Guide To Clinical Management of Idiopathic Pulmonary Fibrosis

Steven D Nathan · A Whitney Brown
Christopher S King
Guide to Clinical
Management of
Idiopathic
Pulmonary
Fibrosis
Guide to Clinical
Management of Idiopathic
Pulmonary Fibrosis
Steven D Nathan • A Whitney Brown
Christopher S King
Guide to Clinical
Management of
Idiopathic Pulmonary
Fibrosis
Steven D Nathan Christopher S King
Inova Fairfax Medical Campus Inova Fairfax Medical Campus
Falls Church Falls Church
Virginia Virginia
USA USA
A Whitney Brown
Inova Fairfax Medical Campus
Falls Church
Virginia
USA
ISBN 978-3-319-32792-1 ISBN 978-3-319-32794-5 (eBook)

DOI 10.1007/978-3-319-32794-5
Library of Congress Control Number: 2016942888
© Springer International Publishing Switzerland 2016

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Preface
When contemplating and collaborating on this book, the three

of us jokingly referred to it as the 50 shades of IPF. Indeed,
there are many gray zones in the diagnosis and management of
idiopathic pulmonary fibrosis (IPF) and more often than not
nothing is black or white. The hope with this handbook is to
provide practical tips and guidance for practitioners while
demystifying this emerging disease entity. We set out to accom-
plish this by drawing on our own clinical experience; having
seen many patients with IPF and other conditions that tend to
mimic IPF. Through our accrued experience, shaded with our
synthesis of the existing literature, we hope to provide an easy
read that can serve as a resource to all clinical providers. This
book is intended for anyone involved in the care of patients
with possible IPF, including students, residents, fellows, primary
care providers, and pulmonologists, as well as patients them-
selves. In other words, we just want to sell as many copies of
this book as possible. This is obviously stated in jest, but the
three of us have directed all royalties from this book to the
William and Catherine Goodrum Pulmonary Fibrosis Fund,
the mission of which is to fund pulmonary fibrosis research at
our institution. We dedicate this book to all patients with inter-
stitial lung disease who have molded our collective experience
and helped shed light on the shaded areas that are frequently
encountered in medicine.
Steven D Nathan, MD
A Whitney Brown, MD
Christopher S King, MD
v
Contents
1 Overview of Idiopathic Pulmonary Fibrosis . . . . . . . 1

1.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Incidence and Prevalence . . . . . . . . . . . . . . . . . 5
1.3 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.4 Course and Prognosis. . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2 Clinical Presentation and Diagnosis . . . . . . . . . . . . . . 15

2.1 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2 Patient History . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3 Physical Examination. . . . . . . . . . . . . . . . . . . . . 17
2.4 Pulmonary Function Tests . . . . . . . . . . . . . . . . . 17
2.5 Chest X-Ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.6 Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.7 Chest Computed Tomography Scan. . . . . . . . . 22
2.8 Lung Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.8.1 Bronchoscopy . . . . . . . . . . . . . . . . . . . . . 24
2.8.2 Cryobiopsy via Bronchoscopy . . . . . . . 25
2.8.3 Video-Assisted Thoracoscopic
Surgical Lung Biopsy . . . . . . . . . . . . . . . 25
2.9 Making the Diagnosis . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3 Diseases that Mimic Idiopathic Pulmonary Fibrosis. . . 33

3.1 Non-specific Interstitial Pneumonia. . . . . . . . . 33
3.2 Connective Tissue Disease-Associated
Interstitial Lung Disease . . . . . . . . . . . . . . . . . . 35
vii
viii Contents
3.3 Chronic Hypersensitivity Pneumonitis . . . . . . 36

3.4 Unclassifiable Interstitial Lung Disease . . . . . 38
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4 Pathogenesis of Idiopathic Pulmonary Fibrosis . . . . 43

4.1 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.2 Alveolar Epithelial Cell Injury . . . . . . . . . . . . . 43
4.3 Disease Heterogeneity. . . . . . . . . . . . . . . . . . . . 44
4.4 The Role of the Fibroblast . . . . . . . . . . . . . . . . 45
4.4.1 Inciting Events . . . . . . . . . . . . . . . . . . . . 45
4.4.2 Collagen Deposition . . . . . . . . . . . . . . . 46
4.5 Cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
4.6 Pathways and Mechanisms . . . . . . . . . . . . . . . . 47
4.6.1 Wnt Pathway. . . . . . . . . . . . . . . . . . . . . . 47
4.6.2 Lysyl Oxidase-Like 2 Pathway . . . . . . . 47
4.6.3 Telomeres and Apoptosis . . . . . . . . . . . 47
4.7 Pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5 Prognosis, Clinical Course, and Monitoring

of Patients with Idiopathic Pulmonary Fibrosis. . . . . 53
5.1 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5.1.1 Patient Discussion About Prognosis. . . 53
5.2 Clinical Course . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5.3 Prognostic Indicators . . . . . . . . . . . . . . . . . . . . . 54
5.3.1 Pulmonary Function Testing . . . . . . . . . 54
5.3.2 The Six Minute Walk Test . . . . . . . . . . . 56
5.3.3 Computed Tomography Scan
of the Chest . . . . . . . . . . . . . . . . . . . . . . . 57
5.3.4 Composite Scores . . . . . . . . . . . . . . . . . . 58
5.3.5 Pulmonary Hypertension . . . . . . . . . . . 59
5.3.6 Hospitalization . . . . . . . . . . . . . . . . . . . . 59
5.3.7 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . 60
5.4 Monitoring the Clinical Course . . . . . . . . . . . . 62
5.5 Clinical Scenario of Increasing
Shortness of Breath . . . . . . . . . . . . . . . . . . . . . . 63
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Contents ix
6 Comorbidities and Complications of Idiopathic

Pulmonary Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
6.1 Gastroesophageal Reflux Disease . . . . . . . . . . 67
6.2 Cardiovascular . . . . . . . . . . . . . . . . . . . . . . . . . . 68
6.2.1 Coronary Artery Disease. . . . . . . . . . . . 68
6.2.2 Heart Failure . . . . . . . . . . . . . . . . . . . . . . 69
6.2.3 Thromboembolic Disease . . . . . . . . . . . 69
6.3 Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.3.1 Pulmonary Hypertension . . . . . . . . . . . 69
6.3.2 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . 71
6.3.3 Combined Pulmonary Fibrosis
Emphysema. . . . . . . . . . . . . . . . . . . . . . . 72
6.3.4 Obstructive Sleep Apnea. . . . . . . . . . . . 72
6.4 Anxiety and Depression . . . . . . . . . . . . . . . . . . 73
6.5 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
6.5.1 Acute Exacerbations of Idiopathic
Pulmonary Fibrosis. . . . . . . . . . . . . . . . . 73
6.5.2 Pneumothorax. . . . . . . . . . . . . . . . . . . . . 75
6.5.3 Aspergilloma. . . . . . . . . . . . . . . . . . . . . . 75
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
7 Treatment of Idiopathic Pulmonary Fibrosis . . . . . . . 81

7.1 Pirfenidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
7.1.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
7.1.2 Mechanism of Action . . . . . . . . . . . . . . . 82
7.1.3 Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
7.1.4 Pharmacokinetics . . . . . . . . . . . . . . . . . . 85
7.1.5 Side-Effects . . . . . . . . . . . . . . . . . . . . . . . 85
7.1.6 Administration . . . . . . . . . . . . . . . . . . . . 86
7.2 Nintedanib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.2.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.2.2 Mechanism of Action . . . . . . . . . . . . . . . 87
7.2.3 Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.2.4 Pharmacokinetics . . . . . . . . . . . . . . . . . . 87
7.2.5 Side-Effects . . . . . . . . . . . . . . . . . . . . . . . 88
7.2.6 Administration . . . . . . . . . . . . . . . . . . . . 88
x Contents
7.3 Common Questions for Anti-fibrotic

Drug Administration . . . . . . . . . . . . . . . . . . . . . 91
7.3.1 How Do We Know the Medication
Is Working? . . . . . . . . . . . . . . . . . . . . . . . 91
7.3.2 To Whom Do I Prescribe an
Anti-fibrotic Agent?. . . . . . . . . . . . . . . . 91
7.3.3 When Do I Start the Drug?. . . . . . . . . . 91
7.3.4 When Should I Stop the
Anti-fibrotic Medication, If Ever? . . . . 92
7.3.5 What Constitutes a Treatment
Failure? . . . . . . . . . . . . . . . . . . . . . . . . . . 92
7.3.6 What is the Role of
Combination Therapy? . . . . . . . . . . . . . 92
7.4 Drugs to Be Avoided . . . . . . . . . . . . . . . . . . . . . 93
7.4.1 Azathioprine and Steroids. . . . . . . . . . . 93
7.4.2 Warfarin. . . . . . . . . . . . . . . . . . . . . . . . . . 93
7.4.3 Ambrisentan . . . . . . . . . . . . . . . . . . . . . . 94
7.4.4 Other Agents. . . . . . . . . . . . . . . . . . . . . . 94
7.5 Pulmonary Hypertension . . . . . . . . . . . . . . . . . 94
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
8 Non-pharmacologic Management of Idiopathic

Pulmonary Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
8.1 Oxygen Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 99
8.2 Pulmonary Rehabilitation . . . . . . . . . . . . . . . . . 100
8.3 Palliative Care. . . . . . . . . . . . . . . . . . . . . . . . . . . 104
8.4 Hospice Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
8.5 Lung Transplantation . . . . . . . . . . . . . . . . . . . . . 105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
9 The Future for Idiopathic Pulmonary Fibrosis . . . . . 111

9.1 Medical Therapies . . . . . . . . . . . . . . . . . . . . . . . 112
9.1.1 Drugs Currently Approved
for Other Indications . . . . . . . . . . . . . . . 112
9.1.2 Novel Therapies . . . . . . . . . . . . . . . . . . . 115
9.2 Other Areas of Investigation . . . . . . . . . . . . . . 117
9.2.1 Laparoscopic Reflux Surgery . . . . . . . . 117
9.2.2 Pulmonary Rehabilitation . . . . . . . . . . . 117
Contents xi
9.2.3 Cryobiopsy . . . . . . . . . . . . . . . . . . . . . . . 117

9.2.4 Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . 117
9.2.5 Treatment of Acute Exacerbation
of Idiopathic Pulmonary Fibrosis . . . . . 118
9.2.6 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . 118
9.3 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
About the Authors
A Whitney Brown, MD is Director of Clinical Operations

and the Cystic Fibrosis Program of the Inova Advanced Lung
Disease and Transplant Program at Inova Fairfax Hospital in
Falls Church, Virginia. Dr. Brown received her BS in Public
Health from the University of North Carolina at Chapel Hill,
North Carolina. She attended medical school at Emory
University in Atlanta, Georgia, and completed her residency
in Internal Medicine at New York Presbyterian Hospital/
Cornell University. Dr. Brown undertook her pulmonary and
critical care training at the University of North Carolina at
Chapel Hill, North Carolina. Dr. Brown has been with the
Inova Advanced Lung Disease and Transplant Program since
2010. She has special interest in idiopathic pulmonary fibro-
sis, lung transplant outcomes, and the care of adult patients
with cystic fibrosis.
Christopher S King, MD is a pulmonologist in the Inova

Advanced Lung Disease and Transplant Program and a medi-
cal intensivist at the Medical Critical Care Service at Inova
Fairfax Hospital in Falls Church, Virginia. Dr. King received his
BS degree in Biology from Loyola College in Baltimore,
Maryland, where he focused on cell and molecular biology. He
completed his medical training at the University of Maryland,
Baltimore, and completed his residency and fellowship train-
ing with the United States Army at Walter Reed Army Medical
Center in Washington, DC. After completing his service in the
military, Dr. King joined the staff of Inova Fairfax Hospital
where he works in the Advanced Lung Disease and Lung
Transplantation Clinic.
xiii
xiv About the Authors
Steven D Nathan, MD is the Director of the Advanced Lung

Disease Program and the Medical Director of the Lung
Transplant Program at Inova Fairfax Hospital in Falls Church,
Virginia. Dr. Nathan received his medical degree at the
University of the Witwatersrand Medical School in
Johannesburg, South Africa. He completed his internship in
Internal Medicine and General Surgery at the Johannesburg
Hospital. Dr. Nathan performed his Internal Medicine resi-
dency at Long Island Jewish Hospital in New York City, and
completed his fellowships in Pulmonary Medicine, Critical
Care, and Lung Transplantation at Cedars-Sinai Medical
Center in Los Angeles, California.
Dr. Nathan has authored over 400 publications including
original research manuscripts, abstracts, reviews, electronic
publications, book chapters, and a book on idiopathic pulmo-
nary fibrosis (IPF) that he co-edited. He is a reviewer for
multiple journals, is an Associate Editor for Pulmonary Year
in Review, and is on the editorial board of Thorax. He has
served on multiple committees, including FDA Advisory
Boards as well as steering committees for clinical trials in IPF
and pulmonary hypertension, where he has also served as
chair. He is also chairperson of Pilot for IPF, an international
educational initiative for pulmonary fibrosis.
Abbreviations
5-LO 5-Lipoxygenase
6MWT 6-Minute walk test
ABCA3 Adenosine triphosphate-binding cassette
transporter A3
ACS Acute coronary syndrome
AEC Alveolar epithelial cell
AE-IPF Acute exacerbation of idiopathic pulmonary
fibrosis
AIP Acute interstitial pneumonia
ANA Anti-nuclear antibody
ARDS Adult respiratory distress syndrome
ATP Adenosine triphosphate
αvβ6 Alpha v beta 6
BNP Brain natriuretic peptide
bpm Beats per minute
CAD Coronary artery disease
CCP Cyclic citrullinated peptide
CK Creatinine kinase
COP Cryptogenic organizing pneumonia
COPD Chronic obstructive pulmonary disease
CPAP Continuous positive airway pressure
CPFE Combined pulmonary fibrosis/emphysema
CPI Composite physiologic
CTD Connective tissue disease
CTD-ILD Connective tissue disease-associated intersti-
tial lung disease
CTEPH Chronic thromboembolic pulmonary hypertension
CTGF Connective tissue growth factor
CYP Cytochrome P450
xv
xvi Abbreviations
DAH Diffuse alveolar hemorrhage

DIP Desquamative interstitial pneumonia
DLco Diffusing capacity of the lungs for carbon monoxide
dsDNA Double stranded DNA
EMT Epithelial-mesenchymal transition
FEV1 Forced expiratory volume in the first one second
FGF Fibroblast growth factor
FiO2 Fraction of inspired oxygen
FPF Familial pulmonary fibrosis
FVC Forced vital capacity
GAP Gender, age, physiology
GERD Gastroesophageal reflux disease
GI Gastrointestinal
HP Hypersensitivity pneumonitis
HRCT High resolution computed tomography
IIPs Idiopathic interstitial pneumonias
IL-13 Interleukin-13
ILD Interstitial lung disease
IPF Idiopathic pulmonary fibrosis
KL-6 Krebs von der Lungen-6
LAM Lymphangiolyomyomatosis
LIP Lymphocytic interstitial pneumonia
LT Leukotriene
MCTD Mixed connective tissue disease
mPAP Mean pulmonary artery pressure
mTOR Mammalian target of rapamycin
NSIP Non-specific interstitial pneumonia
NT-proBNP N-terminal pro brain natriuretic peptide
OP Organizing pneumonia
OR Odds ratio
OSA Obstructive sleep apnea
PA Pulmonary artery
PDGF Platelet derived growth factor
PFT Pulmonary function testing
P-gp P-glycoprotein
PH Pulmonary hypertension
PLCH Pulmonary Langerhans’ cell histocytosis
PPFE Pleuroparenchymal fibroelastosis
Abbreviations xvii
PRR Pulse rate recovery

PRR=Δ Max pulse – pulse 1 minute after cessation of walk
RA Rheumatoid arthritis
RB-ILD Respiratory bronchiolitis associated interstitial
lung disease
RCT Randomized controlled trial
RDW Red cell distribution width
RF Rheumatoid factor
RVSP Right ventricular systolic pressure
SLE Systemic lupus erythematosus
SNPs Single nucleotide polymorphisms
sPAP Systolic pulmonary artery pressure
SpO2 Arterial oxygen saturation
TGF-β Transforming growth factor-beta
TLC Total lung capacity
TNF-α Tumor necrosis factor-alpha
U1-RNP U1-ribonuclear protein
UIP Usual interstitial pneumonia
VATS Video-assisted thoracoscopic surgery
VEGF Vascular endothelial growth factor
Chapter 1
Overview of Idiopathic
Pulmonary Fibrosis
1.1 History
Interstitial lung diseases (ILDs) represent a broad category
of diseases affecting the interstitium of the lung in a diffuse
fashion. Idiopathic pulmonary fibrosis (IPF) is a distinct sub-
type and one of the most common forms of ILD. It is a
chronic fibrosing condition that is limited to the lungs, tends
to be progressive in nature, and results in significant morbid-
ity and mortality. IPF needs to be differentiated from the
many other causes ILDs. Table 1.1 categorizes all the ILDs by
a simple mnemonic of five ‘I’s, a ‘C’, and an ‘N’ [1].
IPF was formerly referred to as cryptogenic fibrosing
alveolitis, but this term has since been abandoned. Indeed,
the definition of IPF has evolved over the past two decades
[2]. IPF used to be a ‘wastebasket’ term that encompassed
many of the idiopathic fibrosing conditions; this group of
disorders is now referred to as the idiopathic interstitial
pneumonias (IIPs) [3] (Table 1.2).
The ‘pneumonia’ or ‘pneumonitis’ aspect of this broad cat-
egory of diseases is somewhat of a misnomer; none of these
entities are infectious in etiology and many lack a significant
inflammatory component. Indeed, it used to be commonly
thought that IPF was an inflammatory disease and that the
fibrosis was the end product of chronic inflammation. This
paradigm evolved from bronchoalveolar lavage studies in the
S. Nathan et al., Guide to Clinical Management 1

of Idiopathic Pulmonary Fibrosis,
DOI 10.1007/978-3-319-32794-5_1,
2
Table 1.1 Categories of interstitial lung disease. N/A, not applicable
Category Diseases Sub-categories/examples
Idiopathic Idiopathic interstitial pneumonias (IIPs) Major IIPs:
Idiopathic pulmonary fibrosis (IPF)
Sarcoidosis
Non-specific interstitial pneumonia (NSIP)
Amyloidosis
Respiratory bronchiolitis associated interstitial lung
Lymphangiolyomyomatosis (LAM)
disease (RB-ILD)
Pulmonary Langerhans’ cell
Desquamative interstitial pneumonia (DIP)
histocytosis (PLCH)
Cryptogenic organizing pneumonia (COP)
Eosinophilic pneumonia
Acute interstitial pneumonia (AIP)
Neurofibromatosis
Rare IIPs:
Diffuse alveolar hemorrhage (DAH)
Lymphocytic interstitial pneumonia (LIP)
Pleuroparenchymal fibroelastosis (PPFE)
Unclassifiable IIP
Immunologic Connective tissue disorders Scleroderma, rheumatoid arthritis, systemic lupus
Guide to Clinical Management of IPF
erythematosus, mixed connective tissue disease,

Sjogren’s Syndrome, inflammatory myositis
Inhalational Inorganic Asbestosis, silicosis, coal miners, pneumoconiosis, hard
metal lung disease, berylliosis, siderosis
Chapter 1.
Organic: chronic hypersensitivity Bird fanciers disease, farmer’s lung

pneumonitis
Iatrogenic Antiarrhythmics, antimicrobials, Amiodarone, nitrofurantoin, bleomycin, busulfan,
chemotherapy agents, biologics, cyclophosphamide, rituximab, interferon (alpha,
radiation beta)
Infectious Viral CMV, influenza
Fungal Pneumocystis carinii
Congestive heart N/A N/A
failure
Neoplastic Lymphangitic carcinomatosis N/A
Bronchoalveolar carcinoma
Overview of Idiopathic Pulmonary Fibrosis
3
4 Guide to Clinical Management of IPF
Table 1.2 The idiopathic interstitial pneumonias. N/A, not applicable

Category of
Idiopathic interstitial idiopathic interstitial
pneumonias Acronym Mnemonic pneumonia
Idiopathic IPF I Major
pulmonary fibrosis
Non-specific NSIP N Major
interstitial
pneumonia
Cryptogenic COP C Major
organizing pneumonia
Respiratory RB-ILD R Major
bronchiolitis-
associated interstitial
lung disease
Acute interstitial AIP A Major
pneumonia
Pleuroparenchymal PPFE P Rare
fibroelastosis
Desquamative DIP D Major
interstitial pneumonia
Unclassifiable N/A U Unclassifiable
Lymphoid interstitial LIP L Rare
pneumonia
late 1970s that described an excess of inflammatory cells [4–6].

