The Epidemiology Disclosures of At Risk groups for Pediatric PH - PowerPoint PPT Presentation

3/10/2017 The Epidemiology Disclosures of At Risk groups for Pediatric PH The University Medical Center Groningen has received fees for advisory board and steering committee activities of Prof. Berger from: - Actelion, R.M.F. Berger - Bayer, - Glaxo-Smith-Kline, - Lilly 10th International Conference Neonatal and Childhood Pulmonary Vascular Disease San Francisco 2017 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands Modified classification of PH: 5 th WSPH (Nice 2013) The Epidemiology 1. Pulmonary arterial hypertension 3. PH due to lung diseases and/or hypoxia of At Risk groups 1.1 Idiopathic PAH 3.1 COPD 1.2 Heritable PAH 3.2 Interstitial lung disease 1.2.1 BMPR2 3.3 mixed restrictive and obstructive pattern for Pediatric PH 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 3.4 Sleep-disordered breathing 1.2.3 Unknown 3.5 Alveolar hypoventilation disorders 1.3 Drug- and toxin-induced 3.6 Chronic exposure to high altitude 1.4 Associated with: 3.7 Developmental lung diseases 1.4.1 Connective tissue disease 3.7.1 Congenital diaphragmatic hernia 1.4.2 HIV infection 3.7.2 Bronchopulmonary dysplasia 4. CTEPH 1.4.3 Portal hypertension 5. PH with unclear multifactorial mechanisms 1.4.4 Congenital heart disease 5.1 Haematological disorders: chronic haemolytic 1.4.5 Schistosomiasis anaemia, myeloproliferative disorders, 1’ Pulmonary veno-occlusive disease &/or splenectomy pulmonary capillary haemangiomatosis 5.2 Systemic disorders: sarcoidosis, pulmonary 1’’ Persistent PH of the newborn (PPHN) Langerhans cell histiocytosis, 2. PH due to LHD lymphangioleiomyomatosis, neurofibromatosis, 2.1 LV systolic dysfunction vasculitis 2.2 LV diastolic dysfunction 5.3 Metabolic disorders: glycogen storage disease, 2.3 Valvular disease Gaucher disease, thyroid disorders 2.4 Congenital/acquired left heart 5.4 Others: segmental PH, tumoural obstruction, inflow/outflow obstruction fibrosing mediastinitis, chronic renal failure University Medical Center Groningen University Medical Center Groningen Simonneau G, et al . J Am Coll Cardiol 2013; The Netherlands The Netherlands 1

3/10/2017 Genetics in Pediatric iPAH/HPAH Epidemiology of Pediatric PAH known PAH-genes data from large registries BMPR2 ACVRL1 ENG TBX4 Total Levy et al. 5 4 NT 3 37 TOPP 1 Reveal-children 2 Eur Resp J 2016 14% 11% 8% 100% Patients, n 362 216 Harrison et al 2 1 1 NT 16 Age (yrs), median 7.5 7 Circulation 2005 13% 7% 7% 100% Female, % 59 64 Kerstjens et al NT NT NT 3 20 Group 1: PAH 317 (88) 216 (100) J Med Genet 2013 15% 100% IPAH/HPAH 212 (53) 122 (56) Rosenzweig et al 8 NT NT NT 78 CHD 160 (40) 23 (36) JHLT 2008 10% 100% CTD 9 (3) 10 (5) Portopulmonary 2 (1) 3 (1) Pfarr 4 2 1 (VUS) NT 29 Respir Res 2013 Other 14 (4) 4 (2) 14% 7% 4% 100% Group 3: Lung disease 42 (12) NE Compared to adult PAH, the genetic architecture of pediatric PAH Other 3 (1) NE seems enriched in ACVRL1 and TBX4 mutations 1. Berger et al; Lancet 2012. (Levy et al, 2016 ) NT=Not Tested Values given are n (%) unless otherwise indicated 2. Barst et al; Circulation 2012 University Medical Center Groningen University Medical Center Groningen 5 The Netherlands The Netherlands Congenital Heart Disease Pediatric PAH in Hereditary Hemorrhagic Cumulative incidence of PH after shunt closure Telangiectasia (HHT) Dutch ConCor registry HHT presents at all ages • 50% ACVRL1 mutation • Of these 16% PAH • ACVRL1 mutation carriers are younger at PAH diagnosis, but have • worse prognosis Smoot et al, Arch Dis Child 2009 Van Riel et al. JACC 2016 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 2

