In the year 2000, mutations in the bmpr2 gene were identified as the major genetic cause of pulmonary arterial hypertension pah. Asthma control consists of an assessment of the illness over a period of a few weeks, in terms of clinical and functional respiratory events and their consequences. This group includes chronic myeloproliferative disorders that can cause ph by various potential mechanisms, including high. Vascular endothelial cells mainly produce and secrete endothelin et1 in vessels that lead to a potent and longlasting vasoconstrictive effect in pulmonary. Respiratory medicine and research journal elsevier. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. Methods we prospectively analysed the kdr gene by targeted panel sequencing in a series of 311 pah patients referred to a clinical molecular laboratory. Patients were identified from two prospective cohorts from the us and france. Pulmonary arterial hypertension pah is a severe and incurable pulmonary vascular disease. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare. Loss of vascular distensibility during exercise is an. Orphan lung diseases differ from the more common pulmonary disorders, due to the fact that the respiratory physician will only see a few of them each year or even during their career. Pulmonary venoocclusive disease pvod is a rare form of pulmonary hypertension ph characterised by preferential remodelling of the pulmonary venules.
The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in ssc patients with ph. It may present as discrete disease or as complication of a broad spectrum of other conditions, such as connective tissue disease, congenital heart disease, liver disease, lung disease or left heart disease. Mutations in the bmpr2 gene, and more rarely in acvrl1, endoglin, caveolin1, kcnk3 and tbx4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Screening for pulmonary arterial hypertension in patients. Pulmonary hypertension plays an increasingly important role in contemporary medicine. David montani, md, phd is professor at the french national referral centre for pulmonary hypertension in the department of respiratory medicine headed by pr marc humbert, at the hopital bicetre. Recent studies have elucidated the potential mechanisms of tkiinduced pah and have better clarified the longterm outcomes.
Widening the landscape of heritable pulmonary hypertension. Idiopathic pulmonary fibrosis ipf is a steadily progressive and ultimately fatal disease of unknown origin. Clinical phenotypes and outcomes of heritable and sporadic pulmonary venoocclusive disease. But many questions remain unanswered, particularly surrounding probable versus definite ipf. As reported by the authors, research on the toxic effects of occupational and environmental exposures. Pulmonary venoocclusive disease pvod is a rare disorder that can be misdiagnosed as idiopathic pulmonary arterial hypertension pah and accounts for 510% of cases initially considered as idiopathic pah. Deterioration of pulmonary hypertension and pleural effusion with. New molecular targets of pulmonary vascular remodeling in. Pharmacotherapy of pulmonary hypertension marc humbert. Correspondence and requests for reprints should be addressed to david montani, m. To send an email to david montani please complete the short form below.
Some small studies have examined the effect of bmpr2 mutations on the presentation, haemodynamic profile, and outcomes in patients with pah. This provisional pdf corresponds to the article as it appeared upon acceptance. We thank dr harbaum and colleagues for their comments on our study in chest. Plateletderived growth factor expression and function in idiopathic pulmonary arterial hypertension fre. Pvod and idiopathic pah share a similar clinical presentation, genetic background and hemodynamic profile. Oclcs webjunction has pulled together information and resources to assist library staff as they consider how to handle coronavirus. Since 2006 and 2007, patients in france with severe pulmonary hypertension ph who are at imminent risk of death, despite optimal treatment in the intensive care unit, are placed on a highpriority list hpl for heartlung transplantation hlt or doublelung transplantation dlt. Mutation in kcnk3 gene is responsible for the first channelopathy identified in pah. Pulmonary arterial hypertension induced by tyrosine kinase.
