Pulmonary Veno-occlusive Disease

A rare form of pulmonary arterial hypertension in which small pulmonary veins and venules are narrowed by fibrous intimal thickening, causing post-capillary obstruction, pulmonary oedema and secondary arterial remodelling.

• Accounts for about 5 to 10% of patients with a clinical picture of idiopathic pulmonary arterial hypertension; incidence is about 0.1 to 0.5 per million per year; it occurs in all ages, with a male predominance in the sporadic form (about 2:1).
• Causes: heritable (biallelic EIF2AK4 mutations, autosomal recessive, with onset at a median age of about 30 years); acquired after chemotherapy (mitomycin C, cyclophosphamide, bleomycin, carmustine), radiotherapy, stem cell transplant, solvents (trichloroethylene), systemic sclerosis, sarcoidosis and HIV; idiopathic.
• Mechanism: injury to the pulmonary venous endothelium leads to intimal fibrosis and occlusion of septal veins and venules, raising capillary pressure and causing oedema, capillary congestion and haemorrhage; vasodilators increase pulmonary flow into obstructed veins and cause pulmonary oedema.

Progressive exertional breathlessness, fatigue, exertional syncope, chest pain, orthopnoea, haemoptysis, cough.

• Signs: cyanosis, clubbing (about 30%), loud pulmonary second sound, right heart failure (raised jugular venous pressure, oedema), basal crackles, pleural effusion.
• Hypoxaemia is more severe than in other forms of pulmonary hypertension, with marked desaturation on exercise.
• Acute pulmonary oedema after starting a pulmonary vasodilator is a diagnostic clue.
• Differential diagnosis: idiopathic pulmonary arterial hypertension, pulmonary capillary haemangiomatosis, left heart disease (mitral stenosis, heart failure with preserved ejection fraction), interstitial lung disease, chronic thromboembolic pulmonary hypertension, fibrosing mediastinitis, pulmonary vein stenosis, sarcoidosis.
• Complications: right heart failure, pulmonary oedema, haemoptysis and alveolar haemorrhage, pleural effusion, arrhythmia, respiratory failure, and sudden death.

Echocardiography: raised pulmonary pressure, right ventricular dilatation and hypertrophy, normal left ventricular function and normal left atrium.

• Right heart catheterisation: mean pulmonary artery pressure of more than 20 mmHg, pulmonary vascular resistance of more than 2 Wood units, and pulmonary artery wedge pressure of 15 mmHg or less (normal in most); do not perform vasoreactivity testing with nitric oxide or epoprostenol without precautions.
• High-resolution CT: smooth interlobular septal thickening, centrilobular or patchy ground glass opacities, mediastinal lymph node enlargement (more than 10 mm), pleural effusions, dilated pulmonary arteries; the combination of the three signs is highly specific.
• Pulmonary function: markedly reduced diffusing capacity for carbon monoxide (often less than 50% predicted), mild restriction, hypoxaemia.
• Genetic testing for EIF2AK4 biallelic mutations confirms heritable disease and removes the need for biopsy.
• Ventilation and perfusion scanning (to exclude chronic thromboembolic disease); bronchoalveolar lavage with haemosiderin-laden macrophages and bloody return; autoimmune tests, HIV test, liver ultrasound.
• Lung biopsy is hazardous and is avoided; histology shows fibrous obliteration of septal veins and preseptal venules with capillary congestion.

Refer at diagnosis to a pulmonary hypertension and lung transplant centre; median survival from diagnosis is about 1 to 2 years without transplantation.

• Oxygen: long-term and ambulatory oxygen to keep SpO2 at 92% or more, and at sleep and exertion.
• Diuretics: furosemide 20 to 120 mg daily (or IV infusion 5 to 20 mg/h for decompensation), and spironolactone 25 to 100 mg daily; cautious volume reduction with daily weights, potassium and creatinine monitoring.
• Pulmonary arterial hypertension drugs only in specialist units, with admission and oxygen monitoring for the first doses (about 50% develop pulmonary oedema; if oedema occurs, stop the drug):
  • Sildenafil 20 mg once daily, then 20 mg three times daily, or tadalafil 20 mg daily increased to 40 mg daily.
  • Epoprostenol or treprostinil infusion only as a bridge to transplant, starting at 1 to 2 ng/kg/min with increments of 1 to 2 ng/kg/min every 1 to 2 weeks while watching for oedema.
  • Calcium channel blockers are avoided because the response is absent and there is a risk of deterioration.
• Anticoagulation is not routine; consider warfarin to INR 2.0 to 3.0 if recurrent thrombosis is shown, with careful consideration of haemoptysis; prophylactic enoxaparin 40 mg SC daily during admission.
• Haemoptysis: tranexamic acid 1 g three times daily for 3 to 5 days (evidence limited), and bronchial artery embolisation for massive bleeding.
• Lung transplantation (double lung or heart-lung) is the only treatment that improves survival: refer at diagnosis and list early; the waiting-list mortality is high, so bridging with extracorporeal support may be required.
• Treat associated disease: connective tissue disease, sarcoidosis, HIV (antiretroviral therapy).
• Supportive: annual influenza vaccination and pneumococcal conjugate vaccine, avoid altitude (above 1500 m) without oxygen, iron replacement when iron deficient (ferrous sulfate 200 mg three times daily, or ferric carboxymaltose 1000 mg IV once).
• Special groups: pregnancy (contraindicated; maternal mortality of 30 to 50%; use an intrauterine device or progestogen implant; if pregnant, manage in a specialist centre with a multidisciplinary team); children (genetic testing, early transplant referral); elderly (palliation); renal impairment (cautious diuresis); relatives (genetic counselling and EIF2AK4 testing).
• Red flags: pulmonary oedema (especially after a vasodilator), massive haemoptysis, syncope, worsening hypoxaemia, right heart failure.
• Follow-up: every 3 months with SpO2, natriuretic peptide and 6 minute walk test; echocardiogram every 6 months; CT of the chest for new symptoms; transplant review at least every 6 months.