Idiopathic

Pulmonary
Fibrosis
UPDATE 2021
Guidelines for Diagnosis
and Management

An ATS Pocket Publication

Funding for this project was provided by Boehringer Ingelheim Pharmaceuticals, Inc.
GUIDELINES FOR THE DIAGNOSIS
AND MANAGEMENT OF IDIOPATHIC
PULMONARY FIBROSIS: UPDATE 2019
AN AMERICAN THORACIC SOCIETY
POCKET PUBLICATION

This pocket guide is a condensed version of the 2011, 2015 and 2018
American Thoracic Society (ATS), European Respiratory Society (ERS),
Japanese Respiratory Society (JRS), and Latin American Thoracic Association
(ALAT) Evidence-Based Guidelines for Diagnosis and Management of
Idiopathic Pulmonary Fibrosis (IPF). This pocket guide was complied by
Ganesh Raghu, MD and Bridget Collins, MD, University of Washington,
Seattle from excerpts taken from the published official documents of the
ATS. Readers are encouraged to consult the full versions as well as the
online supplements, which are available at
http://ajrccm.atsjournals.org/content/183/6/788.long.

All information in this pocket guide is derived from the 2011, 2015 and
2018 IPF guidelines unless otherwise noted. Some tables and figures are
reprinted with the permission from the journals referenced.

Produced in Collaboration with Boehringer Ingelheim Pharmaceuticals, Inc.

Table of contents

List of Figures and Tables 2

List of Abbreviations and Acronyms 3
Definition and Epidemiology 3
Definition 3
Clinical Presentation 4
Incidence/Prevalence 5
Potential Risk Factors 5
Genetic Factors 5
Features of Usual Interstitial Pneumonia Pattern 6
High Resolution Computed Tomography Image Patterns 7
High-Resolution Computed Tomography (HRCT) Scans of Chest 7
HRCT Pattern Suggestive of Diagnosis Alternative To UIP 9
Histopathology Features and Patterns of UIP 10
UIP Patterns: 2018 ATS-ERS-JRS-ALAT Guideline 13
and Fleischner Society Document
Guideline Methodology 14
Diagnosis 16
IPF Diagnosis 16
Summary of 2018 ATS-ERS-JRS-ALAT Recommendations Made For Diagnosis of IPF 17
Diagnostic Algorithm for IPF 18
Clinical Course 21
Natural History of IPF 21
Mortality Risks and Acute Exacerbation 24
Treatment 26
Identification and Treatment of Selected Complications
and Co-Morbid Conditions in IPF 28
Palliative Care 29
Monitoring the Clinical Course of Disease 29
Summary of Clinical Management of IPF 30
Conclusion 31
References 32

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 1

 List of figures and tables
Figures
Figure 1: Usual Interstitial Pneumonia (UIP) Pattern 7
Figure 2:  Probable Usual Interstitial Pneumonia (UIP) Pattern 7
Figure 3:  Indeterminate for Usual Interstitial Pneumonia (UIP) Pattern (Early UIP Pattern) 8
Figure 4:  Indeterminate for Usual Interstitial Pneumonia (UIP) Pattern 8
Figure 5:  Pattern Suggestive of Alternative Diagnosis 9
Figure 6:  Histopathology Demonstrating Usual Interstitial Pneumonia (UIP) 11
Figure 7:  Diagnostic Algorithm for Idiopathic Pulmonary Fibrosis (IPF) 18
Figure 8:  Natural History of IPF 21
Figure 9:  Idiopathic Pulmonary Fibrosis: Rate of FVC Decline/Disease Progression 23
Figure 10: Proposed Conceptual Framework for Evaluation of Acute Respiratory
Deterioration in Idiopathic Pulmonary Fibrosis (IPF) 25
Figure 11: Schematic Pathway for Clinical Management of Patients with I
(Modified from the 2011 Guideline) 30

Tables
Table 1:  High Resolution Computed Tomography Image Patterns 6
Table 2:  High-Resolution Computed Tomography Scanning Technique and Parameters 10
Table 3:  Histopathology Patterns and Features 12
Table 4:  Comparison of Radiographic and Histopathologic Diagnostic Components for
IPF Proposed by the 2018 IPF Guideline and the Fleischner Society White Paper 13
Table 5:  Quality of Evidence Determination 14
Table 6:  Quality of the Evidence Rating and Implications 15
Table 7:  Implications of Strong and Conditional Recommendations 15
Table 8:  Idiopathic Pulmonary Fibrosis Diagnosis Based Upon HRCT and Biopsy Patterns 20
Table 9:  Selected Features Associated with Increased Risk of Mortality in IPF 24
Table 10: Proposed Definition and Diagnostic Criteria for Acute Exacerbation
of Idiopathic Pulmonary Fibrosis 24
Table 11: Pharmacological Treatment Recommendations (Updated in the 2015 Guideline) 26
Table 12: Other Treatment Recommendations as Per the 2011 IPF Guideline
(These Recommendations were not Updated in the 2015 Guideline) 27

All information in this pocket guide is derived from the 2011, 2015 and 2018 IPF guidelines unless otherwise noted.
Tables and figures are referenced so the reader can look up the original document published for further reading.

2 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

List of abbreviations and acronyms
6MW: 6-minute-walk test hTERT: Human telomerase reverse
ALAT = Latin American Thoracic transcriptase
Association hTR: Human telomerase RNA
ATS = American Thoracic Society IIP: Idiopathic interstitial pneumonia
BAL: Bronchoalveolar lavage ILD: Interstitial lung disease
CCL18: Chemokine (C-C motif) ligand 18 IPF: Idiopathic pulmonary fibrosis
CHP: Chronic hypersensitivity pneumonitis JRS: Japanese Respiratory Society
CPI: Composite physiologic index KL-6: Krebs von den Lungen-6
CT: Computed tomography MDD: Multidisciplinary discussion
DLCO: Diffusing capacity for carbon MMP: Matrix metalloproteinase
monoxide NAC: N-acetyl-cysteine
dx: Diagnosis NSIP: Nonspecific interstitial pneumonia
EBV: Epstein-Barr virus OSA: Obstructive sleep apnea
ERS: European Respiratory Society P(A-a)O2: Alveolar-arterial oxygen
FEV1: Forced expiratory volume in difference in partial pressures
1 second PH: Pulmonary hypertension
FVC: Forced vital capacity QoL: Quality of life
GER: Gastroesophageal reflux RCT: Randomized controlled trial
GERD: Gastroesophageal reflux disease TLC: Total lung capacity
GGO: Ground-glass opacities UIP: Usual interstitial pneumonia
GRADE: Grading of Recommendations VATS: Video-assisted thoracoscopic
Assessment, Development and Evaluation surgery
HRCT: High-resolution computed
tomography

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 3

 Definition and Epidemiology
• Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive
fibrosing interstitial pneumonia of unknown cause, occurring primarily in
older adults, limited to the lungs, and associated with the histopathologic
and/or radiologic pattern of usual interstitial pneumonia (UIP) defined in
(Table 1; Table 3).1-3
5. Computed
• The diagnosis oftomography
IPF requires the exclusion (CT) pattern
of other forms suggest
of interstitial
pneumonia including other idiopathic interstitial pneumonias (IIP) and
ion showing disseminated
interstitial lung lung
disease (ILD) associated with infiltration,
environmental exposure, spari
medication, or connective tissue disease.
on confirming lobular air trapping, all findings be
Clinical Presentation
• IPF should be considered in all adult patients with unexplained chronic
exertional dyspnea, and commonly presents with cough, bibasilar inspiratory
crackles, and finger clubbing.
American Journal of Re
• The incidence of IPF increases with older age, with presentation typically
occurring in the sixth and seventh decades.
• IPF is rare in patients younger than 50 years of age.
• IPF is more common among men than among women.
• The majority of patients with IPF have a history of cigarette smoking.

4 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Incidence/Prevalence
• The annual incidence of IPF among US medicare beneficiaries 65 years and
older was 93.7 cases per 100,000 person years between 2001 and 2011 and
remained stable.4
• The annual cumulative prevalence increased to 494.5 cases per 100,000
people in 2011 from 202.2 cases per 100,000 people in 2001.4

Potential Risk Factors

• Cigarette smoking (particularly a smoking history of >20 pack-years).
• Abnormal gastroesophageal reflux (GER) through its presumed association
with microaspiration.
• Age >60 yrs.
• Male.

