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Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociacion Latinoamericana de Torax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results: 1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumoniawith impaired survival. Previous guidelines recommend antacidmedication to improve respiratory outcomes in patientswith IPF. Objectives: This systematic review was undertaken during the development of an American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociacion Latinoamericana del Torax guideline. The clinical question was, "Should patients with IPF who have documented abnormal gastroesophageal reflux (GER) with or without symptoms of GER disease 1) be treated with antacidmedication or 2) undergo antireflux surgery to improve respiratory outcomes?"Methods: Medline, Embase, the Cochrane Central Register of Controlled Trials, and the gray literature were searched through June 30, 2020. Studies that enrolled patients with IPF and 1) compared antacid medication to placebo or no medication or 2) compared antireflux surgery to no surgery were selected. Metaanalyses were performed when possible. Outcomes included disease progression, mortality, exacerbations, hospitalizations, lung function, respiratory symptoms, GER severity, and adverse effects/complications. Results: For antacidmedication,when two studieswere aggregated, therewas no statistically significant effect on disease progression, defined as a 10% ormore decline in FVC,more than 50-mdecline in 6-minute walking distance, or death (risk ratio [RR], 0.88; 95% confidence interval [CI], 0.76-1.03).Aseparate study that could not be included in themetaanalysis found no statistically significant effect on disease progression when defined as a 5% ormore decline in FVC or death (RR, 1.10; 95% CI, 1.00-1.21) and an increase in disease progressionwhen defined as a 10% ormore decline in FVC or death (RR, 1.28; 95% CI, 1.08-1.51). For antireflux surgery, therewas also no statistically significant effect on disease progression (RR, 0.29; 95% CI, 0.06-1.26).Neither antacid medications nor antireflux surgerywas associated with improvements in the other outcomes. Conclusions: There is insufficient evidence to conclude that antacid medication or antireflux surgery improves respiratory outcomes in patientswith IPF,most ofwhomhad not had abnormalGER confirmed. Well-designed and adequately powered prospective studieswith objective evaluation forGER are critical to elucidate the role of antacidmedication and antireflux surgery for respiratory outcomes in patientswith IPF.

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.

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a “pre-test” probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into “high” (70–100%), “intermediate” (30–70%), or “low” (0–30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into “definite” (90–100%), “high confidence” (70–89%), “low confidence” (51–69%), or “low” (0–50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF (“pre-test probability of IPF”) with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a “post-test probability of IPF.” The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

The diagnosis of idiopathic pulmonary fibrosis (IPF) is a complex process that requires the multidisciplinary integration of clinical, radiological, and histological variables. Due to its diagnostic yield, surgical lung biopsy has been the recommended procedure for obtaining samples of lung parenchyma, when required. However, given the morbidity and mortality of this technique, alternative techniques which carry a lower risk have been explored. The most important of these is transbronchial cryobiopsy -transbronchial biopsy with a cryoprobe- which is useful for obtaining lung tissue with less comorbidity. Yield may be lower than surgical biopsy, but it is higher than with transbronchial biopsy with standard forceps. This option has been discussed in the recent clinical guidelines for the diagnosis of IPF, but the authors do not go so far as recommend it. The aim of this article, the result of a multidisciplinary discussion forum, is to review current evidence and make proposals for the use of transbronchial cryobiopsy in the diagnosis of IPF.

Background and Objective: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry. Methods: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021. Results: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22–1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either

Background In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib. Methods Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial. Results A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients. Conclusions The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 Graphical Abstract A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication associated with a high mortality. However, evidence and guidance on management is sparse. The aim of this international survey was to assess differences in prevention, diagnostic and treatment strategies for AE-IPF in specialised and non-specialised ILD centres worldwide.Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians' institutions.Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods.Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF.

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 - 2018. Six patients were excluded due to follow-up in other centers. Cluster analysis of 30 variables was performed using approximate singular value-based tensor decomposition method and comparative statistical analysis. Results: The cluster analysis identified 3 different groups of patients according to disease behavior 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.

