Gender Differences in Idiopathic Pulmonary Fibrosis: Are Men and Women Equal?

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a male predominance. The aim of the study was to explore gender differences in a well-designed French multicentre prospective IPF cohort (COhorte FIbrose, COFI) with a 5-year follow-up. Methods: Between 2007 and 2010, 236 patients with incident IPF were included in COFI. Gender characteristics were compared using a t-test, Chi-squared test and ANOVA, as appropriate. Survival analyses were performed. Results: Fifty-one (22%) females and 185 (78%) males with an average age at diagnosis of 70.1 ± 9.20 and 67.4 ± 10.9 years, respectively, were included in the cohort. Women were significantly less exposed to tobacco smoke [never n = 32 (62.7%) vs. n = 39 (21.1%), p < 0.001] and to occupational exposure [n = 7 (13.7%) vs. n = 63 (34.1%), p = 0.012]. Baseline forced vital capacity, % of predicted (FVC%) was significantly better in women compare to men (83.0% ± 25.0 v. 75.4% ± 18.7 p = 0.046). At presentation honeycombing and emphysema on CT scan were less common in women [n = 40 (78.4%) vs. n = 167 (90.3%) p = 0.041] and [n = 6 (11.8%) vs. n = 48 (25.9%) p = 0.029], respectively. During follow-up fewer women were transplanted compared to men [n = 1 (1.96%) vs. n = 20 (10.8%) p = 0.039]. Medians of survival were comparable by gender [31 months (CI 95%: 28-40) vs. 40 months (CI 95%: 33-72) p = 0.2]. After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival. Conclusions: Women appear to have less advanced disease at diagnosis, maybe due to less exposure history compare to men. Disease progression and overall survival remains comparable regardless gender, but women have less access to lung transplantation.

Low income and outcome in idiopathic pulmonary fibrosis: An association to uncover.

BACKGROUND: Low income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF. METHODS: Patients were selected from the French national prospective cohort COFI. Patients' income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as "low income" vs. "higher income" depending on whether their annual income was estimated to be < or ≥18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis. RESULTS: 200 patients were included. The average follow-up was 33.8 ± 22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p < 0.006), and to have at least one occupational exposure (p < 0.0001), and they tended to have a higher cumulative exposure to fine particles PM2.5 (p = 0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI95%: 1.24-2.62, p = 0.001) and overall survival (HR: 1.49; CI95%: 1.0006-2.23, p = 0.049). CONCLUSIONS: Low income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures.

Predictors of massive haemoptysis after a first episode of mild-to-moderate haemoptysis in patients with cystic fibrosis.

Mild-to-moderate haemoptysis (m-mH) is common in patients with cystic fibrosis but the risk of subsequent massive haemoptysis (MH) is not known. Allergic bronchopulmonary aspergillosis and diabetes were significant predictors of MH subsequent to m-mH. https://bit.ly/30093Hw.

Impact of Achromobacter xylosoxidans isolation on the respiratory function of adult patients with cystic fibrosis.

BACKGROUND: The prevalence of Achromobacter xylosoxidans lung isolation in cystic fibrosis (CF) patients has increased, but the impact on lung function is controversial. The aim of this study was to evaluate the long-term effects of A. xylosoxidans isolation on respiratory function of adult patients with CF in the first 3 years after identification of A. xylosoxidans isolation. METHODS: This was a case-control retrospective study performed at a single CF centre in Lille, France. Data for 36 patients with CF who had at least one sputum culture positive for A. xylosoxidans (Ax+) were evaluated and compared with control CF patients uninfected by A. xylosoxidans (Ax-). Respiratory function and exacerbation frequency were evaluated between 1 year prior to and 3 years after A. xylosoxidans isolation. RESULTS: Compared with the Ax- group, the Ax+ group had a lower forced expiratory volume in 1 s (FEV1) at baseline (median (interquartile range): 55.2% (50.6-59.8%) versus 73.8% (67.2-80.4%); p=0.005), a greater decline in FEV1 (±se) in the first year after A. xylosoxidans identification (-153.6±16.1 mL·year-1 versus -63.8±18.5 mL·year-1; p=0.0003), and more exacerbations in the first 3 years after A. xylosoxidans identification (9 (7-12) versus 7 (5-10); p=0.03). Ax+ patients co-colonised with Pseudomonas aeruginosa (n=27, 75%) had a greater FEV1 decline (p=0.003) and more exacerbations in the year after A. xylosoxidans identification (p=0.037) compared with patients colonised with A. xylosoxidans alone. Patients with chronic A. xylosoxidans isolation (n=23, 64%) had more exacerbations than intermittently colonised patients in the 3 years after A. xylosoxidans identification (p=0.012). CONCLUSION: A. xylosoxidans isolation is associated with a decline in respiratory function in patients with CF. Chronic A. xylosoxidans isolation and P. aeruginosa co-isolation may be markers of more severe respiratory disease in Ax+ patients.

