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Introduction Idiopathic pulmonary fibrosis (IPF) is progressive and irreversible. Some discrepancies about IPF staging exists, especially in mild phases. Forced vital capacity (FVC) higher than 80% has been considered early or mild IPF even for the design of clinical trials. Methods Spanish multicentre, observational, retrospective study of IPF patients diagnosed between 2012 and 2016, based on the ATS/ERS criteria, which presented FVC greater or equal 80% at diagnosis. Clinical and demographic characteristics, lung function, radiological pattern, treatment, and follow-up were analyzed. Results 225 IPF patients were included, 72.9% were men. The mean age was 69.5 years. The predominant high-resolution computed tomography (HRCT) pattern was consistent usual interstitial pneumonia (UIP) (51.6%). 84.7% of patients presented respiratory symptoms (exertional dyspnea and/or cough) and 33.33% showed oxygen desaturation below 90% in the 6 min walking test (6MWT). Anti-fibrotic treatment was initiated at diagnosis in 55.11% of patients. Median FVC was 89.6% (IQR 17) and 58.7% of patients had a decrease of diffusion lung capacity for carbon monoxide (DLCO) below 60% of theoretical value; most of them presented functional progression (61.4%) and higher mortality at 3 years (20.45%). A statistically significant correlation with the 3-years mortality was observed between DLCO Conclusions Patients with preserved FVC but presenting UIP radiological pattern and moderate–severe DLCO decrease at diagnosis associate an increased risk of progression, death or lung transplantation. Therefore, in these cases, preserved FVC would not be representative of early or mild IPF.

Supported by the National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis (GNT1116371), and by foundation partner, Boehringer Ingelheim, and program partners, Roche and Galapagos. Rationale : The interstitial lung disease (ILD) multidisciplinary meetings (MDM), composed of pulmonologists, radiologists, and pathologists, is integral to the rendering of an accurate ILD diagnosis. However, there is significant heterogeneity in the conduct of ILD MDMs, and questions regarding their best practices remain unanswered. Objectives : To achieve consensus among ILD experts on essential components of an ILD MDM. Methods : Using a Delphi methodology, semi-structured interviews with ILD experts were used to identify key themes and features of ILD MDMs. These items informed two subsequent rounds of online questionnaires that were used to achieve consensus among a broader, international panel of ILD experts. Experts were asked to rate their level of agreement on a five-point Likert scale. An a priori threshold for consensus was set at a median score 4 or 5 with an interquartile range of 0. Results : We interviewed 15 ILD experts, and 102 ILD experts participated in the online questionnaires. Five items and two exploratory statements achieved consensus on being essential for an ILD MDM following two questionnaire rounds. There was consensus that the presence of at least one radiologist, a quiet setting with a visual projection system, a high-quality chest high-resolution computed tomography, and a standardized template summarizing collated patient data are essential components of an ILD MDM. Experts also agreed that it would be useful for ILD MDMs to undergo an annual benchmarking process and a validation process by fulfilling a minimum number of cases annually. Twenty-seven additional features were considered to be either highly desirable or desirable features based on the degree of consensus. Although our findings on desirable features are similar to the current literature, several of these remain controversial and warrant further research. The study also showed an agreement among participants on several future concepts to improve the ILD MDM, such as performing regular self-assessments and conducting research into shared practices to develop an international expert guideline statement on ILD MDMs. Conclusions : This Delphi study showed consensus among international ILD experts on essential and desirable features of an ILD MDM. Our data represent an important step toward potential collaborative research into future standardization of ILD MDMs. Postprint