It has since been learned that the inflammatory milieu is
mostly a secondary phenomenon. Nonetheless, this did lead to
the notion that therapy for IPF should be aimed at managing
inflammation. Accordingly, the wide-spread use of steroids
and cytotoxic agents, such as azathioprine and cyclophospha-
mide, was common practice. It is only recently that azathio-
prine and prednisone have been shown to not only be
ineffective, but also possibly harmful to patients with IPF [7].
Until recently, there were no effective medical therapies to
treat IPF. The only recourse for patients was to be evaluated
Chapter 1. Overview of Idiopathic Pulmonary Fibrosis 5
for enrollment in a clinical trial or to undergo lung transplan-

tation; unfortunately, both of these options are not readily
available to the majority of patients. Other ancillary manage-
ment tools include participation in pulmonary rehabilitation
and implementation of supplemental oxygen for those with
resting, nocturnal, or exercise-induced hypoxemia. Recently,
two drugs (pirfenidone and nintedanib) have been shown to
slow the rate of deterioration or loss of lung function in
patients with IPF [8]. Pirfenidone and nintedanib are avail-
able in many countries around the world (approved in 2014
and 2015, respectively, by the US Food and Drug
Administration for use in patients with IPF) [9]. While nei-
ther of these drugs are a cure or panacea, their availability
has heralded a new era in the management of patients with
IPF and resulted in renewed interest and hope for this other-
wise deadly disease.
The pathologic correlate of IPF is referred to as usual
interstitial pneumonia (UIP), which has now also crept its
way into the radiographic lexicon in the context of high reso-
lution computed tomographic (HRCT) image patterns. The
name UIP evolved very simply because this was the pattern
of injury most commonly seen by pathologists in IPF. It is
important to note that this pathologic pattern is not synony-
mous with the clinical entity of IPF and can be seen in other
lung diseases (such as connective tissue disease related ILD,
occupational lung disease, and chronic hypersensitivity pneu-
monitis) [3].
1.2 Incidence and Prevalence

IPF tends to be a disease of the elderly and affects males more
often than females [2]. There is evidence to suggest that the
prevalence of IPF is increasing [10]. It is estimated that there
are approximately 120,000 cases in the US and probably equiva-
lent numbers in Europe [2], although the true prevalence is
likely higher than this. There is no apparent ethnic or racial
predilection for IPF, but the estimated prevalence of the
Table 1.3 Common occupational causes of interstitial lung disease

Exposure Lung disease Associated occupations
Asbestos Asbestosis Shipbuilding
Building maintenance
Mining
Milling
Automobile mechanic
Railroad worker
Electrician
Coal dust Coal miner’s Coal mining
pneumoconiosis
Rock and sand Silicosis Mining
Sandblasting
Quarrying
Construction
Foundry work
Beryllium Berylliosis Mining
Aerospace manufacturing
Electronics
manufacturing
Cobalt (from hard Hard metal lung Diamond polishing
metal tools used for disease Dental laboratories
cutting/drilling) Manufacturing of cutting/
drilling tools
disease in other countries remains poorly defined. The course

of the disease is similar in patients from diverse geographic
areas; in general, males and the elderly tend to have a worse
prognosis [11]. Interestingly, patients with higher body mass
index and active smokers appear to have better outcomes,
however, this could be due to lead time bias with these patients
presenting and being diagnosed earlier in their disease course
[12, 13]. Most patients (60–70 %) with IPF have been or are
current smokers [14]. Other risk factors include various occu-
pational exposures (Table 1.3), which have been associated
with a higher incidence of the disease [15]. It therefore seems
likely that significant (especially long-term exposure) to any
noxious inhaled substance may heighten the risk for IPF.
1.3 Genetics
Familial pulmonary fibrosis (FPF) accounts for 0.5–3.7 % of
IPF cases [16] and is defined by a history of pulmonary fibro-
sis in at least two first degree relatives. The clinical presenta-
tion of FPF is similar to that of sporadic IPF, although the age
of onset tends to be younger [17], therefore FPF should be
suspected in patients who present at an earlier age.
Additionally, any family history of IPF or unknown lung dis-
ease may provide a clue to the familial variant. There are a
number of genetic variants that have been linked to FPF [16, 18–29];
each of which has a variable influence on the development of
pulmonary fibrosis. For example, within families not all per-
sons with the same mutation will develop pulmonary fibrosis,
suggesting that epigenetics are important. In other words,
there seems to be variability in the way in which an individu-
al’s genetic predisposition interacts with the environment
and other factors [18, 23, 26, 30].
In addition to the typical Mendelian inheritance pattern in
the familial variant, potential genetic factors in all afflicted
patients are being investigated. Single nucleotide polymor-
phisms (SNPs) — elucidated through gene-wide association
studies — that have been shown to be important in the pre-
dilection for IPF include:
• MUC5B — a polymorphism in the promoter region of
MUC5B, the mucin gene, has been found in approximately
34 % of patients with FPF versus 9 % of healthy controls [22, 27].
This variant of MUC5B has been found to be associated with
the development of IPF (odds ratios [OR] of developing
disease: 9.0 and 21.8 for heterozygotes and homozygotes,
respectively) [31]. It also holds prognostic information, para-
doxically conferring a twofold survival advantage to patients
with IPF who carry the polymorphism [32].
• TERT and TERC — mutations in TERC and TERT ,
the genes encoding telomerase, may also increase risk
for the development of IPF [ 29 , 33 ]. Telomeres
are regions of repetitive, non-coding nucleotide
sequences at the end of chromosomes, and telomerase
is a polymerase (enzyme) that adds telomere repeats to

chromosomes. Mutations in TERC and TERT affect
telomerase function. In a study by Tsakiri et al. [34] it
was demonstrated that individuals with IPF have shorter
telomeres in comparison to age-matched family mem-
bers. Progressive telomere shortening ultimately leads to
apoptosis or cell-cycle arrest and may play a role in the
pathogenesis of IPF [29].
– Heterozygous TERT mutations are present in
approximately 18 % of FPF and 3 % of sporadic IPF
cases [35].
– TERC mutations have a rare association with IPF [34].
• A2 and C surfactant proteins — pulmonary surfactant
reduces surface tension within the lungs and prevents end-
expiratory atelectasis. Mutations in surfactant protein A2
and C impair surfactant function leading to pulmonary
fibrosis in affected individuals [20, 21].
• Adenosine triphosphate (ATP)-binding cassette trans-
porter A3 (ABCA3) — ABCA3 is produced in the lung by
type II pneumocytes, where it transports surfactant lipids
into lamellar bodies and is essential in the maintenance of
pulmonary surfactant lipid homeostasis. Recessive muta-
tions in the ABCA3 gene are increasingly being recog-
nized as a cause of ILD (specifically in IPF) in older
children and young adults [36].
The above mentioned genetic abnormalities account for a

small minority of cases of IPF; there are likely a number of as
yet unrecognized genetic abnormalities that contribute to the
development of IPF. Improved understanding of the genetics
of IPF will be essential to the development of more effective
treatment strategies. In the future, the hope is that genetic
testing will allow for phenotyping and individualized targeted
therapy of this deadly disease. Given the current uncertainty
regarding the clinical significance of the identified common
genotypes, routine genotyping in IPF is not recommended.
1.4 Course and Prognosis

The course of IPF is notoriously difficult to predict on a case-
by-case basis. Some patients remain stable for many years,
some have an inextricable downhill course, while others have
periods of stability punctuated by episodes of deterioration
with progression in a so-called ‘stepwise’ pattern (Fig. 1.1) [2, 11].
Acute exacerbations (clinical worsening that occurs over 30
days or less without identifiable cause) may also occur unpre-
dictably in these patients. Acute exacerbations tend to occur
at a rate of about 5–15 % per patient year and invariably are
accompanied by a very poor prognosis [37]. Some patients
may present with an acute exacerbation as their heralding
event. This should always be borne in mind for patients who
present with an adult respiratory distress syndrome (ARDS)-
like picture with no apparent precipitating factor. The patho-
logic findings of acute exacerbation in IPF are indistinguishable
Disease
progression Variable onset of symptoms
Diagnosis
Unpredictable patterns of progression
Demise
Time
Figure 1.1 Course and prognosis of idiopathic pulmonary fibrosis

(Adapted from Raghu et al. [2] and Ley et al. [11])
from ARDS, with a diffuse alveolar damage pattern, but

superimposed on a background of UIP [38].
The prognosis of IPF is poor, with an estimated average sur-
vival of 2.5–4 years from the time of diagnosis [39]. Patients
with IPF also have a propensity for comorbidities, likely due to
advanced age, and some patients may succumb with their IPF,
rather than from their IPF. Comorbidities that may lead to
death include cardiovascular disease, thromboembolic disease,
and lung cancer (more common in patients with IPF compared
to age-matched controls) [40]. Other common comorbidities
include obstructive sleep apnea and gastroesophageal reflux
disease (GERD). These will be discussed in Chap. 6.
Key Points
• IPF has a typical pattern on HRCT such that lung
biopsy is usually not necessary for diagnosis.
• Other identifiable causes of ILD must be excluded.
• A very small percentage of IPF cases are familial
(defined as 2 or more first degree relatives with pul-
monary fibrosis).
• Mutations in MUC5B and certain telomerase muta-
tions appear to be associated with a higher risk of
IPF, but account for the minority of cases.
• Prognosis, although heterogeneous, is generally poor,
with an average of survival of 2.5–4 years from the
time of diagnosis.
• The first treatments for IPF, pirfenidone and ninte-
danib, were approved in 2014 and 2015, respectively.
References
1. Wallis A, Spinks K. The diagnosis and management of interstitial
lung diseases. BMJ. 2015;350:h2072.
2. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/
ALAT statement: idiopathic pulmonary fibrosis: evidence-based
guidelines for diagnosis and management. Am J Respir Crit Care
Med. 2011;183:788–824.
3. Travis WD, Costabel U, Hansell DM, 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;188:733–48.
4. Hunninghake GW, Gadek JE, Kawanami O, Ferrans VJ, Crystal
RG. Inflammatory and immune processes in the human lung in
health and disease: evaluation by bronchoalveolar lavage. Am
J Pathol. 1979;97:149–206.
5. Reynolds HY, Fulmer JD, Kazmierowski JA, Roberts WC, Frank
MM, Crystal RG. Analysis of cellular and protein content of
broncho-alveolar lavage fluid from patients with idiopathic pul-
monary fibrosis and chronic hypersensitivity pneumonitis. J Clin
Invest. 1977;59:165–75.
6. Weinberger SE, Kelman JA, Elson NA, et al. Bronchoalveolar
lavage in interstitial lung disease. Ann Intern Med. 1978;89:459–66.
7. Idiopathic Pulmonary Fibrosis Clinical Research Network,
Raghu G, Anstrom KJ, King Jr TE, Lasky JA, Martinez
FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmo-
nary fibrosis. N Engl J Med. 2012;366:1968–77.
8. King CS, Nathan SD. Practical considerations in the pharmaco-
logic treatment of idiopathic pulmonary fibrosis. Curr Opin
Pulm Med. 2015;21:479–89.
9. Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idio-
pathic pulmonary fibrosis–FDA review of pirfenidone and nint-
edanib. N Engl J Med. 2015;372:1189–91.
10. Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in
US Medicare beneficiaries aged 65 years and older: incidence, preva-
lence, and survival, 2001–11. Lancet Respir Med. 2014;2:566–72.
11. Ley B, Collard HR, King Jr TE. Clinical course and prediction of
survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care
Med. 2011;183:431–40.
12. Alakhras M, Decker PA, Nadrous HF, Collazo-Clavell M, Ryu
JH. Body mass index and mortality in patients with idiopathic
pulmonary fibrosis. Chest. 2007;131:1448–53.
13. Antoniou KM, Hansell DM, Rubens MB, et al. Idiopathic pul-
monary fibrosis: outcome in relation to smoking status. Am
J Respir Crit Care Med. 2008;177:190–4.
14. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron
JA. Cigarette smoking: a risk factor for idiopathic pulmonary
fibrosis. Am J Respir Crit Care Med. 1997;155:242–8.
15. Miyake Y, Sasaki S, Yokoyama T, et al. Occupational and envi-
ronmental factors and idiopathic pulmonary fibrosis in Japan.
Ann Occup Hyg. 2005;49:259–65.
16. Lawson WE, Grant SW, Ambrosini V, et al. Genetic mutations in

surfactant protein C are a rare cause of sporadic cases of
IPF. Thorax. 2004;59:977–80.
17. Garcia CK. Idiopathic pulmonary fibrosis: update on genetic
discoveries. Proc Am Thorac Soc. 2011;8:158–62.
18. Chibbar R, Shih F, Baga M, et al. Nonspecific interstitial pneumonia
and usual interstitial pneumonia with mutation in surfactant protein
C in familial pulmonary fibrosis. Mod Pathol. 2004;17:973–80.
19. Guillot L, Epaud R, Thouvenin G, et al. New surfactant protein
C gene mutations associated with diffuse lung disease. J Med
Genet. 2009;46:490–4.
20. Maitra M, Wang Y, Gerard RD, Mendelson CR, Garcia
CK. Surfactant protein A2 mutations associated with pulmonary
fibrosis lead to protein instability and endoplasmic reticulum
stress. J Biol Chem. 2010;285:22103–13.
21. Nogee LM, Dunbar 3rd AE, Wert SE, Askin F, Hamvas A,
Whitsett JA. A mutation in the surfactant protein C gene associ-
ated with familial interstitial lung disease. N Engl J Med.
2001;344:573–9.
22. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B
promoter polymorphism and pulmonary fibrosis. N Engl J Med.
2011;364:1503–12.
23. Thomas AQ, Lane K, Phillips 3rd J, et al. Heterozygosity for a surfac-
tant protein C gene mutation associated with usual interstitial pneumo-
nitis and cellular nonspecific interstitial pneumonitis in one kindred.
Am J Respir Crit Care Med. 2002;165:1322–8.
24. van Moorsel CH, van Oosterhout MF, Barlo NP, et al. Surfactant
protein C mutations are the basis of a significant portion of adult
familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit
Care Med. 2010;182:1419–25.
25. Verleden GM, du Bois RM, Bouros D, et al. Genetic predisposi-
tion and pathogenetic mechanisms of interstitial lung diseases of
unknown origin. Eur Respir J Suppl. 2001;32:17–29s.
26. Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant
protein A2 are associated with pulmonary fibrosis and lung can-
cer. Am J Hum Genet. 2009;84:52–9.
27. Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the pro-
moter of MUC5B and idiopathic pulmonary fibrosis. N Engl
J Med. 2011;364:1576–7.
28. Ono S, Tanaka T, Ishida M. Surfactant protein C G100S mutation
causes familial pulmonary fibrosis in Japanese kindred. Eur
Respir J. 2011;38:861–9.
29. Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations
in families with idiopathic pulmonary fibrosis. N Engl J Med.
2007;356:1317–26.
30. Lawson WE, Loyd JE, Degryse AL. Genetics in pulmonary
fibrosis–familial cases provide clues to the pathogenesis of idio-
pathic pulmonary fibrosis. Am J Med Sci. 2011;341:439–43.
31. Mathai SK, Yang IV, Schwarz MI, Schwartz DA. Incorporating
genetics into the identification and treatment of idiopathic pul-
monary fibrosis. BMC Med. 2015;13:191.
32. Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the
MUC5B promoter polymorphism and survival in patients with
idiopathic pulmonary fibrosis. JAMA. 2013;309:2232–9.
33. Diaz de Leon A, Cronkhite JT, Yilmaz C, et al. Subclinical lung
disease, macrocytosis, and premature graying in kindreds with
telomerase (TERT) mutations. Chest. 2011;140:753–63.
34. Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary
fibrosis caused by mutations in telomerase. Proc Natl Acad Sci
U S A. 2007;104:7552–7.
35. Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere
lengths, pulmonary fibrosis and telomerase (TERT) mutations.
PLoS One. 2010;5:e10680.
36. Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch
GH. Usual interstitial pneumonia in an adolescent with ABCA3
mutations. Chest. 2008;134:192–5.
37. Sgalla G, Biffi A, Richeldi L. Idiopathic pulmonary fibrosis: diag-
nosis, epidemiology and natural history. Respirology. 2015.
doi:10.1111/resp.12683. [Epub ahead of print].
38. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations
of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med.
2007;176:636–43.
39. Nathan SD, Shlobin OA, Weir N, et al. Long-term course and
prognosis of idiopathic pulmonary fibrosis in the new millen-
nium. Chest. 2011;140:221–9.
40. King C, Nathan SD. Identification and treatment of comorbidi-
ties in idiopathic pulmonary fibrosis and other fibrotic lung dis-
eases. Curr Opin Pulm Med. 2013;19:466–73.
Chapter 2
Clinical Presentation
and Diagnosis
2.1 Symptoms
Patients typically present with insidious onset of shortness of
breath. This may or may not be accompanied by a chronic dry
cough. Cough is the presenting symptom in approximately
12 % of patients [1]. Patients who are physically more active
and robust in their daily lives or who exercise regularly are
more likely to notice the onset of their symptoms sooner
compared to those patients who are more sedentary. Given
the non-specific symptoms of idiopathic pulmonary fibrosis
(IPF), patients are frequently misdiagnosed initially. Non-
specific symptoms include:
• shortness of breath;
• dry cough;
• tiredness;
• loss of appetite; and
• weight loss.
Some patients may be diagnosed while still asymptomatic,
either based on findings from physical examination or chest
imaging. An astute clinician may hear inspiratory crackles
(present in 96.8 % of symptomatic patients [1]) on routine
auscultation of the lung bases and initiate an evaluation with
imaging. Alternatively, pulmonary fibrosis may be initially
detected as an incidental finding on imaging carried out for

DOI 10.1007/978-3-319-32794-5_2,
other reasons. Chest imaging tends to be ubiquitous and fre-

quently unrelated to any specific pulmonary condition or
symptoms. Some examples include:
• routine chest X-ray performed for other reasons (e.g., a
preoperative assessment prior to surgery for an unrelated
condition);
• computed tomographic (CT) scan of the chest for lung
cancer screening;
• abdominal CT obtained for gastrointestinal (GI) com-
plaints with abnormalities noted at the lung bases (which
are captured with upper abdominal cuts); and
• fluoroscopy during cardiac catheterizations to diagnose
coronary artery disease (CAD) in patients presenting with
shortness of breath.
2.2 Patient History

A detailed patient history is mandatory to evaluate for risk
factors of IPF as well as to exclude other conditions that may
be in the differential. Patient history should ascertain whether
any of the following are present:
• Predisposing factors:
– smoking (former or current); and
– family history of interstitial lung disease (ILD) or IPF.
• Professions at higher risk for IPF:
– farmers;
– hairdressers;
– wood workers; and
– metal workers.
• Clues to alternative causes of ILD:
– pet bird exposure, frequent hot tub use, mold expo-
sure (chronic hypersensitivity pneumonitis [HP]);
Chapter 2. Clinical Presentation and Diagnosis 17
– occupational exposures: asbestos (asbestosis), silica

(silicosis), tin (stannosis), coal (coal miners’ pneumo-
coniosis); and
– stigmata of an underlying connective tissue disease
(CTD) including gastroesophageal reflux disease
(GERD) symptoms, Raynaud’s phenomenon, joint
pain, skin rash, and muscle weakness (Table 2.1).
2.3 Physical Examination

Vital signs are almost invariably normal, with the exception
of pulse oximetry, which may be low at rest. However, a nor-
mal pulse oximetry reading does not rule out IPF or any
other pulmonary condition. A minority of patients may have
digital clubbing at presentation. Chest auscultation may
reveal inspiratory coarse crackles at the bases of the lungs;
these crackles have been described as ‘Velcro®’ in nature
since their sound is very similar to that of Velcro® being
pulled apart. In more advanced disease, crackles may prog-
ress so that they can be heard throughout the lung fields, both
posteriorly and anteriorly. Pulmonary hypertension (PH)
may complicate the course of IPF, so clinicians should look
for signs of this complication on physical exam. A clinical clue
to its presence may be an increased P2 heart sound. Overt
evidence of right heart failure, including jugular venous dis-
tention, ascites, and lower extremity edema, is very unusual
even in the presence of advanced IPF.
2.4 Pulmonary Function Tests

All patients with suspected lung disease should undergo
pulmonary function testing (PFT). In IPF, spirometry usu-
ally shows a restrictive pattern, with the forced vital
capacity (FVC) and the forced expiratory volume in the
first one second (FEV1) both reduced, resulting in a normal
Table 2.1 Signs and symptoms of connective tissue disease

Disease and most Presentation/symptoms Signs of CTD
common radiographic/ of possible underlying
pathologic patterns CTD
Scleroderma Demographics:
-NSIP Female
-UIP Young age (especially Telangiectasia
-Unclassifiable <50 years)
-Rare: OP, DAH GERD symptoms
Dysphagia
Early satiety
Diarrhea or constipation Dilated esophagus on CT
Sclerodactyly
Rheumatoid arthritis
-UIP Joint pains Arthritic changes-hands
-NSIP
-OP
MCTD Morning hand joint stiffness Arthritic changes of small

-NSIP Raynaud’s and large joints
-Rare: AIP, DAH Phenomenon
SLE Alopecia Oral ulceration

-Acute pneumonitis
-DAH Photosensitivity Maculopapular rash
-OP
-NSIP
-UIP
Sjogren’s syndrome Dry mouth, dry eyes Uveitis

-LIP
-Bronchiolitis
-OP
-NSIP
-UIP
-Lymphoma
Polymyositis/ Skin rash Heliotrope rash

dermatomyositis
-NSIP Muscle pains, weakness Proximal muscle weakness
-UIP
-OP Mechanic’s hands
-Rare: AIP, DAH Gottron’s nodules
The colored squares indicate a specific disease entity, features of sclero-

derma are marked in blue; rheumatoid arthritis in green; mixed connec-
tive tissue disease in gray; systemic lupus erythematosus in red; Sjogren’s
syndrome in purple; and polymyositis/dermatomyositis in yellow
AIP acute interstitial pneumonia, CT computed tomography, CTD con-
nective tissue disease, DAH diffuse alveolar hemorrhage, GERD gastro-
esophageal reflux disease, LIP lymphoid interstitial pneumonia, MCTD
mixed connective tissue disease, NSIP non-specific interstitial pneumo-
nitis, OP organizing pneumonia, UIP usual interstitial pneumonia
Figure 2.1 Chest X-ray and computed tomographic imaging dem-

onstrating combined pulmonary fibrosis and emphysema. The com-
puted tomography scan demonstrates typical subpleural fibrosis as
well as bullous disease that are characteristic of emphysema
FEV1/FVC ratio. This preserved ratio differentiates the

ILDs from the obstructive lung diseases (which typically
manifest with a reduced FEV1/FVC ratio). Some cases of
restrictive lung disease, IPF included, can have increased
FEV1/FVC ratios that reflect the ‘snappiness’ of the non-
compliant or stiff lungs, which results in more of the lung
volume being expelled in the first one second. On the other
end of the spectrum, a slightly reduced or normal FEV1/FVC
ratio may be present when IPF occurs in combination with
emphysema. This is a distinct entity that is referred to as
combined pulmonary fibrosis/emphysema (CPFE) (Fig. 2.1).
Normal spirometry and lung volumes do not exclude IPF,
with approximately 14 % of patients presenting with FVC
>80 % predicted (commonly regarded as the lower limit of
normal) [1]. The single breath diffusing capacity (DLco) is
commonly reduced, usually more so than the FVC, reflecting
loss of the pulmonary capillary bed.
a b
Figure 2.2 Chest X-rays showing (a), early and (b), advanced inter-
stitial changes
2.5 Chest X-Ray

Plain chest film typically demonstrates increased interstitial
markings at the bases of the lungs in the early stages of dis-
ease (Fig. 2.2a). IPF is a disease that typically involves the
lower lobes first, with abnormalities most notable on the
periphery of the lungs. As the disease progresses these abnor-
malities extend and involve other regions of the lung.
Similarly, as the disease progresses, the lung volumes on chest
X-rays become progressively smaller (Fig. 2.2b).
2.6 Laboratory Tests

There is no specific diagnostic marker for IPF, however,
laboratory testing is important to exclude other conditions
that may mimic IPF (including the various connective tissue
disorders and chronic HP). Most patients should, at a mini-
mum, have a screening test for anti-nuclear antibody (ANA)
and rheumatoid factor (RF), or ANA and anti-cyclic citrul-
linated peptide (CCP). Depending on the clinical presenta-
tion, especially for younger patients, a full CTD panel should
be considered. Autoimmune serologic testing should be
Table 2.2 Serologic tests to consider when evaluating a patient with

interstitial lung disease
Serologic test Associated diseases
Hypersensitivity pneumonitis Hypersensitivity pneumonitis
panel
Anti-nuclear antibody (ANA) Systemic lupus
Double stranded DNA (dsDNA) erythematosus
Anti-Smith
Anti-Ro (Sjögren’s-syndrome- Sjogren’s syndrome
related antigen A)
Anti-La (Sjögren’s-syndrome-
related antigen B)
U1-ribonuclear protein (U1-RNP) Mixed connective tissue
disease
Anti-centromere, topoisomerase I Scleroderma
(SCL-70)
Creatinine kinase (CK), aldolase, Myositis
Jo-1
Comprehensive myositis panel
Rheumatoid factor, cyclic Rheumatoid arthritis
citrillunated peptide
considered when evaluating patients with ILD (Table 2.2). In

addition to the anti-Jo antibody test, which may be positive
in patients with polymyositis, there are also other antibodies
that may be present in the anti-synthetase syndrome. A com-
prehensive myositis panel is only available at certain refer-
ence labs and is normally ordered only when clinical
suspicion is high.
The utility of a hypersensitivity panel is uncertain since a
positive test to a specific antigen does not necessarily infer
causation, similarly a negative test does not rule out chronic
HP. The decision to obtain such testing is left to the discretion
of the physician, but can be helpful in diagnosing chronic HP
given the right constellation of exposure history, CT changes,
and lung biopsy findings.
2.7 Chest Computed Tomography Scan

