Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: A systematic review.

BACKGROUND: There are several medications available to treat pulmonary arterial hypertension (PAH): PAH-targeted drugs. However, in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH), rare diseases that cause pulmonary hypertension, the effectiveness and safety of vasodilators, including PAH-targeted drugs, are unclear. METHODS: We searched English-language publications listed in three electronic databases (PubMed, Cochrane Library, and the Japan Medical Abstracts Society). Reports with efficacy outcomes (survival, improvement in 6-minute walk distance, and pulmonary vascular resistance) and data on development of pulmonary edema after administration of vasodilators to patients with PVOD/PCH were selected (1966 to August 2015). RESULTS: We identified 20 reports that met our criteria. No randomized controlled or prospective controlled studies were reported. The survival time ranged from 71 minutes to 4 years or more after initiation of vasodilators. Most of the reported cases showed an improvement in the 6-minute walk distance and pulmonary vascular resistance. Pulmonary edema was reported in 15 articles, some cases of which were lethal. CONCLUSIONS: The present study demonstrates the potential efficacy and difficulties in the use of vasodilators in patients with PVOD/PCH; however, drawing a firm conclusion was difficult because of the lack of randomized controlled trials. Further research is needed to ascertain if vasodilator use is beneficial and safe in patients with PVOD/PCH.

Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study.

BACKGROUND: Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the effect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. METHODS: We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicêtre, University Paris-Sud) with either confirmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specific therapy for pulmonary arterial hypertension was defined by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2·5 L/min per m2 at the first reassessment after initiation of specific therapy for pulmonary arterial hypertension. FINDINGS: We obtained data from Jan 1, 2003, to June 1, 2016, and identified 94 patients with sporadic or heritable PVOD/PCH (confirmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26·0 years [range 0-50.3] vs 60·0 years [6·7-81·4] years; p<0·0001). At diagnosis, both mutations carriers and non-carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in five (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefined criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No significant differences occurred in event-free survival between the 2 groups (p=0·38). Among the 33 patients who had lung transplantation, estimated post-transplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively. INTERPRETATION: Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients. FUNDING: None.

Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension: report of 2 new cases and review of 35 cases from the literature.

Pulmonary capillary hemangiomatosis (PCH) is a rare cause of primary pulmonary hypertension characterized by thin-walled microvessels infiltrating the peribronchial and perivascular interstitium, the lung parenchyma, and the pleura. These proliferating microvessels are prone to bleeding, resulting in accumulation of hemosiderin-laden macrophages in alveolar spaces. Here we report 2 cases of PCH with pulmonary hypertension, 1 of them associated with mechanical intravascular hemolysis, a feature previously reported in other hemangiomatous diseases, but not in PCH. Case 2 was diagnosed by pulmonary biopsy; to our knowledge the patient is the second adult to be treated with interferon alpha-2a. Review of the literature identified 35 patients with PCH and pulmonary hypertension. The prognosis is poor and median survival was 3 years from the first clinical manifestation. Dyspnea and right heart failure are the most common findings of the disease. Hemoptysis, pleural effusion, acropachy, and signs of pulmonary capillary hypertension are less common. Chest X-ray or computed tomography scan usually shows evidence of interstitial infiltrates, pulmonary nodules, or pleural effusion. Hemodynamic features include normal wedge pressures. Radiologic and hemodynamic findings are undifferentiated from those of pulmonary veno-occlusive disease but differ from other causes of primary pulmonary hypertension. Epoprostenol therapy, considered the treatment of choice in patients with primary pulmonary hypertension, may produce pulmonary edema and is contraindicated in patients with PCH. Regression of lesions was reported in 1 patient treated with interferon therapy and 2 other patients stabilized, including our second patient. PCH was treated successfully by lung transplantation in 5 cases. Early recognition of PCH in patients with suspected primary pulmonary hypertension is possible based on clinical and radiologic characteristics. Diagnosis by pulmonary biopsy is essential for allowing appropriate treatment.