Objective To test whether the use of rituximab (RTX) is effective and safe as a rescue therapy add-on treatment to mycophenolate (MMF) in patients with progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) in whom conventional immunosuppressants (IS) have failed. Methods Longitudinal retrospective observational study of a cohort of patients with SSc-ILD that started treatment with RTX due to ongoing lung function impairment despite treatment with glucocorticoids and IS (cyclophosphamide and/or MMF). All patients were treated with 2 or more cycles of RTX and evaluated for at least 12 months. Results Twenty-four patients were included. Before initiation of RTX the mean decline in%pFVC and %pDLCO during the previous 2 years (delta) was −12.9% and −12.5%, respectively. After 1 year of treatment with RTX, a significant improvement in %pFVC (∆+8.8% compared to baseline, 95% CI: −13.7 to −3.9; p = 0.001) and%pDLCO (∆+4.6%, 95% CI: −8.2 to −0.8; p = 0.018) was observed. In addition, there was a significant reduction in the median dose of prednisone and it could be suspended in 25% of patients. At 2 years of treatment, RTX had been discontinued in 9 patients (due to adverse events in 3 cases and inefficacy in 6). In the 15 patients (62.5%) that completed 24 months of therapy, the statistically significant amelioration in pulmonary function test parameters was maintained: ∆%pFVC: +11.1% (95% CI: −17.6 to −4.5; p = 0.003) and ∆%pDLCO: +8.7% (95% CI: −13.9 to −8.3; p = 0.003). Conclusion Based on our results, RTX's use as an add-on treatment to MMF appears to be effective as a rescue therapy in patients with a more aggressive SSc-ILD phenotype.

Purpose: Idiopathic pulmonary fibrosis (IPF) is a complex progressive chronic lung disease where epithelial to mesenchymal interaction, extracellular matrix (ECM) contact, and pro-fibrotic cytokines dynamics take part in the development of the disease. The study of IPF in the widespread in vitro two-dimensional (2 D) culture fails to explain the interaction of cells with the changing environment that occurs in fibrotic lung tissue. A three-dimensional (3 D) co-culture model might shed light on the pathogenesis of IPF by mimicking the fibrotic environment. Materials and Methods: Fibroblasts from nine IPF were isolated and embedded in collagen matrices with the alveolar epithelial human cell line (A549) on the top. Cells were also cultured in 2 D with and without TGF-β1 as a conventional model to compare with. Both types of cells were isolated separately. Protein and gene expression of the main fibrotic markers were measured by qPCR, Western blot, and ELISA. Results: IPF fibroblasts to myofibroblasts differentiation was observed in the 3 D model and in cells stimulated with TGF-β1. In addition, ECM-related genes were highly up-regulated in the 3 D collagen matrix. A549 co-cultured 3 D with IPF fibroblasts showed EMT activation, with down-regulation of E-cadherin (CDH1). However, other pro-fibrotic genes as VIM, TGFB1, and MMP7 were up-regulated in A549 co-cultured 3 D with fibroblasts. Conclusions: 3 D-collagen matrices might induce fibroblasts’ fibrotic phenotype as in the classic TGF-β1 model, by up-regulating genes associated with matrix production. In addition, IPF lung fibroblasts seem to exert a pro-fibrotic influence in A549 cells when they are co-cultured. These results suggest that an improved 3 D co-culture model might serve as an important tool to study the fibrotic process and its regulation.

Introduction Idiopathic pulmonary fibrosis (IPF) prognosis is heterogeneous despite antifibrotic treatment. Cluster analysis has proven to be a useful tool in identifying interstitial lung disease phenotypes, which has yet to be performed in IPF. The aim of this study is to identify phenotypes of IPF with different prognoses and requirements. Methods Observational retrospective study including 136 IPF patients receiving antifibrotic treatment between 2012 and 2018. Six patients were excluded due to follow-up in other centres. Cluster analysis of 30 variables was performed using approximate singular value-based tensor decomposition method and comparative statistical analysis. Results The cluster analysis identified three different groups of patients according to disease behaviour and clinical features, including mortality, lung transplant and progression-free survival time after 3-year follow-up. Cluster 1 (n=60) was significantly associated (p=0.02) with higher mortality. Diagnostic delay was the most relevant characteristic of this cluster, as 48% of patients had ≥2 years from first respiratory symptoms to antifibrotic treatment initiation. Cluster 2 (n=22) had the longest progression-free survival time and was correlated to subclinical patients evaluated in the context of incidental findings or familial screening. Cluster 3 (n=48) showed the highest percentage of disease progression without cluster 1 mortality, with metabolic syndrome and cardiovascular comorbidities as the main characteristics. Conclusion This cluster analysis of IPF patients suggests that diagnostic and treatment delay are the most significant factors associated with mortality, while IPF progression was more related to metabolic syndrome and cardiovascular comorbidities., Diagnostic delay and cardiovascular comorbidities impact IPF outcomes https://bit.ly/3lk2Z5y

