Position Paper

Interstitial lung abnormalities detected incidentally on CT:
a Position Paper from the Fleischner Society
Hiroto Hatabu*, Gary M Hunninghake, Luca Richeldi, Kevin K Brown, Athol U Wells, Martine Remy-Jardin, Johny Verschakelen,
Andrew G Nicholson, Mary B Beasley, David C Christiani, Raúl San José Estépar, Joon Beom Seo, Takeshi Johkoh, Nicola Sverzellati,
Christopher J Ryerson, R Graham Barr, Jin Mo Goo, John H M Austin, Charles A Powell, Kyung Soo Lee, Yoshikazu Inoue, David A Lynch†
Lancet Respir Med 2020;
8: 726–37*Chair and †co-chair of the
Fleischner Society Writing
Committee for Position Paper oninterstitial lung abnormalities
Department of Radiology(Prof H Hatabu MD,
R San José Estépar PhD), andDepartment of Pulmonary andCritical Care Medicine(G M Hunninghake MD),
Brigham and Women’s
Hospital, Harvard Medical
School, Boston, MA, USA;
Unità Operativa Complessa di
Pneumologia, Università
Cattolica del Sacro Cuore,
Fondazione Policlinico A
Gemelli IRCCS, Rome, Italy(Prof L Richeldi MD);
Department of Medicine(Prof K K Brown MD), andDepartment of Radiology(Prof D A Lynch MB), National
Jewish Health, Denver, CO, USA(Prof K K Brown); Departmentof Respiratory Medicine(Prof A U Wells MD) and
Department of Histopathology(Prof A G Nicholson DM), Royal
Brompton and Hospital NHS
Foundation Trust, London, UK;
National Heart and Lung
Institute, Imperial College
London, London, UK(Prof A U Wells,
Prof A G Nicholson);
Department of Thoracic
Imaging, Hospital Calmette,
University Centre of Lille, Lille,
France (Prof M Remy-Jardin MD);
Department of Radiology,
University Hospitals Leuven,
Leuven, Belgium(Prof J A Verschakelen MD);
Department of Pathology(M B Beasley MD), andPulmonary, Critical Care andSleep Medicine(Prof C A Powell MD), Icahn
School of Medicine at Mount,
New York, NY, USA;
Department of Environmental
Health, Harvard T.H. Chan
School of Public Health,Boston, MA, USA(Prof D C Christiani MD);
Massachusetts General
Hospital, Harvard Medical

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The term interstitial lung abnormalities refers to specific CT findings that are potentially compatible with interstitiallung disease in patients without clinical suspicion of the disease. Interstitial lung abnormalities are increasingly
recognised as a common feature on CT of the lung in older individuals, occurring in 4–9% of smokers and 2–7% of
non-smokers. Identification of interstitial lung abnormalities will increase with implementation of lung cancer
screening, along with increased use of CT for other diagnostic purposes. These abnormalities are associated withradiological progression, increased mortality, and the risk of complications from medical interventions, such as
chemotherapy and surgery. Management requires distinguishing interstitial lung abnormalities that represent
clinically significant interstitial lung disease from those that are subclinical. In particular, it is important to identify
the subpleural fibrotic subtype, which is more likely to progress and to be associated with mortality. This
multidisciplinary Position Paper by the Fleischner Society addresses important issues regarding interstitial lungabnormalities, including standardisation of the definition and terminology; predisposing risk factors; clinicaloutcomes; options for initial evaluation, monitoring, and management; the role of quantitative evaluation; and future
research needs.

Introduction
Interstitial lung disease (ILD) comprises a diverse groupof lung diseases with overlapping clinical, radiological,
physiological, and pathological features.1 Interstitial lungabnormalities (ILAs) refer to the presence of CT scanfindings that are potentially compatible with ILD inpatients who have partial (eg, abdominal CT including
the lower lung zones) or complete chest CT examinations
without previous clinical suspicion of ILD. As ILAs areassociated with respiratory symptoms, functional impair­ment, risk of progression, and increased all-cause
mortality,2–10 their identification has clinical implications.
The term ILAs does not imply the absence of respiratory
signs, symptoms, or functional impairment, but whenthese clinically significant findings are present, ILAs arelikely to represent mild ILD rather than subclinical
Key messages
Background• Early interstitial lung abnormalities (ILAs) are common
incidental findings on CT, particularly in older individuals• The presence of ILAs is an independent predictor ofmortality• About 20% of ILAs progress over 2 years, and more than
40% progress over 5 years• Individuals with subpleural predominant fibrotic ILAs aremost likely to progress
Management of ILAs
• Identify potential risk factors for interstitial lung disease• Identify clinical or functional impairment• Establish whether there is current evidence of clinicallysignificant interstitial lung disease• Undertake clinical and imaging follow-up as appropriate