Genetic Factors
• Familial IPF represents <5% of all cases. It is clinically and histologically
indistinguishable from sporadic IPF, although it may develop at an earlier age.
• Genetic variants within the human telomerase reverse transcriptase (hTERT)
or human telomerase RNA (hTR) components of the telomerase gene are
found in ≤15% of familial pulmonary fibrosis kindreds and 3% of sporadic
IIP cases. At present, there are no genetic factors that are consistently
associated with sporadic IPF. Genetic factors reported subsequent to the
published 2011 document include MUC5B promoter polymorphism, ABCA3,
AKAP13, TOLLIP genotypes, mutations in TERT/TERC and other telomere
maintenance components leading to shortened telomeres.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 5

 Features of Usual Interstitial
Pneumonia Pattern

Table 1: High Resolution Computed Tomography Image Patterns3

UIP Probable UIP Indeterminate for UIP Alternative Diagnosis

Subpleural and
 Subpleural and
 Subpleural and basal
 Findings suggestive

basal predominant; basal predominant; predominant of another diagnosis,
distribution is often distribution is often including:
heterogeneous heterogeneous Subtle reticulation;

may have mild GGO CT features:
Honeycombing
  Reticular pattern with
 or distortion • Cysts
with or without peripheral traction (“early UIP pattern”) • Marked mosaic
peripheral traction bronchiectasis or attenuation
bronchiectasis or bronchiolectasis CT features and/or
 • Predominant GGO
bronchiolectasis distribution of lung • Profuse micronodules
May have mild GGO
 fibrosis that do not • Centrilobular nodules
suggest any specific • Nodules
etiology (“truly • Consolidation
indeterminate for UIP”)
Predominant distribution:
• Peribronchovascular
• Perilymphatic
• Upper or mid-lung

Other:
• Pleural plaques
(consider asbestosis)
• Dilated esophagus
(consider CTD)
• Distal clavicular erosions
(consider RA)
• Extensive lymph node
enlargement (consider
other etiologies)
• Pleural effusions, pleural
thickening (consider CTD/
drugs)

6 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

 High-Resolution Computed
Tomography (HRCT) Scans of Chest

AMERICAN THORACIC SOCIETY DOCUMENTS

Figure 1: Usual Interstitial Pneumonia (UIP) Pattern3
AMERICAN THORACIC SOCIETY DOCUMENTS

A B C

D E Figure 1. Images demonstrating a usual interstitial pneumonia

pattern. (A–C) Transverse CT section and (D) coronal
reconstruction illustrating the presence of honeycombing with
subpleural and basal predominance. Note the concurrent
presence of mild ground-glass opacity. (E) Magnified view
of the left lower lobe showing typical characteristics of
honeycombing, consisting of clustered cystic airspaces with
well-defined walls and variable diameters, seen in single or
multiple layers (arrows).
Figure 1. High-resolution computed tomography (CT) images demonstrating a usual interstitial pneumonia pattern. (A–C) Transverse CT section and (D)
coronal reconstruction illustrating the presence of honeycombing with subpleural and basal predominance. Note the concurrent presence of mild ground-
Figure 1. High-resolution
glass opacity. computed
(E) Magnified view of the lefttomography (CT) images
lower lobe showing typical demonstrating
characteristics ofahoneycombing,
usual interstitial pneumonia
consisting pattern.
of clustered (A–C)
cystic Transverse
airspaces CT section and (D)
with well-
coronal reconstruction
defined walls illustrating
and variable diameters,the presence
seen in singleof
orhoneycombing with subpleural and basal predominance. Note the concurrent presence of mild ground-
multiple layers (arrows).
glass opacity. (E) Magnified view of the left lower lobe showing typical characteristics of honeycombing, consisting of clustered cystic airspaces with well-
defined wallsofand variable adiameters, AMERICAN THORACIC SOCIETY DOCUMENTS
seen in single or multiple layers (arrows).
Figure 2: Probable Usual Interstitial Pneumonia (UIP) Pattern
the benefits establishing secure diagnosis Histopathology Features of the diagnosis of the UIP pattern can be made
3
of IPF; therefore, the final decision regarding UIP Pattern when all of the above features are present,
whether
the or not
benefits to pursue a biopsy
of establishing a securemust be The histopathologic
diagnosis Histopathology AMERICAN
hallmark and chief
Features ofTHORACIC SOCIETY
the particularlydiagnosis of theDOCUMENTS
when honeycombing UIP ispattern can be made
tailored to the clinical
the situation of the regardingdiagnostic criterion of UIP is a low present. However,
when alleven in the absence of are present,
of IPF; therefore, final decision UIP Pattern of the above features
individualA patient. Multiple biopsies should B
magnification appearance of patchy dense honeycombing, aC definite diagnosis of a
whether or not to pursue a biopsy must be The histopathologic hallmark and chief particularly when honeycombing is
be obtained from two to three lobes, because fibrosis that 1) is causing remodeling of lung UIP pattern can still be made if all of the
tailored to thepatterns
the histologic clinicalonsituation of the
SLB specimens diagnostic
architecture, criterion
2) often resultsofinUIP is a low other typical
honeycomb present.
featuresHowever,
are present. even in the absence of
individual
obtained from patient. Multiple
different biopsies
segments can beshouldchange,magnification appearance
and 3) alternates with areas of of
patchy
less- dense Key histologic
honeycombing, features acan definite diagnosis of a
be helpful
be obtained from two to three lobes, because fibrosis that 1)
discordant (e.g., coexisting UIP pattern and affected parenchyma (Figure 7). These is causing remodeling of lung UIP pattern can
in excluding alternate diagnoses, such still be made
as if all of the
the histologic
fibrotic patterns
NSIP pattern from ondifferent
SLB specimens
lobes). architecture,
histopathologic 2) often
changes results
typically in the
affect honeycomb other pneumonitis
hypersensitivity typical features (e.g.,are present.
Methods
obtained fromfordifferent
processing SLBs arecan be subpleural
segments change, andand
paraseptal parenchyma
3) alternates areas ofbronchiolocentric
with most less- Keydistribution
histologicwith features can be helpful
variable and(e.g.,
discordant require careful handling
coexisting UIP patternof andseverely. Inflammation
affected parenchyma is usually
(Figuremild7). andTheselymphocyte-rich bronchiolitis,
in excluding alternateextensive
diagnoses, such as
samples to avoid iatrogenic mechanical
fibrotic NSIP pattern from different lobes). consists of a patchy interstitial infiltrate
histopathologic changes typically affect the of peribronchiolar
hypersensitivity poorly
metaplasia, pneumonitis (e.g.,
atelectasis and use of inflation techniques to lymphocytes and plasma cells associated
Methods for processing SLBs are subpleural and paraseptal parenchymaformed most nonnecrotizing
bronchiolocentric granulomas
distribution with
preserve normal lung architecture. Special with hyperplasia of type 2 pneumocytes and in peribronchiolar interstitium), acute
variable
stains may and be require careful