Background Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF. Methods All patients randomized to placebo (n = 624) in the CAPACITY and ASCEND studies were categorized by antihypertensive treatment at baseline. Outcomes of disease progression (first occurrence of ≥ 10% absolute decline in % predicted FVC, ≥ 50-m decline in 6-min walk distance, or death) and all-cause mortality were assessed over 52 weeks. Results At baseline, 111 and 121 patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), respectively; 392 were receiving neither. In multivariable analyses adjusted for differences in baseline characteristics compared with the non-ACEi/ARB group, ACEi treatment (hazard ratio [HR], 0.6 [95% CI, 0.4-0.9]; P = .026), but not ARB (HR, 0.9 [95% CI, 0.6-1.2]; P = .413), was associated with slower disease progression. Furthermore, the increase in all-cause mortality associated with cardiovascular disease was not observed in the ACEi group (HR, 1.1 [95% CI, 0.5-2.9]; P = .782), which presented a similar percentage of IPF-related mortality as the non-ACEi/ARB group (3.6% vs 3.6%). In contrast, patients in the ARB group had greater risk of all-cause mortality (HR, 2.5 [95% CI, 1.2-5.2]). These observations were validated in a pooled analysis that included patients from the INSPIRE trial. Conclusions Prospective clinical trials are needed to evaluate whether angiotensin modulators may be beneficial to clinical outcomes in IPF. Trial Registry ClinicalTrials.gov ; Nos.: NCT01366209 , NCT00287716 , NCT00287729 , NCT00075998 ; URL: www.clinicaltrials.gov ).

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

Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth.

© 2021 Merino et al., [Background]: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options in which the telomere shortening is a strong predictive factor of poor prognosis. Mesenchymal stromal cells (MSC) administration is probed in several experimental induced lung pathologies; however, MSC might stimulate fibrotic processes. A therapy that avoids MSC side effects of transformation would be an alternative to the use of living cells. Membranes particles (MP) are nanovesicles artificially generated from the membranes of MSC containing active enzymes involved in ECM regeneration. We aimed to investigate the anti-fibrotic role of MP derived from MSC in an in vitro model of pulmonary fibrosis. [Methods]: Epithelial cells (A549) and lung fibroblasts, from IPF patients with different telomere length, were co-cultured with MP and TGF-β for 48h and gene expression of major pro-fibrotic markers were analyzed. [Results]: About 90% of both types of cells effectively took up MP without cytotoxic effects. MP decreased the expression of profibrotic proteins such as Col1A1, Fibronectin and PAI-1, in A549 cells. In fibroblasts culture, there was a different response in the inhibitory effect of MP on some pro-fibrotic markers when comparing fibroblast from normal telomere length patients (FN) versus short telomere length (FS), but both types showed an inhibition of Col1A1, Tenascin-c, PAI-1 and MMP-1 gene expression after MP treatment. [Conclusions]: MP conserve some of the properties attributed to the living MSC. This study shows that MP target lung cells, via which they may have a broad anti-fibrotic effect., This collaboration project is co-funded by the PPP Allowance made available by Health Holland, Top Sector Life Sciences & Health, of the Dutch Ministry of Economic affairs to stimulate public-private partnerships, and by the Institute of Health Carlos III (ISCIII, PI18/00367), co-funded by FEDER funds/European Regional Development Fund (ERDF) – “a Way to Build Europe” and Biomedical National Research Network CIBER.

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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.