abnormalities. The definition of ILAs is purely
radiological and is based on the incidental identificationof CT abnormality. Differentiation between ILAs andclinical and subclinical ILD must be on the basis ofclinical evaluation.
ILAs are increasingly recognised on chest CT scans.2
Systematic evaluation of large cohorts has shown aprevalence of ILAs in older individuals (>60 years) of 4–9%
in smokers and 2–7% in non-smokers (table).3–9 However,their presence is not routinely recorded on radiology
reports, even at academic centres.20 ILAs are likely to be
increasingly identified with the implementation of lungcancer screening and increased use of CT for otherdiagnostic purposes. Still, our understanding of ILAs isminimal, with insufficient evidence to provide definitive
management recommendations. This Fleischner Society
Position Paper provides multidisciplinary perspectives on
definition and terminology; predisposing risk factors;
clinical outcomes; options for initial evaluation,
monitoring, and management; the role of quantitativeevaluation; and future research needs.

What definition and terminology could be used
to describe and characterise ILAs?
High-resolution CT is highly sensitive for detecting
subclinical interstitial abnormalities in high-risk
populations, such as patients with connective tissue
disease (eg, systemic sclerosis) or occupational exposures(eg, asbestos).21–23 Systematic evaluation of large cohortsof smokers screened by CT for lung cancer, or undergoingCT as part of epidemiological evaluation of chronic
obstructive pulmonary disease (COPD) or cardiovascularrisk factors, has shown that these incidental abnormalities
are relatively common, particularly in older individuals(table).4,7,9,15 Terms applied to this finding have included
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Position Paper

Population-based cohorts

Smoking and lung cancer screening cohorts

MESA11,12,13,14

Nagano,Japan*15

FHS6,8,9

AGESReykjavik9

ECLIPSE9NLST7,16

COPDGene4,9,17 MILD18

DLCST19

Total number of chest
CT scans evaluated

3137

3061

2633

5320

1670

884

9292

692

1990

Prevalence of ILAs

310 (10%)80 (3%)

177 (7%)377 (7%)157 (9%)86 (10%)708 (8%)28 (4%)

332 (17%)

Mean age of those with ILAs
(years)

75

62

70

78

64

62

64

60

60

NA

46%,
4 years

43%,
6 years

63%,
5 yearsNA

20%,
2 yearsNA

20%,
2 years

NA

NA

NA

2·7
(1·1–6·5)

1·3(1·2–1·4)

1·4(1·1–2·0)NA

1·8(1·1–2·8)NA

2·0(1·4–2·7)

Study characteristics

Radiological progression
Overall progression,
follow-up time
Mortality
Relative risk of death,(hazard ratio [95% CI])

ILAs=interstitial lung abnormalities. NA=not available. *Patients participating in a health screening programme from Nagano prefecture, Japan.

