MIIA KÄRKKÄINEN. PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences
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1 PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences MIIA KÄRKKÄINEN ASSESSMENT OF DISEASE PROGRESSION IN IDIOPATHIC PULMONARY FIBROSIS Predictors of Mortality, Course of Disease, Comorbidities and Causes of Death
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3 Assessment of Disease Progression in Idiopathic Pulmonary Fibrosis Predictors of Mortality, Course of Disease, Comorbidities and Causes of Death
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5 MIIA KÄRKKÄINEN Assessment of Disease Progression in Idiopathic Pulmonary Fibrosis Predictors of Mortality, Course of Disease, Comorbidities and Causes of Death To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Kuopio, on Wednesday, May 29 th 2019, at 12 noon Publications of the University of Eastern Finland Dissertations in Health Sciences Number 506 Department of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland Kuopio 2019
6 Grano Oy Jyväskylä, 2019 Series Editors: Professor Tomi Laitinen, M.D., Ph.D. Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences Associate professor (Tenure Track) Tarja Kvist, Ph.D. Department of Nursing Science Faculty of Health Sciences Professor Kai Kaarniranta, M.D., Ph.D. Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences Associate Professor (Tenure Track) Tarja Malm, Ph.D. A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences Lecturer Veli-Pekka Ranta, Ph.D. School of Pharmacy Faculty of Health Sciences Distributor: University of Eastern Finland Kuopio Campus Library P.O.Box 1627 FI Kuopio, Finland ISBN (print): ISBN (pdf): ISSN (print): ISSN (pdf): ISSN-L:
7 III Author s address: Supervisors: Department of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland KUOPIO FINLAND Professor Riitta Kaarteenaho, M.D., Ph.D. Research Unit of Internal Medicine Medical Research Center Oulu Department of Internal Medicine and Respiratory Medicine University of Oulu and Oulu University Hospital OULU FINLAND Docent Minna Purokivi, M.D., Ph.D. Center of Medicine and Clinical Research Division of Respiratory Medicine Kuopio University Hospital KUOPIO FINLAND Reviewers: Docent, Maija Halme, M.D., Ph.D. Heart and Lung Center Department of Pulmonary Diseases University of Helsinki Helsinki University Hospital HELSINKI FINLAND Docent Maritta Kilpeläinen, M.D., Ph.D. Operational Division of Medicine Department of Pulmonary Diseases Turku University Hospital TURKU FINLAND Opponent: Docent Paula Rytilä, M.D., Ph.D., Adj. Prof. University of Helsinki Chief Medical Officer, Vice President Global Medical Affairs and Pharmacovigilance, R&D Orion Corporation, Orion Pharma ESPOO FINLAND
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9 V Kärkkäinen, Miia Assessment of Disease Progression in Idiopathic Pulmonary Fibrosis Predictors of Mortality, Course of Disease, Comorbidities and Causes of Death University of Eastern Finland, Faculty of Health Sciences Publications of the University of Eastern Finland. Dissertations in Health Sciences p. ISBN (print): ISBN (pdf): ISSN (print): ISSN (pdf): ISSN-L: ABSTRACT Idiopathic pulmonary fibrosis (IPF) is one of the most common idiopathic interstitial lung disease (ILD) affecting the lung parenchyma. The diagnosis is usually made at ages between 60 and 70 years. Males with current or past smoking histories have been reported to carry an increased risk of IPF. Typical symptoms are cough and shortness of breath during exercise. The diagnosis is usually made after observing the characteristic findings with highresolution computed tomography (HRCT), but in atypical cases, a lung biopsy is needed for accurate diagnosis. Currently, the only curative treatment for IPF is lung transplantation, but anti-fibrotic medication may prevent disease progression in some patients. The clinical course of disease is variable and difficult to predict. Most commonly, the disease leads to death within 3 4 years. Some patients undergo acute exacerbations (AEx) that are usually severe and can even be lethal. Prediction of the time-point for initiating therapeutic treatment, palliative care and lung transplantation is difficult due to the lack of any generally accepted staging system as well as difficulties in predicting AEx. Composite physiologic index (CPI) and Gender-Age-Physiology (GAP) staging system have been the most commonly applied indexes for estimating the prognosis of patients with IPF. The aims of this study were to re-evaluate a retrospective cohort of patients with IPF from Kuopio University Hospital (KUH) using the prevailing international guidelines and to study retrospectively the clinical factors, which could identify patients with different courses of disease and stages at the time of diagnosis. The functionality of staging systems was investigated and clinical features as well as lung function parameters were assessed on their abilities to predict mortality. Comorbidities, medications and causes of death were examined. The mortality rates of IPF patients in KUH as well as from pulmonary fibrosis (PF) in Finland were investigated. CPI and GAP staging were more useful than pulmonary function tests at baseline in evaluating disease severity, but only a minority of patients with a rapid disease course were accurately staged using GAP. Current smokers developed IPF and died at a younger age than either non-smokers or ex-smokers. The number of comorbidities did not have any effect on survival, but chronic obstructive pulmonary disease and cardiovascular diseases as comorbidities and the use of insulin were related to poorer survival. IPF was the most common cause of death, but compared to females, males had more often comorbidities as the underlying cause of death. Patients with a rapid disease course (survival less than 2 years after diagnosis) had more often AEx preceding death in comparison with patients with a slower course of disease. The mortality from IPF and PF has been rising in the 21 st century.