used in some severely.
handling of bronchiolar
patients, Inflammation
epithelium. is usually
The fibrotic zonesmildexacerbation
and lymphocyte-rich
of IPF or acute bronchiolitis,
interstitial extensive
samples
includingtoiron avoid
stainsiatrogenic
to identifymechanical
asbestos consists of
are composed a patchy
mainly of denseinterstitial
collagen,infiltrate of
pneumonia peribronchiolar metaplasia, poorly
(i.e., hyaline membranes),
atelectasis and usewith
bodies in patients of inflation techniques toalthough
incriminating lymphocytes and plasma
scattered convex cells associated
subepithelial formedofnonnecrotizing
cicatricial variants cryptogenic organizing granulomas
exposure D
preserve normal
histories lung architecture.
and elastic SpecialfociEof
tissue stains with hyperplasia
proliferating of typeand
fibroblasts Figure
2 pneumocytes 2. pneumonia
(A–C)
and inTransverse
peribronchiolar
with computed
fibrosis (prominent interstitium), tomography
acute (CT) section,
stains may in
for patients bewhom
used vascular
in someabnormalities
patients, bronchiolar
myofibroblasts epithelium.
(so-called fibroblastThefoci)
fibrotic zones organizingexacerbation of IPF or acute interstitial
pneumonia), pneumoconiosis
including iron stains to identify asbestos are aare
differ from the secondary changes consistent
composed mainly
finding. of(D)
Microscopicdensecoronal reconstruction
(e.g.,
collagen, asbestos of both
bodies, prominent
pneumonia (i.e., dust
hyaline lungs, and (E) magnified sagittal
membranes),
common
bodies in inpatients
the UIPwith pattern. Connective
incriminating honeycombing
although is characterized
scattered convex view of themacules
by subepithelial
cystic
rightand/or
lower lobe
silicotic
cicatricial illustrating
nodules),
variants of cryptogenic the presence of a reticular
organizing
tissue stains
exposure may also
histories and have valuetissue
elastic in fociairspaces
stainsfibrotic that are frequently
of proliferating lined and sarcoidosispneumonia
(prominent with well-formed
fibrosis (prominent
distinguishing patterns of fibrosis but are of by bronchiolar epithelium and pattern
myofibroblasts (so-called fibroblastwith foci) peripheral bronchiolectasis
in a lymphatic with subpleural and basal
fibroblasts
filled with nonnecrotizing granulomas
for patients in whom vascular abnormalities organizing pneumonia), pneumoconiosis
limited incremental value compared with
differ from
biopsies the secondary
processed changes
with high-quality
mucus and inflammatory cells. Smooth
routine muscle aremetaplasia
a consistentin thefinding. predominance.
Microscopic
interstitium is fibrosis Depending
(e.g., asbestos
(extensive onbodies,
respiratory their
distribution), smoking-related interstitial
orientation
prominent
bronchiolitis dust relative to the plane
common in the UIP
staining techniques
tissue
likepattern. Connective commonly
hematoxylin
stains may also have value in
honeycombing
seen in areas
fibrotic airspaces
of
is characterized
of fibrosis
thatpathologic
the
and
are frequently lined
CT andsection,
by cystic macules
exquisitely peripheral
and/orand/or
subpleural
sarcoidosis
traction
silicotic
(prominent
nodules),bronchiolectasis appear
and eosin. honeycombing. A definitive peribronchiolar paucicellular denselywell-formed
distinguishing patterns of fibrosis but are of by bronchiolar epithelium asand tubularfilled with(arrows) or cystic
nonnecrotizing (arrowheads)
granulomas structures. Note the
in a lymphatic
limited incremental value compared with
American Thoracic Society Documents
mucus and inflammatory concurrent
cells. Smoothpresence of mild smoking-related
distribution), ground-glass e51 opacities in the subpleural
interstitial
biopsies processed with high-quality routine muscle metaplasia in the interstitium is fibrosis (extensive respiratory bronchiolitis
Figure 2. Probable usual interstitial pneumonia (UIP) pattern. (A–C) Transverse computed
staining areas of and
tomography both (CT) lungs and
section, (D) thereconstruction
coronal absenceand/or of of
bothhoneycombing. UIP was
lungs, and (E) techniques like hematoxylin
magnified sagittal commonly
view of the right lower lobe seen
illustrating the in areas
presence of of fibrosis
a reticular and exquisitely
pattern with peripheral subpleural
bronchiolectasis with subpleural
and and predominance. Depending on their orientation honeycombing.
basaleosin. relative to the plane the proven
A ofdefinitive pathologic
CT section, at histology.
peripheral peribronchiolar
traction bronchiolectasis paucicellular densely
appear as tubular
Figure
(arrows)2.orProbable usual interstitial
cystic (arrowheads) pneumonia
structures. (UIP) pattern.
Note the concurrent presence(A–C) Transverse
of mild computed
ground-glass opacities tomography (CT)
in the subpleural section,
areas of both(D) coronal
lungs reconstruction of both
and the
lungs, andof(E)
absence magnified sagittal
honeycombing. UIP wasview of the
proven right lower lobe illustrating the presence of a reticular pattern with peripheral bronchiolectasis with subpleural
at histology.
and basal predominance.
American Depending
Thoracic Society on their orientation relative to the plane of the CT section, peripheral traction bronchiolectasis appear
Documents e51 as tubular
(arrows) or cystic
eosinophilic (arrowheads)
collagen structures. Note
without architectural the concurrent
or any presencepattern
other histopathologic of mildofground-glass opacities
It is based in the
on these subpleural
2018 guidelinesareas of both lungs and the
and the
absence of honeycombing.
distortion), UIP was proven atfibrotic
and pleuroparenchymal histology.
interstitial pneumonia and, in some 2011 guidelines (2) and similar to that
fibroelastosis (prominent subpleural cases, may favor an alternative diagnosis suggested by a task force sponsored by the
intraalveolar fibrosis
eosinophilic collagenandwithout and GUIDELINES
while not
elastosisarchitectural FOR THEhistopathologic
categorically
or any other DIAGNOSIS
excluding the
visceral pleura fibrosis most marked in the possibility of sampling bias in a patient who
AND Fleischner
pattern MANAGEMENT
of Society OF IDIOPATHIC
It is (82).
based on these 2018 PULMONARY
Patients with suspected IPF as
FIBROSIS
guidelines and the 7
distortion), and pleuroparenchymal
upper lobes). The specificity of these
fibrotic interstitial pneumonia and, described
ultimately proves to have UIP. A subset of
in some above 2011 guidelines (2) and similar to that
are initially evaluated for
fibroelastosis (prominent
findings is variable subpleural
and ranges from only patientscases, may favoroccult
with previously an alternative
IPF may diagnosis suggested
identifiable causes of ILD, by
sucha as
task force sponsored by the
domestic
intraalveolar and will
fibrosis that
suggesting alternatives elastosis and presentwhile
be resolved notacute
with an categorically excluding
exacerbation, which is theand occupational
Fleischner Society
environmental (82).
exposures,
 Figure THORACIC
AMERICAN 3: Indeterminate for Usual
SOCIETY Interstitial Pneumonia (UIP) Pattern
DOCUMENTS
(Early UIP Pattern)3
AMERICAN THORACIC SOCIETY DOCUMENTS
A B C