Table: Interstitial lung abnormalities across study populations

interstitial lung changes at an early phase,15 early ILD,4
ILD,18 subclinical ILD,23 and preclinical ILD.24 Quantitative
abnormalities, such as an abnormally high proportion ofhigh-attenuation areas of the lung, have also been
identified in cohort studies and are thought to suggest
subclinical parenchymal lung disease.11
ILAs are not synonymous with subclinical ILD because asubset of patients with ILAs has symptoms and lungfunction impairment without suspected ILD. A further
subset of patients with ILAs is at risk of progression to clin­
ically significant disease. Abnormalities identified during
screening for ILD in high-risk groups (eg, those withrheumatoid arthritis, systemic sclerosis, or familial ILD)
are not considered as ILAs because they are not incidental;
these might be referred to as preclinical ILD and their
management is beyond the scope of this Position Paper.
ILAs have been described as non-dependent abnor­
malities affecting more than 5% of any lung zone (upper,
middle, and lower lung zones are demarcated by the levelsof the inferior aortic arch and right inferior pulmonaryvein). In initial descriptions, ILAs included ground-glassor reticular abnormalities, diffuse centri­lobular nodularity,
traction bronchiectasis, honeycomb­ing, and non-emphy­
sematous cysts (figure 1).4 In the definition proposed inthis Position Paper, centrilobular nodul­arity, which is the
typical presentation of smoking-related respiratory bron­chiolitis,27,28 is not included as this feature is common,
typically non-progressive, and not associated with fibrosis(panel 1).7,29,30 Although the 5% threshold is arbitrary andimprecise, it is retained to exclude minimal opacities andto conform to previous published literature. Focal or
unilateral patchy ground-glass opacity seldom represents
an ILD, and is classified as equivocal. Dependent
abnormalities are regarded as equivocal unless persistentin the prone position. Pleuropulmonary fibroelastosis,
sometimes an incidental finding on CT, is a clearly defined
entity,31,32 which has not been included within ILAs in
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published series. Other findings not considered as ILAs
are shown in panel 1 and figure 2.
Ensuring that specific descriptors of CT findings areprovided in radiology reports is essential, as different
imaging findings have very different implications.
Relevant descriptors include craniocaudal and axial
distribution and individual features, such as ground-glassor reticular abnormalities, traction bronchiectasis,architectural distortion, honeycombing, and non-emphy­s­ematous cysts (panel 1). Among these findings, thefollowing subcategories are of prognostic significance:
first, ground-glass opacity and reticular opacities without apredominant subpleural localisation; second, groundglass opacity and reticular opacities with a predominant
subpleural localisation without evidence of fibrosis;
and finally, traction bronchiectasis, architectural distor­tion, and honeycombing, providing evidence of lungfibrosis.7,29,30,33 Non-emphysematous cysts, defined as
lucencies with irregular, well-defined walls, are often seenin cigarette smokers34 with or without other features of
ILAs. These cysts can be distinguished from emphy­sema
by the presence of a well-defined wall and fromhoneycombing by their irregular shape, varying size, andthe absence of subpleural predominance.35 On histo­logicalanalysis, non-emphysematous cysts usually correlate withairspace enlargement and fibrosis or smoking-related
interstitial fibrosis,34,35 and might have prognostic
significance,7,29,30 although they are not usually associatedwith imaging evidence of fibrosis.
ILAs with a non-subpleural distribution are usually nonprogressive29 and not associated with increased mortality.
Subpleural ILAs have potentially greater clinicalsignificance and are further subcategorised according to
the presence or absence of fibrosis (figure 1, panel 1).29
Fibrotic ILAs are associated with a higher rate ofprogression and death on 5-year follow-up.7,29 If fibrosis ispresent, the pattern can be further classified according to

School, Boston, MA, USA(Prof D C Christiani);
Department of Radiology, Asan
Medical Center, University of
Ulsan College of Medicine,
Seoul, South Korea(Prof J B Seo MD); Departmentof Radiology, Kansai Rosai
Hospital, Hyogo, Japan(Prof T Johkoh MD); Departmentof Medicine and Surgery,
University of Parma, Parma,
Italy (N Sverzellati MD);
Department of Medicine,
University of British Columbia
and Centre for Heart Lung
Innovations, St Paul’s Hospital,
Vancouver, BC, Canada(C J Ryerson MD); Departmentof Medicine and Department of
Epidemiology(Prof R Graham Barr MD), andDepartment of Radiology(Prof J H M Austin, MD),
Columbia University Medical
Center, New York, NY, USA;
Department of Radiology,
Seoul National University
College of Medicine, Seoul,
South Korea (Prof J M Goo MD);
Department of Radiology,
Samsung Medical Center,
Sungkyunkwan University
School of Medicine, Seoul,
South Korea (Prof K S Lee MD);and Clinical Research Center,
National Hospital Organization
Kinki-Chuo Chest Medical
Center, Osaka, Japan(Prof Y Inoue MD)
Correspondence to:Prof Hiroto Hatabu, Departmentof Radiology, Center for
Pulmonary Functional Imaging,
Brigham and Women’s Hospital,
Harvard Medical School, Boston,
MA 02215, USA
hhatabu@partners.org

727

Position Paper

A

B

C

precursor to idiopathic pulmonary fibrosis (IPF) or otherprogressive fibrotic ILDs.

What CT protocol should be used to evaluate
and follow up patients with ILAs?

