3/10/2017 Disclosures • No relevant disclosures Guidelines For Screening • Although, worth mentioning: Those at Risk of PH – Limited evidence exists from formal studies on Eric D. Austin, MD, MSCI Screening in pediatric population Director, Vanderbilt Pediatric PH Program Vanderbilt University Medical Center Screening Screen � Secondary Prevention • The process of detecting disease early, with • Detect a disease in its earliest stages, before the intention of intervening to halt its symptoms appear progression. • Intervene to slow or stop disease progression As Yogi Berra said: • Key Assumption: “You can observe a lot by just watching.” – Earlier detection & intervention is helpful U.S. Department of Health & Human Services. https://www.ahrq.gov/professionals/quality-patient-safety/quality-resources/tools/ppip/ppipslides/ppiplongsl10.html 1
3/10/2017 Screening To Facilitate Prevention Symptomatic PH is a Late Finding “Secondary Prevention” ‘Development’ ‘Peak’ Austin, Kawut, Gladwin, Abman. Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann Am Thorac Soc 2014 Apr; 11(Suppl 3): S178–S185. Current Approach Secondary Prevention ‘Development’ ‘Peak’ ‘Development’ ‘Peak’ Austin, Kawut, Gladwin, Abman. Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention Austin, Kawut, Gladwin, Abman. Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann Am Thorac Soc 2014 Apr; 11(Suppl 3): S178–S185. of Chronic Lung Diseases. Ann Am Thorac Soc 2014 Apr; 11(Suppl 3): S178–S185. 2
3/10/2017 Issues for Screening for a Rare A. Potential Screening Methods Condition (e.g., PH) • Noninvasive Studies A. Employ low risk, high yield method(s) – Genetic testing • BMPR2 , ALK1 , ENG , EIF2AK4 , TBX4 , etc… B. Target high risk individuals – Blood or Urine studies (e.g., NT-proBNP) – ‘-Omics’: independent or integrated • Noninvasive Measures of ‘Function’ – Echocardiogram (ECHO), ECG – cMRI, PET/CT, Metabolic imaging (e.g., FDG-PET) • Invasive Measures – Cath +/- Pulmonary Angiography, Lung Bx, RV Bx A. Potential Screening Methods B. Target high risk individuals • Noninvasive Studies – Genetic testing • BMPR2 , ALK1 , ENG , EIF2AK4 , TBX4 , etc… – Blood or Urine studies (e.g., NT-proBNP) – ‘-Omics’: independent or integrated • Noninvasive Measures of ‘Function’ – Echocardiogram (ECHO), ECG – cMRI, PET/CT, Metabolic imaging (e.g., FDG-PET) • Invasive Measures – Cath +/- Pulmonary Angiography, Lung Bx, RV Bx 3
3/10/2017 Developmental Lung Diseases Developmental Lung Diseases • Congenital diaphragmatic hernia (CDH) • Premature / Bronchopulmonary dysplasia (BPD) • Alveolar Capillary Dysplasia with MPV • Congenital diaphragmatic hernia (CDH) Reasonable Approach: • Lung Hypoplasia • Alveolar Capillary Dysplasia with MPV • Surfactant Protein Abnormalities • Lung Hypoplasia Screening ECHO (& BNP) at time of Lung Disease Dx • Pulmonary Alveolar Proteinosis • Surfactant Protein Abnormalities Serial Screening: q1-2 yrs and as clinically indicated • Pulmonary Lymphangiectasia • Pulmonary Alveolar Proteinosis • Pulmonary Lymphangiectasia Prematurity and PH Prematurity and PH • Criteria: • Criteria: 316 enrolled 316 enrolled 316 enrolled 316 enrolled – < 34 wks – < 34 wks – 500–1,250 g – 500–1,250 g 20 died, 17 20 died, 17 20 died, 17 20 died, 17 LTF, 2 w/draw LTF, 2 w/draw LTF, 2 w/draw LTF, 2 w/draw • ECHOs performed • ECHOs performed – 7 days of age – 7 days of age 7 day PH, 7 day PH, 7 day No PH, 7 day No PH, 7 day PH, 7 day PH, 7 day No PH, 7 day No PH, n=115 (42%) n=115 (42%) n=162 (58%) n=162 (58%) n=115 (42%) n=115 (42%) n=162 (58%) n=162 (58%) – 36 weeks PMAge – 36 weeks PMAge 36 wks PH 36 wks PH 36 wks PH 36 wks PH 36 wks PH 36 wks PH 36 wks PH 36 wks PH 21% 21% 9% 9% 21% 21% 9% 9% 36 wks No PH 36 wks No PH 36 wks No PH 36 wks No PH 36 wks No PH 36 wks No PH 36 wks No PH 36 wks No PH 79% 79% 90% 90% 79% 79% 90% 90% Mourani PM et al. Am J Respir Crit Care Med. 2015;191:87-95. Mourani PM et al. Am J Respir Crit Care Med. 2015;191:87-95. 4