The cornerstone of IPF diagnosis is high resolution computed
tomography (HRCT). The high resolution of this technique
(≤2.5 mm cuts) enables greater detail of the lung parenchyma
compared to the standard technique (5 mm cuts). In addition,
prone imaging can be helpful in more subtle cases to distin-
guish between atelectasis and true changes of ILD. Expiratory
images, in addition to inspiratory images, should be requested
to assess for air trapping that can accompany chronic HP and
other kinds of lung disease. Distinctive radiographic changes
seen in IPF include:
• bilateral sub-pleural reticular infiltrates;
• honeycombing;
• traction bronchiectasis; and
• the absence of atypical features that suggest other forms of
ILD (consolidation, alveolar or ground glass infiltrates, air
trapping and areas of hyperlucency [may be seen in
chronic HP], and cysts).
If a patient has all four of the above radiographic features in the
appropriate clinical context, this is usually sufficient to make the
diagnosis of IPF. If patients lack one or more of the features, then
the patient may be categorized as having probable, possible, or
unlikely IPF. Figure 2.3 provides example of an inconsistent usual
interstitial pneumonia (UIP) pattern (unlikely to be IPF), a pos-
sible UIP pattern (could possibly be IPF), and a typical UIP pat-
tern (which in the right clinical context is very likely to be IPF).
In the first two scenarios, a lung biopsy may be required to make
the diagnosis. CT imaging of the chest has additional benefit
beyond the lung parenchyma; it enables visualization of other
structures that may provide clues to the diagnosis, presence of
comorbidities, and potentially even prognosis.
Extra-pulmonary findings are important to note, and can
include the following (Fig. 2.4):
• Esophagus — an enlarged patulous esophagus can be a
clue to the presence of comorbid GERD and/or the pres-
ence of scleroderma. An air-fluid level within the esopha-
gus may provide additional evidence for aspiration risk.
a UIP pattern
Subpleural, basal predominance
Reticular abnormality
Honeycombing with or without traction bronchiectasis (red arrow)
Absence of inconsistent features
b Possible UIP pattern

Subpleural, basal predominance
Reticular abnormality
Absence of inconsistent features
c Inconsistent UIP pattern

Upper or mid-lung predominance
Peribronchovascular predominance
Extensive ground glass abnormality (extent > reticular abnormality)
Profuse micronodules
Discrete cysts (multiple, bilateral, away from areas of honeycombing)
Diffuse mosaic attenuation/air-trapping (bilateral in 3 or more lobes)
Consolidation in bronchopulmonary segment(s)/lobe(s)
Figure 2.3 High resolution computed tomography examples of (a),

typical usual interstitial pneumonia (UIP) pattern, (b) possible UIP
pattern, and (c) inconsistent with UIP pattern
• Coronary calcification — can be seen on the mediastinal

images and may indicate underlying coronary artery
disease [2].
• Pleura — thickening of the pleura may be seen as a resid-
ual after prior pleuritis (possible underlying CTD), while
pleural plaques might indicate underlying asbestosis.
• Mediastinal adenopathy — enlarged nodes (up to 1 cm in
diameter) can be seen in IPF, but more prominent adenop-
athy should raise the suspicion for other entities, the most
common being sarcoidosis.
• Pulmonary artery segment — an enlarged pulmonary
artery with a diameter greater than that of the adjacent
aorta is associated with the presence of pulmonary hyper-
tension and attenuated survival (see Chap. 5) [3].
a b
c d
Figure 2.4 Extra-pulmonary structures to evaluate on computed

tomography scans: (a) patulous esophagus, (b) thickened esophagus,
(c) enlarged pulmonary artery (red arrow), and (d) coronary artery
calcifications. LAD left anterior descending artery, RCA right coro-
nary artery
2.8 Lung Biopsy

A confirmatory lung biopsy is required to confirm the diag-
nosis in some cases (approximately 30 %) [1]. The types of
procedures that may be employed to obtain lung tissue are
outlined in the following sections.
2.8.1 Bronchoscopy
The pieces of tissue obtained with transbronchial biopsies are

usually too small and inadequate to make the diagnosis of
IPF. If tissue is needed for pathological evaluation, standard
bronchoscopy is typically not recommended.
2.8.2 Cryobiopsy via Bronchoscopy
The pieces of tissue obtained by cryobiopsy are typically

larger than those obtained with standard transbronchial for-
ceps and therefore may be sufficient to make the diagnosis of
IPF at experienced centers [4].
2.8.3 Video-Assisted Thoracoscopic Surgical

Lung Biopsy
Video-assisted thoracoscopic surgical (VATS) lung biopsy is
the gold-standard in terms of obtaining tissue for the diagno-
sis of IPF. The decision to proceed with this should take into
consideration the age and comorbidities of the patient and the
likelihood of an IPF diagnosis (versus another entity). If there
is a very good chance that the patient has IPF (based on clini-
cal features) then a surgical lung biopsy is usually not neces-
sary for confirmation. Similarly, if the patient has a documented
CTD or features consistent with another cause of ILD (e.g.,
pleural plaques in someone with a history of asbestos expo-
sure) then a lung biopsy may not be needed. Lung biopsies are
most helpful when there is true diagnostic uncertainty and
biopsy results will influence clinical management.
2.8.3.1 Tips for the VATS Surgeon
Biopsy samples should be obtained from at least two, prefer-

ably three areas of the lung. Biopsies from the most diseased
looking areas of the lung should be avoided. These typically
show non-specific ‘end-stage’ fibrosis and may not provide
the necessary features to make an accurate diagnosis. Areas
adjacent to obvious fibrotic lung should be targeted. Even
areas of grossly appearing normal lung will usually show
changes typical of IPF.
The anesthesiologist should be instructed to limit the frac-
tion of inspired oxygen (FiO2) and only give sufficient oxygen
to maintain adequate oxygen saturation. Use of high oxygen
concentrations and high tidal volumes in the setting of single

lung ventilation may induce lung injury and precipitate an
acute exacerbation of IPF [5]. Additionally, judicious use of
intravenous fluids intraoperatively may reduce the risk for
acute exacerbations [6].
Patients with severe disease and/or evidence of PH are
usually not good candidates for VATS lung biopsies. The rela-
tive risks and benefits of the procedure need to be weighed
carefully in such cases.
2.9 Making the Diagnosis

There is no single gold-standard test for the diagnosis of
IPF. What is typically regarded as the gold-standard is a
multidisciplinary consensus, including a clinician (usually
a pulmonologist), a radiologist (ideally a thoracic radiolo-
gist), and a pathologist [7]. However, in most instances,
the diagnosis can be made without a tissue diagnosis and
therefore this multidisciplinary approach in reality may
be bi-disciplinary between the pulmonologist and radiolo-
gist. The diagnosis requires the exclusion of other condi-
tions as a cause of the ILD in the context of a HRCT that
is typical or probable for IPF. A simple mnemonic to
remember other causes of ILD is shown in Table 1.1 (see
Chap. 1). The conditions that are most difficult to differ-
entiate from IPF include non-specific interstitial pneumo-
nia (NSIP), chronic HP, underlying connective tissue
disorders, and the newly described entity of interstitial
pneumonia with autoimmune features [8].
A thorough history is an essential first step. Particular
attention to possible occupational exposures, hobbies that
might involve organic or inorganic particles, and exposure to
birds are especially important. Inhalational agents that may
cause other forms of lung disease or increase the risk for IPF
or other types of ILD are listed in Table 2.3.
Patients with IPF may demonstrate clubbing of their digits
and typically have bibasilar inspiratory ‘Velcro®’ crackles,
Table 2.3 Inhalational exposures/activities that increase the risk for

Exposure Occupations/industries Disease associations
Tobacco N/A IPF, COPD, CPFE,
smoke lung cancer
Aerosols Hairdressers IPF
Dusts Farmers IPF, chronic HP
Wood Wood workers IPF
dust
Metal Metal workers IPF
dust
Silica Mining, foundries, Silicosis
sandblasting
Asbestos Mining, ship building, Asbestosis
building maintenance,
milling, automobile
mechanics, railroad workers,
electricians
Coal Mining Coal miner’s
pneumoconiosis
Beryllium Aerospace, automotive, Berylliosis
electronics
COPD combined obstructive pulmonary disease, CPFE combined
pulmonary fibrosis and emphysema, HP hypersensitivity pneumonitis,
IPF idiopathic pulmonary fibrosis, N/A not applicable
however, the absence of these does not rule out IPF. Physical
examination may yield signs that are suggestive of conditions
that may mimic IPF, specifically signs of an underlying con-
nective tissue disorder (Table 2.1). Tests that should be con-
sidered to exclude other conditions, primarily connective
tissue disorders, are shown in Table 2.2.
Radiographic imaging, in particular the HRCT, is integral
and necessary to establish the diagnosis of IPF. The HRCT
of the chest should be placed in the context of the clinical
picture. Older age, in particular, increases the pretest
Suspected
ILD
Thorough PFTs
Identifiable
history and
cause of PF
physical exam
High Some Low

suspicion suspicion suspicion 6MWT
HRCT CTD panel
for IPF for IPF for IPF
(+/- CXR) +/- HP panel Functional/severity
assessment
UIP pattern
Possible UIP pattern
Inconsistent with UIP pattern
Consider
Diagnose Not IPF
VATS
IPF
biopsy
Figure 2.5 Diagnostic algorithm for idiopathic pulmonary fibrosis.

6MWT 6-min walk test, CTD connective tissue disease, CXR chest
X-ray, HP hypersensitivity pneumonitis, HRCT high resolution
computed tomography, ILD interstitial lung disease, IPF idiopathic
pulmonary fibrosis, PFT pulmonary function test, UIP usual intersti-
tial pneumonia, VATS video-assisted thoracoscopic surgery
probability of IPF. The likelihood of a patient having IPF is

much higher with increasing age (for example >70 years)
versus a younger patient (for example <50 years) with the
same clinical presentation.
The results of surgical lung biopsy do not provide a
default diagnosis and the pathologic findings need to be
interpreted in the context of the clinical and radiographic
presentations. There can be instances in which the HRCT
pattern may ‘trump’ the pathologic pattern in determining
the final diagnosis. A recommended diagnostic algorithm is
shown in Fig. 2.5. HRCT findings and histopathological
findings can be incorporated to determine the probability of
IPF (Table 2.4).
In some cases, the diagnosis of IPF may be a dynamic one,
for example, a patient could be diagnosed with IPF, but
Table 2.4 Idiopathic pulmonary fibrosis diagnosis, incorporating

histopathology and high resolution computed tomography
HRCT Inconsistent with UIP Possible UIP pattern UIP pattern
pattern Subpleural, basal Subpleural, basal
Upper or mid-lung predominance predominance
predominance Reticular Reticular
Peribronchovascular abnormality abnormality
predominance Absence of Honeycombing
Extensive ground inconsistent +/- traction
glass abnormality features bronchiectasis
Profuse micronodules Absence of
Discrete cysts inconsistent
Mosaic features
attenuation/air
trapping
Consolidation
Histopathology Biopsy indicated or to be considered Biopsy generally not
indicated
UIP pattern IPF probable IPF yes

Marked
fibrosis/architectural
distortion
+/-honeycombing,
predominantly
Subpleural/paraseptal
Patchy fibrosis
Fibroblastic foci
Absence of atypical
features
Probable UIP pattern IPF no IPF yes
Marked
fibrosis/architectural
distortion
+/- honeycombing
Absence of either IPF yes
patchy fibrosis or
fibroblastic foci
Absence of atypical
features
Honeycomb changes
only
Possible UIP pattern IPF no IPF probable
Patchy or diffuse
fibrosis
+/-interstitial
inflammation
Absence of other
criteria for UIP
Absence of features
suggesting alternate
diagnosis
Non-classifiable fibrosis
Not UIP pattern (any of 6) IPF no IPF no IPF no*
Hyaline membranes
Organizing pneumonia
Granulomas
Marked interstitial
inflammation
Predominant airway
centered changes
Other features
suggestive of alternate
diagnosis
HRCT high resolution computed tomography, IPF idiopathic pul-

monary fibrosis, UIP usual interstitial pneumonia
a
Histopathology dominates over HRCT
months or years later manifest signs of an underlying CTD. In

such a case, the diagnosis may change from IPF to CTD-
associated ILD (CTD-ILD) as the clinical picture evolves.
Key Points
• IPF diagnosis requires thorough patient history to
assess for risk factors or alternative diagnoses.
• Diagnosis should include blood-work to assess for
other causes of UIP pattern (such as CTD or hyper-
sensitivity pneumonitis).
• IPF is more common in men than women and
increases with age (>65–70 years of age).
• Typical physical exam findings are dry ‘Velcro®’
crackles at lung bases +/− digital clubbing.
• Diagnosis can be made on HRCT alone if radio-
graphic diagnostic criteria are met.
• If HRCT is inconclusive, VATS lung biopsy may be
advised (if the patient is suitable for surgery).
• Bronchoscopy is not generally recommended as it is
likely to be non-diagnostic.
• The standard of care for diagnosis is a multidisci-
plinary approach with radiologic and pathologic (if
applicable) findings considered in clinical context.
References
nium. Chest. 2011;140:221–9.
2. Nathan SD, Basavaraj A, Reichner C, et al. Prevalence and impact
of coronary artery disease in idiopathic pulmonary fibrosis.
Respir Med. 2010;104:1035–41.
3. Shin S, King CS, Brown AW, et al. Pulmonary artery size as a pre-
dictor of pulmonary hypertension and outcomes in patients with
chronic obstructive pulmonary disease. Respir Med. 2014;108:
1626–32.
4. Hernández-González F, Lucena CM, Ramírez J, et al. Cryobiopsy

in the diagnosis of diffuse interstitial lung disease: yield and cost-
effectiveness analysis. Arch Bronconeumol. 2015;51:261–7.
5. Sakamoto S, Homma S, Mun M, Fujii T, Kurosaki A, Yoshimura K.
Acute exacerbation of idiopathic interstitial pneumonia follow-
ing lung surgery in 3 of 68 consecutive patients: a retrospective
study. Intern Med. 2011;50:77–85.
6. Mizuno Y, Iwata H, Shirahashi K, et al. The importance of intra-
operative fluid balance for the prevention of postoperative acute
exacerbation of idiopathic pulmonary fibrosis after pulmonary
resection for primary lung cancer. Eur J Cardiothorac Surg.
2012;41:e161–5.
guidelines for diagnosis and management. Am J Respir Crit Care
Med. 2011;183:788–824.
8. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung
disease: a distinct entity. Chest. 2011;140:1292–9.
Chapter 3
Diseases that Mimic Idiopathic
Pulmonary Fibrosis
There are number of conditions that may commonly be

confused and difficult to differentiate from idiopathic pulmo-
nary fibrosis (IPF). This chapter discusses these conditions in
more detail.
3.1 Non-specific Interstitial Pneumonia

Non-specific interstitial pneumonia (NSIP) is a pathologic
entity that was first described in 1994 [1]. It is the second
most common of the idiopathic interstitial pneumonias
(IIPs) and can be difficult to differentiate from IPF [2]. The
diagnosis of NSIP should only be made pathologically and,
unlike IPF, is never a diagnosis that can be made based upon
radiography alone. Pathologically, NSIP is characterized by
diffuse homogenous fibrotic and/or cellular infiltrates, and
therefore, can be further subcategorized into fibrotic NSIP,
cellular NSIP, or mixed cellular fibrotic NSIP [3]. This
pathologic pattern of injury may be idiopathic in nature or
result from other causes of interstitial lung disease (ILD)
including chronic hypersensitivity pneumonitis (HP), con-
nective tissue diseases (CTDs), or autoimmune featured
ILD. NSIP is the pathologic entity that is most commonly
seen in all of the CTDs [4], not including rheumatoid arthri-
tis where usual interstitial pneumonia (UIP) is the most

DOI 10.1007/978-3-319-32794-5_3,
Figure 3.1 The radiographic appearance of non-specific interstitial

pneumonia with characteristic rim of subpleural sparing, as indicated
by the arrows
common [5]. Therefore, when the diagnosis of NSIP is made

pathologically, it is incumbent on the clinician to make sure
that there is no identifiable cause before the diagnosis of
idiopathic NSIP can be made. It is a condition that has a
distinctly better course than IPF, with a 5-year survival of
approximately 80 % of patients [6]. However, patients with
severe functional impairment have a grim prognosis similar
to those with IPF [7]. Given the prognostic implications, it is
important to differentiate NSIP from IPF. Idiopathic NSIP
tends to occur in younger patients and tends to be more
predominant in females, in contrast to IPF, which has a male
predominance [8]. The clinical presentation is very similar
to that of IPF, with insidious onset of shortness of breath,
and sometimes associated with a chronic non-productive
cough [8]. Unlike IPF, there is no characteristic radiographic
appearance, hence why this diagnosis always requires the
pathologic specimen [3]. One radiographic finding that has
some measure of specificity for NSIP is a rim of subpleural
sparing (unaffected lung in the subpleural space), a finding
reported in 21–64 % of cases [6, 9] (Fig. 3.1).
Chapter 3. Diseases that Mimic IPF 35
a b
Figure 3.2 High resolution computed tomographic images showing

the cellular variant of non-specific interstitial pneumonia. (a) Before
treatment, and (b) improvement in infiltrates after treatment with
corticosteroids
The treatment approach for NSIP is also quite different to

that of IPF, with immunosuppressive therapy commonly
regarded as standard of care, although studies attesting to this
are lacking [8]. The cellular variant of NSIP (less common) is
felt to be more responsive to immunosuppressive therapy
(Fig. 3.2). Whether fibrotic NSIP is a disease that may be
responsive to anti-fibrotic therapy is unknown and requires
independent studies.
3.2 Connective Tissue Disease-Associated

Interstitial Lung Disease
ILD is commonly present in many of the CTDs. The prevalence
of connective tissue disease-associated interstitial lung disease
(CTD-ILD) for the various CTDs is estimated to be [10]:
• scleroderma 40–100 %;
• rheumatoid arthritis 20–30 %;
• polymyositis/dermatomyositis 20–50 %;
• systemic lupus erythematosus 2–8 %; and
• Sjogren’s syndrome up to 25 %.
CTD-ILD is a relatively easy diagnosis to make in the con-

text of a patient with pre-existing CTD. In such situations a
diagnosis of idiopathic interstitial pneumonitis (such as IPF
or idiopathic NSIP) cannot be made being that there is a pre-
existing identifiable etiology for the ILD. A thorough patient
history and physical examination may provide important
clues to an underlying CTD since, in many cases, the onset of
respiratory symptoms and ILD may herald the onset of the
underlying CTD. In rarer instances, patients may present
without any CTD features, which might only manifest months
to years after the diagnosis of the underlying ILD [11].
Therefore, patients who are initially diagnosed with an IIP
can have their diagnosis evolve over time if an underlying
CTD subsequently manifests. The radiographic features of
CTD-ILD tend to be non-specific and, in many cases, a UIP
pattern occurs [11]. Various radiographic examples are shown
in Fig. 3.3. Table 2.1 (see Chap. 2) summarizes the major
pathologic entities and presenting signs and symptoms of the
more common CTDs.
3.3 Chronic Hypersensitivity Pneumonitis

Chronic HP is perhaps the one disease that is most difficult to
differentiate from IPF. HP can present acutely, subacutely, or
chronically. Patients who develop chronic HP do not neces-
sarily have a history of either acute or subacute HP or a docu-
mented history to a known allergen. Chronic HP can occur as
a result of exposure in either an occupational or home setting
following long-term inhalation of a wide spectrum of organic
antigens from mammalian and avian proteins, fungi, thermo-
philic bacteria, and certain chemical compounds [12]. Chronic
HP occurs most commonly in those with some type of expo-
sure to birds, especially bird droppings (Bird fancier’s lung),
among farmers (Farmer’s lung), or after exposure to moldy
hay grain or silage, or contaminated forced-air systems and
water reservoirs [12]. There are many other potential expo-
sures that can result in chronic HP, underscoring the need for
a b
c d
Figure 3.3 High resolution computed tomographic images demon-

strating the heterogeneous radiographic appearance of connective
tissue disease-interstitial lung disease. (a) Organizing pneumonia
(rheumatoid arthritis), (b) fibrotic non-specific interstitial pneumo-
nia (mixed connective tissue disease), (c) usual interstitial pneumo-
nia (systemic lupus erythematosus), and (d) lymphocytic interstitial
pneumonia (Sjögren’s) with characteristic cystic changes as indi-
cated by the arrows
a thorough social and occupational history in anyone pre-

senting with ILD. Patients can present very similarly to those
with IPF with chronic insidious onset of shortness of breath.
An important clinical clue is if shortness of breath and cough
worsen in any specific environment, either at work or at home.
However, this is more likely to indicate acute or subacute HP
and is not very sensitive for chronic HP. Chest imaging may
demonstrate distinct changes, including poorly formed small
nodules, ground-glass attenuation (either patchy or diffuse),
peribronchiolar infiltrates, or areas of air trapping that are
best seen on expiratory computed tomography (CT) imaging
(Fig. 3.4) [13]. Pathologically, the presence of poorly formed
Figure 3.4 The typical radiographic appearance of chronic hyper-

sensitivity pneumonitis with peribronchiolar infiltrates and mosaic
appearance from air trapping
granulomas, especially in a peribronchiolar distribution, are

suggestive of HP. Peribronchiolar fibrosis should also raise
the index of suspicion for chronic HP. Treatment includes
identification and avoidance of the offending antigen and
in some cases immunosuppressive therapy with steroids ± a
cytotoxic agent [12]. At present there are no firm guidelines
for the diagnosis or treatment of chronic HP.
3.4 Unclassifiable Interstitial Lung Disease

Even in the best hands, under the best circumstances, and
despite everyone’s best efforts, there are number of patients
with ILD that remains unclassifiable. This represents approx-
imately 10 % of patients with ILD [14]. Patients with unclas-
sifiable disease likely represent a mix of ILDs, including IPF,
NSIP, and chronic HP. It makes sense therefore, that these
patients tend to have an unpredictable disease course [14, 15].

