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

doi:10.1016/S2213-2600(16)30438-6

The Lancet Respiratory Medicine

Volume 5, Issue 2, February 2017, Pages 125-134

https://doi.org/10.1016/S2213-2600(16)30438-6 Get rights and content

Summary

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.

Introduction

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.

Section snippets

Study design and participants

We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network,² which includes all patients with pulmonary hypertension at the French Referral Centre for Severe Pulmonary Hypertension (Hôpital Bicêtre, Université Paris-Sud, Le Kremlin-Bicêtre, France) and the 22 associated centres across France. The French Referral Centre offers genetic counselling and mutation screening to all patients diagnosed with idiopathic,

Results

Between Jan 1, 2003, and June 1, 2016, 109 patients with PVOD/PCH (47 confirmed and 62 highly probable) underwent genetic counselling and testing (figure 1). 15 patients with highly probable PVOD/PCH were excluded from the final analysis because of chronic respiratory disease. Thus, 94 patients were included in this study, of which 27 were carriers of bi-allelic EIF2AK4 mutations (mutations listed in appendix) and 67 were non-carriers of these mutations. Non-carriers corresponded to 47 highly

Discussion

PVOD/PCH occurring in patients with bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis compared with non-carriers. Regardless of mutation status, all patients with PVOD/PCH presented with severe clinical, functional, and haemodynamic impairment. Despite the possible occurrence of drug-induced pulmonary oedema, a mild improvement with pulmonary arterial hypertension therapy occurred in the entire cohort, as reported previously.¹³ However, clinical and haemodynamic

