Christophe Pison

Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era

Background— Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. Methods and Results— Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. Conclusions— In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation.

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Background— The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results— This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (⩽20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions— Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

An Integrative Systems Biology Approach to Understanding Pulmonary Diseases

Chronic inflammatory pulmonary diseases such as COPD and asthma are highly prevalent and associated with a major health burden worldwide. Despite a wealth of biologic and clinical information on normal and pathologic airway structure and function, the primary causes and mechanisms of disease remain to a large extent unknown, preventing the development of more efficient diagnosis and treatment. We propose to overcome these limitations through an integrative systems biology research strategy designed to identify the functional and regulatory pathways that play central roles in respiratory pathophysiology, starting with severe asthma. This approach relies on global genome, transcriptome, proteome, and metabolome data sets collected in cross-sectional patient cohorts with high-throughput measurement platforms and integrated with biologic and clinical data to inform predictive multiscale models ranging from the molecular to the organ levels. Working hypotheses formulated on the mechanisms and pathways involved in various disease states are tested through perturbation experiments using model simulation combined with targeted and global technologies in cellular and animal models. The responses observed are compared with those predicted by the initial models, which are refined to account better for the results. Novel perturbation experiments are designed and tested both computationally and experimentally to arbitrate between competing hypotheses. The process is iterated until the derived knowledge allows a better classification and subphenotyping of severe asthma using complex biomarkers, which will facilitate the development of novel diagnostic and therapeutic interventions targeting multiple components of the molecular and cellular pathways involved. This can be tested and validated in prospective clinical trials.

Prevalence of asthma and asthma-like symptoms in three French cities

BACKGROUND This study is part of the European Community Respiratory Health Survey (ECRHS), which uses a common methodology in different areas throughout the world. This paper describes the prevalences of reported asthma, asthma-like symptoms and nasal allergies, their relationships to age group and sex, and the relationships of asthma-like symptoms to current asthma, in the general population aged 20-44 years of three French urban areas. METHODS The study population of 2804 subjects in Grenoble, 3774 in Montpellier and 3152 in Paris (18th district), randomly selected from electoral rolls, answered a postal questionnaire (stage I of ECRHS). The response rates were 77.8%, 68.6% and 74.4%, respectively. RESULTS The prevalences were approximately 14% for wheezing, 16% for chest tightness and 4.5% for nocturnal shortness of breath in the three areas. Asthma attacks in the last 12 months were reported by 2.7% of subjects in Grenoble, 3.5% of subjects in Montpellier and 4.0% of subjects in Paris (P = 0.02). For nasal allergies, the prevalences were 28.0%, 34.3% and 30.8%, respectively (P < 0.001). Asthma was inversely correlated to age (higher prevalence in the youngest) but was not related to sex. Neither age distribution nor sex ratio explained the differences between areas. Among the asthma-like symptoms, wheezing and nocturnal shortness of breath correlated strongly with asthma, chest tightness correlated moderately and nocturnal coughing correlated poorly. CONCLUSION The prevalences observed were higher than expected from previous comparable French studies in young adults. These results are consistent with the hypothesis of a recent increase of asthma and allergies.

Masitinib, a c‐kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid‐dependent asthmatics

Background:  Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c‐kit) and platelet‐derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c‐kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma.

Phenotypic determinants of uncontrolled asthma

BACKGROUND Although uncontrolled asthma remains frequent, determinants of asthma control are poorly studied. OBJECTIVES The aim was to estimate the distribution and the phenotypic characteristics of asthma control in 2 groups of subjects defined by the use of inhaled corticosteroids (ICS) in the past 12 months, in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). METHODS Five hundred one adult current patients with asthma who participated in the follow-up of the EGEA study were included. Asthma control was assessed from survey questions reflecting asthma control, as defined in the 2006 Global Initiative for Asthma guidelines. The factors analyzed were age, sex, educational level, body mass index, active and passive smoking, sensitization to aeroallergens, total IgE, rhinitis, chronic cough/phlegm, and age at asthma onset. Analyses were stratified according to ICS use. RESULTS Uncontrolled asthma was more frequent in ICS users (27.6%, 35.0%, and 37.4% with controlled, partly-controlled, and uncontrolled asthma respectively) compared with non-ICS users (60.0%, 23.9%, and 16.1%, respectively). In ICS users, chronic cough or phlegm and female sex were independently and significantly related to uncontrolled asthma. In non-ICS users, high total IgE and sensitization to molds were associated with uncontrolled asthma. Smoking and rhinitis were not associated with asthma control. CONCLUSION Optimal asthma control remained unachieved in the majority of patients with asthma in this study. Factors associated with uncontrolled asthma were different in ICS users (chronic cough/phlegm, female sex) and non-ICS users (high total IgE and sensitization to molds).

Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial

IMPORTANCE Therapeutic options for severe emphysema are limited. Lung volume reduction using nitinol coils is a bronchoscopic intervention inducing regional parenchymal volume reduction and restoring lung recoil. OBJECTIVE To evaluate the efficacy, safety, cost, and cost-effectiveness of nitinol coils in treatment of severe emphysema. DESIGN, SETTING, AND PARTICIPANTS Multicenter 1:1 randomized superiority trial comparing coils with usual care at 10 university hospitals in France. Enrollment of patients with emphysema occurred from March to October 2013, with 12-month follow-up (last follow-up, December 2014). INTERVENTIONS Patients randomized to usual care (n = 50) received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen; those randomized to bilateral coil treatment (n = 50) received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures. MAIN OUTCOMES AND MEASURES The primary outcome was improvement of at least 54 m in the 6-minute walk test at 6 months (1-sided hypothesis test). Secondary outcomes included changes at 6 and 12 months in the 6-minute walk test, lung function, quality of life as assessed by St Georges Respiratory Questionnaire (range, 0-100; 0 being the best and 100 being the worst quality of life; minimal clinically important difference, ≥4), morbidity, mortality, total cost, and cost-effectiveness. RESULTS Among 100 patients, 71 men and 29 women (mean age, 62 years) were included. At 6 months, improvement of at least 54 m was observed in 18 patients (36%) in the coil group and 9 patients (18%) in the usual care group, for a between-group difference of 18% (1-sided 95% CI, 4% to ∞; P = .03). Mean between-group differences at 6 and 12 months in the coil and usual care groups were +0.09 L (95% CI, 0.05 L to ∞) (P = .001) and +0.08 L (95% CI, 0.03 L to ∞) (P = .002) for forced expiratory volume in the first second, +21 m (95% CI, -4 m to ∞) (P = .06) and +21 m (95% CI, -5 m to ∞) (P = .12) for 6-minute walk distance, and -13.4 points (95% CI, -8 points to ∞) and -10.6 points (95% CI, -5.8 points to ∞) for St Georges Respiratory Questionnaire (1-sided P < .001 for both). Within 12 months, 4 deaths occurred in the coil group and 3 in the usual care group. The mean total 1-year per-patient cost difference between groups was

Multimodal nutritional rehabilitation improves clinical outcomes of malnourished patients with chronic respiratory failure: a randomised controlled trial

47,908 (95% CI,

Nutritional assessment and therapy in COPD: a European Respiratory Society statement

47,879-

Relationships of allergic sensitization, total immunoglobulin E and blood eosinophils to asthma severity in children of the EGEA Study.

48,073) (P < .001); the incremental cost-effectiveness ratio was