One of the main reasons patients remain unclassifiable is due
to the lack of a surgical lung biopsy, which may be contrain-
dicated because of patient comorbidities or severity of illness.
However, there are some patients who remain unclassifiable
despite a surgical lung biopsy that may show changes that are
non-specific or unclassifiable, including ‘end-stage fibrotic
lung disease.’ There are also patients who have conflicting
clinical, radiographic, and pathologic changes and therefore a
specific clinical diagnosis is unattainable.
Key Points
• NSIP:
• Can be idiopathic or more commonly secondary
to CTD.
• Diagnosis requires lung biopsy.
• Treatment is with immunosuppressive therapy in
most cases.
• CTD-ILD
• ILD can be the presenting symptom in some cases.
• Diagnosis can be made on clinical history and
positive serologies.
• If lung biopsy is obtained, it can show NSIP, UIP,
OP, pleuritis, or any combination thereof.
• Treatment is with immunosuppressive therapy in
most cases.
• Chronic HP
• Can occur in the absence of an identifiable
exposure.
• Chest imaging may show poorly formed small
nodules, ground-glass attenuation, peribronchio-
lar infiltrates, or areas of air trapping.
• Histopathologic findings include granulomas,

NSIP, and/or UIP pattern in peribronchiolar
distribution.
• Treatment is withdrawal of exposure (if known)
and immunosuppression in some cases.
• Unclassifiable ILD
• Specific diagnosis may not be possible in a minor-
ity of ILD cases.
• Frequently results from inability to safely perform
lung biopsy or non-specific findings on lung biopsy.
References
1. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/
fibrosis. Histologic features and clinical significance. Am J Surg
Pathol. 1994;18:136–47.
2. Kligerman SJ, Groshong S, Brown KK, Lynch DA. Nonspecific
interstitial pneumonia: radiologic, clinical, and pathologic consid-
erations. Radiographics. 2009;29:73–87.
2013;188:733–48.
4. Kim EJ, Collard HR, King Jr TE. Rheumatoid arthritis-associated
interstitial lung disease: the relevance of histopathologic and
radiographic pattern. Chest. 2009;136:1397–405.
5. Gutsche M, Rosen GD, Swigris JJ. Connective tissue disease-
associated interstitial lung disease: a review. Curr Respir Care
Rep. 2012;21(1):224–32.
6. Travis WD, Hunninghake G, King Jr TE, et al. Idiopathic nonspe-
cific interstitial pneumonia: report of an American Thoracic
Society project. Am J Respir Crit Care Med. 2008;177:1338–47.
7. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic
interstitial pneumonia: the prognostic value of longitudinal func-
tional trends. Am J Respir Crit Care Med. 2003;168:531–7.
8. Glaspole I, Goh NS. Differentiating between IPF and

NSIP. Chron Respir Dis. 2010;7:187–95.
9. Silva CI, Müller NL, Lynch DA, et al. Chronic hypersensitivity
pneumonitis: differentiation from idiopathic pulmonary fibrosis
and nonspecific interstitial pneumonia by using thin-section
CT. Radiology. 2008;246:288–97.
10. Castelino FV, Varga J. Interstitial lung disease in connective tis-
sue diseases: evolving concepts of pathogenesis and manage-
ment. Arthritis Res Ther. 2010;12:213.
11. Vij R, Strek ME. Diagnosis and treatment of connective tissue
disease-associated interstitial lung disease. Chest. 2013;143:
814–24.
12. Selman M, Buendía-Roldán I. Immunopathology, diagnosis, and
management of hypersensitivity pneumonitis. Semin Respir Crit
Care Med. 2012;33:543–54.
13. Wuyts W, Sterclova M, Vasakova M. Pitfalls in diagnosis and
management of hypersensitivity pneumonitis. Curr Opin Pulm
Med. 2015;21:490–8.
14. Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prog-
nosis of unclassifiable interstitial lung disease. Eur Respir
J. 2013;42:750–7.
15. Skolnik K, Ryerson CJ. Unclassifiable interstitial lung disease: a
review. Respirology. 2016;21:51–6.
Chapter 4
Pathogenesis of Idiopathic
Pulmonary Fibrosis
4.1 Etiology
The etiology of idiopathic pulmonary fibrosis (IPF) remains
incompletely understood. Historically, IPF was thought to be
a condition characterized by inflammation, leading to fibro-
sis. The current understanding is based on the concept of
repetitive injury with an abnormal wound healing response in
a genetically susceptible host [1]. The initial injury appears to
be to the alveolar epithelial cells (AECs), particularly type II
AECs. The current understanding of the pathogenesis of IPF
is depicted in Fig. 4.1 [2].
4.2 Alveolar Epithelial Cell Injury

There are two types of AECs, type I and type II. Type I AECs
are extremely thin squamous cells that facilitate gas exchange
between the alveoli and the blood stream. Type II AECs pro-
duce, secrete, and recycle pulmonary surfactant [3].
Additionally, AECs assist in regulating fluid balance in the
lung and produce compounds of the innate immune system
[3]. Injury to AECs results not only in AEC death, but also in
phenotypic transformation of the surviving cells, which
potentiates further injury. The downstream consequences of
injury to the AECs include [2]:

DOI 10.1007/978-3-319-32794-5_4,
Alveolar
collapse and
Fibroblast re-epithelialization
Lung
Epithelium injury
Capillary
Epithelial cell Matrix
death or accumulation
Macrophage reprogramming and cross-linking
Immune Alveolus
activation and
polarization
Fibroblast
activation and
Vascular leak and myofibroblast
extravascular differentiation
coagulation
Fibrin Fibroblast
clot recruitment,
Myofibroblast
invasion,
proliferation,
and persistence
Figure 4.1 Pathogenesis of idiopathic pulmonary fibrosis [2]. Injury

to alveolar epithelial cells triggers a cascade of aberrant healing,
which results in fibrosis (Reproduced with permission from © The
American Thoracic Society)
• vascular leak;
• extravascular coagulation;
• fibroblast recruitment and activation; and
• activation of the innate immune system.
4.3 Disease Heterogeneity

The repetitive injury concept parallels the heterogeneous
nature of the disease in its distribution and progression. In a
single lung, or even a biopsy from a lobe of one lung, there is
temporal and spatial gradation of injury, from ‘burnt-out’ or
‘end-stage’ fibrotic changes (that usually manifest pathologi-
cally as areas of microscopic honeycombing), to areas of fresh
Chapter 4. Pathogenesis of Idiopathic Pulmonary Fibrosis 45
collagen deposition and thickened or fibrotic alveolar septae,

to areas of normal, uninvolved lung. The demarcation between
abnormal and normal lung can be fairly abrupt. The spatial
heterogeneity pathologic pattern mimics what is typically
noted radiographically, in that the disease tends to start at the
periphery where more of the advanced changes are noted
and ‘marches’ medially to the more central areas of the lung.
This pattern of progression also tends to occur in a caudo-
cranial direction with the most diseased areas present at the
lung bases.
4.4 The Role of the Fibroblast

At the interface of abnormal–normal lung, the presence of
fibroblasts (spindle-shaped cells) in clusters (or foci) can be
noted. The prevailing paradigm is that fibroblasts are central
to the propagation of the disease. Specifically, the fibroblasts
proliferate in a disinhibited or unchecked fashion. Whereas a
fibroblastic response is normal in the context of any injury in
any tissues, for reasons unknown, the fibroblasts are stimu-
lated and fail to be ‘turned off’ in patients with IPF. Whether
this is inherent to the fibroblast itself or a result of the local
lung milieu remains to be determined. Potential sources of
fibroblasts include any or all of the following:
• endogenous lung fibroblasts;
• circulating bone marrow-derived fibrocytes [4];
• epithelial cells that undergo transformation to mesenchy-
mal cells, so-called epithelial-mesenchymal transition
(EMT) [5]; and
• pleural mesothelial cells (this is an attractive hypothesis and
could explain the peripheral predilection of the disease) [6].
4.4.1 Inciting Events
The following may play a role in the initiation or perpetua-

tion of the disease [2]:
• gastroesophageal contents: acid, non-acid, food;

• infections;
• cigarette smoke;
• other volitional inhalants;
• environmental inhalants (see Table 2.3 in Chap. 2 for risk
factors for IPF);
• high FiO2;
• lung ‘stretch’ (i.e., high tidal volumes) in the context of
mechanical ventilation; and
• aging.
4.4.2 Collagen Deposition
Collagen deposition and extracellular matrix formation results

from the persistently activated fibroblasts. This may take place
within the interstitium or the alveoli. Collagen deposition pro-
vides the scaffold for the fibrosis that eventually evolves.
4.5 Cytokines
There are multiple cytokine derangements that have been
found in patients with IPF. Presently, the role of these cyto-
kines remains investigational and has not been incorporated
into routine clinical practice. The major cytokine culprits
thought to play a pivotal role in the genesis and perpetuation
of IPF include [2]:
• transforming growth factor-beta (TGF-β);
• platelet derived growth factor (PDGF);
• connective tissue growth factor (CTGF);
• vascular endothelial growth factor (VEGF); and
• fibroblast growth factor (FGF).
Other important cytokines include:
• endothelin;
• tumor necrosis factor-alpha (TNF-α); and
• interleukin-13 (IL-13).
4.6 Pathways and Mechanisms

Several potential signaling pathways may be activated and
drive the development of fibrosis. These include the Wnt and
lysyl oxidase-like 2 (LOXL2) pathway. Telomere shortening
may predispose cells to type II AECs to apotosis, setting the
stage for the aberrant pathways leading to progressive fibro-
sis. These mechanisms are discussed in more detail below.
4.6.1 Wnt Pathway
The Wnt pathway is an evolutionarily conserved pathway

crucial to cell-fate determination and organogenesis during
embryological development [7]. The best characterized path-
way, the canonical/β-catenin pathway, appears essential to
lung development, as deletion of β-catenin prevents forma-
tion of distal airways in animal models [8]. Nuclear accumula-
tion of β-catenin has been found in fibroblastic foci of IPF
lungs, suggesting pathogenic re-activation of the Wnt path-
way as a possible mechanism in IPF [9].
4.6.2 Lysyl Oxidase-Like 2 Pathway
LOXL2 is essential in the formation of connective tissue; it is

an enzyme produced by fibroblasts that catalyzes the cross-
linking of matrix proteins. Expression of LOXL2 is increased
in IPF [2, 10], leading to increased cross-linking of matrix
proteins, which may contribute to the increased matrix stiff-
ness encountered in IPF.
4.6.3 Telomeres and Apoptosis
Telomeres are regions of repetitive, non-coding nucleoside

sequences on the ends of chromosomes that serve to protect
the chromosome from deterioration. Telomeres shorten with
each cell division, and when a critical length is reached, apop-
tosis is initiated. The enzyme telomerase combats the succes-

sive shortening of chromosomes by creating new telomeres
[11]. Telomere shortening is responsible for one-sixth of cases
of familial IPF (Chap. 1), and appears to play a role in spo-
radic cases as well. In cross-sectional studies, patients with
IPF have significantly shorter telomere lengths than age-
matched controls [12]. Aging is the primary factor contribut-
ing to telomere shortening, which may explain the predilection
of IPF for the elderly.
4.7 Pathology
Pathologic features that are important in the diagnosis of IPF
include subpleural fibrosis, microscopic honeycombing, nor-
mal lung tissue, and fibroblastic foci [13]. Fibroblasts are typi-
cally seen clumped in groups and are recognized by their
elongated spindle-like appearance. They are frequently noted
adjacent to areas of fresh collagen deposition at the interface
with normal lung. They are felt to represent the ‘leading edge’
of the injurious process.
Other pathologic features that may be seen, that are not
diagnostic features but are permissible in the context of a
lung biopsy that is otherwise diagnostic for IPF, include mild
to moderate inflammation and a few very poorly formed
granulomas. However, the presence of multiple granulomas
always should be an alert to the possible diagnosis of chronic
hypersensitivity pneumonitis (HP).
Typical histopathologic changes of IPF (usual interstitial
pneumonia pattern) are shown in Fig. 4.2.
Pathologic features suggestive of a diagnosis other than
IPF include [14]:
• multiple poorly formed granulomas — suggestive of
chronic HP, especially if they are seen in a bronchiolocen-
tric distribution;
• lymphoid aggregates — suggestive of an underlying con-
nective tissue disease (CTD), especially rheumatoid arthri-
tis or Sjögren’s syndrome (especially if extensive);
a b
c d
Figure 4.2 Typical histopathologic changes of idiopathic pulmonary

fibrosis (usual interstitial pneumonia pattern). The central panel
demonstrates the lung under low power microscopy with the various
heterogeneous changes of a usual interstitial pneumonia-pattern
demonstrated, including dense fibrosis, honeycombing, and normal
lung. These changes are also shown under high power microscopy:
(a) microscopic honeycombing (arrows), (b) areas of fibrosis (lower)
transitioning to more normal aerated alveoli (upper), (c) areas of
dense fibrosis (right) with well-demarcated transition to normal
lung (left), and (d) cluster of elongated spindle-shaped cells that
characterize a fibroblastic focus (arrow)
• moderate to severe inflammation — can be consistent with

many other conditions including an underlying CTD or
cellular non-specific interstitial pneumonia (NSIP);
• pleuritis — suggestive of an underlying CTD;
• peribronchiolar fibrosis — might be consistent with
chronic HP, aspiration, or the idiopathic entity of bronchi-
olocentric fibrosis;
• elastosis — consistent with pleuroparenchymal fibroelas-
tosis, especially in the upper lobes; and
• homogeneous changes in the lung tissue — characteristic
and more typical of NSIP.
Key Points
• The pathogenesis of IPF is not well elucidated
at present.
• IPF is thought to arise from initial repetitive injury to
AECs and an abnormal wound healing process.
• Fibroblasts appear to be central to the propagation
of disease when they fail to be ‘turned off’ and pro-
liferate in a disinhibited manner.
• Persistently activated fibroblasts deposit an
increased amount of collagen, which provides a scaf-
fold for fibrosis.
• Cytokine imbalances have been found in patients
with IPF, but the clinical relevance has yet to be proven.
• Telomere shortening, increased LOXL2 expression,
and re-activation of the Wnt pathway are factors
linked to IPF development.
References
1. Borensztajn K, Crestani B, Kolb M. Idiopathic pulmonary fibro-
sis: from epithelial injury to biomarkers–insights from the bench
side. Respiration. 2013;86:441–52.
2. Ahluwalia N, Shea BS, Tager AM. New therapeutic targets in
idiopathic pulmonary fibrosis. Aiming to rein in runaway
wound-healing responses. Am J Respir Crit Care Med. 2014;
190:867–78.
3. Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C,
Markart P. Unravelling the progressive pathophysiology of idio-
pathic pulmonary fibrosis. Eur Respir Rev. 2012;21:152–60.
4. Phillips RJ, Burdick MD, Hong K, et al. Circulating fibrocytes
traffic to the lungs in response to CXCL12 and mediate fibrosis.
J Clin Invest. 2004;114:438–46.
5. Marmai C, Sutherland RE, Kim KK, et al. Alveolar epithelial
cells express mesenchymal proteins in patients with idiopathic
pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol.
2011;301:L71–8.
6. Batra H, Antony VB. Pleural mesothelial cells in pleural and

lung diseases. J Thorac Dis. 2015;7:964–80.
7. Komiya Y, Habas R. Wnt signal transduction pathways.
Organogenesis. 2008;4:68–75.
8. Sasaki T, Kahn M. Inhibition of β-catenin/p300 interaction proxi-
malizes mouse embryonic lung epithelium. Transl Respir Med.
2011;2:8.
9. Chilosi M, Poletti V, Zamò A, et al. Aberrant Wnt/beta-catenin
pathway activation in idiopathic pulmonary fibrosis. Am J Pathol.
2003;162:1495–502.
10. Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhi-
bition of lysyl oxidase-like-2 impedes the development of a
pathologic microenvironment. Nat Med. 2010;16:1009–17.
11. Armanios M. Syndromes of telomere shortening. Annu Rev
Genomics Hum Genet. 2009;10:45–61.
12. Armanios M. Telomerase and idiopathic pulmonary fibrosis.
Mutat Res. 2012;730:52–8.
guidelines for diagnosis and management. Am J Respir Crit
Care Med. 2011;183:788–824.
2013;188:733–48.
Chapter 5
Prognosis, Clinical Course,
and Monitoring of Patients
with Idiopathic Pulmonary
Fibrosis
5.1 Prognosis
The prognosis of idiopathic pulmonary fibrosis (IPF) is gener-
ally regarded as quite poor with a median survival from the
time of diagnosis of anywhere from 2.5 to 4 years [1]. However,
it is difficult a priori to predict the course of the disease in
individual patients [2]. There are some patients who have a
protracted course and survive 5 years or more, but this disease
phenotype can only be recognized in retrospect. This repre-
sents about 20–25 % of all patients with IPF [3].
5.1.1 Patient Discussion About Prognosis
When talking to patients about the prognosis, it is imperative

to place it in the appropriate context. It is important for the
patient to appreciate the following:
• Their prognosis depends on when they present, ie, what is
their time ‘zero.’ Patients who are diagnosed late in their
disease course intuitively will have a worse prognosis.
Patients who are elderly and sedentary with multiple

DOI 10.1007/978-3-319-32794-5_5,
comorbidities tend to be diagnosed late, while younger,

more robust patients tend to be diagnosed earlier.
• Not all patients live 2.5–4 years; this is just the range of the
average survival from different natural history studies.
There are patients with IPF who live well beyond this.
Paradoxically, there is data to suggest that the longer
patients live with their IPF, the more likely it is that they
will live longer. This is an important ‘patient friendly’ con-
cept and underscores the importance of re-visiting progno-
sis over time as it can be dynamic in nature [1].
• It is very difficult to predict the course of the disease and
therefore it is never too early to talk about medical ther-
apy and transplant. Similarly, it is never too early to
address end-of-life issues. This can be couched by the fol-
lowing introductory statement, ‘Let’s hope for the best, but
prepare for the worst.’
5.2 Clinical Course

The course of IPF may be characterized by a slow and steady
deterioration, rapid progression, acute exacerbations, a ‘stair-
step’ pattern of progression with periods of stability punctu-
ated by episodes of progression, or a combination of patterns
(see Fig. 1.1 in Chap. 1). Importantly, the past disease course
does not predict the future trajectory [4].
5.3 Prognostic Indicators
5.3.1 Pulmonary Function Testing
Pulmonary function testing (PFT) is the primary tool by

which IPF disease severity is assessed.
5.3.1.1 The Forced Vital Capacity

The forced vital capacity (FVC) (expressed as a percentage)
predicted at baseline has prognostic implications, with those
Chapter 5. Prognosis, Clinical Course, and Monitoring 55
patients who present with lower levels of lung function hav-

ing worse outcomes [5]. Lower FVCs tend to imply more
fibrosis and less compliant lungs and suggest that such
patients are presenting later in their disease course. However,
what is unknown in individual patients is the level of their
lung function prior to disease onset since not all patients start
with a baseline FVC of 100 % predicted. This also explains
why some patients may present with ‘normal’ FVCs and yet
still have significant disease if their baseline FVC was
>100 %. Change in the FVC over time provides more precise
and important prognostic information than the baseline FVC
alone, since this demonstrates progression of disease [4]. In
particular, a decline of 10 % in the FVC% predicted portends
a poor outcome. This change can be either the absolute
change (e.g., a decrease from 60 to 50 %) or the relative
change (e.g., 60–54 %). Although the latter change is gener-
ally less in terms of absolute measures (milliliters), it is asso-
ciated with almost equivalent prognostic significance. A
decrease in the FVC of as little as 5 % also portends worse
outcomes, albeit less striking than larger changes [6]. Change
in the FVC has been used as the primary endpoint in many of
the clinical drug trials [7].
5.3.1.2 The Single Breath Diffusing Capacity

for Carbon Monoxide
The baseline single breath diffusing capacity for carbon mon-

oxide (DLco) may impart more significant prognostic implica-
tions than FVC% [2]. However, there tends to be more
variability around this measurement, which limits the value
and prognostic significance of any change. With that being
said, a decrease of 15 % is generally regarded as significant [6].
5.3.1.3 The Total Lung Capacity
The total lung capacity (TLC) % predicted, while commonly

measured at baseline and sometimes in follow-up, has not
gained traction as the primary measure of pulmonary func-
tion in patients with IPF (which remains the FVC). TLC is
generally regarded as the gold standard for lung volume

measurement since it incorporates the residual volume that
remains unmeasured following the FVC maneuver. However,
there may be more variability around this measurement and
it is more cumbersome to measure. In general, there should
be good correlation between the TLC and FVC in patients
with interstitial lung disease (ILD), except perhaps in those
patients with combined pulmonary fibrosis/emphysema
(CPFE), in whom there might be more air trapping and
hence a higher residual volume.
5.3.2 The Six Minute Walk Test
The 6 min walking test (6MWT) is a simple test performed on a

long (at least 30 m) uninterrupted corridor where patients are
instructed to walk as far as they can in 6 min while being moni-
tored. They are allowed to rest if they get tired or short of breath,
but this will affect the primary outcomes measure — the distance
achieved. In addition to distance, it is also now recommended that
the arterial oxygen saturation (SpO2), measured by pulse oxime-
try and pulse rate, be monitored and the amount of supplemental
oxygen administered be recorded. Patients may walk with supple-
mental oxygen and it is recommended that they be halted if their
SpO2 declines below 80 % during the course of the test [8].
5.3.2.1 Distance
The distance attained during the 6MWT has been shown to

correlate with subsequent outcomes [9]. Both the baseline dis-
tance and the change in distance over time have been shown to
provide important prognostic information that is independent
of the prognostic information provided by PFT measurements
[10, 11]. Therefore, the 6MWT compliments PFTs in terms of
the baseline assessment and the serial monitoring of patients.
The minimally important difference in the 6MWT distance
is generally regarded as approximately 20–45 m [9, 11]. The
bottom end of this range is useful to discern differences in
large population-based studies, while the top end of the range

is generally regarded as the better threshold to denote true
change in individual patients.
5.3.2.2 Desaturation
Some studies suggest the degree of desaturation during the

course of the 6MWT imparts more important prognostic
information than distance achieved [10].
5.3.2.3 Pulse Rate Recovery
Pulse rate recovery (PRR) is calculated by the difference in

the pulse rate at the end of the 6MWT and after 1 min of
recovery. For example, if the pulse rate is 120 beats per min-
ute (bpm) at the end of the 6MWT and then is 110 bpm after
1 min of rest, this equates to a PRR of 10 bpm. The lower the
PRR the worse the prognosis. The proposed cut-off point
defining an abnormal PRR is less than 13 bpm [12].
5.3.3 Computed Tomography Scan of the Chest
A limited number of studies have attempted to correlate

objective scoring of fibrosis on high resolution computed
tomography (HRCT) to PFT and outcomes [13, 14], however,
further study of the clinical utility of this technique is
required. Currently, no well-validated fibrosis scoring system
is available in the clinical setting.
Recent data suggests that measurement of the pulmonary
artery diameter on computed tomography (CT), expressed as
a ratio of the aortic diameter at the same level (pulmonary
artery to aorta [PA/A] ratio), might impart important inde-
pendent prognostic information. A PA/A ratio >1 is associ-
ated with higher risk of mortality (Fig. 5.1). An enlarged PA
segment could be indicative of underlying pulmonary hyper-
tension (PH), although enlargement could also be due to
traction on the vessel from surrounding fibrosis.
A
PA
Figure 5.1 Enlarged pulmonary artery segment on computed

tomography scan. The ratio of the pulmonary artery (blue line) to
the aorta (red line) (PA/A >1) is predictive of survival in IPF
5.3.4 Composite Scores