10 VI This thesis increases our knowledge of the clinical course of patients with IPF and clarifies the usability of the staging systems. It is essential to monitor carefully and regularly the course of the disease in each individual IPF patient. National Library of Medicine Classification: WF 600, WF 141, WA 900 Medical Subject Headings: Idiopathic Pulmonary Fibrosis; Disease Progression; Mortality; Prognosis; Comorbidity; Smoking; Cause of Death; Respiratory Function Tests; Severity of Illness Index; Retrospective Studies; Finland
11 VII Kärkkäinen, Miia Idiopaattisen keuhkofibroosin taudinkulun arviointi kuolemanriskiä ennustavat tekijät, sairauden etenemisnopeus, liitännäissairaudet ja kuolinsyyt Itä-Suomen yliopisto, terveystieteiden tiedekunta Publications of the University of Eastern Finland. Dissertations in Health Sciences s. ISBN (print): ISBN (pdf): ISSN (print): ISSN (pdf): ISSN-L: TIIVISTELMÄ Interstitiaaliset keuhkosairaudet (interstitial lung disease, ILD) ovat ryhmä sairauksia, jotka vaurioittavat keuhkorakkuloita ja pienimpiä ilmateitä. Idiopaattinen keuhkofibroosi (IPF) on yksi tavallisimmista ILD-tyypeistä. IPF-diagnoosi tehdään yleensä 60 ja 70 ikävuoden välillä. Miessukupuolen ja tupakoinnin on todettu lisäävän sairastumisriskiä. Tyypillisiä oireita ovat yskä ja rasitushengenahdistus. Diagnoosi tehdään kliinisten löydösten ja keuhkojen ohutleiketietokonetomografian (HRTT) perusteella, joka usein varmistaa diagnoosin. Mikäli kuvantamislöydös ei ole tyypillinen, mutta IPF-epäily on vahva, diagnoosin varmistamiseen tarvitaan keuhkokudoksen koepalan tutkimista. Sairauden hoitoon on käytössä lääkkeitä, joiden on todettu hidastavan taudin etenemistä joillakin potilailla, mutta ainoa parantava hoito on keuhkonsiirto. Sairauden etenemisnopeutta on vaikea ennustaa, koska taudinkulku on hyvin yksilöllinen. Tyypillisesti tauti etenee vähitellen johtaen kuolemaan 3 4 vuodessa. Osalla potilaista on äkillisiä pahenemisvaiheita, jotka voivat johtaa kuolemaan. Lääkehoidon aloittamisen, palliatiivisen hoidon tai keuhkonsiirron oikeaa ajankohtaa on vaikea arvioida, sillä ei ole olemassa yleisesti hyväksyttyä sairauden vaikeusasteen luokittelua. Myös äkilliset pahenemisvaiheet vaikeuttavat taudinkulun arviointia. Sairauden vaikeusasteen arviointiin on tutkimuksissa yleisimmin käytetty yhdistettyä keuhkojentoimintakoe indeksiä (CPI) sekä sukupuoli-ikä-keuhkojentoimintakoe (GAP) mallia. Tämän tutkimuksen tavoitteena oli arvioida takautuvasti Kuopion yliopistollisessa sairaalassa (KYS) vuosina hoidettujen IPF-potilaiden otos nykyisten kansainvälisten diagnoosikriteerien mukaan ja tutkia potilaiden taudinkulkua. Potilaat jaoteltiin ryhmiin elinajan sekä eri vaikeusasteluokkiin keuhkojen toimintakokeiden ja GAP-mallin mukaan. Etsimme tekijöitä, joita voitaisiin käyttää taudin etenemisnopeuden arvioinnissa. Lisäksi testasimme CPI:n ja GAP:n toimivuutta aineistossa. Tutkimme myös potilaiden liitännäissairauksien ja lääkitysten vaikutusta ennusteeseen sekä selvitimme potilaiden kuolinsyyt. Kuolleisuutta tutkittiin myös koko Suomen alueella Tilastokeskuksen tietojen pohjalta. Tutkimuksessa todettiin, että CPI ja GAP olivat keuhkojen toimintakokeita toimivampia ennusteen arvioinnissa, joskaan nekään eivät kaikkien potilaiden kohdalla toimineet aukottomasti. Tupakoitsijat sairastuivat ja kuolivat nuorempina kuin tupakoimattomat ja tupakoinnin lopettaneet. Liitännäissairauksien määrällä ei ollut vaikutusta ennusteeseen, mutta keuhkoahtaumatauti, sydän- ja verisuonisairaudet sekä insuliinin käyttö olivat yhteydessä huonompaan ennusteeseen. Potilaiden yleisin kuolinsyy oli IPF, mutta miehillä muut sairaudet, kuten sepelvaltimotauti ja keuhkosyöpä, olivat naisia useammin peruskuolinsyinä. Diagnoosin jälkeen alle kaksi vuotta eläneillä potilailla oli enemmän
12 VIII pahenemisvaiheita ennen kuolemaa kuin pitempään eläneillä luvulla sekä IPFkuolleisuus KYSin alueella että kuolleisuus keuhkofibroosiin koko Suomessa ovat nousseet. Tutkimuksemme lisää tietoutta IPF:n taudinkulusta ja selventää riskinarviomallien, CPI:n ja GAP:n, käytettävyyttä ennusteen arvioinnissa. Potilaiden säännöllinen ja tarkka seuranta on tärkeää yksittäisten potilaiden taudinkulun arvioimisessa. Luokitus: WF 600, WF 141, WA 900 Yleinen Suomalainen asiasanasto: keuhkosairaudet; keuhkofibroosi; diagnoosi; riskinarviointi; ennusteet; hoito; seuranta; komorbiditeetti; liitännäistaudit; tupakointi; sairauden eteneminen; kuolleisuus; kuolemansyyt; Pohjois-Savo; Suomi
13 IX Tulla lujaksi, pysyä pehmeänä. Siinä haavetta kylliksi yhdelle elämälle. Tommy Taberman
