1 Practice Guidelines for the Diagnosis of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis

[ Diffuse Lung Disease Special Features ]
Integration and Application of Clinical
Practice Guidelines for the Diagnosis of
Idiopathic Pulmonary Fibrosis and Fibrotic
Hypersensitivity Pneumonitis
Daniel-Costin Marinescu, MD; Ganesh Raghu, MD; Martine Remy-Jardin, MD; William D. Travis, MD;
Ayodeji Adegunsoye, MD; Mary Beth Beasley, MD; Jonathan H. Chung, MD; Andrew Churg, MD; Vincent Cottin, MD;
Ryoko Egashira, MD; Evans R. Fernández Pérez, MD; Yoshikazu Inoue, MD; Kerri A. Johannson, MD;
Ella A. Kazerooni, MD; Yet H. Khor, MD; David A. Lynch, MD; Nestor L. Müller, MD; Jeffrey L. Myers, MD;
Andrew G. Nicholson, MD; Sujeet Rajan, MD; Ryoko Saito-Koyama, MD; Lauren Troy, MD; Simon L. F. Walsh, MD;
Athol U. Wells, MD; Marlies S. Wijsenbeek, MD; Joanne L. Wright, MD; and Christopher J. Ryerson, MD
Recent clinical practice guidelines have addressed the diagnosis of idiopathic pulmonary fibrosis
(IPF) and fibrotic hypersensitivity pneumonitis (fHP). These disease-specific guidelines were
developed independently, without clear direction on how to apply their respective recommendations concurrently within a single patient, where discrimination between these two fibrotic
interstitial lung diseases represents a frequent diagnostic challenge. The objective of this review,
created by an international group of experts, was to suggest a pragmatic approach on how to
apply existing guidelines to distinguish IPF and fHP. Key clinical, radiologic, and pathologic features described in previous guidelines are integrated in a set of diagnostic algorithms, which then
are placed in the broader context of multidisciplinary discussion to guide the generation of a
consensus diagnosis. Although these algorithms necessarily reflect some uncertainty wherever
strong evidence is lacking, they provide insight into the current approach favored by experts in
the field based on currently available knowledge. The authors further identify priorities for future
research to clarify ongoing uncertainties in the diagnosis of fibrotic interstitial lung diseases.
CHEST 2022; 162(3):614-629
KEY WORDS: clinical practice guidelines; hypersensitivity pneumonitis; idiopathic pulmonary fibrosis;
multidisciplinary discussion; usual interstitial pneumonia
ABBREVIATIONS: ALAT = Latin American Thoracic Association; ATS =
American Thoracic Society; CTD-ILD = connective tissue disease-related
interstitial lung disease; CPG = clinical practice guideline; fHP = fibrotic
hypersensitivity pneumonitis; FPF = familial pulmonary fibrosis; IA =
inciting antigen; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; JRS = Japanese Respiratory Society; MDD = multidisciplinary discussion; NSIP = nonspecific interstitial pneumonia; UIP =
usual interstitial pneumonia
AFFILIATIONS: From the Department of Medicine (D.-C. M. and C. J.
R.), the Department of Radiology (N. L. M.), University of British
Columbia, the Department of Pathology (A. C.), Vancouver General
Hospital, University of British Columbia, the Centre for Heart Lung
Innovation (D.-C. M. and C. J. R.), St. Paul’s Hospital, the Department
of Pathology (J. L. W.), St. Paul’s Hospital and University of British
Columbia, Vancouver, BC, the Department of Medicine (K. A. J.),
University of Calgary, Calgary, AB, Canada; the Center for Interstitial
Lung Diseases (G. R.), Department of Medicine, University of Washington, Seattle, WA, the Department of Pathology (W. D. T.), Memorial Sloan Kettering Cancer Center, the Department of Pathology
614 Special Features
(M. B. B.), Molecular and Cell-Based Medicine, Icahn School of
Medicine at Mount Sinai, New York, NY, the Section of Pulmonary
and Critical Care (A. A.), Department of Medicine, the Department of
Radiology (J. H. C.), University of Chicago, Chicago, IL, the Division of
Pulmonary, Critical Care and Sleep Medicine (E. R. F. P.), Department
of Medicine, the Department of Radiology (D. A. L.), National Jewish
Health, Denver, CO, the Departments of Radiology & Internal Medicine (E. A. K.), University of Michigan Medical School, the Department
of Pathology (J. L. M.), University of Michigan, Ann Arbor, MI; the
Department of Thoracic Imaging (M. R.-J.), Institut Coeur Poumon,
Boulevard Jules Leclercq, Lille, the National Reference Center for Rare
Pulmonary Diseases (V. C.), Louis Pradel Hospital, Hospices Civils de
Lyon, Claude Bernard University Lyon, Lyon, France; the Department
of Radiology (R. E.), Faculty of Medicine, Saga University, Saga, the
Clinical Research Center (Y. I.), National Hospital Organization
Kinki-Chuo Chest Medical Center, Osaka, the Department of
Pathology (R. S.-K.), Tohoku University Graduate School of Medicine, Miyagi, Japan; the Respiratory Research@Alfred (Y. H. K.),
[ 162#3 CHEST SEPTEMBER 2022 ]
Fibrotic interstitial lung disease (ILD) includes a variety
of entities in which a precise diagnosis informs therapy
and prognosis. Idiopathic pulmonary fibrosis (IPF) and
fibrotic hypersensitivity pneumonitis (fHP) are common
distinct causes of ILD; however, these often have
overlapping characteristics that make their separation
one of the most challenging diagnostic dilemmas
encountered by ILD clinicians.1 Nevertheless, the
distinction between these two entities remains critical. In
IPF, management centers on antifibrotic therapy,
whereas antigen remediation represents a key initial
intervention in fHP, commonly followed by
immunosuppressive therapy that is harmful and should
be avoided in IPF.2-9 Some patients with fHP also benefit
from antifibrotic agents, but unlike IPF, this medication
is considered secondarily in the setting of progressive
disease.10 Although fHP historically has been associated
with comparatively better outcomes, increasing evidence
suggests that this entity may have similar rates of
progression as IPF.11
The recent American Thoracic Society (ATS)/European
Respiratory Society/Japanese Respiratory Society (JRS)/
Latin American Thoracic Association (ALAT) guidelines
for IPF and its 2022 update as well as both the ATS/JRS/
ALAT and CHEST guidelines for fHP describe the
approach to these two conditions with carefully
developed diagnostic algorithms5-8 but do not specify
how these multiple algorithms should be applied within
a single patient. The objective of this international
working group was to develop a pragmatic approach
that integrates current IPF and fHP guidelines in a
manner that is applicable in a variety of clinical settings.
