Risk populations moving to screening programs
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1 Risk populations moving to screening programs Maurice Beghetti Pediatric Cardiology University Children s Hospital HUG and CHUV Pulmonary Hypertension Program HUG Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique Congenital Cardiac Center (CURCCCP) University of Geneva and Lausanne, Switzerland
2 Prevalence of PAH in adults 4-15% for CHD 8-10% for SSC % for portopulmonary 0.5% for HIV 2% for Sickle cell These data are in adults However, we do not have data in Pediatrics!
3 Recommendations for pulmonary arterial hypertension screening Eur Respir J 2015; 46: ; Eur Heart J 2016; 37:67-119
4 Echocardiographic probability of PH in symptomatic patients Peak tricuspid regurgitation velocity (m/s) Presence of other echo PH signs a Echocardiographic probability of PH 2.8 or not measurable No Low 2.8 or not measurable Yes No Yes > 3.4 Not required Intermediate High a Echocardiographic signs from at least two different categories (A/B/C) from the list should be present to alter the level of echocardiographic probability of PH. Galiè N, et al. Eur Heart J 2016; 37:
5 The value of screening Results of a disease registry in France without screening, the majority of patients were diagnosed in WHO FC III or FC IV and only 24% of patients were in WHO FC II at diagnosis 1 with screening, PAH was detected at an earlier stage 2 1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Hachulla E et al. Arthritis Rheum
6 DETECT two-step decision tree for screening SSc patients Step 1 Step 2 6 non-echo variables: - FVC % pred./dlco % pred. - Anti-centromere antibodies - Telangiectasias - NT-proBNP - ECG: Right axis deviation - Serum urate (uric acid) YES Step 1 total risk score plus 2 echo variables: - Right atrium area - TR velocity YES RHC for diagnosis of presence / absence of PAH Is total risk score > 300? NO Is total risk score > 35? NO No referral for echo No referral for RHC Coghlan JG, et al. Ann Rheum Dis 2014; 73:
7 Survival rate (%) Screening improves long-term outcomes in SSc patients % 81% 73% p = HR = 4.15 (95% CI ) % 31% 25% 64% 17% Screened PAH-SSc (n = 16) Routine practice PAH-SSc (n = 16) 0 1 year 3 years 5 years 8 years Follow-up (years) Humbert M, et al. Arthritis Rheum 2011; 63:
8 Etiology in pediatric registries/studies: Fasnacht Swiss Med wkly 2007 Beghetti Pediatr Res 2008 Van Loon J Ped 2009 Fraisse Arch Cardiovasc Dis 2010 Rosenzweig JACC 2005 Haworth Heart 2010 Number of patients Age (median in to NA years) Female (%) /52 + Group 1 PAH 20 (87%) 131 (90%) 54 (86%) 50 (100%) 86 (100%) 173 (80%) (%) Idiopathic PAH 8 (35%) 59 (40%) 29 (46%) 30 (60%) 36 (42%) 60 (28%) (%) Heritable (%) 5 (10%) CHD (%) 12 (52%) 66 (45%) 23 (37%) 12(24%)* 48 (56%) 104 (48%) CTD (%) 4 (2.8%) 2 (3%) 2 (2%) 9 (4%) Portopulmonary (%) HIV(%) 1 (0.7%) Group 3: lung 3(13%) 2 (1%) 8 (12%) NI 29 (14%) disease (%) Other (%) 13 (9%) 1 (2%) 14 (7%)
9 Rational for screening In Pediatrics? Genetic CHD SSC HIV Portopulmonary BPD
10 Genetics PAH : PVOD : - BMPR2, ALK1, END, KCNK3, Calveolin-1, Smad1/5/8, TBX4 - Autosomal dominant - Incomplete penetrance (BMPR2: 14% in males, 42% in females) - EIF2AK4 - Autosomal recessive - Penetrance to be determined (presumably #100%) Strategy in the French PAH network: Genetic couselling and testing are offered to all patients with: - PAH (idiopathic / familial / drug and toxin-induced) - PVOD (idiopathic / familial / drug and toxin-induced) Informed written consent is mandatory Genetic counselling is done in an individual consultation Next generation Sequencing (NGS) BMPR2, ACVRL1, ENG, CAV1, KCNK3, SMAD9, TBX4, SMAD4, EIF2AK4 The prescriber informs directly the person who underwent the genetic test in an individual consultation A consultation with the psychologist is systematically offered because of the psychological impact of the genetic result Patients with PAH and BMPR2 mutations (448 adult patients over 1550) present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations Childhood-onset PAH in children,12 over 66 screened carrying a mutation in one of the genes tested has a more severe presentation at diagnosis but a similar outcome to that observed in non-carriers. Levy et al ERJ 2016 Evans et al Lancet Respir Med 2016
11 Recommendations: screening can be offered to asymptomatic relatives carriers of mutation in PAH predisposing genes (IIb-C) Eur Respir J 2015; 46: ; Eur Heart J 2016; 37:67-119
12 Recommendations for pulmonary arterial hypertension screening Eur Respir J 2015; 46: ; Eur Heart J 2016; 37:67-119
13 Congenital heart disease We can consider that in the pediatric age, patients with CHD are followed and screened for PH. Current adult recommendations suggest regular follow up even in adult age after correction of CHD (even simple defects such as ASD).
14 Connective tissue disease pediatrics Few patients in Registries Extremely poor outcome Own experience Yearly echo screening since 3 years Limited number of patients but none with suspected PH
15 HIV Swiss survey 71 patients followed in the swiss cohort No patients diagnosed with PAH However, the questionnaire showed that patients were not specifically screened for PAH L Huiller et al Frontiers in Pediatrics % of HIV vertically infected children had PAH (Africa) Ferrand et al Clin Inf Disease 2012
16 Sickle cell /hemoglobinopathies Patient usually have a yearly echocardiography for different reasons (current practice in my center) Patients may have different forms of PH PAH, High flow PH, left heart problems! Over the last 5 years no PAH diagnosed in my center ( regular yearly screening for 55 patients) Echocardiography screening for cardiac problems including PH.
17 121 patients TRV cut off >2.9m/s plus other parameters 5.5 % moderate risk for high PAP. 20.9% if TRV 2.5 was used No subjects had echo risk constellation for more than mild PH Older (>13y), homozygote, more anemic Sickle cell Lilje et al Ped Blood Cancer 2017
18 BPD LINICAL APPROACH Krishnan et al J Ped 2017
19 Conclusions There is a rationale to screen at risk population such as heritable forms, CHD, Portopulmonary, BPD, diaphragmatic hernia HIV, Hemoglobinopathies, Renal failure Questions How to screen ( echo +/- biological markers) Cost-effectivness Ethics (heritable forms) Final diagnosis (cath?)
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