The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-ß and Pulmonary Fibrosis.

Rationale: Given the paucity of effective treatments for idiopathic pulmonary fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. TGF-ß (transforming growth factor-ß) is the main profibrotic factor, but its inhibition is associated with severe side effects because of its pleiotropic role. Objectives: To determine if downstream noncoding effectors of TGF-ß in fibroblasts may represent new effective therapeutic targets whose modulation may be well tolerated. Methods: We investigated the whole noncoding fraction of TGF-ß-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblasts. Differential expression of the long noncoding RNA (lncRNA) DNM3OS (dynamin 3 opposite strand) and its associated microRNAs (miRNAs) was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonucleotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis. Measurements and Main Results: We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-ß-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to three distinct profibrotic mature miRNAs (i.e., miR-199a-5p/3p and miR-214-3p), which influence SMAD and non-SMAD components of TGF-ß signaling in a multifaceted way. In vivo, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis. Conclusions: Pharmacological approaches aiming at interfering with the lncRNA DNM3OS may represent new effective therapeutic strategies in IPF.

Study protocol: exploring the efficacy of cyclophosphamide added to corticosteroids for treating acute exacerbation of idiopathic pulmonary fibrosis; a randomized double-blind, placebo-controlled, multi-center phase III trial (EXAFIP).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, with a median survival of 2-3 years and variable natural history, characterized by gradual and progressive deterioration. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication, associated with poor survival and a mortality > 50%. To date, no treatment has proven effective in AE-IPF, with cyclophosphamide (CYC) the only therapy suggested to be effective on survival, primarily based on retrospective series. Considering the high fatality rates of AE-IPF, evaluating the efficacy of immunosuppressive agents in a randomized controlled trial proves crucial, as the results could significantly impact treatment and prognosis of AE-IPF. METHODS: The EXAFIP study is a French national multicenter double-blind placebo-controlled randomized trial. Its primary objective is to evaluate the efficacy of CYC compared to placebo on early survival in patients treated with corticosteroids. We hypothesize that adding CYC to high-dose corticosteroids would reduce 3-month mortality in AE-IPF patients. The primary outcome is all-cause mortality rate at Month 3; secondary objectives are to evaluate the efficacy of CYC compared to placebo on overall survival at Months 6 and 12, respiratory disease-specific mortality, respiratory morbidity, and chest high-resolution computed tomography features, and to determine prognostic factors in AE-IPF and compare the safety of the two treatment arms during 6 months' follow-up. DISCUSSION: There is an urgent unmet clinical need for effective AE-IPF treatment. The EXAFIP study is the first large Phase III placebo-controlled randomized trial evaluating the efficacy and safety of CYC added to corticosteroids in treating AE-IPF. The results of this study could significantly impact treatment strategy and prognosis of AE-IPF. TRIAL REGISTRATION: Clinical trials, NCT02460588 ; Date: June 2, 2015, prospectively; Issue date: 14/11/2017; Protocole Amendment Number: 03.

Cardiorespiratory adaptation during 6-Minute Walk Test in fibrotic idiopathic interstitial pneumonia patients who did or did not respond to pulmonary rehabilitation.