The current work complements the evidence-based
guidelines for these two distinct entities and does not
replace or supersede them; it is intended to facilitate ILD
Central Clinical School, Monash University, Melbourne, the Department of Respiratory and Sleep Medicine (Y. H. K.), Austin Health,
Heidelberg, VIC, the Department of Respiratory and Sleep Medicine
(L. T.), Royal Prince Alfred Hospital, Camperdown, NSW, Australia;
the Department of Histopathology (A. G. N.), Royal Brompton and
Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust, the
National Heart and Lung Institute (A. G. N. and S. L. F. W.), Imperial
College, the Interstitial Lung Disease Unit (A. U. W.), Royal Brompton
Hospital, London, England; the Department of Chest Medicine (S. R.),
Bombay Hospital Institute of Medical Sciences, Bhatia Hospital,
Mumbai, India; and the Center of Excellence for Interstitial Lung
Diseases and Sarcoidosis (M. S. W.), Department of Respiratory
Medicine, Erasmus University Medical Center, Rotterdam, The
Netherlands.
CORRESPONDENCE TO: Daniel-Costin Marinescu, MD; email: daniel.
[email protected]
Copyright Ó 2022 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: https://doi.org/10.1016/j.chest.2022.06.013
chestjournal.org
diagnosis for the common clinical situation in which IPF
and fHP are two leading diagnoses being considered.
The review is structured around the clinical, radiologic,
and pathologic assessment of fibrotic ILD, recognizing
that these domains should be evaluated concurrently in
a multidisciplinary discussion (MDD) and carefully
integrated at multiple steps of the diagnostic process.
Throughout this review, radiologic and pathologic
patterns of usual interstitial pneumonia (UIP) and fHP
are delineated carefully from corresponding clinical
diagnoses of IPF and fHP, emphasizing that these
radiologic and pathologic patterns frequently suggest
these diseases, but also can occur in a variety of other
diagnoses.
Clinical Assessment
Background
Several clinical features are common to both IPF and
fHP, whereas some can help to distinguish these two
entities (Fig 1).5-7 Commonly shared features include
dyspnea, cough, gastroesophageal reflux disease, and
inspiratory crackles. Although originally described in
IPF,12 it is also recognized increasingly that a family
history of ILD and the presence of abnormal genetic
biomarkers also occur in fHP.13 Similarly, features of
airflow obstruction can occur in fHP because of airways
involvement but can also occur in IPF because of
concomitant emphysema in patients with an extensive
smoking history.
Clinical Features of IPF
Features that favor a diagnosis of IPF include male sex,
age older than 60 years, and a history of cigarette
smoking.5 The likelihood of IPF further increases with
increasing age and when features are seen in
combination (eg, an older male smoker), representing a
classic IPF clinical profile.14,15 Multivariate models
incorporating key clinical features, often alongside
important radiologic findings, may help to estimate the
pretest probability of IPF in a more reproducible way
and thus inform decisions on whether to pursue invasive
investigations.16
Clinical Features of fHP
In contrast to IPF, fHP lacks a clear age or sex
predilection, and identification of a causative antigen is
central to establishing a high pretest probability.6,7,17
Exposure assessment for fHP includes a comprehensive
systematic history of both home and occupational
exposures, ideally complemented by locally adapted
615
Favors IPF
Favors fHP
No known sex predominance
Any age
Smoker, former smoker, or nonsmoker
Male predominance
Older age (eg, > 60 y)
Smoker or former smoker
Demographics and
smoking history
Clinical/laboratory characteristics
Seen in both IPF and fHP
Family history
and genetics
Family history of fibrosis and/or predisposing genetic
factors (eg, MUC5B, telomere biology disorders)
Symptoms
Dyspnea and cough
Insidious onset (except acute exacerbation)
Absence of symptoms to suggest multisystem
disease
Exposure history
No identified antigen
No identifiable or indeterminate antigen
Potentially worsening with re-exposure
Identified antigen
May stabilize or improve with antigen avoidance
Antigen Assessment
Inspiratory squawks
IA likelihood increased by:
• Strength of association
• Consistency of association
• Temporality: Exposure parallels
disease development/worsening
• Dose response
Consider:
• IA likelihood in epidemiologic
context (geography, climate,
season)
• Longitudinal and iterative IA
assessment over time
• Use of structured questionnaire
Physical exam
findings
Inspiratory crackles
Clubbing (may be more common in IPF)
Physiologic features
Restrictive ventilatory defect
Obstructive or mixed pattern (eg, smoker in IPF, fHP)
Laboratory findings
Negative or only weakly positive autoimmune serologic
findings BAL neutrophilia and absence of lymphocytosis
BAL lymphocytosis
Disease behavior
Typically progressive over months to y
May be stable and/or slowly progressive over y
Pretest probability of
clinical diagnosis of
IPF or fHP
IPF
Classic IPF clinical profile
Male, older age
Smoker or former smoker
Restrictive physiology
No identifiable antigen
fHP
Indeterminate clinical profile, intermediate between IPF and fHP
Overlapping and/or indeterminate features
Classic fHP clinical profile
Male or female of any age
Smoker, former smoker or nonsmoker
Restrictive physiologic features
Inspiratory squawks
Identifiable antigen exposure that temporally parallels disease
Figure 1 – Diagram showing an approach to assessment of clinical features in patients with IPF, fHP, or both as primary diagnostic considerations in
the absence of alternative causes (eg, after exclusion of connective tissue disease-related interstitial lung disease or inorganic exposures). fHP ¼ fibrotic
hypersensitivity pneumonitis; IA ¼ inhaled antigen; IPF ¼ idiopathic pulmonary fibrosis.
questionnaires,7,18 and possibly accompanied by serumspecific IgG testing in patients with an indeterminate
exposure.7,19 Any exposure should be considered along a
probability spectrum based on the strength of the
identified antigen’s association with fHP, the intensity of
the exposure, and the timing of exposure in relation to
disease activity.7 The strength of an antigen’s association
with fHP is driven by the frequency with which the
disease actually develops in patients with the exposure.
