Kevin R Flaherty, Athol U Wells, Vincent Cottin, Anand Devaraj, Simon L F Walsh, Yoshikazu Inoue, Luca Richeldi, Martin Kolb, Kay Tetzlaff, Susanne Stowasser, Carl Coeck, Emmanuelle Clerisme-Beaty, Bernd Rosenstock, Manuel Quaresma, Thomas Haeufel, Rainer-Georg Goeldner, Rozsa Schlenker-Herceg, Kevin K Brown, INBUILD Trial Investigators
Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.
N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.1056/NEJMoa1908681. Epub 2019 Sep 29.
Abstract/Text
BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.
METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.
RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.
CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).
Copyright © 2019 Massachusetts Medical Society.
Ganesh Raghu, Martine Remy-Jardin, Luca Richeldi, Carey C Thomson, Yoshikazu Inoue, Takeshi Johkoh, Michael Kreuter, David A Lynch, Toby M Maher, Fernando J Martinez, Maria Molina-Molina, Jeffrey L Myers, Andrew G Nicholson, Christopher J Ryerson, Mary E Strek, Lauren K Troy, Marlies Wijsenbeek, Manoj J Mammen, Tanzib Hossain, Brittany D Bissell, Derrick D Herman, Stephanie M Hon, Fayez Kheir, Yet H Khor, Madalina Macrea, Katerina M Antoniou, Demosthenes Bouros, Ivette Buendia-Roldan, Fabian Caro, Bruno Crestani, Lawrence Ho, Julie Morisset, Amy L Olson, Anna Podolanczuk, Venerino Poletti, Moisés Selman, Thomas Ewing, Stephen Jones, Shandra L Knight, Marya Ghazipura, Kevin C Wilson
Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.
Am J Respir Crit Care Med. 2022 May 1;205(9):e18-e47. doi: 10.1164/rccm.202202-0399ST.
Abstract/Text
Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax 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.
Aryeh Fischer, Katerina M Antoniou, Kevin K Brown, Jacques Cadranel, Tamera J Corte, Roland M du Bois, Joyce S Lee, Kevin O Leslie, David A Lynch, Eric L Matteson, Marta Mosca, Imre Noth, Luca Richeldi, Mary E Strek, Jeffrey J Swigris, Athol U Wells, Sterling G West, Harold R Collard, Vincent Cottin, “ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD”
An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features.
Eur Respir J. 2015 Oct;46(4):976-87. doi: 10.1183/13993003.00150-2015. Epub 2015 Jul 9.
Abstract/Text
Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort.
Copyright ©ERS 2015.
日本呼吸器学会薬剤性肺障害の診断・治療の手引き第2版作成委員会編. 薬剤性肺障害の診断・治療の手引き（第2版）2018. メディカルビュー. 2018.
特発性間質性肺炎 診断と治療の手引き(改訂第4版) 2022.日本呼吸器学会びまん性肺疾患 診断・治療ガイドライン作成委員会編.南江堂. 2022.
Jin Woo Song, Kyung-Hyun Do, Mi-Young Kim, Se Jin Jang, Thomas V Colby, Dong Soon Kim
Pathologic and radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia.
Chest. 2009 Jul;136(1):23-30. doi: 10.1378/chest.08-2572. Epub 2009 Mar 2.
Abstract/Text
BACKGROUND: Patients with usual interstitial pneumonia (UIP) associated with collagen vascular disease (CVD) have been reported to have a better prognosis than those with idiopathic pulmonary fibrosis with a UIP pattern (IPF/UIP) seen on histology. The aim of this study was to evaluate the pathologic and radiologic differences between the two conditions and their relationship with clinical outcome.
METHODS: A retrospective review of 100 patients (CVD-UIP, 39 patients; IPF/UIP, 61 patients) with UIP pattern diagnosed by surgical lung biopsy at one tertiary referral center.
