension in 1998 or after were collected from 21 referral and nonreferral centers. We included all Nice etiologies, estimated incidence and prevalence of pulmonary hypertension in the Spanish pediatric population, and analyzed risk factors for mortality (Nice etiologic group, clinical and hemodynamic variables). Patients were classified as follows: group I, pulmonary arterial hypertension (n = 142; 61%); group II, left heart disease (n = 31; 14%); group III, respiratory disease (n = 41; 18%); group IV, thromboembolic pulmonary hypertension (n = 2; 1%); or group V, mostly inherited metabolic diseases (n = 10; 4.5%).
The development of pulmonary hypertension (PH) registries in adults has improved the knowledge regarding
Measurements and Main Results: Mean age at diagnosis was 4.3 6 4.9 years (50% , 2 yr). Survival rates at 1 and 3 years were 80 and 74% for the whole cohort, and 89 and 85% for patients with pulmonary arterial hypertension. Independent risk factors for mortality included an etiologic group other than pulmonary arterial hypertension (P , 0.001), age at diagnosis younger than 2 years old (P , 0.001), advanced functional class at diagnosis (P , 0.001), and high right atrial pressure at diagnosis (P = 0.002). Conclusions: In moderate to severe pediatric pulmonary
hypertension, the prognosis is better in pulmonary arterial hypertension than in other Nice categories. In pediatric pulmonary hypertension age at diagnosis younger than 2 years is a risk factor for mortality, in addition to the previously established risk factors. Keywords: pulmonary hypertension; pediatrics; registries;
epidemiology; survival
epidemiology and responses to treatment in the adult population with PH. Pulmonary hypertensive vascular disease (PHVD) in
the pediatric population (mean pulmonary arterial pressure [mPAP] . 25 mm Hg and pulmonary vascular resistance . 3 Wood
( Received in original form June 8, 2014; accepted in final form November 4, 2014 ) *A complete list may be found before the beginning of the REFERENCES. The REHIPED Registry is supported by unrestricted educational grants from Actelion, Ferrer, GlaxoSmithKline, Lilly, and Pfizer. Author Contributions: Conception and design, M.J.d.C.M., A.S.R., M.Q.J., D.C.A.B., and A.M.G. Analysis and interpretation, M.J.d.C.M., A.S.R., A.R.O., J.L.G.C., I.R.S., and A.M.B. Drafting the manuscript for important intellectual content, M.J.d.C.M., A.S.R., M.Q.J., and A.M.G. Final approval of the version to be published, M.J.d.C.M., A.S.R., A.R.O., A.M.S., M.Q.J., J.L.G.C., I.R.S., A.M.B., D.C.A.B., and A.M.G. Correspondence and requests for reprints should be addressed to Maria Jesus del Cerro Mar´ın, M.D., Ph.D., Department of Pediatric Cardiology, Ramon y Cajal University Hospital, Madrid, Spain. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 190, Iss 12, pp 1421–1429, Dec 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201406-1052OC on November 7, 2014 Internet address: www.atsjournals.org
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ORIGINAL ARTICLE
At a Glance Commentary
reported at scientific meetings as oral communications and posters (11–13).
Scientific Knowledge on the Subject: Consensus documents
Methods
and registries about pulmonary hypertension in children have been published but focused mainly on pulmonary arterial hypertension. What This Study Adds to the Field: This registry provides
information about epidemiology and outcomes of pediatric pulmonary arterial hypertension in Spain, and the phenotypical characterization of pulmonary hypertension in pediatric patients. It is the first registry reporting outcomes for moderate to severe pulmonary hypertensive vascular disease in Nice groups II, III, IV, and V in the pediatric population. units [WU] $ m2) was classified in the Nice consensus (1) in five basic etiopathogenic groups common to the ones used for the adult population: group I, pulmonary arterial hypertension (PAH); group II, PH caused by heart disease; group III, PH caused by lung diseases and/or hypoxia; group IV, chronic thromboembolic PH (CTEPH); and group V, PH with unclear multifactorial mechanisms (Table 1). Nevertheless, pediatric PHVD has distinctive features (2). The epidemiology of PHVD in children and its phenotypic characterization is vital for understanding of the pathogenetic mechanisms of the disease, for designing clinical trials, and to guide research. Consensus documents about PHVD in children (2, 3) have been published, and pediatric registries (4–10) with different inclusion criteria have yielded epidemiologic data, but focused mainly on PAH (6–9). Therefore, there is a lack of knowledge on “non-PAH” pediatric patients with PHVD belonging to Nice (1) groups II, III, IV, and V. The Spanish Registry for Pediatric Pulmonary Hypertension (REHIPED) was started in January 2009 to provide data on the nationwide epidemiology, clinical characterization, management, and survival of children with PHVD in Spain. This is the first pediatric registry reporting survival for all Nice PH subgroups (1) in the pediatric population. Some of the results of this registry have been previously 1422
In Spain, health care is regionalized: more than 21 medical centers throughout the country have pediatric cardiology departments, and 17 centers perform surgeries for congenital heart defects. PH-targeted therapies can be prescribed at and reimbursed to any hospital. From January 2009 to June 2012, a total of 21 referral and nonreferral centers participated in the registry. Patients diagnosed between 1998 and 2008 were entered retrospectively (including historical patients with complete collection data who had died before 2009), and patients diagnosed in January 2009 and later were entered prospectively. Data were collected using electronic data capture, starting at the initial baseline assessment reported in the medical records. Once the enrollment criteria were satisfied, no tests or study visits were required. Potential data inconsistencies were primarily identified by the electronic
data capture system at the point of entry. The protocol was reviewed and approved as a multicenter study by the institutional review board of “La Paz” Hospital in Madrid, Spain. Informed consent was obtained from the patients or their guardians. Because one of the aims of the registry was to study the use of targeted therapies for PHVD, all patients receiving PHVDtargeted therapies were included (344 patients in June 2012). Nevertheless, for the present study, patients with congenital heart disease (CHD) with univentricular circulation (hypoplastic left heart syndrome after stage one, or Glenn or Fontan patients with any type of univentricular heart) were excluded. Transient forms of PH (hyperkinetic PH, PH crises, early postoperative PH that resolves over weeks or months, and persistent PH of the newborn) were also excluded. The inclusion criteria for the present study were patients with biventricular circulation, aged 2 months to 18 years, diagnosed in or after 1998, with mPAP greater than 25 mm Hg, and pulmonary vascular
Table 1. Diagnosis of Pulmonary Hypertension Patients Included in the REHIPED Registry According to the Nice Classification (1) N 1. Pulmonary arterial hypertension (n = 142) IPAH, FPAH Connective tissue disease HIV infection Portal hypertension CHD PVOD 2. Pulmonary hypertension caused by left heart disease (n = 30) Left ventricular systolic dysfunction Left ventricular diastolic dysfunction Valvular disease Congenital/acquired left heart inflow/outflow obstruction and congenital cardiomyopathies 3. Pulmonary hypertension caused by lung diseases and/or hypoxia (n = 41) Chronic obstructive lung disease Interstitial lung disease Alveolar hypoventilation disorders Sleep-disordered breathing Developmental lung diseases Congenital diaphragmatic hernia Bronchopulmonary dysplasia Lung hypoplasia 4. Chronic thromboembolic pulmonary hypertension (n = 2) 5. Pulmonary hypertension with unclear multifactorial mechanisms (n = 10) Metabolic disorders Mitochondrial diseases Thyroid disorders Neonatal hemochromatosis
31 1 1 3 105 1 1 2 27 2 7 2 1 2 22 5
8 1 1
Definition of abbreviations: CHD = congenital heart diseases; FPAH = familiar pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; PVOD = pulmonary venoocclusive disease.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
ORIGINAL ARTICLE resistance index greater than 3 WU $ m2 (2). The starting point was chosen to be 1998 because in that year pediatric lung transplantation and prostanoids treatments became widely available in Spain, and to concur with the Spanish adult registry for PAH (REHAP) (14) that had gathered data from 1998. The date of diagnosis of the patients included in REHIPED is shown in Figure E1 in the online supplement. All Nice etiologies were studied. There was a trend to include mostly patients with moderate or severe PHVD, especially in groups II (left heart disease) and III (respiratory disease), because right heart catheterization was one of the inclusion criteria. In the few patients who had not been catheterized (because of very low weight or hemodynamic instability), clinical records and echocardiographic data were reviewed by two members of the registry board, who decided whether the case should be included in the registry. After this review, three patients were excluded for inconsistent or incomplete data. Patients were classified using the Nice classification (1) into groups I through V. Patients with multifactorial etiology were assigned to one specific Nice group according to the following criteria: Patients with CHD, mPAP greater than 25 mm Hg, pulmonary vascular resistance index greater than 3 WU $ m2, and associated lung disease were included in group I unless they had persistent arterial PCO2 greater than 55 mm Hg or need of any modality of ventilatory assistance (then they were included in group III). d Patients with shunt CHD and associated left heart disease with pulmonary capillary wedge pressure less than 15 mm Hg were classified in group I; if the pulmonary capillary wedge pressure was greater than 15 mm Hg, then they were included in group II. d Patients with abnormalities of lung development (congenital diaphragmatic hernia, scimitar syndrome, or severe bronchopulmonary dysplasia [BPD]) were classified in group III even if they associated a cardiac shunt or stenosis of any pulmonary vein. We calculated survival from diagnosis and analyzed differences in survival according to clinical and hemodynamic variables for both the whole cohort and patients with PAH. d
Incidence and Prevalence Calculations
The annual incidence was calculated by dividing the number of newly diagnosed (incident) patients by the total number of children (0–18 yr old) in Spain in each corresponding year for 2009, 2010, and 2011 and then obtaining an average annual incidence for these 3 years. The national numbers were obtained from the official Spanish National Statistics Institute (http://www.ine.es). The point prevalence for PAH on the closing date of the study (June 1, 2012) was calculated from the number of incident patients between January 1998 and June 2012, excluding those who had died or were lost to follow-up. Since the REHAP Registry (11) had started in Spain in 1998 and compiled data for patients older than 14 years who were diagnosed with PAH, consecutive cases diagnosed with PAH and younger than 18 years of age in both registries from January 2009 to June 2012 were selected to provide data on the average annual PAH incidence (from 2009 to 2012) and point prevalence (June 2012). Statistical Analysis
Statistical evaluations were performed using a chi-square test to identify significant differences or associations for qualitative variables, whereas analysis of variance and Student t test were used for quantitative variables. Survival for all patient subgroups was depicted using Kaplan-Meier curves from the time of diagnosis. Cox regression was performed and the log-rank ratio was used to identify differences in survival. Cox proportional hazards regression models were used for the multivariate analysis. All statistical analyses were performed using SPSS 18.0 for Windows (SPSS, Chicago, IL).