For example, birds and molds are well-established causes
of fHP that should be regarded with high suspicion,
whereas less robustly established exposures may have
minimal impact on the pretest probability of fHP.18,20
The intensity of the exposure can be estimated through
detailed history, with greater importance placed on
exposures that have a greater likelihood of large
amounts of aerosolized antigen (eg, living with a pet bird
typically yields a higher-intensity exposure and greater
suspicion than using down bedding). The timing of an
exposure in relation to disease activity can be considered
in terms of disease onset (ie, exposure predates disease),
association of disease activity with periods of more
intense exposure, and stabilization and occasionally
improvement with exposure avoidance, recognizing that
fHP can progress even after antigen remediation.7,18
Despite some patients with fHP having a clear exposure
history, many patients with other ILDs also report
616 Special Features
exposures without these identified as likely causative
antigens,21 emphasizing that a potential exposure does
not necessarily equate to a diagnosis of fHP and must be
integrated with other features that can increase or
decrease the likelihood of fHP. Conversely, a lack of
exposure does not rule out fHP, with no clear identified
antigen in approximately half of all patients.6,7
Lymphocytosis (especially > 30%) in BAL fluid
increases the likelihood of fHP compared with IPF, but
this finding may lack sensitivity in patients with more
established fibrosis and may be less able to distinguish
fHP from other non-IPF causes.22 Inspiratory squeaks
on chest auscultation also are more suggestive of fHP.23
Similar to IPF, multivariate models predicting the
likelihood of fHP have been developed, but these rely
heavily on radiologic findings and generally include few
clinical features apart from the presence or absence of a
causative antigen, again highlighting the importance of
exposure assessment.24-26
Proposed Integrated Approach
Existing guidelines do not emphasize specific clinical
phenotypes5-7; however, this is a common approach
used by experienced clinicians. We propose approaching
the clinical pretest probability of disease as described in
Figure 1 when both IPF and fHP are prominent
diagnostic considerations, using all available features to
[ 162#3 CHEST SEPTEMBER 2022 ]
form a clinical gestalt and ideally categorizing patients
into a more distinct clinical phenotype that favors IPF,
favors fHP, or is indeterminate. An indeterminate
profile, where IPF and fHP are approximately equally
likely, may emerge under a variety of conditions. This
most commonly includes patients with overlapping
features (eg, an older male smoker with a possible
exposure) or features that are relatively indeterminate
(eg, lacking distinguishing clinical findings of either IPF
or fHP). Regardless of the clinical phenotype, it is critical
that all features are contextualized and integrated with
radiologic findings, which is especially helpful in the
setting of an indeterminate clinical profile.
Radiologic Assessment
Background
High-resolution CT imaging is a central and essential
component of ILD classification. Although a radiologic
UIP pattern frequently is associated with IPF, this
pattern also may occur in other clinical diagnoses such
as connective tissue disease and fHP, making distinction
between these entities difficult on the basis of imaging
alone.8 Conversely, although the presence of fibrosis and
small airways abnormality is suggestive of fHP, these
features can also be seen concurrently in other ILDs.
This includes IPF, in which concomitant asthma,
smoking, or gastroesophageal reflux disease can cause
mosaic attenuation in a significant minority of
patients,27-29 as well as connective tissue disease-related
ILD (CTD-ILD) and particularly rheumatoid arthritis.30
This lack of specificity of both UIP and fHP radiologic
patterns indicates the importance of considering these
patterns within the clinical context.
Radiologic Features of a UIP Pattern
UIP is typified by basal-predominant subpleural
reticulation, traction bronchiectasis, and honeycombing
and is associated with a UIP pattern on histologic
analysis in > 95% of patients (Fig 2A, 2B).5,8,31,32
Probable UIP shares the same features, but without the
presence of honeycombing, and is also highly likely to be
Figure 2 – High-resolution CT scan images showing examples of radiologic features relevant to identification of a usual interstitial pneumonia (UIP)
pattern of fibrosis. A, B, Axial and coronal images of a typical UIP pattern showing basal and subpleural reticulation with honeycombing (arrows),
defined by as few as two adjacent honeycomb cysts along the pleural surface or stacked on one another.31 C, D, Axial and coronal images of a probable
UIP pattern showing basal and subpleural reticulation with traction bronchiectasis, but without honeycombing or considerable ground-glass opacity.
Although honeycombing occasionally is challenging to identify and has some interreader variation,32 the impact of this difference on diagnosis is
mitigated by both definite and probable UIP patterns being sufficient for a presumptive diagnosis of IPF without pathologic confirmation.
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associated with UIP on histologic analysis in patients
with a high clinical likelihood of IPF (Fig 2C, 2D).8,33-35
Although UIP characteristically is basal and subpleural
predominant,35,36 the distribution occasionally is nearly
uniform from apex to base,8,36,37 which still may
otherwise be consistent with UIP or probable UIP.
Distributions that argue against UIP include the
presence of peribronchovascular disease and sparing of
the costophrenic angles; however, current IPF guidelines
do not explicitly discuss how to consider these features,
given the limited available evidence.
An indeterminate pattern for UIP describes difficult
cases in which substantial uncertainty exists, either
because features are mild and not suggestive of a specific
cause or because a mixture of features, distribution, or
both exists that raises significant suspicion for another
pattern (Fig 3A, 3B). For example, although
predominantly peribronchovascular involvement suggests
a pattern alternative to UIP, it is unclear whether minor
peribronchovascular extension of subpleural fibrosis
could still represent UIP, and some experts may
categorize this as indeterminate for UIP (Fig 3C, 3D).
Similarly, complete sparing of the extreme costophrenic
angles is unlikely to represent UIP and favors fHP, but
the interpretation of relative sparing of the costophrenic
angles is more challenging and also might be categorized
as indeterminate for UIP (Fig 3E, 3F).
The alternative category for UIP encompasses two
radiologic phenotypes. The first is characterized by the
presence of features suggesting a different pattern from
UIP (Fig 4A), such as nonspecific interstitial pneumonia
(NSIP; eg, significant ground-glass opacity). The second
phenotype still meets all criteria for a radiologic pattern
of UIP but with additional superimposed features that
suggest a clinical diagnosis other than IPF (Fig 4B-F).
We propose that such patterns that otherwise still meet
criteria for definite or probable UIP be classified as such,
a practice that emphasizes the negative prognostic
significance of a radiologic UIP pattern in non-IPF ILD.
