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Competing Interests: JAK reports grant funding from Boehringer Ingelheim Pharmaceuticals, and consulting or scientific advisory board participation for APIE Therapeutics and ARDA Therapeutics. ASM declares no competing interests.

Background: Lung transplantation remains the sole curative option for patients with idiopathic pulmonary fibrosis (IPF), but donor organs remain scarce, and many eligible patients die before transplant. Tools to optimize the timing of transplant referrals are urgently needed., Methods: Least absolute shrinkage and selection operator was applied to clinical and proteomic data generated as part of a prospective cohort study of interstitial lung disease (ILD) to derive clinical, proteomic, and multidimensional logit models of near-term death or lung transplant within 18 months of blood draw. Model-fitted values were dichotomized at the point of maximal sensitivity and specificity, and decision curve analysis was used to select the best-performing classifier. We then applied this classifier to independent IPF and non-IPF ILD cohorts to determine test performance characteristics. Cohorts were restricted to patients aged ≤72 years with body mass index 18 to 32 to increase the likelihood of transplant eligibility., Results: IPF derivation, IPF validation, and non-IPF ILD validation cohorts consisted of 314, 105, and 295 patients, respectively. A multidimensional model comprising 2 clinical variables and 20 proteins outperformed stand-alone clinical and proteomic models. Following dichotomization, the multidimensional classifier predicted near-term outcome with 70% sensitivity and 92% specificity in the IPF validation cohort and 70% sensitivity and 80% specificity in the non-IPF ILD validation cohort., Conclusions: A multidimensional classifier of near-term outcomes accurately discriminated this end-point with good test performance across independent IPF and non-IPF ILD cohorts. These findings support refinement and prospective validation of this classifier in transplant-eligible individuals., (Published by Elsevier Inc.)

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained an MIL algorithm using a pooled dataset ( n  = 2,143) and tested it in three independent populations: data from a prior publication ( n  = 127), a single-institution clinical cohort ( n  = 239), and a national registry of patients with pulmonary fibrosis ( n  = 979). We tested UIP classification performance using receiver operating characteristic analysis, with histologic UIP as ground truth. Cox proportional hazards and linear mixed-effects models were used to examine associations between MIL predictions and survival or longitudinal FVC. Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve, 0.77 [ n  = 127] and 0.79 [ n  = 239]) compared with visual assessment (area under the curve, 0.65 and 0.71). In cohorts with survival data, MIL-UIP classifications were significant for mortality ( n  = 239, mortality to April 2021: unadjusted hazard ratio, 3.1; 95% confidence interval [CI], 1.96-4.91; P  < 0.001; and n  = 979, mortality to July 2022: unadjusted hazard ratio, 3.64; 95% CI, 2.66-4.97; P  < 0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/yr vs. -45 ml/yr; n  = 979; P  < 0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.

Background: Idiopathic Pulmonary Fibrosis (IPF) is one of the most common idiopathic interstitial pneumonia, which can occur all over the world. The median survival time of patients is about 3-5 years, and the mortality is relatively high., Objective: To reveal the potential molecular characteristics of IPF and deepen the understanding of the molecular mechanism of IPF. In order to provide some guidance for the clinical treatment, new drug development, and prognosis judgment of IPF. Although the preliminary conclusion of this study has certain guiding significance for the treatment of IPF and so on, it needs more accurate analytical approaches and large sample clinical trials to verify., Methods: 220 patients with IPF were divided into different subgroups according to the gene expression profiles, which were obtained from the Gene Expression Omnibus (GEO) database. In addition, these subgroups present different expression forms and clinical features. Therefore, weighted gene coexpression analysis (WGCNA) was used to seek the differences between subtypes. And six subgroup-specific WGCNA modules were identified., Results: Combined with the characteristics of WGCNA and KEGG enrichment modules, the autophagic pathway was only upregulated in subgroup I and enriched significantly. The differentiation pathways of Th1 and Th2 cells were only upregulated and enriched in subgroup II. At the same time, combined with clinical information, IPF patients in subgroup II were older and more serious, which may be closely related to the differentiation of Th1 and Th2 cells. In contrast, the neuroactive ligand-receptor interaction pathway and Ca + signaling pathway were significantly upregulated and enriched in subgroup III. Although there was no significant difference in prognosis between subgroup I and subgroup III, their intrinsic biological characteristics were very different. These results suggest that the subtypes may represent risk factors of age and intrinsic biological characteristics and may also partly reflect the severity of the disease., Conclusion: In conclusion, current studies have improved our understanding of IPF-related molecular mechanisms. At the same time, because the results show that patients from different subgroups may have their own unique gene expression patterns, it reminds us that patients in each subgroup should receive more personalized treatment., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Ning Zhang et al.)

The purpose of this study was to evaluate the implications of the 2018 updated guideline for the diagnosis of idiopathic pulmonary fibrosis (IPF) in clinical practice compared to 2011 guideline. This study involved 535 patients including 339 IPF and 196 non-IPF, and we retrospectively evaluated CT classifications of usual interstitial pneumonia (UIP) by two guidelines. Interobserver agreement of 2018 criteria showed moderate reliability (κ = 0.53) comparable to 2011 (κ = 0.56) but interobserver agreement for probable UIP was fair (κ = 0.40). CT pattern of indeterminate for UIP was associated with better prognosis compared with the other groups (adjusted hazard ratio [HR] = 0.36, p < 0.001). Compared to possible UIP, probable UIP demonstrated a lower positive predictive value (PPV, 62.9% vs 65.8%). In analysis of patients with CT patterns of non-definite UIP, diagnosing IPF when CT pattern showed probable UIP with lymphocyte count ≤ 15% in BAL fluid, and either male sex or age ≥ 60 years showed a high specificity of 90.6% and a PPV of 80.8% in the validation cohort. The 2018 criteria provide better prognostic stratification than the 2011 in patients with possible UIP. BAL fluid analysis can improve the diagnostic certainty for IPF diagnosis in patients with probable UIP CT pattern., (© 2021. The Author(s).)

