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This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term “progressive pulmonary fibrosis” (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.

Introduction: Nocturnal desaturation may contribute to long-term pulmonary vascular stress in interstitial lung disease (ILD). We studied the prevalence and prognostic utility of nocturnal desaturation across ILDs. Methods: ILD patients with overnight oximetry (January 2010-December 2013) were included (n=437; Idiopathic Pulmonary Fibrosis, n=122; Connective Tissue Disease-ILD, n=48; Hypersensitivity Pneumonitis, n=60; Non-specific Interstitial Pneumonia, n=56; unclassifiable, n=27; Sarcoidosis, n=66; other, n=58). Desaturation index (DI) was defined as the number of desaturation events >4%/hr. Results: DI was higher in NSIP and CTD-ILD than in IPF (p=0.03 and p=0.02 respectively). In the whole cohort, DLco and serum BNP predicted mortality (HR 0.95; 95% CI 0.94, 0.96; p Conclusion: DI is more prevalent and it is a stronger predictor of mortality in immune-mediated ILDs than in IPF and may be an important manifestation of these disorders.

IntroductionThe King’s Brief Interstitial Lung Disease (KBILD) is a 15-item validated health-related quality of life (HRQOL) questionnaire. The method of scoring the KBILD has recently changed to incorporate a logit-scale transformation from one that used raw item responses, as this is potentially a more linear scale. The aim of this study was to re-evaluate the KBILD minimal clinically important difference (MCID) using the new logit -transformed scoring.Methods57 patients with interstitial lung disease (17 idiopathic pulmonary fibrosis, IPF) were asked to complete the KBILD questionnaire on two occasions in outpatient clinics. At the second visit, patients also completed a 15-item global rating of change of health status questionnaire (GRCQ). The MCID was calculated as the mean of four different methods: the change in KBILD for patients indicating a small change in GRCQ, patients with a 7%–12% change in FVC, 1 SE of measurement of baseline KBILD and effect size (ES) of 0.3.ResultsThe mean (SD) KBILD total score for all patients was 55.3 (15.6). 16 patients underwent a therapeutic intervention. 36 patients reported a change in their condition on the GRCQ; 22 deteriorated, 14 improved and 21 were unchanged. There was a significant change in KBILD total score in patients reporting a change in GRCQ; mean (SD) 57.0 (13.6) versus 50.0 (9.7); mean difference 7.0; 95% CI of difference 3.0 to 11.0; pConclusionThe KBILD is a responsive tool for longitudinal assessment of HRQOL in patients with ILD. The MCID of the KBILD total score is a 5-unit change.

Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF), reduces annual forced vital capacity (FVC) decline in these patients by ∼50% with combined analysis of data from clinical trials showing a trend towards reduction in mortality [1–3]. Nintedanib prescription criteria for the treatment of IPF vary between countries and in 2016, the National Institute for Health and Care Excellence approved nintedanib in England and Wales for patients with an FVC between 50% and 80% predicted [4]. Prior to this approval, nintedanib was available through a manufacturer-funded programme with varying prescribing criteria. We investigated the safety and tolerability of nintedanib in UK clinical practice during this period in which FVC prescription criteria differed from those now available in routine practice., In IPF, commencement of antifibrotic therapy in patients with preserved lung volume may increase the duration of therapy http://ow.ly/4HeM30lFS67

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial disease characterised by accumulation of elastin-rich fibrosis and predominant upper lobe shrinkage. The pathogenesis is poorly understood but idiopathic and secondary forms are recognised; an association with Aspergillus infection has been reported. We evaluated computed tomography (CT) and clinical/serological indices to identify factors influencing progression and mortality in patients with PPFE. CT studies in 72 patients, with a multidisciplinary diagnosis of PPFE, were consensus scored by two thoracic radiologists. The presence and severity of traction bronchiectasis in areas of PPFE correlated with the extent, severity and progression of PPFE (all p 40 mgA/L) was seen in 18/72 (25%) patients and was higher than in reference cohorts of idiopathic pulmonary fibrosis (20/105; 19%) and chronic hypersensitivity pneumonitis (12/111; 11%) (p=0.04). These data highlight the importance of platythorax as a clinico-radiological marker of volume loss and, more importantly, an index of poor outcome in PPFE, potentially reflecting inexorable physiological decline. The possibility that fungal sensitisation may form part of a pathogenetic or progressive PPFE profile warrants further investigation.