For example, CTD-ILD is suggested by the anterior
Figure 3 – A, B, High-resolution CT
scan patterns that may be classified as
indeterminate for usual interstitial
pneumonia (UIP) include minimal
disease where it is difficult to characterize specific features (A) and cases
where ground-glass opacity and reticulation are present in relatively similar
amounts (B). In addition, some challenging distributions in the setting of
features otherwise consistent with UIP
include (C-D) the presence of a minor
peribronchovascular component of
disease (thin arrows) and (E-F) relative sparing of the extreme costophrenic angles, where fibrosis is
typically prominent in UIP. Although
not explicitly addressed in the idiopathic pulmonary fibrosis guidelines,
experts often categorize such cases as
indeterminate for UIP.
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[ 162#3 CHEST SEPTEMBER 2022 ]
upper lobe, straight edge, or exuberant honeycombing
signs,38,39 as well as a dilated esophagus and osseous
erosions,40 whereas pleural plaques suggest asbestosis.41
Radiologic Features of an fHP Pattern
Both guidelines addressing fHP emphasize that a
radiologic pattern of fHP requires a combination of
fibrosis and small airways abnormality, although minor
differences exist between guidelines in the definitions of
typical and compatible patterns of fHP.6,7 The most
apparent disparity is in the distribution of disease. The
ATS/JRS/ALAT guidelines emphasize a mid, mid and
lower, or diffuse lung zone involvement in the
craniocaudal axis as most typical of fHP, whereas the
CHEST guidelines do not consider distribution and
assign all forms of mosaic attenuation other than the
three-density pattern to the less specific compatible
category. Despite this difference, both guidelines agree
that mid or upper lung predominance favors fHP
compared with IPF,31,42-44 whereas a purely basal
distribution does not rule out fHP. Additionally, diffuse
involvement in the axial plane, or at least the presence of
a distinct peribronchovascular component, is also
suggestive of fHP. Given the lack of strong evidence, we
propose a simplified approach to distribution
comparable with the CHEST guidelines, emphasizing
that distribution is less critical in determining a fHP
pattern compared with signs of small airways
abnormality.
Small airways abnormality is the hallmark of fHP and is
suggested by centrilobular nodularity or mosaic
attenuation, a term that can encompass various
combinations of hypoattenuating, preserved, and
hyperattenuating lung lobules on inspiratory or
expiratory imaging (Fig 5). Different forms of mosaic
attenuation suggest fHP with varying degrees of
sensitivity and specificity, leading to different levels of
confidence in identifying an fHP pattern.45 The threedensity pattern (Fig 6A) is a special case of mosaic
attenuation where hypoattenuating, normal, and
hyperattenuating lobules are present in close proximity
on inspiratory imaging. Both guidelines emphasize that
Figure 4 – High-resolution CT scan
images showing examples of patterns
alternative to usual interstitial pneumonia (UIP). A, This may be because
of excessive ground-glass opacity
exceeding reticulation, present outside
areas of fibrosis, or both, recognizing
that this also can represent a superimposed process such as infection or
acute exacerbation on any other
pattern. Although ancillary radiologic
features suggestive of a non-idiopathic
pulmonary fibrosis cause of disease
also were categorized previously as an
alternative to UIP, we suggest that
such patterns that otherwise still meet
criteria for definite or probable UIP
are classified as such (eg, UIP with
features suggesting connective tissue
disease-related interstitial lung disease
[CTD-ILD]). B-F, This includes instances of a dilated esophagus (arrow)
(B) and exuberant honeycombing
suggestive of CTD-ILD (C, D), as well
as bilateral calcified pleural plaques
(arrows) suggestive of asbestosis (E, F).
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619
Hypoattenuating Lobules
Well-demarcated lobules of low-density
lung surrounded by normal lung
Normal (preserved) Lobules
Hyperattenuating Lobules
Well-demarcated lobules of normal
density surrounded by
low- or high-attenuation lobules
Well-demarcated lobules of patchy GGO
surrounded by normal lung
Pathophysiology: Low-density due to
hypoperfusion, airway disease,
or both
Constricted vessels
Increase in attenuation
on expiratory views
or
Pathophysiologic Findings: GGO suggesting
infiltrative disease
Airway disease
Lack of normal increase
in attenuation on expiratory
views
“Mosaic perfusion”
“Air trapping”
Hypoattenuating Lobules + Normal
Mosaic
attenuation
Normal + Hyperattenuating Lobules
Three-Density Sign = Hypoattenuating Lobules + Normal + Hyperattenuating Lobules
Figure 5 – Diagram showing definitions of forms of mosaic attenuation, an umbrella term indicating a combination of hypoattenuating, normal, and/
or hyperattenuating lobules on high-resolution CT imaging. GGO ¼ ground-glass opacity.
the three-density pattern and diffuse centrilobular
nodularity are highly specific features of fHP when
associated with fibrosis. Other forms of mosaic
attenuation involve pairings of hypoattenuating,
preserved, and hyperattenuating lung (Fig 6B-D), with
these being less specific and not clearly standardized.
The presence of hypoattenuating lobules on inspiratory
imaging is often indeterminate as a sign of airways
disease, and expiratory imaging is suggested to confirm
air trapping. An increasing number of lobules involved
in these patterns across three or more lobes increases the
specificity for fHP at the expense of sensitivity, although
this finding is based on a single study and requires
validation.46 In the absence of a three-density pattern,
the presence of mosaic attenuation in three lobules or
more and five lobules or more in at least three lobes
Figure 6 – High-resolution CT scan
images showing examples of radiologic
features relevant to identification of a
fibrotic hypersensitivity pneumonitis
pattern of fibrosis. A, Three-density
pattern showing ground-glass opacification (thin white arrows), lobules of
low attenuation (thick black arrows),
and normal-density lung parenchyma
(thin black arrows) all coexisting
within the same lobe. B, Lobules of
hyperattenuating ground-glass opacification surrounded by normal lung
(arrows). C, D, Hypoattenuating lobules suggestive of underlying air trapping alongside normal lung on
inspiratory imaging (C), with subsequent lack of increased attenuation on
expiration (arrows) (D), confirming
the presence of air trapping.
