Idiopathic Pulmonary Fibrosis

Transcription

1 Hiroyuki Nakamura Kazutetsu Aoshiba Editors Idiopathic Pulmonary Fibrosis Advances in Diagnostic Tools and Disease Management 123

2 Idiopathic Pulmonary Fibrosis

3 ThiS is a FM Blank Page

4 Hiroyuki Nakamura Kazutetsu Aoshiba Editors Idiopathic Pulmonary Fibrosis Advances in Diagnostic Tools and Disease Management

5 Editors Hiroyuki Nakamura Department of Respiratory Medicine Tokyo Medical University Ibaraki Medical Center Ibaraki, Japan Kazutetsu Aoshiba Department of Respiratory Medicine Tokyo Medical University Ibaraki Medical Center Ibaraki, Japan ISBN ISBN (ebook) DOI / Library of Congress Control Number: Springer Tokyo Heidelberg New York Dordrecht London Springer Japan 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer Japan KK is part of Springer Science+Business Media (

6 Preface Owing to the remarkable advances in the fields of molecular biology and genomics/ genetics in recent years, medicine has progressed rapidly in various fields, including respiratory medicine. Many advances that have been made in this field include the advent of novel molecular-targeted therapies for lung cancer, the widespread use of inhaled corticosteroids, anti-cholinergic agents and long-acting beta-adrenergic agonists in the treatment of bronchial asthma/chronic obstructive pulmonary disease (COPD), and the development of novel antimicrobial agents for the treatment of respiratory tract infections. In regard to idiopathic pulmonary fibrosis, however, there have been no important additions to the armamentarium for managing this intractable disease over the last these 3 decades, since I graduated from medical school, with definitive therapeutics still lacking. Lung tissue can be roughly divided into parenchyma and interstitium. In the narrower sense, the term interstitium refers to the alveolar septum which separates the alveoli from one another. Idiopathic interstitial pneumonias (IIPs) are characterized by hypertrophy of the alveolar septa due to inflammation. With progression of the disease, lung tissue remodeling through fibrosis takes place. According to the ATS/ERS International Multidisciplinary Consensus Classification (2013), IIPs can be classified into the following six major types: (1) idiopathic pulmonary fibrosis (IPF), (2) idiopathic nonspecific interstitial pneumonia, (3) respiratory bronchiolitis interstitial lung disease, (4) desquamative interstitial pneumonia, (5) cryptogenic organizing pneumonia, and (6) acute interstitial pneumonia [1]. This classification is still not complete and is expected to be modified with advances in this research field. IPF is the most frequent type of IIPs. Recent cohort studies and computed tomography (CT)-based epidemiological studies in Japan have indicated a high prevalence of IPF [2]. IPF is a disease characterized by intense lung fibrosis that follows a chronic and progressive course. In comparison to other types of IIPs, IPF responds poorly to steroid and immunosuppressant drug treatment and in general carries a poor prognosis. Approximately half of the patients with IPF die within 3 5 years of the diagnosis. Acute exacerbations increase the mortality of IPF to as v