Results A total of 225 patients with PHVD in biventricular circulation were included. Only two patients were lost to follow-up (0.88%). Patient Characteristics
The mean age at diagnosis was 4.3 6 4.9 years. Age at diagnosis was 2 months to 2 years, 50.7% (n = 114); 2–8 years, 26.7% (n = 60); and 8–18 years, 22.7% (n = 51). One hundred two patients (45.3%) were prospective cases. The female to male ratio was 1:1. The patients’ ethnicity was white, 79.1% (n = 178); South American origin, 13.8% (n = 31); black, 0.9% (n = 2); and
Asian, 0.9% (n = 2). Comorbidities, personal and family histories, and symptoms at diagnosis are shown in Table 2. The functional class (FC) at diagnosis was FC I (n = 30; 13.3%), FC II (n = 76; 33.7%), FC III (n = 73; 32.4%), or FC IV (n = 46; 20.4%). The mean interval between the initiation of symptoms and diagnosis was 11 6 25 months, with shorter intervals in the youngest patients: 1.6 6 2.4 months in patients aged 2 months to 2 years, 5.7 6 11 months in patients 2–8 years old, and 19 6 25 months in patients 8–18 years old. Diagnostic Work-up
Chest radiographs were abnormal in 184 of 225 patients (82%). Echocardiography was performed in all patients; lung function tests in 16% (n = 36); lung scintigraphy in 24% (n = 54); and magnetic resonance imaging or computed tomography scanning in 52.4% (n = 118), which Table 2. Personal and Family History, Comorbidities, and Symptoms at Diagnosis of the Whole Cohort of Children with Pulmonary Hypertension N (%) Comorbidities Chromosomopathy or MCAS Down syndrome Hypothyroidism Neurologic impairment Thoracic cage abnormality OSAS GERD Obesity More than one comorbidity Family history Parental consanguinity Congenital heart defect Pulmonary hypertension Premature birth ,34 wk gestational age Symptoms at diagnosis Dyspnea Heart failure Syncope Chest pain Respiratory symptoms Edemas Hemoptysis Failure to thrive Weight , p3
86 (38) 36 32 63 22 19 43 5 42
(17) (14.3) (28) (9.8) (8.5) (19.2) (2.2) (18.7)
7 (3.1) 20 (9) 12 (5.4) 49 (21.8) 172 102 21 14 90 34 8 50 86
(76.4) (45.3) (9.3) (6.2) (40) (15.1) (3.6) (22.2) (38.2)
Definition of abbreviations: GERD = gastroesophageal reflux disease; MCAS = multiple congenital abnormalities syndromes; OSAS = obstructive sleep apnea syndrome; weight , p3 = weight below third percentile.
Cerro Mar´ın, Sabate´ Rotes, ´ Rodriguez Ogando, et al.: Spectrum of PHVD in Childhood
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ORIGINAL ARTICLE identified pulmonary vein stenosis in 6.2% (n = 14) of the patients. At diagnosis, 27% of the patients had ferropenia and 8% abnormal liver function tests (elevated aspartate aminotransferase, alanine aminotransferase, and g-glutamyltransferase). Catheterization data were available for 86% of the patients (n = 195) in the whole cohort and in 95% (n = 135) of the patients with PAH. The number of patients catheterized in each subgroup is shown in Table 3. The catheterization conditions included general anesthesia and mechanical ventilation, 86.7% (n = 170); conscious sedation, 8% (n = 18); and spontaneous breathing, 3.1% (n = 7). A total of 5.1% of the patients (n = 10 of 195) had severe complications related to the catheterization (cardiorespiratory arrest or exitus), with 1.5% experiencing periprocedure death (3 of 195). Thirtyfive percent of the patients (68 of 195) had already been started on PH-targeted drugs. Etiologies
The distribution of patients using the Nice classification is shown in Tables 1 and 3. Multifactorial PH was present in 30.7%
of the patients (n = 69). The association between CHD-PAH and lung disease (n = 33) was the most frequent cause, followed by the association between CHD-PAH and left heart disease (n = 12). The two cases in group IV (CTEPH), were related to the chronic use of a central venous catheter; they were a preterm infant, and a child with leukemia that had a port-a-catheter related septic thromboembolism and underwent thrombectomy. Pulmonary thromboembolism was also reported as a contributing factor to PHVD in another two patients with CHD. The clinical and hemodynamic characteristics of the patients included in the different etiologic Nice groups are shown in Table 3. With the exception of pulmonary capillary wedge pressure (significantly higher in group II), there were no significant differences in the hemodynamic variables among patients in the different etiologic groups. No statistically significant differences were observed in the diastolic transpulmonary gradient among the different Nice groups (Table 3). Retrospectively, we classified the patients according to the Pediatric Panama classification of PHVD (see Table E1).
Outcomes for the Whole Cohort (n = 225)
By June 2012, a total of 46 patients had died, 6 had undergone lung transplantation, and 2 were lost to follow-up. The mean follow-up time from diagnosis was 2.93 6 3.2 years (median, 1.95 yr; range, 0.0–14.7). The 1and 3-year survival rates were 80% (95% confidence interval, 74–86%) and 74% (95% confidence interval, 67–80%), respectively. Risk factors for 3-year mortality/lung transplantation for the whole cohort (univariate analysis) are shown in Table E2. Survival was significantly different in each Nice etiologic group (Figure 1). In the whole cohort, patients in group I (PAH), diagnosed after 2 years of age, and in FC I–II had better survival. Figure 2 shows the estimates for survival by FC and by age at diagnosis. Survival estimates, confidence intervals, and causes of death are shown in the online supplement (see Tables E3 and E4, respectively). In the multivariate analysis, the Nice etiologic group (P , 0.001), age at diagnosis (P , 0.001), FC at diagnosis (P , 0.001), and right atrial pressure (P = 0.002) were all independent prognostic factors (Table 4).