BACKGROUND: Pulmonary rehabilitation (PR) improves performance in the 6-min walk test (6MWT) in a subset of patients with fibrotic idiopathic interstitial pneumonia (f-IIP); however, a large proportion of patients does not respond to PR. AIM: To investigate the effects of a PR program on cardiorespiratory responses during a 6MWT and to identify the characteristics of patients who do not show improved performance after PR. DESIGN: An observational study. SETTING: Patients were recruited from the Competence Centre for Rare Pulmonary Diseases at Lille University Hospital, France and completed an 8-week home-based PR program. POPULATION: A total of 19 patients with f-IIP; 12 with idiopathic pulmonary fibrosis (IPF) and 7 with fibrotic non-specific interstitial pneumonia. METHODS: Patients underwent spirometry and completed a 6MWT before and after an 8-week PR program. Gas exchange, heart rate, and pulse O2 saturation were measured continuously during the 6MWT. Quality of life, dyspnea, and anxiety/depression were assessed using the Short-Form 36 (SF-36), the baseline/transition dyspnea index (BDI/TDI), and the Hospital Anxiety and Depression Scale (HADS) questionnaires. RESULTS: Patients who did and did not improve the distance walked in the 6MWT by at least 30 m after PR were classified as responders (N.=9) and non-responders (N.=10), respectively. O2 uptake, ventilation rate, and distance covered during the 6MWT were significantly improved only in the responder group (P<0.05). Changes in SF-36, BDI/TDI, and HADS scores did not differ significantly between responders and non-responders. The non-responder group contained significantly more patients with IPF (P<0.05) and experienced greater arterial oxygen desaturation during the 6MWT compared with the responder group. CONCLUSIONS: Failure to improve performance in the 6MWT after PR was associated with a diagnosis of IPF, non-improvement in gas exchange, and greater arterial oxygen desaturation. CLINICAL REHABILITATION IMPACT: Most f-IIP patients who did not respond to PR were diagnosed with IPF and displayed greater hypoxemia during exercise. Clinical practitioners should seek to determine why patients fail to improve exercise performance after PR and propose an alternative exercise regimen to these patients.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

The immediate effects of a single autogenic drainage session on ventilatory mechanics in adult subjects with cystic fibrosis.

INTRODUCTION: The aim of this study was to gain insight into the physiological changes occurring in subjects with cystic fibrosis (CF) after autogenic drainage (AD). Changes in respiratory system resistance (Rrs), reactance (Xrs), and spirometry were analyzed in adult CF subjects after a single AD physiotherapy session. METHODS: This prospective observational study was conducted during the annual check-up of adult CF subjects in stable condition. Spirometry and Rrs and Xrs measurements using the forced oscillations technique at 5, 11, and 19 hertz (Hz) were performed before and 30 min after a 20-min AD session. Control CF subjects were tested at baseline and 50 min without AD. Results are expressed as mean ± standard deviation or median [interquartile range]. RESULTS: Thirty subjects were included in the physiotherapy group (age 29 [25-34] years, forced expiratory volume in 1 s (FEV1) 40.3 [30.1-57.9]% predicted) and 11 in the control group (age 31 [28.5-36.5] years, FEV1 43.6 [31.1-51.9] % predicted). No significant changes in any parameter were observed in the control group. AD modestly but significantly increased the forced vital capacity (FVC) and FEV1 (p<0.001). Inspiratory resistance was also significantly improved by AD: Rrs5 from 5.74±2.39 to 5.24±2.17 cmH2O/L/s, p<0.05; Rrs11 from 4.83±1.98 to 4.32±1.7 cmH2O/L/s, p = 0.003; and Rrs19 from 4.18 [3.46-5.07] to 3.86 [2.76-4.98] cmH2O/L/s, p<0.001. In contrast, AD had no significant effects on frequency dependence of resistance (Rrs5-Rrs19) or expiratory resistance. Inspiratory Xrs5, but not ΔXrs5 (expiratory-inspiratory Xrs), was improved by AD (p<0.05). Moderate correlations were detected between the improvement in FEV1 and FVC and inspiratory resistance (r = 0.53, p = 0.005 and r = 0.44, p = 0.02, respectively). CONCLUSION: A single session of AD improved inspiratory airway resistance, except in the distal airways. The forced oscillations technique provides a new tool for understanding the pathophysiological effects of airway clearance physiotherapy in CF.