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[ 162#3 CHEST SEPTEMBER 2022 ]
provides reasonable thresholds for compatible and
typical patterns, respectively; however, this currently
remains largely a research tool, and clinical assessment is
typically more qualitative. Both guidelines also describe
an indeterminate for fHP category that lacks any signs
suggestive of small airways abnormality or other
findings to suggest an alternative diagnosis. This
category represents a collection of patterns, including
UIP and NSIP, that may be associated with a clinical
diagnosis of fHP, despite lacking more specific airways
features.6,7
Proposed Integrated Approach
The integrated approach to assessing the radiologic
probability of IPF and fHP is shown in Figure 7,
illustrating that imaging of these two diseases exists as a
continuum rather than the discrete UIP and fHP
patterns described in each of the guidelines. Imaging
consistent with definite or probable UIP, in the
appropriate clinical context, yields a high enough
likelihood of a histopathologic UIP pattern such that
further invasive testing is unnecessary. Imaging that is
typical of or compatible with an fHP pattern can lead to
a diagnosis of fHP but with the need to also consider a
differential diagnosis of either CTD-ILD or IPF with
obstructive airways disease, depending on the clinical
context. The indeterminate radiologic pattern
encompasses a variety of possibilities that are more likely
to be clarified by histopathologic analysis, particularly
when combined with an indeterminate clinical profile.
Pathologic Assessment
Background
Lung biopsy has traditionally been sought to clarify the
diagnosis in patients with contradictory or
indeterminate clinical and radiologic findings. Surgical
lung biopsy is commonly used to obtain lung tissue,
although the less invasive transbronchial lung
cryobiopsy is increasingly used and represents an
acceptable alternative in experienced centers.8 However,
high-confidence histologic diagnoses are made more
often with surgical lung biopsy than with transbronchial
lung cryobiopsy because larger biopsy samples are more
likely to show diagnostic abnormalities.46-50 Similarly,
the risk of sampling error and discordant histologic
patterns from different biopsies indicate the importance
of acquiring multiple biopsy samples.51,52 Given that
Fibrosis on HRCT imaging
Features inconsistent with UIP and fHP OR
Features consistent with other fibrosing process
Alternative to UIP &
Alternative to fHP
Favors UIP pattern
Indeterminate features
Favors fibrotic HP pattern
Distribution
• Craniocaudal: Basal predominant, occasionally diffuse,
includes costophrenic angles
• Axial: Subpleural predominant
Fibrosis
• Reticular pattern and traction bronchiectasis
• Ground glass may be present, but is not the dominant feature
Subtle reticulation not suggestive of a specific cause or
suggestion of UIP pattern but with atypical features, including:
• Presence of some peribronchovascular involvement
• Relative sparing of extreme costophrenic angles
• Extent of ground-glass opacity similar to that of reticulation
Distribution
• Could be variable, but:
- Craniocaudal: Mid or upper lung zone is suggestive
- Axial: Peribronchovascular involvement is suggestive
Fibrosis
• Reticular pattern and traction bronchiectasis
• Honeycombing may be present but does not predominate
AND
Not enough signs of small airways disease to suggest fHP
• Hypoattenuating lobules on inspiratory imaging suggestive of
gas trapping, but without expiratory imaging to confirm
• Few hypoattenuating or preserved lobules
• No signs of small airways disease
Absence of signs of small airways disease
AND
Consider non-IPF &
non-fHP diagnoses,
including:
• Sarcoidosis
• Silicosis
• PPFE
• Other
AND
Presence of signs of small airways disease
Small airways signs
High confidence
Honeycombing present
Moderate confidence
Honeycombing absent
UIP
Probable UIP
Radiologic
pattern
Likelihood of
clinical diagnosis
Additional
major diagnostic
considerations
Moderate confidence
High confidence
• Hypoattenuating lobules on inspiratory imaging
with gas trapping on expiratory imaging
• Well-demarcated preserved lobules with
intervening diffuse ground glass opacities
• Three-density sign
• Profuse poorly defined ground
glass centrilobular nodules
Indeterminate for UIP and fHP
Typical of fHP
fHP
IPF
UIP radiologic pattern commonly suggests IPF, but consider
UIP radiologic pattern in non-IPF clinical diagnoses including:
• CTD-ILD/IPAF: Exuberant honeycombing sign, anterior upper lobe
sign, straight-edge sign, dilated esophagus, osseous erosions
• fHP
• Asbestosis: Bilateral pleural plaques
Compatible with fHP
Consider clinical diagnoses including:
• Idiopathic NSIP, CTD-ILD/IPAF: Subpleural sparing,
some peribronchovascular involvement
• IPF (potentially with acute exacerbation)
• fHP
• Drug induced
fHP radiologic pattern commonly suggests fHP, but
consider fHP radiologic pattern in non-fHP clinical diagnoses
including:
• CTD-ILD/IPAF
• IPF plus obstructive airways disease (eg, asthma, COPD)
Figure 7 – Diagram showing an approach to assessment of radiologic features in patients with IPF, fHP, or both as primary diagnostic considerations.
Individual imaging features are integrated and the overall pattern is evaluated as favoring UIP, favoring fHP, or indeterminate for both. The presence
of specific features further separates high-confidence radiologic patterns as described in recent clinical practice guidelines (eg, UIP and typical of fHP),
with the collection of features then informing the likelihood of a diagnosis of IPF and fHP across a diagnostic spectrum. Other features occasionally can
suggest additional major diagnostic considerations, as shown at the bottom of the figure. Of note, fHP occasionally can have an imaging appearance of
typical UIP on HRCT imaging, just as IPF sometimes can involve small airways signs, especially in the setting of extensive smoking and obstructive lung
disease. CTD-ILD ¼ connective tissue disease-related interstitial lung disease; fHP ¼ fibrotic hypersensitivity pneumonitis; HP ¼ hypersensitivity
pneumonitis; HRCT ¼ high-resolution CT; NSIP ¼ nonspecific interstitial pneumonia; IPAF ¼ interstitial pneumonia with autoimmune features;
IPF ¼ idiopathic pulmonary fibrosis; PPFE ¼ pleuroparenchymal fibroelastosis; UIP ¼ usual interstitial pneumonia.
chestjournal.org
621
patient-specific risks and benefits should be weighed
before deciding on proceeding with a biopsy and could
guide the choice of biopsy technique, we make no
suggestion regarding the method of obtaining lung
tissue. Multiple studies suggest that molecular testing
may also provide useful information for distinguishing
UIP from other histologic patterns53,54; however, such
testing has not been shown to distinguish the cause of
UIP (eg, UIP resulting from IPF, CTD-ILD, or another
diagnosis) and has not yet been endorsed by recent
clinical practice guidelines.8
Pathologic Features of a UIP Pattern
On histologic examination, UIP transitions sharply from
less affected parenchyma to areas with patchy fibrosis
consisting of paucicellular dense collagen, fibroblast foci,
and architectural distortion, often with honeycombing,
in a subpleural and paraseptal distribution (Fig 8A, 8B).