BackgroundNon-invasive biomarkers for the assessment of disease severity in idiopathic pulmonary fibrosis (IPF) are urgently needed. Calprotectin belongs to the S-100 proteins produced by neutrophils, which likely contribute to IPF pathogenesis. Calprotectin is a well-established biomarker in inflammatory bowel diseases. In this cross-sectional study, we aimed to establish the potential role of calprotectin as a biomarker in IPF. Specifically, we hypothesised that patients with IPF have higher serum calprotectin levels compared with healthy controls, and that calprotectin levels are associated with disease severity.MethodsBlood samples were obtained from healthy volunteers (n=26) and from two independent IPF cohorts (derivation cohort n=26, validation cohort n=66). Serum calprotectin levels were measured with a commercial kit adapted for that purpose and compared between healthy controls and patients with IPF. Clinical parameters, including forced vital capacity, diffusing capacity for carbon monoxide (DLCO) and the Composite Physiologic Index (CPI), were correlated with calprotectin serum levels.ResultsThe IPF derivation cohort showed increased serum calprotectin levels compared with healthy controls (2.47±1.67 vs 0.97±0.53 µg/mL, pConclusionSerum calprotectin levels are significantly increased in patients with IPF compared with healthy controls and correlate with DLCO and CPI. Calprotectin might be a potential new biomarker for disease severity in IPF.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Background Currently there is major lack of agreement on the diagnostic and therapeutic management of patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. Our aim was to identify variations in diagnostic and management strategies across different institutions and provide rationale for a consensus statement on this issue. Methods This was a joint-survey by European Respiratory Society (ERS) Assemblies 8, 11 and 12. The survey consisted of 25 questions. Results Four hundred and ninety-four (n=494) physicians from 68 different countries and five continents responded to the survey. Ninety-four per cent of participants were pulmonologists, 1.8% thoracic surgeons and 1.9% oncologists; 97.7% were involved in multidisciplinary team approaches on diagnosis and management. Regular low-dose high-resolution computed tomography (HRCT) scan was used by 49.5% of the respondents to screen for lung cancer in IPF. Positron emission tomography (PET) scan and endobronchial ultrasound (EBUS) is performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. Eighty-three per cent of respondents continue anti-fibrotics following lung cancer diagnosis; safety precautions during surgical interventions including low tidal volume are applied by 67%. Stereotactic radiotherapy is used to treat patients with advanced IPF (diffusing capacity of the lung for carbon monoxide (DLCO), The diagnosis and management of IPF-LC is heterogeneous with most survey respondents calling for a consensus statement https://bit.ly/2Smie0o

© 2021 The Authors., Idiopathic pulmonary fibrosis is a lethal lung fibrotic disease, associated with aging with a mean survival of 2-5 years and no curative treatment. The GSE4 peptide is able to rescue cells from senescence, DNA and oxidative damage, inflammation, and induces telomerase activity. Here, we investigated the protective effect of GSE4 expression in vitro in rat alveolar epithelial cells (AECs), and in vivo in a bleomycin model of lung fibrosis. Bleomycin-injured rat AECs, expressing GSE4 or treated with GSE4-PLGA/PEI nanoparticles showed an increase of telomerase activity, decreased DNA damage, and decreased expression of IL6 and cleaved-caspase 3. In addition, these cells showed an inhibition in expression of fibrotic markers induced by TGF-β such as collagen-I and III among others. Furthermore, treatment with GSE4-PLGA/PEI nanoparticles in a rat model of bleomycin-induced fibrosis, increased telomerase activity and decreased DNA damage in proSP-C cells. Both in preventive and therapeutic protocols GSE4-PLGA/PEI nanoparticles prevented and attenuated lung damage monitored by SPECT-CT and inhibited collagen deposition. Lungs of rats treated with bleomycin and GSE4-PLGA/PEI nanoparticles showed reduced expression of α-SMA and pro-inflammatory cytokines, increased number of pro-SPC-multicellular structures and increased DNA synthesis in proSP-C cells, indicating therapeutic efficacy of GSE4-nanoparticles in experimental lung fibrosis and a possible curative treatment for lung fibrotic patients., R.P laboratory was funded by grants P17-01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds), CIBER 576/805_ER16PE06P2016 and MINECO from the Spanish Government (INNPACTO, IPT-2012-0674-090000). M.M-M. laboratory was funded by Instituto de Salud Carlos III PI18/00367, supported by FEDER (Fondos Europeos de Desarrollo Regional (a way to build Europe)), JC received funds from MINECO CICYT SAF2014-55322-P, and GG laboratory was funded by grant SAF2015-68073-R (MINECO/FEDER) supported by FEDER funds. C.MG and R G-L are granted by the CIBERER.