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15 XI Acknowledgements This study was carried out in the Department of Respiratory Medicine in the University of Eastern Finland and at the Center of Medicine and Clinical Research, Division of Respiratory Medicine in Kuopio University Hospital between the years I would like to express my deep gratitude to my supervisor, Professor Riitta Karteenaho, for her extraordinary professionalism, patient guidance, enthusiastic encouragement and useful critiques of this research work. Any time of the year, week or day, she was able to answer even my stupidest questions as this work progressed. I am also deeply thankful to my other supervisor, Docent Minna Purokivi, for her guidance, support and feedback throughout these years. I would also like to thank my coauthors and study group members: radiologist Hannu-Pekka Kettunen, for his excellent and hard work with the radiological data, statistician Tuomas Selander for his help with methodology and statistical data analysis, and Hanna Nurmi for her support and friendship during this project. In addition, I want to thank Minna Mononen for mutual aid at the end of this project. I also warmly thank research nurses Merja Esselström and Satu Nenonen for their assistance. I would like to offer my special thanks to Ewen MacDonald for his assistance with English grammar and proof-reading all the manuscripts, point-by-point responses and finally this thesis. I want to express my humble thanks to Docent Maija Halme and Docent Maritta Kilpeläinen for their commitment in reviewing this thesis and I thank both of you for the inspirational discussions. The reviewers of the published manuscripts are also much appreciated. The financial support from The Foundation of The Finnish Anti-Tuberculosis Association, The Organization for Respiratory Health in Finland, Väinö and Laina Kivi Foundation, The Kuopio Region Respiratory Foundation, Jalmari and Rauha Ahokas Foundation and the Center of Medicine and Clinical Research in Kuopio University Hospital is gratefully acknowledged. I would like to express my deep appreciation to my work colleagues in the Department of Respiratory Medicine in Kuopio University Hospital: Päivi, Heikki, Jouko, Riitta-Liisa, Aki, Queen Anne and Princess Anne, Matti, Jukka K. and Margit. I have been extraordinarily lucky to have been able to learn the basics of pulmonology from and with you. My gratitude extends to Heli Mattila, the Head of Kuopio City Home Care, Rehabilitation and Medical Services for the Elderly, for making it possible to arrange flexible working hours to ensure completion of this work. I also want to thank my colleagues Marja-Liisa, Marika, Elina, Päivi and Tapio, for taking responsibility for my patients when I was absent from work. I am extremely enthusiastic about taking on the new challenges in geriatric medicine with you. I warmly want to thank the football mums and dads who have taken my children to football training and travelled with them to football tournaments, when I ve been busy with this work. A special thanks is sent to Marianne and Tomi for their unconditional help. I want to thank my parents Marja and Olavi for making me believe in myself and supporting me in every step of my way from childhood to this current moment. In addition, I am extremely thankful to my mother and her spouse Mikko, who have helped me very much with the children during these last years. Because of you, I have been able to find
16 XII some time for myself and relax. I also thank my uncle Juhani, who has also believed in me and took good care of my precious grandmother, Elmi, in her last years. I am very grateful to you, Mika, for your example in all fields of life. I am extremely proud to be able to call you my brother. I thank you, Jukka, the love of my life, my partner in crime and my soul mate, for keeping my feet solidly on the ground, supporting me during this project and helping me to see the bright side of everything. Furthermore, you have taught me valuable lessons in the field of pulmonology and I highly appreciate you also as a colleague. And most importantly I want to thank my sons, Eeli and Eppu, without you I would never have finished this project. You have given me opportunity to put this project aside at times and given me other things to do and think. No achievement has been or ever will be greater than having you. You two are the most valuable things that I will ever have - I love you both very much. Miia Kärkkäinen Kuopio, March 2019
17 XIII List of the original publications: This dissertation is based on the following manuscripts: I Kärkkäinen M, Kettunen H-P, Nurmi H, Selander T, Purokivi M, Kaarteenaho R. Comparison of disease progression subgroups in idiopathic pulmonary fibrosis. Submitted II Kärkkäinen M, Kettunen H-P, Nurmi H, Selander T, Purokivi M, Kaarteenaho R (2017). Effect of smoking and comorbidities on survival in idiopathic pulmonary fibrosis. Respir Res 18:160. published online, DOI: /s III Kärkkäinen M, Nurmi H, Kettunen H-P, Selander T, Purokivi M, Kaarteenaho R (2018). Underlying and immediate causes of death in patients with idiopathic pulmonary fibrosis. BMC Pulm Med May 11;18(1):69. published online, DOI: /s The publications were adapted with the permission of the copyright owners.