Organizing Pneumonia (OP) is classified as an Idiopathic Interstitial Pneumonia (IIP).1 Clinically, the patients present dyspnea, cough, and low fever, and usually respond well to corticosteroids, reaching clinical and radiologic resolution in a short timeframe. However, sometimes infiltrates do recur and may not resolve. Radiologically, migratory consolidations are identified in high-resolution computed tomography (HRCT), sometimes associated with progressive fibrosis with reticulation and areas of persistent consolidation.1 The histology reveals “proliferation of fibroblastic tissue within small airways, alveolar ducts, and alveolar spaces”.2 OP can be secondary to other pathologies such as common variable immunodeficiency3 and malignant disease among others.4 At times no etiology is identified and the term Cryptogenic Organizing Pneumonia (COP) is used.1 Furthermore, OP could coexist or mimic a malignant disease.4,5

BACKGROUND AND OBJECTIVE The abnormal shortening of telomeres is a mechanism linking ageing to idiopathic pulmonary fibrosis (IPF) that could be useful in the clinical setting. The objective of this study was to identify the IPF patients with higher risk for telomere shortening and to investigate the outcome implications. METHODS Consecutive Spanish patients were included at diagnosis and followed up for 3 years. DNA blood samples from a Mexican cohort were used to validate the results found in Spanish sporadic IPF. Prior to treatment, telomere length was measured through quantitative polymerase chain reaction (qPCR) and Southern blot. Outcome was assessed according to mortality or need for lung transplantation. A multivariate regression logistic model was used for statistical analysis. RESULTS Family aggregation, age of

Background and objective The relationship between IPF development and environmental factors has not been completely elucidated. Analysing geographic regions of idiopathic pulmonary fibrosis (IPF) cases could help identify those areas with higher aggregation and investigate potential triggers. We hypothesize that cross-analysing location of IPF cases and areas of consistently high air pollution concentration could lead to recognition of environmental risk factors for IPF development. Methods This retrospective study analysed epidemiological and clinical data from 503 patients registered in the Observatory IPF.cat from January 2017 to June 2019. Incident and prevalent IPF cases from the Catalan region of Spain were graphed based on their postal address. We generated maps of the most relevant air pollutant PM2.5 from the last 10 years using data from the CALIOPE air quality forecast system and observational data. Results In 2018, the prevalence of IPF differed across provinces; from 8.1 cases per 100 000 habitants in Barcelona to 2.0 cases per 100 000 in Girona. The ratio of IPF was higher in some areas. Mapping PM2.5 levels illustrated that certain areas with more industry, traffic and shipping maintained markedly higher PM2.5 concentrations. Most of these locations correlated with higher aggregation of IPF cases. Compared with other risk factors, PM2.5 exposure was the most frequent. Conclusion In this retrospective study, prevalence of IPF is higher in areas of elevated PM2.5 concentration. Prospective studies with targeted pollution mapping need to be done in specific geographies to compile a broader profile of environmental factors involved in the development of pulmonary fibrosis.

Introduction: Pulmonary alveolar microlithiasis (PAM) is an infrequent autosomal recessive lung disease, caused by a homozygous mutation in the SLC34A2 gene, which encodes a type IIb sodium-dependent phosphate cotransporter expressed in lungs and small intestine. The altered function of this cotransporter causes the intra-alveolar accumulation of phosphate leading to the formation of microliths. Case report: A 27-year-old Moroccan female was studied because of lumbar pain one year after pregnancy. The lumbar spine x-ray showed interstitial pattern in lung bases. Pulmonary evaluation was then requested with a chest CT scan. She was visited at the ILD-Unit admitting a history of progressive dyspnea on exertion and dry cough for 5 years, and co-sanguinity between her parents (first cousins). The physical examination revealed basal bilateral dry crackles, 98% oxygen saturation at rest and clubbing. Pulmonary function tests showed a mild restrictive pattern with moderate alteration of DLCO, and a desaturation of 6% at the 6MWT when walking 415 meters. Blood analysis showed negative autoimmunity and an increase in parathyroid hormone with a decrease in calcidiol levels and low fractional urinary calcium excretion which improved with vitamin D replacement therapy. Thorax HRCT revealed widespread micro‑calcifications, ground‑glass opacities, interlobular septal thickening and subpleural cysts. Microliths were identified in the BAL sample. Genetic study was performed and the pathogenic variant c.1328delT (p.Leu443Argfs*6) was detected in the SLC34A2 gene. Conclusions: Calcium metabolism disorder is concomitant to PAM in this patient and is not associated to the altered SLC34A2 gene.