RESULTS: The median follow-up period was 34.4 months. The CVD-UIP group was younger, included more women and nonsmokers, and showed better survival than the IPF/UIP group. Pathologically, CVD-UIP patients had fewer fibroblastic foci and smaller honeycombing (HC) spaces with higher germinal centers and total inflammation scores than IPF/UIP patients. Radiologically, CVD-UIP patients had a lower emphysema score and more likely a nontypical UIP pattern without HC. The germinal centers score was the best distinguishing feature between CVD-UIP and IPF/UIP patients (odds ratio, 2.948; p = 0.001) and was marginally related to survival (p = 0.076). The HC score (hazard ratio [HR], 1.134; p < 0.001), total lung capacity (TLC) [HR, 0.932; p = 0.004], and age (HR, 1.052; p = 0.017) were significant predictors of survival in all patients with UIP histology, regardless of the presence of CVD. Among IPF/UIP patients, those with positive autoantibodies were pathologically more similar to CVD-UIP than to IPF/UIP without autoantibodies, despite no difference in survival between them.
CONCLUSIONS: The germinal centers score was the best discriminative between CVD-UIP and IPF/UIP patients; it was of marginal prognostic significance. Age, TLC, and HC score were independent prognostic factors in all patients with UIP histology.
Motoki Natsuizaka, Hirofumi Chiba, Koji Kuronuma, Mitsuo Otsuka, Kazumi Kudo, Mitsuru Mori, Masashi Bando, Yukihiko Sugiyama, Hiroki Takahashi
Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences.
Am J Respir Crit Care Med. 2014 Oct 1;190(7):773-9. doi: 10.1164/rccm.201403-0566OC.
Abstract/Text
RATIONALE: Idiopathic pulmonary fibrosis (IPF) has an unknown etiology and poor prognosis. Several large-scale epidemiologic studies have been conducted predominantly in Western countries. There are few studies reported from Asian countries. It remains unclear whether ethnic difference exists in IPF. It is important to determine the current IPF status in Asian populations and compare it with that of Western populations.
OBJECTIVES: To provide the epidemiologic status of IPF in Japan and to investigate ethnic differences.
METHODS: We selected Hokkaido prefecture (population, 5.6 million) as the epidemiologic cohort of IPF among Japanese. On the basis of the clinical records of 553 patients with IPF who were accepted based on the application of the Certificate of Medical Benefit between 2003 and 2007, we conducted a retrospective epidemiologic and prognostic analysis.
MEASUREMENTS AND MAIN RESULTS: The prevalence and cumulative incidence of IPF was 10.0 and 2.23 per 100,000 population, respectively, with 72.7% predominance of males and an increase in frequency with age. The median survival time was 35 months, and the most common (40%) cause of death was acute exacerbation. The most important factor influencing IPF prognosis was the percent vital capacity.
CONCLUSIONS: The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.
Yasuhiro Kondoh, Hiroyuki Taniguchi, Kensuke Kataoka, Taiki Furukawa, Masahiko Ando, Kenta Murotani, Michiaki Mishima, Yoshikazu Inoue, Takashi Ogura, Masashi Bando, Koichi Hagiwara, Takafumi Suda, Hirofumi Chiba, Hiroki Takahashi, Yukihiko Sugiyama, Sakae Homma
Disease severity staging system for idiopathic pulmonary fibrosis in Japan.
Respirology. 2017 Nov;22(8):1609-1614. doi: 10.1111/resp.13138. Epub 2017 Aug 8.
Abstract/Text
BACKGROUND AND OBJECTIVE: In Japan, the classification of disease severity of idiopathic pulmonary fibrosis (IPF) (J-system) has been used in making decisions on medical care subsidies. The present J-system consists of arterial partial pressure of oxygen (PaO2 ) and exercise desaturation in stages of I-IV. It provides a good prognostic classification in stages III and IV, but not in stages I and II. Therefore, we propose a revised system to improve discriminative ability in stages I and II.
METHODS: We compared the revised J-system with the present J-system using Cox proportional hazards model to predict mortality rate. We also evaluated the recently proposed GAP (Gender, Age and Physiology) system in comparison to both J-systems.
