Disclosure Objectives Pulmonary veno-occlusive disease Tilman Humpl The Hospital for Sick Children University of Toronto, Canada Advisor/Research Grants Actelion Pfizer Historical aspects Epidemiology/Genetics Clinical characteristics Pulmonary veno-occlusive disease 48 year old male Previously healthy One year history of weak heart Suspicion of mitral valve disease Autopsy Dilated right atrium and ventricle Sclerosis with intimal changes in pulmonary arteries Odd changes of the small pulmonary veins Isolated pulmonary venous sclerosis Obstructive disease of the pulmonary veins Clinico-pathologic syndrome Term coined 1966 1 st pediatric report: K. Weisser (1967) Frankfurter Z Pathol 47, 1934-35 Brown CH et al, Lancet 1966 Heath D et al, Circulation 1966 1
Pathogenesis Unknown Multi-factorial Incidence - Adults Not precisely known Proportion of primary pulmonary hypertension fulfilling PVOD criteria 5-25% Incidence - Children 7 series of primary pulmonary hypertension 1970-1991 465 patients PVOD present in 10% Mandel J et al., Am J Respir Crit Care 2000 Epidemiology - Risk factors First week of life 7 th decade Male : female 1 : 1 Chemotherapy Bleomycin, mitomycin, carmustine Post bone marrow transplantation Thoracic radiation Infection HIV Toxoplasma gondii Measles Collagen vascular disease Genetics - Familial pattern 8 weeks / 3 months 2 years 14 years / 13 years Several months Non-heritable risk factors not excluded Genetics - BMPR2 mutations Mutations present in ipah patients Similar pattern in PVOD Absence of mutations suggest other genetic risk factors Voordes CG et al, Thorax 1977 Davies P & Reid L, Hum Pathol 1982 Runo JR et al, Am J Respir Crit Care Med 2003 Machado RD et al, Hum Mut 2006 Aldred MA et al, Hum Mut 2006 2
Clinical characteristics Similar to idiopathic PAH Worsening dyspnea Exertion, lethargy Chronic cough Hemoptysis Chest pain Right heart failure Pleural effusions FC III and IV Syncope Sudden death Disease process Natural history Progressive obstruction of small pulmonary veins Elevated pulmonary vascular resistance/pressure Right ventricular failure Death PVOD - PAH Time PVOD PAH p to death or LTx to death to LTx 1 st symptom to death or LTx 1 st symptom to death 1 st symptom to LTx 22 11.8 ±16.4 15 14.3 ±19.3 7 6.4 ±3.8 22 24.4 ±22.2 15 24.7 ±24.8 7 23.8 ±16.9 23 42.3 ±29.9 9 53.3 ±22.8 14 35.2 ±32.5 23 57.9 ±38.2 9 70 ±24.2 14 50.1 ±44.1 0.0001 <0.001 0.03 <0.001 <0.001 0.14 Pathology Postcapillary Septal veins Fibrous remodeling of intima Possible occlusion of lumen Interstitial edema Interlobular septal veins Centrilobular pulmonary artery Small pulmonary arteries Intimal fibrosis and medial hypertrophy Hemosiderosis Capillary network Frazier AA et al, RadioGraphics 2007 3
Gold standard: histology Surgical risk Establishing diagnosis Listing for lung transplantation Pulmonary function testing Mild obstructive/restrictive pattern Normal mean values for FEV1 Normal ratio FEV1:FVC Normal TLC Lower DCLO Lower nadir pulse oxygen saturation 6MWT Computed tomography Holcomb BW Jr et al., Chest 2000 Resten A et al., AJR 2004 Computed tomography Ground-glass opacities Septal lines Pericardial/pleural effusion Lymph nodes Resten A et al., AJR 2004 4
Hemodynamics Hemodynamics Wedge pressure does not reflect true capillary pressure Pressure in larger veins Normal wedge pressure No discrimination between ipah and PVOD Acute vasoreactivity testing Safe? Useful? ino 5-10 min 10ppm No pulmonary edema No prediction for Development of pulmonary edema Prognosis Montani et al., Eur Respir J 2009 Golde Score Bronchoalveolar lavage Alveolar haemorrhage Grading for hemosiderin p=0.02 Lack of controlled trials Anecdotal case reports/series Expert opinion Pulmonary vasodilators May cause increase of pulmonary arteriolar blood flow against fixed resistance Progress to severe pulmonary edema Rabiller A et al, Eur Respir J 2006 5
Prostacyclin 12 adults, 41±12y to initiation: 66 (1-358) d Before PGI After 3-4 m p Class III 4 11 <0.01 Class IV 8 1 6MWT (m) 281±162 322±160 0.11 PVRi WUxm 2 28.4±8.4 17±5.2 <0.0001 Montani D et al., Eur Resp J 2009 Prostacyclin Maximal dose: 13 (5-22) ng kg -1 min -1 Time to reach maximal dose: 150 (5-1065) d Additional therapies Oxygen Anticoagulation Diuretics Endothelin receptor antagonist Dobutamine Montani D et al., Eur Resp J 2009 Prostacylin Lung transplantation: 9 (+1) patients Death: 2 patients Montani D et al., Eur Resp J 2009 Case reports/series Inhaled prostacyclin Oral phosphodiesterase inhibitors V Endothelin Receptor Antagonist Hoeper MM et al., Respir Med 1999 Barreto AC et al., Braz J Med Biol Res 2005 Kuroda T et al., Heart Lung Circ 2006 General measures Limit physical activity to tolerance O 2 to maintain saturations >90% Vaccinations Diuretics (Avoid tobacco exposure) Anticoagulation Based on data on primary pulmonary hypertension Immunosuppression Steroids Antimetabolites Experimental therapy Imatinib Antiproliferative effect Lung transplantation Overbeek MJ et al., Eur Resp J 2008 6
Treatment failure for ipah Summary Take home Idiopathic/scleroderma-associated PAH Non-responders to medical therapy In retrospect: 86% PVOD Treatment refractory ipah In retrospect: 17.2% PVOD Rare subgroup of pulmonary hypertension Etiology in the majority of cases unknown Most likely underdiagnosed Combination of: CT, BAL, DLCO, SpO 2 Worse prognosis compared to ipah No specific medical treatment options Lung transplantation Eur Respir Rev 2009 Brown CH & Harrison CV, Lancet 1966 Harch S et al., Chest 2009 Dorfmüller P et al., Hum Pathol 2007 7