The incidence of gastrointestinal adverse events (AEs) associated with pirfenidone varies in IPF patients. We hypothesized that the type of dietary fatty acids (FA) affects digestibility and gastric motility, with a decrease in saturated-SFA or an increase in monounsaturated-MUFA. Objective: To compare the incidence of gastrointestinal AEs in patients with IPF initiating pirfenidone therapy, according to diet; MUFA vs SFA. Methods: 90 patients agreeing to maintain the same diet for 4 months were included. Allocation to SFA or MUFA-diet was determined by the Food Frequency Questionnaire (FFQ) assessed by an independent Central Committee. 7 centres, 4 in northern and 3 in southern Europe, have participated. Patient diet and AEs were recorded over 16 weeks; FVC and DLCO were measured at V1 and V5. Results: Interim results are based on 64 patients (38 MUFA and 26 SFA arm). Most patients were male (70%), mean age 71 (8.08), mean BMI 29 (without differences between groups). Baseline lung functions: FVC 81.5%, DLCO 55.4% for the MUFA group and FVC 75%, DLCO 44% for the SFA group. Except for the Netherlands, SFA diet was prevalent in the northern centres. Gastrointestinal AEs were reported in 31% of the SFA group and 17% of the MUFA group. Full dose of pirfenidone was taken by 73.1% of SFA and 94.7% of MUFA patients. Skin rash-photosensitivity did not differ between groups (1.2% and 1.5%, respectively). Medication withdraw was reported in 2 cases of SFA group. Conclusions: SFAdiet is associated with more gastrointestinal AEs during pirfenidone treatment in patients with IPF compared to MUFAdiet. Diet may be explored for improving medication adherence. Supported by Roche

Introduction: LAM is a rare and lethal disease characterized by progressive cystic lung destruction. Inhibition of mTOR with rapamycin is the current standard of care, which can slow-down disease. Plasma major histamine metabolite (Methylimidazoleacetic acid [MIAA]) is increased in LAM. Loratadine is a histamine receptor antagonist (HR1), which inhibits LAM cell proliferation. Therefore, a novel phase-II clinical trial for assessing safety and potential benefits of loratadine in LAM has been initiated. Methods:LORALAM clinical trial, phase-II, double-blind, randomized, placebo controlled, parallel-group, multicentre study initiates recruitment in July 2020. Enrollment plan includes 62 subjects with LAM on treatment with rapamycin ≥3 months, randomized 1:1 to add oral loratadine 10mg/day or placebo, once daily, for 52 weeks. Recruitment will end in June 2021. The primary endpoints are 1) to assess the safety profile of loratadine associated with rapamycin, 2) lung function decline after 52 weeks of treatment. The secondary endpoints are a) quality of life and progression free-survival time, b) changes in the established LAM serum biomarker VEGFD, c) the utility of MIAA for monitoring disease progression and biological treatment effect. Ethics and Dissemination: The study will be carried out in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and each ethical committee. This clinical trial contemplates the possibility of increasing the number of centers and including patients from patients support groups (LAM foundation, AELAM). Clinicaltrials.gov registered

Telomere dysfunction has been related to post-transplant morbi-mortality.Study aim´s: post-transplant survival and morbidity evaluation in fibrotic ILD with and without telomeropathy Methods: Prospective observational study of fibrotic ILD cases from Bellvitge Hospital that underwent lung transplant(LT) in V.Hebron Hospital. Telomere length was measured from lymphocytes DNA, through quantitative PCR. Whole-exome sequencing for telomere maintenance genes was performed in case of telomere shortening(TS) Results: 20 patients(IPF 40%, FPF 40%, hypersensitivity pneumonitis 5%, CPFE 5%, descamative interstitial pneumonia 5%, CTD-ILD 5%). Twelve(60%) patients had TS and mutations in RTEL1, TERT, DKC1,PARN. A similar pre-LT functional status was reported regardless of TS. LT morbidity: patients with TS had a greater need for extracorporeal circulation, longer ICU admission period and higher number of hospital admissions(p=0.033) with 2.9 times higher risk for readmission[(CI 1.11-7.59)(p=0.029)]; being the only ones with hematological complications during the first month. At long term, no differences in morbidity were found regardless of TS. Survival: 17/20(85%) patients,[10/12(83.3%) with TS and 7/8(87.5%) without]. Quality of life: overall mean FVC post-LT increase of 0.55 liters(p=0.0003)[CI95%: 0.21;0.89]. Oxygen withdrawal in 16/17(94.1%) cases with independence for daily life activities[15/17(88.2%)] and active life[11/17(64.7%)] regardless of TS(p=1.000) Conclusions: Post-LT morbidity differs accoding to elapsed time from LT and genetic susceptibility.However, a positive impact in post-LT survival and quality of life was shown for fibrotic ILD regardless of telomeropathy