The gender, age, physiology (GAP) index is the composite
index that is gaining the most recognition and acceptance. It
is easy to calculate from readily available variables, including
demographics. The physiology component is constituted by
the FVC% predicted and DLco% predicted [15].
The composite physiologic score (CPI) is the oldest of the
composite scoring systems. It has been used in some clinical
trials, but it has not garnered favor in the clinical setting
largely due to the difficulty calculating the score [16].
A risk stratification score (ROSE) index scoring system
[17] has a nice acronym, but is exceedingly difficult to calcu-
late and therefore is not frequently used in clinical practice.
The distance-saturation product is a score constituted by
the product of the distance walked in meters and lowest oxy-
gen saturation achieved on 6MWT, expressed as a fraction. It
has only been studied in patients walking only using room air
and still requires further validation [18].
5.3.5 Pulmonary Hypertension
The development of PH is associated with a significantly

worse prognosis and functional status in IPF [19]. Even mild
elevations in pulmonary pressure are associated with worse
outcomes in IPF, as demonstrated by Hamada et al. [20], who
showed that a mean pulmonary artery pressure (mPAP)
>17 mmHg was associated with significantly worse 5-year
survival. Right heart catheterization remains the gold stan-
dard to diagnose PH. In approximately half of IPF cases the
mPAP is in the range of 25–30 mmHg, while more severe PH
(mPAP >40 mmHg) has been described in ~9 % of patients
with advanced IPF [21]. Although echocardiography is a
good screen for the presence of PH, it is not used to make the
diagnosis since it only provides an estimate of the systolic
pulmonary artery pressure (sPAP), whereas it is the mPAP
that defines the presence of PH. Nonetheless, the presence of
PH inferred from echocardiographic estimates of the sPAP
has also been associated with a significantly worse prognosis.
Two echocardiographic studies found that those patients with
sPAP >60 mmHg and >50 mmHg had median survivals of
only 6.7 and 8.4 months, respectively [22, 23]. Table 5.1 pro-
vides clues that may be important in risk stratifying patients
for the presence of underlying PH.
5.3.6 Hospitalization
Any hospitalization after the diagnosis of IPF, even non-

respiratory, but especially those that are respiratory in nature
are associated with worse outcomes. Patients who are hospi-
talized for a respiratory reason have been shown to have a
subsequent risk of in-hospital mortality of 22.4 % [24]. If end-
of-life issues have not previously been discussed, it is prudent
to do so as soon as possible, since intubation and mechanical
ventilation generally carry a very poor prognosis with mean-
ingful recovery a very unlikely outcome. Hospitalization is
gaining increasing acceptance as an endpoint (alone or part
of a composite of clinical worsening) in IPF clinical trials [7].
Table 5.1 Features that suggest the presence of pulmonary hyper-

tension in patients with idiopathic pulmonary fibrosis
Signs/symptoms of pulmonary hypertension
History Shortness of breath on exertion out of
proportion to the extent of interstitial lung
disease
Presyncope/syncope with exertion
Physical Loud P2 heart sound
examination Signs of right heart failure
Elevated jugular venous pressure
Lower extremity edema
PFT DLco <40 %
FVC%/DLco% ratio >1.5
6MWT Distance <200 m
SpO2 <88 % on room air during walk
Limited (<13 beats per minute) pulse rate
recovery
Imaging Ratio of PA to aorta diameter >1 on
computed tomography of the chest
Labwork Elevated NT-proBNP or BNP
Echocardiogram Elevated RVSP
Dilated right atrium and/or right ventricle
Right ventricle dysfunction
6MWT 6 min walking test, BNP brain natriuretic peptide, DLco dif-
fusing capacity of the lungs for carbon monoxide, FVC forced vital
capacity, NT-proBNP N-terminal pro brain natriuretic peptide,
PA pulmonary artery, PFT pulmonary function testing, PRR = Δ
max pulse – pulse 1 min after cessation of walk, RVSP right ven-
tricular systolic pressure
5.3.7 Biomarkers
Biomarkers are objectively quantifiable measurements that

serve as a surrogate marker to clinical variables [25]. In 1998,
the National Institutes of Health Biomarkers Definitions
Working Group defined a biomarker as ‘a characteristic that
is objectively measured and evaluated as an indicator of nor-
mal biological processes, pathogenic processes, or pharmacologic
responses to a therapeutic intervention’ [25]. Therefore, any

of the prognostic indicators in the previous section could be
regarded as biomarkers, including PFT. Ideally, a biomarker
would be acquired non-invasively and have high validity and
reliability. The general inference of a ‘biomarker’ is that of a
blood test(s), which will be the remaining focus of this sec-
tion. Biomarkers could serve multiple purposes in IPF,
including identification of patients at risk for IPF, screening
for patients with subclinical disease, predicting disease pro-
gression, and identifying patients likely to respond to ther-
apy [26]. Unfortunately, there are no well-established,
reliable, and commercially available blood biomarkers spe-
cific to IPF. Given the complexity of the pathogenesis of IPF,
it is unlikely a single biomarker will prove to be ‘the holy
grail’ in IPF diagnosis. It seems more likely that multi-
marker panels designed to assess the multiple biologic pro-
cesses at play will be required to improve patient care. Some
of the biomarkers assessed in IPF to date are detailed in the
following sections.
5.3.7.1 Brain Natriuretic Peptide or N-Terminal

Pro Brain Natriuretic Peptide
Levels of brain natriuretic peptide (BNP) or N-terminal pro

brain natriuretic peptide (NT-proBNP) have been shown to cor-
relate with outcomes. Whether these reflect the presence of
underlying PH and or occult heart failure remains uncertain [23].
5.3.7.2 Red Cell Width Distribution
Red cell distribution width (RDW) is a readily available

parameter that can be found on complete blood count
reports. High levels (>15) have been shown to correlate with
poor outcomes [27].
5.3.7.3 Krebs Von DerLungen-6
Krebs von derLungen-6 (KL-6) is a glycoprotein expressed

on the surface of type II alveolar epithelial cells that has been
associated with poor outcomes in IPF. However, RCTs have

failed to demonstrate a correlation between changes in KL-6
and treatment response [28].
5.3.7.4 Surfactant Protein A and D
Surfactant proteins A and D are both elevated in patients

with IPF when compared to healthy controls and elevated
levels are independent predictors of mortality or need for
lung transplantation [26].
5.3.7.5 Vascular Endothelial Growth Factor (VEGF)
Pathologic angiogenesis has been implicated as a possi-

ble contributor to the development of fibrotic lung dis-
ease. Vascular endothelial growth factor (VEGF) is a
major regulator of angiogenesis. Elevated serum concen-
trations of VEGF are associated with decreased survival
in IPF [ 29 ].
5.4 Monitoring the Clinical Course

The course of IPF is highly variable and largely unpredict-
able. Patients therefore should be followed closely. It is rec-
ommended that patients be seen at least every 3–6 months
and on an as needed basis. There are no specific guidelines or
data to suggest serial monitoring alters the course of patients
with IPF. In the absence of such, the following provides a sug-
gested guideline for consideration:
• PFT every 3 months;
• 6MWT every 3 months; and
• annual CT chest scan.
Comorbidities should also be monitored and treatment
implemented where possible, the following comorbidities are
particularly important to monitor:
• gastroesophageal reflux disease;

• PH;
• obstructive sleep apnea;
• congestive heart failure;
• coronary artery disease;
• venous thromboembolism;
• lung cancer;
• depression and anxiety; and
• deconditioning.
5.5 Clinical Scenario of Increasing Shortness

of Breath
The increasing shortness of breath experienced by a patient
with IPF may be acute, subacute, or chronic. Differential
diagnosis should be considered, including:
• pulmonary embolism;
• congestive heart failure;
• pneumonia;
• acute exacerbation of IPF;
• cardiac ischemia;
• disease progression; and
• pneumothorax.
Testing should be carried out to investigate and rule out dif-
ferential diagnosis. Recommended testing includes:
• routine laboratory tests (e.g., complete blood count and
chemistry panel);
• BNP or NT-proBNP;
• evaluation for myocardial infarction with electrocardio-
gram (ECG) and cardiac enzymes;
• appropriate evaluation for pulmonary embolism (deter-
mine pre-test probability, D-dimer, imaging);
• echocardiogram; and
• chest imaging (chest radiograph at a minimum with strong
consideration of chest CT, perform CT angiogram to rule
pulmonary embolism if appropriate).
Key Points
• The disease progression of IPF is highly variable.
• Lower FVC, DLCO, 6MWT distance, and nadir SpO2
during 6MWT portend decreased survival rates.
• Disease progression is monitored through evaluation
of PFT and 6MWT.
• At this time there are no widely available blood bio-
markers for IPF.
• Presence of PH and need for hospitalization increase
the risk of mortality or lung transplantation.
• Common causes of acute worsening in IPF include
pulmonary embolism, systolic or diastolic heart fail-
ure, cardiac ischemia, or infection.
References
1. Brown AW, Shlobin OA, Weir N, et al. Dynamic patient counsel-
ing: a novel concept in idiopathic pulmonary fibrosis. Chest.
2012;142:1005–10.
nium. Chest. 2011;140:221–9.
3. Brown AW, Shlobin OA, Weir N, Albano MC, Ahmad S, Smith M,
Leslie K, Nathan SD. Dynamic patient counseling: a novel con-
cept in idiopathic pulmonary fibrosis. Chest. 2012;142:
1005–10.
4. Ley B, Collard HR, King Jr TE. Clinical course and prediction of
survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care
Med. 2011;183:431–40.
5. Erbes R, Schaberg T, Loddenkemper R. Lung function tests in
patients with idiopathic pulmonary fibrosis. Are they helpful for
predicting outcome? Chest. 1997;111:51–7.
6. Zappala CJ, Latsi PI, Nicholson AG, et al. Marginal decline in
forced vital capacity is associated with a poor outcome in idio-
pathic pulmonary fibrosis. Eur Respir J. 2010;35:830–6.
7. Nathan SD, Meyer KC. IPF clinical trial design and endpoints.
Curr Opin Pulm Med. 2014;20:463–71.
8. Holland AE, Spruit MA, Troosters T, et al. An official European

Respiratory Society/American Thoracic Society technical stan-
dard: field walking tests in chronic respiratory disease. Eur
Respir J. 2014;44:1428–46.
9. Singh SJ, Puhan MA, Andrianopoulos V, et al. An official sys-
tematic review of the European Respiratory Society/American
Thoracic Society: measurement properties of field walking tests
in chronic respiratory disease. Eur Respir J. 2014;44:1447–78.
10. Flaherty KR, Andrei AC, Murray S, et al. Idiopathic pulmonary
fibrosis: prognostic value of changes in physiology and six-
minute-walk test. Am J Respir Crit Care Med. 2006;174:803–9.
11. du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in
idiopathic pulmonary fibrosis: test validation and minimal clini-
cally important difference. Am J Respir Crit Care Med.
2011;183:1231–7.
12. Swigris JJ, Olson AL, Shlobin OA, Ahmad S, Brown KK,
Nathan SD. Heart rate recovery after six-minute walk test pre-
dicts pulmonary hypertension in patients with idiopathic pulmo-
nary fibrosis. Respirology. 2011;16:439–45.
13. Battista G, Zompatori M, Fasano L, Pacilli A, Basile B. Progressive
worsening of idiopathic pulmonary fibrosis. High resolution
computed tomography (HRCT) study with functional correla-
tions. Radiol Med. 2003;105:2–11.
14. Oda K, Ishimoto H, Yatera K, et al. High-resolution CT scoring
system-based grading scale predicts the clinical outcomes in
patients with idiopathic pulmonary fibrosis. Respir Res. 2014;15:10.
15. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional
index and staging system for idiopathic pulmonary fibrosis. Ann
Intern Med. 2012;156:684–91.
16. Watters LC, King TE, Schwarz MI, Waldron JA, Stanford RE,
Cherniack RM. A clinical, radiographic, and physiologic scoring
system for the longitudinal assessment of patients with idiopathic
pulmonary fibrosis. Am Rev Respir Dis. 1986;133:97–103.
17. Mura M, Porretta MA, Bargagli E, et al. Predicting survival in
newly diagnosed idiopathic pulmonary fibrosis: a 3-year pro-
spective study. Eur Respir J. 2012;40:101–9.
18. Lettieri CJ, Nathan SD, Browning RF, Barnett SD, Ahmad S,
Shorr AF. The distance-saturation product predicts mortality in
idiopathic pulmonary fibrosis. Respir Med. 2006;100:1734–41.
19. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF.
Prevalence and outcomes of pulmonary arterial hypertension in
advanced idiopathic pulmonary fibrosis. Chest. 2006;129:746–52.
20. Hamada K, Nagai S, Tanaka S, et al. Significance of pulmonary

arterial pressure and diffusion capacity of the lung as prognosti-
cator in patients with idiopathic pulmonary fibrosis. Chest.
2007;131:650–6.
21. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD.
Pulmonary hypertension in patients with pulmonary fibrosis
awaiting lung transplant. Eur Respir J. 2007;30:715–21.
22. Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hyper-
tension in patients with idiopathic pulmonary fibrosis. Chest.
2005;128:2393–9.
23. Song JW, Song JK, Kim DS. Echocardiography and brain natri-
uretic peptide as prognostic indicators in idiopathic pulmonary
fibrosis. Respir Med. 2009;103:180–6.
24. Brown AW, Fischer CP, Shlobin OA, et al. Outcomes after hospi-
talization in idiopathic pulmonary fibrosis: a cohort study. Chest.
2015;147:173–9.
25. Biomarkers Definitions Working Group. Biomarkers and sur-
rogate endpoints: preferred definitions and conceptual frame-
work. Clin Pharmacol Ther. 2001;69:89–95.
26. Hambly N, Shimbori C, Kolb M. Molecular classification of idio-
pathic pulmonary fibrosis: personalized medicine, genetics and
biomarkers. Respirology. 2015;20:1010–22.
27. Nathan SD, Reffett T, Brown AW, et al. The red cell distribution
width as a prognostic indicator in idiopathic pulmonary fibrosis.
Chest. 2013;143:1692–8.
28. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-
controlled trial of pirfenidone in patients with idiopathic pulmo-
nary fibrosis. Am J Respir Crit Care Med. 2005;171:1040–7.
29. Ando M, Miyazaki E, Ito T, et al. Significance of serum vascular
endothelial growth factor level in patients with idiopathic pul-
monary fibrosis. Lung. 2010;188:247–52.
Chapter 6
Comorbidities
and Complications
of Idiopathic Pulmonary
Fibrosis
Idiopathic pulmonary fibrosis (IPF) tends to be a disease of

the elderly and therefore patients are apt to present with or
develop various comorbidities during the course of their dis-
ease (Table 6.1). Independent of age, patients with IPF have
been shown to have a higher propensity for certain comor-
bidities that can impact their quality of life and outcomes.
6.1 Gastroesophageal Reflux Disease

There is a very strong association between gastroesophageal
reflux disease (GERD) and IPF. Specifically, GERD has
been described in more than 80 % of patients with IPF [1, 2].
In less than half of cases it can be silent and therefore the lack
of any symptoms does not rule out GERD [2]. Whether
GERD is involved in the pathogenesis or perpetuation of the
disease is uncertain. Nonetheless, GERD therapy in the form
of proton pump inhibitors and H2 blockers have an associa-
tion with improved survival, in one retrospective study, and
with greater preservation of lung function in another study [3, 4].
There is also at least one case series documenting improve-
ment in lung function with Nissen fundoplication [5].

DOI 10.1007/978-3-319-32794-5_6,
Table 6.1 Common comorbidities of idiopathic pulmonary fibrosis

Pulmonary Non-pulmonary
Chronic obstructive pulmonary Anxiety
disease Congestive heart failure
Lung cancer Coronary artery disease
Pulmonary hypertension Deconditioning
Sleep disordered breathing Depression
Venous thromboembolism Gastroesophageal reflux disease
Hypogonadism
Conversely, there is also emerging data that GERD therapy

might not have any effect on outcomes. Treatment for GERD
has been endorsed by the American Thoracic Society/
European Respiratory Society/Japanese Respiratory Society/
Latin American Thoracic Association 2015 Clinical Practice
guidelines with a ‘conditional recommendation for use’ [6].
At present it is not clearly defined which patients require
testing for GERD and whether or not all patients with IPF
should be placed on anti-reflux therapy is uncertain and will
require further studies.
6.2 Cardiovascular
6.2.1 Coronary Artery Disease
Patients with IPF have been shown to have a higher preva-

lence of coronary artery disease (CAD) and acute coronary
syndrome (ACS) [7]. The presence of CAD should be consid-
ered in all patients with IPF, especially the elderly and those
with additional risk factors including hypertension, hyperlip-
idemia, history of tobacco use, diabetes mellitus, and a family
history of premature coronary artery disease. The presence of
coronary calcification on computed tomography (CT) medi-
astinal images may be a crude, yet readily available screening
tool [8]. Patients with IPF and associated significant CAD
have been shown to have worse outcomes [9].
Chapter 6. Comorbidities and Complications 69
6.2.2 Heart Failure
Patients with IPF have a predisposition for heart failure, both

systolic and diastolic. The estimated prevalence of heart fail-
ure with preserved ejection fraction is 9–16 % [10–12].
Whether IPF heightens this risk or if it is a reflection of IPF
being a disease of the elderly is uncertain.
6.2.3 Thromboembolic Disease
Patients with IPF have a heightened propensity for thromboem-

bolic events that can manifest as deep vein thrombosis or pul-
monary embolism. One study documented a fourfold increased
likelihood of a prothrombotic state in patients with IPF com-
pared to healthy controls [13]. A pulmonary embolus should be
suspected and ruled out in any patient with IPF who presents
with acute on chronic shortness of breath or chest pain [7].
6.3 Pulmonary
6.3.1 Pulmonary Hypertension
Pulmonary hypertension (PH) can be regarded as a complica-

tion of IPF and a comorbidity. Reported prevalence ranges
between 3 and 86 %, although most estimates are between 30
and 50 % [14]. The presence of PH is associated with signifi-
cantly worse outcomes and is an important independent prog-
nostic indicator [15, 16]. Clues to the presence of PH include:
• dyspnea out of proportion to pulmonary function test
abnormalities;
• reduced distance on 6 min walking test and/or excessive
desaturation and oxygen requirements;
• disproportionately low DLco;
• enlarged pulmonary artery segment on CT scan (see Chap. 5,
Fig. 5.2);
Vasculocentric Parenchymal Comorbidities
Fibrosis
Cytokines Neovascularization COPD
Vessel Capillary bed

destruction and Periadventitial Obstructive sleep
distortion fibrosis apnea
vascular ablation
Vasculopathy
Ventilation/ ↓ Vascular
perfusion mismatch capacitance Diastolic
dysfunction
Shear stress Hypoxic
vasoconstriction
Coronary artery
Acute and chronic disease
PVOD
pulmonary emboli
IPF associated
pulmonary
hypertension
Figure 6.1 Pathophysiology of pulmonary hypertension in idio-

pathic pulmonary fibrosis. Depicted in this figure under three broad
categories are the various factors that may interact in the genesis of
pulmonary hypertension complicating idiopathic pulmonary fibro-
sis. COPD chronic obstructive pulmonary disease, IPF idiopathic
pulmonary fibrosis, PVOD pulmonary veno-occlusive disease
• elevated brain natriuretic peptide (BNP) or N-terminal

proBNP; and
• echocardiographic evidence of PH from estimate of sys-
tolic pulmonary artery pressure sPAP or evidence of right
ventricular dysfunction or enlargement.
PH is defined by a pulmonary capillary wedge pressure of
25 mmHg or greater [17] and is diagnosed and categorized
with mandatory right heart catheterization. The pathophysi-
ology of PH is likely multifactorial and not due to progres-
sive fibrosis and vascular obliteration alone (Fig. 6.1).
Other factors and comorbidities that could be contributing
to PH should be ruled out before management can be imple-
mented, including:
• heart failure (especially heart failure with preserved ejec-

tion fraction);
• untreated or inadequately treated hypoxemia;
• obstructive sleep apnea (OSA); and
• chronic thromboembolic PH (CTEPH).
At present, there are no medications approved for treating
PH in patients with IPF. There is data to suggest treating
more severe PH in this population might be helpful [18],
however, the type of patient in terms of PH severity and
interstitial lung disease (ILD) severity that is most likely to
respond to pulmonary vasoactive therapy remains unknown
and is an area of ongoing active research [18]. There is a
potential downside to empirically treating patients with IPF
with PH medications, including worsening of the ventilation-
perfusion ratio by dilating blood vessels to poorly ventilated
areas. If there is consideration of treating PH in a patient
with IPF, then the patient is best served by referral to an
expert center [18, 19].
6.3.2 Lung Cancer

Patients with IPF are at higher risk for the development of
lung cancer compared to the general population. Multivariate
analyses have demonstrated that the increased risk of lung
cancer is not attributable to smoking alone and that other
elements of fibrotic lung disease heighten the risk for lung
cancer [7]. In contrast to lung cancers in those without
fibrotic lung disease, tumors in patients with IPF are most
commonly located peripherally and in the lower lobes [7]. It
has been estimated that approximately 10 % of patients
with IPF will succumb to lung cancer [20]. Annual chest CT
imaging should be considered, since lung nodules are
exceedingly difficult to recognize on plain chest X-rays in
the context of background fibrosis. Early diagnosis is essen-
tial so that patients who are appropriate surgical candidates
can be identified.
6.3.3 Combined Pulmonary Fibrosis Emphysema
Emphysema in the context of pulmonary fibrosis (see Chap. 2,

Fig. 2.1) may be seen in approximately one third of patients.
Whether this is a comorbidity or a distinct clinical phenotype
is uncertain. These patients are very commonly male and
invariably have a significant history of smoking. The effects
on prognosis is uncertain as patients with combined pulmo-
nary fibrosis emphysema (CPFE) have been described to
have worse, equivalent, or better prognosis than those with
IPF alone [7]. It is clear that such patients have a higher pro-
pensity for PH [7]. Marked symptoms and exertional hypox-
emia in the context of normal spirometry can provide clues to
the presence of CPFE. The opposing mechanical forces from
the restrictive and obstructive process result in ‘pseudo-
normalization’ of the lung volumes. Another clue to the pres-
ence of CPFE is a disproportionately reduced DLco in
comparison to lung volumes, since both disease processes
cause vascular obliteration.
6.3.4 Obstructive Sleep Apnea

The prevalence of OSA has been demonstrated to be as
high as 88 % in patients with IPF, with as many as 65 % hav-
ing moderate to severe OSA (apnea/hypopnea index >15
events/h) [21]. This high prevalence may be attributable to
the effect of reduced lung volumes on the geometry of the
upper airways. Another contributing factor may be reduced
lung compliance and associated increased work of breathing
with greater negative intrathoracic pressure resulting in col-
lapse of the upper airways. In any event, this comorbidity is
essential to screen for as treatment can improve quality of
life through reduction in daytime somnolence and improve-
ment in energy level and general wellbeing. In this setting,
the use of continuous positive airway pressure (CPAP) (±
supplemental O2, depending on sleep study results) reduces
nocturnal hypoxemia and may prevent the development or
worsening of PH [7]. There is no documented correlation

between the severity of IPF and the prevalence or severity
of OSA.
6.4 Anxiety and Depression

The psychological consequences of IPF are underappreciated
and frequently go undetected and unaddressed. They are
quite common, affecting approximately 20 % of patients [7].
If depression is diagnosed traditional treatment measures,
including antidepressant medications and cognitive behav-
ioral therapy should be instituted. In addition, referral to
pulmonary rehabilitation should be considered as studies
have demonstrated a reduction in fatigue and symptoms of
depression and anxiety [22]. Patient support groups may be
helpful too; local availability of support groups can be
searched for on the Pulmonary Fibrosis Foundation website
at www.pulmonaryfibrosis.org.
6.5 Complications
6.5.1 Acute Exacerbations of Idiopathic
Pulmonary Fibrosis
The annual incidence of acute exacerbations of IPF (AE-IPF)
ranges from 1 to 20 % of patients with IPF, depending on the
population studied and the definition used [23]. AE-IPF
accounts for more than 50 % of hospital admissions and up to
40 % of all deaths [23]. The classic definition of an acute exac-
erbation includes [25]:
• the subacute onset of shortness of breath; accompanied by
• new alveolar infiltrates on the background of radiographic
usual interstitial pneumonia; with
• other potential etiologies such as heart failure, pneumonia,
or pulmonary embolism excluded.
The classic definition of AE-IPF has been called into ques-

tion given the frequent inability to perform invasive proce-
dures, such as bronchoscopy, to rule out infection. In addition,
outcomes appear similar between AE-IPF and suspected
AE-IPF and exacerbations of IPF due to identifiable causes
such as infection or aspiration. The optimal definition of
AE-IPF remains an ongoing area of debate [23].
Evaluation of patients with potential AEs should be based
on excluding other entities [25]. Respiratory cultures should
be obtained, preferably by bronchoscopic lavage if feasible.
In patients who have a tenuous respiratory situation this may
not be feasible or only becomes feasible once they are placed
on mechanical ventilation. Although performance of a bron-
choscopy should not be the primary reason to intubate
patients, many of these patients will require mechanical ven-
tilation for progressive respiratory failure. Patients may not
fulfill all the criteria for an AE, in which case they can be
regarded as having a ‘suspected’ AE. While such cases may
represent true AE-IPF, it is also possible that the event could
be due to other entities that can cause alveolar infiltrates,
such as infection or heart failure.
The prognosis for AE-IPF is poor, with a short-term mor-
tality of approximately 50 % in most patients and approxi-
mately 80 % in those requiring intensive care unit admission
[24]. Those who survive the initial hospitalization continue to
have a high mortality rate over the next year [23]. It is there-
fore very important to have early end-of-life discussions with
patients and their families, and to present a realistic prognos-
tic outlook. The likelihood of liberation from mechanical
ventilation is extremely low, especially in elderly patients
with IPF or those with multiple comorbidities for whom lung
transplantation is not an option. With this information,
patients and families may wish to avoid mechanical ventila-
tion and opt for palliative care measures.
There are no proven therapies for AE-IPF. Patients are
generally managed with high-dose intravenous steroids at
doses of anywhere from methylprednisolone 40 mg every 6 h
to bolus dose methylprednisolone 500–1000 mg daily for 3
days with subsequent tapering. However, this is not proven and
there are no firm guidelines or data to support this approach.