Rationale: Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP. Objectives: We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern. Methods: Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists' reports was compared with histopathology. Measurements and Main Results: In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6-98.3%) and a sensitivity of 60.3% (CI, 46.6-73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5-48.3%) and a specificity of 96.9% (CI, 83.8-100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%). Conclusions: In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

Pulmonary hypertension and pulmonary vascular remodeling (PVR) are common in many lung diseases leading to right ventricular dysfunction and death. Differences in PVR result in significant prognostic divergences in both the pulmonary arterial and venous compartments, as in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), respectively. Our goal was to identify compartment-specific molecular hallmarks of PVR, considering the risk of life-threatening pulmonary edema in PVOD, if treated by conventional pulmonary hypertension therapy. Formalin-fixed and paraffin-embedded tissues from fresh explanted human lungs of patients with PVOD (n = 19), PAH (n = 20), idiopathic pulmonary fibrosis (n = 13), and chronic obstructive pulmonary disease (n = 15), were analyzed for inflammation and kinome-related gene regulation. The generated neuronal network differentiated PVOD from PAH samples with a sensitivity of 100% and a specificity of 92% in a randomly chosen validation set, a level far superior to established diagnostic algorithms. Further, various alterations were identified regarding the gene expression of explanted lungs with PVR, compared with controls. Specifically, the dysregulation of microtubule-associated serine/threonine kinase 2 and protein-o-mannose kinase SGK196 in all disease groups suggests a key role in pulmonary vasculopathy for the first time. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The new 2018 international guidelines for diagnosing usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) by CT scan split the old pattern possible UIP (2011 IPF guidelines) into two new patterns: probable UIP and indeterminate for UIP. However, the proportions and prognoses of these new CT-scan patterns are not clear., Methods: We used a monocentric retrospective cohort of 322 patients suspected of having IPF (University Hospital of Rennes; Competence Center for Rare Lung Diseases; 1 January 2012-31 December 2017). All patients initially diagnosed by CT scan as possible UIP were included. The chest CT-scans were then reclassified according to the new 2018 international guidelines by 3 observers. These data were then subjected to survival analysis with multivariate Cox regression using a composite endpoint of death, lung transplantation, a decline of≥10% in forced vital capacity (FVC), or hospitalization., Results: Of the 89 possible UIP patients included, 74 (83%) were reclassified as probable UIP and 15 (17%) as indeterminate for UIP. Probable UIP patients were more likely to meet the composite endpoint (56/74 [75.7%] vs. 5/15 [33%] patients; HR [IC 95%] =3.12 [1.24; 7.83], P=0.015). Multivariate analysis indicated that the probable UIP pattern was associated with significantly increased risk of reaching the composite endpoint (HR [95% CI]=2.85[1.00; 8.10], P=0.049)., Conclusion: The majority of possible UIP diagnoses corresponded to probable UIP, which was associated with a significantly worse prognosis than indeterminate for UIP. This distinction between these two CT patterns emphasizes the relevance of the new international guidelines for the diagnosis of IPF., (Copyright © 2020 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: The safety of pirfenidone on pulmonary fibrosis patients with other kinds of interstitial lung diseases (ILDs) in addition to idiopathic pulmonary fibrosis (IPF) is unknown. Furthermore, its effectiveness-related factors on IPF patients are not quite explored., Methods: A retrospective study, on patients prescribed pirfenidone for pulmonary fibrosis, was conducted to assess effectiveness on IPF patients and tolerability of all patients with lung fibrosis. The effectiveness of pirfenidone was tested on 110 IPF subjects receiving treatment for ≥3 months by high-resolution computed tomography (HRCT). Response-linked factors and progression-free survival (PFS) were also analyzed. The data about safety outcomes and drug dose adjustments were collected from all included subjects., Results: A total of 176 subjects were included: 117 were IPF, 19 connective tissue disease-associated interstitial lung disease (CTD-ILD), and 40 unclassifiable ILD. Out of the 110 IPF subjects, 89 subjects were assessed as stable and 21 as progressive, out of which 10 died of acute exacerbation and 11 progressed. The effectiveness was significantly related to their baseline body mass index (BMI). IPF subjects with BMI>25kg/m2 or diffusion capacity of carbon monoxide (DLco)>30% had higher PFS rate. The most common adverse events were skin-related and gastrointestinal-related. Drug discontinuation owing to adverse events occurred similarly in these three groups., Conclusion: Pirfenidone was well tolerated in most of the lung fibrosis patients besides IPF, with a similar pattern of adverse events. Nearly 80% of IPF subjects were assessed as stable. More benefits were seen in IPF patients with higher BMI or mild-to-moderate disease., Competing Interests: The authors have declared that no competing interests exist.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia with an unpredictable course. The aims of this study were to retrospectively re-evaluate a cohort of patients with IPF according to the 2011 international IPF guidelines and 1) to characterize the subgroups of patients when classified according to their observed survival times and 2) to evaluate whether Composite Physiologic Index (CPI), Gender-Age-Physiology (GAP) Index or clinical variables could predict mortality., Methods: Retrospective data was collected and patients were classified into subgroups according to their observed lifespans. Differences in clinical variables, CPI and GAP stages as well as in comorbidities were investigated between the subgroups. Predictors of mortality were identified by COX proportional hazard analyses., Results: A total of 132 patients were included in this study. The disease course was rapid (≤ 2 years) in 30.0%, moderate (2-5 years) in 28.0% and slow (≥ 5 years) in 29.0% of the patients. Pulmonary function tests (PFT) and CPI at baseline differentiated significantly between the rapid disease course group and those patients with longer survival times. However, the predictive accuracy of the investigated clinical variables was mainly less than 0.80. The proportions of patients with comorbidities did not differ between the subgroups, but more patients with a rapid disease course were diagnosed with heart failure after the diagnosis of IPF. Most patients with a rapid disease course were categorized in GAP stages I and II, but all patients in GAP stage III had a rapid disease course. The best predictive multivariable model included age, gender and CPI. GAP staging had slightly better accuracy (0.67) than CPI (0.64) in predicting 2-year mortality., Conclusions: Although the patients with a rapid disease course could be differentiated at baseline in terms of PFT and CPI, the predictive accuracy of any single clinical variable as well as CPI and GAP remained low. GAP staging was unable to identify the majority of patients with a rapid disease progression. It is challenging to predict disease progression and mortality in IPF even with risk prediction models.