Involvement is typically worse in the periphery of the
lobule and spares the bronchovascular bundles; however,
lobules may be overrun as disease progresses. In contrast
to fibrotic NSIP, in which fibrosis predominantly follows
the original alveolar walls, the fibrosis of UIP replaces
the underlying lung architecture, either in the form of
honeycombing or simply large areas of dense fibrosis.
Fibroblast foci are small tufts of loose fibrosis consisting
of myofibroblasts within a myxoid stroma that has few
collagen fibers. Despite greater numbers of fibroblast
foci per square centimeter in UIP compared with fHP
pathologic patterns,55 no threshold is required to
diagnose IPF in MDD, and too much overlap exists to
support using the number of fibroblast foci as a
diagnostic discriminator.
In the appropriate clinical context, a pathologic pattern
of UIP in the absence of any ancillary findings is
suggestive of IPF, but is not specific. UIP suggestive of
Figure 8 – Photomicrographs showing lung biopsy samples with examples of pathologic features relevant to identification of a usual interstitial
pneumonia (UIP) pattern of fibrosis. A, UIP pathologic pattern in a patient with idiopathic pulmonary fibrosis (IPF) showing patchy paucicellular
dense interstitial fibrosis, architectural distortion, honeycombing, and fibroblastic foci. The fibrosis has a subpleural and paraseptal distribution (thin
arrows). Honeycombing consists of cystic remodelling of fibrotic lung parenchyma (thick arrows). The insert shows a fibroblastic focus consisting of a
nodular collection of myofibroblasts within a myxoid stroma juxtaposed against a dense fibrotic scar. B, Early UIP in a patient with IPF. Fibrosis
largely is confined to the periphery of the lobule (arrows). C, UIP pattern in a patient with rheumatoid arthritis showing patchy dense interstitial
fibrosis and architectural distortion (arrows). D, Higher power in the same patient showing prominent lymphoid follicles and germinal centers (arrows).
The insert shows that numerous plasma cells are present in the interstitial chronic inflammation. The lymphoid follicles and numerous plasma cells are
suggestive of connective tissue disease-related interstitial lung disease, which correlates with the patient’s diagnosis of rheumatoid arthritis.
622 Special Features
[ 162#3 CHEST SEPTEMBER 2022 ]
IPF is distinct from a background pattern of UIP with
superimposed findings that suggest a non-IPF cause. For
example, lymphoid follicles with germinal centers,
prominent chronic fibrous pleuritis, or both in the
presence of UIP suggest underlying CTD-ILD (Fig 8C,
8D), whereas significant peribronchiolar involvement on
a background of UIP suggests fHP.
Pathologic Features of an fHP Pattern
Identification of an fHP pattern on histologic
examination is challenging because the background
pattern of fibrosis may resemble UIP or fibrosing
NSIP, may manifest as airway-centered fibrosis, or
may have overlapping or unclassifiable features.56-59
Although some cases of fHP may be indistinguishable
histologically from the pathologic UIP pattern of IPF,
the presence of peribronchiolar fibrosis,
peribronchiolar metaplasia, and granulomas are
helpful in suggesting a clinical diagnosis of fHP over
IPF (Fig 9A-C). These features, in combination with a
background of chronic fibrosing interstitial
pneumonia, are essential in defining typical fHP
histologic findings in both hypersensitivity
pneumonitis guidelines.6,7
Figure 9 – Photomicrographs showing lung biopsy samples with examples of pathologic features relevant to identification of a fibrotic hypersensitivity
pneumonitis (fHP) pattern of fibrosis. A, Biopsy sample showing patchy paucicellular fibrosis causing architectural distortion (thin arrows) and in a
subpleural and perilobular distribution, potentially in keeping with a usual interstitial pneumonia (UIP) pathologic pattern. However, one lobule shows
prominent centrilobular fibrosis (thick arrow), an ancillary finding superimposed on a background of UIP that should raise suspicion of fHP. Imaging
showed predominantly upper zone fibrosis with air trapping and was read as compatible with fHP, and the patient was assigned a clinical diagnosis of
fHP. B, Biopsy sample showing bronchiolar fibrosis and a poorly formed granuloma in a patient with fHP. The bronchiole is replaced by a nodular
fibrotic scar with moderate interstitial chronic inflammation (thick arrows). The peribronchiolar interstitium shows a small poorly formed nonnecrotizing granuloma (thin arrow). The insert shows a magnified view of the granuloma, which consists of a loose cluster of epithelioid cells and
multinucleated giant cells. C, Peribronchiolar metaplasia (arrows) in a patient with fHP. This lesion consists of proliferation of bronchiolar epithelium
along fibrotically thickened alveolar walls in the peribronchiolar lung parenchyma (arrows). When present in > 50% of bronchioles, peribronchiolar
metaplasia favors fHP. D, In rare instances, fHP may manifest as pure bronchiolar disease without a background of fibrosis. This biopsy sample
demonstrates multiple evenly distributed nodules of fibrosis corresponding to bronchiolar fibrosis (arrows). Mild to moderate chronic inflammation and
minimal diffuse interstitial fibrosis are present.
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623
Peribronchiolar disease, with or without peribronchiolar
metaplasia, may be the result of airway insults such as
smoking or gastroesophageal reflux disease and can also
occur in CTD-ILD; however, this finding on a
background of fibrosing interstitial pneumonia should
raise the possibility of fHP, particularly when > 50% of
bronchioles are involved and show peribronchiolar
metaplasia.55,60,61 Less frequently, fHP manifests as only
peribronchiolar disease without fibrosing interstitial
pneumonia (Fig 9D).62,63
Granulomas, which are typically peribronchiolar,64 are
a major histologic feature of fHP and are classically
described as small and poorly formed, although in
some cases, only giant cells or Schaumann bodies may
be present.57 The presence or absence of granulomas
differentiates typical from compatible categories of
fHP. Although helpful when present, giant cells or
granulomas are frequently lacking in fHP and are
occasionally present when a background UIP pattern
is present.65-67 As such, no threshold exists for the
number of granulomas required for the diagnosis of
fHP in favor of IPF, and the finding of granulomas
must be interpreted within the totality of the
histologic findings.