RESULTS: Two-hundred and fifteen IPF patients were studied retrospectively. A univariate model showed that the present and revised J-systems and a modified GAP system were all significant prognostic factors. The C-statistic for discriminating prognosis was higher in the revised J-system than the modified GAP system and the present J-system (0.677, 0.652 and 0.659, respectively). The C-statistics of these models produced from the 10 000 bootstrap samples were similar to those of the original models, suggesting good internal validation (0.665 (95% CI: 0.621-0.705), 0.645 (0.600-0.686) and 0.659 (0.616-0.700), respectively). Multivariate analysis revealed that the revised J-system (P = 0.0038) and the modified GAP system (P = 0.0029) were independent prognostic factors.
CONCLUSION: The revised J-system can provide a better mortality prediction than the present one. Both the revised J-system and the modified GAP system are independent and valuable tools for prognostication and clinical management for IPF.
© 2017 Asian Pacific Society of Respirology.
Brett Ley, Christopher J Ryerson, Eric Vittinghoff, Jay H Ryu, Sara Tomassetti, Joyce S Lee, Venerino Poletti, Matteo Buccioli, Brett M Elicker, Kirk D Jones, Talmadge E King, Harold R Collard
A multidimensional index and staging system for idiopathic pulmonary fibrosis.
Ann Intern Med. 2012 May 15;156(10):684-91. doi: 10.7326/0003-4819-156-10-201205150-00004.
Abstract/Text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an overall poor prognosis. A simple-to-use staging system for IPF may improve prognostication, help guide management, and facilitate research.
OBJECTIVE: To develop a multidimensional prognostic staging system for IPF by using commonly measured clinical and physiologic variables.
DESIGN: A clinical prediction model was developed and validated by using retrospective data from 3 large, geographically distinct cohorts.
SETTING: Interstitial lung disease referral centers in California, Minnesota, and Italy.
PATIENTS: 228 patients with IPF at the University of California, San Francisco (derivation cohort), and 330 patients at the Mayo Clinic and Morgagni-Pierantoni Hospital (validation cohort).
MEASUREMENTS: The primary outcome was mortality, treating transplantation as a competing risk. Model discrimination was assessed by the c-index, and calibration was assessed by comparing predicted and observed cumulative mortality at 1, 2, and 3 years.
RESULTS: Four variables were included in the final model: gender (G), age (A), and 2 lung physiology variables (P) (FVC and Dlco). A model using continuous predictors (GAP calculator) and a simple point-scoring system (GAP index) performed similarly in derivation (c-index of 70.8 and 69.3, respectively) and validation (c-index of 69.1 and 68.7, respectively). Three stages (stages I, II, and III) were identified based on the GAP index with 1-year mortality of 6%, 16%, and 39%, respectively. The GAP models performed similarly in pooled follow-up visits (c-index ≥71.9).
LIMITATION: Patients were drawn from academic centers and analyzed retrospectively.
CONCLUSION: The GAP models use commonly measured clinical and physiologic variables to predict mortality in patients with IPF.
Shun Kondoh, Hirofumi Chiba, Hirotaka Nishikiori, Yasuaki Umeda, Koji Kuronuma, Mitsuo Otsuka, Gen Yamada, Hirofumi Ohnishi, Mitsuru Mori, Yasuhiro Kondoh, Hiroyuki Taniguchi, Sakae Homma, Hiroki Takahashi
Validation of the Japanese disease severity classification and the GAP model in Japanese patients with idiopathic pulmonary fibrosis.
Respir Investig. 2016 Sep;54(5):327-33. doi: 10.1016/j.resinv.2016.02.009. Epub 2016 Mar 30.
Abstract/Text
BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) shows great inter-individual differences. It is important to standardize the severity classification to accurately evaluate each patient׳s prognosis. In Japan, an original severity classification (the Japanese disease severity classification, JSC) is used. In the United States, the new multidimensional index and staging system (the GAP model) has been proposed. The objective of this study was to evaluate the model performance for the prediction of mortality risk of the JSC and GAP models using a large cohort of Japanese patients with IPF.
METHODS: This is a retrospective cohort study including 326 patients with IPF in the Hokkaido prefecture from 2003 to 2007. We obtained the survival curves of each stage of the GAP and JSC models to perform a comparison. In the GAP model, the prognostic value for mortality risk of Japanese patients was also evaluated.