D E Figure 3. (A and B) Transverse computed tomography (CT)

section, (C) coronal reconstruction of both lungs, and (D)
magnified view of the right lung in supine position showing
ground-glass opacity and subtle reticulation in the subpleural
areas (arrows) with a basal predominance. (E) Transverse CT
section of the lower lung zones in prone position showing
persistence of lung infiltration in nondependent areas, thus
excluding gravitational abnormalities. UIP was proven at
histology.
Figure 3. Indeterminate for usual interstitial pneumonia (UIP) pattern (early UIP pattern). (A and B) Transverse computed tomography (CT) section, (C)
coronal reconstruction of both lungs, and (D) magnified view of the right lung in supine position showing ground-glass opacity and subtle reticulation in the
subpleural areas (arrows) with a basal predominance. (E) Transverse CT section of the lower lung zones in prone position showing persistence of lung
infiltration
Figure 3.inIndeterminate
nondependent areas, thus excluding
for usual interstitialgravitational
pneumonia abnormalities. UIP was
(UIP) pattern proven
(early UIPatpattern).
histology. (A and B) Transverse computed tomography (CT) section, (C)
coronal reconstruction of both lungs, and (D) magnified view of the right lung in supine position showing ground-glass opacity and subtle reticulation in the
subpleural areas (arrows) with
symptomatic or asymptomatic bilateral a basal predominance. (E) Transverse CT section of the lower lung zones
proposed course of action, so a motherhood stone polishing and cutting, medications in prone position showing persistence of lung
infiltration
pulmonaryinfibrosis
nondependent
on a chestareas, thus excluding
radiograph statementgravitational
was made abnormalities.
to take a detailed UIP was taken,
provencurrent
at histology.
or recent occupations (e.g.,
or chest CT scan, bibasilar inspiratory history of medication use and hair dressing), and current or recent hobbies
crackles, and an age typically older than environmental exposures at home, AMERICAN
work, THORACIC
(27, 87–92). Although someSOCIETY panelists use theDOCUMENTS
60 years. Figure
It must be 4: Indeterminate
recognized
symptomatic or asymptomatic bilateral that the and for
other Usual
places that Interstitial
the patient frequently
proposed course of action, so a motherhood Pneumonia
presence of antibody(UIP)
stone Pattern
in serum
3
againstand cutting, medications
polishing
questions addressed are not restricted
pulmonary fibrosis on a chest radiograph to visits, to identify or exclude potential
statement was made to take a detailed causes specific antigen to prompt further evaluation
taken, current or recent occupations (e.g.,
patients older than 60 years, as middle-aged of ILD (e.g., hypersensitivity pneumonitis, for hypersensitivity pneumonitis, themyoglobin,
phosphokinase, test
oradults
chest A
(.40CTyrscan,
and ,60 bibasilar inspiratory pneumoconiosis,
yr), especially B drug
history of medication
toxicity). Thisuse is and is not standardized Cantisynthetase
hair
and dressing),
the specificity and currentand or aldolase),
recent hobbies
crackles, and an age typically older than environmental exposures at home, work, (27, 87–92). antibodiessome
Although (Jo-1 panelists
and others use the
patients with risks for familial pulmonary supported by an observational study that and sensitivity for the diagnosis of
if available), anti–MDA5 (melanoma
60 years.canItrarely
fibrosis, mustpresent
be recognized that theenrolled and
with the otherwise 1,084other
patients places that the ILD
with new-onset patient frequently pneumonitis
hypersensitivity presence isofunknown.antibody in serum against
same clinicaladdressed
scenario as arethe typical patient of unknown cause differentiation-associated protein 5), anti–
questions not restricted to visits, toreporting
identifythat 47% of thepotential
or exclude The panelists
causeswho specific
use serumantigen
antibodyto prompt further evaluation
older than 60 years. The recommendations patients were identified as having testing believe thatMi-2,such anti-NXP2 (nuclear matrix protein 2),
tests may identify
patients older than 60 years, as middle-aged of ILD (e.g., hypersensitivity pneumonitis, for hypersensitivity
anti–TIF1-g pneumonitis, the test
in this guideline are for the patterns and hypersensitivity pneumonitis on detailed an antigen that was not suspected(transcriptional
by clinical intermediary
adults (.40 yr and ,60 yr),
distributions of images obtained by HRCT especially pneumoconiosis, drug
assessment, suggesting that a cause can be toxicity). This is
history and, therefore, is not
factormay standardized
1-g), anti-SRP
prompt and therecognition
further(signal specificity
patients
and, thus,with
requirerisks for familial
that patients be subjected to found insupported
pulmonary many patients bywhoan observational
present with study that for particle),
investigations and
the sensitivity
suspected for the(3-hydroxy-3-
etiology;
anti-HMGCR diagnosis of
HRCT ofcan
fibrosis, the rarely
chest forpresent with the otherwise
evaluation. ILD (84).enrolled
The panel’s 1,084 patients
clinical withisnew-onset
experience ILDantibody
also, if serum hypersensitivity
testing is negative,
methylglutaryl-CoA pneumonitis is unknown.
reductase), anti-SAE
same clinical scenario as the typical patient that identification
of unknown and removal of potentialthat
cause reporting the47%
results
of reinforce
the (smallThethe panelists
conclusion who that the use serum antibody
ubiquitin-related modifier–
Question 1: Should Patients with causative environmental factors may result patient does not have hypersensitivity
older than 60 years. The recommendations
Newly Detected ILD of Unknown
patients were identified as having
in improved clinical outcomes. pneumonitis.
testing believe
activating enzyme), that anti-U1RNP
such tests may (U1identify
inCause
this guideline are for the
Who Are Clinically patterns and
Suspected Many hypersensitivity
panelists use publishedpneumonitis on detailed ATS/ERS/JRS/ALAT an antigen
ribonucleoprotein), that was
recommendation. not suspected by clinical
anti-PM/Scl75
distributions
of Having IPFofUndergo
4.images aobtained
Detailed,by HRCT assessment, suggesting thatto a cause
d Forcan be
Figure (polymyositis/scleroderma
history
4. and, therefore,
Indeterminate may
forofusual 75), anti-PM/
prompt
interstitial further pattern. (A
pneumonia
Figure (A–C) Transverse computed tomography
questionnaires
sections
in their clinical
showing
practices
extensive
patients
lung
with
infiltration
newly detected
combining
ILD
Prompted
and, Historythat
thus, require of Medication
patients beUse subjectedconsider
to found environmental
in many exposures
patientsat home,
who present withtomography
apparently Scl100,
unknown sections
cause
investigations whoshowing
and anti-Ku for the extensive
are (93). If systemic
suspected lung infiltration combining
sclerosis
etiology;
HRCT honeycombing,
and Environmental
of the chest Exposures mild to
for evaluation.atmarked ground-glass
work, and opacity,
frequently visited asymmetrical
places (84–86).
ILD (84). The panel’s clinical experience distribution between
clinically ground-glass
suspected
is (i.e., both
ofifhaving
serumIPF,
opacity,
also,scleroderma)
lungs, and no
iswesuspected,
asymmetrical
antibody distribution
testingadditional between both lung
is negative,
Home, subpleural
Work, and Other predominance.
Places the Such questionnaires may be tailored to
that identification
recommend taking tests ainclude:
detailedanti–Scl-70/topoisomerase-1,
history of
Patient Frequently Visits to Exclude cultural habits and geographicaland removal ofboth
differences. potential
medicationthe use results reinforce the conclusion that the
and environmental
Question 1: Should Question 2: Should
anti-centromere, Patients
notanti-RNA polymerase III, newly identi
Potential Causes of thePatients
ILD? with Examplescausativeof pertinentenvironmental
exposures includefactors may result
exposures patient
at home, work,does
and other have hypersensitivity
Newly Detected ILD of Unknown mold, birds, in improved
down feathers, clinical
animals,outcomes.
metal places thewithpatientNewly
anti-U1RNP,
pneumonitis. Detected
frequently visits to ILD of
anti-Th/To, Unknown
anti-PMScl, U3 overwhelmin
Cause RNP Who(fibrillarin),
ofAre ILDand anti-Ku.
the Clinically If Sjögren
Suspected
Discussion.
Cause Who TheAre
guideline panel recognized
Clinically Suspected dusts (e.g., brass,
Manylead, steel), wood use
panelists dust published
(e.g., exclude potential causesATS/ERS/JRS/ALAT recommendation.serological te
syndrome IPFisUndergo
suspected, Serological
additional tests
there is no reasonable alternative to the
of Having IPF Undergo a Detailed, pine), vegetable dust, exposure
questionnaires to livestock,
in their (motherhood
clinical practices toof Having
statement).
For patients with newly detected ILD of
d about which
include:
Testing anti-SSA/Ro
to Exclude CTDs(Sjögren-specific
ascause
Potential The ma
Prompted History of Medication Use consider environmental exposures at home, apparently unknown who are
antibody
Causes A) ILD?
of the and anti-SSB/La. If vasculitis is routinely tes
and Environmental
American Exposures
Thoracic Society Documents at work, and frequently visited places (84–86). suspected, clinically suspected
e53 of having IPF, we
an additional test includes anti- protein), ery
Home, Work, and Other Places the Such questionnaires may be tailored to recommend
cytoplasmic takingA asmall
antibodies. detailed history
minority of
of rate,
Figure 4. Indeterminate for usual interstitial pneumonia pattern. (A–C) Transverse computed Discussion. Diagnosis of IPF mandates antinuc
Patient Frequently
tomography sectionsVisits
showingtoextensive
Exclude cultural
lung infiltration habitshoneycombing,
combining and geographical
mild todifferences.
marked the both medication
panelists include alluseof and environmental
the detailed tests immunofluo
Potential Causes of the ILD? distribution between Examples of pertinent exposures include exclusion of other
exposures causes of ILD, including
ground-glass opacity, asymmetrical both lungs, and no subpleural predominance. listed above as at an home, work,atand
“ILD panel” other
initial
mold, birds, down feathers, animals, metalCTD-ILD (Table
places theE2).
screening/baseline
The guideline
patient visits to myositis pan
frequentlypanel
evaluation.
Discussion.
Question The2:guideline panel recognized dusts
Should Patients newly(e.g., brass, lead,
identified steel), wood
ILD. Although dust
there concluded
was(e.g., thatguideline
exclude
The foregoing
potential serological
causesdoofnot
panelists ILDall peptide. Oth
testing
therefer
therewith
is noNewly
reasonable
Detected alternative to the
ILD of Unknown pine), vegetableagreement
overwhelming dust, exposure
to perform was not
to livestock, a reasonable
with newalternative.
(motherhood
patients statement). Therefore, a on a case-by
ILD to a rheumatologist;
8 Cause GUIDELINES FOR THE Suspected
Who Are Clinically DIAGNOSIS ANDserological MANAGEMENT OF was
testing, there IDIOPATHIC motherhood
PULMONARY
far less agreement statement
rather,FIBROSIS
referring wasthose
only madewith positive associated sy
to perform
of Having IPF Undergo Serological about which serological tests to perform. routine serological
clinical testing inserologies,
manifestations, other include mus
all patientsorwith
Testing
American to Exclude
Thoracic CTDsDocuments
Society as Potential The majority of panelists acknowledged characteristics atypical for IPF (e.g., female,e53
Causes of the ILD? routinely testing for CRP (C-reactive age ,60 yr). In many CTD-ILDs, the lung
Figure 4. Indeterminate for usual interstitial pneumonia pattern. (A–C) Transverse computed
tomography sections showing extensive lung infiltration combining honeycombing, mild to marked the panelists include all of the detailed tests
ground-glass opacity, asymmetrical distribution between both lungs, and no subpleural predominance. listed above as an “ILD panel” at initial
screening/baseline evaluation.
Question 2: Should Patients newly identified ILD. Although there was The guideline panelists do not refer all
with Newly Detected ILD of Unknown overwhelming agreement to perform patients with new ILD to a rheumatologist;
Cause Who Are Clinically Suspected serological testing, there was far less agreement rather, referring only those with positive

 RCT Pattern Suggestive of

H
of Having IPF Undergo Serological about which serological tests to perform. clinical manifestations, serologies, or other
Testing to Exclude CTDs as Potential The majority of panelists acknowledged characteristics atypical for IPF (e.g., female,
Causes of the ILD? routinely testing for CRP (C-reactive age ,60 yr). In many CTD-ILDs, the lung

Diagnosis Alternative to UIP

Discussion. Diagnosis of IPF mandates
exclusion of other causes of ILD, including
protein), erythrocyte sedimentation
rate, antinuclear antibodies (by
immunofluorescence), rheumatoid factor,
disease is the first, dominant, or only feature
of the CTD and, therefore, some patients will
not fit standard rheumatologic diagnostic
CTD-ILD (Table E2). The guideline panel myositis panel, and anti–cyclic citrullinated criteria at presentation. The term “interstitial
concluded that foregoing serological testing peptide. Other detailed tests are performed pneumonia with autoimmune features” has
was not a reasonable alternative. Therefore, a on a case-by-case basis according to been suggested to describe such patients;
motherhood statement was made to perform associated symptoms and signs. These however, this is a research definition that
Figure 5: Pattern Suggestive of Alternative Diagnosis
routine serological testing in all patients with include muscle enzymes (creatinine 3 requires validation (94).