3/10/2017 Prevalence of PAH-CHD Cumulative incidence of PH after shunt closure per clinical subclassification specified per age at closure ConCor Dutch National Registry for adults with CHD, 2014 Van Riel , Int J Cardiol 2014 Children, Epidemiological survey 1991-2005 in the Netherlands PAH No PAH Total % D. Post-operative PAH 17 1112 1129 1,5 (A ge at repair: median 0.6 yrs, range 0.2-7.6 yrs) Van Riel et al. JACC 2016 Van Loon, Circulation 2010 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands Pediatric PortoPulmonary Hypertension Pediatric PAH associated with CTD POPH chilldren , single center study • Juvenile systemic sclerosis (rare) • - PAH in 0.5% of the children with portal hypertension, Prevalence of PAH is < 10% • - and in 0.9% of the children with end-stage liver disease awaiting transplantation Systemic juvenile idiopathic arthritis (JIA) • - Portosystemic shunts PAH and ILD rare, underestimated? • Hepatopulmonary syndrome • Systemic Lupus Erythematosus • - pulmovary AV malformations more frequent (6-20%) • Sporadic cases • Median survival: 3 months untreated 80% 5-year probability of survival whentreated • Case reports and small series, in line with registry data • (CPSS closure, pulmonary vasodilators, and/or liver Tx). Screening? • Rabinovich CE; Nat Rev Rheumatol 2011 Ecochard-Dugelay et al; J Pediatr Gastroenterol Nutr. 2015 Kimura et al; Arthr Care Res 2013 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 3

3/10/2017 Congenital portosystemic shunts Other congenital AV shunts Abernethy malformation Vein of Galen malformation (cerebral) • presenting features: severe PH and high-output cardiac failure in • the newborn period The natural history mortality of 42–91% if untreated. • University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands Pediatric PAH associated with HIV PH in preterm infants HIV in Africa • The prevalence of PH in a pooled sample of 664 (adult) patients was 14% (95% CI 6%-23%) Prevalence reduced (eliminated) with early and adequate treatment of HIV? Non/hardly-existing in children in developed countries? Arjaans et al, in preparation Bigna JJR, et al. BMJ 2016 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 4

3/10/2017 PH in childhood interstitial lung disease PH in preterm infants chILD 1.0 0.8 0.6 Proportion PH 0.4 0.2 0.0 - Heterogeneity - Bias No BPD Mild BPD Moderate BPD Severe BPD Bronchopulmonary Dysplasia Classification Incidence reported as - Presence of PH associated with increased mortality - 3.6 cases per million in Ireland and the UK (2002) - Lack of data on longer term follow up - 1.3 cases per million in Germany (2009) Arjaans et al, in preparation University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands chILD chILD Occurrence of Pulmonary Hypertension Survival 100 Only observational case series, mainly retrospective • 90 No clinical trials or population-based observational studies . • 80 70 • 10 availble studies: survival 60 frequencies of PH ranged from 1% to 64%. 50 only 50% of the studies described the investigative tests used to 40 • 30 diagnose pulmonary hypertension 20 (cardiac cath and/or echo and/or ECG) 10 In these latter studies: • 0 0 2 4 5 frequencies of PH ranging from 25% to 64%. Years Fan et al AJRCCM 1997 Bromley et al. Pediatr Pulmonol 2016 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 5

3/10/2017 chILD Pediatric PAH, Comorbidities Risk factors for Mortality OR CI TOPP Patients, n 362 Female sex 1.75 0.73-4.20 Age (yrs), median 8.9 CHD 0.49 0.17-1.37 Comorbidities 86 (24) Prematurity 3.60 1.18-10.96 T risomy 21 42 (12) Pulmonary 6.84 2.57-18.20 Other 44 (12) Hypertension chromosomal, non-chromosomal, Deutsch et al AJRCCM 2007 syndromes 5-year survival History of PPHN 8 (2*) ≥ 10 times normal; Children with DLD (1 month to 18 yrs) 64% ≥ 2.5 times higher controlling Those who presented with PH 38% for trisomy 21 Berger et al. Lancet 2012 Fan et al AJRCCM 1997, University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands PH in children with Down Syndrome PAH with abnormal pulmonary vasculature Increased frequency of PH in tris 21, accelerated PVD Congenital Diaphragmatic Hernia • • • Early PH ~100% Risk factors: • • Late PH ~ 20-30%? PPHN (prevalence 5%) • CHD (prevalence 40-50%) • Obstructive upper airway (OSAS) • Airway infections / immune system • • Developmental lung anomalies • Alveolar rarefaction • Vascular anomalies Lung hypoplasia • University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 6