Figure 1: Subcategories of interstitial lung abnormalities(A) Non-subpleural and non-fibrotic. CT shows widespread ground-glass abnormality with central predominance(circled). (B) Subpleural non-fibrotic. CT shows predominantly subpleural ground-glass and linear abnormality
without evidence of fibrosis (arrows). (C) Subpleural fibrotic. Traction bronchiectasis and architectural distortion
are indicated by the ovals in the lingula and left lower lobe. This pattern would correspond to a probable usualinterstitial pneumonia pattern.25,26

Panel 1: Definitions and subcategories of interstitial lung abnormalities
What are interstitial lung abnormalities (ILAs)?
• Incidental identification of non-dependent abnormalities, including ground-glass orreticular abnormalities, lung distortion, traction bronchiectasis, honeycombing, andnon-emphysematous cysts• Involving at least 5% of a lung zone (upper, middle, and lower lung zones aredemarcated by the levels of the inferior aortic arch and right inferior pulmonary vein)• In individuals in whom interstitial lung disease is not suspected
What are not ILAs?
Imaging findings restricted to:• Dependent lung atelectasis• Focal paraspinal fibrosis in close contact with thoracic spine osteophytes (figure 2A)• Smoking-related centrilobular nodularity in the absence of other findings (figure 2B)• Mild focal or unilateral abnormality (figure 2C)• Interstitial oedema (eg, in heart failure)• Findings of aspiration (patchy ground-glass, tree in bud; figure 2C)
Preclinical and clinical identification:• Preclinical interstitial abnormalities identified during screening of high-risk individuals(eg, those with rheumatoid arthritis, scleroderma, occupational exposure, familial
interstitial lung disease)• Findings in patients with known clinical interstitial lung disease
Subcategories of ILAs
• Non-subpleural: ILAs without predominant subpleural localisation (figure 1A)• Subpleural non-fibrotic: ILAs with a predominant subpleural localisation and without
evidence of fibrosis* (figure 1B)• Subpleural fibrotic: ILAs with a predominant subpleural localisation and with evidenceof pulmonary fibrosis* (figure 1C)* Fibrosis is characterised by the presence of architectural distortion with traction bronchiectasis or honeycombing (or both).

the 2018 Fleischner and American Thoracic Society,
European Respiratory Society, Japanese Respiratory
Society, and Latin American Thoracic Society criteria as
typical, probable, or indeterminate for usual interstitialpneu­monia.25,26,29 About 2% of patients in the AGESReykjavik cohort had a probable or definite usualinterstitial pneu­monia pattern, were more likely to have
subpleural ILA progression, and had worse survival
compared with individuals without these patterns.29 It
seems likely that fibrotic ILAs might be an important
728

When ILAs are detected, a dedicated chest CT examination
could help to confirm and characterise the abnormality,
especially if dependent atelectasis was present, if the initialscan of the lungs was incomplete (eg, an abdominal CT),or if the scan was done without thin sections, with an ultralow dose technique, or using first-generation, hybrid-type,
iterative reconstruction methods, all of which might
obscure fine lung details. On the dedicated CT examination(if indicated), thin sections (<1·5 mm) with moderateedge-enhancing reconstruction are helpful. Prone views
are particularly important to distinguish dependent
atelectasis and true interstitial abnormality, whereas
expiratory imaging could potentially identify lobular air
trapping as a clue to hypersensitivity pneumonitis.
Potential recommended imaging protocols are outlined in2018 guidelines.25 Subsequent CTs to evaluate for pro­
gression should use similar scanning protocols.

Pathological correlation of ILA
ILA is a radiological term with few published studies on
pathological correlates. Pulmonary resection specimens
for lung cancer in current or former cigarette smokers
have a high frequency of background inter­stitial fibrosis.
Katzenstein and colleagues36 reported a 60% prevalence ofclinically occult fibrosis occupying more than 25% of theresected lobe. Most of these cases were viewed as smokingrelated interstitial fibrosis, but usual interstitial pneu­
monia, pulmonary Langerhans’ cell histiocytosis, andasbestosis were also found. Similarly, in a larger study by
Kawabata and colleagues,37 most cases of fibrosis were
defined as airspace enlarge­ment and fibrosis or respiratory
bronchiolitis, the remainder being usual interstitial
pneumonia. ILAs were not specifically identified on CT inthese studies, but on the basis of the association between
smoking and interstitial fibrosis it seems likely that many
ILAs in smokers represent subclinical smoking-related
fibrosis or macrophage accumulation.38–46 In 2018, Miller
and colleagues47 evaluated histological correlates of ILAs
in 424 lung nodule resections. Of 26 patients with ILAs,
histology showed fibrosis in 19 (73%), with usualinterstitial pneumonia in two (8%) individuals. Of note,
207 (52%) of 398 patients with no ILAs or an indeterminate
status also showed histological fibrosis, suggesting thatfibrosis can be below the resolution of imaging. Apartfrom usual interstitial pneumonia, the histological fibrosis
seemed predominantly smoking related. In a similar
study, Hung and colleagues48 found fibrotic ILD in 10% of
406 specimens from 397 patients, consisting of smokingrelated interstitial fibrosis in 7%, usual interstitial
pneumonia in 1%, non-specific interstitial pneumonia in
1%, and undefined in 1%. ILAs were present in 10% ofcases with smoking-related interstitial fibrosis and in
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Position Paper