Table 3. Clinical Characteristics and Hemodynamic Data of Patients Included in Each Nice Etiopathogenic Group
Etiologic Group Age at diagnosis, yr, mean (SD) Male sex, n (%) Patients catheterized, n (%) FC at diagnosis, n (%) I–II III IV MPAP, mm Hg, mean (SD) PVRI, WU $ m2, mean (SD) PVRI/SVRI, mean (SD) CI, L/min/m2, mean (SD) RAP, mm Hg, mean (SD) PCWP, mm Hg, mean (SD) dTPG, mm Hg, mean (SD)
I: PAH (n = 142)
II: Left Heart Disease (n = 30)
III: Lung Diseases (n = 41)
IV: CTEPH (n = 2)
V: Metabolic Diseases (n = 10)
5.2 (4.8)
3.3 (4.4)
2.5 (3.9)
3.8 (2.5)
0.8 (1.0)
0.002
63 (44) 135 (95)
16 (53) 29 (67)
23 (56) 23 (56)
1 (50) 2 (100)
4 (40) 6 (60)
0.338
19 5 6 41
11 19 11 38
70 49 23 46
(49) (35) (16) (18)
(63) (17) (20) (19)
(27) (46) (27) (11)
P Value for I, II, and III
4 (40) 2 (100)
0.019
37 (27)
6 (60) 40 (14)
0.132
8.7 (7.8)
6.7 (6.2)
6.7 (5.0)
23 (27)
5.0 (1.5)
0.275
0.7 (0.5) 4.1 (1.6)
0.5 (0.3) 4.1 (2.3)
0.6 (0.4) 4.8 (2.3)
0.6 (0.4) 2.4 (0.8)
0.7 (0.3) 6.1 (2.4)
0.130 0.575
9.2 (4.0)
8.1 (3.0)
8.2 (3.2)
12 (8.5)
9.6 (6.7)
0.224
12 (5.3)
17 (6.7)
11 (3.5)
6.0 (1.4)
9.8 (6.1)
,0.001
22 (17)
14 (13)
15 (11)
19 (21)
19 (8.8)
0.052
Definition of abbreviations: CI = cardiac index; CTEPH = chronic thromboembolic pulmonary hypertension; dTPG = diastolic transpulmonary gradient; FC = WHO functional class; MPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PVRI = pulmonary vascular resistance index (Wood units $ m2); RAP = right atrial pressure; SVRI = systemic vascular resistance index (Wood units $ m2).
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American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
ORIGINAL ARTICLE with PAH with coincidental CHD or postoperative PAH, who showed similar survival than patients with IPAH, although the differences were not statistically significant. Risk factors for 3-year mortality/lung transplantation for patients with PAH (univariate analysis) are shown in Table E6. In the multivariate analysis, age at diagnosis younger than 2 years (P = 0.009), advanced FC at diagnosis (P , 0.001), low cardiac index (P , 0.001), and high right atrial pressure (P = 0.012) were independent risk factors (see Table E7).
1.0 Group IPAH
Cumulative survival
0.8
0.6
Group II Group III
0.4
0.2
Group V
0
Epidemiology 0
1
2
3
4
5
The comparisons of the incidence and prevalence of PAH, IPAH, and CHD-PAH between the pediatric and adult Spanish populations are shown in Table 5.
Years
Group I Group II Group III Group IV Group V
0–6 months 131 27 37 2 10
6–12 months 105 18 25 2 4
12–18 months 97 16 19 2 1
18–24 months 88 16 15 1 1
24–30 months 77 14 13 1 1
30–36 months 70 12 11 1 1
Discussion This is the first registry to provide outcomes for moderate/severe PHVD in Nice groups II, III, IV, and V in the pediatric population.
Figure 1. Survival curves, estimates by Nice etiologic group. Group I, pulmonary arterial hypertension (PAH); group II, left heart disease; group III, respiratory disease; group IV, chronic thromboembolic pulmonary hypertension; group V, metabolic disease. Because there were only two patients in etiologic group IV, the survival curve for this group is not shown.
Outcomes for the Patients with PAH (n = 145)
Survival rates at 1 and 3 years were 89% and 85%, respectively, without significant differences between idiopathic PAH (IPAH)
Epidemiology and Etiologies
The incidence and prevalence rates obtained for PAH, IPAH, and CHD-PAH in the Spanish pediatric population were similar to those reported by other European registries based on mandatory reporting (5–7). Although incidence and prevalence of PAH were similar between the Spanish adult
and PAH-CHD. The survival rates in the different CHD subgroups are shown in Figure 3 and Table E5. Eisenmenger syndrome patients and patients with left-toright shunt had better survival than patients
A
B 1.0
1.0
2–8 years
0.8
Cumulative survival
Cumulative survival
FC I FC II
0.6 FC III 0.4 FC IV
0.2 0
0.8
8–18 years
0.6
0–2 years
0.4 0.2 0
0
1
2
3
4
5
0
1
Years
Group I–II Group III Group IV
Number of patients exposed to risk 0–6 6–12 12–18 18–24 24–30 30–36 months months months months months months 95 78 70 65 60 53 68 55 49 42 35 32 43 21 15 14 12 10
2
3
4
5
Years
< 2 years 2–8 years > 8 years
Number of patients exposed to risk 0–6 6–12 12–18 18–24 24–30 30–36 months months months months months months 104 66 55 52 45 39 40 33 55 45 30 36 39 34 29 47 42 26
Figure 2. Survival curves and estimates by (A) functional class (FC) at diagnosis and (B) age at diagnosis.
Cerro Mar´ın, Sabate´ Rotes, ´ Rodriguez Ogando, et al.: Spectrum of PHVD in Childhood
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ORIGINAL ARTICLE Table 4. Risk Factors for Mortality/Lung Transplantation for the Whole Cohort of Children with Pulmonary Hypertension (Multivariate Analysis) P Value
HR (95% CI) Etiologic group* II III IV–V Age at diagnosis, yr WHO FC at diagnosis† III IV Right atrial pressure
(4.18–23) (1.43–7.09) (2.12–23) (0.78–0.94)
,0.001 0.005 ,0.001 0.002
4.56 (1.83–11.3) 11.9 (4.82–29) 1.13 (1.05–1.21)
0.001 ,0.001 0.002
9.82 3.18 7.09 0.86
Definition of abbreviations: CI = confidence interval; FC = functional class; HR = hazard ratio; WHO = World Health Organization. *Nice classification etiologic group I is used as a reference for comparison. † WHO FC I and II are used as a reference for comparison.
and pediatric population, CHD-PAH was more prevalent and IPAH less prevalent in children compared with adults. The proportion of PAH and IPAH in our series (62 and 21%) is lower than those in the REVEAL (8) (92 and 56%) and TOPP (10) (82 and 53%) registries. REHIPED results are more similar to those reported in the Netherlands national registry (5)
(72% of progressive PAH was associated with CHD and 23% with IPAH), the UK national registry (7) (IPAH 34%, CHD 59%), and the Necker hospital experience (15) (75% PAH and 16% IPAH). Multinational registries, especially referral center–based registries (8, 10), contain data on selected populations, with older age at the time of inclusion in the registry, higher proportion of
1,0
Cumulative survival
0,8
0,6
Diagnostic Procedures
0,4 S. Eisenmenger Left to right shunt PAH with coincidental CHD Post-operative PAH Idiopathic PAH
0,2
0,0 0
1
2
3
4
5
Years Number exposed to risk
0–1 years 1–2 years 2–3 years 3–4 years
4–5 years
Eisenmenger syndrome
21
19
16
12
10
Left to right shunt
30
22
18
14
7
PAH with coincidental CHD
10
7
5
4
3
Post-operative
44
28
20
16
10
Idiopathic
30
20
17
17
14
Figure 3. The survival rates in the different congenital heart disease (CHD) subgroups. PAH = pulmonary arterial hypertension.
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prevalent patients, and higher proportion of PAH and IPAH patients (see Table E8). This selection bias could also influence data on survival and on prognostic risk factors, because the patients with worse prognosis could die before reaching the expert centers. We found a high percentage of patients (31%) with multifactorial PH. Although the database was created in 2009 according to the etiopathogenic groups of Dana Point classification, the assignment of multifactorial cases was helped by the Panama classification (2). For example, all patients with BPD and PH were assigned to Nice group III, although 31.8% of them had pulmonary vein stenosis, and 63% had associated systemic pulmonary shunts because these are characteristic features of the BPD phenotype. Patients with scimitar complex were assigned to group III, despite their common association of shunts. Nice classification provides a clear and simple frame to understand the basic etiopathogenic mechanisms involved in PH, and to guide the use of targeted therapies. Nevertheless, Panama classification describes specific pediatric phenotypes (in which several etiopathogenic mechanisms can coexist); it will be useful to design diagnostic and therapeutic algorithms and evaluate the outcomes for these particular subgroups. In addition, the comorbidities found in this pediatric registry differ significantly from those found in adult registries (16).
The diagnostic work-up of this cohort was similar to the one reported by the TOPP pediatric referral center–based registry (17), with increasing use of magnetic resonance imaging and computed tomography scanning (18) but lower use of lung scintigraphy, which could partially explain their low reported incidence of CTEPH in children (19–21). Also, our incidence of catheterization-related severe complications was comparable with that reported in other pediatric registries (17, 22–24). The incidence of a positive vasoreactivity test in our patients with IPAH was similar to that reported in the UK registry. Comparison of the percentage of patients with vasoresponder IPAH among the different pediatric registries is shown in Table E8. Outcomes
To date, only the Dutch registry (5) included epidemiologic data about all etiologies of
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
ORIGINAL ARTICLE Table 5. Comparison between Epidemiology of Pulmonary Hypertension in Adults and Children in the Spanish Population as Taken from the REHAP Registry (14) Children (REHIPED) Incidence Prevalence (Cases/Million/ (Cases/ yr) Million) PH (all groups) Group I (PAH) IPAH CHD-PAH Group IV (CTEPH)
4.03 2.56 0.49 1.87 0.076
20.2 14 2.9 10.1 0.22
Adults (REHAP) Incidence Prevalence (Cases/Million/ (Cases/ yr) Million)
3.7 1.2
16 5.6 3 3.2
Definition of abbreviations: CHD = congenital heart defects; CTEPH = chronic thromboembolic pulmonary hypertension; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension. The estimated prevalence and incidence for PH refers to nontransient forms (hyperkinetic PH, PH crises, and persistent PH of the newborn were not included). PH is classified according to Nice (1).