Context.—: High-resolution computed tomography (HRCT) imaging has an increasingly important role in clinical decision-making in patients with interstitial lung diseases. The recent Fleischner Society white paper on the diagnostic criteria for idiopathic pulmonary fibrosis highlights the advances in our understanding of HRCT imaging in interstitial lung diseases., Objective.—: To discuss the evidence and recommendations outlined in the white paper as it pertains to the radiologic diagnosis of interstitial lung disease, specifically highlighting the current limitations of HRCT in confidently predicting histopathologic findings., Data Sources.—: The recent Fleischner Society white paper and other studies pertaining to the role of HRCT in predicting histopathology in interstitial lung diseases are reviewed., Conclusions.—: High-resolution computed tomography is highly predictive of a usual interstitial pneumonia (UIP) pattern on histopathology when the HRCT shows a typical UIP pattern on a "confident" read by the radiologist. A probable UIP pattern is also very predictive of a UIP pattern on histopathology, and histopathologic confirmation is not needed for most patients demonstrating this pattern in the appropriate clinical setting. A UIP pattern may be seen in a substantial proportion of patients with an "indeterminate UIP" pattern on HRCT and in many patients for whom the HRCT suggests an alternative diagnosis; histopathologic confirmation should be considered in patients demonstrating these patterns whenever feasible.

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is defined as a sudden acceleration of the disease with the appearance of pulmonary infiltrates superimposed on the characteristic pattern of IPF that leads to a significant decline in lung function. It has high in-hospital mortality rates, despite medical treatment with systematic steroids. We sought to investigate whether there were in-hospital mortality differences according to clinical stratification (AE, suspected AE, or AE of known cause) and/or treatment with systemic steroids. We reviewed the clinical characteristics and outcomes of patients with IPF admitted to our hospital during the years 2003-2014 due to a worsening of their clinical status. We identified 50 IPF patients, 9 with AE (18%), 12 with suspected exacerbation (24%), and 29 with AE of known cause (58%), mostly respiratory infections. In-hospital mortality was similar in the three groups (33% vs. 17% vs. 34%, respectively). Likewise, we did not find differences between them with respect to the use of systemic steroids (length of treatment duration or total dose). Nevertheless, there was an independent association between in-hospital mortality and high average daily steroid dose. We did not observe significant differences in prognosis or use of systemic steroids according to current diagnostic stratification groups in patients hospitalized because of an exacerbation of IPF.