There is growing evidence of the role of infection in the pathogenesis and progression of idiopathic pulmonary fibrosis (IPF) [1–4]. Over a third of patients with IPF will be hospitalised, at least once, during the course of their disease [5]. These events not only carry a significant morbidity and mortality, but also a health care cost and burden [6]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Macaluso has nothing to disclose. Conflict of interest: Dr. Alzaher has nothing to disclose. Conflict of interest: Dr. Chaube has nothing to disclose. Conflict of interest: Dr. Chua has nothing to disclose. Conflict of interest: Dr. Wells reports speakers and consultancy fees from Intermune Roche, Boehringer ingelheim and Bayer Conflict of interest: TMM has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speakers fees from Apellis, Astra Zeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB. Conflict of interest: Dr. George reports personal fees from Roche Pharmaceuticals, personal fees from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr. Renzoni has recieved speakers fees from BI, Roche and Mundipharma Conflict of interest: Dr. Molyneaux has nothing to disclose. Conflict of interest: Dr. Maritano Furcada has nothing to disclose.

Background and objective: The aim of the present study was to report the features of five patients with concurrent histopathological features of pulmonary alveolar proteinosis (PAP) and hypersensitivity pneumonitis (HP) and their high-resolution CT (HRCT) appearances. Methods: Patients with histopathological features of both HP and PAP on surgical lung biopsy referred for tertiary review were retrospectively identified. The pathology and HRCT images were semi-quantitatively scored to evaluate the relative contribution to HP and PAP. Results: Five patients had histopathological features of HP and PAP but had varied HRCT appearances. All had imaging features of PAP to a varying degree with two patients also showing characteristics of HP but three patients had ill-defined thickened interlobular septa, not typical of either disease. Conclusions: We describe the coexistence of PAP and HP in five patients and discuss possible linkages between these two distinct pathologies.

Objective To evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets. Methods Two hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence-specific primer–polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, −1370 (T-1370G) of the promoter, +138 of exon 1 (+138 A/−), +85 of exon 3 (E106E), and +23 of exon 5 (K198N); for EDNRA, −231 of exon 1 (G-231A), and +69(H323H) and +105 (E335E) of exon 6; for EDNRB, +2841 of exon 2 (EDNRB-3), −2547 of exon 3 (EDNRB-2), and −2446 of exon 3 (EDNRB-1). Results No significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB-1A (76.8% versus 54.4%; P = 0.002), EDNRB-2A (79.7% versus 60.2%; P = 0.006), and EDNRB-3G (79.7% versus 56.6%; P = 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti–RNA polymerase (anti-RNAP) antibodies, compared with both anti-RNAP–negative SSc patients (P < 0.05) and control subjects (P < 0.005). Conclusion The finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies.

Rationale: Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. Objectives: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. Methods: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. Measurements and Main Results: Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m2 and reduced cardiac index of 2.21 (± 0.5) L/min/m2 were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). Conclusions: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).

To evaluate the impact of parental smoking on childhood asthma and wheezing, we studied two random samples of subjects ages 6-7 and 13-14 years in ten areas of northern and central Italy. Standardized questionnaires were completed by parents of 18,737 children and 21,068 adolescents (response rates, 92.8% and 96.3%, respectively) about their smoking habits and the respiratory health of their children. Adolescents were asked about their respiratory health and personal smoking. We compared two groups of cases with healthy subjects: (1) "current asthma" (children, 5.2%; adolescents, 6.2%) and (2) "current wheezing" not labeled as asthma (children = 4.5%, adolescents = 8.5%). Exposure to smoke of at least one parent increased the relative risk of current asthma among children [odds ratio (OR) = 1.34; 95% confidence interval (CI) = 1.11-1.62] and of current wheezing among adolescents (OR = 1.24; 95% CI = 1.07-1.44). Maternal smoking had a stronger effect than paternal smoking. Maternal smoking during pregnancy was associated with current asthma (OR = 1.62; 95% CI = 1.34-1.96) and current wheezing in children (OR = 1.31; 95% CI = 1.06-1.62); the effects were lower among adolescents. Among subjects with a negative history of parental asthma, maternal smoking was associated with current wheezing in both age groups, whereas among those with a positive history of parental asthma it was associated with current asthma in children, but not in adolescents. We estimated that 15% (95% CI = 12-19) of the current asthma cases among children and 11% (95% CI = 8.3-14) of the current wheezing cases among adolescents are attributable to parental smoking in Italy.