PHVD in children, but it analyzed only the outcomes of PAH. The UK registry (7) provided survival data for PAH and lung disease PH, but not for left heart disease PH. The REHIPED registry provides detailed phenotypic information and survival data for all Nice PH etiopathogenic groups in the pediatric population. The survival for pediatric PAH in Spain was similar to that reported in other pediatric registries (4–10) (see Table E8), without statistically significant differences between IPAH and CHD-PAH in the 1- and 3-year survival rates (in concordance with the REVEAL registry analysis for CHD survival [26]). The worse survival (compared with PAH) observed in the Nice groups II, III, and V was probably related to the nature of the underlying disease, because there were no significant differences in the hemodynamic parameters between these etiologic groups. We are aware that the small number of patients in groups II–V could have biased the differences found in survival. Nevertheless, the UK pediatric registry (7) also reported worse survival in pediatric lung disease than in several PAH subgroups. In group II, congenital isolated pulmonary vein stenosis has a dismal prognosis, and in patients with Shone complex (who develop PH because of endocardial fibroelastosis, and/or residual valvular lesions [27–30]) the association of PH worsens the prognosis for the cardiac condition. Also, in group III, the association with PH worsens the prognosis of interstitial disease and BPD (31–34). In Group V, most patients had inherited errors of metabolism or mitochondrial
diseases (35–37), which explained the poor prognosis. Our data regarding worse outcomes for non-PAH cases of pediatric PH are concordant with the worse outcomes reported for adult patients in groups III and V in the ASPIRE registry (38). Risk Factors for Mortality in Patients with PAH
We found age younger than 2 years at diagnosis to be a significant risk factor not only for the whole cohort (Nice groups I–V) but also for group I (PAH). This finding is discordant from the observations published by Barst and coworkers (39, 40) and the REVEAL registry (8), which reported younger age at diagnosis to be associated with better prognosis in PAH. Nevertheless, in the pediatric IPAH series published by Moledina and coworkers (7) (UK registry) and Sandoval and coworkers (41), younger age did not confer benefit for survival. Also, the Dutch registry (5) identified age-group specific presentations of PAH-CHD, such as accelerated PAH-CHD and CHD with abnormal development of pulmonary vasculature, with worse survival than other PAH types with later presentation. These discrepancies regarding younger age (protective or risk factor) among different pediatric registries could be attributed to selection bias in referral center registries (older age at diagnosis and inclusion), differences in the definition of age groups and methodology (in the Barst and coworkers series, only 10 patients with IPAH younger than 2 yr old were included;
in the REVEAL registry, age was analyzed as risk factor by each 5-yr increment), and/or genetic differences among different populations. Higher right atrial pressure and lower cardiac index were also found to be significant risk factors for mortality in both adult (25) and pediatric IPAH (41); and advanced FC has been found to be a significant risk factor in other pediatric registries (5, 6). We did not find statistically significant differences between IPAH and CHDPAH in the 1- and 3-year survival rates (in concordance with the REVEAL registry analysis for CHD survival [26]). Nevertheless, analyzing separately the outcomes for the different subgroups of CHD, survival was better for patients with Eisenmenger syndrome and with left-to-right shunt than for patients with postoperative CHD or IPAH (Figure 3) in concordance with the findings in the UK pediatric registry (7). The differences were not statistically significant, probably because of the small number of patients in the subgroups. PAH (group I) includes heterogeneous subgroups with essentially different genetics, phenotypic characterization, and outcomes, and these differences apply even among the different subgroups of CHD. These results highlight the importance of using a precise phenotypical characterization of the pediatric patients with PHVD to establish a prognosis. Limitations
The retrospective nature of part of the study and the voluntary reporting are the main limitations of this registry. Additionally, patients with unrecognized PH or mild PH could have been missed, thus underestimating the true incidence and prevalence of the disease. The authors also recognize that the small number of patients in some of the Nice categories could have influenced the statistical power. Conclusions
In moderate-to-severe pediatric PH, the prognosis is better in PAH than in the other Nice etiologic groups. In pediatric PH, besides the already known risk factors (FC and right atrial pressure), age younger than 2 years at diagnosis is also a risk factor for mortality. The REHIPED registry provides the estimated incidence and prevalence for all PH Nice groups in the Spanish pediatric population. The estimated
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ORIGINAL ARTICLE incidence and prevalence of PAH, IPAH, and PAH-CHD were comparable with those provided by other European countries with mandatory registration. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The authors gratefully acknowledge all investigators who form part of the REHIPED Registry. They thank the Registry Coordinating Centre, S&H Medical Science Service, for their quality control, logistic, and administrative support, and Professor Salvador Ortiz, Universidad Autonoma ´ de Madrid and
Statistical Advisor for S&H Medical Science Service for the statistical analysis of the data presented in this paper. They also thank Dr. Pilar Escribano Subias and the REHAP members for the collaboration to obtain complete epidemiologic data on pulmonary arterial hypertension, and Dr. Pilar Escribano Subias and Dr. Shahin Moledina for their critical review of the first draft of this manuscript. REHIPED is a project of the Pulmonary Circulation Working Group of the Spanish Society of Pediatric Cardiology, with the collaboration of the Spanish Society of Pediatric Pulmonology. Coordinator of the REHIPED Registry: Dr. M. J. del Cerro (Spain). REHIPED Steering
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ORIGINAL ARTICLE 25. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve´ P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–788. 26. Barst RJ, Ivy DD, Foreman AJ, McGoon MD, Rosenzweig EB. Four- and seven-year outcomes of patients with congenital heart disease-associated pulmonary arterial hypertension (from the REVEAL Registry). Am J Cardiol 2014;113:147–155. 27. Burch M, Kaufman L, Archer N, Sullivan I. Persistent pulmonary hypertension late after neonatal aortic valvotomy: a consequence of an expanded surgical cohort. Heart 2004;90:918–920. 28. Robinson JD, Del Nido PJ, Geggel RL, Perez-Atayde AR, Lock JE, Powell AJ. Left ventricular diastolic heart failure in teenagers who underwent balloon aortic valvuloplasty in early infancy. Am J Cardiol 2010;106:426–429. 29. Tuo G, Khambadkone S, Tann O, Kostolny M, Derrick G, Tsang V, Sullivan I, Marek J. Obstructive left heart disease in neonates with a “borderline” left ventricle: diagnostic challenges to choosing the best outcome. Pediatr Cardiol 2013;34:1567–1576. 30. Oliver JM, Gallego P, Gonzalez AE, Sanchez-Recalde A, Bret M, Aroca A. Pulmonary hypertension in young adults with repaired coarctation of the aorta: an unrecognised factor associated with premature mortality and heart failure. Int J Cardiol 2014;174: 324–329. 31. Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012;129:e682–e689. 32. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007;120: 1260–1269.
33. del Cerro MJ, Sabate´ Rotes ´ A, Carton ´ A, Deiros L, Bret M, Cordeiro M, Verdu´ C, Barrios MI, Albajara L, Gutierrez-Larraya F. Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes. Pediatr Pulmonol 2014;49:49–59. 34. Clement A, Eber E. Interstitial lung diseases in infants and children. Eur Respir J 2008;31:658–666. 35. del Toro M, Arranz JA, Macaya A, Riudor E, Raspall M, Moreno A, Vazquez E, Ortega A, Matsubara Y, Kure S, et al. Progressive vacuolating glycine leukoencephalopathy with pulmonary hypertension. Ann Neurol 2006;60:148–152. 36. Menendez ´ Suso JJ, Del Cerro Mar´ın MJ, Dorao Mart´ınez-Romillo P, Labrandero de Lera C, Fernandez ´ Garc´ıa-Moya L, Rodr´ıguez Gonzalez ´ JI. Nonketotic hyperglycinemia presenting as pulmonary hypertensive vascular disease and fatal pulmonary edema in response to pulmonary vasodilator therapy. J Pediatr 2012;161:557–559. 37. Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, Del Toro M, Labayru MT, Landa J, Font A, Garcia-Villoria J, et al. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am J Hum Genet 2011;89:656–667. 38. Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, Capener D, Sephton P, Hamilton N, Armstrong IJ, et al. ASPIRE registry: Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre. Eur Respir J 2012;39:945–955. 39. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation 1999;99:1197e208 40. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation 2004;110:660–665. 41. Sandoval J, Bauerle O, Gomez A, Palomar A, Mart´ınez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol 1995;25:466–474.