A value of mpap used in isolation is not accurate enough to characterise a clinical condition. Recently, preliminary evidence of the involvement of the kdr gene was found in a large genetic association study. Human herpes virus 8 in hiv and nonhiv infected patients wi. In the current ph classification, pvod and pulmonary capillary haemangiomatosis pch are considered to be a common entity and represent varied expressions of the same disease. The potential for macitentan, a new dual endothelin receptor. One of the primary origins of pah is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelialtomesenchymal transition, thrombosis and inflammation. Clinical phenotypes and outcomes of heritable and sporadic. Comparative safety and tolerability of prostacyclins in. Therapeutic advances in pulmonary arterial hypertension. David montani editorinchief and deputy editorinchief. Biallelic mutations in the eif2ak4 gene predispose to heritable pulmonary venoocclusive diseasepulmonary capillary haemangiomatosis, an autosomal recessive disease with. Colas tcherakian, david montani, stephane jouneau collection cahiers des ecn 0 avis donner votre avis.
Clinical, pulmonary function, highresolution chest. Kaposis sarcomaassociated herpesvirus or human herpesvirus 8 hhv8 is a vasculotrope virus associated with kaposis sarcoma, hivassociated castlemans disease and primary effusion lymphoma. All of these forms have different features and their management is never the same. Haemodynamic definitions and updated clinical classification.
Olivier sitbon, marc humbert, gerald simonneau, and david montani. Please note that all enquiries should relate specifically to respiratory medicine and research. Whatever the mpap cutoff value considered for defining ph. A definite diagnosis of pvod thus requires a lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. Pulmonary venoocclusive disease as an occupational lung. Bmpr2 mutations and survival in pulmonary arterial. However, as a specialist, it is necessary to identify and confirm such a diagnosis in a patient. Valerie domergue 7, sharon mumby 6, david montani 3,4,8, ian m.
Pulmonary venoocclusive disease european respiratory society. Dasatinib causes direct pulmonary artery endothelial cell toxicity through the production of mitochondrial reactive oxygen species, but. Williams7 and rogerio souza 8 number 4 in the series. Spontaneous reporting is the primary method used in pharmacovigilance pv to detect drug safety signal. We assessed the effect of this approach on the waiting list and outcomes after transplantation. Prostacyclin pgi2 is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has antiinflammatory, antithrombotic and antiproliferative effects. Recently, kcnk3 has been identified as a new predisposing gene for pulmonary arterial hypertension pah by wholeexome sequencing. Abstractpulmonary venoocclusive disease pvod is defined by specific pathologic changes of the pulmonary veins. Plateletderived growth factor expression and function in. Small platelet microparticle levels are increased in pulmonary arterial hypertension. Publishing your article with us has many benefits, such as having access to a personal dashboard.
Screening of pulmonary arterial hypertension in bmpr2. Reliable information about the coronavirus covid19 is available from the world health organization current situation, international travel. Editorinchief and deputy editorinchief, respiratory medicine and research le kremlin bicetre, france send an email to david montani. Deterioration of pulmonary hypertension and pleural. Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases melanie eyries1,2, david montani 3, sophie nadaud2, barbara girerd3. Characteristics of pulmonary arterial hypertension in aff. Clinical outcomes of pulmonary arterial hypertension in patients carrying an acvrl1 alk1 mutation. The bet bromodomain inhibitor ibet151 induces structural. David montani hopital bicetre pneumologie 78 rue du general leclerc 94270 le kremlinbicetre, fr prof. Marco maggiorini universitatsspital zurich institut fur intensivmedizin ramistrasse 100 8091 zurich, ch prof.
Pneumologie french edition david montani, colas tcherakian, ste. Pah due to kcnk3 mutations is an autosomal dominant disease with an incomplete penetrance as. In human pah and experimental pulmonary hypertension ph, we demonstrated that kcnk3 expression and function are severely reduced in pulmonary vascular cells. Idiopathic pulmonary fibrosis european respiratory society. Does circulating il17 identify a subset of patients with. Clinical pharmacology of endothelin receptor antagonists used. Loss of kcnk3 is a hallmark of rv hypertrophydysfunction. Thelper 17 cell polarization in pulmonary arterial hypertension. Pulmonary arterial hypertension pah is a lifethreatening disease that can be induced by dasatinib, a dual src and bcrabl tyrosine kinase inhibitor.