Background: Based on international diagnostic guidelines, high-resolution CT plays a central part in the diagnosis of fibrotic lung disease. In the correct clinical context, when high-resolution CT appearances are those of usual interstitial pneumonia, a diagnosis of idiopathic pulmonary fibrosis can be made without surgical lung biopsy. We investigated the use of a deep learning algorithm for provision of automated classification of fibrotic lung disease on high-resolution CT according to criteria specified in two international diagnostic guideline statements: the 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) guidelines for diagnosis and management of idiopathic pulmonary fibrosis and the Fleischner Society diagnostic criteria for idiopathic pulmonary fibrosis., Methods: In this case-cohort study, for algorithm development and testing, a database of 1157 anonymised high-resolution CT scans showing evidence of diffuse fibrotic lung disease was generated from two institutions. We separated the scans into three non-overlapping cohorts (training set, n=929; validation set, n=89; and test set A, n=139) and classified them using 2011 ATS/ERS/JRS/ALAT idiopathic pulmonary fibrosis diagnostic guidelines. For each scan, the lungs were segmented and resampled to create a maximum of 500 unique four slice combinations, which we converted into image montages. The final training dataset consisted of 420 096 unique montages for algorithm training. We evaluated algorithm performance, reported as accuracy, prognostic accuracy, and weighted κ coefficient (κw) of interobserver agreement, on test set A and a cohort of 150 high-resolution CT scans (test set B) with fibrotic lung disease compared with the majority vote of 91 specialist thoracic radiologists drawn from multiple international thoracic imaging societies. We then reclassified high-resolution CT scans according to Fleischner Society diagnostic criteria for idiopathic pulmonary fibrosis. We retrained the algorithm using these criteria and evaluated its performance on 75 fibrotic lung disease specific high-resolution CT scans compared with four specialist thoracic radiologists using weighted κ coefficient of interobserver agreement., Findings: The accuracy of the algorithm on test set A was 76·4%, with 92·7% of diagnoses within one category. The algorithm took 2·31 s to evaluate 150 four slice montages (each montage representing a single case from test set B). The median accuracy of the thoracic radiologists on test set B was 70·7% (IQR 65·3-74·7), and the accuracy of the algorithm was 73·3% (93·3% were within one category), outperforming 60 (66%) of 91 thoracic radiologists. Median interobserver agreement between each of the thoracic radiologists and the radiologist's majority opinion was good (κw=0·67 [IQR 0·58-0·72]). Interobserver agreement between the algorithm and the radiologist's majority opinion was good (κw=0·69), outperforming 56 (62%) of 91 thoracic radiologists. The algorithm provided equally prognostic discrimination between usual interstitial pneumonia and non-usual interstitial pneumonia diagnoses (hazard ratio 2·88, 95% CI 1·79-4·61, p<0·0001) compared with the majority opinion of the thoracic radiologists (2·74, 1·67-4·48, p<0·0001). For Fleischner Society high-resolution CT criteria for usual interstitial pneumonia, median interobserver agreement between the radiologists was moderate (κw=0·56 [IQR 0·55-0·58]), but was good between the algorithm and the radiologists (κw=0·64 [0·55-0·72])., Interpretation: High-resolution CT evaluation by a deep learning algorithm might provide low-cost, reproducible, near-instantaneous classification of fibrotic lung disease with human-level accuracy. These methods could be of benefit to centres at which thoracic imaging expertise is scarce, as well as for stratification of patients in clinical trials., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Respiratory-related hospitalization, in particular acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), is common and associated with increasing mortality in patients with IPF. We aimed to evaluate the implications of a newly proposed framework of acute respiratory deterioration (ARD) and AE-IPF in hospitalized patients., Methods: Using the data of an IPF cohort consisting of 225 consecutive patients, we retrospectively studied first hospitalizations from January 2008 to December 2017. We analysed the demographics and 90-day mortality of patients with AE-IPF and those with parenchymal cause of ARD other than AE., Results: Among 122 patients with first hospitalization for ARD, 35 patients were diagnosed with AE-IPF, including 11 patients with triggered AE. Parenchymal cause of ARD other than AE was diagnosed in 71 patients, and extra-parenchymal cause in 16 patients. Almost all hospitalized patients (93%) underwent chest CT, and 83% of patients with AE-IPF underwent bronchoalveolar lavage. There was a significant difference in the anti-inflammatory therapy between the AE-IPF group and parenchymal cause of ARD other than AE group (p < 0.001). AE-IPF was independently associated with poor survival in multivariate Cox proportional regression analysis., Conclusions: AE-IPF accounted for about 30% of first hospitalizations for ARD, and differentiation between AE-IPF and the other categories in ARD is important from a therapeutic and a prognostic point of view., (Copyright © 2018. Published by Elsevier Ltd.)

Background and Objective: Criteria for interstitial pneumonia with autoimmune features (IPAF) were recently established for research purposes in a joint statement from the European Respiratory Society (ERS) and American Thoracic Society (ATS). We reviewed the utility of these criteria in patients previously diagnosed as broadly defined undifferentiated connective tissue disease (UCTD) and noted overlapping IPAF findings. Additional review was given to IPAF patients with usual interstitial pneumonia (UIP) on histopathology or radiology in terms of survival and outcome., Methods: Patients with prior UCTD-interstitial lung disease (ILD) were screened by ERS/ATS criteria for IPAF. Clinical data along with all-cause mortality were collated and compared with selected idiopathic pulmonary fibrosis (IPF) patients from the same study period. Survival was compared between IPAF subgroups with and without UIP features., Results: One hundred and one UCTD-ILD subjects (91%) evaluated from 2005 to 2012 also met strict criteria for IPAF. Frequent clinical findings included Raynaud's phenomenon, positive anti-nuclear antibody (ANA) and non-specific interstitial pneumonia (NSIP) pattern on chest computed tomography (CT). Nineteen had features of UIP either on histopathology or CT imaging. As compared with IPF, IPAF patients had overall better survival except in those with UIP features., Conclusion: Current IPAF criteria encompassed the majority of broadly defined UCTD-ILD and included those with UIP findings. Survival compared with IPF in those with UIP was similar. Further studies are necessary to refine IPAF definitions for clinical use and guide directed management strategies., (© 2018 Asian Pacific Society of Respirology.)

