Precapillary pulmonary hypertension is defined at right-heart catheterisation by a sustained increase in mean pulmonary artery pressure of at least 25 mm Hg and a normal pulmonary artery wedge pressure of no more than 15 mm Hg.1 Precapillary pulmonary hypertension can be heritable in the context of pulmonary arterial hypertension, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH).1
Pulmonary arterial hypertension is an uncommon cause of pulmonary hypertension characterised by proliferative remodelling and fibrosis of the small pulmonary arteries.1, 2 Heritable pulmonary arterial hypertension can develop in patients carrying heterozygous mutations of the BMPR2 gene3 and other less common heterozygous gene mutations (such as ACVRL1, ENG, CAV-1, and KCNK3).4, 5, 6 Patients with pulmonary arterial hypertension and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death or transplantation, compared with those without BMPR2 mutations.7, 8, 9 An autosomal recessive form of heritable precapillary pulmonary hypertension due to mutations of the EIF2AK4 gene (coding for eukaryotic translation initiation factor 2 α kinase 4) has been identified.10, 11, 12 Histological examination of the lungs from carriers of bi-allelic EIF2AK4 mutations has revealed extensive occlusion of pulmonary veins by fibrous tissue, intimal thickening of venules and small veins in the lobular septa, and localised capillary proliferation.10, 13 These histological features correspond to the clinical entities of PVOD and PCH, which are believed to be manifestations of the same rare underlying condition (lowest estimate of prevalence is <1 case per million).1, 10, 12, 13 The EIF2AK4 gene is the only gene identified in heritable PVOD/PCH. Beside heritable forms, environmental risk factors such as occupational organic solvent exposure and chemotherapy have also been associated with the development of PVOD/PCH.14, 15, 16
Research in context
Evidence before this study
Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) are rare causes of pulmonary hypertension. Currently, PVOD and PCH are believed to represent spectrums of a common disease entity (PVOD/PCH). In 2014, bi-allelic mutations of the EIF2AK4 gene were shown to be a cause of heritable PVOD/PCH, but no information was available about whether the clinical phenotype and outcomes of heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations are different to cases of sporadic disease.
Added value of this study
Our study provides the first systematic assessment of the effect of bi-allelic EIF2AK4 mutations in a large cohort of patients with PVOD/PCH at the French Referral Centre. We identified 27 patients with PVOD/PCH with EIF2AK4 mutations and 67 patients with sporadic PVOD/PCH. Bi-allelic EIF2AK4 mutation carriers were characterised by younger age at diagnosis with an equal sex ratio, whereas more male patients were affected in the non-carrier group. Both groups displayed similar pulmonary haemodynamic characteristics indicative of severe precapillary pulmonary hypertension, functional class impairment, and high-resolution CT findings. In the overall population with PVOD/PCH, treatment with drugs for pulmonary arterial hypertension led to mild haemodynamic and functional improvement but this was associated with a significant risk of pulmonary oedema (21%). Transplantation-free survival for both EIF2AK4 mutations carriers and non-carriers was equally poor, with 32% and 34% of patients, respectively, who were event free at 3 years.
Implications of all the available evidence
Patients with PVOD/PCH with bi-allelic EIF2AK4 mutations are substantially younger at diagnosis but have similarly severe disease in terms of haemodynamic characteristics and functional impairment, compared with patients without EIF2AK4 mutations. Sustained response to drugs for pulmonary arterial hypertension was not observed, resulting in the need for early lung transplantation in eligible patients.
Distinguishing PVOD/PCH from pulmonary arterial hypertension on clinical grounds can be challenging, since the physical and haemodynamic findings for all three diseases are broadly similar, and PVOD/PCH might represent 5%–10% of cases initially thought to be idiopathic pulmonary arterial hypertension.13, 17, 18, 19 An important clinical hallmark of PVOD/PCH is the possible occurrence of pulmonary oedema induced by medical therapies approved for pulmonary arterial hypertension.13, 17, 20 On the basis of these findings, PVOD/PCH are classified as a distinct subgroup in the updated clinical classification of pulmonary hypertension.1, 21
Since PVOD/PCH can result from bi-allelic EIF2AK4 mutations in its heritable form or from environmental factors, the possibility is raised that EIF2AK4 mutation status might be associated with a distinct phenotype of PVOD/PCH, as shown in patients with pulmonary arterial hypertension and BMPR2 mutations. To test this hypothesis, we obtained data from all adult and paediatric patients with PVOD/PCH in whom EIF2AK4 mutations were screened for and referred to the French Referral Centre for Severe Pulmonary Hypertension. Clinical, functional, and haemodynamic characteristics and outcomes were compared between patients with heritable PVOD/PCH with bi-allelic EIF2AK4 mutations and patients with PVOD/PCH without identifiable EIF2AK4 mutations.