Grégory Marin

Prognostic value of cluster analysis of severe asthma phenotypes

BACKGROUND Cross-sectional severe asthma cluster analysis identified different phenotypes. We tested the hypothesis that these clusters will follow different courses. OBJECTIVE We aimed to identify which asthma outcomes are specific and coherently associated with these different phenotypes in a prospective longitudinal cohort. METHODS In a longitudinal cohort of 112 patients with severe asthma, the 5 Severe Asthma Research Program (SARP) clusters were identified by means of algorithm application. Because patients of the present cohort all had severe asthma compared with the SARP cohort, homemade clusters were identified and also tested. At the subsequent visit, we investigated several outcomes related to asthma control at 1 year (6-item Asthma Control Questionnaire [ACQ-6], lung function, and medication requirement) and then recorded the 3-year exacerbations rate and time to first exacerbation. RESULTS The SARP algorithm discriminated the 5 clusters at entry for age, asthma duration, lung function, blood eosinophil measurement, ACQ-6 scores, and diabetes comorbidity. Four homemade clusters were mostly segregated by best ever achieved FEV1 values and discriminated the groups by a few clinical characteristics. Nonetheless, all these clusters shared similar asthma outcomes related to asthma control as follows. The ACQ-6 score did not change in any cluster. Exacerbation rate and time to first exacerbation were similar, as were treatment requirements. CONCLUSION Severe asthma phenotypes identified by using a previously reported cluster analysis or newly homemade clusters do not behave differently concerning asthma control-related outcomes, which are used to assess the response to innovative therapies. This study demonstrates a potential limitation of the cluster analysis approach in the field of severe asthma.

Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials

Inconsistent results have been reported regarding IL‐5 blockade treatment in asthma. There were no direct between‐treatment comparisons. Only differences between each drug and placebo were studied. We identified all RCTs with anti‐IL5 treatments for patients with asthma over the 1990‐September 2015 period. RCTs were searched on Medline, Cochrane and Embase. At least 50 patients were enrolled in each study. Outcomes considered were exacerbation rate reduction, FEV1 changes, ACQ‐5 improvement, adverse events and serious adverse events. A global meta‐analysis was first conducted followed by an indirect comparison of each IL‐5‐targeting drug: benralizumab, reslizumab and mepolizumab. Further eosinophilic subgroup analysis and sensitivity analysis were also conducted in case of heterogeneity. Ten trials involving 3421 patients were eligible for meta‐analysis. IL‐5 blockade significantly reduced annual exacerbation rates vs. placebo by 40% [29–50] (P < 0.01, I2 = 0.61). ACQ‐5 was significantly improved vs. placebo but below the recognized MCID level (−0.31 [−0.41, −0.21], P < 0.01, I2 = 0.11). FEV1 changes from baseline were improved vs. placebo by 0.09 L [0.05–0.12] (P < 0.01, I2 = 0.28). The subgroup analysis identified a slight additional improvement in mean treatment effects in eosinophilic (> 300 mm3/L) patients with severe asthma. Similar patterns and rates of adverse events and severe adverse events were reported with the three drugs. The data interpretations were not affected by the sensitivity analysis. IL‐5 blockade appears to be a relevant treatment strategy to improve severe asthma management, particularly for eosinophilic patients. No clear superiority appeared between the drugs when appropriate doses were compared.

Relationship between CT air trapping criteria and lung function in small airway impairment quantification.

BackgroundSmall airways are regarded as the elective anatomic site of obstruction in most chronic airway diseases. Expiratory computed tomography (CT) is increasingly used to assess obstruction at this level but there is no consensus regarding the best quantification method. We aimed to evaluate software-assisted CT quantification of air trapping for assessing small airway obstruction and determine which CT criteria better predict small airway obstruction on single breath nitrogen test (SBNT).MethodsEighty-nine healthy volunteers age from 60 to 90 years old, underwent spirometrically-gated inspiratory (I) and expiratory (E) CT and pulmonary function tests (PFTs) using SBNT, performed on the same day. Air trapping was estimated using dedicated software measuring on inspiratory and expiratory CT low attenuation area (LAA) lung proportion and mean lung density (MLD). CT indexes were compared to SBNT results using the Spearman correlation coefficient and hierarchical dendrogram analysis. In addition, receiver operating characteristic (ROC) curve analysis was performed to determine the optimal CT air-trapping criterion.Results43 of 89 subjects (48,3%) had dN2 value above the threshold defining small airway obstruction (i.e. 2.5% N2/l). Expiratory to inspiratory MLD ratio (r = 0.40) and LAA for the range −850 -1024 HU (r = 0.29) and for the range −850 -910 HU (r = 0.37) were positively correlated with SBNT results. E/I MLD was the most suitable criterion for its expression. Expiratory to inspiratory MLD ratio (E/I MLD) showed the highest AUC value (0.733) for small airway obstruction assessment.ConclusionAmong all CT criteria, all correlating with small airway obstruction on SBNT, E/I MLD was the most suitable criterion for its expression in asymptomatic subjects with mild small airway obstructionTrial registrationRegistered at Clinicaltrials.gov, identifier: NCT01230879.