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis., info:eu-repo/semantics/published

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: Mesenchymal stem cells (MSCs) are multipotent cells with an impressive potential for regeneration and immunomodulation. The niche of resident MSCs in the lung is believed to play an important role in pulmonary disease; however, most of the studies are focused on MSC from other origin as bone marrow. Here, we performed a comprehensive study of the characteristics of lung MSCs in both donor and in idiopathic pulmonary fibrosis (IPF) patients. Results and methods: MSCs were isolated from donor and IPF human lung tissue and mesenchymality was confirmed by flow cytometry (Stemflow hMSC Analysis) and Rohart MSC in silico test. The differentiation capacity was assessed using the Human MSC Functional Identification kit and both conditions were able to differentiate into osteoblasts and adipocytes after 21 days, although less potential was observed in IPF lung MSCs for the last one. Moreover, functional analyses were performed for migration and proliferation by real-time monitoring cell assay. Notably, profibrotic stimulation by TGF-s induced a significant change by increasing migration and decreasing proliferation in the IPF-lung MSCs when compared to donor. Furthermore, the regenerative ability to close an epithelial wound was significantly reduced in lung MSCs from IPF patients as tested by scratch assay in indirect and direct co-culture. Conclusions: Lung MSCs were successfully isolated from both donor and IPF and could differentiate into other cell types. However, IPF lung MSCs displayed a decreased proliferation and an increased migration profile in response to fibrotic stimulus possibly due to an increased sensibility to profibrotic factors. Moreover, IPF lung MSCs had reduced regenerative potential which might be involved in the impaired repair in IPF pathogenesis.

The diagnostic process of idiopathic interstitial pneumonias (IIPs) is complex and the underlying mechanisms that participate in these diseases still need to be fully understood. In 2015, the European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-Associated Interstitial Lung Disease introduced the term “interstitial pneumonia with autoimmune features” (IPAF) to identify subjects with IIP and features suggesting background autoimmunity but not characterisable connective tissue disease (CTD) [1]. The need for a proper clinical, serological and morphological assessment of IIP was highlighted to identify potential subjects with IPAF and CTD-ILD. However, the measurement of anti-neutrophil cytoplasmic antibodies (ANCAs) is not included in the definition of IPAF and ANCA serological testing is only recommended in idiopathic pulmonary fibrosis (IPF) when a clinical suspicion of vasculitis exists [2]. As current research evaluates the prognostic relevance of autoimmune features in IIP, the clinical importance of ANCA positivity still needs to be determined., ANCA positivity is uncommon in North American IPF patients. However, women with IPF who areMPO-positive have a considerable risk for developing clinical manifestations of vasculitis. http://bit.ly/2RlsQNP

Publisher's version (útgefin grein), Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P, R.J.A. is an Action for Pulmonary Fibrosis Research Fellow. L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. R.G.J. is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). I.N. is supported by the NHLBI (R01HL130796). B.G.-G. is funded by Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) cofunded by European Social Fund. J.M.O. is supported by the NHLBI (K23HL138190). C.F. is supported by the Spanish Ministry of Science, Innovation and Universities (grant RTC-2017-6471-1; Ministerio de Ciencia e Innovacion/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea) cofinanced by the European Regional Development Funds “A way of making Europe” from the European Union and by agreement OA17/008 with Instituto Tecnológico y de Energías Renovables to strengthen scientific and technological education, training, research, development and innovation in Genomics, Personalized Medicine and Biotechnology. The Spain Biobank array genotyping service was performed at CEGEN-PRB3-ISCIII, which is supported by PT17/0019, of the PE I+D+i 2013–2016, funded by Instituto de Salud Carlos III, and cofinanced by the European Regional Development Funds. P.L.M. is an Action for Pulmonary Fibrosis Research Fellow. M.O. is a fellow of the Parker B. Francis Foundation and a Scholar of the Michael Smith Foundation for Health Research. B.D.H. is supported by NIH K08 HL136928, Parker B. Francis Research Opportunity Award. M.H.C. and G.M.H. are supported by NHLBI grants R01HL113264 (M.H.C.), R01HL137927 (M.H.C.), R01HL135142 (M.H.C. and G.M.H.), R01111024 (G.M.H.), and R01130974 (G.M.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. T.M.M. is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017) and a British Lung Foundation Chair in Respiratory Research (C17-3). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health. I.P.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. I.S. is supported by Medical Research Council (G1000861) and Asthma UK (AUK-PG-2013-188). D.F. was supported by an Intermediate Fellowship from the Wellcome Trust (097152/Z/11/Z). This work was partially supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. V.N. is funded by an NIHR Clinical Lectureship. G.G. is supported by project grant 141513-051 from the Icelandic Research Fund and Landspitali Scientific Fund A-2016-023, A-2017-029, and A-2018-025. D.J.L. and A.M. are supported by Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, Massachusetts) using the Affymetrix Genome-Wide Human SNP Array 6.0. This work was supported by NIH grants R01 HL131565 (A.M.), R01 HL103676 (D.J.L.), and R01 HL137234 (D.J.L.).