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19 XV Table of contents 1 INTRODUCTION REVIEW OF THE LITERATURE INTERSTITIAL LUNG DISEASES HISTORY OF PULMONARY FIBROSIS IDIOPATHIC PULMONARY FIBROSIS (IPF) Prevalence and incidence Clinical presentation Definition Pathogenesis and histological features Diagnosis RISK FACTORS OF IPF Genetic factors and family history Smoking Other risk factors NATURAL HISTORY OF IPF Course of disease Acute exacerbation of IPF RISK PREDICTION AND STAGING OF IPF Age Gender Pulmonary function tests Six-minute walking distance Composite Physiologic Index Gender-Age-Physiology Index and staging system Other scoring systems for IPF Biomarkers COMORBIDITIES IN IPF Respiratory comorbidities Non-respiratory comorbidities MORTALITY AND CAUSES OF DEATH IN IPF Mortality Causes of death TREATMENT OF IPF Previous pharmacological treatment... 31
20 XVI Currently recommended treatment for IPF Ongoing studies of pharmacological treatment Treatment of acute exacerbations Non-pharmacological treatment Lung transplantation Pulmonary rehabilitation Symptom management and palliative care AIMS OF THE STUDY MATERIAL AND METHODS GATHERING AND EVALUATION OF THE STUDY POPULATION COLLECTION OF DEMOGRAPHIC DATA ASSESSMENT OF THE DATA Staging Course of disease Acute exacerbations STATISTICAL ANALYSIS ETHICAL CONSIDERATIONS RESULTS PATIENT CHARACTERISTICS Confirming the diagnosis Prevalence and incidence Demographics Management of the patients STAGING (I) COURSE OF THE DISEASE (I) PREDICTORS OF MORTALITY (I) GENDER AND SMOKING HISTORY (II) COMORBIDITIES (I AND II) MORTALITY AND CAUSES OF DEATH (III) DISCUSSION STUDY DESIGN AND GATHERING OF THE DATA DEMOGRAPHICS LUNG FUNCTION IN PREDICTING MORTALITY GAP AND CPI IN PREDICTING MORTALITY COURSE OF DISEASE SMOKING HISTORY COMORBIDITIES AND CAUSES OF DEATH... 75
21 XVII 6.8 MORTALITY FUTURE PERSPECTIVES CONCLUSIONS REFERENCES... 81
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23 XIX Abbreviations 6MWD 6-minute walking distance CVD cardiovascular disease 6MWT 6-minute walk test DDS dyspnea, diffusion capacity, AEx acute exacerbation of spirometry index idiopathic pulmonary fibrosis DIP desquamative interstitial AIP acute interstitial pneumonia pneumonia ALAT Latin American Thoracic DLco diffusion capacity of carbon Association monoxide ATS American Thoracic Society DLco/VA diffusion capacity per unit of AZA azathioprine lung volume BAL bronchoalveolar lavage DNA deoxyribonucleic acid BIP bronchiolitis interstitial DSP distance-saturation product pneumonia index BDI Magnitude of Task of Basal ERS European Respiratory Society Dyspnea Index EU European Union CAD coronary artery disease FEV1 forced expiratory volume in CI confidence interval one second COP cryptogenic organizing FGFR fibroblast growth factor pneumonia receptor COPD chronic obstructive FVC forced vital capacity pulmonary disease GAP gender-age-physiology index CPFE combined pulmonary fibrosis GER gastro-esophageal reflux and emphysema GIP giant cell interstitial CPI composite physiologic index pneumonia CRP clinical, radiological and HP hypersensitivity pneumonitis physiological scoring system HR hazard ratio CT computed tomography HRCT high-resolution computed CTD connective tissue disease tomography
24 XX ICU intensive care unit OSA obstructive sleep apnea IHD ischemic heart disease PDGR platelet-derived growth factor IIP idiopathic interstitial receptor pneumonia PF pulmonary fibrosis ILD interstitial lung disease PH pulmonary hypertension ICD-10 International Classification of PFT pulmonary function tests Diseases version 10 PPFE pleuroparenchymal IPF idiopathic pulmonary fibrosis fibroelastosis ISHLT International Society of Heart RA rheumatoid arthritis and Lung Transplantation RB-ILD respiratory bronchiolitis JRS Japanese Respiratory interstitial lung disease Association ROC receiver operating KL-6 Krebs von den Lungen-6 characteristic antigen ROSE risk stratifications score KUH Kuopio University Hospital SGRQ St George s Respiratory LIP lymphoid interstitial Questionnaire pneumonia SLB surgical lung biopsy MDD multidisciplinary discussion SP-A/D Surfactant protein A or D mmhg millimeter of mercury TIA transient ischemic attack MMP matrix metalloproteinase TLC total lung capacity MRCDS medical research council UIP usual interstitial pneumonia dyspnea score UK United Kingdom MVV maximum voluntary USA United States of America ventilation VATS video-assisted thoracoscopic NAC N-acetylcysteine surgery NSCLC non-small cell lung cancer VC vital capacity NSIP non-specific interstitial VEGFR vascular endothelial growth pneumonia factor receptor N % Volume on normally WHO World Health Organization attenuated lung as % of whole-lung volume
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27 1 Introduction Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of the idiopathic interstitial lung diseases (ILD) (1). The clinical course of IPF disease is variable and difficult to predict, since % of the patients experience acute exacerbations (AEx) that are usually severe or even lethal (2). It has been estimated that approximately 25 % of the patients will live over 5 years after the diagnosis and the median survival in several studies has been 3 4 years after diagnosis (3,4). Nearly half of all patients dying from IPF had experienced a deterioration of their lung disease prior to their death (5,6). The most common cause of death has been reported to be the lung disease itself (7,8). Global mortality from IPF has been increasing (9-12). Males have been reported to have higher mortality than females (12). An increase in median mortality has also been seen in the European Union (EU) when the highest mortality rates in 2013 were reported from the United Kingdom (UK) and the second highest from Finland (12). Currently, the only curative treatment for IPF is lung transplantation. Two anti-fibrotic drugs have been approved for the treatment of IPF; these may prevent disease progression in some, but not all, patients (13). It is difficult to determine the optimal time-point for initiating therapeutic treatment, palliative care and lung transplantation due to the lack of an accurate and generally accepted staging system as well as AEx. The composite physiologic index (CPI) and Gender-Age-Physiology (GAP) staging system have been the most commonly applied indexes for estimating the prognosis of patients with IPF (14-16). Although there are no official criteria for distinguishing between the stages of disease severity in IPF, the values of forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLco) have been utilized. Many clinical trials have used FVC values % and DLco values % as thresholds for differentiating severe disease from mild-tomoderate stages (17). Cigarette smoking has been associated with the risk of developing IPF (18). In particular, males with current or past smoking histories and occupational exposures have been reported to carry an increased risk of IPF as compared to females without exposures (19). However, it is not clear how smoking affects survival in IPF. Current smokers at the time of IPF diagnosis have been reported to have longer survival times than ex-smokers as well as non-smokers and ex-smokers (20,21). On the contrary, also ever-smokers (i.e. current and ex-smokers) with IPF have been reported to live longer than never-smokers (22). Healthy smoker effect has been used to describe the phenomenon of current smokers exhibiting milder disease than non-smokers and ex-smokers in terms of pulmonary function tests (PFT) and CPI (21,23). Several common comorbidities are associated with IPF e.g. pulmonary hypertension (PH), obstructive sleep apnea (OSA), lung cancer, chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD) and gastro-esophageal reflux (GER) (24,25). Thyroid disease, diabetes, CAD and lung cancer have been reported to associate with shortened survival in IPF, whereas the use of GER medication has been associated with longer survival times (26-30). Patients with several comorbidities have been claimed to exhibit worse survival than those without comorbidities (7). The aims of the present study were to re-evaluate a retrospective cohort of patients with IPF from Kuopio University Hospital (KUH) using the prevailing international guidelines (1) and to study retrospectively the clinical factors differentiating between patients with
28 2 different stages at the time of diagnosis and courses of disease, when disease progression was categorized according to observed lifetime into rapid (< 2 years), moderate (2 5 years) and slow (> 5 years) groups. The functionality of GAP staging and CPI in this IPF cohort with a known disease course was investigated and clinical features and lung function parameters as well as their ability to predict mortality were assessed. The differences in survival between patients with different smoking histories and genders were examined. In addition, the numbers and types of comorbidities and medications were investigated. The mortality rates of patients with IPF in KUH were examined and the underlying and immediate causes of death were explored in the whole study group as well as separately for females and males, different smoking histories, disease progression categories as well as GAP stages. The mortality from pulmonary fibrosis (PF) was also investigated in Finland.
