Zhonghua Yi Xue Za Zhi. 2021 Jun 1;101(20):1453-1457. doi: 10.3760/cma.j.cn112137-2020831-02514.

ABSTRACT

Interstitial lung disease (ILD), consisting of more than 200 subtypes of diseases, is a large group of heterogeneous diseases characterized by varying degrees of alveolitis and pulmonary parenchymal fibrosis. There are many challenges in its diagnosis and treatment. In recent years, new understanding of the clinical classification, disease behavior, early diagnosis, and treatment of ILD has been obtained. The anti-fibrotic drugs have been expanded successfully from treatment of idiopathic pulmonary fibrosis (IPF) to progressive-fibrosing interstitial lung diseases (PF-ILD). A new international clinical practice guideline categorized hypersensitivity pneumonitis (HP) into two clinical phenotypes, namely nonfibrotic and fibrotic HP. The clinical classification of ILD according to disease behavior and a progressing fibrotic phenotype is of important value for the establishment of treatment strategies for patients with ILD. Interstitial pulmonary abnormalities (ILA) may represent the subclinical stages of different types of ILD, and long-term follow-up of ILA is key to improving the early diagnosis of ILD. Interstitial pneumonia with autoimmune features (IPAF) may represent an early phase or prodromal state of a connective tissue disease (CTD), and patients with IPAF need to be under longitudinal surveillance for evolution to CTD.

PMID:34044517 | DOI:10.3760/cma.j.cn112137-2020831-02514

Respiration. 2021 May 27:1-6. doi: 10.1159/000516291. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease with a heterogeneous disease course. Timely initiation of palliative care is often lacking. The surprise question "Would you be surprised if this patient died within the next year?" is increasingly used as a clinical prognostic tool in chronic diseases but has never been evaluated in IPF.

OBJECTIVE: We aimed to evaluate the predictive value of the surprise question for 1-year mortality in IPF.

METHODS: In this prospective cohort study, clinicians answered the surprise question for each included patient. Clinical parameters and mortality data were collected. The sensitivity, specificity, accuracy, negative, and positive predictive value of the surprise question with regard to 1-year mortality were calculated. Multivariable logistic regression analysis was performed to evaluate which factors were associated with mortality. In addition, discriminative performance of the surprise question was assessed using the C-statistic.

RESULTS: In total, 140 patients were included. One-year all-cause mortality was 20% (n = 28). Clinicians identified patients with a survival of <1 year with a sensitivity of 68%, a specificity of 82%, an accuracy of 79%, a positive predictive value of 49%, and a negative predictive value of 91%. The surprise question significantly predicted 1-year mortality in a multivariable model (OR 3.69; 95% CI 1.24-11.02; p = 0.019). The C-statistic of the surprise question to predict mortality was 0.75 (95% CI 0.66-0.85).

CONCLUSIONS: The answer on the surprise question can accurately predict 1-year mortality in IPF. Hence, this simple tool may enable timely focus on palliative care for patients with IPF.

PMID:34044401 | DOI:10.1159/000516291

Front Med (Lausanne). 2021 May 10;8:680997. doi: 10.3389/fmed.2021.680997. eCollection 2021.

ABSTRACT

Interstitial lung disease (ILD) comprises a heterogenous group of diffuse lung disorders that commonly result in irreversible pulmonary fibrosis. While idiopathic pulmonary fibrosis (IPF) is the prototypical progressive fibrosing ILD (PF-ILD), a high proportion of patients with other ILD subtypes develop a PF-ILD phenotype. Evidence exists for shared pathobiology leading to progressive fibrosis, suggesting that biomarkers of disease activity may prove informative across the wide spectrum of ILDs. Biomarker investigation to date has identified a number of molecular markers that predict relevant ILD endpoints, including disease presence, prognosis, and/or treatment response. In this review, we provide an overview of potentially informative biomarkers in patients with ILD, including those suggestive of a PF-ILD phenotype. We highlight the recent genomic, transcriptomic, and proteomic investigations that identified these biomarkers and discuss the body compartments in which they are found, including the peripheral blood, airway, and lung parenchyma. Finally, we identify critical gaps in knowledge within the field of ILD biomarker research and propose steps to advance the field toward biomarker implementation.