Nov 25, 2014 pulmonary arterial hypertension pah is a devastating lifethreatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Background beyond the major gene bmpr2, several new genes predisposing to pah have been identified during the last decade. Pneumologie rue gabrielleperretgentil 4 1205 geneve, ch prof. Precapillary pulmonary hypertension ph in systemic sclerosis ssc is a heterogeneous condition with an overall bad prognosis. Cette troisieme edition reste fidele a l esprit des precedentes editions qui leur a valu leur succes. Haemodynamic definitions and updated clinical classification of pulmonary hypertension gerald simonneau1,2, david montani 1,2, david s. Pulmonary hypertension european respiratory society.
David montani, peter dorfmuller, and natalia gambaryan are supported by a grant from association htapfrance. Girerd b, montani d, coulet f, sztrymf b, yaici a, jais x, tregouet d, reis a, drouingarraud v, fraisse a, sitbon o, ocallaghan ds, simonneau g, soubrier f, humbert m. Pap elevation may indeed have several different causes. This monograph comprehensively covers the most common andor complex of these orphan lung diseases. Recent findings in addition to the known association between dasatinib and pah, several other tkis have recently been reported to cause pah, including ponatinib, bosutinib and lapatinib. The potential for macitentan, a new dual endothelin. Frederic perros and laura price are supported by longterm research fellowship grants from the european respiratory society. Eif2ak4 mutations cause pulmonary venoocclusive disease. The authors proposed a detailed overview of the acute and chronic respiratory diseases associated with established and novel occupational exposures. Methods we prospectively analysed the kdr gene by targeted panel sequencing in a series of 311 pah patients referred to a clinical molecular laboratory for.
View enhanced pdf access article on wiley online library html view. Pneumologie pilon partiel 15 2 16 colas tcherakian. In pulmonary arterial hypertension pah, pgi2 levels and pgi2 synthase expression are reduced, contributing to the vasoconstriction and vascular smooth. In this prospective study, the investigators will implement a systematic screening program and 3year followup in a cohort of asymptomatic bmpr2 mutation carriers. David montani, 1,2,3 and marc humbert 1inserm umr s 999, hopital marie lannelongue, le plessisrobinson, france. Isolated cases of precapillary ph have been reported in patients who have chronic myelogenous. The recent discovery of biallelic mutations in the eif2ak4 gene. Backgroundthe french pulmonary hypertension ph registry allows the survey of epidemiological trends. Recent years have seen advances in our understanding of ipf and a number of guidelines have been published. Pulmonary arterial hypertension in patients treated by. Pulmonary arterial hypertension induced by tyrosine kinase i. Pulmonary arterial hypertension pah is a severe, lifelimiting complication of systemic sclerosis ssc.
Impact of highpriority allocation on lung and heartlung. Fully formatted pdf and full text html versions will be made available soon. Boutet, david montani, xavier jais, azzedine yaici, oliver sitbon, gerald simonneau, and marc. This monograph aims to discuss the latest achievements in ipf, and covers key. Florent soubrier and colleagues identify biallelic mutations in eif2ak4 as a major cause of pulmonary venoocclusive disease, a rare form of pulmonary hypertension. Pneumologie broche david montani, colas tcherakian. Pdf epub telecharger by david montani,colas tcherakian, title. Ckitpositive cells accumulate in remodeled vessels of. Biallelic mutations in the eif2ak4 gene predispose to heritable pulmonary venoocclusive diseasepulmonary capillary haemangiomatosis, an autosomal recessive disease with an. Pulmonary endothelial cell dna methylation signature in.
1445 1355 53 1298 1396 1161 1600 1474 190 1097 417 1631 1615 877 840 184 332 561 1121 1526 1284 1245 964 48 314 504 1004 414 480 702 118 1149 210 1542 619 817 862 1243 278 333 252 881