100% with usual interstitial pneumonia. Similar to Miller
and colleagues,47 Hung and colleagues48 found fibroticchanges in 51% of specimens with no radiological ILAs,
although there were no cases of usual interstitial
pneumonia in this category. A small number of cases with
ILAs had granulomatous disease, non-specific interstitial
pneumonia, undefined fibrosis, aspiration, or pulmonary
Langerhans’ cell histiocytosis.48 Overall, these studies
suggest that although usual interstitial pneu­
monia issometimes present in patients with ILAs, a larger
proportion of ILAs represent smoking-related changes.
However, there is potential bias because the few studies
published focus on findings in smokers or consist of lungcancer resections. Further study is needed to determine
the frequency with which incidental histological fibroticchanges progress to clinically significant disease. To
facilitate this research, reporting guidelines recommendthat pathologists should record and categorise thepresence in resection specimens of non-neoplastic lungparenchymal changes, such as emphysema, respiratory
bronchiolitis, and interstitial fibrosis (with identificationof a discernible pattern if possible).49,50

What are the risk factors for ILAs?
Advanced age, a common feature of patients with IPF,49 isstrongly associated with ILAs in almost all studies inwhich it has been assessed.4,6,7,9,12,15,18,19,51,52 For example, insmokers with and without COPD, each 10-year increase in
age was associated with about a 2·2 times increase in theodds of detecting ILAs.3 Male sex has also been identified
as a demographic risk factor in some studies of IPF53 andhas been associated with ILAs in some,9,16 but not in
all,4,6,7,9,12,15,18,19,51,52 cohorts. For example, in smokers with andwithout COPD, each male patient had about a 1·7 times
increase in the odds of having ILAs compared with female
patients.3
Tobacco smoke exposure, commonly cited as anenvironmental risk factor for IPF as well as for otherforms of ILD,53,54 is associated with ILAs in nearly all
populations in which it has been evaluated.4,6,7,9,12,15,18,51,52
ILAs are associated with both the activity (eg, current
smoking status) and the quantity (eg, pack years) of
tobacco smoke exposure.4,6,7,9,12,15,18 For example, current
smokers had about a 1·8 times increase in the odds of
having ILAs compared with former smokers.3
In a general population-based cohort, analyses ofparticipants in MESA showed that self-reported
occupational exposures to vapours, gases, dusts, andfumes were associated with an increased prevalence ofhigh-attenuation areas and ILAs.13 In the MESA-Lungstudy,55 increased exposure to nitrogen oxides, a marker
of exposure to traffic-related air pollution, was also
associated with ILAs. Similarly, in the Framingham
Heart Study,56 elemental carbon exposure (anothercommon metric of traffic-related air pollution) was
associated with ILAs and ILA progression.
The most consistent genetic risk for both IPF and
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A

B

C

Figure 2: Imaging abnormalities that do not represent interstitial lung abnormalities(A) Focal paraspinal fibrosis. Coronal CT shows a linear fibrotic band in the medial right lower lobe, closely related
to osteophytes (arrow). (B) Centrilobular nodularity in a heavy smoker. CT shows numerous poorly definedground-glass centrilobular nodules without other findings of interstitial abnormality (circled). (C) Unilateral mild
focal abnormality. CT shows patchy ground-glass abnormality in the left lower lobe that is thought to be due toaspiration (circled).

familial interstitial pneumonia has been increased copiesof the minor allele of a common variant in the promoter ofthe MUC5B gene (rs35705950).5,57–60 Similarly, the assoc­
iations between the MUC5B promoter genotype, ILAs,6,17,61
and ILA progression27,62 have been consistently replicated.
For example, in the Framingham Heart Study, COPDGene
study, and AGES-Reykjavik cohorts,6,8,29,30,63 each copy of theminor allele of the MUC5B promoter poly­morphism is
associated with between a 1·5 and 2·7 times increase in
the risk of presenting with ILAs, particularly in those with
subpleural ILA (eg, the MUC5B promoter genotype ismore strongly associated with subpleural abnormalities
than with centrilobular nodules).5,29 Although additional
overlapping findings of genetic association have beenshown in comparisons of genome-wide association
analyses of IPF5,57–60,64 and ILAs,59 novel genetic association
with ILAs suggests that disorders other than IPF are also
likely to be present among some research participants
with these imaging abnormalities.

