Pulmonary Capillary Haemangiomatosis

A very rare cause of pulmonary hypertension in which thin-walled capillary-like channels proliferate in the alveolar walls, interlobular septa, pleura and around small vessels, occluding the pulmonary microcirculation.

• It forms one spectrum with pulmonary veno-occlusive disease: both are caused by biallelic mutations in EIF2AK4 in heritable cases, and they share pathology (venous and capillary involvement), imaging and prognosis.
• Occurs in young and middle-aged adults (peak age 20 to 40 years), men and women equally, and rarely in children; incidence is estimated at fewer than 1 per million.
• Risk factors: EIF2AK4 mutation (autosomal recessive), previous chemotherapy (mitomycin, bleomycin, cyclophosphamide), solvent exposure, systemic sclerosis and HIV infection.
• Mechanism: capillary proliferation (not true neoplasia) with downstream venous congestion, producing pulmonary oedema if pulmonary vasodilators are given, and alveolar haemorrhage.

Progressive exertional breathlessness, fatigue, dry cough, haemoptysis (about 20 to 30%), chest pain, exertional syncope, hypoxaemia disproportionate to the obstruction.

• Signs: loud pulmonary second sound, right ventricular heave, raised jugular venous pressure, peripheral oedema, finger clubbing (in about 30%), basal crackles, cyanosis.
• Rapid deterioration and pulmonary oedema after starting pulmonary vasodilators.
• Differential diagnosis: pulmonary arterial hypertension, pulmonary veno-occlusive disease, chronic thromboembolic pulmonary hypertension, left heart disease, interstitial lung disease, pulmonary vasculitis, mitral stenosis, haemosiderosis, fibrosing mediastinitis.
• Complications: right heart failure, recurrent haemoptysis and diffuse alveolar haemorrhage, pulmonary oedema with vasodilators, respiratory failure, arrhythmia, sudden death.

Echocardiography: right ventricular dilatation and hypertrophy, estimated pulmonary systolic pressure of more than 40 mmHg, small left ventricle, no left heart disease.

• Right heart catheterisation: mean pulmonary artery pressure of more than 20 mmHg with pulmonary vascular resistance of more than 2 Wood units and pulmonary artery wedge pressure of 15 mmHg or less (the wedge is normal even though the disease is post-capillary).
• High-resolution CT: centrilobular ground glass nodules, smooth interlobular septal thickening, mediastinal lymphadenopathy, small pleural effusions, dilated pulmonary arteries; the triad of septal lines, centrilobular ground glass and lymph node enlargement is strongly suggestive.
• Pulmonary function: diffusing capacity for carbon monoxide markedly reduced (less than 50% predicted, often 30 to 40%), mild restriction, hypoxaemia on exercise.
• Genetic testing for EIF2AK4 biallelic mutations avoids lung biopsy; ventilation and perfusion scan to exclude thromboembolic disease; bronchoalveolar lavage with haemosiderin-laden macrophages (more than 20%) supports the diagnosis.
• Surgical lung biopsy is high risk and is rarely needed when genetics and imaging are typical; exclude connective tissue disease (antinuclear antibody, anti-centromere, anti-Scl-70), HIV and liver disease.

Refer early to a pulmonary hypertension centre and for lung transplantation assessment at diagnosis, because medical therapy rarely changes the course; median survival without transplant is about 1 to 3 years from diagnosis.

• Avoid pulmonary arterial hypertension drugs unless supervised in a specialist unit, because about 50% of patients develop pulmonary oedema; if used, start at the lowest dose in hospital with monitoring of oxygenation:
  • Sildenafil 20 mg once daily, titrated slowly to 20 mg three times daily if tolerated.
  • Avoid prostacyclin infusions, calcium channel blockers (nifedipine, diltiazem, amlodipine) and endothelin antagonists when possible; if a prostanoid is used as a bridge, start at 1 to 2 ng/kg/min and increase very slowly (by 1 ng/kg/min every 1 to 2 weeks).
• Diuretics: furosemide 20 to 80 mg daily, with spironolactone 25 to 50 mg daily; aim for euvolaemia with daily weights; monitor potassium and creatinine.
• Oxygen: long-term oxygen for PaO2 of 8.0 kPa or less (or SpO2 of 88% or less), and ambulatory oxygen.
• Anticoagulation is not recommended routinely because of haemoptysis; give prophylactic enoxaparin 40 mg SC daily in hospital.
• Haemoptysis: tranexamic acid 1 g three times daily for 3 to 5 days (evidence limited), bronchial artery embolisation for massive bleeding, and stopping anticoagulants.
• Immunosuppression and interferon alpha-2a have been tried, with limited and inconsistent evidence and substantial toxicity.
• Lung transplantation (double lung) is the definitive treatment: refer early, and list when functional class is III or IV (breathless on minimal exertion) or when there is haemoptysis or hospital admission; recurrence in the graft has not been described.
• Supportive: annual influenza and pneumococcal conjugate vaccine, avoid altitude and air travel without oxygen, pulmonary rehabilitation under supervision.
• Special groups: pregnancy (contraindicated, with maternal mortality of 30 to 50%; effective contraception with a progestogen implant or intrauterine device, not oestrogen; terminate or manage in a specialist centre if conceived); children (very rare, genetic testing, transplant referral); elderly (palliative focus); renal impairment (reduce diuretic doses cautiously); relatives (genetic counselling and EIF2AK4 testing).
• Red flags: acute pulmonary oedema, massive haemoptysis, syncope, worsening hypoxaemia, right heart failure, new fever.
• Follow-up: clinical review every 3 months with oxygen saturation, natriuretic peptide and 6 minute walk; echocardiogram every 6 months; chest CT if symptoms change; transplant centre review at least every 6 months.