PEDIATRIC Pulmonary Vascular Disease: ‘Focus’ on Pulmonary Hypertension Eric Austin Disclosure • No financial or other relationships to disclose Outline • • • • Background: normal and PH Pediatric pulmonary hypertension Approaches to PH evaluation in Pediatrics Therapeutic approaches to Pediatric PH Outline • • • • Background: normal and PH Pediatric pulmonary hypertension Approaches to PH evaluation in Pediatrics Therapeutic approaches to Pediatric PH Normal Pediatric Heart Aorta 90 / 60 100% PAP 20 / 5 (mean 8-20) 90/ 60 75% 20/8 75% 100% 6-10 0-5 20/ 20 / 0-5 90 / 0-10 90/ Pulmonary Vascular Reserve 100% 30 Working Vessels (0%) Pulmonary Vascular Resistance (Wood units) 1 0% Pulmonary artery pressure Courtesy of John Newman Diagnosis of PH • Gold Standard: Cardiac Catheterization Normal PH Resting PAP 8 – 20 mm Hg > 25 mm Hg PVR index 0-2 Wood units m2 >3 Wood units m2 • Pulmonary arterial hypertension (PAH) – mean PAP > 25 mm Hg – pulmonary artery wedge pressure ≤ 15 mm Hg Badesch JACC 2009 Clinical Classification of (adult) PH 1. PULMONARY ARTERIAL HYPERTENSION (PAH) 3. PH DUE TO LUNG DISEASES AND/OR HYPOXIA - Idiopathic PAH - Bronchopulmonary dysplasia (BPD), COPD - Heritable PAH (Family and/or gene mutation) - Interstitial Lung Disease (ILD) - Drug- and toxin-induced - Other lung dz’s w/ mixed restrictive/obstructive defects - Associated with: - Sleep-disordered breathing - Alveolar hypoventilation disorders - Chronic exposure to high altitude - Developmental lung abnormalities Connective tissue diseases Congenital heart diseases HIV Portal hypertension Schistosomiasis Chronic hemolytic anemia 1’. PULMONARY VENO-OCCLUSIVE DZ (PVOD) AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS (PCH) 2. PH DUE TO LEFT HEART DISEASE - Systolic dysfunction - Diastolic dysfunction - Valvular disease 4. CHRONIC THROMBOEMBOLIC PH (CTEPH) 5. PH UNCLEAR MULTIFACTORIAL MECHANISMS - Hematologic d/o’s: myeloproliferative, splenectomy - Systemic d/o’s: sarcoidosis, LCH, LAM, NF, vasculitis - Metabolic d/o’s: glycogens storage dz, Gaucher’s Thyroid - Others: tumurol obstruction, fibrosing mediastinitis, CRF Simonneau et al, JACC 2009 Clinical Classification of PH 1. PULMONARY ARTERIAL HYPERTENSION (PAH) 3. PH DUE TO LUNG DISEASES AND/OR HYPOXIA - Idiopathic PAH - COPD - Heritable PAH (Family and/or gene mutation) - ILD - Drug- and toxin-induced - Other lung dz’s w/ mixed restrictive/obstructive defects - Associated with: - Sleep-disordered breathing - Alveolar hypoventilation disorders - Chronic exposure to high altitude - Developmental lung abnormalities Connective tissue diseases Congenital heart diseases HIV Portal hypertension Schistosomiasis Chronic hemolytic anemia 1’. PULMONARY VENO-OCCLUSIVE DZ (PVOD) AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS (PCH) 2. PH DUE TO LEFT HEART DISEASE - Systolic dysfunction - Diastolic dysfunction - Valvular disease 4. CHRONIC THROMBOEMBOLIC PH (CTEPH) 5. PH UNCLEAR MULTIFACTORIAL MECHANISMS - Hematologic d/o’s: myeloproliferative, splenectomy - Systemic d/o’s: sarcoidosis, LCH, LAM, NF, vasculitis - Metabolic d/o’s: glycogens storage dz, Gaucher’s Thyroid - Others: tumurol obstruction, fibrosing mediastinitis, CRF Simonneau et al, JACC 2009 Clinical Classification of PH 1. PULMONARY ARTERIAL HYPERTENSION (PAH) - Idiopathic PAH Formerly called: - Heritable PAH (family and/or gene mutation) Primary Pulmonary Hypertension (PPH) - Drug- and toxin-induced - Associated with: Connective tissue diseases Congenital heart diseases HIV Portal hypertension Schistosomiasis Chronic hemolytic anemia 1’. PULMONARY VENO-OCCLUSIVE DZ (PVOD) AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS (PCH) Simonneau et al, JACC 2009 Vanderbilt & Familial PAH Loyd, Primm, Newman, Am Rev