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Genetic counselling and testing in pulmonary arterial hypertension – A consensus statement on behalf of the International Consortium for Genetic Studies in PAH – French version
2023, Revue des Maladies Respiratoires
L’hypertension artérielle pulmonaire (HTAP) est une maladie rare qui peut être causée par des variants génomiques germinaux pathogènes. Au-delà du gène BMPR2 (bone morphogenetic protein receptor 2) qui est le gène le plus fréquemment associé à l’HTAP, plusieurs gènes ont été identifiés comme prédisposant au développement de la maladie. En conséquence, les cliniciens spécialistes et non spécialistes de l’HTAP, ainsi que les professionnels de santé, sont de plus en plus confrontés à des questions concernant les indications, les interprétations et les bénéfices/risques des tests génétiques pour les patients atteints d’HTAP et/ou leurs apparentés. Nous proposons des recommandations par une approche de consensus concernant le conseil génétique et l’évaluation des pratiques actuelles pour les tests génétiques dans l’HTAP. Nous proposons un cadre et les informations à fournir aux patients et aux apparentés dans le cadre du conseil génétique et listons les gènes causals de la maladie qui devraient faire partie de l’analyse génétique de ces patients. Les avantages de la réalisation des tests génétiques dans la prise en charge des patients atteints d’HTAP incluent la correction de certains diagnostics , la meilleure caractérisation du phénotype et du pronostic, et grâce au dépistage "en cascade" des apparentés, la détection de porteurs sains de variants causals, chez qui un programme de dépistage devrait être proposé.
Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.
Treatment of pulmonary arterial hypertension: recent progress and a look to the future
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Pulmonary arterial hypertension (PAH) is a severe but treatable form of pre-capillary pulmonary hypertension caused by pulmonary vascular remodelling. As a result of basic science discoveries, randomised controlled trials, studies of real-world data, and the development of clinical practice guidelines, considerable progress has been made in the treatment options and outcomes for patients with PAH, underscoring the importance of seamless translation of information from bench to bedside and, ultimately, to patients. However, PAH still carries a high mortality rate, which emphasises the urgent need for transformative innovations in the field. In this Series paper, written by a group of clinicians, researchers, and a patient with PAH, we review therapeutic approaches and treatment options for PAH. We summarise current knowledge of the cellular and molecular mechanisms of PAH, with an emphasis on emerging treatable pathways and optimisation of current management strategies. In considering future directions for the field, our ambition is to identify therapies with the potential to stall or reverse pulmonary vascular remodelling. We highlight novel therapeutic approaches, the important role of patients as partners in research, and innovative approaches to PAH clinical trials.
Usefulness of genetics for clinical reclassification and refinement of prognostic stratification in pulmonary arterial hypertension
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La evaluación del riesgo en la hipertensión arterial pulmonar (HAP) es esencial de cara a administrar un tratamiento más agresivo a aquellos pacientes de mayor riesgo. Sin embargo, las escalas pronósticas más recientes olvidan el trasfondo genético. Además, la enfermedad venooclusiva pulmonar (EVOP) no se ha considerado nunca en las estrategias de evaluación del riesgo.
Se consideraron para este trabajo pacientes consecutivos incluidos en el registro Español de HAP (REHAP) analizados genéticamente entre los años 2011 y 2022. Se aplicó en ellos el modelo COMPERA 2.0 de 4 estratos, comparando este resultado con el obtenido de un modelo ampliado que incluyó la genética. Se usaron modelos de regresión de Cox y el estadístico C de Harrel para comparar los distintos modelos. Se estudiaron específicamente estos modelos en la población EVOP antes de su inclusión.
Se seleccionaron 298 pacientes con HAP idiopática, familiar, inducida por fármacos y EVOP del registro REHAP. Considerando únicamente aquellos con todas las variables de interés disponibles al diagnóstico (clase funcional, prueba de la marcha de los 6 minutos, NT-proBNP o BNP), e incluidos en el modelo de 4 estratos (n = 142), después de una mediana de seguimiento de 58,2 meses hasta el 17,6% de los pacientes fallecieron y un 11,3% necesitaron trasplante pulmonar. La aplicación del modelo de 4 estratos en nuestra población demostró una buena capacidad pronóstica (C de Harrel de 0,689). La introducción de la genética no mejoró ésta (índice C de 0,690). Este último modelo ampliado mostró una tendencia a una mejor identificación de pacientes en riesgo intermedio-bajo e intermedio-alto, sin diferencias en la identificación entre los estratos de riesgo intermedio-alto y alto.
En este trabajo la adición del resultado del estudio genético al modelo de 4 estratos COMPERA alcanzó una capacidad pronóstica total similar al modelo original, pero cambió la identificación de los estratos de riesgo en una cohorte de pacientes jóvenes analizados genéticamente.
Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies.
We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion.
We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n = 142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata.
In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.
Pursuing functional biomarkers in complex disease: Focus on pulmonary arterial hypertension
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Citation Excerpt :
Since 2000, technological advances in next generation sequencing platforms (candidate gene, whole exome, and whole genome sequencing) expanded the number of variants associated with PAH, which are potentially useful in improving PAH precision medicine.65 Those included rare variants in SMAD family member 1 (SMAD1), SMAD4 and SMAD957,59,66, caveolin-1 (CAV-1), potassium channel subfamily K member 3 (KCNK3) and KCNK555, T-box 4 (TBX4)46,53,67, SRY-box transcription factor 17 (SOX17)47, and eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) loci.68 Among these variants, some are particularly useful in improving PAH diagnosis and classification.
A major gap in diagnosis, classification, risk stratification, and prediction of therapeutic response exists in pulmonary arterial hypertension (PAH), driven in part by a lack of functional biomarkers that are also disease-specific. In this regard, leveraging big data-omics analyses using innovative approaches that integrate network medicine and machine learning correlated with clinically useful indices or risk stratification scores is an approach well-positioned to advance PAH precision medicine. For example, machine learning applied to a panel of 48 cytokines, chemokines, and growth factors could prognosticate PAH patients with immune-dominant subphenotypes at elevated or low-risk for mortality. Here, we discuss strengths and weaknesses of the most current studies evaluating omics-derived biomarkers in PAH. Progress in this field is offset by studies with small sample size, pervasive limitations in bioinformatics, and lack of standardized methods for data processing and interpretation. Future success in this field, in turn, is likely to hinge on mechanistic validation of data outputs in order to couple functional biomarker data with target-specific therapeutics in clinical practice.

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^†: Contributed equally

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet Respir Med

Chest

Am J Pathol

Chest

J Am Coll Cardiol

Eur Respir J

Pulmonary arterial hypertension in France: results from a national registry

Am J Respir Crit Care Med

Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred

N Engl J Med

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

N Engl J Med

A novel channelopathy in pulmonary arterial hypertension

N Engl J Med

Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension

Circ Cardiovasc Genet

Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation

Am J Respir Crit Care Med

Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation

Am J Respir Crit Care Med

EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension

Nat Genet

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies

Clin Genet

Pulmonary veno-occlusive disease

Eur Respir J

Occupational exposure: a risk factor for pulmonary veno-occlusive disease

Eur Respir J

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