The authors are indebted to the collaborators in the participating centres and all parents, children, teachers and other school staff who participated in the surveys. There are many field workers and funding agencies who supported data collection and national, regional and international meetings, including the meetings of the ISAAC Steering Committee. Unfortunately, these are too numerous to mention (they are acknowledged elsewhere) but the authors particularly wish to thank the funders who supported the ISAAC International Data Centre including the Health Research Council of New Zealand, the Asthma and Respiratory Foundation of New Zealand, the National Child Health Research Foundation, the Hawke’s Bay Medical Research Foundation, the Waikato Medical Research Foundation, Glaxo Wellcome New Zealand and Astra New Zealand, as well as Glaxo Wellcome International Medical Affairs for finding the regional coordinating centres. The International Data Centre is now supported by a grant from the BUPA Foundation., The International Study of Asthma and Allergies in Childhood (ISAAC) Phase One showed large worldwide variations in the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, up to 10 to 20 fold between countries. Ecological analyses were undertaken with ISAAC Phase One data to explore factors that may have contributed to these variations, and are summarised and reviewed here. In ISAAC Phase One the prevalence of symptoms in the past 12 months of asthma, rhinoconjunctivitis and eczema were estimated from studies in 463,801 children aged 13 - 14 years in 155 centres in 56 countries, and in 257,800 children aged 6-7 years in 91 centres in 38 countries. Ecological analyses were undertaken between symptom prevalence and the following: Gross National Product per capita (GNP), food intake, immunisation rates, tuberculosis notifications, climatic factors, tobacco consumption, pollen, antibiotic sales, paracetamol sales, and outdoor air pollution. Symptom prevalence of all three conditions was positively associated with GNP, trans fatty acids, paracetamol, and women smoking, and inversely associated with food of plant origin, pollen, immunisations, tuberculosis notifications, air pollution, and men smoking. The magnitude of these associations was small, but consistent in direction between conditions. There were mixed associations of climate and antibiotic sales with symptom prevalence. The potential causality of these associations warrant further investigation. Factors which prevent the development of these conditions, or where there is an absence of a positive correlation at a population level may be as important from the policy viewpoint as a focus on the positive risk factors. Interventions based on small associations may have the potential for a large public health benefit., peer-reviewed

Background Chronic Obstructive Pulmonary Disease (COPD) is a chronic condition characterised by progressive airflow limitation that is at most partially reversible. Despite the lack of reversibility patients often report symptomatic improvement with short-acting beta 2 bronchodilator medications. They are used on either an "as required" or a "regular plus as required basis" and they may be used in conjunction with other bronchodilator medicines such as ipratropium and methylxanthines. These medicines are used in the management of both stable and acute exacerbations of COPD. This review examined the effect of short-acting beta 2 bronchodilators given by inhalation in stable COPD. Objectives To determine the clinical effect and assess the adverse effects of inhaled short-acting beta 2 agonist bronchodilators compared with placebo in stable COPD. Search strategy Only randomised controlled trials (RCTs) were considered. RCTs were identified using the Cochrane Airways Group database (CENTRAL). In addition, the reference lists of review articles and RCTs retrieved in full were searched for other potentially relevant citations. Selection criteria Only trials with adult patients with stable COPD, as defined by internationally accepted guidelines (ATS, ERS or BTS) were included in this review. All trials had a minimum duration of 7 days of regular treatment with short-acting beta 2 bronchodilators given by inhalation and compared with placebo. Data from trials where beta 2 agonists were used alone or in combination with other medicines (e.g. ipratropium bromide) were used only if there was a direct comparison between beta 2 bronchodilator alone and placebo. Data collection and analysis Outcomes were analysed as continuous or dichotomous outcomes, using standard statistical techniques. For continuous outcomes, the weighted mean difference (WMD) and 95% confidence intervals were calculated and for dichotomous outcomes, the odds ratio was calculated with 95% confidence intervals by Peto's methods. Funnel plots were used to test for publication bias. Main results Thirteen studies were included in this review. Most had small sample sizes and some of the sutides used very short-acting outdated compounds. All the studies used a cross-over design and were of high quality. Spirometry done at the end of study period was measured after administration of treatment (post-bronchodilator) which showed both FEV1 (0.150 L/min, 95%CI: 0. 02-0.28) and FVC (0.310 L, 95%CI: 0.00-0.62) to improve significanly but slightly when compared to placebo. A few studies measured FRC, airway resistance or conductance at the end of the study period. In all cases these measurements were done several hours after treatment, and no significant differences (p>0.05 in all cases) were found between the bronchodilator and placebo groups. Walking test Large increases in 6MW distance was observed in two studies, however one study did not show any positive improvements. There was a large increase in the 12MW distance as shown by one study. Due to the small number of studies reporting this outcome no significant differences were found in the walking distance between the bronchodilator and placebo groups. Peak Flow Rate Both morning (36. 04 L/min; 95%CI: 0.80-71.27) and evening (36.68 L/min; 95%CI: 2. 47-70.89) PEFR were significantly higher during active treatment than during placebo. Symptoms Breatlessness was measured on various scales therefore data that were presented in a suitable form were combined using standardized means for inclusion in the analysis. A significant improvement (-0.33; 95%CI: -0.58 to -0.07 with p=0.01) in the breathlessness score was observed during treatment with beta-2 agonist when compared to placebo. Cough was reported to improve significantly (data not usable) during treatment with beta2 agonist in one study but not in two others. A non-significant decrease in sputum production was reported by Wilson 1980, however four other studies reported no