Bridging fibrosis is described as airway-centered fibrosis
that spans bronchioles to the pleura or interlobular
septa. Although this is included as a diagnostic feature of
fHP in the ATS/JRS/ALAT guidelines,6 additional
studies have shown that it also may be present in UIP.
For this reason, bridging fibrosis is not included as a
feature supporting fHP in the CHEST guidelines.7
Proposed Integrated Approach
A key challenge is discriminating UIP suggestive of IPF
from cases with a pathologic pattern of UIP with
superimposed findings indicative of a non-IPF cause,
including fHP. These two entities fall along a spectrum
where the extent of ancillary features of fHP plays an
important role in determining the final histologic pattern.
Similar to the clinical and radiologic domains, this
continuum may be separated into three categories in
which UIP suggestive of IPF is favored, fHP is favored, or
the histologic pattern is indeterminate (Fig 10); however,
evidence to guide separation of these categories is limited.
This is in part related to the absence of clear thresholds
used to define any given feature, with the exception that
peribronchiolar metaplasia in > 50% of bronchioles more
reliably distinguishes fHP from UIP of IPF.55 Although
Alternative diagnosis
Fibrosis on biopsy
Features inconsistent with IPF and fHP OR
Features consistent with other fibrosing process
Features suggesting IPF or fHP
Indeterminate
Favors UIP pattern
UIP pattern
• Dense fibrosis with architectural distortion
• Patchy
• Fibroblastic foci
• Predominantly subpleural/paraseptal distribution
Features favoring a pattern other than UIP of IPF or fibrosing
process with features suggestive of UIP in setting other than IPF
AND
Not enough ancillary features of fHP
AND
Consider non-IPF & non-fHP diagnoses
• CTD-ILD (eg, lymphoid follicles ±
germinal centers, plasma cells >
lymphocytes)
• Drug reaction
• Aspiration
• Sarcoidosis
• Other
Favors fibrotic HP pattern
A background of fibrosis (eg, UIP, fNSlP, difficult to classify)
AND
Ancillary features of fHP:
• Predominantly peribronchiolar fibrosis OR
• Peribronchiolar metaplasia > 50% of bronchioles OR
• Poorly formed granuloma(s)
No significant features of fHP
OR
Pure peribronchiolar fibrosis
High confidence
All features of UIP present
Moderate confidence
Some features of UIP present
OR only honeycombing
UIP
Probable UIP
Histopathologic
pattern
Likelihood of
clinical diagnosis
Additional
major diagnostic
considerations
Indeterminate for UIP and fHP
High confidence
Poorly formed, nonnecrotizing granulomas
Compatible with fHP
Typical of fHP
fHP
IPF
UIP pathologic pattern commonly suggests IPF if there are no
ancillary features to suggest an alternative diagnosis, but it is
important to consider:
• CTD-ILD/IPAF: Associated lymphoid follicles ± germinal centres,
plasma cells > lymphocytes
• fHP
• Asbestosis: Asbestos or ferruginous bodies
Moderate confidence
No granulomas
Consider clinical diagnoses including:
• CTD-ILD/IPAF: NSIP pattern, lymphoid follicles ±
germinal centres, plasma cells > lymphocytes
• IPF
• fHP
• Drug induced
• Aspiration
Features of peribronchiolar disease or granulomas commonly
suggest fHP, but consider other clinical diagnoses including:
• Drug induced
• Aspiration
• CTD-ILD/IPAF: lymphoid follicles ± germinal centres,
plasma cells > lymphocytes
Figure 10 – Diagram showing an approach to assessment of histopathologic features in patients with IPF, fHP, or both as primary diagnostic considerations. Individual pathologic features are integrated, and the overall pattern is evaluated as favoring UIP, favoring fHP, or indeterminate for both.
The presence of specific features further separates high-confidence pathologic patterns as described in recent clinical practice guidelines (eg, UIP
suggestive of IPF, typical of fHP), with the collection of features then informing the likelihood of a diagnosis of IPF and fHP across a diagnostic
spectrum. Other features occasionally can suggest additional major diagnostic considerations, as shown at the bottom of the figure. CTD-ILD ¼
connective tissue disease-related interstitial lung disease; fHP ¼ fibrotic hypersensitivity pneumonitis; fNSIP ¼ fibrotic nonspecific interstitial pneumonia; IPAF ¼ interstitial pneumonia with autoimmune features; IPF ¼ idiopathic pulmonary fibrosis; UIP ¼ usual interstitial pneumonia.
624 Special Features
[ 162#3 CHEST SEPTEMBER 2022 ]
occasionally clear cases of IPF and fHP can be identified
on histologic analysis, many will show a pattern of UIP
with a mild amount of peribronchiolar or granulomatous
features that are difficult to classify. The indeterminate
pathologic category represents a collection of
miscellaneous biopsy samples that are difficult to classify.