Respir Disease 1984 Jan;129(1):194-7. Today The Initial Loyd/Newman Family: 36 Confirmed PAH 29 Female 7 Male Updated Summer 2011 (Pulm Circ)—initial pub by Loyd, Primm, Newman Am Rev Resp Diseases 1984 Children & Adults get PAH % FPAH patients deceased by Age Replicated by Columbia University personal communication, W. Chung Humbert et al. AJRCCM 2006 Austin et al. Eur Resp J 2009 PAH • Onset at any age • ≥ 2:1 ratio (F: M) • ~ Consistent histopathology across subtypes • Progressive disease: RV failure  Death • No curative therapies Normal Courtesy BO Meyrick – Current Rx: vasodilators • Peds: no FDA approval PAH Zaiman AJRCCM 2005 Courtesy of Drs. Meyrick and Loyd ‘Pruning’ of distal pulmonary arterioles Normal ‘Pruning’ Courtesy of Drs. Meyrick and Loyd ‘Pruning’ of distal pulmonary arterioles • Vasoconstriction • Endothelial Cell migration & proliferation • VSMC hyperplasia & proliferation • In situ thrombosis • Small PA obliteration • Plexiform lesions ‘Pruning’ PAH is fatal despite therapy McLaughlin VV et al. CHEST 2004 Current therapies attack vasoconstriction: No curative therapy Bone morphogenetic protein receptor type 2 gene (BMPR2) 570 in bloodline including 421 alive Updated Dec 2011 (Pulm Circ)—initial pub by Loyd, Primm, Newman Am Rev Resp Diseases 1984 BMPR2 mutations in PAH • Population prevalence: unknown but very rare Type of PAH Reported mutation prevalence FPAH ≥ 80% IPAH 10-40% Congenital heart disease 6% Scleroderma Not detected HIV Not detected Hemolytic disease Not reported PAH with BMPR2 mutation: more severe disease Elliott Circ 2006 Rosenzweig J HLT 2008 Sztrymf AJRCCM 2008 Austin Resp Res 2009 Pfarr Resp Res 2011 1. Age at Dx and Death: younger 2. Vasodilators: poor response 3. More severe hemodynamics 4. Survival: shorter Genetic Testing: BMPR2 • Cost: expensive – No known mutation: $1000 to $2500 – Known mutation: ~$300 to $400 • Clinical lab required • Familial disease: test proband first • Research role: may inform mutation status, but confirmation in clinical lab remains mandatory – www.genetests.org Patients: Clinical role • Familial and IPAH patients – Consider BMPR2 testing, and discussion of heritability – Less value for testing other genes at this time • Genetic testing to advise treatment and prognosis not ready for ‘prime time’ • Important and evolving role in research Machado JACC 2009 Patients: Genetic testing and counseling Pros • Assess heritability • Research to propel field Cons • No current clinical role • ‘Guilt of heritability’ – Psychologic impact • Genetic modifiers • Environmental modifiers • Pathogenesis • Genetic discrimination – Insurability – Employment • Cost • Personalized therapy • Personalized prognosis – $1000-2500 if mutation unknown – Provider time Relatives of PAH mutation carriers: counseling and testing • Case by case, careful peds – Negative result helpful • Active research ongoing – – – – Risk Prevention Prognosis Screening But PH is more than PAH, and PEDIATRIC PH does not fit the adult classification scheme very well Outline • • • • Background: normal and PH Pediatric pulmonary hypertension Approaches to PH evaluation in Pediatrics Therapeutic approaches to Pediatric PH Chromosomal or Genetic Syndromes Pathologic Insults to the Growing Lung PH Multifactorial Conditions Adapted from: del Cerro, Adatia et al. Pulm Circ Vol 1 2011 Dev’t Abnormalities: Lung Hypoplasia ~ Realistic Pediatric PH • • • • • • • • • Prenatal or Developmental Pulm Vasc Dz (PVD) Perinatal pulm vascular maladaptation (Ex: PPHN) Congenital Heart Disease BPD Isolated pediatric pulm arterial hypertension (PAH) Congenital malformations w/ multifactorial dz Pediatric lung disease Thromboembolic disease PVD associated w/ other system d/o (Ex: CTD) Adapted from: del Cerro, Adatia et al. Pulm Circ Vol 1 2011 Textbook of Pulmnary Vascular Disease. 