What are the clinical outcomes of ILAs?
ILAs have been associated with adverse clinical outcomesin numerous populations.7–9,12,14–19,29,65–68 These include
general population cohorts8,9,12,15,29,67,68 and populations ofsmokers enriched for the presence of COPD or under­
going lung cancer screening.7,9,16–19

Progression of ILAs
Estimates of the rate of imaging progression of ILAs range
from 20% over 2 years in the National Lung Screening
Trial7 to 48% over 5 years in the AGES-Reykjavik study(figure 3).29 Thus, although not all cases of ILAs progress,
progression is more likely to be detected when followed
up over longer time periods. Additionally, patients with
ILAs without clear pulmonary fibrosis might subsequently
develop traction bronchiect­
asis, honeycombing, or
patterns consist­­ent with usual interstitial pneumonia.8,29
However, the proportion of such cases that evolve to usualinterstitial pneumonia on long-term follow-up remains
unclear.
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A

B

Figure 3: Progression from subpleural non-fibrotic to subpleural fibroticinterstitial lung abnormality
High-resolution CT examination obtained in an asymptomatic, 61-year-old
ex-smoker referred for suspicion of radiographic abnormality. (A) Prone highresolution CT section at the lung bases shows subpleural lung abnormality,
primarily ground-glass opacity (arrows). (B) Prone high-resolution CT section
obtained 7 years later shows increased severity and extent of abnormality, withnew traction bronchiectasis and honeycomb cysts in the anterior and posterior
left lower lobe, indicating the interim development of lung fibrosis (arrows).
This patient was still asymptomatic at the time of this follow-up CT
examination.

Specific imaging features and patterns can identify
ILAs that are most likely to progress over a 5-year
interval.29 For example, in a study by Putman andcolleagues,29 patients with subpleural reticular changes,
lower lobe predominant changes, or traction bronchi­
ectasis had more than a six times increase in their odds
of imaging progression than those with ILAs without
these features, even after adjusting for important
covariates (eg, age and smoking history). In that study, allcases of honeycombing progressed over 5 years.
Conversely, the presence of centrilobular nodules was
associated with ILAs that were unlikely to progress.29
ILA progression and lung function decline were
explored in a Framingham Heart Study cohort.8
Progression (including both the development of new
ILAs and the progression of existing ILAs) occurred in
6% of the population over approximately 6 years. Patientswith imaging progression in the Framingham Heart
Study had an accelerated decline in forced vital capacity(FVC) compared with those patients without ILAs or
those with ILAs that did not progress. However, theannual decline in FVC in patients with ILA progression
in the Framingham Heart Study (about 60 mL per year,with an excess annual decline of about 30 mL per year
compared with those without ILAs) is substantially lessthan the annual decline in FVC generally noted among
patients with IPF (approximately 200 mL per year).
Whether the excess FVC decline associated with ILA
progression on imaging represents a small subgroupwith major FVC decline (averaging to a small FVC
decline across all progressing patients) or a larger
subgroup with subclinical disease that tends to be lesspronounced than clinically apparent IPF is not clear.

Mortality
One of the most consistent findings with regard to ILAs
is the association with increased mortality, both ingeneral population samples and among populations ofsmokers enriched for COPD or undergoing lung cancer
screening (table).8,9,16,19,29 In the Framingham Heart Study
730