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

Idiopathic pulmonary fibrosis is defined as chronic fibrosing interstitial pneumonia limited to the lung, with poor prognosis. The incidence has been rising in recent years probably due to improved diagnostic methods and increased life expectancy. In 2013, the SEPAR guidelines for the diagnosis and treatment for idiopathic pulmonary fibrosis were published. Since then, clinical trials and meta-analyses have shown strong scientific evidence for the use of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis. In 2015, the international consensus of 2011 was updated and new therapeutic recommendations were established, prompting us to update our recommendation for the medical treatment of idiopathic pulmonary fibrosis accordingly. Diagnostic aspects and non-pharmacological treatment will not be discussed as no relevant developments have emerged since the 2013 guidelines.

Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and/or histological pattern of usual interstitial pneumonia. Its aetiology is unknown, but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition. Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other aetiologies. Its clinical evolution is variable, although the mean survival rate is 2-5 years as of its clinical presentation. Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease's clinical course and prognosis. In the mild-moderate disease, the treatment consists of the administration of anti-fibrotic drugs. In severe disease, the best therapeutic option is pulmonary transplantation. In this paper we review the diagnostic and therapeutic aspects of the disease.

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.

EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown. Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB. Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues. Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04). Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood>70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by progressive lung interstitial fibrosis of unknown cause [1]. IPF incidence increases with older age and clinical manifestations include dry cough, exertional dyspnoea and overall progressive deterioration of patient quality of life (QOL) [1]. In the past decade, new treatment options have become available to treat IPF, such as nintedanib, an intracellular tyrosine kinase inhibitor. The INPULSIS trials evaluated the efficacy and safety of nintedanib versus placebo in 1066 IPF patients with a diffusing capacity of the lung for carbon monoxide (DLCO) of 30–79% of the predicted value [2]. These trials showed that treatment with nintedanib slowed the rate of forced vital capacity (FVC) decline but no significant difference was observed in the St George's Respiratory Questionnaire (SGRQ) score [2]., The addition of sildenafil to nintedanib treatment does not improve outcomes to a greater extent than monotherapy with nintedanib, and it is not recommended for IPF subjects http://ow.ly/Gaq530o9kEg

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.ObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.Methods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Main resultsWe identified and replicated three new genome-wide significant (P-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.ConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

International audience; Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, fatal, fibrosing lung disease. Pirfenidone and nintedanib are oral antifibrotics with demonstrated efficacy in reducing lung function decline in individuals with IPF, independent of baseline lung function. Intervention with an antifibrotic as early as possible in the disease course might be the most appropriate strategy to preserve lung capacity. However, many physicians are reluctant to initiate antifibrotics at diagnosis, and delay treatment until disease progression is observed. Furthermore, certain countries do not reimburse antifibrotic treatment for individuals with preserved lung function (% predicted forced vital capacity [FVC] > 80%). These post hoc analyses aimed to assess: 1) FVC decline during long-term pirfenidone treatment in RECAP in individuals with IPF categorized by baseline % predicted FVC; and 2) the impact of deferring pirfenidone treatment on annual FVC decline in individuals with IPF during CAPACITY and RECAP.