RESULTS: In the JSC, patient prognoses were roughly divided into two groups, mild cases (Stages I and II) and severe cases (Stages III and IV). In the GAP model, there was no significant difference in survival between Stages II and III, and the mortality rates in the patients classified into the GAP Stages I and II were underestimated.
CONCLUSIONS: It is difficult to predict accurate prognosis of IPF using the JSC and the GAP models. A re-examination of the variables from the two models is required, as well as an evaluation of the prognostic value to revise the severity classification for Japanese patients with IPF.
Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Hirotaka Nishikiori, Hirofumi Chiba, Sang Hoon Lee, Shun Kondoh, Ken-Ichi Kamo, Koshi Nakamura, Kimiyuki Ikeda, Koji Kuronuma, Man Pyo Chung, Yasuhiro Kondoh, Sakae Homma, Naohiko Inase, Moo Suk Park, Hiroki Takahashi
A modified GAP model for East-Asian populations with idiopathic pulmonary fibrosis.
Respir Investig. 2020 Sep;58(5):395-402. doi: 10.1016/j.resinv.2020.04.001. Epub 2020 Jul 24.
Abstract/Text
BACKGROUND: The easy-to-calculate gender, age, and lung physiology (GAP) model shows good predictive and discriminative performance in the prognosis of idiopathic pulmonary fibrosis (IPF). However, the GAP model was not effective in predicting the prognosis accurately in previous Japanese and Korean IPF cohort studies. Therefore, we developed a modified GAP model for the East-Asian populations by weighing the GAP variables. The validity of the modified GAP model was subsequently evaluated in East-Asian IPF patients.
METHODS: The derivation cohort comprised 326 patients with IPF. Weights of the variables were adjusted on the basis of coefficients derived from Cox regression models. The total points were distributed to the three stages of the disease so that the number of patients included in each stage was appropriate. The validity of the modified model was analyzed in another Japanese cohort of 117 patients with IPF and a nationwide cohort of Korean patients with IPF.
RESULTS: Predicted survival rates differed significantly in the derivation cohort using the modified GAP model for each stage of IPF (log-rank test: stage I vs. stage II, p < 0.001; stage II vs. stage III, p < 0.001). Model performance improved according to Harrell's C-index (at three years: 0.696 in the original GAP model to 0.738 in the modified model). The performance of the modified model was validated in the Japanese validation and Korean national cohorts.
CONCLUSIONS: Our modification of the original GAP model showed improved performance in East-Asian IPF patient populations.
Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Y Kondoh, H Taniguchi, Y Kawabata, T Yokoi, K Suzuki, K Takagi
Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases.
Chest. 1993 Jun;103(6):1808-12.
Abstract/Text
We treated three patients with idiopathic pulmonary fibrosis who had an acute clinical exacerbation. We analyzed their clinical, radiographic, therapeutic, and pathologic findings. Their initial symptoms were influenza-like illness or cough with fever, and all had leukocytosis and elevation of C-reactive protein. Infectious events were ruled out by extensive bacteriologic and serologic examination. The patients' lung injury scores progressed rapidly to severe lung injury compatible with adult respiratory distress syndrome. Findings from bronchoalveolar lavage fluid showed marked neutrophilia and elevation of albumin concentrations. All patients showed various degrees of improvement following corticosteroid therapy. Histologic findings from open lung biopsy specimens showed both usual interstitial pneumonia (UIP) and organizing acute lung injury pattern. Whether these two forms of interstitial pneumonia (UIP and acute lung injury pattern) are variants of one disease or are unrelated and also the effectiveness of corticosteroid therapy on such conditions remain to be determined by further studies.