and AGES-Reykjavik cohorts, this increase in mortality
was most strongly associated with imaging progressionof ILAs.8,29 In the AGES-Reykjavik cohort, specificimaging patterns indicative of pulmonary fibrosis wereassociated with earlier mortality.29 In addition to increased
all-cause mortality, ILAs were associated with increased
respiratory mortality in the AGES-Reykjavik cohort.9
From a Brigham and Women’s Hospital cohort ofpatients with systemic inflammatory response syndromeor sepsis, ILAs were associated with increased rates ofacute respiratory distress syndrome and increased inhospital mortality.65 ILAs are also associated withincreased mortality in patients with COPD and lungcancer,9,19,66 and in individuals who undergo transcatheter
aortic valve replacement.69 Increased quantitative metrics
of ILAs (based on an increased number of highattenuation areas of the lung12 and local histogram-based
methods designed to identify ILAs17) are also associatedwith increased mortality.
Although ILAs have been associated with increased
mortality from pulmonary fibrosis,9 it is important torecognise that the contribution of ILAs to these elevatedmortality rates far exceeds the expected rate of progression
to clinically detectable ILD. It is also important to notethat respiratory-related deaths, which were more common
among those with ILAs in the AGES-Reykjavik cohort,
were reported in less than 15% of those with ILAs.9 Thisobservation suggests that although some of theassociation between ILAs and death could be due topulmonary fibrosis, those patients with ILAs could
possibly be at an excess risk of death because ofaccelerated physiological ageing or other causes of deaththat are not directly related to pulmonary disease.

Lung cancer mortality and treatment toxicity
Several studies have shown an association between
pretreatment ILAs and cancer-associated mortality,
including patients with early stage cancer treated withsurgical resection,70,71 as well as patients with advanced
stage 4 disease treated with systemic therapy.66,72 The cause
of increased mortality is not clear, but other studies suggestthat lung injury risk associated with ILAs and cancer
therapies might be important. Specifically, lung irradiationand systemic treatment with chemotherapy and targetedtyrosine kinase inhibitors, immunotherapy checkpoint
inhibitors, and antibody–drug conjugates are associatedwith an increased risk of pneumonitis in patients with preexisting ILAs (figure 4). Pre-existing ILAs increase the riskof extensive radiation pneumonitis in patients with earlystage lung cancer treated with stereotactic body radio­
therapy73 and in patients with small-cell lung cancer treatedwith 50–60 Gy of thoracic radiotherapy.74
Immune checkpoint inhibitors have emerged as
standard first-line therapy for patients with advanced nonsmall-cell lung cancer and for other malignancies. Overall,
the rate of immunotherapy-associated pneumonitis isapproximately 5%, and this toxicity is manageable when
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Position Paper

recognised early and treated appropriately in accordancewith the National Cancer Institute’s Common Terminology
Criteria for Adverse Events grade at presentation.75,76
Evidence indicates that pneumonitis risk is increased by
ILAs. Nakanishi and colleagues77 examined pretreatment
chest CT scans for ILAs in 83 patients treated with the anti
PD-1 antibodies nivolumab or pembrolizumab. The
incidence of immunotherapy-associated ILD was high at
17% (n=14). Multivariate analysis showed that pre-existing
ILAs were associated with a six times increase in the riskof drug-associated ILD, with a predominant ground-glass
pattern of pneumonitis. Given the life-threatening natureof malignancies treated with immune checkpoint
inhibitors, the benefits of the therapy, and the undefinedrisks associated with ILAs, clinicians should discuss thepossible increased risk of pneumonitis with patients who
have ILAs. Additionally, clinicians should consider active
monitoring for symptoms, physiological alterations, andradiological progression of drug-associated pneumonitis(figure 5).

A

B

Figure 4: Interstitial lung abnormalities after surgery and chemotherapy forlung cancer
High-resolution CT examination in a 79-year-old man with lung cancer.
(A) A preoperative CT showed mild subpleural interstitial abnormality without
evident fibrosis (subpleural non-fibrotic). The patient developed shortness ofbreath following a fourth cycle of pemetrexed. (B) Subsequent CT showedbilateral peribronchovascular ground-glass abnormality compatible with drugrelated pneumonitis, as well as a postoperative effusion (arrows).

ILA identified (see definition in panel 1)

