The Epidemiology of At Risk groups for Pediatric PH R.M.F. Berger Disclosures The has received fees for advisory board and steering committee activities of Prof. Berger from: - Actelion, - Bayer, - Glaxo-Smith-Kline, - Lilly 10th International Conference Neonatal and Childhood Pulmonary Vascular Disease San Francisco 2017 The Epidemiology of At Risk groups for Pediatric PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 Modified classification of PH: 5 th WSPH (Nice 2013) 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3 Drug- and toxin-induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1 Pulmonary veno-occlusive disease &/or pulmonary capillary haemangiomatosis 1 Persistent PH of the newborn (PPHN) 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 3.7.1 Congenital diaphragmatic hernia 3.7.2 Bronchopulmonary dysplasia 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: segmental PH, tumoural obstruction, fibrosing mediastinitis, chronic renal failure Simonneau G, et al. J Am Coll Cardiol 2013; 1
Epidemiology of Pediatric PAH data from large registries TOPP 1 Reveal-children 2 Patients, n 362 216 Age (yrs), median 7.5 7 Female, % 59 64 Group 1: PAH 317 (88) 216 (100) IPAH/HPAH 212 (53) 122 (56) CHD 160 (40) 23 (36) CTD 9 (3) 10 (5) Portopulmonary 2 (1) 3 (1) Other 14 (4) 4 (2) Group 3: Lung disease 42 (12) NE Other 3 (1) NE Values given are n (%) unless otherwise indicated 1. Berger et al; Lancet 2012. 2. Barst et al; Circulation 2012 Genetics in Pediatric ipah/hpah known PAH-genes Levy et al. Eur Resp J 2016 Harrison et al Circulation 2005 Kerstjens et al J Med Genet 2013 Rosenzweig et al JHLT 2008 Pfarr Respir Res 2013 BMPR2 ACVRL1 ENG TBX4 Total 5 14% 2 13% 4 11% 1 7% NT 3 8% 1 7% NT NT NT 3 15% 8 10% 4 14% 37 NT 16 20 NT NT NT 78 2 7% 1 (VUS) 4% NT 29 Compared to adult PAH, the genetic architecture of pediatric PAH seems enriched in ACVRL1 and TBX4 mutations (Levy et al, 2016) NT=Not Tested 5 Pediatric PAH in Hereditary Hemorrhagic Telangiectasia (HHT) HHT presents at all ages 50% ACVRL1 mutation Of these 16% PAH ACVRL1 mutation carriers are younger at PAH diagnosis, but have worse prognosis Congenital Heart Disease Cumulative incidence of PH after shunt closure Dutch ConCor registry Smoot et al, Arch Dis Child 2009 Van Riel et al. JACC 2016 2
Cumulative incidence of PH after shunt closure specified per age at closure Prevalence of PAH-CHD per clinical subclassification 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 (Age at repair: median 0.6 yrs, range 0.2-7.6 yrs) Van Riel et al. JACC 2016 Van Loon, Circulation 2010 Pediatric PAH associated with CTD Juvenile systemic sclerosis (rare) Prevalence of PAH is < 10% Systemic juvenile idiopathic arthritis (JIA) PAH and ILD rare, underestimated? Systemic Lupus Erythematosus Sporadic cases Case reports and small series, in line with registry data Screening? Rabinovich CE; Nat Rev Rheumatol 2011 Kimura et al; Arthr Care Res 2013 Pediatric PortoPulmonary Hypertension POPH chilldren, single center study - PAH in 0.5% of the children with portal hypertension, - and in 0.9% of the children with end-stage liver disease awaiting transplantation - Portosystemic shunts Hepatopulmonary syndrome - pulmovary AV malformations more frequent (6-20%) Median survival: 3 months untreated 80% 5-year probability of survival whentreated (CPSS closure, pulmonary vasodilators, and/or liver Tx). Ecochard-Dugelay et al; J Pediatr Gastroenterol Nutr. 2015 3
