Vincent Cottin

Pulmonary Vascular Manifestations of Hereditary Hemorrhagic Telangiectasia (Rendu-Osler Disease)

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a genetic disorder with autosomal dominance and variable penetrance, characterized by epistaxis, telangiectasia and visceral manifestations of the disease. The estimated minimal prevalence is 1/10,000 inhabitants. The diagnosis is established on clinical criteria, and may be further confirmed by the identification of causative mutations in either the ENG or the ACVRL1 gene coding for endoglin and ALK1, respectively. Pulmonary vascular manifestations of HHT include pulmonary arteriovenous malforma- tions (PAVMs; especially in patients with ENG mutations) and less frequently pulmonary hypertension (especially in patients with ACVRL1 mutations). In 15–33% of patients with HHT, PAVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting, and thus, frequently hypoxemia and dyspnea on exertion, although PAVMs may remain asymptomatic and frequently undiagnosed unless complications occur. PAVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e.g. transient ischemic attack and cerebral stroke (10–19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5–19% of patients), and rarely massive hemoptysis or hemothorax. Infections in HHT are related to the right-to-left shunting that bypasses the pulmonary capillaries and facilitates the passage of septic or aseptic emboli into the systemic and especially cerebral circulation, and potentially to minor defects in innate immunity. Treatment of PAVMs based on transcatheter coil vaso-occlusion of the feeding artery significantly decreases right-to-left shunting, hypoxemia and dyspnea on exertion, and reduces the risk of systemic complications. Long-term follow-up is warranted after transcatheter vaso-occlusion of PAVMs due to frequent recanalization of treated PAVMs and development or growth of untreated PAVMs. Patients with HHT should be informed of the risk of PAVM and potentially severe complications occurring in heretofore asymptomatic subjects. All adult patients with HHT should be proposed systematic screening for PAVM, by contrast echocardiography (preceded by anteroposterior chest radiograph) or computed tomography of the chest. Pulmonary hypertension is rare in HHT, and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Pulmonary hypertension is detected by systematic examination of right cardiac cavities and tricuspid regurgitation flow at echocardiography, and the diagnosis is established by right heart catheterization.

ANCA-associated lung fibrosis: Analysis of 17 patients

In this retrospective study, we analyzed 17 patients presenting with pulmonary fibrosis and a positive ANCA testing. This group was compared with a control group of 12 patients with IPF and negative ANCA testing. Patients were 15 males and 2 females, with a mean age of 66 years. Eight patients were past smokers, 3 current smokers and 6 non-smokers. Lung function tests at diagnosis were as follows (% predicted): total lung capacity 73%+/-18, vital capacity 82%+/-23, forced expiratory volume in 1 s (FEV(1)) 88%+/-24, carbon monoxide diffusion capacity of the lung 49%+/-2 (% predicted). Bronchoalveolar lavage results showed an increased cellularity with increased neutrophils counts. High resolution computed tomography of the chest showed prominent fibrosis with some degree of ground-glass attenuation in all patients. These characteristics were similar to the control group. Microscopic polyangiitis (MPA) was a major complicating event in ANCA-positive patients, occurring in 7 patients (anti-myeloperoxidase specificity in 5 patients). Pulmonary fibrosis predated occurrence of MPA in 6 patients and was diagnosed concomitantly with MPA in 1 patient. During the follow-up, 10/17 patients died. The death was directly related to vasculitis in 3 patients. We conclude that patients with pulmonary fibrosis should be evaluated for the presence of ANCA. Patients with positive ANCA testing, particularly if anti-myeloperoxidase, should be carefully monitored to detect the occurrence of microscopic polyangiitis.

Right isovolumic contraction velocity predicts survival in pulmonary hypertension.

BACKGROUNDnRight ventricular function is a strong determinant of prognosis in severe pulmonary hypertension.nnnMETHODSnThe aim of this study was to evaluate the prognostic value of estimates of right ventricular function obtained by echocardiography and Doppler tissue imaging and of functional class and 6-min walk distance (6MWD) in 142 patients with either pulmonary arterial hypertension (nxa0= 104) or chronic thromboembolic pulmonary hypertension (nxa0= 38). Echocardiography was prospectively performed, and demographics, medications, associated medical conditions, New York Heart Association class, and 6MWD at inclusion in addition to vital status, transplantation, and hospital admission related to pulmonary hypertension at follow-up were then collected by review of the medical records.nnnRESULTSnVariables associated with overall survival by univariate analysis were 6MWD (Pxa0= .009), functional class (Pxa0= .024), tricuspid annular plane systolic excursion (Pxa0= .03) and isovolumic peak velocity at the tricuspid annulus (IVCv) (Pxa0= .003). On multivariate analysis, IVCv (Pxa0= .015) and 6MWD (Pxa0= .016) were the only independent predictors of survival. Kaplan-Meier estimates of survival at 1 year were 95% in patients with IVCv > 9 cm/sec and 80% in those with IVCv ≤ 9 cm/sec (Pxa0= .002). Intraobserver and interobserver variability of IVCv measurement were 5% and 9%, respectively.nnnCONCLUSIONSnMeasurement of right ventricular function by Doppler tissue imaging, an easy, noninvasive, and reproducible method, is an independent predictor of clinical outcomes in patients with severe pulmonary hypertension.

Rare lung disease and orphan drug development

Rare diseases are a major health-care burden worldwide. Very little is known about the cause, behaviour, and treatment of these disorders, and thus non-specialist health-care providers and patients are left without sufficient knowledge to manage these diseases. Up to 3 million Europeans are estimated to have a rare lung disease. Several organisations-many of which are patient led-attempt to raise the profile of rare lung diseases to improve understanding and management of these disorders. Incentives have now been introduced in the USA and Europe that encourage the pharmaceutical industry to invest in targets that might otherwise not appeal because of small target populations. Despite many intrinsic challenges and obstacles, considerable progress is constantly being made in the research and development of drugs for rare disorders.

Eosinophilic Lung Diseases.

Eosinophilic lung diseases especially comprise eosinophilic pneumonia or as the more transient Löffler syndrome, which is most often due to parasitic infections. The diagnosis of eosinophilic pneumonia is based on characteristic clinical-imaging features and the demonstration of alveolar eosinophilia, defined as at least 25% eosinophils at BAL. Peripheral blood eosinophilia is common but may be absent at presentation in idiopathic acute eosinophilic pneumonia, which may be misdiagnosed as severe infectious pneumonia. All possible causes of eosinophilia, including drug, toxin, fungus related etiologies, must be thoroughly investigated. Extrathoracic manifestations should raise the suspicion of eosinophilic granulomatosis with polyangiitis.

Pulmonary Vascular Disorders in Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder with autosomal dominance and variable penetrance, characterized by epistaxis, telangiectasia, and visceral manifestations, with an est