The utility of anti-fibrotic therapies in AEs is unknown. It is
recommended to continue anti-fibrotic therapy in patients
already on it, but de novo initiation of therapy in the setting of
an AE has not been demonstrated to be helpful [24]. Most
patients are also invariably managed with broad-spectrum
antibiotics in the event of an occult infection. The most effec-
tive treatment is lung transplantation, but this is only feasible
in a small minority of patients and usually in those who were
already evaluated and listed prior to acute worsening. In some
patients the institution of extracorporeal membrane oxygen-
ation may be warranted as a bridge to transplantation. There is
recent single center data suggesting that the use of plasma-
pheresis and rituximab may have a role in the treatment of
AEs, however this requires further study [26].
6.5.2 Pneumothorax
Pneumothorax is an unusual complication of IPF and is more

likely to be seen in patients with more advanced disease, par-
ticularly in the context of CPFE and as a complication of
mechanical ventilation. The possibility of pneumothorax
should be considered in patients who present with acute or
chronic shortness of breath of abrupt worsening in oxygen-
ation. A CT scan of the chest might be needed to make the
diagnosis since the pneumothorax may be loculated in a plane
that escapes detection on chest X-ray. These should be man-
aged with tube thoracostomy. In patients with ‘stiff’ or poorly
compliant lungs, these might prove difficult to re-expand.
6.5.3 Aspergilloma
Aspergilloma is a contained area of aspergillus infection and,

although rare, can be seen in large areas of honeycombing or
in bullae that accompany CPFE (Fig. 6.2). This is usually an
incidental radiographic finding, but in rare cases may present
with hemoptysis.
Figure 6.2 Computed tomography scan showing aspergilloma. The

red arrow highlights an aspergilloma (fungal ball within a cyst) in a
patient with idiopathic pulmonary fibrosis
Key Points
• Comorbidities are common and contribute to the
morbidity and mortality of IPF.
• GERD may be occult and has an association with
IPF, perhaps as a cause of lung injury.
• Patients with IPF have a higher incidence of pulmonary
embolism and lung cancer than age-matched controls.
• CAD and heart failure are common in this aging
population.
• Pulmonary hypertension may develop and is associ-
ated with worse outcomes.
• Depression and anxiety are prevalent and likely
related to impaired quality of life and poor prognosis.
• AEs generally do not respond well to treatment and
result in high mortality (50–90 %).
References
1. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of
abnormal acid gastro-oesophageal reflux in idiopathic pulmo-
nary fibrosis. Eur Respir J. 2006;27:136–42.
2. Tobin RW, Pope 2nd CE, Pellegrini CA, Emond MJ, Sillery J,
Raghu G. Increased prevalence of gastroesophageal reflux in
patients with idiopathic pulmonary fibrosis. Am J Respir Crit
Care Med. 1998;158:1804–8.
3. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux
therapy is associated with longer survival in patients with idio-
pathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;
184:1390–4.
4. Hoppo T, Jarido V, Pennathur A, et al. Antireflux surgery pre-
serves lung function in patients with gastroesophageal reflux
disease and end-stage lung disease before and after lung trans-
plantation. Arch Surg. 2011;146:1041–7.
5. Raghu G, Yang ST, Spada C, Hayes J, Pellegrini CA. Sole treat-
ment of acid gastroesophageal reflux in idiopathic pulmonary
fibrosis: a case series. Chest. 2006;129:794–800.
6. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/
ALAT clinical practice guideline: treatment of idiopathic pulmo-
nary fibrosis. An update of the 2011 clinical practice guideline.
Am J Respir Crit Care Med. 2015;192:e3–19.
7. King C, Nathan SD. Identification and treatment of comorbidi-
ties in idiopathic pulmonary fibrosis and other fibrotic lung dis-
eases. Curr Opin Pulm Med. 2013;19:466–73.
8. Nathan SD, Weir N, Shlobin OA, et al. The value of computed
tomography scanning for the detection of coronary artery dis-
ease in patients with idiopathic pulmonary fibrosis. Respirology.
2011;16:481–6.
9. Nathan SD, Basavaraj A, Reichner C, et al. Prevalence and
impact of coronary artery disease in idiopathic pulmonary fibro-
sis. Respir Med. 2010;104:1035–41.
10. Panos RJ, Mortenson RL, Niccoli SA, King Jr TE. Clinical dete-
rioration in patients with idiopathic pulmonary fibrosis: causes
and assessment. Am J Med. 1990;88:396–404.
11. Nathan SD, Shlobin OA, Ahmad S, Urbanek S, Barnett
SD. Pulmonary hypertension and pulmonary function testing in
idiopathic pulmonary fibrosis. Chest. 2007;131:657–63.
12. Raghu G, Nathan SD, Behr J, et al. Pulmonary hypertension in

idiopathic pulmonary fibrosis with mild-to-moderate restriction.
Eur Respir J. 2015;46:1370–7.
13. Navaratnam V, Fogarty AW, McKeever T, et al. Presence of a
prothrombotic state in people with idiopathic pulmonary fibro-
sis: a population-based case–control study. Thorax. 2014;69:
207–15.
14. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in
idiopathic pulmonary fibrosis patients: a systematic literature
review. Eur Respir J. 2015;46:1113–30.
15. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF.
Prevalence and outcomes of pulmonary arterial hypertension in
advanced idiopathic pulmonary fibrosis. Chest. 2006;129:
746–52.
16. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD.
Pulmonary hypertension in patients with pulmonary fibrosis
awaiting lung transplant. Eur Respir J. 2007;30:715–21.
17. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical
classification of pulmonary hypertension. J Am Coll Cardiol.
2013;62(25 Suppl):D34–41.
18. Hoeper MM, Behr J, Held M, et al. Pulmonary hypertension in
patients with chronic fibrosing idiopathic interstitial pneumo-
nias. PLoS One. 2015;10, e0141911.
19. Saggar R, Khanna D, Vaidya A, et al. Changes in right heart
haemodynamics and echocardiographic function in an advanced
phenotype of pulmonary hypertension and right heart dysfunc-
tion associated with pulmonary fibrosis. Thorax. 2014;69:123–9.
20. Tomassetti S, Gurioli C, Ryu JH, et al. The impact of lung cancer
on survival of idiopathic pulmonary fibrosis. Chest. 2015;147:
157–64.
21. Mermigkis C, Bouloukaki I, Antoniou K, et al. Obstructive sleep
apnea should be treated in patients with idiopathic pulmonary
fibrosis. Sleep Breath. 2015;19:385–91.
22. Swigris JJ, Fairclough DL, Morrison M, et al. Benefits of pulmo-
nary rehabilitation in idiopathic pulmonary fibrosis. Respir Care.
2011;56:783–9.
23. Ryerson CJ, Cottin V, Brown KK, Collard HR. Acute exacerba-
tion of idiopathic pulmonary fibrosis: shifting the paradigm. Eur
Respir J. 2015;46:512–20.
24. Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerba-
tion of idiopathic pulmonary fibrosis: incidence, risk factors and
outcome. Eur Respir J. 2011;37:356–63.
25. Maher TM, Whyte MK, Hoyles RK, et al. Development of a

consensus statement for the definition, diagnosis, and treatment
of acute exacerbations of idiopathic pulmonary fibrosis using the
Delphi technique. Adv Ther. 2015;32:929–43.
26. Donahoe M, Valentine VG, Chien N, et al. Autoantibody-
targeted treatments for acute exacerbations of idiopathic pulmo-
nary fibrosis. PLoS One. 2015;10:e0127771.
Chapter 7
Treatment of Idiopathic
Pulmonary Fibrosis
The treatment of idiopathic pulmonary fibrosis (IPF) can be

broadly divided into pharmacologic therapies and non-
pharmacologic interventions (Chap. 8). There are two agents
that have been shown to slow the rate of deterioration in lung
function in IPF. These two drugs, pirfenidone and nintedanib,
have been variably approved in countries around the world.
7.1 Pirfenidone
Pirfenidone is an orally bioavailable synthetic compound that
has anti-fibrotic, anti-inflammatory, and antioxidant effects.
7.1.1 History
Pirfenidone has been studied in IPF since the 1990s. Early

studies in Japan resulted in its approval by the Japanese
Ministry of Health, Labor, and Welfare in 2008 [1, 2].
Two pivotal Phase III randomized placebo-controlled
trials, CAPACITY I (NCT00287729) and CAPACITY II
(NCT00287716), were undertaken in North America and
Europe [3]. The primary endpoint for both studies was
the change in forced vital capacity (FVC) at 72 weeks.

DOI 10.1007/978-3-319-32794-5_7,
While the first study was positive, the other failed to show
a difference in FVC between the treatment and placebo
groups. Although the combined data was positive, the US
Food and Drug Administration (FDA) initially elected
not to approve the drug, while the European Medicines
Agency (EMA) did issue an approval. A third ‘tiebreaker’
randomized controlled trial (RCT), the ASCEND study
(NCT01366209), was therefore undertaken in the US. The
52-week trial again studied change in the FVC as the
primary endpoint [4]. ASCEND was a positive study and
resulted in the approval of pirfenidone in October of 2014.
The data from the three pirfenidone Phase III RCTs are
shown in Table 7.1.
7.1.2 Mechanism of Action
The exact mechanism through which pirfenidone exerts its

effects in IPF are unknown. However, it is a pleiotropic mol-
ecule with effects at multiple domains that could be impor-
tant in the pathogenesis of IPF. Possible mechanisms of
action include [5]:
• Anti-inflammatory effects through suppression of tumor
necrosis factor α (TNF-α), interleukin-6 (IL-6), IL-12, and
IL-8.
• Anti-fibrotic properties likely from inhibition of expres-
sion of transforming growth factor β (TGF-β), a pro-
fibrotic cytokine. A number of other anti-fibrotic pathways
might be targeted as well.
• Antioxidant properties.
7.1.3 Dose
Pirfenidone is administered as three capsules three times a

day. Each capsule contains 267 mg of active drug for a total
daily dose of 2403 mg.
Table 7.1 Data from the phase III randomized controlled trials of pirfenidone
Number Primary
Study Year of patients Study design Inclusion criteria outcome Secondary outcomes
Chapter 7.
Taniguchi 2010 275 Phase III IPF per ATS/ERS Vital capacity Progression free
et al. [2] double-blind, guideline decline at survival (p = 0.028)
placebo- Age 20–75 years week 52:
controlled O2 desaturation ≥5 % Placebo
on 6MET (−0.16 L)
SpO2 ≥ 85 % during High dose
6MET (−0.09 L)
p = 0.042
CAPACITY 2011 435 Phase III Definite IPF by CT or Change in % Progression free
study double-blind, biopsy proven predicted FVC survival (p = 0.023)
004 [3] placebo- Age 40–80 years at week 72:
controlled FVC ≥50 % Placebo
DLco ≥35 % (−12.4 %)
Either FVC or DLco High dose
≤90 % (−8.0 %)
6MWT ≥150 m p = 0.001
Treatment of Idiopathic Pulmonary Fibrosis
(continued)
83
Table 7.1 (continued)
84
Number Primary
Study Year of patients Study design Inclusion criteria outcome Secondary outcomes
CAPACITY 2011 344 Phase III Definite IPF by CT or Change in % Mean change in
study 006 [3] double-blind, biopsy proven predicted FVC 6MWT distance:
placebo- Age 40–80 years at week 72: Placebo (−76.9 m)
controlled FVC ≥50 % Placebo Pirfenidone
DLco ≥35 % (−9.6 %) (−45.1 m)
Either FVC or DLco Pirfenidone p = 0.0009
≤90 % (−9.0 %)
6MWT ≥150 m p = 0.501
ASCEND 2014 555 Phase III Definite IPF by CT or Change in % 6MWT change at
[4] double-blind, biopsy proven predicted FVC week 52:
placebo- Age 40–80 years at week 52: p = 0.04
controlled FVC 50–90 % p < 0.001 Progression free
DLco 30–90 % survival:

FEV1/FVC ratio ≥0.8 p < 0.001
6MWT distance
≥150 m
6MET 6 min steady-state exercise test, 6MWT 6 min walking test, ATS American Thoracic Society, CT computed
tomography, DLco diffusing capacity of the lungs for carbon monoxide, ERS European Respiratory Society,
FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, IPF idiopathic pulmonary fibrosis, L liters
Chapter 7. Treatment of Idiopathic Pulmonary Fibrosis 85
7.1.4 Pharmacokinetics
Metabolism is primarily in the liver through the cytochrome

P450 1A2 (CYP1A2). The use of CYP1A2 inhibitors there-
fore increase pirfenidone levels and the following guidance
should be taken into account before initiating treatment:
• strong CYP1A2 inhibitors should be avoided, e.g.,
fluvoxamine;
• moderate CYP1A2 inhibitors (including ciprofloxacin and
amiodarone) should warrant the consideration of reduc-
tion in the dose of pirfenidone [5]; and
• inducers of CYPA12, including cigarette smoking and
omeprazole, may reduce levels of pirfenidone and should
be avoided [6].
Patients with mild or moderate hepatic dysfunction may
be treated with pirfenidone but require careful monitor-
ing. Use of pirfenidone is contraindicated in severe
hepatic dysfunction. Pirfenidone can be used to treat
patients with comorbid renal dysfunction, but is contrain-
dicated in end-stage renal disease. No dose adjustments
are required for age, gender, race, or body size. Although,
dose adjustments can be made on a case-by-case basis to
reduce side-effects, especially if the side-effects are
adversely impacting quality of life.
7.1.5 Side-Effects
The most common side-effects are gastrointestinal (GI) and

dermatologic. Indigestion is common and improves when
medication is taken with food. Specifically, rash and photo-
sensitivity may be seen and appropriate patient counseling
about sun exposure avoidance is prudent. Common side-
effects are shown in Table 7.2.
Table 7.2 Common side-effects of pirfenidone and nintedanib

Pirfenidone Nintedanib
Gastrointestinal Anorexia (8 %), nausea Diarrhea (44 %),
(20 %), dyspepsia (12 %), nausea (17 %),
vomiting (7 %), diarrhea vomiting (9 %),
(6 %), loss of weight (5 %) GI perforation (0.3 %)
Dermatologic Rash (20 %) N/A
Photosensitivity (8 %)
Cardiovascular N/A Myocardial
infarction (1.1 %)
Hematologic N/A Bleeding events
(3 %)
Hepatic Transaminitis (2.5 %) Transaminitis
Embryo fetal N/A Yes
toxicity
The incidences of these side-effects are all placebo-corrected based
on data from the respective Phase III clinical trials [2–4, 7]
GI gastrointestinal, N/A not applicable
7.1.6 Administration
Prior to prescription of pirfenidone it is important to fully inform

patients about the details of medication administration and moni-
toring that will occur throughout the course of treatment:
• Baseline liver function tests should be done, then repeated
monthly for the first 6 months and every 3 months thereafter.
• Pirfenidone capsules should be taken with meals. This is
important to abrogate GI side-effects since co-
administration with food results in reduced peak exposure
(related to some of the side-effects).
• The importance of sun exposure precautions should be
discussed.
– avoid direct sunlight exposure for extended periods; and
– use appropriate sunscreen, at least SPF 30.
• Manage patient expectations about treatment results
and goals.
7.2 Nintedanib
7.2.1 History
Nintedanib was initially developed as an anti-cancer drug. It

is a pleiotropic molecule and is a triple kinase inhibitor. There
have been three RCTs of this drug, the Phase II TOMORROW
study (NCT00514683) [8] and the two pivotal Phase III clini-
cal trials, INPULSIS I (NCT01335464) and INPULSIS II
(NCT01335477) [7]. All three studies were positive based on
the primary endpoint of change in the FVC over 52 weeks. In
addition, the TOMORROW study and one of the INPULSIS
trials showed reduction in the rate of acute exacerbations of
IPF. Table 7.3 summarizes the results of RCTs of nintedanib.
7.2.2 Mechanism of Action
Nintedanib is multiple-receptor tyrosine kinase inhibitor that

inhibits three receptor families implicated in angiogenesis
that also serve as important pro-fibrotic mediators [5]:
• anti-vascular endothelial growth factor (VEGF);
• anti-fibroblast growth factor (FGF); and
• anti-platelet derived growth factor (PDGF).
7.2.3 Dose
Nintedanib is available in 100 and 150 mg tablets, and the stan-

dard dose is 150 mg twice a day. Dose adjustments and drug holi-
days are permissible for intractable or intolerable side-effects.
7.2.4 Pharmacokinetics
Nintedanib is metabolized in the liver via cytochrome P450

3A4 (CYP3A4) and P-glycoprotein (P-gp). Drugs that affect
these enzymes can alter drug levels and exposure; the follow-
ing drug interactions should be taken into account:
• P-gp and CYP3A4 inhibitors (e.g., ketoconazole, erythro-

mycin) may result in increased exposure to nintedanib.
Dose adjustments or discontinuation of these drugs may
be necessary [5].
• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenyt-
oin, and St. John’s Wort) should be avoided as they
decrease exposure to nintedanib [5].
• Patients with mild hepatic impairment can be treated with
nintedanib with close monitoring. Nintedanib is not rec-
ommended in moderate or severe liver disease.
• No dose adjustment is required in mild or moderate renal
insufficiency. The safety and efficacy of nintedanib in
severe renal insufficiency has not been established.
7.2.5 Side-Effects
The most common side-effect is diarrhea, which occurs in

over 60 % of patients [5]. This is usually manageable with
anti-motility agents and/or dose reduction. A small percent-
age of patients have to discontinue medication for this side-
effect. A full list of side-effects is shown in Table 7.2.
7.2.6 Administration
Prior to prescription of the drug it is important to:

• Carry out baseline liver function testing, then follow up
monthly for the first 6 months and every 3 months
thereafter.
• Manage patient expectations in terms of diarrhea and
management strategies.
• Counsel patient that the medication will not improve lung
function and therefore does not make patients feel better.
• It is important for patients to understand that the medica-
tion only slows the rate of loss of lung function. The goal is
clinical stability, but clinical decline does not necessarily
mean that the drug is not working.
Table 7.3 Randomized, controlled trials of nintedanib [7, 8]
Number
of Study Inclusion
Chapter 7.
Study Year patients design criteria Primary outcomes Secondary outcomes

TOMORROW 2011 432 Phase II IPF by ATS/ERS Annual rate of Acute exacerbations:
[8] double- criteria decline in FVC: Placebo (15.7 per
blind, FVC ≥50 % Placebo (0.19 100 patient years)
placebo- predicted L/year) 150 mg twice daily
controlled DLco 30–79 % 150 mg twice (2.4 per 100 patient
predicted daily (0.06 years)
PaO2 ≥ 55 mmHg L/year) p = 0.02
up to 1500 m p = 0.06
altitude
PaO2 > 50 mmHg
>1500 m altitude
INPULSIS-1 2014 513 Phase III IPF Annual rate of Time to acute
[7] double- adjudicated decline in FVC: exacerbation:
blind, prior to Placebo No difference
placebo- enrollment (−239.9 mL/year) (p = 0.67)
Treatment of Idiopathic Pulmonary Fibrosis
controlled FVC ≥50 % Nintedanib

predicted (−114.7 mL/year)
DLco 30–79 % p < 0.001
predicted
89
(continued)
Table 7.3 (continued)
90
Number
of Study Inclusion
Study Year patients design criteria Primary outcomes Secondary outcomes
INPULSIS-2 2014 548 Phase III IPF Annual rate of Time to acute
[7] double- adjudicated decline in FVC: exacerbation:
blind, prior to Placebo HR = 0.38
placebo- enrollment (−207.3 mL/year) (p = 0.005)
controlled FVC ≥50 % Nintedanib
predicted (−113.6 mL/year)
DLco 30–79 % p < 0.001
predicted
ATS American Thoracic Society, DLco diffusing capacity of the lungs for carbon monoxide, ERS European Respiratory
Society, FVC forced vital capacity, HR hazard ratio, IPF idiopathic pulmonary fibrosis, L liters, PaO2 partial pressure
arterial oxygen
7.3 Common Questions for Anti-fibrotic

Drug Administration
7.3.1 How Do We Know the Medication Is
Working?
Anti-fibrotics slow down the loss of lung function rather than

improving it, therefore, it can be difficult for the patient and
physician to determine how effectively the drug is working.
The medication will not improve lung function and there-
fore does not necessarily make patients feel better.
At present there is no test or biomarker to inform if the
medication is working in individual patients.
The medication only slows the rate of loss of lung function.
Patients should not expect improvement in pulmonary function
tests and their disease will likely progress even with therapy.
7.3.2 To Whom Do I Prescribe an Anti-fibrotic

Agent?
All patients with IPF are potential candidates for therapy, and
initiation of therapy is a discussion to be had with all patients
once an accurate diagnosis of IPF has been made. Of note,
patients with ‘possible’ IPF were also included in the
INPULSIS trials and therefore there is data to support the use
of this agent in such cases as well.
7.3.3 When Do I Start the Drug?
Since both agents only slow the rate of loss of lung function, a
cogent argument can be made for starting the drug as soon as
possible after the diagnosis, even in the context of patients who
are asymptomatic and/or who have normal lung function.
In the clinical trials of both agents, patients with FVC
50–90 % with DLco >30 % were studied [2–4, 7, 8], although
therapy may be beneficial outside of that lung function range.
Initiation of an anti-fibrotic drug needs to be considered in

the context of the patient’s functional status, comorbidities,
concomitant medications, risk of side-effects, cost of medica-
tion, as well as the patient’s wishes and desires.
7.3.4 When Should I Stop the Anti-fibrotic

Medication, If Ever?
Although the studies that resulted in their approval were only

of intermediate duration (52–72 weeks), there is data attesting
to the long-term safety of both agents [9, 10]. It makes intuitive
sense that therapy should be a life-long commitment in the
absence of intolerable side-effects.
7.3.5 What Constitutes a Treatment Failure?
Even if there is apparent progression of disease based on

serial reduction in the FVC, it does not mean that the medi-
cation is not beneficial and is not a reason to discontinue
the drug. There is no proven way to gauge treatment success
or failure in individual patients. Even those patients who
have a 10 % decrement in their FVCs while on therapy have
been shown to do significantly better if they continue on
drug [11].
7.3.6 What is the Role of Combination Therapy?
While it likely that combination therapy will be more effica-

cious than monotherapy, this remains to be proven in the con-
text of appropriate RCTs. Issues to consider with the
implementation of combination therapy include:
• drug-drug interactions;
• increased risk of side-effects; and
• proof of efficacy.
7.4 Drugs to Be Avoided
7.4.1 Azathioprine and Steroids
Antimetabolite agents, such as azathioprine, in conjunction

with prednisone were formerly regarded as the standard of
care for patients with IPF from 2000 up until 2014 [12].
However, the results of the National Institute of Health
(NIH) sponsored PANTHER-IPF study (NCT00650091)
showed that azathioprine in conjunction with prednisone
not only did not help patients, but that it was harmful, lead-
ing to increased hospitalizations and mortality in the treat-
ment group [13]. Whether the azathioprine component, the
steroid component, or the dose of the combination caused
harm is uncertain. This form of combination therapy is still
used in other idiopathic interstitial pneumonias (IIPs)
including non-specific interstitial pneumonia (NSIP),
although the data to support its use in other IIPs is lacking.
Whether the deleterious effects of azathioprine can be
extrapolated to other similar agents, such as cyclophospha-
mide is also uncertain. Regardless, immunosuppressive
agents should not be used in IPF.
7.4.2 Warfarin
There are theoretical reasons to believe that anti-throm-

botic therapy might benefit patients with IPF. This is predi-
cated on the notion of alveolar fibrin-like deposition in the
early stages of the disease. However, the ACE-IPF study
(NCT00957242) of warfarin versus placebo undertaken by
the NIH IPF network showed that warfarin as a treatment
for IPF is associated with increased risk of hospitalization
and mortality [14]. If patients with IPF require anticoagula-
tion for other indications, such as atrial fibrillation, then
these study results should not preclude the implementation
of warfarin.
7.4.3 Ambrisentan
This endothelium receptor antagonist was studied for its anti-

fibrotic properties in patients with IPF in the ARTEMIS-IPF
trial (NCT00768300). This study was stopped early at the sug-
gestion of the Data Safety Monitoring Board for a trend
towards increased hospitalization amongst the patients who
received the active drug [15].
7.4.4 Other Agents
Other agents shown not to work in the context of completed

but negative Phase III clinical trials include [16]:
• imatinib;
• etanercept;
• bosentan;
• macitentan;
• N-acetylcysteine;
• interferon-γ 1b; and
• interferon-α.
7.5 Pulmonary Hypertension