To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease (RA-ILD) in whom more conventional therapy has failed.Longitudinal retrospective observational study of a cohort of patients with RA-ILD that started treatment with RTX due to ongoing progressive ILD despite treatment with glucocorticoids and csDMARDs or immunosuppressants (IS). All patients were treated with two or more cycles of RTX and evaluated for at least 12 months. Ongoing therapy with csDMARDs or IS remained unchanged.Thirty-one patients were analyzed. Before initiation of RTX the mean decline (delta) in %pFVC and %pDLCO from the ILD diagnosis (median 21 months) was -16.5% and -19.7%, respectively. After 1 year of treatment, RTX was able to reverse the decline of pulmonary function test (PFTs) parameters: ∆%pFVC +8.06% compared to baseline (95% CI: -10.9 to -5.2; p0.001) and ∆%pDLCO +12.7% (95% CI: -16.3 to -9.1; p0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 26% of cases. Dividing the population into UIP and non-UIP patterns, we observed a significant increase in PFTs parameters in both groups. In the 25 patients (80.6%) that completed 2 years of treatment, the statistically significant amelioration in PFTs parameters observed at one year was maintained: ∆%pFVC +11.2% (95% CI: -15.6 to -6.8; p0.001) and ∆%pDLCO +14.8% (95% CI: -19.3 to -10.3; p0.001). At the end of the follow-up period (median 32 months; IQR 25th-75th 26-64), only 23 of the 31 patients (74.2%) were still undergoing treatment with RTX: in 3 cases (10%) it was stopped due to adverse events, in another 3 (10%) treatment failed ultimately requiring a lung transplant, and 2 patients (6%) died due to progression of the ILD and infectious complications. The frequency of adverse events reached 32% of cases.Based on our results, RTX appears to be effective as rescue therapy in a considerable proportion of patients with progressive RA-ILD unresponsive to conventional treatment.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of IPF. No focussed international guidelines for the management of AE-IPF exist. The aim of this international survey was to assess the global variability in prevention, diagnostic and treatment strategies for AE-IPF.Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel.509 pulmonologists from 66 countries responded. Significant geographical variability in approaches to manage AE-IPF was found. Common preventive measures included antifibrotic drugs and vaccination. Diagnostic differences were most pronounced regarding use of Krebs von den Lungen-6 and viral testing, while high-resolution computed tomography, brain natriuretic peptide and D-dimer are generally applied. High-dose steroids are widely administered (94%); the use of other immunosuppressant and treatment strategies is highly variable. Very few (4%) responders never use immunosuppression. Antifibrotic treatments are initiated during AE-IPF by 67%. Invasive ventilation or extracorporeal membrane oxygenation are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (64%).Approaches to the prevention, diagnosis and treatment of AE-IPF vary worldwide. Global trials and guidelines to improve the prognosis of AE-IPF are needed.