Idiopathic pulmonary fibrosis (IPF) remains a truly idiopathic fibrotic disease, with a modest genetic predilection and candidate triggers but no overall explanation for the development of disease in non-familial cases. Agreement on terminology has contributed to major clinical and translational advances since the millennium. It is likely that the entity currently captured by the term "IPF" will be radically reclassified over the next decade, either through "splitting" (into IPF subgroups responding selectively to individual disease-modifying agents) or through "lumping" of IPF with other forms of progressive fibrotic lung disease (with shared pathogenetic mechanisms and IPF-like disease behaviour). In this perspective, we summarise the clinical and pathogenetic justification for a focus on "the progressive fibrotic phenotype" in future clinical and translational research. By this means, we can hope to address the needs of non-IPF patients with inexorably progressive fibrotic disease, currently disenfranchised by lack of access to agents that are efficacious in IPF. In this regard, ongoing trials of anti-fibrotic therapies in non-IPF patients with progressive fibrosis may be highly influential. Future revision of IPF nomenclature may be warranted if there are major conceptual changes but without compelling justification, the benefits of renaming IPF are likely to be outweighed by the resulting confusion., Competing Interests: Conflict of interest: A.U. Wells reports personal fees for consultancy and lecturing from Intermune/Roche, Boehringer Ingelheim and Bayer, and personal fees for consultancy from Gilead, outside the submitted work. Conflict of interest: K.K. Brown reports multiple lung fibrosis grants from NHLBI, personal fees from AstraZeneca, Biogen, Fibrogen, Galecto, Gilead, MedImmune, Novartis, Aeolus, ProMetic, Patara, Third Pole, aTyr, Galapagos and Boehringer Ingelheim, has a submitted grant with Roche/Genentech, and conversation under CDA only with Global Blood Therapeutics and Genoa, outside the submitted work. Conflict of interest: K.R. Flaherty reports grants and personal fees from Boehringer Ingelheim and Roche/Genentech, grants from Afferent, personal fees from Veracyte, Fibrogen, Immuneworks, Aeolus, Pharmakea, Sanofi-genzyme and Celgene, outside the submitted work. Conflict of interest: M. Kolb reports grants and personal fees from Roche, Boehringer Ingelheim, GSK and Prometic, personal fees from Gilead and Genoa, and grants from Actelion, Respivert, Alkermes and Pharmaxis, outside the submitted work., (Copyright ©ERS 2018.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrosing lung disease of unknown cause. The advent of anti-fibrotic medications known to slow disease progression has revolutionised IPF management in recent years. However, little is known about the natural history of IPF patients with mild physiological impairment. We aimed to assess the natural history of these patients using data from the Australian IPF Registry (AIPFR)., Methods: Using our cohort of real-world IPF patients, we compared FVC criteria for mild physiological impairment (FVC ≥ 80%) against other proposed criteria: DLco ≥ 55%; CPI ≤40 and GAP stage 1 with regards agreement in classification and relationship with disease outcomes. Within the mild cohort (FVC ≥ 80%), we also explored markers associated with poorer prognosis at 12 months., Results: Of the 416 AIPFR patients (mean age 70.4 years, 70% male), 216 (52%) were classified as 'mild' using FVC ≥ 80%. There was only modest agreement between FVC and DLco (k = 0.30), with better agreement with GAP (k = 0.50) and CPI (k = 0.48). Patients who were mild had longer survival, regardless of how mild physiologic impairment was defined. There was, however, no difference in the annual decline in FVC% predicted between mild and moderate-severe groups (for all proposed criteria). For patients with mild impairment (n = 216, FVC ≥ 80%), the strongest predictor of outcomes at 12 months was oxygen desaturation on a 6 min walk test., Conclusion: IPF patients with mild physiological impairment have better survival than patients with moderate-severe disease. Their overall rate of disease progression however, is comparable, suggesting that they are simply at different points in the natural history of IPF disease.

Background: Two antifibrotic drugs, pirfenidone and nintedanib, are approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis (IPF). In this analysis, treatment patterns of European patients with IPF were investigated to understand antifibrotic prescribing and identify unmet needs in IPF treatment practice., Methods: Between February and March 2016, respiratory physicians from France, Germany, Italy, Spain, and the UK participated in an online questionnaire designed to collect information on IPF treatment patterns in patients under their care. Patients were categorized as treated (received approved antifibrotics) or untreated (did not receive approved antifibrotics, but may have received other unapproved therapies). Classification of IPF diagnosis (confirmed/suspected) and severity ('mild'/'moderate'/'severe') for each patient was based on the individual physician's report. Patients' perspectives were not recorded in this study., Results: In total, 290 physicians responded to the questionnaire. Overall, 54% of patients with IPF did not receive treatment with an approved antifibrotic. More patients had a confirmed IPF diagnosis in the treated (84%) versus the untreated (51%) population. Of patients with a confirmed diagnosis, 40% did not receive treatment. The treated population was younger than the untreated population (67 vs 70 years, respectively; p ≤ 0.01), with more frequent multidisciplinary team evaluation (83% vs 57%, respectively; p ≤ 0.01). A higher proportion of untreated patients had forced vital capacity > 80% at diagnosis versus treated patients. Of patients with 'mild' IPF, 71% did not receive an approved antifibrotic versus 41% and 60% of patients with 'moderate' and 'severe' IPF, respectively., Conclusions: Despite the availability of antifibrotic therapies, many European patients with confirmed IPF do not receive approved antifibrotic treatment. Importantly, there appears to be a reluctance to treat patients with 'mild' or 'stable' disease, and instead adopt a 'watch and wait' approach. More education is required to address diagnostic uncertainty, poor understanding of IPF and its treatments, and issues of treatment access. There is a need to increase physician awareness of the benefits associated with antifibrotic treatment across the spectrum of IPF severity.