29 3 2 Review of the literature 2.1 INTERSTITIAL LUNG DISEASES The lung parenchyma includes the pulmonary alveolar epithelium, capillary epithelium and the space between these structures as well as the septae including perivascular and perilymphatic tissues and more centrally, the peribronchiolar and peribronchial tissues (31). ILDs are a heterogeneous group of disorders affecting these tissues in a diffuse manner and with varying degrees of fibrosis and inflammation (31,32). ILDs can be coarsely divided in subgroups with different etiologies: exposure-related, connective tissue disease (CTD) related, granulomatous, idiopathic and other interstitial lung diseases (Table 1) (33). Table 1. Classification of interstitial lung diseases (adapted from Ryerson et al. (33)). Exposure-related Occupational Environmental Medications Other Connective tissue disease related Granulomatous Idiopathic Other Scleroderma Rheumatoid arthritis Sjögren syndrome Polymyositis, dermatomyositis Sarcoidosis Major idiopathic interstitial pneumonias (see table 2) Rare idiopathic interstitial pneumonias (see table 2) Vasculitis, diffuse alveolar hemorrhage Langerhans cell histiocytosis Eosinophilic pneumonia Neurofibromatosis Lymphangioleiomyomatosis Different ILDs have similarities and dissimilarities in their clinical, radiological and histological findings and their treatment as well as their prognosis usually depends on the
30 4 underlying ILD subtype (33). Idiopathic interstitial pneumonias (IIP) can be differentiated by anamnestic, clinical, radiological and histological findings and by laboratory tests from the diseases with known etiologies (34). Similarly, different forms of IIP can be differentiated from each other via their clinical histories, radiological and in some cases also histological findings; these are crucial for obtaining a precise diagnosis (35). It is also necessary to re-evaluate the diagnosis at regular times since many patients receive an IIP diagnosis due to an inadequate anamnesis (34). 2.2 HISTORY OF PULMONARY FIBROSIS In the German-language literature, cases with autopsy findings consistent with PF were reported as early as 1872 (36). However, Hamman and Rich have been commonly considered to be the first authors to describe PF in 1935 when they described four unusual cases of pulmonary fibrosis examined in Johns Hopkins Hospital (37). The clinical characteristics of the four patients were dyspnea, cough and cyanosis and they died between 31 days and 24 weeks after hospital admission from a slowly progressing suffocation accompanied by congestive heart failure (37). In 1944, based on these cases, Hamman and Rich published a detailed description of the clinical and pathological features of ILD; they called the disease acute diffuse interstitial fibrosis of the lungs and their pioneer work helped to identify further cases (36,38). Between 1944 and 1952, 15 cases of Hamman-Rich syndrome were reported and for several decades, the syndrome was thought to be IPF (39,40). In 1957, Rubin and Lubier described variants of IPF and observations that similar types of tissue reaction could be found in the lungs of patients with collagen diseases and that the diffuse interstitial fibrosing pneumonia was not always as fatal a disease as initially believed (39,40). Similarly in 1964, Sheridan et al. observed that many cases were more chronic with an average survival of 2 4 years (41). The Hamman-Rich syndrome is nowadays regarded as acute interstitial pneumonia (AIP), but for almost fifty years, this aspect of IPF dominated the literature until the cases were revisited and the classification of IIP was refined (40,42). In the 1960s, Liebow and Carrington described five histopathological subgroups of chronic IIP that were usual interstitial pneumonia (UIP), bronchiolitis interstitial pneumonia (BIP), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP) and giant cell interstitial pneumonia (GIP) (40). This classification created the grounds for the understanding of cellular and molecular events that explain the histologic patterns of ILD (40). In 1998, Katzenstein and Myers revised the classification of IIPs and included UIP, DIP/respiratory bronchiolitis interstitial lung disease (RB-ILD), AIP and non-specific interstitial pneumonia (NSIP) in their classification (43). In the year 2002, American Thoracic Society (ATS) and European Respiratory Society (ERS) presented a multidisciplinary consensus statement on the classification of IIPs and it was updated in the year 2013 (Table 2) (34,35).