A B C

Figure 5. Computed tomography (CT) pattern suggestive of an alternative diagnosis for lung fibrosis. (A and B) Transverse CT sections obtained at deep
Figure
inspiration 5. Suggestive
showing disseminatedoflung
an alternative diagnosis
infiltration, sparing some for lung fibrosis.
secondary (A and
pulmonary B) inTransverse
lobules lung bases.CT(C)sections obtained
Transverse at obtained
CT section deep at
inspiration
expiration confirmingshowing
lobular airdisseminated lung infiltration,
trapping, all findings sparing some
being highly suggestive secondary
of chronic pulmonary
hypersensitivity lobules in lung bases. (C)
pneumonitis.
Transverse CT section obtained at expiration confirming lobular air trapping, all findings being highly suggestive of
chronic hypersensitivity pneumonitis.
e54 American Journal of Respiratory and Critical Care Medicine Volume 198 Number 5 | September 1 2018

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 9

 Table 2: High-Resolution Computed Tomography Scanning
Technique and Parameters3

Recommended Scanning Protocol Advantages of Updated Recommendations

1 Noncontrast examination —

2.
Volumetric acquisition with selection of: A. Acquisition covering the entire lung volume (vs. analysis
Sub-millimetric collimation of 10% of lung volume with sequential scanning)
Shortest rotation time No risk of missing subtle infiltrative abnormalities
Highest pitch Possibility of multiplanar reformations, helpful
Tube potential and tube current appropriate to for analysis of the ILD pattern and predominant
patient size: distribution of lung changes
Typically 120 kVp and ≤240 mAs Possibility of post-processing to optimize detection
Lower tube potentials (e.g., 100 kVp) of subtle hypoattenuated lesions (minimum intensity
with adjustment of tube current projection) and micronodular infiltration (maximum
encouraged for thin patients intensity projection)
Use of techniques available to avoid unnecessary Possibility of detection of additional lesions
radiation exposure (e.g., tube current modulation) (e.g., incidental identification of lung nodule or
focal consolidation in lung fibrosis that may
correspond to lung carcinoma)
Optimal to assess progression or improvement
in patient’s follow-up
B. Dramatic increase in temporal resolution and speed of
data acquisition
Motion-free images
C. Availability of numerous dose-reduction tools

3. Reconstruction of thin-section CT images (≤1.5 mm):

Contiguous or overlapping
Using a high-spatial-frequency algorithm —
Iterative reconstruction algorithm if validated on the
CT unit (if not, filtered back projection)

4. Number of acquisitions: A. Expiratory scans useful to detect air trapping

Supine: inspiratory (volumetric) B. Prone scans allow analysis of peripheral lung changes
Supine: expiratory (can be volumetric or sequential) without dependent lung atelectasis that may be
Prone: only inspiratory scans (can be sequential or mistaken for abnormal lung infiltration or mimic disease
volumetric); optional (see text) (e.g., pseudohoneycombing when combined with
Inspiratory scans obtained at full inspiration paraseptal emphysema)
C. Inadequate inspiration increases lung attenuation (which
should not be interpreted as ground-glass attenuation)
and is responsible for dependent lung atelectasis (which
may mimic abnormal lung infiltration or mask subtle
abnormalities)

5. Recommended radiation dose for the inspiratory A. Considerable dose reduction compared to
volumetric acquisition: conventional scanning
1–3 mSv (i.e., “reduced” dose)
Strong recommendation to avoid “ultralow-dose
CT” (<1 mSv)

10 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Histopathology Features
And Patterns of UIP

Histopathology Features
• The histopathologic hallmark and chief diagnostic criterion is a
heterogeneous appearance at low magnification in which areas of fibrosis
of UIP change alternate with areas of less affected or normal parenchyma
(Figure 6; Table 3).

Figure 6: Histopathology Demonstrating Usual Interstitial Pneumonia (UIP)3

A B C

D E

Figure 6. (A) Low-magnification photomicrograph showing classical UIP/idiopathic pulmonary fibrosis (IPF)
pattern characterized by dense fibrosis with a predilection for subpleural and paraseptal parenchyma with
associated architectural distortion in the form of microscopic honeycomb change (arrow) juxtaposed with
relatively unaffected lung parenchyma (*). Visceral pleura is seen in the upper portion of the figure. (B) Higher-
magnification photomicrograph showing subpleural scarring and honeycomb change with associated fibroblast
foci (arrow). (C) Low-magnification photomicrograph showing probable UIP/IPF pattern characterized by subpleural
and paraseptal predominant patchwork fibrosis that is less well developed and lacks the degree of associated
architectural distortion in the form of either destructive scarring or honeycomb change illustrated in A and B. (D)
Higher-magnification photomicrograph showing patchy fibrosis and fibroblast foci (*) but without the extent of
scarring and honeycomb change illustrated in A and B. (E) Indeterminate for UIP/IPF pattern in which there is mild
nonspecific fibrosis that lacks a well-developed patchy and predominantly subpleural/paraseptal distribution,
architectural distortion, and fibroblast foci characteristic of classical UIP/IPF. There is associated osseous
metaplasia, a common but nonspecific finding in UIP. Although these findings are not diagnostic, they do not
preclude a diagnosis of UIP/IPF in a patient with supportive clinical and radiological findings.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 11

 Table 3: Histopathology Patterns and Features3

UIP Probable UIP Indeterminate for UIP Alternative Diagnosis

Dense fibrosis with

 Some histologic
 Fibrosis with or
  Features of other
 
architectural distortion features from column without architectural histologic patterns of
(i.e., destructive 1 are present but to an distortion, with IIPs (e.g., absence of
scarring and/or extent that precludes features favoring fibroblast foci or loose
honeycombing) a definite diagnosis of either a pattern fibrosis) in all biopsies
UIP/IPF other than UIP or
Predominant
 features favoring UIP Histologic findings
 
subpleural and/or And secondary to another indicative of other
paraseptal distribution Absence of features to cause* diseases (e.g.,
of fibrosis suggest an alternate hypersensitivity
diagnosis Some histologic
  pneumonitis,
Patchy involvement of
  features from column Langerhans cell
lung parenchyma by Or 1, but with other histiocytosis,
fibrosis Honeycombing only
 features suggesting sarcoidosis, LAM)
an alternative
Fibroblast foci
  diagnosis**

 
Absence of features to
suggest an alternative
diagnosis

* Granulomas, hyaline membranes (other than when associated with acute exacerbation of IPF, which may be the
presenting manifestation in some patients), prominent airway-centered changes, areas of interstitial inflammation
lacking associated fibrosis, marked chronic fibrous pleuritis, organizing pneumonia. Such features may not be overt
or easily seen to the untrained eye and often need to be specifically sought.
** Features that should raise concerns about the likelihood of an alternative diagnosis include a cellular
inflammatory infiltrate away from areas of honeycombing, prominent lymphoid hyperplasia including
secondary germinal centers, and a distinctly bronchiolocentric distribution that could include extensive
peribronchiolar metaplasia.

12 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

UIP Patterns: 2018 ATS -ERS-JRS-ALAT
Guideline And Fleischner Society Document
Table 4: Comparison of Radiographic and Histopathologic Diagnostic Components
for IPF Proposed by the 2018 IPF Guideline and the Fleischner Society White Paper5

ATS/ERS/JRS/ALAT Clinical Practice Guidelines Fleischner White Paper Consensus Statement

Age Limit for Increased Diagnostic Confidence: 60

HRCT Pattern UIP Typical UIP
Subpleural and basal predominance Subpleural and basal predominance
Presence of honeycombing with or without Presence of honeycombing with or without
peripheral traction bronchiectasis peripheral traction bronchiectasis
Biopsy NOT recommended Biopsy NOT recommended

Probable UIP
Subpleural and basal predominance Subpleural and basal predominance
Presence of peripheral traction bronchiectasis Presence of peripheral traction bronchiectasis
Biopsy recommended [conditional] Biopsy NOT recommended

Intermediate for UIP

Subpleural and basal predominant Variable or diffuse
May have mild GGO or distortion Features suggestive of non-UIP pattern
Biopsy recommended Biopsy recommended

Alternative Diagnosis Most Consistent with Non-IPF Diagnosis

Findings suggestive of another diagnosis Findings suggestive of another diagnosis
Biopsy recommended Biopsy recommended

Histopathology UIP Definite UIP

Pattern Dense fibrosis with architecture remodeling Dense fibrosis with architecture remodeling
Predominant subpleural or paraseptal Predominant subpleural or paraseptal
distribution of fibrosis distribution of fibrosis
Patchy lung involvement by fibrosis Patchy lung involvement by fibrosis
Presence of fibroblastic foci Presence of fibroblastic foci

Probable UIP
Honeycomb fibrosis only Honeycomb fibrosis only
Fibroblastic foci may or may not be present Fibroblastic foci may or may not be present

Intermediate UIP
Fibrosis with or without architecture distortion Occasional foci of centrilobular injury or scarring
Some histological features from the Rare granulomas or giant cells
UIP pattern Minor degree of lymphoid hyperplasia or
diffuse inflammation
Diffuse homogeneous fibrosis flavoring fibriotic
nonspecific interstitial pneumonia

Alternative Diagnosis Features Most Consistent with

an Alternative Diagnosis
Histopathological findings indicative of A UIP pattern with ancillary features strongly
other diseases suggesting an alternative diagnosis
A non-UIP pattern

This table is reproduced with permission from the ERJ.5 Criteria have been summarized for purposes of comparison.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 13

 Guideline Methodology
• Relevant section topics and questions were identified by committee
members after which, additional input was sought from general
pulmonologists in the community and at academic centers. An
evidence profile was created for each question using the Grading of
Recommendations Assessment, Development and Evaluation (GRADE)
methodology. The quality of evidence (Table 5; Table 6) was determined
according to the ATS GRADE criteria. The strength of the recommendations
is either “strong” or “conditional” based on the quality of evidence and the
voting of the committee members (Table 7).