Harold R Collard, Bethany B Moore, Kevin R Flaherty, Kevin K Brown, Robert J Kaner, Talmadge E King, Joseph A Lasky, James E Loyd, Imre Noth, Mitchell A Olman, Ganesh Raghu, Jesse Roman, Jay H Ryu, David A Zisman, Gary W Hunninghake, Thomas V Colby, Jim J Egan, David M Hansell, Takeshi Johkoh, Naftali Kaminski, Dong Soon Kim, Yasuhiro Kondoh, David A Lynch, Joachim Müller-Quernheim, Jeffrey L Myers, Andrew G Nicholson, Moisés Selman, Galen B Toews, Athol U Wells, Fernando J Martinez, Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators
Acute exacerbations of idiopathic pulmonary fibrosis.
Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43. doi: 10.1164/rccm.200703-463PP. Epub 2007 Jun 21.
Abstract/Text
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
Ganesh Raghu, Harold R Collard, Jim J Egan, Fernando J Martinez, Juergen Behr, Kevin K Brown, Thomas V Colby, Jean-François Cordier, Kevin R Flaherty, Joseph A Lasky, David A Lynch, Jay H Ryu, Jeffrey J Swigris, Athol U Wells, Julio Ancochea, Demosthenes Bouros, Carlos Carvalho, Ulrich Costabel, Masahito Ebina, David M Hansell, Takeshi Johkoh, Dong Soon Kim, Talmadge E King, Yasuhiro Kondoh, Jeffrey Myers, Nestor L Müller, Andrew G Nicholson, Luca Richeldi, Moisés Selman, Rosalind F Dudden, Barbara S Griss, Shandra L Protzko, Holger J Schünemann, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis
An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824. doi: 10.1164/rccm.2009-040GL.
Abstract/Text
This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effort of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question-based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with patients to discuss patients' values and preferences and decide on the appropriate course of action.
Osamu Nishiyama, Hiroyuki Taniguchi, Yasuhiro Kondoh, Tomoki Kimura, Keisuke Kato, Tomoya Ogawa, Fumiko Watanabe, Shinichi Arizono
Dyspnoea at 6-min walk test in idiopathic pulmonary fibrosis: comparison with COPD.
Respir Med. 2007 Apr;101(4):833-8. doi: 10.1016/j.rmed.2006.06.030. Epub 2006 Sep 8.
Abstract/Text
The characteristics of dyspnoea in idiopathic pulmonary fibrosis (IPF) during a 6-min walk test are not clear. This study was designed to evaluate dyspnoea and desaturation during the 6-min walk test in IPF in comparison with that in chronic obstructive pulmonary disease (COPD), which is one of the most studied chronic lung diseases. The 41 consecutive patients with IPF included in this study were assessed by a 6-min walk test and concurrent measures of disease severity. Forty-one age-matched and resting PaO(2) value-matched COPD patients who had undertaken the test during the same period were selected as the control. Only O(2) saturation at the end of the test was an independent predictor of dyspnoea in IPF (r(2)=0.27, P=0.0005), whereas forced expiratory volume in 1s (FEV(1)) was the only predictor in COPD (r(2)=0.16, P=0.0096). Desaturation was significantly more severe in IPF (83.6+/-9.1% in IPF versus 88.0+/-5.9% in COPD, P<0.001). In contrast, dyspnoea assessed with the Borg scale was significantly more severe in COPD (3.6+/-2.1 in IPF versus 4.6+/-1.9 in COPD, P<0.05). O(2) saturation is an independent predictor of dyspnoea at the end of a 6-min walk test in IPF. In comparison with COPD, desaturation is more severe, although dyspnoea is milder.
Vibha N Lama, Kevin R Flaherty, Galen B Toews, Thomas V Colby, William D Travis, Qi Long, Susan Murray, Ella A Kazerooni, Barry H Gross, Joseph P Lynch, Fernando J Martinez
Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia.
Am J Respir Crit Care Med. 2003 Nov 1;168(9):1084-90. doi: 10.1164/rccm.200302-219OC. Epub 2003 Aug 13.
Abstract/Text
Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.
吉村邦彦、中谷竜王、中森祥隆．特発性間質性肺炎の急性増悪に関する臨床的検討ならびに考察．日胸疾会誌 1984;22(11):1012-1020.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).
Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):646-64. doi: 10.1164/ajrccm.161.2.ats3-00.