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Assessing Pulmonary Hypertensive Vascular Disease in Childhood Data from the Spanish Registry 1 M. J. del Cerro Marı´n1, A. Sabate´ Rotes ´ 2, A. Rodriguez Ogando3, A. Mendoza Soto4, M. Quero Jimenez ´ , 5 6 7 8 J. L. Gavilan ´ Camacho , I. Raposo Sonnenfeld , A. Moya Bonora , D. C. Albert Brotons , and A. Moreno Galdo´ 9, on behalf of the REHIPED Investigators* 1 Department of Pediatric Cardiology, Hospital Universitario Ramon ´ y Cajal, Madrid, Spain; 2Universitat Autonoma ` de Barcelona, Barcelona, Spain; 3Department of Pediatric Cardiology, Hospital Gregorio Maran˜on, ´ Madrid, Spain; 4Department of Pediatric Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain; 5Department of Pediatric Cardiology, Complejo Hospitalario Virgen del Roc´ıo, Sevilla, Spain; 6Department of Pediatric Cardiology, Complejo Hospitalario Universitario Juan Canalejo, Corun˜a, Spain; 7Department of Pediatric Cardiology, Hospital Infantil Universitario la Fe, Valencia, Spain; and 8Department of Pediatric Cardiology, and 9 Pediatric Pulmonology Unit, Hospital Vall d’Hebron, Universitat Autonoma ` de Barcelona, Barcelona, Spain
Abstract
Of the patients studied, 31% had multifactorial pulmonary hypertension.
Rationale: There is a lack of knowledge regarding the epidemiology, clinical characterization, and survival in pediatric pulmonary hypertension. Objectives: To describe the epidemiology, outcomes, and risk factors for mortality in pediatric pulmonary hypertension in Spain. Methods: We analyzed data from the Spanish Registry for Pediatric Pulmonary Hypertension. From January 2009 to June 2012, a total of 225 patients diagnosed with pulmonary hypertension in 1998 or after were collected from 21 referral and nonreferral centers. We included all Nice etiologies, estimated incidence and prevalence of pulmonary hypertension in the Spanish pediatric population, and analyzed risk factors for mortality (Nice etiologic group, clinical and hemodynamic variables). Patients were classified as follows: group I, pulmonary arterial hypertension (n = 142; 61%); group II, left heart disease (n = 31; 14%); group III, respiratory disease (n = 41; 18%); group IV, thromboembolic pulmonary hypertension (n = 2; 1%); or group V, mostly inherited metabolic diseases (n = 10; 4.5%).
The development of pulmonary hypertension (PH) registries in adults has improved the knowledge regarding
Measurements and Main Results: Mean age at diagnosis was 4.3 6 4.9 years (50% , 2 yr). Survival rates at 1 and 3 years were 80 and 74% for the whole cohort, and 89 and 85% for patients with pulmonary arterial hypertension. Independent risk factors for mortality included an etiologic group other than pulmonary arterial hypertension (P , 0.001), age at diagnosis younger than 2 years old (P , 0.001), advanced functional class at diagnosis (P , 0.001), and high right atrial pressure at diagnosis (P = 0.002). Conclusions: In moderate to severe pediatric pulmonary
hypertension, the prognosis is better in pulmonary arterial hypertension than in other Nice categories. In pediatric pulmonary hypertension age at diagnosis younger than 2 years is a risk factor for mortality, in addition to the previously established risk factors. Keywords: pulmonary hypertension; pediatrics; registries;
epidemiology; survival
epidemiology and responses to treatment in the adult population with PH. Pulmonary hypertensive vascular disease (PHVD) in
the pediatric population (mean pulmonary arterial pressure [mPAP] . 25 mm Hg and pulmonary vascular resistance . 3 Wood
( Received in original form June 8, 2014; accepted in final form November 4, 2014 ) *A complete list may be found before the beginning of the REFERENCES. The REHIPED Registry is supported by unrestricted educational grants from Actelion, Ferrer, GlaxoSmithKline, Lilly, and Pfizer. Author Contributions: Conception and design, M.J.d.C.M., A.S.R., M.Q.J., D.C.A.B., and A.M.G. Analysis and interpretation, M.J.d.C.M., A.S.R., A.R.O., J.L.G.C., I.R.S., and A.M.B. Drafting the manuscript for important intellectual content, M.J.d.C.M., A.S.R., M.Q.J., and A.M.G. Final approval of the version to be published, M.J.d.C.M., A.S.R., A.R.O., A.M.S., M.Q.J., J.L.G.C., I.R.S., A.M.B., D.C.A.B., and A.M.G. Correspondence and requests for reprints should be addressed to Maria Jesus del Cerro Mar´ın, M.D., Ph.D., Department of Pediatric Cardiology, Ramon y Cajal University Hospital, Madrid, Spain. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 190, Iss 12, pp 1421–1429, Dec 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201406-1052OC on November 7, 2014 Internet address: www.atsjournals.org
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At a Glance Commentary
reported at scientific meetings as oral communications and posters (11–13).
Scientific Knowledge on the Subject: Consensus documents
Methods
and registries about pulmonary hypertension in children have been published but focused mainly on pulmonary arterial hypertension. What This Study Adds to the Field: This registry provides
information about epidemiology and outcomes of pediatric pulmonary arterial hypertension in Spain, and the phenotypical characterization of pulmonary hypertension in pediatric patients. It is the first registry reporting outcomes for moderate to severe pulmonary hypertensive vascular disease in Nice groups II, III, IV, and V in the pediatric population. units [WU] $ m2) was classified in the Nice consensus (1) in five basic etiopathogenic groups common to the ones used for the adult population: group I, pulmonary arterial hypertension (PAH); group II, PH caused by heart disease; group III, PH caused by lung diseases and/or hypoxia; group IV, chronic thromboembolic PH (CTEPH); and group V, PH with unclear multifactorial mechanisms (Table 1). Nevertheless, pediatric PHVD has distinctive features (2). The epidemiology of PHVD in children and its phenotypic characterization is vital for understanding of the pathogenetic mechanisms of the disease, for designing clinical trials, and to guide research. Consensus documents about PHVD in children (2, 3) have been published, and pediatric registries (4–10) with different inclusion criteria have yielded epidemiologic data, but focused mainly on PAH (6–9). Therefore, there is a lack of knowledge on “non-PAH” pediatric patients with PHVD belonging to Nice (1) groups II, III, IV, and V. The Spanish Registry for Pediatric Pulmonary Hypertension (REHIPED) was started in January 2009 to provide data on the nationwide epidemiology, clinical characterization, management, and survival of children with PHVD in Spain. This is the first pediatric registry reporting survival for all Nice PH subgroups (1) in the pediatric population. Some of the results of this registry have been previously 1422
In Spain, health care is regionalized: more than 21 medical centers throughout the country have pediatric cardiology departments, and 17 centers perform surgeries for congenital heart defects. PH-targeted therapies can be prescribed at and reimbursed to any hospital. From January 2009 to June 2012, a total of 21 referral and nonreferral centers participated in the registry. Patients diagnosed between 1998 and 2008 were entered retrospectively (including historical patients with complete collection data who had died before 2009), and patients diagnosed in January 2009 and later were entered prospectively. Data were collected using electronic data capture, starting at the initial baseline assessment reported in the medical records. Once the enrollment criteria were satisfied, no tests or study visits were required. Potential data inconsistencies were primarily identified by the electronic
data capture system at the point of entry. The protocol was reviewed and approved as a multicenter study by the institutional review board of “La Paz” Hospital in Madrid, Spain. Informed consent was obtained from the patients or their guardians. Because one of the aims of the registry was to study the use of targeted therapies for PHVD, all patients receiving PHVDtargeted therapies were included (344 patients in June 2012). Nevertheless, for the present study, patients with congenital heart disease (CHD) with univentricular circulation (hypoplastic left heart syndrome after stage one, or Glenn or Fontan patients with any type of univentricular heart) were excluded. Transient forms of PH (hyperkinetic PH, PH crises, early postoperative PH that resolves over weeks or months, and persistent PH of the newborn) were also excluded. The inclusion criteria for the present study were patients with biventricular circulation, aged 2 months to 18 years, diagnosed in or after 1998, with mPAP greater than 25 mm Hg, and pulmonary vascular
Table 1. Diagnosis of Pulmonary Hypertension Patients Included in the REHIPED Registry According to the Nice Classification (1) N 1. Pulmonary arterial hypertension (n = 142) IPAH, FPAH Connective tissue disease HIV infection Portal hypertension CHD PVOD 2. Pulmonary hypertension caused by left heart disease (n = 30) Left ventricular systolic dysfunction Left ventricular diastolic dysfunction Valvular disease Congenital/acquired left heart inflow/outflow obstruction and congenital cardiomyopathies 3. Pulmonary hypertension caused by lung diseases and/or hypoxia (n = 41) Chronic obstructive lung disease Interstitial lung disease Alveolar hypoventilation disorders Sleep-disordered breathing Developmental lung diseases Congenital diaphragmatic hernia Bronchopulmonary dysplasia Lung hypoplasia 4. Chronic thromboembolic pulmonary hypertension (n = 2) 5. Pulmonary hypertension with unclear multifactorial mechanisms (n = 10) Metabolic disorders Mitochondrial diseases Thyroid disorders Neonatal hemochromatosis
31 1 1 3 105 1 1 2 27 2 7 2 1 2 22 5
8 1 1
Definition of abbreviations: CHD = congenital heart diseases; FPAH = familiar pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; PVOD = pulmonary venoocclusive disease.