Such biopsy samples may show occasional foci of
centrilobular fibrosis, rare granulomas or giant cells, very
focal lymphoid hyperplasia, diffuse inflammation, or
diffuse homogeneous fibrosis favoring fibrotic NSIP.5,68
Multidisciplinary Integration of Clinical,
Radiologic, and Pathologic Features
We suggest the integrated approach to the diagnosis of
IPF and fHP shown in Figure 11 for patients with
these two diagnoses as the primary considerations,
highlighting the concept of an IPF-fHP diagnostic
continuum based on diagnostic confidence. The initial
evaluation involves mandatory clinical and radiologic
assessments. Patients with a characteristic and
concordant clinical profile and radiologic pattern
typically do not require further evaluation to be
provided with a confident diagnosis.5,7,8 Patients with
discordant clinical and radiologic features or with
indeterminate findings in at least one of these
domains require careful consideration of all available
information by a group of experts.69 Conflicting
findings and exceptions are commonly identified
during clinical and radiologic evaluation, which
emphasizes the need for regular MDD in all but the
clearest cases. Of note, familial pulmonary fibrosis
often manifests with atypical clinical and radiologic
findings (eg, younger age, indeterminate imaging
pattern)70 but does not constitute a specific clinical
diagnosis and requires special attention and an
attempt to classify patients according to defined ILD
subtypes. Integration of clinical and radiologic features
in MDD frequently involves assigning relative weights
to each domain considered, with this process
providing a leading diagnosis and confidence level.71 A
moderate or high confidence, often defined as $
70% confidence, is considered a key threshold where a
Clinical Assessment
IPF clinical profile
Indeterminate profile
fHP clinical profile
Radiological Assessment
Favors IPF
(UIP or Probable UIP pattern)
Indeterminate for
IPF and fHP
Favors fHP
(Typical or Compatible fHP pattern)
Multidisciplinary Discussion: Consensus diagnosis and confidence
Moderate, or high confidence diagnosis of IPF
Moderate, or high confidence diagnosis of fHP
Indeterminate
Consider other diagnostic testing
Pathologic Assessment (if appropriate)
Indeterminate for
IPF and fHP
Favors IPF
Favors fHP
Multidisciplinary Discussion: Consensus diagnosis and confidence
Low, moderate, or high confidence diagnosis of IPF
IPF
Low, moderate, or high confidence diagnosis of fHP
Unclassifiable ILD OR
Diagnosis alternative to both IPF and fHP
fHP
Figure 11 – Diagram showing an integrated multidisciplinary approach to assessment of patients with IPF, fHP, or both as primary diagnostic
considerations. The clinical profile and radiologic pattern are combined in multidisciplinary discussion to generate a leading diagnosis and diagnostic
confidence. Patients with clear and concordant clinical profile and radiologic pattern may not require a full multidisciplinary discussion (MDD) to
secure a confident diagnosis. In indeterminate cases with a low-confidence diagnosis or unclassifiable disease despite MDD, the need for and safety of
additional invasive diagnostic testing such as surgical lung biopsy should be considered. When a pathologic specimen is obtained, MDD is repeated to
combine the clinical-radiologic profile with pathologic findings so as to arrive at a final diagnosis, which should be revisited further as long-term
information becomes available during subsequent follow-up. Indeterminate cases where pathologic assessment is unsafe or not possible may be assigned
a low-confidence diagnosis to guide management or otherwise are labelled as unclassifiable. fHP ¼ fibrotic hypersensitivity pneumonitis; ILD ¼
interstitial lung disease; IPF ¼ idiopathic pulmonary fibrosis; UIP ¼ usual interstitial pneumonia.
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625
TABLE 1 ]
Areas of Priority for Future Research on the Diagnosis of IPF and fHP
Uncertainties in guideline-defined features, phenotypes, and patterns and their outcomes
Clinical domain
Develop, validate, and disseminate standardized exposure assessment tools
Determine usefulness of common clinical features in distinguishing IPF and fHP, with integration of features in validated
clinical prediction models
Radiologic domain
Determine usefulness of nonclassical distributions in predicting histopathologic findings:
(a) Diffuse craniocaudal involvement
(b) Minor peribronchovascular in addition to predominant subpleural involvement
(c) Relative costophrenic angle sparing or tapering of disease
Validate specific thresholds of small airways signs that characterize an fHP pattern
Re-evaluate how to categorize radiologic UIP in the setting of superimposed features suggesting a non-IPF diagnosis
Identify radiologic features most strongly associated with UIP and typical fHP patterns
Assess the association of UIP and fHP guideline-defined radiologic patterns with the final clinical diagnosis
Identify radiologic features and patterns that predict prognosis and response to therapy in IPF and fHP
Pathologic domain
Evaluate the clinical usefulness of ancillary findings that distinguish IPF from other causes of UIP
Determine the accuracy of TBLC in distinguishing fHP from UIP
Evaluate and validate clinical and radiologic factors that predict an informative surgical biopsy
Identify pathologic features most associated with UIP and typical fHP patterns
Assess the association of UIP and fHP guideline-defined pathologic patterns with final clinical diagnosis
Identify pathologic features and patterns that predict prognosis and response to antifibrotic or immunomodulatory
therapy, or both
Overarching ILD framework and comprehensive diagnostic algorithm
Explore novel ways to classify ILD subtypes based on underlying biological features and anticipated response to therapy
Develop clear terminology that distinguishes radiologic and histopathologic patterns (eg, UIP) from clinical diagnoses
(eg, IPF)
Define radiologic and pathologic features typifying an NSIP pattern
Integrate other common patterns (eg, NSIP) and fibrotic ILD diagnoses (eg, CTD-ILD) within a pragmatic and
comprehensive diagnostic algorithm alongside IPF and fHP
Develop and validate comprehensive multivariate models incorporating clinical and radiologic data to classify IPF, fHP,
and other fibrotic ILDs accurately and reproducibly
Incorporate genetic information in the classification and management of fibrotic ILD
Role of advanced diagnostic techniques
Further investigate genetic, serum, and bronchoalveolar biomarkers
Evaluate the ability of molecular or genetic testing to distinguish clinical diagnoses and potential pharmacotherapies of
IPF, fHP, and other fibrotic ILDs
Further validate optical coherence tomography for its ability to distinguish various pathologic patterns
Evaluate the ability of machine learning algorithms to distinguish radiologic and pathologic patterns, as well as to explore
novel informative ways to classify ILD subtypes
fHP ¼ fibrotic hypersensitivity pneumonitis; ILD ¼ interstitial lung disease; IPF ¼ idiopathic pulmonary fibrosis; NSIP ¼ nonspecific interstitial pneumonia;
TBCL ¼ transbronchial lung cryobiopsy; UIP ¼ usual interstitial pneumonia.
diagnosis can be secured and pharmacotherapy
initiated without need for further testing.72
Additional information may be sought in appropriately
selected patients whose disease remains unclassifiable or
whose findings have low diagnostic confidence and for
whom obtaining a more definite diagnosis will have
626 Special Features
therapeutic implications. This has traditionally involved
surgical lung biopsy, ideally performed within
73
experienced centers. Repeat MDD then allows
incorporation of pathologic data that typically offers
important insight into the underlying biology and cause
of the fibrotic process, recognizing that this information
still must be considered in the context of clinical and
[ 162#3 CHEST SEPTEMBER 2022 ]
radiologic findings even in highly suggestive pathologic
patterns, given the possibility of various patterns existing
in multiple disease entities. Even when pathologic
analysis is sought, in approximately 10% of all patients
with fibrotic ILD, the disease remains unclassifiable,74
and others may receive a diagnosis alternative to both
IPF and fHP. In cases of unclassifiable disease,
additional findings and longitudinal disease behavior
may be incorporated over time to inform the diagnosis,
highlighting that multidisciplinary assessment is a longterm and iterative process.
Acknowledgments
Funding/support: The authors have reported to CHEST that no
funding was received for this study.
Financial/nonfinancial disclosures: None declared.
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