Congenital portosystemic shunts Abernethy malformation Other congenital AV shunts 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. 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? Bigna JJR, et al. BMJ 2016 Arjaans et al, in preparation 4
PH in preterm infants PH in childhood interstitial lung disease child Proportion PH 0.0 0.2 0.4 0.6 0.8 1.0 No BPD Mild BPD Moderate BPD Severe BPD Bronchopulmonary Dysplasia Classification - Heterogeneity - Bias - Presence of PH associated with increased mortality - Lack of data on longer term follow up Arjaans et al, in preparation Incidence reported as - 3.6 cases per million in Ireland and the UK (2002) - 1.3 cases per million in Germany (2009) child Occurrence of Pulmonary Hypertension Only observational case series, mainly retrospective No clinical trials or population-based observational studies. 10 availble studies: frequencies of PH ranged from 1% to 64%. only 50% of the studies described the investigative tests used to diagnose pulmonary hypertension (cardiac cath and/or echo and/or ECG) In these latter studies: frequencies of PH ranging from 25% to 64%. Bromley et al. Pediatr Pulmonol 2016 child Survival 0 0 2 Years 4 5 100 90 80 70 60 50 40 30 20 10 Fan et al AJRCCM 1997 survival 5
child Risk factors for Mortality Pediatric PAH, Comorbidities OR CI Female sex 1.75 0.73-4.20 CHD 0.49 0.17-1.37 Prematurity 3.60 1.18-10.96 Pulmonary Hypertension 6.84 2.57-18.20 Deutsch et al AJRCCM 2007 5-year survival Children with DLD (1 month to 18 yrs) 64% Those who presented with PH 38% Fan et al AJRCCM 1997, TOPP Patients, n 362 Age (yrs), median 8.9 Comorbidities 86 (24) Trisomy 21 42 (12) Other 44 (12) chromosomal, non-chromosomal, syndromes History of PPHN 8 (2*) 10 times normal; 2.5 times higher controlling for trisomy 21 Berger et al. Lancet 2012 PH in children with Down Syndrome PAH with abnormal pulmonary vasculature Increased frequency of PH in tris 21, accelerated PVD Risk factors: PPHN (prevalence 5%) CHD (prevalence 40-50%) Obstructive upper airway (OSAS) Airway infections / immune system Developmental lung anomalies Alveolar rarefaction Vascular anomalies Congenital Diaphragmatic Hernia Early PH ~ Late PH ~ 20-30%? Lung hypoplasia 6
PAH with abnormal pulmonary vasculature Scimitar syndrome (1-3 in every 100,000 live births) Pediatric CTEPH Extremely rare or non-existing? Mostly, thromboembolic processes proximal in PA and associated with indwelling lines, procedures etc Pediatric CTEPH : Ventriculo-atrial drain Isolated unilateral absence of PA (~1 in 200.000 pers) PH in 40% over time Ped PH associated with Sickle Cell Disease Other risk groups Prevalence of PH (TR Vmax >2,5m/s) in children with SCD was 21 % (95 % CI 16--26) PH is confirmed in about 10% of patients with elevated TRVmax Prevalence of elevated TRJV declined to 11 % (95 % CI 9 13) when using cutoff of 3 m/s. Fourfold higher risk of death among persons with SCD who have increased TR Vmax Musa et al Ann Hematol 2016 Gladwin et al NEJM 2004 Heterotaxia Metabolic diseases (e.g cobalamin C deficiency) Syndromes Schistosomiasis 100 years of neglect in paediatric schistosomiasis Bustinduy et al Parasitology 2017 Pulmonary venous diseases 7
Conclusions Pediatric PH is a rare disease Pediatric PH may complicate many neonatal and pediatric disease conditions Epidemiological data often insufficient The occurrence of PH is often associated with a dramatic worsening of outcome (mortality) It is important to know the risks of complicating PH in neonatal and pediatric conditions Early detection and treatment is required in order to strive for improved oucome 8