Obesity in women with asthma: Baseline disadvantage plus greater small-airway responsiveness.

BACKGROUND: Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small-airway responsiveness. The objective of this study was therefore to compare small-airway responsiveness, as represented by the change in expiratory:inspiratory mean lung density ratios (MLDe/i , as determined by computed tomography [CT]) throughout methacholine testing in obese versus non-obese women with asthma. METHODS: Thoracic CT was performed during methacholine bronchoconstriction challenges to produce standardized response curves (SRC: response parameter versus ln[1 + % PD20], where PD20 is the cumulative methacholine dose) for 31 asthma patients (n = 18 non-obese and n = 13 obese patients). Mixed models evaluated obesity effects and interactions on SRCs while adjusting for age and bronchial morphology. Small airway responsiveness as represented by SRC slope was calculated for each third of the MLDe/i response and compared between groups. RESULTS: Obesity-associated effects observed during experimental bronchoconstriction included: (i) a significant baseline effect for forced expiratory volume in 1 second with lower values for the obese (73.11 ± 13.44) versus non-obese (82.19 ± 8.78; p = 0.002) groups prior to methacholine testing and (ii) significantly higher responsiveness in small airways as estimated via differences in MLDe/i slopes (group×ln(1 + % PD20 interaction; p = 0.023). The latter were pinpointed to higher slopes in the obese group at the beginning 2/3 of SRCs (p = 0.004 and p = 0.021). Significant obesity effects (p = 0.035 and p = 0.008) indicating lower forced vital capacity and greater % change in MLDe/I (respectively) throughout methacholine testing, were also observed. CONCLUSION: In addition to baseline differences, small-airway responsiveness (as represented by the change in MLDe/i ) during methacholine challenge is greater in obese women with asthma as compared to the non-obese.

NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome.

Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

Impact of Gender on the Characteristics of Patients with Idiopathic Pulmonary Fibrosis Included in the RaDiCo-ILD Cohort.

BACKGROUND: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes. OBJECTIVES: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort - Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences. METHODS: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender. RESULTS: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George's Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females. CONCLUSIONS: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females.

Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort.

BACKGROUND: Dupilumab is a monoclonal anti-IL-4Rα antibody developed for the treatment of severe asthma (SA). An early access programme for dupilumab was opened in France in SA patients experiencing unacceptable steroids side-effects and/or life-threatening exacerbations. OBJECTIVE: To assess changes in asthma control between baseline and 12 months of treatment. METHODS: Multi-centre (n = 13) retrospective real-life cohort study. This study is registered on ClinicalTrials.gov (NCT04022447). RESULTS: Overall, 64 patients with SA (median age 51, interquartile range [44-61]; 53% females) received dupilumab as add-on therapy to maximal standard of care; and 76% were on oral daily steroids at baseline. After 12 months, median asthma control test score improved from 14 [7-16] to 22 [17-24] (P < .001); median forced expiratory volume in 1 seconds increased from 58% [47-75] to 68% [58-88] (P = .001); and daily prednisone dose was reduced from 20 [10-30] to 5 [0-7] mg/d (P < .001). Annual exacerbations decreased from 4 [2-7] to 1 [0-2] (P < .001). Hypereosinophilia ≥1500/mm3 was observed at least once during follow-up in 16 patients (25%), persisting after 6 months in 8 (14%) of them. Increase in blood eosinophil count did not modify the clinical response during the study period. Injection-site reaction was the most common side effect (14%). Three deaths were observed, none related to treatment by investigators. CONCLUSION & CLINICAL RELEVANCE: In this first real-life cohort study of predominantly steroid-dependent SA, dupilumab significantly improved asthma control and lung function and reduced oral steroids use and exacerbations rate. Despite limitations due to the retrospective study, these results are consistent with controlled trials efficacy data. Further studies are required to assess the clinical significance and long-term prognosis of sustained dupilumab-induced hypereosinophilia.

Poor Concordance between Sequential Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy in the Diagnosis of Diffuse Interstitial Lung Diseases.

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)-versus surgical lung biopsy (SLB) as the current gold standard-in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5-8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01-0.44), percentage agreement = 38% (95% CI, 18-62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06-0.56), percentage agreement = 48% (95% CI, 26-70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27-0.75), percentage agreement = 62% (95% CI, 38-82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

Patient distrust in pharmaceutical companies: an explanation for women under-representation in respiratory clinical trials?