Introduction and Aim: Pirfenidone and nintedanib are anti-fibrotic approved treatments for idiopathic pulmonary fibrosis (IPF). Its efficacy and safety in other fibrotic interstitial lung diseases (ILD) is under study in clinical trials. The aim was to analyse the effect of these drugs in non-IPF progressive fibrotic patients that couldn’t be included in these trials. Methods: Multicenter retrospective study of 34 progressive PF non-IPF patients treated with anti-fibrotic drugs. Demographic, clinical data and treatment-related variables were evaluated. The reason to start off-label anti-fibrotic was disease progression with previous therapy and exclusion from clinical trials. Results: Patients with non-IPF progressive PF were: 38% unclassifiable PF (UPF), 20% familial pulmonary fibrosis (FPF), 18% CTD-ILD, 15% chronic hypersensitivity pneumonitis (CHP) and 9% pneumoconiosis. Mean age was 67±12 years, 74% were male and 47% ex-smokers. 21% of cases had usual interstitial pneumonia HRCT pattern. Mean FVC was 66%±23 and DLCO 45%±12. Co-medications were: low-dose prednisone (20), mycophenolate (5) and sirolimus (1). Twenty-four subjects (71%) received pirfenidone and ten (29%) nintedanib. After one year, a FVC decrease of 5-10% was observed in only 3 patients (1 CHP, 1 pneumoconiosis, 1 UPF), while others showed stability or improvement. Main reported adverse effects were: 20% hypertransaminasemia, 27% diarrhea and 15% weight loss, requiring 5 patients to stop therapy. Conclusion: After one year of anti-fibrotic therapy, most patients with non-IPF progressive PF showed functional stability. Clinical trials are mandatory to evaluate their potential efficacy, but these drugs are a safe option in progressive PF patients.

Background: Transbronchial lung cryobiopsy (TBLC) has been established as a common and safe procedure in the diagnosis of diffuse interstitial lung diseases (ILD). The patient can be discharged after a few hours under observation, except if a complication is presented, mainly bleeding or pneumothorax (PTX). Chest X-ray (CXR) is the conventional examination performed to detect PTX, but sometimes the delay in carrying it out may lengthen the patient’s hospital stay. Chest ultrasound (US) is more sensitive in the detection of PTX. Objective: to assess if chest US could replace CXR to detect PTX. Methods: prospective study in patients with indication of TBLC for the study of ILD from April 2018 to February 2019. Chest US was performed 1 hour after the procedure in the recovery area and a CXR was performed 4 hours after the procedure in the Radiology department, except if the patient had symptoms or if the US showed PTX, performing CXR earlier. Results: 32 patients were included,57.3% males.94% of the biopsies were performed in lower lobes.24 patients did not present PTX on US and this was confirmed with CXR, except in one patient who presented late PTX on the CXR.4 patients presented PTX on US and it was also confirmed with CXR. US detected 1 PTX that was not visible in CXR. In 3 cases there were doubts in the US image due to a bad window, of which 1 had PTX and another 2 did not. About the patients who presented PTX (22%), only two (6.2%) required a chest tube. The rest were discharged after 24-72 hours of observation. Conclusions: Chest US can replace conventional CXR in a large number of patients, allowing early discharge, although the possibility of late PTX (3.1%) must be taken into account.

Background: AE-IPF is a deadly complication of IPF, for which no international guidelines exist, resulting in global variability in prevention, diagnosis and treatment strategies. Methods: Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel. Results: 469 pulmonologists responded (66 countries, 64% experts). Significant geographical variability in approach to managing AE-IPF was found (figure). Common preventive measures include antifibrotics and antacids. Diagnostic differences are most pronounced regarding use of KL-6 and viral testing, while HRCT, BNP and d-dimer are broadly used. High dose steroids are widely administered (92%), but use of immunosuppressant and other strategies is highly variable (fig). Very few (4%) responders never use immunosuppression. Antifibrotics are initiated during AE-IPF by 66%. Invasive ventilation or ECMO are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (63%). Conclusion: International approaches to the prevention, diagnosis and treatment of AE-IPF are diverse. Global international guidelines and trials to evaluate these approaches are needed.