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Fungal and Bacterial Diversity of Airway Microbiota in Adults with Cystic Fibrosis: Concordance Between Conventional Methods and Ultra-Deep Sequencing, and Their Practical use in the Clinical Laboratory.

Given the complexity of the airway microbiota in the respiratory tract of cystic fibrosis (CF) patients, it seems crucial to compile the most exhaustive and exact list of the microbial communities inhabiting CF airways. The aim of the present study was to compare the bacterial and fungal diversity of sputa from adult CF patients during non-exacerbation period by culture-based and molecular methods, and ultra-deep-sequencing (UDS). Sputum samples from four CF patients were cultured and analysed by DNA extractions followed by terminal restriction fragment length polymorphism analysis through resolution of bacterial ribosomal gene (rDNA) fragments, and cloning plus sequencing of part of fungal rRNA genes. These approaches were compared with UDS method targeting 16S rDNA gene and the internal transcribed spacer (ITS) 2 region of rDNA. A total of 27 bacterial and 18 fungal genera were detected from the four patients. Five (18%) and 3 (16%) genera were detected by culture for bacteria and fungi, respectively, 9 (33%) and 3 (16%) by first generation sequencing (FGS) methods, and 26 (96%) and 18 (100%) by UDS. The mean number of genera detected by UDS per patient was statistically higher than by culture or FGS methods. Patients with severe airway disease as assessed by standard spirometry exhibited a reduced fungal and bacterial diversity. UDS approach evaluates more extensively the diversity of fungal and bacterial flora compared with cultures. However, it currently remains difficult to routinely use UDS mainly because of the lack of standardization, and the current cost of this method.

Toward the Standardization of Mycological Examination of Sputum Samples in Cystic Fibrosis: Results from a French Multicenter Prospective Study.

Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: "MucoFong" program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran-rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud-chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20-27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies.

Role of atmospheric pollution on the natural history of idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) has an unpredictable course corresponding to various profiles: stability, physiological disease progression and rapid decline. A minority of patients experience acute exacerbations (AEs). A recent study suggested that ozone and nitrogen dioxide might contribute to the occurrence of AE. We hypothesised that outdoor air pollution might influence the natural history of IPF. METHODS: Patients were selected from the French cohort COhorte FIbrose (COFI), a national multicentre longitudinal prospective cohort of IPF (n=192). Air pollutant levels were assigned to each patient from the air quality monitoring station closest to the patient's geocoded residence. Cox proportional hazards model was used to evaluate the impact of air pollution on AE, disease progression and death. RESULTS: Onset of AEs was significantly associated with an increased mean level of ozone in the six preceding weeks, with an HR of 1.47 (95% CI 1.13 to 1.92) per 10 µg/m3 (p=0.005). Cumulative levels of exposure to particulate matter PM10 and PM2.5 were above WHO recommendations in 34% and 100% of patients, respectively. Mortality was significantly associated with increased levels of exposure to PM10 (HR=2.01, 95% CI 1.07 to 3.77) per 10 µg/m3 (p=0.03), and PM2.5 (HR=7.93, 95% CI 2.93 to 21.33) per 10 µg/m3 (p<0.001). CONCLUSION: This study suggests that air pollution has a negative impact on IPF outcomes, corroborating the role of ozone on AEs and establishing, for the first time, the potential role of long-term exposure to PM10 and PM2.5 on overall mortality.

Physiologic Determinants of Exercise Capacity in Pulmonary Langerhans Cell Histiocytosis: A Multidimensional Analysis.