7 vi Preface high as approximately 80 %. Thus, currently, IPF is among the most challenging of respiratory diseases to manage. Pulmonary fibrosis is also encountered in other conditions including viral infection, smoking, pneumoconiosis, medication, radiotherapy, and others. However, as indicated by its epithet idiopathic, the causes and reasons for the lung fibrosis in IPF remain elusive. According to the current view, the essential feature of IPF is not inflammation caused by immunocompetent cells, but proliferation of fibroblasts (due to apoptosis of alveolar epithelial cells) and their differentiation into myofibroblasts. This view can explain why IPF responds poorly to treatment with steroids (glucocorticoids) (which have long been used clinically as representative anti-inflammatory agents). Furthermore, this view suggests the importance of anti-fibrotic therapy as an essential means of treatment for this condition. Japanese researchers have made remarkable contributions to the study of this disease, some examples of which include the proposal of the concept of acute exacerbation [3], development of serum markers that are relatively highly specific for this disease (KL-6, SP-A, and SP-D) [4, 5], establishment of high-resolution computed tomography (HRCT) for diagnostic imaging, as compared to inflated and fixed lung specimens obtained by open lung biopsy and autopsy [6, 7], and reporting of the treatment outcomes of pirfenidone [8], an antifibrotic agent that was first approved in Japan. Thus, Japanese researchers have made remarkable contributions in the field of research on IIPs and published the results in international journals. Despite these diagnostic and therapeutic improvements, no treatments have been established yet that can boast of being a complete cure for IPF. In addition, interstitial pneumonia with emphysema (combined pulmonary fibrosis and emphysema: CPFE) has been proposed recently as a new entity [9]. CPFE is a condition characterized by emphysematous lesions in the upper lung regions, accompanied by fibrosis in the lower lung regions. This disease is most often seen in male heavy smokers and is clinically characterized by the development of intense hypoxemia with effort, marked reduction in the lung dilatation, elevation of the serum KL-6 level, frequent complication by pulmonary hypertension and lung cancer, and so on. However, because of insufficient knowledge about the pathophysiology of this condition and the absence of a clear-cut definition, physicians in practice are still confused about this entity. IPF is frequently complicated by lung cancer. It is therefore speculated that some common molecular mechanisms might be involved in the onset of IPF and lung cancer. The results of basic studies suggest that injury of the alveolar epithelial cells seen in cases of IPF not only stimulates pulmonary fibrosis, but also induces multiple gene abnormalities that can lead to the onset of lung cancer. It has also been suggested that apart from promoting lung carcinogenesis, pulmonary fibrosis may also be involved in the growth/spread of the cancer. Thus, basic research is under way in Japan to try to decode these associations. One of the important clinical problems associated with IPF is the development of acute exacerbations of the condition following surgery in lung cancer patients, but some very remarkable

8 Preface vii results of treatment are being obtained in large-scale epidemiologic studies in Japan [10]. To date, there have only been a small number of books containing detailed descriptions of IPF, all of which are uniformly organized in the traditional style. This current project presents readers with clinical questions about issues that are not yet fully resolved as the subtitles for the chapters, to authors who have long been engaged in research on IIPs long and are leading experts in this field in Japan. The authors will provide up-to-date information in response to each question. They will describe their thoughts and the future perspectives in response to the clinical questions, based on up-to-date information. Therefore, besides obtaining up-todate information, the readers can also understand the authors real intentions and future perspectives, so that their intellectual curiosity will be satisfied. Considering the nature of this project, useful information will be provided not only for beginning learners studying about IIPs, but also for physicians in clinical practice, instructors, and the many researchers engaged in basic research on this subject. The Editors hope that this book, written by Japanese authors, will provide valuable input that will help all practicing physicians and medical researchers in the world to better understand the pathogenesis of IPF and to attempt to develop innovative treatments for this intractable disease. The Editors will be greatly pleased if this book can thus bring about therapeutic breakthroughs for patients worldwide suffering from IPF. Ibaraki, Japan Hiroyuki Nakamura Kazutetsu Aoshiba References 1. Travis WD, Costabel U, Hansell DM, King TE, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6): Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, et al. Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med. 2014;190(7): Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K. Acute exacerbation in idiopathic pulmonary fibrosis: analysis of clinical and pathologic findings in three cases. Chest. 1993;103(6): Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pneumonitis activity: Sialylated carbohydrate antigen KL-6. Chest. 1989;96(1): Honda Y, Kuroki Y, Matuura E, Nagae H, Takahashi H, Akino T, et al. Pulmonary surfactant protein D in sera and bronchoalveolar lavage fluids. Am J Respir Crit Care Med. 1995;152 (6 pt1): Nishimura K, Kitaichi M, Izumi T, Nagai S, Kanaoka M, Itoh H. Usual interstitial pneumonia: histologic correlation with high-resolution CT. Radiology. 1992;182(2):

