Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (ORPHA:431353)
A disorder that constitutes a rare subgroup of rare pulmonary hypertension characterized by obliterative fibrosis of the small pulmonary veins and venules and/or capillary infiltration of the pulmonary interstitium leading to increased pulmonary vascular resistance and right ventricular dysfunction.
Epidemiology
Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD and/or PCH) annual incidence has been estimated at between 1 in 5-10 millions but this likely to be an underestimate. PVOD and/or PCH is believed to account for up to 5 to 10% of patients initially diagnosed with idiopathic pulmonary arterial hypertension (PAH).
Clinical description
Onset may occur at any age and there is no overall sex predilection in the genetic form of the disease but a male predominance in sporadic PVOD cases. Patients present with non-specific respiratory symptoms, most commonly progressive exertional dyspnea and fatigue. PVOD and/or PCH and idiopathic PAH share the same clinical presentation and clinical examination is unhelpful to distinguish them. As the disease progresses, patients may show signs of right ventricular failure and the use of PAH drugs is associated with a potential risk of life-threatening pulmonary edema.
Etiology
Several factors have been suspected to influence disease development including various chemotherapy regimens as well as bone marrow and hematopoietic blood stem cell transplantation. Occupational exposure is a frequently encountered risk factor for PVOD (mainly organic solvents, as trichloroethylene (a chlorinated solvent)). Pulmonary venous involvement may also occur in patients with connective tissue diseases (systemic sclerosis), sarcoidosis, and adult pulmonary Langerhans cell histiocytosis. Familial cases of PVOD and/or PCH have also been reported and around 10 to 20% of PVOD and/or PCH patients have a heritable form of the disease due to bi-allelic mutations in the EIF2AK4 gene (15q13.3).
Diagnostic methods
Right heart catheterisation confirms pulmonary hypertension and shows pattern of precapillary PH with normal pulmonary artery wedge pressure. Although histology is considered the gold standard for definite diagnosis, lung biopsy carries a high risk of morbidity and mortality. Hence the diagnosis is usually based on the combination of clinical findings, pulmonary function tests and blood gas measurements (resting hypoxemia and low carbon monoxide diffusion capacity), bronchoalveolar lavage (occult alveolar hemorrhage) and high resolution CT scans (septal thickening, ground-glass opacities and lymphadenopathy). Mutations in EIF2AK4 gene confirm the diagnosis.
Differential diagnosis
The main differential diagnoses are PAH (idiopathic or secondary to chronic lung diseases), and chronic thromboembolic pulmonary hypertension.
Antenatal diagnosis
Prenatal diagnosis can be considered in families with identified bi-allelic mutations in EIF2AK4 gene.
Genetic counseling
Genetic counseling and screening for the EIF2AK4 gene are offered to PVOD/PCH patients. Heritable PVOD and/or PCH is an autosomal recessive disease.
Management and treatment
The usual recommended regimens involve oxygen therapy, anticoagulants and antithrombotic agents, immunosuppressants, pneumococcal and influenza vaccinations, and limiting physical activity. The use of PAH-specific therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclins) remains controversial due to the high risk of pulmonary edema. Importantly, PVOD patients who respond acutely to inhaled NO may develop severe pulmonary oedema rapidly after initiation of calcium channel blocker therapy. Given the above considerations, acute vasoreactivity testing is contraindicated in PVOD. At present, it is recommended that PVOD and/or PCH patients be treated in highly specialized centers for PAH and that they be fully informed of the risks if PAH-specific therapies are initiated. Because of poor prognosis, lung transplantation should be discussed early in the course of the disease.
Prognosis
The prognosis for PVOD and/or PCH patients remains poor in the absence of lung transplantation.

                            Last update: 
                            June 2019


                            - Expert reviewer(s): 
                            Dr Barbara GIRERD  - Pr David MONTANI