3/10/2017 ECHO-determined PH @ 36 weeks Approach to Premature Lung Dz Babies: < 34 wks & 500–1,250 g • Early ECHO (& BNP) for Premature with: 50% – <28 weeks Infants w/ p <0.001 40% PH @ – High Vent and/or Oxygen support 36 Wks 30% – Oligohydramnios, IUGR 25% – Slow improvement 20% • Consider repeat q2-4 wks 0 All Subjects None Mild Moderate Severe (n=277) (n=50) (n=100) (n=62) (n=65) BPD Severity Abman SH et al. Circulation. 2015;132:2037-99. Mourani PM et al. Am J Respir Crit Care Med. 2015;191:87-95. Kim DH et al. Neonatology . 2012;101:40-46. Established BPD Prevalence 12-28% Established BPD: screening over time • Screen @ 36 weeks PMA, via 2 approaches: • Serial ECHO (& BNP) q 4-6 months and prn • Caveats 1. All BPD patients @ 36 weeks 2. Severity-based – ECHO may underestimate presence or severity • O 2 need • Consider adding ECG • PPV – ‘Unmask’ PVD during times of stress • Poor growth • Bronchiolitis • Recurrent episodes • IVH, NEC • ASD • etc… Abman SH et al. Circulation. 2015;132:2037-99. Abman SH et al. Circulation. 2015;132:2037-99. Abman SH et al. Neoreviews. 2011;12:e645-e651. Weismann CG et al. J Perinatol . Epub Feb 2017. Mourani PM et al. Pediatrics. 2008;121:317–325. 5
3/10/2017 Some Additional Conditions Healthy Pediatric Relatives, At Risk Condition Recommendation Pediatric Evidence • 1° relative of idiopathic PAH (IPAH) Chronic Hemolytic Anemia 8 y/o; q1-2 yrs and prn limited – No known ‘causative’ PH gene (e.g., SCD) HHT (ACVRL1, ENG) Yearly; and prn limited • Relative of heritable PAH (HPAH) Down Syndrome post CHD 8 y/o; prn limited 1. Familial disease Liver disease @ Dx and @ Liver Tx eval; limited Yearly screen for both POPH 2. Known ‘causative’ PH gene and HPS CTD, including SSc Yearly; and prn limited ECHO, BNP, +/- ECG • Relative of PVOD & PCH, HHT-PAH cases � Consider additional studies for some Conditions; e.g.: DLCO & Lung Volumes in CTD and Chronic Hemolytic Anemia follow same approaches Abman SH et al. Circulation. 2015;132:2037-99. Chaudry RA et al. Arch Dis Child . 2011;96:131–136. Schwaiger JP et al. European Respiratory Review . 2011; 22: 515–525 Relative of heritable PAH (HPAH) case 1° relative of idiopathic PAH (IPAH) BMPR2 -PAH IPAH • Disease & Genetic counseling 100 NS NS BMPR2-PAH • Approach: 80 Age at diagnosis (years) is more – Physical Exam and ECHO q1-3 years Severe 60 40 20 0 Females Males Females Males n=188 n=79 n=81 n=34 Austin ED et al. Resp Res. 2009; 10 :87 doi:10.1186/1465-9921-10-87Elliott CG et al. Circulation. 2006; 113: 2509-2515. Rosenzweig EB et al. J Heart Lung Transplant. 2008; 27:668-674. Sztrymf B et al. Am J Respir Crit Care Med. 2008. 177:1377-83. Pfarr N et al. Resp Res. 2011;12:99http://respiratory-research.com/content/12/1/99. Soubrier F et al. Resp Res. J Am Coll Cardiol 2013;62:D13–21. Brittain CHEST 2013. 6
3/10/2017 Red = Mutation Carrier Red = Mutation Carrier - - + + BMPR2 is more severe. + + + + + + + + But, only ~20% BMPR2 mutation carriers develop PAH in their lifetime - - - - - - + + + + + + + Austin, Ma et al Circ Cardiovasc Genetics, 2012 Austin, Ma et al Circ Cardiovasc Genetics, 2012 Relative of heritable PAH (HPAH) case Conclusions ** Disease & Genetic counseling ** • Screening for PH Gene Mutation Yes No Known? (e.g., BMPR2) – Noninvasive methods: ECHO, BNP, ECG • Goal is to provide Secondary Prevention PE & ECHO Mutation Counsel & q 1-3 yrs detected Genetic Testing No Mutation: PE & ECHO No special yearly Monitoring Soubrier F et al. Resp Res. J Am Coll Cardiol 2013;62:D13–21. 7
3/10/2017 Conclusions Conclusions Needs: • When to Screen? • Can we impact outcome? Conclusions • Screening for PH Eric.austin@vanderbilt.edu – Noninvasive methods: ECHO, BNP, ECG • Goal is to provide Secondary Prevention • Lack of Pediatric data to dictate how and when to Screen for most conditions • Paucity of Pediatric data to convincingly demonstrate benefit from earlier diagnosis 8
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