PMID:34041256 | PMC:PMC8141562 | DOI:10.3389/fmed.2021.680997

Front Pharmacol. 2021 Apr 15;12:645558. doi: 10.3389/fphar.2021.645558. eCollection 2021.

ABSTRACT

It is known that the cell environment such as biomechanical properties and extracellular matrix (ECM) composition dictate cell behaviour including migration, proliferation, and differentiation. Important constituents of the microenvironment, including ECM molecules such as proteoglycans and glycosaminoglycans (GAGs), determine events in both embryogenesis and repair of the adult lung. Mesenchymal stromal/stem cells (MSC) have been shown to have immunomodulatory properties and may be potent actors regulating tissue remodelling and regenerative cell responses upon lung injury. Using MSC in cell-based therapy holds promise for treatment of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, so far clinical trials with MSCs in COPD have not had a significant impact on disease amelioration nor on IPF, where low cell survival rate and pulmonary retention time are major hurdles to overcome. Research shows that the microenvironment has a profound impact on transplanted MSCs. In our studies on acellular lung tissue slices (lung scaffolds) from IPF patients versus healthy individuals, we see a profound effect on cellular activity, where healthy cells cultured in diseased lung scaffolds adapt and produce proteins further promoting a diseased environment, whereas cells on healthy scaffolds sustain a healthy proteomic profile. Therefore, modulating the environmental context for cell-based therapy may be a potent way to improve treatment using MSCs. In this review, we will describe the importance of the microenvironment for cell-based therapy in chronic lung diseases, how MSC-ECM interactions can affect therapeutic output and describe current progress in the field of cell-based therapy.

PMID:34040521 | PMC:PMC8142268 | DOI:10.3389/fphar.2021.645558

Eur Respir Rev. 2021 May 25;30(160):210026. doi: 10.1183/16000617.0026-2021. Print 2021 Jun 30.

ABSTRACT

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.

PMID:34039675 | DOI:10.1183/16000617.0026-2021

Respir Med. 2021 May 19;185:106473. doi: 10.1016/j.rmed.2021.106473. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Benefits of pulmonary rehabilitation in Interstitial Lung Diseases (ILD) have been reported. The aim of this large multicenter study was to identify the success predictors of pulmonary rehabilitation in a real-life setting.

METHODS: Data of 240 in-patients (110 idiopathic pulmonary fibrosis (IPF), 106 ILD other than IPF and 24 undetermined ILD) undergoing pulmonary rehabilitation in a 10-year period were retrospectively evaluated. Six minute walking distance (6MWT), body weight-walking distance product tests, dyspnoea and arterial blood gases were assessed at admission and discharge. Differences in post rehabilitation changes in outcome measures as function of baseline characteristics were evaluated.

RESULTS: After rehabilitation, patients showed improvements in all outcome measures (p < 0.05), regardless of the underlying diagnosis or disease severity. Patients needing oxygen therapy at rest showed reduced benefits. Baseline 6MWD inversely correlated with its changes at discharge. Non-significant greater benefits after rehabilitation were found in IPF patients under antifibrotic therapy. In a subset of 50 patients assessed on average 10.3 ± 3.5 months after discharge, the benefits in 6MWD were not maintained (312.9 ± 139.4, 369.7 ± 122.5 and 310.8 ± 139.6 m at admission, discharge and follow up respectively: p < 0.0001).

CONCLUSION: Pulmonary rehabilitation may improve dyspnoea, exercise capacity and fatigue in patients with ILD of different aethiologies and level of severity. The long-term effects need to be established.

PMID:34038844 | DOI:10.1016/j.rmed.2021.106473

Am J Respir Cell Mol Biol. 2021 May 26. doi: 10.1165/rcmb.2020-0546OC. Online ahead of print.