31 5 Table 2. Categorization of idiopathic interstitial pneumonias (adapted from Travis et al (35)). Major idiopathic interstitial pneumonias Chronic fibrosing interstitial pneumonias Acute and subacute interstitial pneumonias Smoking-related interstitial pneumonias Rare idiopathic interstitial pneumonias Lymphoid interstitial pneumonia (LIP) Pleuroparenchymal fibroelastosis (PPFE) Idiopathic pulmonary fibrosis (IPF) Non-specific interstitial pneumonia (NSIP) Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP) Respiratory bronchiolitis interstitial lung disease (RB-ILD) Desquamative interstitial pneumonia (DIP) At the beginning, the diagnosis of PF was obtained from autopsy, but with time, it was established that the accurate diagnosis could be made before death (36,37,40). Gaensler et al. described 105 patients that underwent open lung biopsy in and later the procedure was gradually modified from wide thoracotomy to a small thoracotomy (36,40,44). In the past decades, histological analysis of lung samples taken by video-assisted thoracoscopic surgery (VATS) has been found to be cost effective and accurate method for diagnosing pulmonary infiltrates (45,46). In recent years, transbronchial cryobiopsy has partly replaced VATS as a mini-invasive procedure, at least in some centers (47,48). In the 1960s Scadding et al. described the physiological presentation of diffuse interstitial fibrosis (49). They had observed that at first, maximum voluntary ventilation (MVV) may be within the normal range and also the volume expired in the first second of a forced expiration (FEV1) is normal, constituting more than 70 % of FVC (49). However, a reduction in diffusion capacity of the lungs was observed and later in the disease also ventilator capacity became reduced (49). Before the development of radiological diagnostic methods, the diagnosis of ILD was based only on histological findings. As computed tomography (CT) and high-resolution computed tomography (HRCT) became available for investigating PF in the 1990s, the knowledge of typical radiological findings increased radically (50). Today, HRCT is a crucial part of the diagnosis of ILDs and IPF, in some cases, it may be the only intervention needed to achieve the diagnosis (1,51).
32 6 The nomenclature and diagnostic criteria of IPF have been changing over the years due to increasing knowledge of histological, radiological and etiological features, and it is still evolving as our understanding of this complex disease improves (52). The first consensus statement on diagnosis and management of IPF was released in 2000 by the ATS and ERS and the diagnostic criteria were updated in 2011 (1,53). Treatment recommendations were updated in 2015 and new diagnostic criteria have been published recently in 2018 (13,51). 2.3 IDIOPATHIC PULMONARY FIBROSIS (IPF) Prevalence and incidence The prevalence of IPF varies between countries and prevalence also depends on the definitions and diagnosis codes used to report IPF (54). In the years , the prevalence of IPF in Finland was reported to be per (55). In 2012, the Finnish IPF-registry reported a prevalence of 17.0 per (56). In European countries, the highest prevalence has been reported in the year 1998 in Norway, 23.4 per (54,57). The IPF incidence has not been calculated in Finland, but the estimated IPF incidence in the Nordic countries has been reported to vary between 0.4 and 10 per per year (58). The prevalence and incidence of IPF vary widely, but in recent studies, the incidence has been reported to be on the increase (9,54,59). The incidence of IPF has been claimed to be higher in males, but there are also reports showing no difference in the incidence between genders (54,60). However, the incidence seems to rise with increasing age with the highest incidences present in patients over 75 years of age (54,57,59) Clinical presentation IPF is rare in patients under 50 years of age and it is usually diagnosed at the ages between 60 and 70 years (1). It is more common in males and the majority of patients have a history of cigarette smoking (1). IPF should be suspected in adult patients with unexplained exercise related shortness of breath, cough and bilateral inspiratory velcro-like crackles in lung auscultation (1). Finger clubbing is observed in % of patients (53). There are two typical findings in pulmonary function tests (PFT) 1) restriction i.e. decreased FVC in spirometry and 2) impairment of gas exchange i.e. decreased DLco (1,61). FVC may appear normal in a patient with concomitant emphysema (61). However, it has been reported that even if the results of spirometry are normal, radiological changes may be present (62). Laboratory findings are non-specific and often used to rule out alternative diagnoses, for example CTD (1). Diagnosis is usually made 6 24 months after the appearance of the symptoms, but some patients have experienced symptoms even 5 years before the diagnosis of IPF (1,63). Early diagnosis has become more important after anti-fibrotic treatment became available (64) Definition IPF is the most common IIP and it accounts for approximately 20 % of the ILDs (61,65-67), but also higher percentages have been reported (68,69). IPF is defined as a chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs and associated with a specific form of histopathologic and/or radiologic patterns (1,51). The process that mediates the fibrosis in the lungs is incompletely understood (1,3).