Table 5: Quality of Evidence Determination1

Quality of Evidence Study Design Lower If Higher If

•  High •  RCT •  Limitation in study •  Strong association, no

•  Moderate •  Downgraded RCT quality plausible confounders
•  Low or upgraded •  Indirectness •  Evidence of a dose–
•  Very low observational study •  Important response gradient
•  Well-conducted inconsistency •  Plausible confounders
observational study •  Sparse or imprecise would have reduced
with control groups data the effect
•  Any other evidence •  High probability of
(e.g., case reports, case publication bias
series)

14 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Table 6: Quality of the Evidence Rating and Implications1

The quality of the evidence is a judgment about the extent to which we can be
confident that the estimates of effect are correct. These judgments are made
using the GRADE system, and are provided for each outcome. The judgments are
Quality of the Evidence
based on the type of study design (randomized trials versus observational studies),
(GRADE)
the risk of bias, the consistency of the results across studies, and the precision of
the overall estimate across studies. For each outcome, the quality of the evidence
is rated as high, moderate, low, or very low using the following definitions:

Further research is very unlikely to change the Committee’s confidence in the

High
estimate of effect

Further research is likely to have an important impact on the Committee’s

Moderate
confidence in the estimate of effect and may change the estimate

Further research is very likely to have an important impact on the Committee’s

Low
confidence in the estimate of effect and is likely to change the estimate

Very Low The Committee is very uncertain about the estimate

Table 7: Implications of Strong and Conditional Recommendations3

Strong Recommendation Conditional Recommendation

(“We recommend…”) (“We suggest…”)

For Patients The overwhelming majority of The majority of individuals in this

individuals in this situation would want situation would want the suggested
the recommended course of action and course of action, but a sizable minority
only a small minority would not. would not.

For Clinicians The overwhelming majority of individ- Different choices will be appropriate for
uals should receive the recommended different patients, and you must help
course of action. Adherence to this each patient arrive at a management
recommendation according to the decision consistent with her or his
guideline could be used as a quality values and preferences. Decision aids
criterion or performance indicator. may be useful to help individuals make
Formal decision aids are not likely to decisions consistent with their values
be needed to help individuals make and preferences. Clinicians should ex-
decisions consistent with their values pect to spend more time with patients
and preferences. when working toward a decision.

For Policy Makers The recommendation can be adapted Policy making will require substantial
as policy in most situations, including debates and involvement of many
for use as performance indicators. stakeholders. Policies are also more
likely to vary between regions. Perfor-
mance indicators would have to focus
on the fact that adequate deliberation
about the management options has
taken place.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 15

 Diagnosis

IPF Diagnosis
• IPF is a specific form of chronic progressive fibrosing interstitial pneumonia of
unknown cause
“The patient suspected to have IPF”
Typical Patient:
- Male >60 yrs., current or ex-cigarette smoker with insidious onset of
cough, exertional dyspnea, basilar crackles and radiological evidence of
fibrosis in lower lobes. (Rarely: Patients manifest acute exacerbation on an
initial presentation).
- Middle aged adults (>40 yrs.), especially patients with risks for familial
pulmonary fibrosis and genetic predisposition factors for IPF can rarely
present with same clinical scenario as the “typical” patients with IPF.
• Diagnosis of IPF requires:
1.  Exclusion of known causes of ILD (e.g., domestic and occupational
environmental exposures, connective tissue disease, drug toxicity and
EITHER (2) or (3).
2.  Presence of HRCT pattern of UIP (sufficient for diagnosis of IPF in the
appropriate clinical setting; i.e. without surgical lung biopsy).
3.  Specific combination of HRCT and histopathology patterns in patients
subjected to lung tissue sampling (Figure 8) (emphasis on multidisciplinary
discussion*).
*  For patients with newly detected ILD of apparently unknown cause who are clinically suspected
to have IPF, MDD is suggested for diagnostic decision making (conditional recommendation, very l
low quality of evidence).

16 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Summary of 2018 ATS-ERS-JRS-ALAT
Recommendations Made for Diagnosis of IPF
I. For adult patients with newly detected ILD of apparently unknown cause who
are clinically suspected of having IPF, the panel recommended the following as
‘motherhood statements’:
1.  Elicit a detailed history of both medication use and environmental
exposures at home, work, and other places the patient frequently visits to
exclude potential causes of ILD.
2. Detailed serological testing beyond ANA (including myositis panel) to
exclude connective tissue disease as a potential cause of the ILD.
II. For patients with newly detected ILD of apparently unknown cause who are
clinically suspected of having IPF and have a HRCT pattern of UIP:
- The panel recommended against transbronchial, transbronchial cryobiopsy
or surgical lung biopsy (strong recommendation, very low quality
evidence).
- The panel suggested NOT performing cellular analysis of their BAL fluid
(conditional recommendation, very low quality of evidence).
III. For patients with newly detected ILD of apparently unknown cause who are
clinically suspected of having IPF and have a HRCT pattern of probable UIP,
indeterminate for UIP, or an alternative diagnosis, the panel suggested:
- Perform bronchoalveolar lavage (BAL) fluid for cellular analyses
(conditional recommendation, very low quality of evidence).
- Surgical lung biopsy (SLB) in patients whose surgical risks are low
(conditional recommendation, very low quality of evidence).
- The panel made no recommendation for or against transbronchial lung
biopsy (TBBx).
- The panel made no recommendation for or against transbronchial lung
cryobiopsy.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 17

 IV. For adult patients with newly detected ILD of apparently unknown cause
who are clinically suspected of having IPF, the panel emphasized the need for
multidisciplinary discussions (MDD) during diagnostic evaluation at several steps
(see algorithm below).
V. Routine testing of serum biomarkers (MMP7, SPD, KL-6, CCL-18) is
not recommended to distinguish IPF from other forms of ILD (strong
recommendation, low quality evidence) regardless of CT pattern.

Diagnostic Algorithm for IPF

AMERICAN THORACIC
Figure 7: Diagnostic SOCIETY
Algorithm DOCUMENTS
for Idiopathic Pulmonary Fibrosis (IPF)3

quality of evidence). Re
Patient suspected to have IPF
0 votes; conditional for
conditional against, 4 v
against, 0 votes.
Potential cause/associated condition d For patients with newl
apparently unknown c
No Yes
clinically suspected of
have an HRCT pattern
Further evaluation recommend NOT perf
(including HRCT) (strong recommendation
of evidence). Remarks: s
conditional for, 2 votes
No
UIP Chest HRCT pattern Specific diagnosis against, 1 vote; strong

Question 5: For Patient

probable UIP, Yes
indeterminate for UIP, Detected ILD of Unkno
alternative diagnosis Who Are Clinically Susp
Having IPF, Is TBBx a R
Alternative to SLB to A
MDD Histopathology Diagno
Pattern?
Alternative
diagnosis Evidence base. Our system
Surgical lung search yielded 945 titles b
BAL
biopsy*
studies that compared cli
among patients who und
those who did not. Thus, w
MDD that measured diagnostic
using an MDD as the dia
maker. The full text of 16
reviewed, and 7 were sele
(128, 130–135) (Table E9
IPF per Table 8 Not IPF
enrolled patients with ILD
Figure 9. Diagnostic algorithm for idiopathic pulmonary fibrosis (IPF). Patients with suspected IPF cause and did not exclud
(i.e., unexplained symptomatic or asymptomatic bilateral pulmonary infiltrates on a chest radiograph HRCT pattern of UIP.
or chest computed tomography [CT] scan, bibasilar inspiratory crackles, and age older than 60 yr), Pooling studies (unw
18 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS
unexplained dyspnea on exertion, and/or cough with evidence of interstitial lung disease (ILD) should that TBBx obtained an ad
be carefully evaluated for potential and/or identifiable causes of ILD, such as domestic and roughly three-fourths of c
occupational environmental exposures, connective tissue disease (CTD), or drug toxicity. Middle- 640 of 825, 77.6%; 95% C
• Patients with suspected IPF (i.e., unexplained symptomatic or asymptomatic
bilateral pulmonary infiltrates on a chest radiograph or chest computed
tomography [CT] scan, bibasilar inspiratory crackles, and age older than 60 yrs.),
unexplained dyspnea on exertion, and/or cough with evidence of interstitial
lung disease (ILD) should be carefully evaluated for potential and/or identifiable
causes of ILD, such as domestic and occupational environmental exposures,
connective tissue disease (CTD), or drug toxicity. Middle-aged adults (>40 yrs.
and <60 yrs.), especially patients with risks for familial pulmonary fibrosis, can
rarely present with the otherwise same clinical scenario as the typical patient
older than 60 yrs. If a potential cause for ILD is identified, the patient should
undergo a thorough evaluation to confirm or exclude other known causes, such
as hypersensitivity pneumonitis, CTD, pneumoconiosis, and iatrogenic causes
(e.g., drug toxicity, irradiation). If a specific diagnosis is not made or no potential
cause for ILD is identified, further evaluation is influenced by the patterns of
high-resolution CT (HRCT) images of the chest and supportive clinical findings
surfaced in the course of multidisciplinary discussion to ascertain or exclude
the diagnosis of IPF. IPF is diagnosed if the appropriate combination of HRCT
patterns and histopathological patterns are present.
*Surgical lung biopsy is not indicated in patients at high risk for intra-, peri-, or postoperative
complications (e.g., severe hypoxemia at rest and/or severe pulmonary hypertension with a diffusion
capacity less than 25% after correction for hemoglobin). Surgical lung biopsy may be unnecessary in
some familial cases.