9 viii Preface 7. Johkoh T, Sakai F, Noma S, Akira M, Fujimoto K, Watadani T, et al. Honeycombing on CT; its definition, pathologic correlation, and future direction of its diagnosis. Eur J Radiol. 2014;83(1): Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, et al. Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171(9): Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblonde I, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26 (4): Sato T, Teramukai S, Kondo H, Watanabe A, Ebina M, Kishi K, et al. Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg. 2014;147(5):

10 Contents Part I Definition, Epidemiology, and Pathogenesis 1 Definition of IPF... 3 Shinji Abe and Akihiko Gemma 2 Epidemiology and Risk Factors of IPF Kazuyoshi Kuwano, Jun Araya, and Hiromichi Hara 3 Acute Exacerbation of IPF Yoshiki Ishii 4 Pathogenesis of IPF Yasuhiko Nishioka Part II Diagnosis 5 Specific Serum Markers of IPF Hirofumi Chiba and Hiroki Takahashi 6 High-Resolution Computed Tomography of Honeycombing and IPF/UIP Fumikazu Sakai 7 Pathology of IPF Yoshinori Kawabata 8 Differential Diagnosis of IPF Hidehiro Watanabe Part III Management and Prognosis 9 Pharmacotherapy of IPF Using Antifibrotic Compounds Tomohiro Handa and Arata Azuma ix

11 x Contents 10 Pharmacotherapy of IPF (Corticosteroids, Immunosuppressants, Etc.) Masashi Bando 11 Non-pharmacological Therapy for IPF Yukihiro Umeda, Tamotsu Ishizuka, and Takeshi Ishizaki 12 Pharmacotherapy of Acute Exacerbation of IPF (Corticosteroids, Immunosuppressants, and Direct Hemoperfusion with Polymyxin) Masayuki Itoh Part IV Topics 13 Combined Pulmonary Fibrosis and Emphysema (CPFE) Yoshiteru Morio and Kazuhisa Takahashi 14 Common Pathways in IPF and Lung Cancer Nobuyuki Koyama 15 Acute Exacerbation of Interstitial Pneumonia After Pulmonary Resection for Lung Cancer Hiroshi Date

12 Part I Definition, Epidemiology, and Pathogenesis

13 Chapter 1 Definition of IPF Is the Latest Classification of IIPs [ATS/ERS] Satisfactory? Shinji Abe and Akihiko Gemma Abstract Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonias (IIPs), is a fatal disease with a mean survival time of 2 4 years from the time of diagnosis. Therefore, the early and accurate diagnosis of IPF is important and essential for management and induction of optimal therapies. In 2002, the American Thoracic Society and European Respiratory Society (ATS/ERS) published an international statement on the diagnosis and management of IPF. The 2002 ATS/ERS statement defined IPF as a distinct clinical entity associated with the histology of usual interstitial pneumonia (UIP). The revised evidence-based guidelines for diagnosis and management of IPF were published by collaboration between the ATS, ERS, Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) in In the revised 2011 criteria, high-resolution CT (HRCT) has a central role for the diagnosis of IPF. The presence of UIP patterns on HRCT is essential and definitive in the diagnosis of IPF without the need for surgical lung biopsy (SLB). The revised 2011 criteria have emphasized the importance of multidisciplinary discussion between clinicians, radiologists, and pathologists experienced in the diagnosis of IPF. Keywords Idiopathic pulmonary fibrosis (IPF) High-resolution CT (HRCT) ATS/ERS statement ATS/ERS/JRS/ALAT statement S. Abe (*) Department of Pulmonary Medicine, Tokyo Metropolitan Hiroo General Hospital, Ebisu, Shibuya-ku, Tokyo , Japan sabe@nms.ac.jp A. Gemma Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo , Japan Springer Japan 2016 H. Nakamura, K. Aoshiba (eds.), Idiopathic Pulmonary Fibrosis, DOI / _1 3