BACKGROUND: Patient skepticism concerning medical innovations can have major consequences for current public health and may threaten future progress, which greatly relies on clinical research. The primary objective of this study is to determine the variables associated with patient acceptation or refusal to participate in clinical research. Specifically, we sought to evaluate if distrust in pharmaceutical companies and associated psychosocial factors could represent a recruitment bias in clinical trials and thus threaten the applicability of their results. METHODS: This prospective, multicenter survey consisted in the administration of a self-questionnaire to patients during a pulmonology consultation. The 1025 questionnaires distributed collected demographics, socio-professional and basic health literacy characteristics. Patients were asked to rank their level of trust for pharmaceutical companies and indicate their willingness to participate in different categories of research (pre or post marketing, sponsored by an academic institution or pharmaceutical company). Logistic regression was used to determine factors contributing to "trust" versus "distrust" group membership and willingness to participate in each category of research. RESULTS: One thousand patients completed the survey, corresponding to a response rate of 97.5%. Data from 838 patients were analyzed in this study. 48.3% of respondents declared that they trusted pharmaceutical companies, while 35.5% declared distrust. Being female (p = 0.042), inactive in the employment market(p = 0.007), and not-knowing the name of one's disease(p = 0.010) are factors related to declared distrust. Distrust-group membership is associated with unwillingness to participate in certain categories of trials such as pre-marketing and industry-sponsored trials. CONCLUSION: Distrust in pharmaceutical companies is associated with a specific patient profile and with refusal to participate in certain subcategories of trials. This potential recruitment bias may explain the under-representation of certain categories of patients such as women in pre-marketing drug trials.

Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes.

Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0-80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.

A 2-Year Observational Study in Patients Suffering from Idiopathic Pulmonary Fibrosis and Treated with Pirfenidone: A French Ancillary Study of PASSPORT.

BACKGROUND: The European observational, prospective PASSPORT study evaluated the long-term safety of pirfenidone under real-world conditions in idiopathic pulmonary fibrosis (IPF), over up to 2 years following its initiation. OBJECTIVES: The FAS (French Ancillary Study) assessed the clinical outcomes of IPF patients participating in PASSPORT (n = 192). METHODS: Efficacy data were collected retrospectively and prospectively. The primary efficacy endpoints were: change in percent predicted forced vital capacity (FVC) and change in the distance travelled during the 6-min walk test (6MWD). RESULTS: The mean baseline FVC was 71.7% of predicted value. The mean absolute change in the percentage of predicted FVC was -2.4% and -3.8% at months 12 and 24. The mean change in 6MWD was 8.6 and 3.1 m at months 12 and 24, with a range of 23.4-51.7 m. Acute IPF exacerbation and pulmonary hypertension occurred in 20.0 and 8.4% of patients, respectively. The most common reasons for prematurely discontinuing PASSPORT were adverse drug reactions (ADRs) related to pirfenidone (31.3%), death (11.5%), and disease progression (10.9%). The median progression-free survival was 18.4 months (95% CI 12.9, not estimable). The median exposure was 16.3 months (0.5-28.5). The most frequently reported ADRs leading to pirfenidone discontinuation were decreased weight (4.2%), rash (4.2%), and photosensitivity reactions (3.1%). CONCLUSIONS: The efficacy data of FAS are consistent with the efficacy results of published phase III clinical trials in IPF. Approximately one third of IPF patients treated with pirfenidone in real-life settings were still under treatment 2 years after initiation. Safety data are consistent with the known safety profile of pirfenidone.

Epithelial ciliated beating cells essential for ex vivo ALI culture growth.

BACKGROUND: Bronchial epithelium plays a key role in orchestrating innate and adaptive immunity. The fate of ex vivo airway epithelial cultures growing at the air liquid interface (ALI) derived from human endobronchial biopsies or brushings is not easy to predict. Calibrating and differentiating these cells is a long and expensive process requiring rigorous expertise. Pinpointing factors associated with ALI culture success would help researchers gain further insight into epithelial progenitor behavior. METHODS: A successful ALI culture was defined as one in which a pseudostratified epithelium has formed after 28 days in the presence of all differentiated epithelial cell types. A 4-year prospective bi-center study was conducted with adult subjects enrolled in different approved research protocols. RESULTS: 463 consecutive endobronchial biopsies were obtained from normal healthy volunteers, healthy smokers, asthmatic patients and smokers with COPD. All demographic variables, the different fiber optic centers and culture operators, numbers of endo-bronchial biopsies and the presence of ciliated cells were carefully recorded. Univariate and multivariate models were developed. A stepwise procedure was used to select the final logistic regression model. ALI culture success was independently associated with the presence of living ciliated cells within the initial biopsy (OR = 2.18 [1.50-3.16], p < 0.001). CONCLUSION: This finding highlights the properties of the cells derived from the epithelium dedifferentiation process. The preferential selection of samples with ciliated beating cells would probably save time and money. It is still unknown whether successful ALI culture is related to indicators of general cell viability or a purported stem cell state specifically associated with ciliated beating cells.

CCSP G38A polymorphism environment interactions regulate CCSP levels differentially in COPD.