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ORIGINAL ARTICLE resistance index greater than 3 WU $ m2 (2). The starting point was chosen to be 1998 because in that year pediatric lung transplantation and prostanoids treatments became widely available in Spain, and to concur with the Spanish adult registry for PAH (REHAP) (14) that had gathered data from 1998. The date of diagnosis of the patients included in REHIPED is shown in Figure E1 in the online supplement. All Nice etiologies were studied. There was a trend to include mostly patients with moderate or severe PHVD, especially in groups II (left heart disease) and III (respiratory disease), because right heart catheterization was one of the inclusion criteria. In the few patients who had not been catheterized (because of very low weight or hemodynamic instability), clinical records and echocardiographic data were reviewed by two members of the registry board, who decided whether the case should be included in the registry. After this review, three patients were excluded for inconsistent or incomplete data. Patients were classified using the Nice classification (1) into groups I through V. Patients with multifactorial etiology were assigned to one specific Nice group according to the following criteria: Patients with CHD, mPAP greater than 25 mm Hg, pulmonary vascular resistance index greater than 3 WU $ m2, and associated lung disease were included in group I unless they had persistent arterial PCO2 greater than 55 mm Hg or need of any modality of ventilatory assistance (then they were included in group III). d Patients with shunt CHD and associated left heart disease with pulmonary capillary wedge pressure less than 15 mm Hg were classified in group I; if the pulmonary capillary wedge pressure was greater than 15 mm Hg, then they were included in group II. d Patients with abnormalities of lung development (congenital diaphragmatic hernia, scimitar syndrome, or severe bronchopulmonary dysplasia [BPD]) were classified in group III even if they associated a cardiac shunt or stenosis of any pulmonary vein. We calculated survival from diagnosis and analyzed differences in survival according to clinical and hemodynamic variables for both the whole cohort and patients with PAH. d
Incidence and Prevalence Calculations
The annual incidence was calculated by dividing the number of newly diagnosed (incident) patients by the total number of children (0–18 yr old) in Spain in each corresponding year for 2009, 2010, and 2011 and then obtaining an average annual incidence for these 3 years. The national numbers were obtained from the official Spanish National Statistics Institute (http://www.ine.es). The point prevalence for PAH on the closing date of the study (June 1, 2012) was calculated from the number of incident patients between January 1998 and June 2012, excluding those who had died or were lost to follow-up. Since the REHAP Registry (11) had started in Spain in 1998 and compiled data for patients older than 14 years who were diagnosed with PAH, consecutive cases diagnosed with PAH and younger than 18 years of age in both registries from January 2009 to June 2012 were selected to provide data on the average annual PAH incidence (from 2009 to 2012) and point prevalence (June 2012). Statistical Analysis
Statistical evaluations were performed using a chi-square test to identify significant differences or associations for qualitative variables, whereas analysis of variance and Student t test were used for quantitative variables. Survival for all patient subgroups was depicted using Kaplan-Meier curves from the time of diagnosis. Cox regression was performed and the log-rank ratio was used to identify differences in survival. Cox proportional hazards regression models were used for the multivariate analysis. All statistical analyses were performed using SPSS 18.0 for Windows (SPSS, Chicago, IL).
Results A total of 225 patients with PHVD in biventricular circulation were included. Only two patients were lost to follow-up (0.88%). Patient Characteristics
The mean age at diagnosis was 4.3 6 4.9 years. Age at diagnosis was 2 months to 2 years, 50.7% (n = 114); 2–8 years, 26.7% (n = 60); and 8–18 years, 22.7% (n = 51). One hundred two patients (45.3%) were prospective cases. The female to male ratio was 1:1. The patients’ ethnicity was white, 79.1% (n = 178); South American origin, 13.8% (n = 31); black, 0.9% (n = 2); and
Asian, 0.9% (n = 2). Comorbidities, personal and family histories, and symptoms at diagnosis are shown in Table 2. The functional class (FC) at diagnosis was FC I (n = 30; 13.3%), FC II (n = 76; 33.7%), FC III (n = 73; 32.4%), or FC IV (n = 46; 20.4%). The mean interval between the initiation of symptoms and diagnosis was 11 6 25 months, with shorter intervals in the youngest patients: 1.6 6 2.4 months in patients aged 2 months to 2 years, 5.7 6 11 months in patients 2–8 years old, and 19 6 25 months in patients 8–18 years old. Diagnostic Work-up
Chest radiographs were abnormal in 184 of 225 patients (82%). Echocardiography was performed in all patients; lung function tests in 16% (n = 36); lung scintigraphy in 24% (n = 54); and magnetic resonance imaging or computed tomography scanning in 52.4% (n = 118), which Table 2. Personal and Family History, Comorbidities, and Symptoms at Diagnosis of the Whole Cohort of Children with Pulmonary Hypertension N (%) Comorbidities Chromosomopathy or MCAS Down syndrome Hypothyroidism Neurologic impairment Thoracic cage abnormality OSAS GERD Obesity More than one comorbidity Family history Parental consanguinity Congenital heart defect Pulmonary hypertension Premature birth ,34 wk gestational age Symptoms at diagnosis Dyspnea Heart failure Syncope Chest pain Respiratory symptoms Edemas Hemoptysis Failure to thrive Weight , p3
86 (38) 36 32 63 22 19 43 5 42
(17) (14.3) (28) (9.8) (8.5) (19.2) (2.2) (18.7)
7 (3.1) 20 (9) 12 (5.4) 49 (21.8) 172 102 21 14 90 34 8 50 86
(76.4) (45.3) (9.3) (6.2) (40) (15.1) (3.6) (22.2) (38.2)
Definition of abbreviations: GERD = gastroesophageal reflux disease; MCAS = multiple congenital abnormalities syndromes; OSAS = obstructive sleep apnea syndrome; weight , p3 = weight below third percentile.
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ORIGINAL ARTICLE identified pulmonary vein stenosis in 6.2% (n = 14) of the patients. At diagnosis, 27% of the patients had ferropenia and 8% abnormal liver function tests (elevated aspartate aminotransferase, alanine aminotransferase, and g-glutamyltransferase). Catheterization data were available for 86% of the patients (n = 195) in the whole cohort and in 95% (n = 135) of the patients with PAH. The number of patients catheterized in each subgroup is shown in Table 3. The catheterization conditions included general anesthesia and mechanical ventilation, 86.7% (n = 170); conscious sedation, 8% (n = 18); and spontaneous breathing, 3.1% (n = 7). A total of 5.1% of the patients (n = 10 of 195) had severe complications related to the catheterization (cardiorespiratory arrest or exitus), with 1.5% experiencing periprocedure death (3 of 195). Thirtyfive percent of the patients (68 of 195) had already been started on PH-targeted drugs. Etiologies
The distribution of patients using the Nice classification is shown in Tables 1 and 3. Multifactorial PH was present in 30.7%
of the patients (n = 69). The association between CHD-PAH and lung disease (n = 33) was the most frequent cause, followed by the association between CHD-PAH and left heart disease (n = 12). The two cases in group IV (CTEPH), were related to the chronic use of a central venous catheter; they were a preterm infant, and a child with leukemia that had a port-a-catheter related septic thromboembolism and underwent thrombectomy. Pulmonary thromboembolism was also reported as a contributing factor to PHVD in another two patients with CHD. The clinical and hemodynamic characteristics of the patients included in the different etiologic Nice groups are shown in Table 3. With the exception of pulmonary capillary wedge pressure (significantly higher in group II), there were no significant differences in the hemodynamic variables among patients in the different etiologic groups. No statistically significant differences were observed in the diastolic transpulmonary gradient among the different Nice groups (Table 3). Retrospectively, we classified the patients according to the Pediatric Panama classification of PHVD (see Table E1).
Outcomes for the Whole Cohort (n = 225)
By June 2012, a total of 46 patients had died, 6 had undergone lung transplantation, and 2 were lost to follow-up. The mean follow-up time from diagnosis was 2.93 6 3.2 years (median, 1.95 yr; range, 0.0–14.7). The 1and 3-year survival rates were 80% (95% confidence interval, 74–86%) and 74% (95% confidence interval, 67–80%), respectively. Risk factors for 3-year mortality/lung transplantation for the whole cohort (univariate analysis) are shown in Table E2. Survival was significantly different in each Nice etiologic group (Figure 1). In the whole cohort, patients in group I (PAH), diagnosed after 2 years of age, and in FC I–II had better survival. Figure 2 shows the estimates for survival by FC and by age at diagnosis. Survival estimates, confidence intervals, and causes of death are shown in the online supplement (see Tables E3 and E4, respectively). In the multivariate analysis, the Nice etiologic group (P , 0.001), age at diagnosis (P , 0.001), FC at diagnosis (P , 0.001), and right atrial pressure (P = 0.002) were all independent prognostic factors (Table 4).