14 4 S. Abe and A. Gemma 1.1 Introduction The idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung diseases of unknown etiology with varying degrees of inflammation and fibrosis [1]. In 1975, Liebow first described five pathologic subgroups of chronic idiopathic interstitial pneumonia: usual interstitial pneumonia (UIP), diffuse lesions similar to UIP with superimposed bronchiolitis obliterans (termed bronchiolitis interstitial pneumonia), desquamative interstitial pneumonia (DIP), lymphocytic interstitial pneumonia (LIP), and giant cell pneumonia [2]. In 1998, Kazenstein and Myers revised the classification including five histopathologically distinct subgroups: UIP, DIP, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), and nonspecific interstitial pneumonia (NSIP). AIP and NSIP were introduced as IIPs [3]. In 2002, the American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary panel proposed a new classification of IIPs that are comprised of seven clinical-pathological entities such as IPF, NSIP, cryptogenic organizing pneumonia (COP), AIP, RB-ILD, DIP, and LIP [1]. The 2002 ATS/ERS statement emphasized the importance of interaction among clinicians, radiologists, and pathologists for the final diagnosis of IIPs. IPF was defined to a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and associated with a surgical lung biopsy showing a histopathologic pattern of UIP. The definitive diagnosis of IPF required histopathologic patterns of UIP on surgical lung biopsy (SLB). In the absence of SLB, a presumptive diagnosis can be made by clinical, radiologic, and physiologic criteria (four major and three minor criteria). IPF is the most common and severe form of IIPs. The prognosis of IPF has been reported to be very poor with a mean survival of 2 4 years after the initial diagnosis. Therefore, an early and accurate diagnosis of IPF is critical, especially for the management and induction of treatment to prevent disease progression [4]. In 2011, the ATS/ERS/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) has published revised evidenced-based guidelines for diagnosis and management of IPF [5]. This chapter focuses on the definition of IPF in the revised 2011 criteria and discusses clinical application and key problems. 1.2 The ATS/ERS/JRS/ALAT 2011 Revised Diagnostic Criteria [5] In the 2011 revised criteria, IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP.

15 1 Definition of IPF 5 The diagnosis of IPF requires: (a) Exclusion of other causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, connective tissue diseases, and drug toxicity) (b) The presence of UIP pattern on high-resolution computed tomography (HRCT) in patients not subjected to surgical lung biopsy (c) Specific combination of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy The major and minor criteria proposed in the 2002 ATS/ERS consensus statement have been eliminated. The accuracy of the diagnosis of IPF increases with multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILDs. IPF is a fatal lung disease; the natural history is variable and unpredictable. Most patients with IPF demonstrate a gradual worsening of lung function over years; a minority of patients remain stable or decline rapidly. Some patients may experience episodes of acute respiratory worsening despite previous stability. Disease progression is manifested by increasing respiratory symptoms, worsening pulmonary function test results, progressive fibrosis on HRCT, acute respiratory decline, or death. Patients with IPF may have subclinical or overt comorbid conditions including pulmonary hypertension, gastroesophageal reflux, obstructive sleep apnea, obesity, and emphysema. The impact of these conditions on the outcome of patients with IPF is unclear. The diagnostic algorithm for adult patients with suspected IPF is shown in Fig HRCT has an essential role in the diagnostic pathway in IPF (Fig. 1.1 and Table 1.1). UIP is characterized on HRCT by the presence of reticular opacities, often associated with traction bronchiectasis. Honeycombing is common and critical for making a definite diagnosis of IPF. Honeycombing is manifested on HRCT as clustered cystic airspaces, typically of comparable diameters in the order rof 3 10 mm but occasionally as large as 25 mm. It is usually subpleural and is characterized by well-defined walls. Ground-glass opacities are common, but usually less extensive than the reticulation. The distribution of UIP on HRCT is characteristically basal and peripheral, though often patchy. The presence of coexistent pleural abnormalities (e.g., pleural plaques, calcifications, significant pleural effusion) suggests an alternative etiology for UIP pattern. Micronodules, air trapping, non-honeycomb cysts, extensive ground-glass opacities, consolidation, or a peribronchovascular-predominant distribution should lead to consideration of an alternative diagnosis. Mild mediastinal lymph node enlargement (usually <1.5 cm in short axis) can be seen. Possible UIP and inconsistent with UIP patterns on