ABSTRACT

Molecular patterns and pathways in idiopathic pulmonary fibrosis (IPF) have been extensively investigated but few studies have assimilated multi-omic platforms to provide an integrative understanding of molecular patterns that are relevant in IPF. Herein, we combine coding and non-coding transcriptome, DNA methylome, and proteome from IPF and healthy lung tissue to identify molecules and pathways associated with this disease. RNA sequencing, Illumina MethylationEPIC array, and liquid chromatography-mass spectrometry (LC-MS) proteomic data were collected on lung tissue from 24 IPF cases and 14 control subjects. Significant differential features were identified using linear models adjusting for age and sex, inflation and bias where appropriate. Data Integration Analysis for Biomarker discovery using a Latent component method for Omics studies (DIABLO) was used for integrative multi-omic analysis. We identified 4,643 differentially expressed transcripts aligning to 3,439 genes, 998 differentially abundant proteins, 2,500 differentially methylated regions (DMRs), and 1,269 differentially expressed lncRNAs that were significant after correcting for multiple tests (false discovery rate [FDR]<0.05). Unsupervised hierarchical clustering using 20 coding mRNA, protein, methylation, and lncRNA features with highest loadings on the top latent variable from the four datasets demonstrates perfect separation of IPF and control lungs. Our analysis confirmed previously validated molecules and pathways known to be dysregulated in disease, and implicated novel molecular features as potential drivers and modifiers of disease. For example, four proteins, 18 DMRs, and 10 lncRNAs were found to have strong correlations (|r|>0.8) with MMP7. Therefore, using a systems biology approach, we have identified novel molecular relationships in IPF.

PMID:34038697 | DOI:10.1165/rcmb.2020-0546OC

FASEB J. 2021 Jun;35(6):e21675. doi: 10.1096/fj.202100339R.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-ɣ (PPARɣ) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

PMID:34038004 | DOI:10.1096/fj.202100339R

Am J Respir Crit Care Med. 2021 May 25. doi: 10.1164/rccm.202102-0407LE. Online ahead of print.

NO ABSTRACT

PMID:34033521 | DOI:10.1164/rccm.202102-0407LE

Respir Res. 2021 May 24;22(1):162. doi: 10.1186/s12931-021-01749-1.

ABSTRACT

BACKGROUND: There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database.

METHODS: The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD.

RESULTS: We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan-Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622-54,287) and the median annual cost per patient was €18,362 (6856-52,026), of which €11,784 (3003-42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests.

CONCLUSIONS: This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842.

PMID:34030695 | DOI:10.1186/s12931-021-01749-1

Methods Mol Biol. 2021;2299:263-274. doi: 10.1007/978-1-0716-1382-5_19.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic pathological disorder that targets alveoli interstitial tissues and is characterized by the progressive stiffening of alveolar membrane. The median survival rate of the patients with IPF is less than 5 years. Currently, IPF has no cure and there are few options to alleviate the progress of this disease. A critical roadblock in developing new anti-fibrosis therapies is the absence of reliable cell based in vitro models that can recapitulate the progressive features of this disease. Here a novel fibrotic microtissue on a chip system is created to model the fibrotic transition of the lung interstitial tissue and the effect of anti-fibrosis drugs on such transitions. This system will not only help to expedite the efficacy analysis of anti-fibrotic therapies but also help to unveil their potential mode of action.

PMID:34028749 | DOI:10.1007/978-1-0716-1382-5_19

Angiogenesis. 2021 May 24. doi: 10.1007/s10456-021-09795-5. Online ahead of print.

ABSTRACT

The loss of normal alveolar capillary and deregulated angiogenesis occurs simultaneously in idiopathic pulmonary fibrosis (IPF); however the contributions of specific endothelial subpopulations in the development of pulmonary fibrosis are poorly understood. Herein, we perform single-cell RNA sequencing to characterize the heterogeneity of endothelial cells (ECs) in bleomycin (BLM)-induced lung fibrosis in rats. One subpopulation, characterized by the expression of Nos3 and Cav1, is mostly distributed in non-fibrotic lungs and also highly expresses genes related to the "response to mechanical stimulus" and "lung/heart morphogenesis" processes. Another subpopulation of ECs expanded in BLM-treated lungs, characterized by Cxcl12, is observed to be closely related to the pro-fibrotic process in the transcriptome data, such as "regulation of angiogenesis," "collagen binding," and "chemokine activity," and spatially localized to BLM-induced neovascularization. Using CellPhoneDB software, we generated a complex cell-cell interaction network, which predicts the potential roles of EC subpopulations in recruiting monocytes, inducing the proliferation of fibroblasts and promoting the production and remolding of the extracellular matrix (ECM). Taken together, our data demonstrate the high degree of heterogeneity of ECs in fibrotic lung and it is proposed that the interaction between ECs, macrophages, and stromal cells contributes to pathologic IPF.