Pulmonary hypertension (PH) is not uncommon in patients
with IPF, however, there are no drugs approved at present to
treat PH associated with IPF. The current best practice for
managing patients with comorbid disease include:
• Look for and treat predisposing factors:
– obstructive sleep apnea;
– occult heart failure; and
– uncorrected/partially corrected hypoxemia.
• Treatment with pulmonary vasodilators is not routinely rec-
ommended. If there is any consideration for the off-label
treatment of PH in the context of IPF, then patients should
be referred to an expert center for further evaluation.
• Beware that more harm than good could result from treat-
ment with pulmonary vasodilator therapy.
– Worsening ventilation perfusion mismatching with
worsening oxygenation.
– Pulmonary veno-occlusive-like lesions have been
described in IPF [17]. Pulmonary veno-occlusive dis-
ease is a contraindication for PH therapies as they
may precipitate pulmonary edema.
– Occult heart failure, specifically heart failure with
preserved ejection fraction is a common comorbidity
(9–16 %) in IPF [18, 19]. This may be worsened by
PH therapies.
• Further prospective randomized, placebo-controlled stud-
ies of pulmonary vasodilator therapy in IPF are warranted
and ongoing.
Key Points
• Two anti-fibrotic agents are currently approved to
treat IPF; nintedanib and pirfenidone.
• These drugs slow down rate of loss of lung function,
but do not reverse or cure disease.
• The older treatment paradigm of treating inflam-
mation with the combination of azathioprine, corti-
costeroids, and N-acetylcysteine has been shown to
be harmful.
• Several drugs are in development and future thera-
pies are likely to be combination in nature.
• There are no approved agents to treat PH associated
with IPF, but this is a target of current clinical trials.
References
1. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-
controlled trial of pirfenidone in patients with idiopathic pulmo-
nary fibrosis. Am J Respir Crit Care Med. 2005;171:1040–7.
2. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic

pulmonary fibrosis. Eur Respir J. 2010;35:821–9.
3. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients
with idiopathic pulmonary fibrosis (CAPACITY): two ran-
domised trials. Lancet. 2011;377:1760–9.
4. King Jr TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3
trial of pirfenidone in patients with idiopathic pulmonary fibro-
sis. N Engl J Med. 2014;370:2083–92.
5. King CS, Nathan SD. Practical considerations in the pharmaco-
logic treatment of idiopathic pulmonary fibrosis. Curr Opin
Pulm Med. 2015;21:479–89.
6. Potts J, Yogaratnam D. Pirfenidone: a novel agent for the treatment
of idiopathic pulmonary fibrosis. Ann Pharmacother. 2013;47:361–7.
7. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of
nintedanib in idiopathic pulmonary fibrosis. N Engl J Med.
2014;370:2071–82.
8. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine
kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med.
2011;365:1079–87.
9. Cottin V, Maher T. Long-term clinical and real-world experience
with pirfenidone in the treatment of idiopathic pulmonary fibro-
sis. Eur Respir Rev. 2015;24:58–64.
10. Richeldi L, Costabel U, Selman M, et al. Efficacy and safety of
nintedanib in patients with IPF beyond week 52: data from the
Phase II TOMORROW trial. Am J Respir Crit Care Med.
2015;191:A1019.
11. Nathan SD, Albera C, Bradford WZ, et al. Effect of continued
treatment with pirfenidone following a clinically meaningful
decline in percent predicted forced vital capacity in patients with
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med.
2015;191:A1016.
guidelines for diagnosis and management. Am J Respir Crit
Care Med. 2011;183:788–824.
13. Idiopathic Pulmonary Fibrosis Clinical Research Network,
Raghu G, Anstrom KJ, King Jr TE, Lasky JA, Martinez FJ.
Prednisone, azathioprine, and N-acetylcysteine for pulmonary
fibrosis. N Engl J Med. 2012;366:1968–77.
14. Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled ran-
domized trial of warfarin in idiopathic pulmonary fibrosis. Am
J Respir Crit Care Med. 2012;186:88–95.
15. Raghu G, Behr J, Brown KK, Egan JJ, et al. Treatment of idio-
pathic pulmonary fibrosis with ambrisentan: a parallel, random-
ized trial. Ann Intern Med. 2013;158:641–9.
16. Tzouvelekis A, Bonella F, Spagnolo P. Update on therapeutic
management of idiopathic pulmonary fibrosis. Ther Clin Risk
Manag. 2015;11:359–70.
17. Sherner J, Collen J, King CS, Nathan SD. Pulmonary hyperten-
sion in idiopathic pulmonary fibrosis: epidemiology, diagnosis,
and therapeutic implications. Curr Respir Care Rep.
2012;1:233–42.
18. Nathan SD, Shlobin OA, Ahmad S, Urbanek S, Barnett SD.
Pulmonary hypertension and pulmonary function testing in idio-
pathic pulmonary fibrosis. Chest. 2007;131:657–63.
19. Raghu G, Nathan SD, Behr J, et al. Pulmonary hypertension in
idiopathic pulmonary fibrosis with mild-to-moderate restriction.
Eur Respir J. 2015;46:1370–7.
Chapter 8
Non-pharmacologic
Management of Idiopathic
Pulmonary Fibrosis
8.1 Oxygen Therapy

Supplemental oxygen for patients with idiopathic pulmo-
nary fibrosis (IPF) who experience rest, nocturnal, or exer-
tional desaturation can improve symptoms and quality of
life. However, there is no data to show that supplemental
oxygen improves survival, although it can improve exercise
capacity [1, 2]. Towards the late stages of IPF, high-flow
oxygen devices such as an oxymizer or high humidity high-
flow nasal cannula may be needed to maintain adequate
oxygen saturations and ameliorate symptoms. Oxymizers
provide a reservoir of oxygen to draw from on inhalation,
which increases the net oxygen concentration delivered to
the patient for a given liter flow. High-flow nasal cannulas
allow the clinician to control the liter flow (typically
30–50 L/min) and percentage FiO2, allowing for very high
concentrations of oxygen to be delivered by a comfortable
interface. Figure 8.1 shows a variety of available devices to
provide higher level flow oxygen for patients with high
oxygen requirements.

DOI 10.1007/978-3-319-32794-5_8,
a c
Figure 8.1 Higher flow oxygen devices. (a) The oxymizer pendant,
(b) the oxymizer ‘moustache’, (c) high humidity high flow nasal can-
nula system with capacity to control liter flow and FiO2 of oxygen
8.2 Pulmonary Rehabilitation

Patients become more symptomatic as IPF progresses and
are prone to a vicious cycle of deconditioning. The more
breathless they are, the less they can do, which results in the
perpetuation of deconditioning. This phenomenon has
downstream consequences of increased dyspnea on exer-
tion, easy fatigue, and psychological consequences in the
form of anxiety and depression. Clinically significant
depression has been described in 23 % of patients with IPF
[3]. As disease progresses, these symptoms are exacerbated
to the point of interference in the simplest of activities of
daily living. Further ramifications include skeletal muscle
deconditioning, social isolation, and reduced emotional
well-being [4].
Chapter 8. Non-pharmacologic Management 101
IPF
Breathlessness
Deconditioning Exercise
Educate
Easy fatigue
Empower
Less activity Integrate
Improve QOL
Social isolation
Recondition
Anxiety
Depression
↓ Emotional
well-being Pulmonary rehabilitation
Figure 8.2 The impact of idiopathic pulmonary fibrosis on quality

of life, with pulmonary rehabilitation as a mitigating intervention.
IPF idiopathic pulmonary fibrosis, QOL quality of life
Pulmonary rehabilitation is a supervised exercise program

designed to reverse this vicious cycle of events. In addition to
exercise training it also includes disease-specific education
and psychosocial support. The goal is to reduce symptoms,
optimize functional status, increase participation in daily life
activities, and improve psychological well-being (Fig. 8.2).
Pulmonary rehabilitation programs were originally designed
for patients with chronic obstructive pulmonary disease
(COPD), although there is growing use and emerging data in
patients with IPF that attests its utility [5–16] (Table 8.1).
A course of pulmonary rehabilitation is recommended for
patients once they become significantly symptomatic or lim-
ited. The nature of the course instituted is generally similar to
that of patients with COPD. The effects of pulmonary reha-
bilitation may not be sustained over time and hence the
importance of follow-up maintenance pulmonary rehabilita-
tion and ongoing exercise.
Table 8.1 Trials of pulmonary rehabilitation in interstitial lung disease [5–16]
102
Number 6MWT
First author, of change
year patients Design Population Duration (meters) Notes
Jastrzebski et al. 31 Prospective ILD (67.7 % 6 weeks NR Improved QOL and
(2006) [5] IPF) dyspnea
Nishiyama et al. 28 RCT IPF 10 weeks 46.3a Improved QOL
(2008) [6]
Holland et al. 57 RCT ILD (59.6 % 8 weeks 35a Improved exercise
(2008) [7] IPF) capacity and
symptoms
Ferreira et al. 99 Retrospective ILD (~50 % 6–8 weeks 56a Improved dyspnea
(2009) [8] IPF)
Ovalevli et al. 17 Prospective IPF 12 weeks 45a Improved QOL

(2010) [9] Home-based study
Rammaert et al. 17 Prospective IPF 8 weeks No Improved dyspnea and
(2011) [10] change endurance
Home-based study
Kozu et al. 90 Prospective IPF (50 %) 8 weeks 16.2a Improved dyspnea
(2011) [11] vs. COPD Benefits not
(50 %) maintained at 6
months
Kozu et al. 65 Prospective IPF 8 weeks Variable Improved 6MWT
(2011) [12] and decreased
Chapter 8.
hospitalization if MRC
dyspnea 2 or 3
Swigris et al. 21 Prospective IPF 6 weeks 61.6a Improved fatigue
(2011) [13]
Huppman et al. 402 Observational ILD (50 % 4 weeks 46a Improved QOL
(2013) [14] IPF)
Jackson et al. 21 RCT IPF 3 month No Increase in exercise
(2014) [15] change time
Vainshelboim 32 RCT IPF 12 weeks 81a Improved dyspnea and
et al. (2014) [16] QOL
6MWT 6 min walk test, COPD chronic obstructive pulmonary disease, ILD interstitial lung disease, IPF idiopathic pulmo-
Non-pharmacologic Management
nary fibrosis, MRC medical research council, NR not reported, QOL quality of life, RCT randomized controlled trial
a
Denotes statistically significant results
103
8.3 Palliative Care

Palliative care is a valuable adjunctive service that is gener-
ally under-utilized or considered late in the patients’ disease
course. Palliation of symptoms (such as shortness of breath
and cough) should be considered early and according to the
following guidance:
• Palliation of shortness of breath
– consider institution of oral morphine in patients with
advanced disease;
– supplemental oxygen may be beneficial (consider
high-flow oxygen devices and non-invasive positive
pressure ventilation on a case-by-case basis).
• Palliation of cough (this can be the most bothersome
symptom to some patients and can be recalcitrant to most
forms of therapy)
– consider treating common causes of cough, like post-
nasal drip and gastroesophageal reflux disease;
– over-the-counter antitussive medications;
– morphine derivatives such as codeine can be helpful;
– other agents to consider include gabapentin, baclofen,
and thalidomide (only at an expert center).
• Fatigue, evaluate for and treat the following conditions:
– obstructive sleep apnea;
– hypothyroidism;
– anemia; and
– hypogonadism (low testosterone)
• Asthenia (abnormal weakness or lack of energy)
– can be a medication-related side effect (eg, pirfeni-
done) or may be seen in advanced stages of disease;
– possibly related to an increased work of breathing
and a catabolic state due to this;
– medication changes and supplemental nutrition may
be helpful in this regard.
8.4 Hospice Care

Hospices offer a comprehensive program of care to patients
and families facing a serious illness, such as IPF, that may
result in death in 6 months or less. Its focus is on palliative
rather than curative treatment, and its implementation can be
at home or in an inpatient setting.
The institution of hospice care may facilitate services that
are otherwise unavailable to patients, such as more holistic
care including social work and chaplaincy services as well as
access to symptom management around the clock. End of life
discussions and patient wishes should be made clear early on
in the disease course (no matter how uncomfortable or seem-
ingly early/unnecessary) owing to the very unpredictable
nature of the disease course in many patients. Futile attempts
at mechanical ventilation should be averted in patients with
progressive disease as their cause of respiratory failure. Short
term attempts at mechanical ventilation are reasonable in
those patients who may have a reversible cause of their
decompensation or who are listed for lung transplantation.
8.5 Lung Transplantation

IPF is now the most common indication for lung transplanta-
tion [17]. Patients who may be candidates for transplant should
be referred to a lung transplant center as soon as possible, even
if they do not appear to need a lung transplant. This enables
them to undergo a comprehensive evaluation and have the
appropriate education provided in a timely fashion. This is
especially important in the context of a disease that has an
unpredictable course. Unfortunately, lung transplantation is an
option for only a minority of patients with IPF. Guidelines of
who to refer and when to list are shown in Table 8.2; the over-
arching belief is that referral soon after diagnosis is advisable,
given the variable rate of disease progression.
Absolute contraindications to lung transplantation are
shown in Table 8.3 [18], although there are certainly a myriad
Table 8.2 Guidelines for referral and listing of patients with idio-
pathic pulmonary fibrosis for lung transplantation
Guidelines for referral of patients with idiopathic pulmonary
fibrosis for lung transplant evaluation
• Histopathologic or radiographic evidence of usual interstitial
pneumonitis irrespective of lung function
• Abnormal lung function:
◦ FVC <80 % predicted or DLco <40 % predicted
• Any dyspnea or functional limitation attributable to lung
disease
• Any oxygen requirement, even if only during exertion
Guidelines for listing of patients with idiopathic pulmonary
fibrosis for lung transplantation
• 10 % or greater drop in FVC during 6 months of follow-up
• 15 % or greater drop in DLco during 6 months of follow-up
• Desaturation to SpO2 < 88 % or distance <250 m on 6MWT or
>50 m decline in 6 min walk distance over a 6 month period
• Pulmonary hypertension on right heart catheterization or
echocardiogram
• Hospitalization due to respiratory decline, pneumothorax, or
acute exacerbation
Adapted from Weill et al. [18]
6MWT 6 min walking test, DLCO diffusing capacity of the lungs for
carbon monoxide, FVC forced vital capacity, SpO2 arterial oxygen
saturation
of relative contraindications that must be considered as well.

Early referral to a lung transplant center can facilitate early
identification of contraindications, some of which may be
modifiable with interventions (eg, weight loss), to help
improve lung transplant candidacy. Historically, patients with
IPF have received more single lung transplants than any
other disease group, although, the most recent International
Society for Heart and Lung Transplantation registry report
indicates that over the last 10 years more bilateral than single
Table 8.3 Contradictions to lung transplantation

• Recent malignancy (other than non-melanoma skin cancer)
• Significant dysfunction of another major organ system (unless
combined organ transplantation can be performed)
• Coronary artery disease without re-vascularization
• Acute medical instability (sepsis, myocardial infarction, etc)
• Uncorrectable bleeding diathesis
• Highly virulent or resistant infection (varies by institution):
◦ Active tuberculosis;
◦ Human immunodeficiency virus;
◦ Hepatitis B and C;
◦ Burkholderia cenocepacia or Burkholderia gladioli infection;
◦ Multi-drug resistant or smear positive Mycobacterial
abscessus infection
• Significant chest wall or spinal deformity expected to cause
restriction post-transplant
• Body mass index ≥35 (absolute contraindication), 30–34.9
(relative contraindication)
• Non-adherence to medical therapy
• Psychiatric issues that may interfere with ability to follow
complex treatment regimen
• Lack of adequate social support system
• Severely limited functional status with poor rehabilitation
potential
• Age >70–75 years (varies by institution)
Adapted from Weill et al. [18]
lung transplants have been performed for IPF, with the most
recent statistics of 60.2 % versus 39.8 %, respectively [19].
Both types of lung transplant have positives and negatives
and which procedure is optimal for patients with IPF remains
controversial in the context of individual demographics,
outcomes, and scarce organ availability. The 1-year survival

post-transplant is approximately 85 % and the 5-year survival
post-transplant is approximately 50 % [19]. There is data to
suggest that survival is better with the bilateral procedure
[19]; however, there is also data demonstrating that once
other factors are accounted for, survival is very similar
between the two procedures [17].
Key Points
• Oxygen therapy can improve symptoms and quality
of life for patients with IPF who experience rest,
nocturnal, or exertional desaturation, especially
towards later stages of disease.
• As disease progresses, symptoms can lead to a
vicious cycle of deconditioning that has downstream
consequences of increased dyspnea, easy fatigue,
psychological imbalances (eg, anxiety and depres-
sion), skeletal muscle deconditioning, social isola-
tion, and reduced emotional well-being.
• Pulmonary rehabilitation is a supervised exercise
program designed to reverse this cycle of events and
improve symptoms, whilst providing education and
psychological support.
• Palliative care is often ignored or considered late in
disease progression, ideally palliation of symptoms
should be considered early on.
• Palliative care or hospice consultation should be con-
sidered longitudinally as quality of life and prognosis
are discussed and re-visited over time.
• Lung transplantation may improve quality and quan-
tity of life in selected patients with little to no
comorbidities.
• Early referral for lung transplantation (even at time
of diagnosis) is advisable given the unpredictable
nature of disease.
References
1. Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG,
Raghu G. The timed walk test as a measure of severity and survival
in idiopathic pulmonary fibrosis. Eur Respir J. 2005;25:96–103.
2. Morrison DA, Stovall JR. Increased exercise capacity in hypox-
emic patients after long-term oxygen therapy. Chest.
1992;102:542–50.
3. Ryerson CJ, Berkeley J, Carrieri-Kohlman VL, Pantilat SZ,
Landefeld CS, Collard HR. Depression and functional status are
strongly associated with dyspnea in interstitial lung disease.
Chest. 2011;139:609–16.
4. Swigris JJ, Brown KK, Make BJ, Wamboldt FS. Pulmonary reha-
bilitation in idiopathic pulmonary fibrosis: a call for continued
investigation. Respir Med. 2008;102:1675–80.
5. Jastrzebski D, Gumola A, Gawlik R, Kozielski J. Dyspnea and
quality of life in patients with pulmonary fibrosis after six weeks
of respiratory rehabilitation. J Physiol Pharmacol. 2006;57 Suppl
4:139–48.
6. Nishiyama O, Kondoh Y, Kimura T, et al. Effects of pulmonary
rehabilitation in patients with idiopathic pulmonary fibrosis.
Respirology. 2008;13:394–9.
7. Holland AE, Hill CJ, Conron M, Munro P, McDonald CF. Short
term improvement in exercise capacity and symptoms following
exercise training in interstitial lung disease. Thorax. 2008;63:549–54.
8. Ferreira A, Garvey C, Connors GL, et al. Pulmonary rehabilita-
tion in interstitial lung disease: benefits and predictors of
response. Chest. 2009;135:442–7.
9. Ozalevli S, Karaali HK, Ilgin D, Ucan ES. Effect of home-based
pulmonary rehabilitation in patients with idiopathic pulmonary
fibrosis. Multidiscip Respir Med. 2010;5:31–7.
10. Rammaert B, Leroy S, Cavestri B, Wallaert B, Grosbois JM.
Home-based pulmonary rehabilitation in idiopathic pulmonary
fibrosis. Rev Mal Respir. 2011;28:e52–7.
11. Kozu R, Senjyu H, Jenkins SC, Mukae H, Sakamoto N, Kohno S.
Differences in response to pulmonary rehabilitation in idio-
pathic pulmonary fibrosis and chronic obstructive pulmonary
disease. Respiration. 2011;81:196–205.
12. Kozu R, Jenkins S, Senjyu H. Effect of disability level on
response to pulmonary rehabilitation in patients with idiopathic
pulmonary fibrosis. Respirology. 2011;16:1196–202.
13. Swigris JJ, Fairclough DL, Morrison M, et al. Benefits of pulmo-

nary rehabilitation in idiopathic pulmonary fibrosis. Respir Care.
2011;56:783–9.
14. Huppmann P, Sczepanski B, Boensch M, et al. Effects of inpa-
tient pulmonary rehabilitation in patients with interstitial lung
disease. Eur Respir J. 2013;42:444–53.
15. Jackson RM, Gómez-Marín OW, Ramos CF, et al. Exercise limi-
tation in IPF patients: a randomized trial of pulmonary rehabili-
tation. Lung. 2014;192:367–76.
16. Vainshelboim B, Oliveira J, Yehoshua L, et al. Exercise training-
based pulmonary rehabilitation program is clinically beneficial
for idiopathic pulmonary fibrosis. Respiration. 2014;88:378–88.
17. Brown AW, Kaya H, Nathan SD. Lung transplantation in IIP: a
review. Respirology. 2015:1–12 [Epub ahead of print].
18. Weill D, Benden C, Corris PA, et al. A consensus document for
the selection of lung transplant candidates: 2014 – an update
from the Pulmonary Transplantation Council of the International
Society for Heart and Lung Transplantation. J Heart Lung
Transplant. 2015;34:1–15.
19. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of
the International Society for Heart and Lung Transplantation:
thirty-second official adult lung and heart-lung transplantation
report – 2015; focus theme: early graft failure. J Heart Lung
Transplant. 2015;34:1264–77.
Chapter 9
The Future for Idiopathic
Pulmonary Fibrosis
The future of idiopathic pulmonary fibrosis (IPF) is bright

and dynamic with innovation and discovery occurring at a
rapid pace. In fact, at the time of writing, there were 107
open and enrolling studies involving IPF diagnosis and
treatment listed on www.clinicaltrials.gov. Future discover-
ies are bound to occur at the genomic level, providing a
clearer understanding of single nucleotide polymorphisms
(SNPs) that predispose to the disease or predetermine the
course in individual patients. As this knowledge evolves, it
is conceivable that the classification of IPF and perhaps
the broad group of idiopathic interstitial pneumonias
(IIPs) will be driven by the genomic profile of patients
rather than their radiographic or pathologic phenotype.
Genomic signature recognition and patterns may enable
biomarker development, in turn allowing for more accu-
rate non-invasive diagnosis of IPF, other IIPs, and chronic
hypersensitivity pneumonitis (HP). It is also conceivable
that the role of pharmacogenomics will evolve such that
individualized or tailored therapies can be matched to
patients’ genomic profile, thereby improving the efficacy
of prescribed medications and reducing the likelihood of
associated toxicities.