Background: The clinicopathological characteristics of lung cancer with concomitant usual interstitial pneumonia (UIP) are insufficiently understood. This study aimed to elucidate a characteristic pathological feature of lung cancer that develops in patients with UIP, with a focus on the location of its onset., Methods: We reviewed surgically obtained specimens, including 547 tumors from 526 patients who underwent lobectomy for lung cancer. Surveyed patients were classified into three groups: patients with UIP (UIP group), patients with lung pathology other than UIP (non-UIP group), and patients without any associated lung pathology (normal group). The histology as well as the lobe and location of the onset of lung cancer were compared among these groups. The peripheral location was subdivided into subpleural, inner and tumor involved centrally secondary to extension., Results: The UIP group comprised 82 patients (male, 71 [87%]; mean age, 71 years; smoking rate, 94%), the non-UIP group comprised 334 patients (male, 267 [80%]; mean age, 69 years; smoking rate, 81%), and the normal group comprised 110 patients (male, 33 [30%]; mean age, 63; smoking rate, 29%). No statistical differences were noted in sex, mean age, or smoking index between the UIP and non-UIP groups. Compared with the non-UIP group, the frequency of squamous cell carcinoma (63% vs. 32%), lower lobe origin (76% vs. 32%), and subpleural location (24% vs. 5%) were significantly higher in the UIP group., Conclusions: Lung cancers in patients with UIP show a predilection for the subpleural region, where UIP is also thought to originate., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that has been recently included in the updated consensus on idiopathic interstitial pneumonias. It shares some clinical features with other chronic interstitial pneumonias (dyspnea, dry cough), and is radiologically characterized by pleural and subpleural parenchymal fibrosis and elastosis, mainly in the upper lobes. The main histological findings include pleural fibrosis and prominent subpleural and parenchymal fibroelastosis. Its characterization is based on the increasing number of cases reported in the literature, so several aspects of the etiology, pathogenesis and natural history are still unknown. Although some cases have been described as idiopathic, PPFE has been reported as a complication after bone marrow transplantation, lung transplantation and chemotherapy, especially with alkylating agents.Spontaneous or iatrogenic pneumothorax is a frequently reported complication of invasive diagnostic tests for identifying PPFE. The disease course is variable, ranging from slow progression to rapid clinical deterioration. No treatment has shown evidence of efficacy, and lung transplantation remains the only option for patients who fulfill the diagnostic criteria for this option. Recognizing and disseminating the specific features of PPFE is essential to raise the level of clinical suspicion for this entity, and to implement appropriate multidisciplinary diagnostic management., (Copyright © 2015 SEPAR. Published by Elsevier Espana. All rights reserved.)

Data on incidence, prevalence and mortality of idiopathic pulmonary fibrosis (IPF) are sparse and vary across studies. The true incidence and prevalence of the disease are unknown. In general, the overall prevalence and incidence reported in European and Asian countries are lower than those reported in American studies. In recent years, the epidemiological approach to IPF has been difficult for many reasons. First, the diagnostic criteria of the disease have changed over time. Secondly, the coding system used for IPF in administrative databases, the most common data source used to study this aspect of the disease, has been modified in the past few years. Finally, the study design, the methodology and the population selected in each of the studies are very different. All these aspects make comparisons among studies very difficult or impossible. In this review, we list the main issues that might arise when comparing different studies and that should be taken into consideration when describing the state of epidemiological knowledge concerning this pathology., (Copyright ©ERS 2015.)

PATIENT PRESENTATION AND DIAGNOSTIC WORK-UP: The patient is a 72-year-old man presenting with dyspnoea on exertion. He is a former heavy smoker (40 pack-years) and his father, now deceased, had rheumatoid arthritis (RA). On physical examination he had mild bi-basilar crackles but no finger clubbing. Autoimmune serology was positive for rheumatoid factor (RF: 25 IU/ml). Lung function tests showed normal FVC, a FEV1/FVC ratio of 72% and a TLCO of 49% predicted. Lung CT showed centrilobular and paraseptal emphysema, subpleural fine reticulation and traction bronchiolectasis, with no clear basal predominance (Figure 1). BAL cytology showed 83% alveolar macrophages, 12% lymphocytes, 3% neutrophils, and 2% eosinophils.

According to current international guidelines the idiopathic interstitial pneumonias (IIPs) are grouped into three categories; major, rare, and unclassifiable. Idiopathic pulmonary fibrosis (IPF) is one of the major IIPs and has been recognised as a distinct clinical entity since 2001. This has led to significant advances in our understanding and treatment of the disease and to the identification of new therapeutic targets. While multidisciplinary team assessment yields a definite diagnosis in many cases of interstitial lung disease (ILD), 15-25% of patients remain unclassifiable. This can be due to inadequate clinical, pathological, or radiological data (e.g., where a biopsy is not performed) or because results of investigations show major discrepancies, overlapping features, or mixed patterns. Patients with unclassifiable disease tend to be of similar age to those with IPF and older than those with connective tissue disorders. Survival of patients with unclassifiable disease is intermediate between IPF and non-IPF ILD. There is no single recommended treatment for patients with unclassifiable disease. However, the ILD-GAP index has recently been validated in this group and can risk-stratify patients based on four easily measurable variables. "Disease behaviour classification" (DBC) is an alternative, pragmatic approach to managing patients with unclassifiable disease. The ILD-GAP index has been shown to provide strong prognostic information in these hard-to-treat patients. In the future, new diagnostic tools such as protein biomarkers may become available to help guide therapeutic decisions.

PATIENT PRESENTATION AND CLINICAL HISTORY: The patient is a 43-year-old male non-smoker who works as a farmer and cheese-maker. He complained of a dry cough for 6-12 months without fever or other clinical signs. His medical history was unremarkable with no use of drugs or alcohol and no signs of Raynaud's syndrome. In his family history he had two first-degree relatives with pulmonary fibrosis, one of whom also had rheumatoid arthritis.