Impaired airway homeostasis in chronic obstructive pulmonary disease (COPD) could be partly related to club cell secretory protein (CCSP) deficiency. We hypothesize that CCSP G38A polymorphism is involved and aim to examine the influence of the CCSP G38A polymorphism on CCSP transcription levels and its regulatory mechanisms. CCSP genotype and CCSP levels in serum and sputum were assessed in 66 subjects with stable COPD included in a 1-yr observational study. Forty-nine of them had an exacerbation. In an in vitro study, the impact on the CCSP promoter of 38G wild-type or 38A variant was assessed. BEAS-2B cells were transfected by either the 38G or 38A construct, in the presence/absence of cigarette smoke extract (CSE) or lipopolysaccharides (LPS). Cotransfections with modulating transcription factors, p53 and Nkx2.1, identified by in silico analysis by using ConSite and TFSEARCH were conducted. A allele carrier COPD patients had lower serum and sputum CCSP levels, especially among active smokers, and a decreased body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) score. In vitro, baseline CCSP transcription levels were similar between the wild and variant constructs. CSE decreased more profoundly the CCSP transcription level of 38A transfected cells. The opposite effect was observed with p53 cotransfection. LPS stimulation induced CCSP repression in 38A promoter transfected cells. Cotransfection with Nkx2.1 significantly activated the CCSP promoters irrespective of the polymorphism. Circulating CCSP levels are associated with smoking and the CCSP G38A polymorphism. CSE, LPS, and the Nkx2.1 and p53 transcription factors modulated the CCSP promoter efficiency. The 38A polymorphism exaggerated the CCSP repression in response to p53 and CSE.

Is generalization of exhaled CO assessment in primary care helpful for early diagnosis of COPD?

BACKGROUND: COPD is largely under-diagnosed and once diagnosed usually at a late stage. Early diagnosis is thoroughly recommended but most attempts failed as the disease is marginally known and screening marginally accepted. It is a rare cause of concern in primary care and spirometry is not very common. Exhaled carbon monoxide (eCO) is a 5-seconds easy-to-use device dedicated to monitor cigarette smoke consumption. We aimed to assess whether systematic eCO measurement in primary care is a useful tool to improve acceptance for early COPD diagnosis. METHODS: This was a two-center randomized controlled trial enrolling 410 patients between March and May, 2013. Whatever was the reason of attendance to the clinic, all adults were proposed to measure eCO during randomly chosen days and outcomes were compared between the two different groups of patients (performing and not performing eCO). Primary outcome was the rates of acceptance for COPD screening. RESULTS: Rate of acceptance for COPD screening was 28% in the eCO group and 26% in the other (P = 0.575). These rates increased to 48 and 51% in smokers (current and former). eCO significantly increased the rate of clinics during which a debate on smoking was initiated (42 vs. 24%, P = 0.001). eCO at 2.5 ppm was the discriminative concentration for identifying active smokers (ROC curve AUC: 0.935). Smoking was the only independent risk factor associated with acceptance for early COPD screening (OR = 364.6 (82.5-901.5) and OR = 78.5 (18.7-330.0) in current and former smokers, respectively) while eCO measurement was not. CONCLUSIONS: Early COPD diagnosis is a minor cause of concern in primary care. Systematic eCO assessment failed to improve acceptance for early COPD screening.

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.

Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. METHODS: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588. FINDINGS: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. INTERPRETATION: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals.

Health-related quality of life and disease progression in pulmonary arterial hypertension patients: a 3-year study.

OBJECTIVES: The role of health-related quality of life (HRQoL) and psychological variables in pulmonary arterial hypertension (PAH) progression remains poorly quantified. We aimed to investigate the relationship between disease progression in PAH patients and HRQoL and psychological characteristics. METHODS: A 3-year longitudinal cohort was initiated. Patients with stable PAH (groups I-IV ineligible for angioplasty/endarterectomy) were included (n=55). Standard clinical variables, including invasive haemodynamic parameters, were prospectively recorded. A battery of questionnaires was used to characterise the psychological status of patients upon study initiation, and HRQoL was quantified using the SF-36 Questionnaire every 3 months for 24 months, and then again at 36 months. Guideline-defined disease progression and progression-free survival were recorded for 36 months. MEASUREMENTS AND MAIN RESULTS: Psychological distress was highly prevalent at baseline. The Physical Component Summary (PCS) and the Mental Component Summary (MCS) of the HRQoL were poor (PCS=37.13±8.18; MCS=42.42±10.88) but stable over 3 years of follow-up. Among PCS subscales, Physical Functioning (PF) (p=0.012) was identified as being independently associated with disease progression (Cox survival model), along with mean pulmonary arterial pressure (p=0.003) and cardiac output (p=0.005). Depression was the unique independent psychological characteristic associated with PF (p=0.0001). CONCLUSIONS: PAH patients have poor HRQoL. In addition to already known criteria related to disease severity, the HRQoL PF subscale is independently associated with disease progression in PAH. This may be explained by depression.