• The panel has no recommendation for or against conventional transbronchial

biopsy and/or cryobiopsy; however, if performed, histopathology may be
sufficient in selected patients (consult the full version for the remarks and
discussions regarding lung biopsy available at
http://ajrccm.atsjournals.org/content/183/6/788.long).

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 19

 Table 8: Idiopathic Pulmonary Fibrosis Diagnosis
Based Upon HRCT and Biopsy Patterns3

Histopathology Pattern

IPF Suspected*
Indeterminate Alternative
UIP Probable UIP
for UIP Diagnosis

UIP IPF IPF IPF Non-IPF dx

Probable UIP IPF IPF IPF (Likely)** Non-IPF dx

HRCT Pattern Indeterminate Indeterminate for

IPF IPF (Likely)** Non-IPF dx
for UIP IPF***

Alternative IPF (Likely)**/

Non-IPF dx Non-IPF dx Non-IPF dx
Diagnosis Non-IPF dx

*  Clinically suspected of having IPF = Unexplained symptomatic or asymptomatic patterns of bilateral
pulmonary fibrosis on a chest radiograph or chest computed tomography, bibasilar inspiratory crackles,
and age >60 yrs. (Middle-aged adults [>40 yrs. and <60 yrs.], especially patients with risks for familial
pulmonary fibrosis, can rarely present with the otherwise same clinical scenario
as the typical patient >60 yrs.)
**  IPF is the likely diagnosis when any of the following features are present:
 Moderate-to-severe traction bronchiectasis/bronchiolectasis (defined as mild traction
bronchiectasis/bronchiolectasis in four or more lobes including the lingual as a lobe, or moderate to
severe traction bronchiectasis in two or more lobes) in a man >50 yrs. or in a woman >60 yrs.
  Extensive (>30%) reticulation on HRCT and an age >70 yrs.

  Increased neutrophils and/or absence of lymphocytosis in BAL fluid

  Multidisciplinary discussion reaches a confident diagnosis of IPF

*** Indeterminate for IPF

  Without an adequate biopsy is unlikely to be IPF
  With an adequate biopsy may be reclassified to a more specific diagnosis after multidisciplinary
discussion and/or additional consultation

20 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Clinical Course

Diagnostic Algorithm for IPF

• IPF is a fatal lung disease; the natural history is variable and unpredictable:

Figure 8: Natural History of IPF¹

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 21

 • There appear to be several possible natural histories for patients with IPF.
The majority of patients experience a slow but steady worsening of their disease
(‘‘Slow progression’’). Some patients remain stable (‘‘Stable’’), while others
have an accelerated decline (‘‘Rapid progression’’). A minority of patients may
experience unpredictable acute worsening of their disease (lightning bolt), either
from a secondary complication such as pneumonia, or for unrecognized reasons.
This event may be fatal or may leave patients with substantially worsened
disease. The relative frequency of each of these natural histories is unknown.

Vital Statistics
• Deaths from pulmonary fibrosis increase with increasing age.
• Evidence suggests that mortality from pulmonary fibrosis has increased over the
past two decades.
• The mortality burden attributable to IPF is higher than that of some cancers.
• Recent evidence suggests that mortality from IPF in the United States is greater
in the winter months.
• Progressive lung disease is responsible for 60% of IPF deaths.
• Additional causes of IPF-related morbidity and mortality include coronary artery
disease, pulmonary embolism, and lung cancer.

22 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

 IDIOPATHIC
Figure 9: Idiopathic Pulmonary Fibrosis: Rate of PULMONARY FIBROSIS
FVC Decline/Disease | G. RAGHU 6
Progression

0.00
Healthy subjects aged 60 years [65]
–0.05
Change from baseline in FVC or VC L

–0.10

–0.15

–0.20

–0.25

–0.30
Patients with IPF and mild or moderate
–0.35 impairment in lung function

–0.40

–0.45
0 12 24 36 48 60 72
Weeks
Studies measuring FVC Studies measuring VC
Martinez et al. 2014 [16] Daniels et al. 2010 [26] Demedts et al. 2005 [14]
Raghu et al. 2004 [17] King Jr et al. 2014 [31] Azum a et al. 2005 [28]
King Jr et al. 2011 [21] Richeldi et al. 2011 [32] Taniguchi et al. 2010 [29]
Raghu et al. 2013 [22] Richeldi et al. 2014 [33]
Raghu et al. 2008 [24] FDA data, 2010 [64]

• Natural course of lung function decline in placebo-treated patients with

idiopathic pulmonary fibrosis (IPF) from the time of enrollment in clinical
trials to 72 weeks. The decline in forced vital capacity (FVC) from baseline is
approximately 150–200 mL·year–1 (0.15–0.2 L·year–1). The symbols denote the
mean (or median [21, 22]) change from baseline in FVC [16, 17, 21, 22, 24, 26,
31–33, 64] or vital capacity (VC) [14, 28, 29] in the placebo groups of Phase-II
and Phase-III clinical trials in patients with IPF. The black line denotes the mean
decline in FVC in healthy subjects aged 60 yrs. based on FVC measurements
taken between 1987–1989, 1990–1992 and 2011–2013 [65].
• This figure and legend are reproduced with permission from the ERJ.6 The
numbers within the [ ] in this legend are the citation numbers referenced in the
article published.6

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 23

 Mortality Risks And Acute Exacerbation
Table 9: Selected Features Associated with Increased Risk of Mortality in IPF1

Baseline factors* Longitudinal factors

Level of dyspnea** Increase in level of dyspnea**
DLCO, 40% predicted Decrease in FVC by >10% absolute value
Desaturation <88% during 6MWT Decrease in DLCO by >15% absolute value
Extent of honeycombing on HRCT** Worsening of fibrosis on HRCT**
Pulmonary hypertension Pulmonary hypertension

*  Baseline FVC is of unclear predictive value.

**  Currently, there is no uniformity in approach to quantification.

• 5-10% of patients with IPF may have an acute exacerbation of IPF, defined
below. Acute exacerbation of IPF often results in respiratory failure,
hospitalization and death.

Table 10: Proposed Definition and Diagnostic Criteria for Acute Exacerbation
of Idiopathic Pulmonary Fibrosis7

Definition
• An acute, clinically significant respiratory deterioration characterized by evidence of new widespread
alveolar abnormality

Revised Diagnostic Criteria

• Previous or concurrent diagnosis of IPF*
• Acute worsening or development of dyspnea typically, 1-month duration
• Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed
on a background pattern consistent with usual interstitial pneumonia pattern**
• Deterioration not fully explained by cardiac failure or fluid overload

Events that are clinically considered to meet the definition of acute exacerbation of IPF but fail to meet all
four diagnostic criteria owing to missing computed tomography data should be termed “suspected acute
exacerbations.”
* If the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and/or
histopathologic changes consistent with usual interstitial pneumonia pattern on the current evaluation.
** If no previous computed tomography is available, the qualifier “new” can be dropped.
This table is reproduced with permission from AJRCCM.7

24 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

by other immunomodulatory therapies the reduction in centrally adjudicated
(50, 55, 66, 68, 70), and polymyxin confirmed or suspected acute exacerbation
B-immobilized fiber column perfusion of IPF with nintedanib therapy (5.7% on Propos
(56, 71–74). Unfortunately, it is not placebo vs. 1.9% on nintedanib, P = 0.01) Framew
possible to determine whether changes (15). A 107-subject phase 2 trial of Respira
in Figure 10: Proposed
the clinical Conceptual
status of these Frameworkpirfenidone
patients for Evaluation of Acuteearly
was stopped Respiratory
because of a
Deterioration in Idiopathic Pulmonary Fibrosis (IPF)7 To better
knowledge
IPF and im
Acute respiratory deterioration in IPF research in
(typically < 1 month duration) working g
conceptua
deteriorati
Not acute exacerbation definition
Yes
Extra-parenchymal cause identified? Alternative diagnosis (e.g., pneumothorax,
pleural effusion, pulmonary embolism) exacerbatio
changes ar
No
Removin
New, bilateral GGO/consolidation on CT? Acute exacerbation of IPF
Definition
Yes
(not fully explained by cardiac failure or There was
fluid overload) Triggered Acute Exacerbation definition
(e.g., infection, post-procedural/post- exacerbati
operative, drug toxicity, aspiration)
No any acute
by new bi
Idiopathic Acute Exacerbation opacificati
Not acute exacerbation
Alternative diagnosis (e.g., infection, aspiration,
No trigger identified explained
drug toxicity, congestive heart failure) overload.
the Berlin
Figure 3. Proposed conceptual framework for evaluation of acute respiratory deterioration in idiopathic distress sy
pulmonary fibrosis (IPF). Acute respiratory deterioration of IPF (defined as “typically ,1 month
exclude is
in duration”) can be categorized as extraparenchymal (e.g., pulmonary embolism, pneumothorax,
• Acute respiratory deterioration of IPF (defined as “typically ,1 month in There was
pleural effusion) or parenchymal. Parenchymal causes that demonstrate new bilateral ground-glass
duration”)
opacification can be categorized
(GGO)/consolidation as extraparenchymal
on computed (e.g.,is pulmonary
tomography (CT) that embolism,
not fully explained by cardiac
the literat
pneumothorax, pleural effusion) or parenchymal. Parenchymal causes that
failure or fluid overload are categorized as acute exacerbations of IPF, regardless of the presence or summariz
or biologi
demonstrate
absence of a knownnew bilateral
trigger ground-glass
(e.g., infection). opacification
Acute exacerbations are (GGO)/consolidation
further categorized as triggered
acute exacerbation or idiopathic acute exacerbation, depending on whether an underlying trigger for idiopathic
acuteonexacerbation
computedistomography
found. (CT) that is not fully explained by cardiac failure or events. De
fluid overload are categorized as acute exacerbations of IPF, regardless of the
presence or absence of a known trigger (e.g., infection). Acute exacerbations
Concise Clinicalcategorized
are further Review as triggered acute exacerbation or idiopathic acute
exacerbation, depending on whether an underlying trigger for acute
exacerbation is found.
• This figure is reproduced with permission from AJRCCM.7