2011 Aschner et al. Pediatric Pulmonary Hypertension Pediatric PH: incidence data Van Loon RL et al. Circulation 2011 TOPP Study of Peds PH: ‘08-’10 Cardiac Cath confirmed (ECHO is ~same) Total patients 362 Female 214 (59% of total) Mean Age Dx, yrs 7.5 (7.0-8.1) Group I (PAH) --IPAH, FPAH --APAH-CHD 317 (88% of total) --182 (50% of total) --115 (32% of total) Group 3 (Lung) --BPD --ILD --CDH --Hypoplasia 42 (12% of total) --11 (3% of total) --10 (3% of total) --4 (1% of total) --5 (1% of total) Comorbid Conditions: • 86/362 (24%) with Chromosomal d/o – 42 of those w/ Trisomy 21 – 21% of Group 3 w/ Trisomy 21 Berger et al. Lancet 2012 Prevalence of PH in Kids • • • • Unclear overall 2% of children with CHD 0.2% of children with Lung Disease < 5% ten yr olds with hemoglobinopathy Outline • • • • What has been going on with PH Program? Background: normal and PH Approaches to PH evaluation in Pediatrics Therapeutic approaches to Pediatric PH Approach to new PH concern Barst RJ et al. Eur Resp Journal 2011 Outline • • • • Background: normal and PH Pediatric pulmonary hypertension Approaches to PH evaluation in Pediatrics Therapeutic approaches to Pediatric PH Current PAH-specific Therapy Humbert M. NEJM 2004 Children: no approved therapies • Limited clinical trial data • As in adults, trials ~all in PAH patients • Approaches based on experience, gestalt PDE5i’s (sildenafil, tadalafil) • 0.25 to 2 mg/kg/dose QID • SE’s are rare – – – – – Priapism Hypotension Diarrhea Headache V/Q mismatch (iv infusion) STARTS-1 Trial • • • • Treatment-naïve PAH Low/Medium/High dose sildenafil vs. Placebo Oral, 3 times daily for 16 weeks Medium dose ~1.4-4mg/kg/day • High dose ~6-8 mg/kg/day ** Target ≤ 4 mg/kg/day Percentage change in peak oxygen consumption ( pVO2) vs. Placebo (CPET) Barst RJ et al. Circulation. 2012 Jan 17;125(2):324-34 2006-2011: BPD Clinic (n=40) Table 4b. Specific information concerning the sildenafil dose administered to the 40 Severe BPD-PH patients. Sildenafil dose: TID Number of Patients 0.5 mg/kg/dose TID 3 1 mg/kg/dose TID 5 1.5 mg/kg/dose TID 2 Sildenafil dose: 4x/day Number of Patients 0.5 mg/kg/dose 4x/day 10 1 mg/kg/dose 4x/day 19 1.5mg/kg/dose 4x/day 1 Droemer & Leedy, manuscript in progress, 2012 Endothelin Receptor Antagonists • Bosentan, Ambrisentan • Contraindication: pregnancy • SE’s (Bosentan) – Hepatic injury: rise AST, ALT (monthly check) – Anemia, dose-related (monthly check) • 62.5 mg; 125 mg tablets – Target ~ 2 mg/kg/dose BID dosing • Slow: start ~½ dose for 4 weeks, then increase to full dose Practical approaches to start Bosentan • • • • < 10 kg: 15.6 mg qDay x 4 wks  15.6 mg BID 10-20 kg: 31.25 mg qDay x 4 wks  31.25 BID 21-40 kg: 31.25 mg BID x 4 wks  62.5 mg BID > 40 kg: 62.5 mg BID x 4 wks  125 mg BID • If able, start low, increase slowly • Ambrisentan: hepatic monitoring not mandatory – Potential alternative to Bosentan Prostanoids • Initial class of drugs for PAH – Vasodilate systemic and pulmonary vasculature – Inhibit platelet aggregation – Inhibit smooth muscle cell proliferation over time • Epoprostenol: Survival benefit (& other metrics) – Unstable at room temp – ½ life < 6 minutes – Continuous infusion via closed cool system – ng/kg/minute – Line infections & breaks; rebound PH crisis iv Treprostinil (Remodulin®) • • • • Prostacylin analogue, alternative to epoprostenol Easier to mix at home Longer ½ life (~4 hours) Stable at room temperature • Inhaled as Tyvaso®  6 times/day; 9mcg/puff • (Iloprost as Ventavis®)  6-9 times/day) Proposed PAH Treatment Algorithm in Pediatrics Vasodilator Response: > 20% fall mPAP > 20% fall PVRI C.I. no Δ or rise Tissot C et al. J Peds Volume 157, Issue 4 2010