DOI 10.1007/978-3-319-32794-5_9,
9.1 Medical Therapies
Typically, any drug that meets the bar for regulatory approval
has to go through three phases of testing:
• Phase I trials in healthy volunteers (primarily for safety
and pharmacokinetics);
• Phase II trials in patients with the disease for further
safety, efficacy, and dosing evaluation; and
• Phase III trials that are the pivotal studies to demonstrate
efficacy prior to approval.
Currently, there are no novel IPF drugs that are in Phase
III clinical trials. Therefore, it is likely that it will be a few
years before any additional novel agents are approved
for IPF. However, there are some agents that are avail-
able and approved for other conditions that are of inter-
est as potential therapies for IPF. Ultimately, it is likely
that management of this complex disorder will include
multimodality therapy targeting different pathways and
consequences of the disease. The sections below outline
some of the therapies being studied as possible treat-
ments for IPF.
9.1.1 Drugs Currently Approved for Other

Indications
9.1.1.1 Cotrimoxazole
Cotrimoxazole is an antibiotic that combines trimethoprim

and sulfamethoxazole and is commonly available for the
treatment of a variety of bacterial infections. Patients with
IPF are susceptible to occult infection and there is evidence
of alterations in the microbiome in such individuals [1]. In
1996, the clinical improvement of a patient with advanced
fibrotic lung disease who was treated with cotrimoxazole was
Chapter 9. The Future for Idiopathic Pulmonary Fibrosis 113
observed, and subsequently 14 patients also demonstrated

improvement [2]. These findings led Varney et al. [2] to
conduct a pilot trial of 20 patients with fibrotic IIPs, whereby
treatment with cotrimoxazole demonstrated improvements
in functional status and forced vital capacity (FVC). This trial
was followed by a larger randomized controlled trial (RCT)
of 181 patients that demonstrated improvements in mortality
and decreased infections in those who were adherent to
therapy [3]. At time of writing, an additional Phase III RCT
assessing the efficacy of cotrimoxazole is enrolling partici-
pants (NCT01777737) [4].
9.1.2.2 Azithromycin
Azithromycin is a commonly used antibiotic that has been

demonstrated to attenuate development of bleomycin-
induced pulmonary fibrosis in a mouse model [5] and is
postulated to reduce cough. At time of writing, a small
Phase III double-blind study is enrolling patients with IPF
to assess the effects of azithromycin on cough
(NCT02173145) [6].
9.1.3.3 Omeprazole
Omeprazole is a proton pump inhibitor that is approved for

the treatment of gastroesophageal reflux disease (GERD).
Patients with IPF commonly have comorbid GERD, and
GERD is considered a risk factor for IPF development
(Chap. 5) [7, 8]. Anti-reflux therapies are therefore associ-
ated with a reduction in mortality in patients with IPF [7].
Additionally, there is data to suggest that anti-reflux ther-
apy slows the rate of decline in the FVC [8]. At time of
writing, a Phase II pilot RCT to assess the efficacy of
omeprazole for treatment of IPF-associated cough is
enrolling participants [9].
9.1.4.4 Riociguat
Riociguat is approved for the treatment of pulmonary

arterial hypertension and chronic thromboembolic
pulmonary hypertension. The efficacy and safety of rio-
ciguat is currently being studied in a Phase II trial, RISE-
IIP, of patients with any of the IIPs and associated
pulmonary hypertension (NCT02138825) [10]. This is the
first trial to include all of the IIPs together and, by virtue
of its higher prevalence, the majority of enrolled patients
are likely to have IPF.
9.1.5.5 Sirolimus
Sirolimus is a macrolide antibiotic that is approved for immu-

nosuppression in transplant patients. This drug exhibits
immunosuppressive activity by inhibiting the activation of
mammalian Target of Rapamycin (mTOR) and thus the acti-
vation and proliferation of B and T cells and the activation of
non-immune cells. At time of writing, a Phase II pilot study to
determine if sirolimus decreases the number of circulating
fibroblasts in patients with IPF is ongoing [11]. Sirolimus has
been associated, however, with the development of pneumo-
nitis in rare cases [12].
9.1.6.6 Rituximab
Rituximab is an anti-CD20 monoclonal antibody that

destroys B cells. It is approved for autoimmune diseases
such as rheumatoid arthritis. Currently, a phase II study
(NCT01969409) is ongoing evaluating the effects of ritux-
imab on production of autoantibodies in patients with IPF
[13]. As noted in Chap. 6, there is some data to suggest that
this drug may have a role in the treatment of acute exacer-
bation of IPF (AE-IPF) [14].
9.1.2 Novel Therapies
9.1.1.1 FG-3019
FG-3019 is a human monoclonal antibody that targets connec-

tive tissue growth factor (CTGF) and is under early investiga-
tion for a number of indications, including IPF. Phase II trials to
evaluate the safety and tolerability of FG-3019 in patients with
IPF are currently underway (NCT01262001), with the primary
end-point being change in FVC [15]. Based on encouraging
initial results from preliminary data, a second higher-dose
group has been added (NCT01890265) [16]. To date, over 200
patients have been enrolled in the various trials of this drug.
9.1.2.2 Tipelukast (MN-001)
Tipelukast is an orally available, small, novel molecule that has

been demonstrated to have anti-fibrotic and-anti-inflammatory
properties in preclinical models. Tipelukast exerts such effects
through inhibition of 5-lipoxygenase (5-LO) and phosphodies-
tereases, and is a leukotriene (LT) receptor antagonist. The
novel aspect of this drug is its inhibitory effect on the 5-LO/LT
pathway (a factor thought to be pathogenic in the develop-
ment of fibrosis) [17]. In 2015, the US Food and Drug
Administration issued Fast Track designation for the develop-
ment of tipelukast for IPF, which is now entering Phase II clini-
cal trials to assess safety and tolerability (NCT02503657) [18].
9.1.3.3 BMS-986020
BMS-986020 is a lysophosphatidic acid receptor antagonist

that has shown promising results in preclinical trials and
has entered Phase II trials (NCT01766817). The primary
endpoint is to reduce the rate of decline in FVC and to be
well tolerated by patients [19].
9.1.4.4 SAR156597
SAR156597 is a bispecific monoclonal antibody directed

against interleukin (IL)-4 and IL-13, two cytokines implicated
in the pathogenesis of IPF. In 2015, the Phase II ESTAIR trial
was initiated to evaluate safety and efficacy of SAR156597 at
two dose levels for 52 weeks (NCT02345070) [20].
9.1.5.5 PRM-151
PRM-151 is a recombinant form of the endogenous protein,

pentraxin-2, which acts as a monocyte and macrophage dif-
ferentiation factor and is believed to have anti-fibrotic prop-
erties [21]. At time of writing, a Phase II pilot study to assess
the efficacy and safety of PRM-151 in patients with IPF is
underway (NCT02550873).
9.1.6.6 BG00011
BG00011 (alternatively known as STX 100) is a humanized

monoclonal antibody that is administered subcutaneously
and targets alpha v beta 6 (αvβ6) integrin. In 2015 a Phase II
dose escalation study assessing the immunogenicity of
BG00011 in patients with IPF was initiated and is currently
ongoing (NCT01371305) [22].
9.1.7.7 Lebrikizumab
Lebrikizumab is a humanized monoclonal antibody that

targets IL-13, and is being investigated for the treatment of
IPF, asthma, chronic obstructive pulmonary disease, and
atopic dermatitis. At time of writing, a Phase II trial investi-
gating the safety and efficacy of lebrikizumab as a mono-
therapy or in combination with pirfenidone is ongoing
(NCT01872689) [23].
9.2 Other Areas of Investigation
9.2.1 Laparoscopic Reflux Surgery
Given the known association between IPF and GERD, there

has been speculation that anti-reflux surgery may halt the
progression of IPF. WRAP-IPF is a Phase II study investigat-
ing the effects of anti-reflux surgery on decline in FVC [24].
9.2.2 Pulmonary Rehabilitation
Studies to determine the effect of pulmonary rehabilitation

on fibrotic lung disease have been carried out [25]; several
are completed, and a couple of trials are currently open and
recruiting (Table 9.1).
9.2.3 Cryobiopsy
Cryobiopsy as a means of diagnosis of IPF is being studied in

patients with interstitial lung disease who were due to undergo
videothoracoscopy-assisted surgical lung biopsy [26].
9.2.4 Stem Cells
Stem cell therapy is an area currently under investigation as

a treatment for IPF; Phase I and II studies designed to assess
the effectiveness of stem cells on pulmonary fibrosis are
ongoing [27, 28]. Patients frequently pose questions about
stem cell therapy. Unfortunately, there is a lot of false hope
generated by unregulated websites with unproven claims of
successful treatment of IPF. It is important for patients to be
aware that stem cell therapy needs to be subjected to the
appropriate clinical trials before it can be recommended as a
therapy for IPF.
Table 9.1 Summary of open clinical studies assessing pulmonary

rehabilitation for patients with pulmonary fibrosis
Study title (clinical trial Comments
identifier) Study design
Long term effects of an Randomized, Effects at 3
inpatient pulmonary open label months of 3
rehabilitation program in weeks inpatient
patients with pulmonary rehabilitation
fibrosis (NCT01772667)
The NIH exercise therapy Randomized, 10 weeks of
for advanced lung disease open label outpatient
trials: response and rehabilitation
adaptation to aerobic
exercise in patients with
(NCT02019641)
9.2.5 Treatment of Acute Exacerbation

of Idiopathic Pulmonary Fibrosis
There are currently no proven therapies for the treatment

of AE-IPF, although, two studies are underway to determine
if they can decrease the mortality of this deadly complica-
tion of IPF:
• Plasmapheresis, rituximab, and steroids — Phase I/II study
(NCT01266317) to assess feasibility, safety, and efficacy in
10 patients with AE-IPF [29].
• Cyclophosphamide — Phase III study (NCT02460588) to
assess safety and efficacy in approximately 120 patients
with IPF [30].
9.2.6 Biomarkers
Biomarkers to diagnose IPF, identify patients at risk for IPF,

screen patients with subclinical disease, predict disease
progression, and predict response to therapy are being

explored (see Chap. 5).
9.3 Conclusion
Considerable advancements have been made in recent years
in the treatment of IPF. Improved understanding of the patho-
genesis of the disease has led to the development of two phar-
macologic treatments for IPF with demonstrated efficacy in
RCTs. Despite this huge leap forward, IPF remains a deadly
disease and there is much work to be done. It is hoped that
continued research into the genetic basis and pathophysio-
logic mechanisms of IPF will lead to improved techniques for
earlier diagnosis and more effective treatment. Until that
time, therapy will rely on the use of currently approved medi-
cations in combination with supportive care including oxygen,
pulmonary rehabilitation, symptom and comorbidity manage-
ment, and lung transplantation when appropriate.
Key Points
• Agents that are approved for other conditions are cur-
rently being explored as potential therapies for IPF.
• There are several novel treatments in the early drug
development stages for IPF.
• The future therapeutic paradigm is likely one of
combination drug therapy.
• There are no drugs approved for PH in any IIP, how-
ever, riociguat is currently in Phase II studies for
comorbid PH and IPF.
• Future developments in pharmacogenomics might
enable the course of disease in individual patients to
be determined, biomarker development (therefore
non-invasive diagnosis of IPF), and tailored thera-
pies for IPF and other forms of IIP.
References
1. Han MK, Zhou Y, Murray S, et al. Lung microbiome and disease
progression in idiopathic pulmonary fibrosis: an analysis of the
COMET study. Lancet Respir Med. 2014;2:548–56.
2. Varney VA, Parnell HM, Salisbury DT, Ratnatheepan S,
Tayar RB. A double blind randomised placebo controlled pilot
study of oral co-trimoxazole in advanced fibrotic lung disease.
Pulm Pharmacol Ther. 2008;21:178–87.
3. Shulgina L, Cahn AP, Chilvers ER, et al. Treating idiopathic pul-
monary fibrosis with the addition of co-trimoxazole: a ran-
domised controlled trial. Thorax. 2013;68:155–62.
4. Fundación Pública Andaluza para la gestión de la Investigación
en Sevilla; Junta de Andalucia. Pilot study Phase III to evaluate
the efficacy and safety of trimethoprim-sulfamethoxazole in the
treatment of idiopathic pulmonary fibrosis. In: ClinicalTrials.gov
[Internet]. Bethesda (MD): National Library of Medicine (US).
2000- [cited 18 Feb 2016]. Available from: https://www.clinicaltri-
als.gov/show/NCT01777737.
5. Wuyts WA, Willems S, Vos R, Vanaudenaerde BM, et al.
Azithromycin reduces pulmonary fibrosis in a bleomycin mouse
model. Exp Lung Res. 2010;36:602–14.
6. University Hospital Inselspital Berne. Azithromycin for the
treatment of cough in idiopathic pulmonary fibrosis- a clinical
trial. In: ClinicalTrials.gov [Internet]. Bethesda: National Library
of Medicine (US). 2000- [cited 18 Feb 2016 ]. Available from:
https://clinicaltrials.gov/show/NCT02173145.
7. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux
therapy is associated with longer survival in patients with idio-
pathic pulmonary fibrosis. Am J Respir Crit Care Med.
2011;184:1390–4.
8. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and
disease progression in idiopathic pulmonary fibrosis: an analysis
of data from three randomised controlled trials. Lancet Respir
Med. 2013;1:369–76.
9. Newcastle-upon-Tyne Hospitals NHS Trust. A randomised,
placebo-controlled trial of omeprazole in idiopathic pulmo-
nary fibrosis (IPF). In: ClinicalTrials.gov [Internet].
Bethesda: National Library of Medicine (US). 2000- [cited
18 Feb 2016]. Available from: https://clinicaltrials.gov/show/
NCT02085018.
10. Bayer. A randomized, double-blind, placebo-controlled Phase II

study to investigate the efficacy and safety of riociguat (0.5 mg,
1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID) in patients with symp-
tomatic pulmonary hypertension associated with idiopathic
interstitial pneumonias (IIP). In: ClinicalTrials.gov [Internet].
Bethesda: National Library of Medicine (US). 2000- [cited 18
Feb 2016]. Available from: https://clinicaltrials.gov/show/
NCT02138825.
11. University of Virginia; National Heart, Lung, and Blood Institute
(NHLBI). Double-blind placebo-controlled pilot study of siroli-
mus in IPF. In: ClinicalTrials.gov [Internet]. Bethesda: National
Library of Medicine (US). 2000- [cited 18 Feb 2016]. Available
from: https://clinicaltrials.gov/show/NCT01462006.
12. Singh U, Gupta A, Jasuja S. Sirolimus-induced pneumonitis.
Indian J Nephrol. 2009;19:80–1.
13. University of Alabama at Birmingham; National Institutes of
Health (NIH). Autoantibody reduction therapy in patients with
idiopathic pulmonary fibrosis (ART-IPF). In: ClinicalTrials.gov
[Internet]. Bethesda: National Library of Medicine (US). 2000-
[cited 18 Feb 2016]. Available from: https://clinicaltrials.gov/
show/NCT01969409.
14. Donahoe M, Valentine VG, Chien N, et al. Autoantibody-
targeted treatments for acute exacerbations of idiopathic pulmo-
nary fibrosis. PLoS One. 2015;10:e0127771.
15. Raghu G, Scholand MB, de Andrade J, et al. Phase 2 trial of
FG-3019, anti-CTGF monoclonal antibody, in idiopathic pulmo-
nary fibrosis (IPF): preliminary safety and efficacy results. Eur
Respir J. 2012;40 (Suppl 56):511s.
16. FibroGen press release: FibroGen announces one-year data sup-
porting the safety and efficacy profilr of FG-3019 in patients
with idiopathic pulmonary fibrosis. 2014. http://investor.fibro-
gen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=
1982805 Accessed 29 Mar 2016.
17. MediciNova: MN-001 Dibrotic diseases. (2016). http://medi-
cinova.com/clinical-development/core/mn-001-nash/. Accessed
18 Feb 2016.
18. MediciNova. A randomized, placebo-controlled, double-blind
six month study followed by an open-label extension Phase to
evaluate the efficacy, safety and tolerability of MN-001 in sub-
jects with idiopathic pulmonary fibrosis (IPF). In: ClinicalTrials.
gov [Internet]. Bethesda: National Library of Medicine (US).
2000- [cited 18 Feb 2016]. Available from: https://clinicaltrials.

gov/show/NCT02503657.
19. Bristol-Myers Squibb. Safety and efficacy of a lysophosphatidic
acid receptor antagonist in idiopathic pulmonary fibrosis. In:
ClinicalTrials.gov [Internet]. Bethesda: National Library of
Medicine (US). 2000- [cited 18 Feb 2016]. Available from: https://
clinicaltrials.gov/show/NCT01766817.
20. Sanofi. Efficacy and safety of SAR156597 in the treatment of
idiopathic pulmonary fibrosis (IPF): A randomized, double-
blind, placebo-controlled, 52-week dose-ranging study. In:
21. Promedior press release: Promedior announces initiation of a
Phase 2 clinical study of PRM-151 in idiopathic pulmonary
fibrosis (IPF). 2015. http://www.promedior.com/news/
releases/2015%200907%20Promedior%20Announces%20
Initiation%20of%20Phase%202%20Study%20of%20PRM-
151%20in%20IPF.html. Accessed 18 Feb 2016.
22. Biogen. Randomized, double-blind, placebo-controlled, multiple
dose, dose-escalation study of STX-100 in patients with idio-
pathic pulmonary fibrosis (IPF). In: ClinicalTrials.gov [Internet].
Feb 2016 ]. Available from: https://clinicaltrials.gov/show/
NCT01371305.
23. Hoffmann-La Roche. A Phase II, randomized, double-blind,
placebo-controlled, study to assess the efficacy and safety of
lebrikizumab in patients with idiopathic pulmonary finbrosis. In:
24. University of California; National Heart, Lung, and Blood
Institute (NHLBI). Weighing risks and benefits of laparoscopic
anti-reflux surgery in patients with idiopathic pulmonary fibro-
sis. In: ClinicalTrials.gov [Internet]. Bethesda: National Library
of Medicine (US). 2000- [cited 18 Feb 2016]. Available from:
25. ClinicalTrials.gov. Results using the search term ‘pulmonary
rehabiliation and ipf’. 2016. https://clinicaltrials.gov/ct2/results?t
erm=pulmonary+rehabilitation+and+ipf&Search=Search .
Accessed 29 Mar 2016.
26. Laval University. Diagnostic yield of transbronchial cryobiopsies

in subjects with interstitial lung disease. In: ClinicalTrials.gov
[Internet]. Bethesda: National Library of Medicine (US). 2000-
[cited 18 Feb 2016]. Available from: https://clinicaltrials.gov/
show/NCT02235779.
27. Clinica Universidad de Navarra, Universidad de Navarra.
Treatment of idiopathic pulmonary fibrosis with bone marrow
derived mesenchymal stem cells. In: ClinicalTrials.gov [Internet].
Feb 2016]. Available from: https://clinicaltrials.gov/show/
NCT01919827.
28. Kasiak Research Pvt. Ltd. A prospective, multicentric, Phase I/II,
open label, randomized, interventional study to evaluate the
safety and efficacy of intravenous autologous adipose derived
adult stem cells for treatment of idiopathic pulmonary fibrosis
(IPF). In: ClinicalTrials.gov [Internet]. Bethesda: National
Library of Medicine (US). 2000- [cited 18 Feb 2016]. Available
from: https://clinicaltrials.gov/show/NCT02135380.
29. University of Pittsburgh. Open-label, feasibility study of com-
bined plasma exchange (PEX), rituximab, and corticosteroids in
patients with acute idiopathic pulmonary fibrosis exacerbations.
In: ClinicalTrials.gov [Internet]. Bethesda: National Library of
Medicine (US). 2000- [cited 18 Feb 2016. Available from: https://
30. Assistance Publique – Hôpitaux de Paris. Cyclophosphamide
added to corticosteroid in the treatment of acute exacerbation of
idiopathic pulmonary fibrosis: a placebo-controlled randomized
trial. In: ClinicalTrials.gov [Internet]. Bethesda: National Library
of Medicine (US). 2000- [cited 18 Feb 2016]. Available from:

Guide To Clinical Management of Idiopathic Pulmonary Fibrosis

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Guide To Clinical Management of Idiopathic Pulmonary Fibrosis

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Steven D Nathan · A Whitney Brown

ISBN 978-3-319-32792-1 ISBN 978-3-319-32794-5 (eBook)

Library of Congress Control Number: 2016942888

© Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Adis imprint is published by Springer Nature

When contemplating and collaborating on this book, the three

1 Overview of Idiopathic Pulmonary Fibrosis . . . . . . . 1

2 Clinical Presentation and Diagnosis . . . . . . . . . . . . . . 15

3 Diseases that Mimic Idiopathic Pulmonary Fibrosis. . . 33

3.3 Chronic Hypersensitivity Pneumonitis . . . . . . 36

4 Pathogenesis of Idiopathic Pulmonary Fibrosis . . . . 43

5 Prognosis, Clinical Course, and Monitoring

6 Comorbidities and Complications of Idiopathic

7 Treatment of Idiopathic Pulmonary Fibrosis . . . . . . . 81

7.3 Common Questions for Anti-fibrotic

8 Non-pharmacologic Management of Idiopathic

9 The Future for Idiopathic Pulmonary Fibrosis . . . . . 111

9.2.3 Cryobiopsy . . . . . . . . . . . . . . . . . . . . . . . 117

A Whitney Brown, MD is Director of Clinical Operations

Christopher S King, MD is a pulmonologist in the Inova

Steven D Nathan, MD is the Director of the Advanced Lung

DAH Diffuse alveolar hemorrhage

PRR Pulse rate recovery

S. Nathan et al., Guide to Clinical Management 1

erythematosus, mixed connective tissue disease,

Organic: chronic hypersensitivity Bird fanciers disease, farmer’s lung

Table 1.2 The idiopathic interstitial pneumonias. N/A, not applicable

late 1970s that described an excess of inflammatory cells [4–6].

for enrollment in a clinical trial or to undergo lung transplan-

1.2 Incidence and Prevalence

Table 1.3 Common occupational causes of interstitial lung disease

disease in other countries remains poorly defined. The course

is a polymerase (enzyme) that adds telomere repeats to

The above mentioned genetic abnormalities account for a

1.4 Course and Prognosis

Unpredictable patterns of progression

Figure 1.1 Course and prognosis of idiopathic pulmonary fibrosis

from ARDS, with a diffuse alveolar damage pattern, but

3. Travis WD, Costabel U, Hansell DM, et al. An official American

16. Lawson WE, Grant SW, Ambrosini V, et al. Genetic mutations in

S. Nathan et al., Guide to Clinical Management 15

other reasons. Chest imaging tends to be ubiquitous and fre-

2.2 Patient History

– occupational exposures: asbestos (asbestosis), silica

2.3 Physical Examination

2.4 Pulmonary Function Tests

Table 2.1 Signs and symptoms of connective tissue disease

MCTD Morning hand joint stiffness Arthritic changes of small

SLE Alopecia Oral ulceration

Sjogren’s syndrome Dry mouth, dry eyes Uveitis

Polymyositis/ Skin rash Heliotrope rash

The colored squares indicate a specific disease entity, features of sclero-

Figure 2.1 Chest X-ray and computed tomographic imaging dem-

FEV1/FVC ratio. This preserved ratio differentiates the

2.5 Chest X-Ray

2.6 Laboratory Tests

Table 2.2 Serologic tests to consider when evaluating a patient with

considered when evaluating patients with ILD (Table 2.2). In