PMID:34028626 | DOI:10.1007/s10456-021-09795-5

Front Med (Lausanne). 2021 May 7;8:644678. doi: 10.3389/fmed.2021.644678. eCollection 2021.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has caused considerable socio-economic burden, which fueled the development of treatment strategies and vaccines at an unprecedented speed. However, our knowledge on disease recovery is sparse and concerns about long-term pulmonary impairments are increasing. Causing a broad spectrum of symptoms, COVID-19 can manifest as acute respiratory distress syndrome (ARDS) in the most severely affected patients. Notably, pulmonary infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the causing agent of COVID-19, induces diffuse alveolar damage (DAD) followed by fibrotic remodeling and persistent reduced oxygenation in some patients. It is currently not known whether tissue scaring fully resolves or progresses to interstitial pulmonary fibrosis. The most aggressive form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). IPF is a fatal disease that progressively destroys alveolar architecture by uncontrolled fibroblast proliferation and the deposition of collagen and extracellular matrix (ECM) proteins. It is assumed that micro-injuries to the alveolar epithelium may be induced by inhalation of micro-particles, pathophysiological mechanical stress or viral infections, which can result in abnormal wound healing response. However, the exact underlying causes and molecular mechanisms of lung fibrosis are poorly understood due to the limited availability of clinically relevant models. Recently, the emergence of SARS-CoV-2 with the urgent need to investigate its pathogenesis and address drug options, has led to the broad application of in vivo and in vitro models to study lung diseases. In particular, advanced in vitro models including precision-cut lung slices (PCLS), lung organoids, 3D in vitro tissues and lung-on-chip (LOC) models have been successfully employed for drug screens. In order to gain a deeper understanding of SARS-CoV-2 infection and ultimately alveolar tissue regeneration, it will be crucial to optimize the available models for SARS-CoV-2 infection in multicellular systems that recapitulate tissue regeneration and fibrotic remodeling. Current evidence for SARS-CoV-2 mediated pulmonary fibrosis and a selection of classical and novel lung models will be discussed in this review.

PMID:34026781 | PMC:PMC8139419 | DOI:10.3389/fmed.2021.644678

Respirol Case Rep. 2021 May 19;9(6):e00782. doi: 10.1002/rcr2.782. eCollection 2021 Jun.

ABSTRACT

In the clinical setting, it is often difficult to judge whether honeycomb-like structures represent progression of fibrosis in pulmonary sarcoidosis or a complication by interstitial pneumonitis. This report described a valuable case in which pathology of video-assisted thoracoscopic surgery specimens collected from the lungs with honeycomb-like structures that were continuous with the dilated bronchioles on chest computed tomography (CT) showed granulomas in the membranous bronchiole walls, thereby demonstrating that the honeycomb-like structures were lung lesions of sarcoidosis. Pathological features of these structures on chest CT included cystic changes attributable to incorporation of peripheral alveoli into dilated bronchioles in lobules: these findings in lung sarcoidosis were different from those corresponding to honeycomb lung in idiopathic pulmonary fibrosis/usual interstitial pneumonia. Radiological and pathological findings showed the possibility that progressive clustering of dilated bronchi and bronchioles causes cystic changes, resulting in the formation of honeycomb-like structures as fibrosis progresses in sarcoidosis with lung involvement.

PMID:34026215 | PMC:PMC8133087 | DOI:10.1002/rcr2.782

Clin Chest Med. 2021 Jun;42(2):365-373. doi: 10.1016/j.ccm.2021.03.012.