Table 3. Clinical Characteristics and Hemodynamic Data of Patients Included in Each Nice Etiopathogenic Group
Etiologic Group Age at diagnosis, yr, mean (SD) Male sex, n (%) Patients catheterized, n (%) FC at diagnosis, n (%) I–II III IV MPAP, mm Hg, mean (SD) PVRI, WU $ m2, mean (SD) PVRI/SVRI, mean (SD) CI, L/min/m2, mean (SD) RAP, mm Hg, mean (SD) PCWP, mm Hg, mean (SD) dTPG, mm Hg, mean (SD)
I: PAH (n = 142)
II: Left Heart Disease (n = 30)
III: Lung Diseases (n = 41)
IV: CTEPH (n = 2)
V: Metabolic Diseases (n = 10)
5.2 (4.8)
3.3 (4.4)
2.5 (3.9)
3.8 (2.5)
0.8 (1.0)
0.002
63 (44) 135 (95)
16 (53) 29 (67)
23 (56) 23 (56)
1 (50) 2 (100)
4 (40) 6 (60)
0.338
19 5 6 41
11 19 11 38
70 49 23 46
(49) (35) (16) (18)
(63) (17) (20) (19)
(27) (46) (27) (11)
P Value for I, II, and III
4 (40) 2 (100)
0.019
37 (27)
6 (60) 40 (14)
0.132
8.7 (7.8)
6.7 (6.2)
6.7 (5.0)
23 (27)
5.0 (1.5)
0.275
0.7 (0.5) 4.1 (1.6)
0.5 (0.3) 4.1 (2.3)
0.6 (0.4) 4.8 (2.3)
0.6 (0.4) 2.4 (0.8)
0.7 (0.3) 6.1 (2.4)
0.130 0.575
9.2 (4.0)
8.1 (3.0)
8.2 (3.2)
12 (8.5)
9.6 (6.7)
0.224
12 (5.3)
17 (6.7)
11 (3.5)
6.0 (1.4)
9.8 (6.1)
,0.001
22 (17)
14 (13)
15 (11)
19 (21)
19 (8.8)
0.052
Definition of abbreviations: CI = cardiac index; CTEPH = chronic thromboembolic pulmonary hypertension; dTPG = diastolic transpulmonary gradient; FC = WHO functional class; MPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PVRI = pulmonary vascular resistance index (Wood units $ m2); RAP = right atrial pressure; SVRI = systemic vascular resistance index (Wood units $ m2).
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American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
ORIGINAL ARTICLE with PAH with coincidental CHD or postoperative PAH, who showed similar survival than patients with IPAH, although the differences were not statistically significant. Risk factors for 3-year mortality/lung transplantation for patients with PAH (univariate analysis) are shown in Table E6. In the multivariate analysis, age at diagnosis younger than 2 years (P = 0.009), advanced FC at diagnosis (P , 0.001), low cardiac index (P , 0.001), and high right atrial pressure (P = 0.012) were independent risk factors (see Table E7).
1.0 Group IPAH
Cumulative survival
0.8
0.6
Group II Group III
0.4
0.2
Group V
0
Epidemiology 0
1
2
3
4
5
The comparisons of the incidence and prevalence of PAH, IPAH, and CHD-PAH between the pediatric and adult Spanish populations are shown in Table 5.
Years
Group I Group II Group III Group IV Group V
0–6 months 131 27 37 2 10
6–12 months 105 18 25 2 4
12–18 months 97 16 19 2 1
18–24 months 88 16 15 1 1
24–30 months 77 14 13 1 1
30–36 months 70 12 11 1 1
Discussion This is the first registry to provide outcomes for moderate/severe PHVD in Nice groups II, III, IV, and V in the pediatric population.
Figure 1. Survival curves, estimates by Nice etiologic group. Group I, pulmonary arterial hypertension (PAH); group II, left heart disease; group III, respiratory disease; group IV, chronic thromboembolic pulmonary hypertension; group V, metabolic disease. Because there were only two patients in etiologic group IV, the survival curve for this group is not shown.
Outcomes for the Patients with PAH (n = 145)
Survival rates at 1 and 3 years were 89% and 85%, respectively, without significant differences between idiopathic PAH (IPAH)
Epidemiology and Etiologies
The incidence and prevalence rates obtained for PAH, IPAH, and CHD-PAH in the Spanish pediatric population were similar to those reported by other European registries based on mandatory reporting (5–7). Although incidence and prevalence of PAH were similar between the Spanish adult
and PAH-CHD. The survival rates in the different CHD subgroups are shown in Figure 3 and Table E5. Eisenmenger syndrome patients and patients with left-toright shunt had better survival than patients
A
B 1.0
1.0
2–8 years
0.8
Cumulative survival
Cumulative survival
FC I FC II
0.6 FC III 0.4 FC IV
0.2 0
0.8
8–18 years
0.6
0–2 years
0.4 0.2 0
0
1
2
3
4
5
0
1
Years
Group I–II Group III Group IV
Number of patients exposed to risk 0–6 6–12 12–18 18–24 24–30 30–36 months months months months months months 95 78 70 65 60 53 68 55 49 42 35 32 43 21 15 14 12 10
2
3
4
5
Years
< 2 years 2–8 years > 8 years
Number of patients exposed to risk 0–6 6–12 12–18 18–24 24–30 30–36 months months months months months months 104 66 55 52 45 39 40 33 55 45 30 36 39 34 29 47 42 26
Figure 2. Survival curves and estimates by (A) functional class (FC) at diagnosis and (B) age at diagnosis.
Cerro Mar´ın, Sabate´ Rotes, ´ Rodriguez Ogando, et al.: Spectrum of PHVD in Childhood
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ORIGINAL ARTICLE Table 4. Risk Factors for Mortality/Lung Transplantation for the Whole Cohort of Children with Pulmonary Hypertension (Multivariate Analysis) P Value
HR (95% CI) Etiologic group* II III IV–V Age at diagnosis, yr WHO FC at diagnosis† III IV Right atrial pressure
(4.18–23) (1.43–7.09) (2.12–23) (0.78–0.94)
,0.001 0.005 ,0.001 0.002
4.56 (1.83–11.3) 11.9 (4.82–29) 1.13 (1.05–1.21)
0.001 ,0.001 0.002
9.82 3.18 7.09 0.86
Definition of abbreviations: CI = confidence interval; FC = functional class; HR = hazard ratio; WHO = World Health Organization. *Nice classification etiologic group I is used as a reference for comparison. † WHO FC I and II are used as a reference for comparison.
and pediatric population, CHD-PAH was more prevalent and IPAH less prevalent in children compared with adults. The proportion of PAH and IPAH in our series (62 and 21%) is lower than those in the REVEAL (8) (92 and 56%) and TOPP (10) (82 and 53%) registries. REHIPED results are more similar to those reported in the Netherlands national registry (5)
(72% of progressive PAH was associated with CHD and 23% with IPAH), the UK national registry (7) (IPAH 34%, CHD 59%), and the Necker hospital experience (15) (75% PAH and 16% IPAH). Multinational registries, especially referral center–based registries (8, 10), contain data on selected populations, with older age at the time of inclusion in the registry, higher proportion of
1,0
Cumulative survival
0,8
0,6
Diagnostic Procedures
0,4 S. Eisenmenger Left to right shunt PAH with coincidental CHD Post-operative PAH Idiopathic PAH
0,2
0,0 0
1
2
3
4
5
Years Number exposed to risk
0–1 years 1–2 years 2–3 years 3–4 years
4–5 years
Eisenmenger syndrome
21
19
16
12
10
Left to right shunt
30
22
18
14
7
PAH with coincidental CHD
10
7
5
4
3
Post-operative
44
28
20
16
10
Idiopathic
30
20
17
17
14
Figure 3. The survival rates in the different congenital heart disease (CHD) subgroups. PAH = pulmonary arterial hypertension.
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prevalent patients, and higher proportion of PAH and IPAH patients (see Table E8). This selection bias could also influence data on survival and on prognostic risk factors, because the patients with worse prognosis could die before reaching the expert centers. We found a high percentage of patients (31%) with multifactorial PH. Although the database was created in 2009 according to the etiopathogenic groups of Dana Point classification, the assignment of multifactorial cases was helped by the Panama classification (2). For example, all patients with BPD and PH were assigned to Nice group III, although 31.8% of them had pulmonary vein stenosis, and 63% had associated systemic pulmonary shunts because these are characteristic features of the BPD phenotype. Patients with scimitar complex were assigned to group III, despite their common association of shunts. Nice classification provides a clear and simple frame to understand the basic etiopathogenic mechanisms involved in PH, and to guide the use of targeted therapies. Nevertheless, Panama classification describes specific pediatric phenotypes (in which several etiopathogenic mechanisms can coexist); it will be useful to design diagnostic and therapeutic algorithms and evaluate the outcomes for these particular subgroups. In addition, the comorbidities found in this pediatric registry differ significantly from those found in adult registries (16).