33 Pathogenesis and histological features The theory on the pathogenesis of IPF suggests that frequent, subclinical injury to alveolar epithelium superimposed on accelerated epithelial aging leads to an abnormal repair of the injured alveolus and deposition of normal tissue with interstitial fibrosis (66). In addition to the epigenetic changes related to aging, combinations of gene polymorphism and transcriptional changes take place in the lung, resulting in the loss of epithelial integrity and spatial orientation (70). As a result, the epithelium reacts abnormally to repetitive micro injuries and stress i.e. infection, GER and cigarette smoke (32,70). Epithelial cells secrete a variety of growth factors and other mediators which induce the proliferation of fibroblasts and myofibroblasts, cause a disruption of the basement membrane and the exaggerated production of extracellular matrix proteins (70). In addition, myofibroblasts secrete several mediators that provoke more epithelial and basement membrane damage leading to lung tissue remodeling and to irreversible honeycombing (70). The histopathological feature of UIP in IPF is patchy fibrosis with scarring and honeycomb changes within areas of less affected and even normal-looking lung parenchyma, usually in the subpleural and paraseptal areas of the lungs (1,71). Fibroblast foci, including proliferating fibroblasts and myofibroblasts, are increased and they are intermingled with dense collagen and smooth muscle metaplasia (1,71). Microscopic honeycombing is usually present even though HRCT shows no visible radiological honeycombing (71) Diagnosis The first international guideline for diagnosing IPF was published in 2000 (53). It recommended that a thorough physical examination should be performed for every patient suspected with ILD and a careful history, including information on medications, exposures, family history and comorbidities should be taken (53). Serologic testing should be performed in patients less than 50 years of age, especially in females, since there is a high possibility of the manifestation of a CTD (53). In some cases, ILD may be the first manifestation of CTD (53). It was also recommended that a thorough history of exposures should be taken, e.g. hypersensitivity pneumonitis (HP) and asbestosis may mimic IPF (53). In addition to typical clinical and HRCT features, the diagnosis of IPF required that there is an abnormality in lung function parameters (53). It was recommended that transbronchial biopsy (TBB) or bronchoalveolar lavage (BAL) procedures be performed in order to exclude alternative diagnoses in patients who did not undergo surgical lung biopsy (SLB) (53). Analysis of BAL has been commonly used in the investigations of patients with ILD and IPF. An increase in the percentage of neutrophils (over 5 %) in BAL fluid has been noted in the majority of IPF patients and approximately half of the patients have an increase (over 5 %) in eosinophils (53,72). Instead, an increase in the numbers of lymphocytes has been reported to be uncommon in IPF (53,72). However, these features are not specific for IPF, since similar findings have been seen in a wide variety of other ILDs (53,73). The increases in the percentage of eosinophils, neutrophils or both in BAL fluid have been associated with worse survival in some studies (53). When the diagnostic criteria were updated in 2011, BAL and TBB were no longer required for diagnosing IPF, but BAL was considered to be feasible for excluding HP, in which more than 40 % lymphocytosis would be suggestive of HP diagnosis (1). When the diagnostic guidelines were again updated in 2018, BAL was recommended for patients with different radiological patterns other than UIP (51). The 2018 guidelines did not provide any recommendation for or against TBB (51). Table 3 presents the radiological criteria for HRCT scanning patterns according to 2011 and 2018 criteria.
34 8 Table 3. Radiological criteria for high-resolution computed tomography (HRCT) patterns (adapted from Raghu et al (1) and 2018 (51)). HRCT scanning patterns according to 2011 diagnostic criteria UIP Pattern Possible UIP Inconsistent with UIP Pattern Subpleural, basal predominance Subpleural, basal predominance Upper or mid-lung predominance Reticular abnormality Reticular abnormality Peribronchovascular predominance Honeycombing with or without traction bronchiectasis Absence of features inconsistent with UIP Absence of features inconsistent with UIP Extensive ground glass abnormality (extent > reticular abnormality) Profuse micro-nodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honeycombing) Diffuse mosaic attenuation / airtrapping (bilateral, in three or more lobes) Consolidation in bronchopulmonary segment(s) / lobes(s) HRCT scanning patterns according to 2018 diagnostic criteria UIP Probable UIP Indeterminate for UIP Alternative diagnosis Subpleural, basal predominance. Distribution often heterogeneous Subpleural, basal predominance. Distribution often heterogeneous Subpleural, basal predominance CT features with cysts, mosaic attenuation, ground-glass opacity, profuse micro-nodules, centrilobular nodules, nodules, consolidation Honeycombing with or without traction bronchiectasis or bronchiolectasis Reticular pattern with peripheral traction bronchiectasis or bronchiolectasis Some reticulation; mild ground-glass opacity or distortion may exist Predominant distribution is peribronchovascular, perilymphatic or in upper or mid-lung Mild ground-glass opacity may exist CT features and/or distribution of fibrosis not suggesting any specific etiology Other features including pleural plaques, dilated esophagus, distal clavicular erosions, lymph node enlargement, pleural effusion or thickening HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; CT, computed tomography
35 9 Figure 1. High-resolution computed tomography images of a patient with definite UIP pattern. Reticular pattern is basal and peripheral. Some bronchiectasis and honeycombing are evident. According to the 2011 guidelines, the diagnosis of IPF required A) the exclusion of other known causes of ILD B) the presence of a UIP pattern in HRCT (Table 3) and C) the specific combination of HRCT and lung biopsy pattern in patients subjected to lung biopsy (Tables 4 and 5, Figure 2) (1). In uncertain cases, the accuracy of an IPF diagnosis increases in a multidisciplinary discussion (MDD) and the MDD group should include at least experienced pulmonologists, pathologists and radiologists (1,74). In addition, a rheumatologist or occupational physician may provide supplemental expertise in some cases (51,75). Several studies have reported that the radiological diagnosis of UIP confirms the diagnosis of IPF with % certainty (1,76,77). It has been suggested that approximately one third of patients with IPF need to undergo a lung biopsy if one