The therapeutic approach in idiopathic pulmonary fibrosis has changed substantially over the past 5 years. National and international guidelines for the pharmacological treatment of IPF recommend 2antifibrotic drugs, nintedanib and pirfenidone. The use of both these drugs is supported by high-level evidence, with benefits including not only slower disease progression but also a reduction in the annual risk of death. Currently, the therapeutic management of these patients prioritizes both the use of drugs that act on the pathogenic mechanisms of the disease, and the positive effect of improving quality of life with integrated multidisciplinary support, including nutrition, physical activity, education, emotional support, and palliation of symptoms. The overall aim is to ensure that the patient remains as well as possible for as long as possible after diagnosis. However, the goal of the new antifibrotic combinations that are currently under evaluation in clinical trials is to use the potential antifibrotic synergy to enhance the therapeutic benefit or completely halt disease progression, by acting simultaneously on different pathogenic pathways. Another line of investigation involves markers that might be useful for identifying patients who may benefit more from certain antifibrotics than from others, which would make it possible to optimize resources and take the first steps toward precision medicine in pulmonary fibrosis. Below, we review the main potential areas for improvement in the pharmacological treatment of idiopathic pulmonary fibrosis in the short, medium, and long term.

More than 100 different conditions are grouped under the term interstitial lung disease (ILD). A diagnosis of an ILD primarily relies on a combination of clinical, radiological, and pathological criteria, which should be evaluated by a multidisciplinary team of specialists. Multiple factors, such as environmental and occupational exposures, infections, drugs, radiation, and genetic predisposition have been implicated in the pathogenesis of these conditions. Asbestosis and other pneumoconiosis, hypersensitivity pneumonitis (HP), chronic beryllium disease, and smoking-related ILD are specifically linked to inhalational exposure of environmental agents. The recent Global Burden of Disease Study reported that ILD rank 40th in relation to global years of life lost in 2013, which represents an increase of 86% compared to 1990. Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrotic ILD. A recent study from the United States reported that the incidence and prevalence of IPF are 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively. These data suggests that, in large populated areas such as Brazil, Russia, India, and China (the BRIC region), there may be approximately 2 million people living with IPF. However, studies from South America found much lower rates (0.4-1.2 cases per 100,000 per year). Limited access to high-resolution computed tomography and spirometry or to multidisciplinary teams for accurate diagnosis and optimal treatment are common challenges to the management of ILD in developing countries.

Telomere related gene (TRG) mutations are found in approximately 20% of patients with familial pulmonary fibrosis and are associated with hepatic, cutaneous and hematologic manifestations. Pirfenidone and nintedanib have been shown to slow the decline of FVC of patients with idiopathic pulmonary fibrosis (IPF). There is limited evidence of efficacy and safety of these treatments in IPF patients carrying a TRG mutation. The objective of this retrospective multicenter study was to analyze the efficacy and safety of antifibrotic drugs in IPF patients carrying a TRG mutation. We identified 103 IPF patients carrying a mutation in TERT (n=74), TERC (n=17), RTEL1 (n=10) or PARN (n=3). from 6 countries (France, Netherlands, Belgium, Spain, Greece and Switzerland) Forty-four patients received nintedanib, 59 received pirfenidone. The mean age at diagnosis was 57.9 ± 13.6 years and the median delay between diagnosis and treatment initiation was 6.0 months [3.0-15.1]. At initiation of treatment, the FVC was 80.8% ± 20.2% and the DLCO was 44.0% ± 13.7%. The median duration of treatment was 10.8 months [6.5-18.1]. Antifibrotic treatment was terminated in 18 patients because of progression of the disease and in 15 patients due to intolerable side effects, mainly digestive (nintedanib, n = 9, pirfenidone, n = 6). The median decline in FVC prior to initiation of treatment was 24.5 mL [10.5-30.1] per month. After initiation of treatment, the median decline in FVC was 18.0 mL [9.0-27.0] per month in patients treated with nintedanib and 25.4 mL per month [14.7-36.7] in patients treated with pirfenidone. This retrospective series shows that antifibrotic therapies are well tolerated in IPF patients with TRG mutations. Further analyses are needed to evaluate the efficacy.