Background: Previous reports showed an imbalance of the soluble receptor for advanced glycation end-products (sRAGE), an immunoglobulin implicated in the maintenance of alveolar structures, with its ligand (AGE), in lung samples from idiopathic pulmonary fibrosis (IPF). The finding of a non-invasive serum biomarker would help in the early diagnosis and prognosis of IPF and would distinguish it from other fibrotic interstitial lung diseases, such as fibrotic nonspecific interstitial pneumonia (fNSIP) or chronic hypersensitivity pneumonitis (cHP). Aims: We analysed the role of AGE and RAGE levels and the ratio of both molecules in serum samples as possible biomarkers that distinguish different fibrotic interstitial lung entities. Method: Serum samples were collected from 48 IPF patients, 15 cHP, 15 fNSIP, and 12 healthy age matched controls. Patient characteristics (age, sex, smoke habits, and pulmonary functional test (PFT)) were recorded. AGEs and sRAGE level were assessed by ELISA following the manufacture’s recommendation. Patient’s data and serum determinations were analysed with SPSS statistic software. Results: Our study demonstrated a decrease in sRAGE together with an increment of AGEs levels in serum in IPF and cHP samples compared with control and fNSIP, which did not show significant differences between them. AGEs levels resulted negative correlated with sRAGE in IPF samples. Moreover, low levels of sRAGE correlates with worse PFT (FVC and DLCO). Conclusions: This findings demonstrate that the imbalance in AGE/sRAGE levels in serum samples could differentiate IPF and cHP from NSIP. Furthermore, the correlation between sRAGE measurements and patient’s PFT could reflect the severity of the disease.

Background: Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. Methods: Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor beta 1 (TGF-beta). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I (COM Al], collagen III [COL3A1] and alpha-smooth muscle actin [alpha-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF-beta-containing media was performed. Results: Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF-beta. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. Conclusions: These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach., This study was supported by Proyectos de Investigacion en Salud del Instituto de Salud Carlos III (FIS PI 15/00710), Hoffmann-La Roche.

Background and objective Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease of unknown etiology. The diagnosis is based on the identification of a pattern of usual interstitial pneumonia either by high resolution computed tomography and/or histology. However, a similar pattern can be observed in other fibrotic lung disorders, and precise diagnosis remains challenging. Studies on biomarkers contributing to the differential diagnosis are scanty, and still in an exploratory phase. Our aim was to evaluate matrix metalloproteinase (MMP)-28, which has been implicated in abnormal wound healing, as a biomarker for distinguishing IPF from fibrotic non-IPF patients. Methods The cell localization of MMP28 in lungs was examined by immunohistochemistry and its serum concentration was measured by ELISA in two different populations. The derivation cohort included 82 IPF and 69 fibrotic non-IPF patients. The validation cohort involved 42 IPF and 41 fibrotic non-IPF patients. Results MMP28 was detected mainly in IPF lungs and localized in epithelial cells. In both cohorts, serum concentrations of MMP28 were significantly higher in IPF versus non-IPF (mostly with lung fibrosis associated to autoimmune diseases and chronic hypersensitivity pneumonitis) and healthy controls (ANOVA, p

Background The soluble receptor for advanced glycation end-products (sRAGE) has been suggested that it acts as a decoy for capturing advanced glycation end-products (AGEs) and inhibits the activation of the oxidative stress and apoptotic pathways. Lung AGEs/sRAGE is increased in idiopathic pulmonary fibrosis (IPF). The objective of the study was to evaluate the AGEs and sRAGE levels in serum as a potential biomarker in IPF. Methods Serum samples were collected from adult patients: 62 IPF, 22 chronic hypersensitivity pneumonitis (cHP), 20 fibrotic non-specific interstitial pneumonia (fNSIP); and 12 healthy controls. In addition, 23 IPF patients were re-evaluated after 3-year follow-up period. Epidemiological and clinical features were recorded: age, sex, smoking habits, and lung function. AGEs and sRAGE were evaluated by ELISA, and the results were correlated with pulmonary functional test values. Results IPF and cHP groups presented a significant increase of AGE/sRAGE serum concentration compared with fNSIP patients. Moreover, an inverse correlation between AGEs and sRAGE levels were found in IPF, and serum sRAGE at diagnosis correlated with FVC and DLCO values. Additionally, changes in serum AGEs and sRAGE correlated with % change of FVC, DLCO and TLC during the follow-up. sRAGE levels below 428.25 pg/ml evolved poor survival rates. Conclusions These findings demonstrate that the increase of AGE/sRAGE ratio is higher in IPF, although the levels were close to cHP. AGE/sRAGE increase correlates with respiratory functional progression. Furthermore, the concentration of sRAGE in blood stream at diagnosis and follow-up could be considered as a potential prognostic biomarker. Electronic supplementary material The online version of this article (10.1186/s12931-018-0924-7) contains supplementary material, which is available to authorized users.