Since 1991, the severity of idiopathic pulmonary fibrosis (IPF) has been classified into 4 stages-stage I (characterized by a resting PaO2 ≥ 80 Torr), stage II (70-79 Torr), stage III (60-69 Torr), or stage IV (<60 Torr)-to aid decisions on medical care subsidization in Japan. Among patients with stage II/III IPF, the severity should be increased by one stage if the lowest oxygen saturation on pulse oximetry (SpO2) is <90% during a 6-min walk test. Patients with stage III/IV IPF receive Japanese government subsidies for incurable diseases. This classification system highly correlates with serial changes in the percentage of vital capacity (%VC), the diffusing capacity for carbon monoxide, the incidence of acute exacerbation, and survival. A phase III trial of pirfenidone showed that IPF patients with an SpO2 on exertion of <90% and either a %VC ≥ 70% or a PaO2 ≥ 70 Torr (which includes most patients with stage III disease) at baseline would benefit from pirfenidone treatment. Recent post-marketing surveillance of 1370 patients--67.3% of whom had stage III/IV IPF--showed that pirfenidone was well-tolerated among those treated for longer than 6 months (63% of patients). A Japanese randomized controlled trial (RCT) demonstrated that inhaled N-acetylcysteine monotherapy benefitted patients with early IPF (stage I/II, with no desaturation on exertion). Thus, N-acetylcysteine monotherapy is suitable for early IPF, and pirfenidone is indicated for advanced disease. The classification of IPF severity is important in identifying clinically responsive patients and those suitable for RCT enrollment., (Copyright © 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease, leading to substantial physical impairment. The distance walked in 6 min (6MWD) is a measure of exercise tolerance and is of prognostic relevance in IPF. While 6MWD is a punctual measurement which may not be representative, self-reported daily life activity may represent the patients' functional capacity more globally even in less severe affected patients., Objectives: We evaluated and characterized a simple classification system based on the patients' self-reported daily activity and analyzed if this would add significantly to the prognostic information of the 6MWD alone in IPF patients., Methods: Daily life activity was assessed in IPF (n = 156) patients with standardized questions and categorized in activity classes (AC I-IV), comprising the less severe impaired in AC I and II. The 6MWD was also assessed., Results: ACs were related to the lung functional impairment and inversely correlated to the 6MWD. Thirty-two patients were in AC I/II, 98 in AC III and 26 patients in AC IV. Thirty-seven (23.7%) patients died during a median follow-up of 14.9 months, comprising 1 patient in AC I/II. In addition, a 6MWD <470 m predicted mortality. Combining AC I/II and a 6MWD >470 m identified a subgroup of patients with favorable outcome., Conclusions: AC is a novel scoring system which can easily be obtained and correlates with lung functional and physical impairments as well as mortality. Moreover, AC adds prognostic information to the 6MWD., (© 2015 S. Karger AG, Basel.)

Idiopathic pulmonary fibrosis (IPF) is the most frequent of the idiopathic interstitial pneumonias. It is a progressive disorderwith a poor prognosis. Its diagnosis requires the careful exclusion of potential causes, and a pattern of usual interstitial pneumonia at high-resolution computed tomography or video-assisted surgical lung biopsy. Several recent randomized trials have profoundly modified the therapeutic management of IPF. The combination of prednisone and azathioprine, often prescribed until recently, has been shown to be harmful and is no longer indicated. N-acetylcystein, also used in the past decade, failed to show an efficacy. However, two new antifibrotic drugs, pirfenidone and nintedanib, have for the first time proven effective in slowing disease progression.

Honeycombing on CT is the clue for the diagnosis of usual interstitial pneumonia (UIP) and its hallmark. According to the ATS-ERS-JRS-ALAT 2010 guideline, the patients with honeycombing on CT can be diagnosed as UIP without surgical biopsy. On CT scans, it is defined as clustered cystic airspaces, typically of comparable diameters of the order of 3-10mm, which are usually subpleural and have well-defined walls. Pathologically, honeycombing consists of both collapsing of multiple fibrotic alveoli and dilation of alveolar duct and lumen Although the definition of honeycombing seems to be strict, recognition of honeycombing on CT is various among each observer Because typical honeycombing is frequently observed in the patients with UIP, we should judge clustered cysts as honeycombing when a diagnosis of UIP is suspected., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has a dismal prognosis. Median age at IPF onset is 60-70 years and it is mainly related to cigarette smoke exposure. Its clinical profile is heterogeneous and different clinical phenotypes are now better defined: familial IPF, slow and rapid progressors, combined pulmonary fibrosis and emphysema, anti-neutrophil cytoplasmic antibodies/microscopic polyangiitis and IPF, and IPF associated with lung cancer. Acute exacerbation associated with rapid functional decline is an event that does not happen infrequently and affects survival. Diagnosis requires a typical usual interstitial pneumonia (UIP) pattern on computed tomography in the appropriate clinical setting or morphological confirmation of the UIP pattern when imaging findings are not characteristic enough. Surgical lung biopsy is the gold standard to obtain valuable information for histological analysis. However, less invasive procedures (transbronchial lung biopsy or even improved transbronchial lung biopsy by cryoprobes) are now under consideration. Prognostic indicators are mainly derived by pulmonary function tests. Recently, staging systems have been proposed.

Background: Pulmonary dendritic cells (DCs) are key regulators of immune responses. An increased accumulation of DCs was reported in the lungs of patients with idiopathic interstitial pneumonia (IIP)., Objective: This study aimed to investigate the number of pulmonary DCs in patients with collagen vascular disease associated interstitial lung diseases (CVD-ILDs)., Design: Lung tissue samples obtained from 27 patients with IIP and 39 patients with CVD-ILD were detected using monoclonal antibodies against CD1a, CD1c, CD83, Langerin and DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)., Results: No significant differences in the number or distribution of DCs were observed between patients with IIP and CVD-ILDs. When DC marker expression was analyzed according to pathological subgroup, patients with idiopathic usual interstitial pneumonia (UIP) showed increased DC-SIGN staining when compared with CVD-UIP (p < 0.05)., Conclusion: Both mature and immature DCs accumulate in CVD-ILDs. The number of DCs expressing DC-SIGN in CVD-UIP was decreased compared with that in idiopathic UIP. The variation in accumulated DC-SIGN-positive cells might help to explain the differences in the development and maintenance of lung inflammation between idiopathic UIP and CVD-UIP.