Introduction Pulmonary fibrosis (PF) and its most common form, idiopathic pulmonary fibrosis (IPF), are chronic, progressive diseases resulting in increasing loss of lung function and impaired quality of life and survival. The aim of this joint expert and patient statement was to highlight the most pressing common unmet needs of patients with PF/IPF, putting forward recommendations to improve the quality of life and health outcomes throughout the patient journey. Methods Two online surveys for patients and healthcare professionals (HCPs) were conducted by the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation (EU-IPFF) in 14 European countries. Results The surveys were answered by 286 patients and 69 HCPs, including physicians and nurses. Delays in diagnosis and timely access to interstitial lung disease specialists and pharmacological treatment have been identified as important gaps in care. Additionally, patients and HCPs reported that a greater focus on symptom-centred management, adequate information, trial information and increasing awareness of PF/IPF is required. Conclusions The surveys offer important insights into the current unmet needs of PF/IPF patients. Interventions at different points of the care pathway are needed to improve patient experience., This joint expert and patient statement highlights the most pressing common unmet needs of patients with pulmonary fibrosis, and puts forward recommendations to improve the quality of life and health outcomes throughout the patient journey http://bit.ly/34cTOeo

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.

IntroductionDespite extensive multidisciplinary team (MDT) assessment, some patients have interstitial lung disease (ILD) that is considered unclassifiable (uILD), for which there are currently no approved treatments. This study will assess the efficacy and safety of the antifibrotic pirfenidone in treating uILD.Methods and analysisThis double-blind, randomised, placebo-controlled phase II trial is enrolling adults with fibrosing ILD, including uILD that fulfils proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), that cannot be classified with moderate or high confidence to any category of ILD following MDT discussion. Study participants must have >10% fibrosis on high-resolution CT scan within the previous 12 months, forced vital capacity (FVC) ≥45% and diffusing capacity of the lung for carbon monoxide ≥30% of predicted values. Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone vs placebo will be assessed by daily measurement of FVC using a handheld spirometer over the treatment period. Other functional parameters, patient-reported outcomes, samples for biomarker analysis and safety endpoints will be collected. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without IPAF.Ethics and disseminationThis trial is being conducted in accordance with the International Conference on Harmonisation E6 guideline for Good Clinical Practice, Declaration of Helsinki and local laws for countries in which the research is conducted.Trial registration numberNCT03099187.

Purpose of review Telomere attrition has been proposed as one of the aging hallmarks in pulmonary fibrosis. Telomere shortening and telomerase gene mutations have been widely evaluated in recent years. Reduced telomere length may be identified in a quarter of patients with sporadic idiopathic pulmonary fibrosis (IPF) and half of those cases with family aggregation. However, telomere studies have not transferred from the research field to the clinic. This review is focused on our current understanding of the pathogenic implication of telomere dysfunction in lung fibrosis and its relevance in the clinical setting. Recent findings The most prevalent clinical expression of telomere dysfunction is IPF. Disease onset is usually seen at a younger age and family aggregation is frequently present. Short telomere syndrome is associated in a minority of cases and includes premature hair greying, bone marrow failure and liver cirrhosis. However, patients often present with some extrapulmonary associated telomeric features and related comorbidities that may help to suspect telomere defects. Telomere shortening confers a poor prognosis and reduced lung-transplant free survival time in IPF and other nonidiopathic pulmonary fibrotic entities. Summary Telomere dysfunction associates some common clinical features that could modify patient management in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rare disease characterized by chronic, progressive, and irreversible interstitial lung fibrosis of unknown cause [1,2]. Main symptoms and signs include dysp...

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.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and typically fatal lung disease characterised by subpleural fibrosis, subepithelial fibroblast foci, and microscopic honeycombing. Although understanding of the pathogenic mechanisms continues to evolve, evidence indicates that distal airway and alveolar epithelial cells are central drivers of the disease. In this Viewpoint, we review the history of naming and classifications used to define the disease now referred to as IPF, in the context of understanding the clinical presentation, causes, and pathogenesis of the disease. We aim to generate discussion on whether, given the substantial progress made in understanding the clinical, genetic, cellular, and molecular mechanisms involved in the development of IPF, a change of name should be considered. To initiate this discussion, we offer new suggestions to update the name of this disease and new approaches to classify all forms of pulmonary fibrosis.

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