ABSTRACT

Current therapeutic strategies have succeeded in slowing down the progression of idiopathic pulmonary fibrosis (IPF). Emerging evidence highlights IPF as a disease of aging and impaired regeneration. Novel antiaging and regenerative medicine approaches hold promise to be able to reverse disease and might present hope for a cure. Research focusing on a deeper understanding of lung stem cell populations and how these are regulated and altered in fibrotic disease continues to drive the field, and accompanied by earlier diagnosis, the adaptation of clinically relevant models and readouts for regeneration of diseased lung, ultimately paves the way for translation into clinics.

PMID:34024411 | DOI:10.1016/j.ccm.2021.03.012

Clin Chest Med. 2021 Jun;42(2):357-364. doi: 10.1016/j.ccm.2021.03.011.

ABSTRACT

Management of patients with interstitial lung disease (ILD) requires accurate classification. However, this process relies on subjective interpretation of nonspecific and overlapping clinical features that could hamper clinical care. The development and implementation of objective biomarkers reflective of specific disease states could facilitate precision-based approaches based on patient-level biology to improve the health of ILD patients. Omics-based studies allow for the seemingly unbiased and highly efficient screening of candidate biomarkers and offer unprecedented opportunities for discovery. This review outlines representative major omics-based discoveries in a well-studied condition, idiopathic pulmonary fibrosis, to develop a roadmap to personalized medicine in ILD.

PMID:34024410 | DOI:10.1016/j.ccm.2021.03.011

Clin Chest Med. 2021 Jun;42(2):321-335. doi: 10.1016/j.ccm.2021.03.008.

ABSTRACT

Nonidiopathic pulmonary fibrosis (non-IPF) progressive fibrotic interstitial lung diseases (PF-ILDs) are a heterogeneous group of ILDs, often challenging to diagnose, although an accurate diagnosis has significant implications for both treatment and prognosis. A subgroup of these patients experiences progressive deterioration in lung function, physical performance, and quality of life after conventional therapy. Risk factors for ILD progression include older age, lower baseline pulmonary function, and a usual interstitial pneumonia pattern. Management of non-IPF P-ILD is both pharmacologic and nonpharmacologic. Antifibrotic drugs, originally approved for IPF, have been considered in patients with other fibrotic ILD subtypes, with favorable results in clinical trials.

PMID:34024407 | DOI:10.1016/j.ccm.2021.03.008

Clin Chest Med. 2021 Jun;42(2):287-294. doi: 10.1016/j.ccm.2021.03.006.

ABSTRACT

We are in the midst of transformative innovation in health care delivery and clinical trials in idiopathic pulmonary fibrosis (IPF). Health systems are uniquely positioned at the crossroad of these shifting paradigms, equipped with the resources to expand the research pipeline in IPF through visionary leadership and targeted investments. The authors hope that by prioritizing development of health information technology, supporting a broader range of clinical trial designs, and cultivating broad stakeholder engagement, health systems will generate data to address knowledge-evidence-practice gaps in IPF. This will continue to improve the ability to deliver high-quality, safe, and effective care.

PMID:34024404 | DOI:10.1016/j.ccm.2021.03.006

Clin Chest Med. 2021 Jun;42(2):275-285. doi: 10.1016/j.ccm.2021.03.004.

ABSTRACT

Progress in the past 2 decades has led to widespread use of 2 medications to slow loss of lung function in patients with pulmonary fibrosis. Treatment of individual patients with currently available pharmacotherapies can be limited by side effects, and neither drug has a consistent effect on patient symptoms or function. Several promising new pharmacotherapies are under development. Comprehensive management of pulmonary fibrosis hinges on shared decision making. Patient and caregiver education, and early identification and management of symptoms and comorbidities, can help improve quality of life.

PMID:34024403 | DOI:10.1016/j.ccm.2021.03.004

Clin Chest Med. 2021 Jun;42(2):263-273. doi: 10.1016/j.ccm.2021.03.005.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s, understanding of IPF has evolved considerably. Such evolution has continually challenged prior diagnostic and treatment paradigms, ushering in an era of higher confidence diagnoses with less invasive procedures and more effective treatments. This review details how research and clinical experience over the past half century have led to a rethinking of IPF. Here, the evolution in understanding of IPF pathogenesis, diagnostic evaluation and treatment approach is discussed.

PMID:34024402 | DOI:10.1016/j.ccm.2021.03.005