The abnormal shortening of telomeres is a mechanism linking ageing to idiopathic pulmonary fibrosis (IPF) that could be useful in the clinical setting. The objective of this study was to identify the IPF patients with higher risk for telomere shortening and to investigate the outcome implications.Consecutive Spanish patients were included at diagnosis and followed up for 3 years. DNA blood samples from a Mexican cohort were used to validate the results found in Spanish sporadic IPF. Prior to treatment, telomere length was measured through quantitative polymerase chain reaction (qPCR) and Southern blot. Outcome was assessed according to mortality or need for lung transplantation. A multivariate regression logistic model was used for statistical analysis.Family aggregation, age of60 years and the presence of non-specific immunological or haematological abnormalities were associated with a higher probability of telomere shortening. Overall, 66.6% of patients younger than 60 years with telomere shortening died or required lung transplantation, independent of functional impairment at diagnosis. By contrast, in patients older than 60 years with telomere shortening, the negative impact of telomere shortening in outcome was not significant.Our data indicate that young sporadic IPF patients (60 years) with some non-specific immunological or haematological abnormalities had higher risk of telomere shortening, and furthermore, they presented a poorer prognosis.

Introduction: The expert multidisciplinary (MDT) approach is crucial for the accurate diagnosis of interstitial lung diseases (ILD), however the presence of this MDT is not always possible in centers with ILD management. Objectives: To evaluate the relevance of each disciplinary approach (clinical, biochemical, radiological, histological) included in the MDT assessment of ILD patients. Methods: Prospective observational study of all first visits evaluated in the ILD Unit during 2014. The assessment was determined by; A-1) detailed history, complete autoimmunity and precipitin, genetic study to family suspected, A-2) identifying radiological pattern of chest tomography (HRCT) by two independent radiologists, A-3) Pathology, A-4): MDT committee discussion (cases in which A1+/- A2 or A3 did not reach the diagnosis). Results: From the included 158 cases (89 men, mean age 64.4 years), 77 patients were referred from primary care centers and local hospitals. The median time from the visit request to the diagnosis was 4.97 months (IQR 7.8). 91 had an initial diagnosis, which was modified in 18 cases: 3 by A-1, 1 by A-3, 5 by A-4, 9 by A-1+A-2. The final diagnosis was obtained in 149 cases. From the 9 patients with no diagnosis: 6 had advanced age and/or comorbidities, and 3 by low diagnostic yield of lung biopsy (incipient disease). A-4 was made in 23 cases (14.6%). 48 samples of lung pathology were analyzed (31 surgical biopsy and 17 cryobiopsy). Conclusions: The MDT committee discussion is mandatory in almost one third of cases for the final diagnosis. An exhaustive clinical and serological study together with an expert radiological evaluation is the most effective requirement to manage ILD patients.

There is growing interest in the development of cell culture assays that enable the rigidity of the extracellular matrix to be increased. A promising approach is based on three-dimensional collagen type I matrices that are stiffened by cross-linking through non-enzymatic glycation with reducing sugars.The present study evaluated the biomechanical changes in the non-enzymatically glycated type I collagen matrices, including collagen organization, the advanced glycation end products formation and stiffness achievement. Gels were glycated with ribose at different concentrations (0, 5, 15, 30 and 240 mM). The viability and the phenotypic changes of primary human lung fibroblasts cultured within the non-enzymatically glycated gels were also evaluated along three consecutive weeks. Statistical tests used for data analyze were Mann-Whitney U, Kruskal Wallis, Student's t-test, two-way ANOVA, multivariate ANOVA, linear regression test and mixed linear model.Our findings indicated that the process of collagen glycation increases the stiffness of the matrices and generates advanced glycation end products in a ribose concentration-dependent manner. Furthermore, we identified optimal ribose concentrations and media conditions for cell viability and growth within the glycated matrices. The microenvironment of this collagen based three-dimensional culture induces α-smooth muscle actin and tenascin-C fibroblast protein expression. Finally, a progressive contractile phenotype cell differentiation was associated with the contraction of these gels.The use of non-enzymatic glycation with a low ribose concentration may provide a suitable model with a mechanic and oxidative modified environment with cells embedded in it, which allowed cell proliferation and induced fibroblast phenotypic changes. Such culture model could be appropriate for investigations of the behavior and phenotypic changes in cells that occur during lung fibrosis as well as for testing different antifibrotic therapies in vitro.