BACKGROUND: Reduced exercise capacity severely impacts quality of life in pulmonary Langerhans cell histiocytosis. Ascertaining mechanisms that impair exercise capacity is necessary to identify targets for symptomatic treatments. METHODS: Dyspnea, pulmonary function tests and cardiopulmonary exercise test were analysed in 62 study participants. Data were compared between subjects with impaired and normal aerobic capacity (V'O2 peak less than 84% versus 84% predicted or more). Data were reduced using a principal component analysis. Multivariate analysis included V'O2 peak as the dependent variable and principal components as covariates. RESULTS: V'O2 peak was reduced in 44 subjects (71%). Subjects with impaired aerobic capacity presented: (i) decreased FEV1, FVC, FEV1/FVC, DLCO and DLCO/VA and increased AaDO2, (ii) increased ventilatory equivalents at ventilatory threshold, VD/VT peak, AaDO2 peak and PaCO2 peak and decreased ventilatory reserve and PaO2 peak. There was no difference between groups in dyspnea scores. Principal component analysis extracted 4 principal components interpreted as follows: PC1: gas exchange; PC2: "pseudorestriction"; PC3: exercise-induced hyperpnea; PC4: air trapping. Multivariate analysis explained 65% of V'O2 peak. The 4 principal components were independently associated with V'O2 peak (ßcoefficients: PC1: 9.3 [4.6; 14], PC2: 7.5 [3; 11.9], PC3: -5.3 [-9.6;-1.], PC4: -9.8 [-14,9;-4.7]). CONCLUSION: Impaired exercise capacity is frequent in pulmonary Langerhans cell histiocytosis. It is mainly caused by pulmonary changes but is not associated with increased dyspnea intensity. Therefore, treating the lung represents a relevant approach for improving exercise capacity, even in patients experiencing mild dyspnea.

Efficacy of Whole-Lung Lavage in Pulmonary Alveolar Proteinosis: A Multicenter International Study of GELF.

BACKGROUND: New therapies have emerged in the treatment of pulmonary alveolar proteinosis (PAP) and, therefore, there is a real need to evaluate the efficacy of whole-lung lavage (WLL) in this rare disease. OBJECTIVES: The aim of this study was to assess the efficacy of WLL in patients with PAP. METHODS: We included 33 patients from 12 centers, which are members of the French-Speaking Thoracic Endoscopy Group, for analysis. Data collection concerned patients and disease characteristics, pulmonary function tests (PFTs) and technical information on the procedure. RESULTS: The median age of the patients was 44 years (range 13-77). There were 23 (71.9%) patients with respiratory insufficiency at presentation. All patients underwent WLL by general anesthesia and selective lung ventilation, except 1 who underwent awake flexible bronchoscopy. We noted differences in the technique, as 12 (36.36%) patients had percussion during the procedure and only 4 (12.1%) patients underwent 2-lung lavage during 1 anesthesia. A median of 12 L was used to perform WLL (1.0-40 L). Complications occurred in 11 (33.3%) patients, and 18 (56.25%) of them relapsed in a median period of 16.9 months. No significant changes were found in any PFT parameters studied, except for PaO2, which was significantly improved by 6.375 mm Hg (p = 0.0213) after the procedure compared to before. CONCLUSIONS: Although the application of the WLL technique was variable, overall, it significantly improved patients' short-term respiratory condition by improving PaO2. However, a long-term effect needs to be confirmed, as many of our patients relapsed.

Lung placental transmogrification presenting as progressive unilateral interstitial lung disease.

Placental transmogrification of the lung is an extremely rare lung disease frequently associated with hamartomas or unilateral bullous emphysema. We report a case of placental transmogrification of the lung in a 44-year-old male who presented with bronchial infections, hyperlucent left lung and progressive cystic and micronodular unilateral interstitial lung disease. Because of interstitial lung disease progression over 13 years, a left pneumonectomy was performed. After a two-year follow-up, the patient was asymptomatic and did not exhibit any lung infections. No recurrence was observed on the right lung. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 188-190).

Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): A study of 157 patients by the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires and the European Respiratory Society Taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVE: To guide nosology and classification of patients with eosinophilic granulomatosis with polyangiitis (EGPA) based on phenotype and presence or absence of ANCA. METHODS: Organ manifestations and ANCA status were retrospectively analyzed based on the presence or not of predefined definite vasculitis features or surrogates of vasculitis in patients asthma, eosinophilia, and at least one systemic organ manifestation attributable to systemic disease. RESULTS: The study population included 157 patients (mean age 49.4±14.1), with a follow-up of 7.4±6.4years. Patients with ANCA (31%) more frequently had weight loss, myalgias, arthralgias, biopsy-proven vasculitis, glomerulonephritis on biopsy, hematuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of arterial wall on biopsy, and other renal disease. A total of 41% of patients had definite vasculitis manifestations (37%) or strong surrogates of vasculitis (4%), of whom only 53% had ANCA. Mononeuritis multiplex was associated with systemic vasculitis (p=0.005) and with the presence of ANCA (p<0.001). Overall, 59% of patients had polyangiitis as defined by definite vasculitis, strong surrogate of vasculitis, mononeuritis multiplex, and/or ANCA with at least one systemic manifestation other than ENT or respiratory. Patients with polyangiitis had more systemic manifestations including arthralgias (p=0.02) and renal disease (p=0.024), had higher peripheral eosinophilia (p=0.027), and a trend towards less myocarditis (p=0.057). Using predefined criteria of vasculitis and surrogates of vasculitis, ANCA alone were found to be insufficient to categorise patients with vasculitis features. CONCLUSION: We suggest a revised nomenclature and definition for EGPA and a new proposed entity referred to as hypereosinophilic asthma with systemic (non vasculitic) manifestations.

Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

The respiratory manifestations of eosinophilic granulomatosis with polyangiitis (EGPA) have not been studied in detail.In this retrospective multicentre study, EGPA was defined by asthma, eosinophilia and at least one new onset extra-bronchopulmonary organ manifestation of disease.The study population included 157 patients (mean±sd age 49.4±14.1 years), with a mean±sd blood eosinophil count of 7.4±6.4×109 L-1 at diagnosis. There was a mean±sd of 11.8±18.2 years from the onset of asthma to the diagnosis of EGPA, of 1.4±8.4 years from the first onset of peripheral eosinophilia to the diagnosis of EGPA, and of 7.4±6.4 years from EGPA diagnosis to the final visit. Despite inhaled and oral corticosteroid treatment, the severity of asthma increased 3-6 months before the onset of the systemic manifestations. Asthma was severe in 57%, 48%, and 56% of patients at diagnosis, at 3 years, and at the final visit, respectively. Persistent airflow obstruction was present in 38%, 30%, and 46% at diagnosis, at 3 years, and at the final visit, respectively.In EGPA, asthma is severe, antedates systemic manifestations by a mean of 12 years, and progresses to long-term persistent airflow obstruction despite corticosteroids in a large proportion of patients, which affects long-term management and morbidity.

Oxygen desaturation during a 6-minute walk test as a predictor of maximal exercise-induced gas exchange abnormalities in sarcoidosis.

BACKGROUND: Common tests for evaluating gas exchange impairment have different strengths and weaknesses. Alveolar-to-arterial oxygen pressure difference (AaDO2) at peak exercise is a sensitive indicator but it cannot be measured repeatedly. Diffusing capacity of the lung for carbon monoxide (DLco) is measured at rest and may be too insensitive to predict the effects of exercise on gas exchange impairment. Oxygen desaturation during a 6-minute walk test (∆SpO2-6MWT) can be measured repeatedly, but its value in sarcoidosis is unknown. Here, we evaluated the ability of ∆SpO2-6MWT and DLco to predict gas exchange impairment during exercise in sarcoidosis. METHODS: This retrospective study of 130 subjects with sarcoidosis investigated the relationship between DLco, ∆SpO2-6MWT, and peak AaDO2 using correlation tests, inter-test reliability analyses, and predictive values. For the analyses of inter-test reliability and predictive values, DLco, peak AaDO2, and ∆SpO2-6MWT were considered as binary variables (normal/abnormal) according to previously defined thresholds. RESULTS: Correlation coefficients between DLco, ∆SpO2-6MWT, and peak AaDO2 were intermediate (0.53-0.67, P<0.0003) and Kappa coefficients were low (0.21-0.42, P=0.0003-0.02). DLco predicted (I) increased peak AaDO2 with a positive predictive value (PPV) of 66% and a negative predictive value (NPV) of 78% and (II) increased ∆SpO2-6MWT with a PPV at 36% and an NPV at 88%. Normal DLco was a good predictor of the absence of severe desaturation during the 6MWT (94% NPV) and at peak exercise during cardiopulmonary exercise test (CPET) (100% NPV). ∆SpO2-6MWT predicted peak AaDO2 increase with a PPV of 74% and an NPV of 60%. CONCLUSIONS: In a large population of sarcoidosis patients, neither ∆SpO2-6MWT nor DLco was a good predictor of increased peak AaDO2. In contrast, normal DLco was a good predictor of the absence of severe desaturation during the 6MWT and at peak exercise during CPET.

Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Oral acetylcysteine (also known as N-acetylcysteine) is used with pirfenidone to treat idiopathic pulmonary fibrosis (IPF) in Europe. However, no randomised studies have investigated the safety and tolerability of this combination. The PANORAMA study assessed the safety and tolerability of acetylcysteine combined with pirfenidone in patients with IPF. Exploratory efficacy endpoints were also assessed. METHODS: We did a double-blind randomised trial at 48 sites in eight countries. Patients with IPF aged 40-80 years and established on pirfenidone (at least 1602 mg/day for 8 weeks or longer) were randomly assigned in a 1:1 ratio by interactive voice response system to receive concomitant oral acetylcysteine (600 mg, three times daily) or placebo for 24 weeks. A stratified blocked randomisation scheme was used with a block size of 4. Randomisation was stratified by dose of pirfenidone (2403 mg/day [the maximum dose] or <2403 mg/day). Patients, physicians, study staff and the sponsor were masked to treatment group allocation. The primary endpoint was assessment of adverse events, which were collected at each visit and for 28 days after the last dose of study drug. Exploratory efficacy measurements included forced vital capacity (FVC), carbon monoxide diffusing capacity, and 6 min walk distance. Analyses were done in the modified intention-to-treat population, which included all patients who were randomised and received at least one dose of study medication. This study is registered with the European Clinical Trials Database (EudraCT number 2012-000564-14) and has been completed. FINDINGS: 123 patients participated in the study between June 28, 2013, and Feb 24, 2015. 61 were assigned to the acetylcysteine group (60 received study medication and included in analysis) and 62 were assigned to the placebo group (all included in analysis). The occurrence of at least one adverse event (46 [77%] patients receiving acetylcysteine vs 50 [81%] receiving placebo), adverse events related to study treatment (17 [28%] vs 16 [26%]), and the number of patients experiencing severe adverse events (three [5%] vs two [3%]), life-threatening adverse events (one [2%] vs one [2%]), or death (one [2%] vs three [5%]) was similar between treatment groups. One case of diarrhoea in the acetylcysteine group was considered severe and related to study treatment. Nine serious adverse events were reported by seven patients: dyspnoea, headache, hypertension, intervertebral disc protrusion, and malignant lung neoplasm in the acetylcysteine group, and aortic aneurysm, contusion, forearm fracture, and worsening IPF in the placebo group. The most common adverse events were cough, nasopharyngitis, and diarrhoea. Photosensitivity occurred more frequently with acetylcysteine (eight [13%] patients) than placebo (one [2%] patient; difference 11·7%; 95% CI 2·6-20·9; p=0·016]), and was not attributable to differences in location, season, or concomitant medication. Four (7%) patients receiving acetylcysteine and three (5%) receiving placebo discontinued study treatment due to adverse events. In the exploratory analysis, change in FVC indicated that clinical benefit from addition of acetylcysteine to pirfenidone is unlikely, with the possibility of a harmful effect in patients with IPF (adjusted rate of decline 125·6 mL/6 months for acetylcysteine vs 34·3 mL/6 months for placebo; difference -91·3 mL; 95% CI -174·4 to -8·3; p=0·031). INTERPRETATION: Findings from the PANORAMA study suggest that addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF. FUNDING: InterMune International AG (Roche).