The diagnostic work-up of this cohort was similar to the one reported by the TOPP pediatric referral center–based registry (17), with increasing use of magnetic resonance imaging and computed tomography scanning (18) but lower use of lung scintigraphy, which could partially explain their low reported incidence of CTEPH in children (19–21). Also, our incidence of catheterization-related severe complications was comparable with that reported in other pediatric registries (17, 22–24). The incidence of a positive vasoreactivity test in our patients with IPAH was similar to that reported in the UK registry. Comparison of the percentage of patients with vasoresponder IPAH among the different pediatric registries is shown in Table E8. Outcomes
To date, only the Dutch registry (5) included epidemiologic data about all etiologies of
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
ORIGINAL ARTICLE Table 5. Comparison between Epidemiology of Pulmonary Hypertension in Adults and Children in the Spanish Population as Taken from the REHAP Registry (14) Children (REHIPED) Incidence Prevalence (Cases/Million/ (Cases/ yr) Million) PH (all groups) Group I (PAH) IPAH CHD-PAH Group IV (CTEPH)
4.03 2.56 0.49 1.87 0.076
20.2 14 2.9 10.1 0.22
Adults (REHAP) Incidence Prevalence (Cases/Million/ (Cases/ yr) Million)
3.7 1.2
16 5.6 3 3.2
Definition of abbreviations: CHD = congenital heart defects; CTEPH = chronic thromboembolic pulmonary hypertension; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension. The estimated prevalence and incidence for PH refers to nontransient forms (hyperkinetic PH, PH crises, and persistent PH of the newborn were not included). PH is classified according to Nice (1).
PHVD in children, but it analyzed only the outcomes of PAH. The UK registry (7) provided survival data for PAH and lung disease PH, but not for left heart disease PH. The REHIPED registry provides detailed phenotypic information and survival data for all Nice PH etiopathogenic groups in the pediatric population. The survival for pediatric PAH in Spain was similar to that reported in other pediatric registries (4–10) (see Table E8), without statistically significant differences between IPAH and CHD-PAH in the 1- and 3-year survival rates (in concordance with the REVEAL registry analysis for CHD survival [26]). The worse survival (compared with PAH) observed in the Nice groups II, III, and V was probably related to the nature of the underlying disease, because there were no significant differences in the hemodynamic parameters between these etiologic groups. We are aware that the small number of patients in groups II–V could have biased the differences found in survival. Nevertheless, the UK pediatric registry (7) also reported worse survival in pediatric lung disease than in several PAH subgroups. In group II, congenital isolated pulmonary vein stenosis has a dismal prognosis, and in patients with Shone complex (who develop PH because of endocardial fibroelastosis, and/or residual valvular lesions [27–30]) the association of PH worsens the prognosis for the cardiac condition. Also, in group III, the association with PH worsens the prognosis of interstitial disease and BPD (31–34). In Group V, most patients had inherited errors of metabolism or mitochondrial
diseases (35–37), which explained the poor prognosis. Our data regarding worse outcomes for non-PAH cases of pediatric PH are concordant with the worse outcomes reported for adult patients in groups III and V in the ASPIRE registry (38). Risk Factors for Mortality in Patients with PAH
We found age younger than 2 years at diagnosis to be a significant risk factor not only for the whole cohort (Nice groups I–V) but also for group I (PAH). This finding is discordant from the observations published by Barst and coworkers (39, 40) and the REVEAL registry (8), which reported younger age at diagnosis to be associated with better prognosis in PAH. Nevertheless, in the pediatric IPAH series published by Moledina and coworkers (7) (UK registry) and Sandoval and coworkers (41), younger age did not confer benefit for survival. Also, the Dutch registry (5) identified age-group specific presentations of PAH-CHD, such as accelerated PAH-CHD and CHD with abnormal development of pulmonary vasculature, with worse survival than other PAH types with later presentation. These discrepancies regarding younger age (protective or risk factor) among different pediatric registries could be attributed to selection bias in referral center registries (older age at diagnosis and inclusion), differences in the definition of age groups and methodology (in the Barst and coworkers series, only 10 patients with IPAH younger than 2 yr old were included;
in the REVEAL registry, age was analyzed as risk factor by each 5-yr increment), and/or genetic differences among different populations. Higher right atrial pressure and lower cardiac index were also found to be significant risk factors for mortality in both adult (25) and pediatric IPAH (41); and advanced FC has been found to be a significant risk factor in other pediatric registries (5, 6). We did not find statistically significant differences between IPAH and CHDPAH in the 1- and 3-year survival rates (in concordance with the REVEAL registry analysis for CHD survival [26]). Nevertheless, analyzing separately the outcomes for the different subgroups of CHD, survival was better for patients with Eisenmenger syndrome and with left-to-right shunt than for patients with postoperative CHD or IPAH (Figure 3) in concordance with the findings in the UK pediatric registry (7). The differences were not statistically significant, probably because of the small number of patients in the subgroups. PAH (group I) includes heterogeneous subgroups with essentially different genetics, phenotypic characterization, and outcomes, and these differences apply even among the different subgroups of CHD. These results highlight the importance of using a precise phenotypical characterization of the pediatric patients with PHVD to establish a prognosis. Limitations
The retrospective nature of part of the study and the voluntary reporting are the main limitations of this registry. Additionally, patients with unrecognized PH or mild PH could have been missed, thus underestimating the true incidence and prevalence of the disease. The authors also recognize that the small number of patients in some of the Nice categories could have influenced the statistical power. Conclusions
In moderate-to-severe pediatric PH, the prognosis is better in PAH than in the other Nice etiologic groups. In pediatric PH, besides the already known risk factors (FC and right atrial pressure), age younger than 2 years at diagnosis is also a risk factor for mortality. The REHIPED registry provides the estimated incidence and prevalence for all PH Nice groups in the Spanish pediatric population. The estimated
Cerro Mar´ın, Sabate´ Rotes, ´ Rodriguez Ogando, et al.: Spectrum of PHVD in Childhood
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ORIGINAL ARTICLE incidence and prevalence of PAH, IPAH, and PAH-CHD were comparable with those provided by other European countries with mandatory registration. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The authors gratefully acknowledge all investigators who form part of the REHIPED Registry. They thank the Registry Coordinating Centre, S&H Medical Science Service, for their quality control, logistic, and administrative support, and Professor Salvador Ortiz, Universidad Autonoma ´ de Madrid and
Statistical Advisor for S&H Medical Science Service for the statistical analysis of the data presented in this paper. They also thank Dr. Pilar Escribano Subias and the REHAP members for the collaboration to obtain complete epidemiologic data on pulmonary arterial hypertension, and Dr. Pilar Escribano Subias and Dr. Shahin Moledina for their critical review of the first draft of this manuscript. REHIPED is a project of the Pulmonary Circulation Working Group of the Spanish Society of Pediatric Cardiology, with the collaboration of the Spanish Society of Pediatric Pulmonology. Coordinator of the REHIPED Registry: Dr. M. J. del Cerro (Spain). REHIPED Steering
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ORIGINAL ARTICLE 25. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve´ P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–788. 26. Barst RJ, Ivy DD, Foreman AJ, McGoon MD, Rosenzweig EB. Four- and seven-year outcomes of patients with congenital heart disease-associated pulmonary arterial hypertension (from the REVEAL Registry). Am J Cardiol 2014;113:147–155. 27. Burch M, Kaufman L, Archer N, Sullivan I. Persistent pulmonary hypertension late after neonatal aortic valvotomy: a consequence of an expanded surgical cohort. Heart 2004;90:918–920. 28. Robinson JD, Del Nido PJ, Geggel RL, Perez-Atayde AR, Lock JE, Powell AJ. Left ventricular diastolic heart failure in teenagers who underwent balloon aortic valvuloplasty in early infancy. Am J Cardiol 2010;106:426–429. 29. Tuo G, Khambadkone S, Tann O, Kostolny M, Derrick G, Tsang V, Sullivan I, Marek J. Obstructive left heart disease in neonates with a “borderline” left ventricle: diagnostic challenges to choosing the best outcome. Pediatr Cardiol 2013;34:1567–1576. 30. Oliver JM, Gallego P, Gonzalez AE, Sanchez-Recalde A, Bret M, Aroca A. Pulmonary hypertension in young adults with repaired coarctation of the aorta: an unrecognised factor associated with premature mortality and heart failure. Int J Cardiol 2014;174: 324–329. 31. Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012;129:e682–e689. 32. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007;120: 1260–1269.
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