wishes to make an accurate diagnosis (78). The lung biopsy can be taken surgically by an open thoracotomy procedure, but currently less invasive methods i.e. VATS and transbronchial cryobiopsy, are more commonly used (1,47,79,80). In the new 2018 recommendations, the taking of a SLB is conditional i.e. SLB should be performed in HRCT patterns other than UIP for the majority of the patients, but not for a sizeable minority (51,81). The benefits of taking the SLB should outweigh the potential risks (51). The decision to perform a SLB should be made in the MDD (51). The new recommendation did not provide any recommendation for or against transbronchial cryobiopsy (51). Similar to the radiological criteria, also a change in the histological categorization of UIP was recommended in the 2018 guideline (Table 4) (51). The histological terms are consistent with radiological terms i.e. UIP, probable UIP, indeterminate for UIP and alternative diagnosis (51). Indeterminate for UIP is characterized by a fibrosing process that does not meet the criteria for a UIP pattern or other forms of fibrotic interstitial pneumonia (Table 4) (51). Similarly to the 2011 guidelines, IPF can be diagnosed when appropriate combinations of the HRCT pattern and the histological pattern are present (Tables 5 and 6) (51). Ascertainment or exclusion of the diagnosis of IPF should be made in the MDD (51). Figure 2 presents the diagnostic criteria of IPF which evolved between the years
36 10 Table 4. Histological criteria for UIP pattern (adapted from Raghu et al (1) and 2018 (51) statements). Histological UIP pattern according to 2011 diagnostic criteria UIP pattern Probable UIP pattern Possible UIP pattern Not UIP pattern Marked fibrosis/architectural distortion, ±honeycombing in a predominantly subpleural / paraseptal distribution Marked fibrosis/architectural distortion, ±honeycombing Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation Hyaline membranes (can be associated with AEx) Presence of patchy involvement of lung parenchyma by fibrosis Absence of either patchy involvement of fibroblastic foci, but not both Absence of other criteria for UIP OP (can be associated with AEx) A mild component of OP may rarely coexist Presence of fibroblast foci Absence of features against a diagnosis of UIP suggesting an alternative diagnosis OR Absence of features against a diagnosis of UIP suggesting an alternative diagnosis Granulomas; An isolated or occasional granuloma may rarely coexist Absence of features against a diagnosis of UIP suggesting an alternative diagnosis Honeycomb changes only Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airway centered changes Other features suggestive of an alternative diagnosis Histological UIP pattern according to 2018 diagnostic criteria UIP Probable UIP Indeterminate for UIP Alternative diagnosis Dense fibrosis with architectural distortion Some histologic features of the UIP pattern, but not to the same extent as in UIP Fibrosis with or without architectural distortion Features of other IIPs Distribution of fibrosis predominantly subpleural and/or paraseptal Absence of features suggesting an alternative diagnosis Some histologic features from the UIP pattern, but with features suggesting an alternative diagnosis Histologic findings indicative of some other diagnosis Patchy fibrosis OR only honeycombing Fibroblast foci Absence of features suggesting an alternative diagnosis UIP, usual interstitial pneumonia; AEx, acute exacerbation of idiopathic pulmonary fibrosis; OP, organizing pneumonia; IIP, idiopathic interstitial pneumonia
37 11 Table 5. Diagnosis of idiopathic pulmonary fibrosis with the 2011 criteria (adapted from Raghu et al. 2011(1)). HRCT Pattern Histology pattern Diagnosis UIP UIP IPF Probable UIP Possible UIP Non-classifiable fibrosis a Not UIP Possible UIP UIP IPF Probable UIP Possible UIP Non-classifiable fibrosis a Not UIP IPF IPF IPF Not IPF IPF Probable IPF Probable IPF Not IPF Inconsistent with UIP UIP Possible IPF Probable UIP Possible UIP Non-classifiable fibrosis a Not UIP Possible IPF Not IPF Not IPF Not IPF a fibrotic pattern that does not meet the criteria of UIP or any other idiopathic interstitial pneumonia HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis Table 6. Diagnosis of idiopathic pulmonary fibrosis with the 2018 criteria (adapted from Raghu et al (51)). HRCT Pattern Histology pattern Diagnosis UIP UIP IPF Probable UIP Indeterminate for UIP Alternative diagnosis Probable UIP UIP IPF Probable UIP Indeterminate for UIP Alternative diagnosis Indeterminate for UIP UIP IPF Probable UIP Indeterminate for UIP Alternative diagnosis IPF IPF Not IPF IPF Likely IPF Not IPF Likely IPF Indeterminate Not IPF Alternative diagnosis UIP Likely IPF or not IPF Probable UIP Indeterminate for UIP Not IPF Not IPF Alternative diagnosis Not IPF HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis
38 ATS/ERS International consensus statement (53): 2011: An official ATS/ERS/JRS/ALAT Statement (1): 2018: ATS/ERS/JRS/ALAT clinical practice guideline (51): Major criteria : *Exclusion of other known causes of ILD *Abnormal pulmonary function studies including evidence of restriction and impared gas exchange *Bibasilar reticular abnormalities with minimal ground glass opacities in HRCT *No features to support alternative diagnosis in TBB or BAL Minor criteria: *age > 50 years *Unexplaned dyspnea on excertion with incidous onset *Duration of symptoms over 3 months *Bibasilar inspiratory crakcles The diagnosis of IPF requires: *Exclusion of other known causes of ILD *UIP pattern in HRCT in patients not subjected to SLB *Spesific combinations of HRCT and SLB pattern if SLB performed *In unclear cases MDD with experienced pulmonologist, pathologist and radiologist The major and minor criteria proposed in 2000 ATS/ERS consensus statement were eliminated *Exclusion of other known causes of ILD with detailed history of medications and environmental exposures as well as serologic testing to exclude CTDs *UIP pattern in HRCT OR *Spesific combinations of HRCT and histopathologic pattern if SLB is performed * BAL, SLB, TBB and cryobipsy not recommended when HRCT pattern is UIP * MDD suggested for decision making Distiguished recommendations on BAL and SLB in patients with UIP HRCT pattern and other patterns Figure 2. Diagnostic criteria of idiopathic pulmonary fibrosis. ATS, American Thoracic Society; ERS, European Respiratory Society; JRS, Japanese Respiratory Association; ALAT, Latin American Thoracic Association; IPF, idiopathic pulmonary fibrosis; ILD, interstitial lung disease; HRCT, high-resolution computed tomography; TBB, transbronchial biopsy; BAL, bronchoalveolar lavage; UIP, usual interstitial pneumonia; SLB, surgical lung biopsy; MDD, multidisciplinary discussion; CTD, connective tissue disease
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