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 25

 Treatment
• Two antifibrotic medications, pirfenidone and nintedanib have been shown
to slow the rate of decline in FVC over time among patients with IPF with
mild to moderate impairment in pulmonary function. Similar effects have
been demonstrated in patients with mild impairment in lung function and
those with advanced disease. Treatment with an antifibrotic was given a
conditional recommendation for use, moderate confidence in estimate of
effect. The recommendation for lung transplantation in appropriate patients
with IPF is strong.

Table 11: Pharmacological Treatment Recommendations

(Updated in the 2015 Guideline)
Strong Conditional

For Against For Against

Nintedanib X

Pirfenidone X

Antiacid treatment X

Dual ERA (bosentan, macitentan ) X

Sildenafil X

Warfarin X

Combination prednisone + azathioprine +

X
N-Acetylcysteine

N-Acetylcysteine X

Selective ERA (ambrisentan) X

Imatinib X

26 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

 Table 12: Other Treatment Recommendations as Per the 2011 IPF Guideline
(These Recommendations were not Updated in the 2015 Guideline)
Strong Conditional*

For** Against** For** Against**

Appropriate patients with IPF should undergo

X
lung transplantation

Supplemental O2 for IPF patients with

X
resting hypoxemia

Pulmonary rehabilitation X

Treatment of pulmonary hypertension X

High dose corticosteroids for acute

X
exacerbation IPF

Corticosteroid monotherapy X

Colchicine X

Cyclosporine A X

Corticosteroid and immunomodulatory

X
therapy (azathioprine or cyclophosphamide)

Etanercept X

Anticoagulation X

Mechanical ventilation in patients with

X
respiratory failure due to IPF

*  Conditional was stated as “weak” in the 2011 guideline

**  “For” was stated as “YES” and “Against” as “NO” in the 2011 guideline

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 27

 Identification and Treatment of Selected Complications
and Co-morbid Conditions in IPF
• While obesity, emphysema, lung cancer and obstructive sleep apnea (OSA)
are among the co-morbid conditions associated with IPF, specific questions
regarding treatment for these conditions were not addressed in the guidelines.
• Acute exacerbation of IPF
- The majority of patients with acute exacerbation should be treated with
corticosteroids, but corticosteroids may not be reasonable in a minority
(weak recommendation).
• Pulmonary hypertension
- Echocardiography is not accurate in estimating pulmonary hemodynamics
in patients with fibrotic lung disease and should not be relied upon to
assess presence and severity of PH.
- Right heart catheterization is required to confirm presence of PH.
- Conditional recommendation against treatment of PH in patients with IPF
reassessment deferred in 2015 guideline.
- If treating pulmonary HTN, strong recommendation against using
ambrisentan (potential for harm).
• GERD
- Conditional recommendation for anti-acid treatment in patients with IPF
(very low confidence).
• Lung Cancer
- No routine recommendation on screening/surveillance imaging can be
made based on lack of data.
• Extrapulmonary manifestations of some genetic forms of IPF
- Bone marrow failure, liver disease.

28 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Palliative Care
• Palliative care should be considered an adjunct to disease-focused care.
• Corticosteroids and thalidomide may be beneficial for chronic cough.
• Chronic opioids may be used for severe dyspnea and cough with careful
monitoring for side effects.
• Advanced directives and end-of-life care issues should be addressed in the
ambulatory setting in all patients with IPF, particularly those with severe
physiologic impairment and co-morbid conditions.
• Hospice care should be considered for patients who are bed bound due to IPF.

Monitoring the Clinical Course of Disease

• Increasing respiratory symptoms, worsening PFTs, progressive fibrosis on HRCT
or acute respiratory decline may be manifestations of disease progression.
• Disease progression is usually monitored over periods of 3-6 months although
optimal time interval for repetition of FVC and DLCO has not been formally
investigated.
• For patients manifesting acute respiratory worsening, the possibility of acute
exacerbation of IPF should be considered and prompt evaluation for alternative
etiologies of acute worsening such as pulmonary embolism, pneumothorax,
respiratory infection or aspiration should ensue.
• Oxygen saturation at rest and with exertion should be measured at baseline and
during follow up at 3-6 month intervals.
- Desaturation < 88% during formal 6MWT generally used to prescribe
supplemental O2.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 29

 Summary of Clinical Management of IPF

Figure 11: Schematic Pathway for Clinical Management of Patients with IPF
(Modified from the 2011 Guideline)

If increased risk of mortality

(Table 9), evaluate and list for
lung transplantation at the time
of diagnosis

TREATMENT DISEASE
CONSIDERATIONS PROGRESSION
(see text)
PHARMACOLOGICAL Monitor every 4-6 months or
Discuss therapies with conditional sooner as clinically indicated
Dx of IPF recommendations (pirfenidone,
nintedanib, anti acid)
(Figure 7 recommendations with patients Evaluate and list for
and based on their individual values lung transplantation
Table 8) and preferences

NON-PHARMACOLOGICAL ACUTE EXACERBATION

*Oxygen supplementation Corticosteroids
(if hypoxemic)
*Pulmonary rehabilitation
RESPIRATORY FAILURE
(Due to progression of IPF)
COMORBIDITIES
*Pulmonary hypertension
*Gastroesophageal
SYMPTOM CONTROL

Patients should be made aware of available clinical

trials for possible enrollment at all stages.

30 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

Conclusion
This pocket guideline for diagnosis and management of IPF includes evidence based
recommendations updated for diagnosis (2018) and treatment (2015) from the
2011 guidelines.
• The panel that made the 2018 recommendations for the diagnosis of IPF
recognized the urgent need for future studies to refine and validate diagnostic
approaches in ILD. These include investigations into the roles of clinical
observations, HRCT, bronchoscopy, histopathology, biomarkers, machine
learning tools and genetic testing.
• Further evidence from studies completed since and newer evidence when
available will need to be synthesized and discussed by an expert committee
and recommendations updated in future guidelines will be incorporated in
subsequent versions of this pocket guide.

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 31

 References
The readership is encouraged to read the original, official ATS documents (guidelines) published in
the AJRCCM:
1. Raghu G, Collard HR, Egan JJ. 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: 37.
2. Raghu G, Rochwerg B, Zhang Y, Cuello Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR,
Cunningham W, Homma S, Jonkoh T, Martinex FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M,
Theodore A, Wells AU, Hoogsteden H, Schunemann HJ. An official ATS/ERS/JRS/ALAT clinical practice
guideline: Treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.
Am J Respir Crit Care Med 2015; 192: 16.
3. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Reyerson CJ, Lederer DJ, Behr J, Cottin V, Danoff SK,
Morell F, Flaherty KR, Wells A, Martinex FJ, Azuma A. Diagnosis of Idiopathic Pulmonary Fibrosis: An
official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2018; 198: 25.

Additional References
4. Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR. Idiopathic pulmonary fibrosis in US
Medicare beneficiaries aged 65 and older: incidence, prevalence, and survival, 2001-11. Lancet Respir
Med 2014; 2: 7.
5. Richeldi L, Wilson KC, Raghu G. Diagnosing idiopathic pulmonary fibrosis in 2018: bridging
recommendations made by experts serving different societies. Eur Respir J 2018; 52.
6. Raghu G. Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years.
Eur Respir J 2017; 50.
7. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, Lee JS, Maher TM, Wells AU,
Antoniou KM, Behr J, Brown KK, Cottin V, Flaherty KR, Fukuoka J, Hansell DM, Johkoh T, Kaminski N,
Kim DS, Kolb M, Lynch DA, Myers JL, Raghu G, Richeldi L, Taniguchi H, Martinez FJ. Acute exacerbation
of Idiopathic Pulmonary Fibrosis. An International Working Group Report. AJRCCM 2016; 194: 11.

32 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS

GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS 33
SC-US-69626 To improve health worldwide by advancing research,
clinical care and public health in respiratory disease