Computed tomography quantification of airway remodelling in normal ageing subjects: a cross-sectional study

Airway remodelling inducing structural and functional decline is a main factor leading to clinical disablement in chronic obstructive pulmonary disease (COPD) [1]. However, whether airway remodelling is also a potential feature of the normal healing process in ordinary lifelong environmental exposure and chronic endogen damage due to senescence is not well elucidated [2]. The relationship between ageing and development of COPD is complex. On one hand, while there is a higher prevalence of COPD in the elderly, ageing is not the direct cause of COPD; on the other hand, it does increase the susceptibility of the lung to extrinsic damage [3]. Airway remodelling with age is a heterogeneous process having a particular tropism towards distal airways http://ow.ly/FeZnN

Impact of Preoperative Marking Coils on Surgical and Pathologic Management of Impalpable Lung Nodules

BACKGROUND The management of occult lung lesions, particularly subsolid opacities, is a new challenge because they are difficult to localize during surgery and the number of lesions detected by computed tomography (CT) is increasing. METHODS Between February 2008 and December 2011, preoperative CT-guided marking with coils was systematically carried out to localize presumed impalpable nodules before video-assisted thoracoscopic surgery (VATS). The procedure feasibility, reliability, and safety as well as its impact on the resection volume and on the pathologic examination strategy were examined. RESULTS This preoperative marking procedure was used for 68 nodules in 60 consecutive patients. The mean procedural time was 25 minutes/patient and complications included minimal asymptomatic pneumothorax (42 cases, 70%) and hemorrhagic suffusion (21 patients, 35%). Patients with non-retrieved coils during VATS required larger resection volumes (94.88 mm3 vs 20.65 mm3; p=0.008). The presence of a coil loop in the pleural space was not statistically associated with higher resected lung volume. Primary pulmonary adenocarcinoma was found in 42 patients (71.2%). Five nodules were associated with atypical adenomatous hyperplasia. Pathologic examination was considered to be improved by the presence of a coil next to the lesion but not within it. Coil placement modified the pathology practices for intraoperative analysis, as tissue sampling in the immediate vicinity of the coil was preferred to systematic sampling. CONCLUSIONS Impalpable lung nodules can be safely marked with coils preoperatively to improve their surgical and pathologic management.

High IFN-γ Release and Impaired Capacity of Multi-Cytokine Secretion in IGRA Supernatants Are Associated with Active Tuberculosis.

Interferon gamma (IFN-γ) release assays (IGRAs) detect Mycobacterium tuberculosis (Mtb) infection regardless of the active (ATB) or latent (LTBI) forms of tuberculosis (TB). In this study, Mtb-specific T cell response against region of deletion 1 (RD1) antigens were explored by a microbead multiplex assay performed in T-SPOT TB assay (T-SPOT) supernatants from 35 patients with ATB and 115 patients with LTBI. T-SPOT is positive when over 7 IFN-γ secreting cells (SC)/250 000 peripheral blood mononuclear cells (PBMC) are enumerated. However, over 100 IFN-γ SC /250 000 PBMC were more frequently observed in the ATB group compared to the LTBI group. By contrast, lower cytokine concentrations and lower cytokine productions relative to IFN-γ secretion were observed for IL 4, IL-12, TNF-α, GM-CSF, Eotaxin and IFN-α when compared to LTBI. Thus, high IFN-γ release and low cytokine secretions in relation with IFN-γ production appeared as signatures of ATB, corroborating that multicytokine Mtb-specific response against RD1 antigens reflects host capacity to contain TB reactivation. In this way, testing cytokine profile in IGRA supernatants would be helpful to improve ATB screening strategy including immunologic tests.