Abstract/Text
H Taniguchi, M Ebina, Y Kondoh, T Ogura, A Azuma, M Suga, Y Taguchi, H Takahashi, K Nakata, A Sato, M Takeuchi, G Raghu, S Kudoh, T Nukiwa, Pirfenidone Clinical Study Group in Japan
Pirfenidone in idiopathic pulmonary fibrosis.
Eur Respir J. 2010 Apr;35(4):821-9. doi: 10.1183/09031936.00005209. Epub 2009 Dec 8.
Abstract/Text
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.
Arata Azuma, Yoshio Taguchi, Takashi Ogura, Masahito Ebina, Hiroyuki Taniguchi, Yasuhiro Kondoh, Moritaka Suga, Hiroki Takahashi, Koichiro Nakata, Atsuhiko Sato, Shoji Kudoh, Toshihiro Nukiwa, Pirfenidone Clinical Study Group in Japan
Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment.
Respir Res. 2011 Oct 28;12:143. doi: 10.1186/1465-9921-12-143. Epub 2011 Oct 28.
Abstract/Text
BACKGROUND: A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial.
METHODS: The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO(2)), and the lowest oxygen saturation by pulse oximetry (SpO(2)) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52.
RESULTS: Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO(2) < 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea.
CONCLUSIONS: IPF patients having %VC ≥ 70% and SpO(2) < 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment.
TRIAL REGISTRATION: This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (REGISTRATION NUMBER: JAPICCTI-050121).
Talmadge E King, Williamson Z Bradford, Socorro Castro-Bernardini, Elizabeth A Fagan, Ian Glaspole, Marilyn K Glassberg, Eduard Gorina, Peter M Hopkins, David Kardatzke, Lisa Lancaster, David J Lederer, Steven D Nathan, Carlos A Pereira, Steven A Sahn, Robert Sussman, Jeffrey J Swigris, Paul W Noble, ASCEND Study Group
A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.
N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.
Abstract/Text
BACKGROUND: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.
METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.
RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.
CONCLUSIONS: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).
Andreas Guenther, Ekaterina Krauss, Silke Tello, Jasmin Wagner, Bettina Paul, Stefan Kuhn, Olga Maurer, Sabine Heinemann, Ulrich Costabel, María Asunción Nieto Barbero, Veronika Müller, Philippe Bonniaud, Carlo Vancheri, Athol Wells, Martina Vasakova, Alberto Pesci, Matteo Sofia, Walter Klepetko, Werner Seeger, Fotios Drakopanagiotakis, Bruno Crestani
The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.
Respir Res. 2018 Jul 28;19(1):141. doi: 10.1186/s12931-018-0845-5. Epub 2018 Jul 28.
Abstract/Text
BACKGROUND: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research.
METHODS: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management.
RESULTS: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001).
CONCLUSIONS: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time.
TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).
Luca Richeldi, Ulrich Costabel, Moises Selman, Dong Soon Kim, David M Hansell, Andrew G Nicholson, Kevin K Brown, Kevin R Flaherty, Paul W Noble, Ganesh Raghu, Michèle Brun, Abhya Gupta, Nolwenn Juhel, Matthias Klüglich, Roland M du Bois
Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.
N Engl J Med. 2011 Sep 22;365(12):1079-87. doi: 10.1056/NEJMoa1103690.
Abstract/Text
BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.
METHODS: In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity.
RESULTS: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.
CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).
Luca Richeldi, Roland M du Bois, Ganesh Raghu, Arata Azuma, Kevin K Brown, Ulrich Costabel, Vincent Cottin, Kevin R Flaherty, David M Hansell, Yoshikazu Inoue, Dong Soon Kim, Martin Kolb, Andrew G Nicholson, Paul W Noble, Moisés Selman, Hiroyuki Taniguchi, Michèle Brun, Florence Le Maulf, Mannaïg Girard, Susanne Stowasser, Rozsa Schlenker-Herceg, Bernd Disse, Harold R Collard, INPULSIS Trial Investigators
Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.
N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056/NEJMoa1402584. Epub 2014 May 18.
Abstract/Text
BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.
METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.
RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).