Objective: To set out a severity classification for idiopathic pulmonary fibrosis (IPF) based on the interaction of pulmonary function parameters with high resolution computed tomography (CT) findings., Introduction: Despite the contribution of functional and radiological methods in the study of IPF, there are few classification proposals for the disease based on these examinations., Methods: A cross-sectional study was carried out, in which 41 non-smoking patients with IPF were evaluated. The following high resolution CT findings were quantified using a semi-quantitative scoring system: reticular abnormality, honeycombing and ground-glass opacity. The functional variables were measured by spirometry, forced oscillation technique, helium dilution method, as well as the single-breath method of diffusing capacity of carbon monoxide. With the interaction between functional indexes and high resolution CT scores through fuzzy logic, a classification for IPF has been built., Results: Out of 41 patients studied, 26 were male and 15 female, with a mean age of 70.8 years. Volume measurements were the variables which showed the best interaction with the disease extension on high resolution CT, while the forced vital capacity showed the lowest estimative errors in comparison to total lung capacity. A classification for IPF was suggested based on the 95% confidence interval of the forced vital capacity %: mild group (>92.7); moderately mild (76.9-92.6); moderate (64.3-76.8%); moderately severe (47.1-64.2); severe (24.3-47.0); and very severe (<24.3)., Conclusion: Through fuzzy logic, an IPF classification was built based on forced vital capacity measurement with a simple practical application.

Objectives: The aim of this study was to assess the clinical characteristics of idiopathic pulmonary fibrosis (IPF) in patients with stage I disease severity based on the criteria of the Japanese Respiratory Society (JRS), which correspond to moderate or severe U.S.A. criteria., Patients and Methods: In 46 consecutive patients with IPF who were admitted to our institution from June 2003 through September 2009, 27 were given diagnoses of stage I disease severity based on JRS criteria. These 27 were classified into 3 groups: Group A (stage I disease severity according to the JRS criteria, corresponding to mild on U.S.A. criteria, n=17), group B (stage I disease severity according to JRS criteria, corresponding to moderate or severe on U.S.A. criteria, n=10), and group C (stage I disease severity based on the JRS criteria, corresponding to severe U.S.A. criteria, n=6). We compared these groups using demographic and spirometric tests, the 6-minute walking test (6MWT), estimated systolic pulmonary arterial pressure (esPAP), and survival rates in each group., Results: stage I disease severity according to the JRS criteria corresponded to the following grade based on U.S.A. criteria: mild, 17 cases; moderate, 4 cases; severe, 6 cases. The values of lowest SpO2 and %DLco in group B and group C were significantly lower than those in group A, and values of the Hugh-Jones score and esPAP were higher than those in group A. In addition, the survival rate in group B and group C was significantly worse than that in group A. The survival rate in patients with stage I disease severity who showed desaturation on exertion with %DLco < or = 50%, was significantly worse than in those who showed SpO2 > or = 90% on exertion with %DLco >50% (23.7 16.5 months vs. 16.6 +/- 11.3 months; P = 0.002)., Conclusions: This study suggested that IPF patients with stage I disease severity according to JRS criteria included the grades of moderate and severe according to U.S.A. criteria. This suggests that we should revise the classification of disease severity for IPF in Japan.

Idiopathic interstitial pneumonias represent a group of complex lung diseases among which the most frequent types are idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (idiopathic NSIP), and cryptogenic organizing pneumonia (COP). Clinicians may rely on a precise classification of these diseases from an America-European consensus that has been published in 2002. However it appears that diagnosis should always be confirmed by a multidisciplinary team discussion with experience in the field. There are generally tremendous prognostic and therapeutic implications for the patient.

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with very high mortality., Objective: We sought to characterize serial changes in pulmonary artery pressures (PAP) in patients with advanced IPF who survive to transplant., Methods: Retrospective analysis of IPF patients comparing mean PAP at the time of initial evaluation for transplan- tation (mPAP(baseline)) with mPAP at the time of transplant (mPAP(follow-up)). The measurements were correlated with New York Heart Association (NYHA) functional class and oxygen requirements., Results: The final cohort consisted of 44 patients with serial right heart catheterization data. The mean mPAP(baseline) and mPAP(follow-up) were 22.5 and 32.7 mm Hg, respectively. 38.6% (17/44) of the patients had pulmonary hypertension (PH) at baseline. The majority of the non-PH patients developed PH during the serial time interval with a subsequent incidence of 77.8%. At the time of transplant, 86.4% of the patients had PH. There was a significant association between transplant NYHA class, severity of PH and oxygen requirements. Transplant NYHA class IV patients had a higher rate of mPAP change. The severity of PH at the time of transplant did not affect transplant outcomes., Conclusion: PH is common and progressive in patients with advanced IPF who are transplant candidates. Serial change and severity of PAP elevations have a significant association with oxygen requirements and functional status, but not transplant outcomes. Whether or not progressive PH has a significant impact on outcomes without transplantation requires further study., (Copyright 2008 S. Karger AG, Basel.)