Distal Airway Impairment in Obese Normoreactive Women

Background. Asthma-like symptoms are frequent in overweight and obesity, but the mechanism is unclear when airway hyperresponsiveness (AHR) is lacking. In this study, we focused on obese women with a clinical suspicion of asthma but negative methacholine challenge and tested distal airway hyperreactivity, explored by Forced Vital Capacity dose-response slope (FVC DRS). Objective. To question AHR at the distal airway level in obese women. Methods. A total of 293 symptomatic obese and nonobese women free of treatment were investigated. Methacholine challenge tests were undertaken, and patients were divided according to their results to the test. In hyperreactive and nonhyperreactive patients and in our total population, correlations, regression analyses, and analyses of covariance were performed to compare distal airway hyperreactivity in three groups of body mass index (BMI). Results. After adjusting for age and baseline respiratory values, the relationship between FVC and FEV1 (forced expiratory volume in one second) DRS was influenced by BMI, with a lower slope in obese than overweight and normal patients in our total population (P = 0.008) and in our nonhyperreactive one (P = 0.028). Conclusion. Distal airway hyperresponsiveness was observed in symptomatic wheezing obese women negative to methacholine challenge.

Impact of psychological factors on the health-related quality of life of patients treated for pulmonary arterial hypertension

OBJECTIVE Pulmonary arterial hypertension (PAH) is a rare and life-threatening disease well-marked by under diagnosis, delayed diagnosis and atypical treatments. Few data are available on the quality of life (QoL) and psychosocial characteristics of patients with PAH. Our aim is to describe the impact of psychological factors on the health-related quality of life (HRQoL) of treated PAH patients in a cross-sectional study. METHODS Consecutive patients presenting at our Competency Centre for PAH were recruited. The aetiology, New York Heart Association (NYHA) stage, haemodynamics, 6-min walk distance (6MWD), delta SPO2 (Pulse oximeter oxygen saturation; baseline lowest value during 6-min walk test (6MWT), current treatments and psychological history were recorded. HRQoL, anxiety, depression and coping strategies were explored using self-administered questionnaires (SF-36, HADS, STAI-Y, CHIP and WCC). RESULTS A total of 55 patients were included. The HRQoL of PAH patients was poor with altered results on several scales. Anxiety and depression were high and coping was focused on medical information strategies. Multivariate analysis indicated a positive relationship between 6MWD and the Physical Composite Score for QoL (p=0.004), as well as a negative relationship between delta SPO2 and the Mental Composite Score (p=0.02), irrespective of other known prognostic factors (such as haemodynamics at right heart catheterization). Depression and Trait-Anxiety were associated with a lower physical (p=0.001) and mental (p<0.001) QoL, respectively. CONCLUSIONS Psychological factors impact the HRQoL of treated patients. A longitudinal and qualitative study should refine these results. TRIAL REGISTRATION Clinical trial N°: NCT01380054.

HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

Human leukocyte antigen (HLA)-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC). Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G) expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing), thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF) binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a multicenter cohort, thus support the pertinence of HLA-G haplotypes as predictive genetic markers for asthma.

Club cell secretory protein serum concentration is a surrogate marker of small-airway involvement in asthmatic patients

Poor asthma control and recurrent exacerbations have been shown to be a phenotypic counterpart of asthma with predominantly small-airway involvement.1 Biomarkers are not always accurate in asthmatic patients, especially in serum, because compartmentalization can occur between the blood and airways. Blood eosinophil counts do not represent an overall view of airway inflammation, and exhaled nitric oxide measurements at different flow rates (fraction of exhaled nitric oxide [Feno] and alveolar nitric oxide [Calvno]) have been developed and validated to reflect more accurately proximal and distal airway inflammation.2 Club cell secretory protein (CCSP) serum concentration has been shown to be associated with chronic obstructive pulmonary disease, bronchiolitis obliterans syndrome, and sarcoidosis, which are all predominantly diseases involving the small airways. Ranges of CCSP concentrations in healthy subjects, reproducibility, and relationships between serum and airway levels are known and can be used as potential surrogate markers. Our aim was to assess small-airway disease in asthmatic patients and to find a related biomarker. We used a dynamic assessment of gas trapping using computed tomographic (CT) imaging of the chest during methacholine challenge as a marker of small-airway disease.