Consider high-resolution CT if initial scan
is incomplete or equivocal

How should ILAs be evaluated and monitored?
To date, only minimal evidence exists to support a specificmanagement plan for ILAs. The following proposal isbased on the available published literature and theconsensus clinical opinion of the authors. The first goal is
to separate those patients with current clinicallysignificant disease from individuals who might be at riskof developing disease. This distinction could beestablished by a series of questions that incorporate ageneral approach to ILD (figure 5). In all patients, astandard evaluation of potential explanations for thepresence of ILAs should occur, including factors such as
cigarette smoking or other inhaled exposures, drug
toxicity, systemic disease (eg, occult connective tissue
disorders), or recurrent aspiration of oroesophageal
contents. Individuals with respiratory symptoms or signs,
clinically relevant pulmonary physiological or gas transfer
abnormalities, or extensive CT abnormality (disease
involving three or more of the six lung zones consistingof the right and left upper, middle, and lower lung zones)
should be referred for pulmonary evaluation, ideally withaccess to multidisciplinary discussion. Management ofpatients with a diagnosed ILD should follow standard
guidelines.
Once ILD is excluded, ILAs can be separated into thoseat higher risk of progression to ILD and those at lower
risk. Risk factors for progression include cigarettesmoking, other inhalational exposures, medications,
physiological or gas exchange findings not felt to reachthe threshold of clinical significance, and specificradiological features such as evidence of fibrosis andsubpleural, basal predominant distribution (panel 2).
Follow-up of patients with ILAs can be based on thepresence of risk factors for progression. Individuals
without risk factors should be advised to return forevaluation if they develop symptoms of respiratory
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Is there evidence of clinically significant disease?
• Respiratory symptoms or physical exam
findings possibly attributable to ILD• Extensive disease on CT*• Decrements in pulmonary function or gas
exchange possibly attributable to ILD

Yes

No

Potentially clinically significant ILD

Evaluation by pulmonologist, ideallywith ILD experience, with access tomultidisciplinary discussion

ILA

Are there radiological or clinical features (panel 2)that indicate increased risk of progression(eg, usual interstitial pneumonia or probableusual interstitial pneumonia pattern)?

Clinically significant ILD

Clinically driven management
Yes
Active monitoring• Recommend risk factor reduction• Reassess clinically and repeat pulmonary
function tests in 3–12 months

No
Expectant management• Recommend risk factor reduction• Reassess if symptoms or other evidenceof progression emerge

Repeat CT at 12–24 months, or sooner
if there is clinical or physiologicalprogression

Figure 5: Proposed schema for management of interstitial lung abnormalities detected on chest CT
Action items for the radiologist are in blue, action items for the treating physician or pulmonologist are ingreen, and action items for a pulmonologist, ideally with ILD experience, are in orange. ILA=interstitital lungabnormality. ILD=interstitial lung disease. *Non-trivial abnormalities present in three or more lung zones (above
the bottom of the aortic arch, between the aortic arch and top of the inferior pulmonary vein, and below theinferior pulmonary vein).

impairment. For example, non-subpleural ILAs seldom
progress, and individuals with only these findings can befollowed up expectantly. In individuals with one or morerisk factors, systematic follow-up should be considered.
The appropriate timing of repeated clinical evaluation(including a focused history and chest exam, chest
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Panel 2: Risk factors for progression of interstitial lungabnormalities

A

B

Clinical risk factors• Cigarette smoking• Other inhalational exposures• Medications (eg, chemotherapy, immune checkpoint
inhibitors)• Radiation therapy• Thoracic surgery• Physiological or gas exchange findings at lower limits ofnormalRadiological risk factors• Non-fibrotic interstitial lung abnormalities (ILAs) withbasal and peripheral predominance• Fibrotic ILAs with basal and peripheral predominance but
without honeycombing (ILAs with probable usualinterstitial pneumonia pattern)• Fibrotic ILAs with basal and peripheral predominance andhoneycombing (ILAs with usual interstitial pneumonia
pattern)

imaging, pulmonary physiology, and gas exchange) is
unknown. In the absence of prospective data, clinicalexperience suggests that a first follow-up at 3–12 months
to look for symptomatic or physiological progression isprobably appropriate in most patients at increased risk.
Individuals with ILAs are likely to benefit from additional
clinical follow-up beyond 1 year, but the optimal
frequency and duration of follow-up is unknown.
Similarly, the optimal interval for follow-up CT scans is
unknown, but might include a follow-up scan at
12–24 months or sooner in patients who develop
symptoms or impaired pulmonary function. Progression
can be defined by the develop­ment of clinically signif­
icant respiratory symptoms and signs (eg, the newpresence of exercise limitation or characteristic crackles
on auscultation, or both), the development of abnormal
pulmonary physio­logy or gas exchange (or a clinicallysignificant decline in normal values), or an increase in
the extent of CT abnormal­
ities, particularly with thedevelopment of specific fibrotic features. Optimal
management of progressive ILAs is unknown, so thispatient group might be an appropriate population for aprospective treatment trial.
In patients with ILAs undergoing surgery or othertherapy, caution should be exercised because they appear
to be at increased risk of rapid disease acceleration or anacute exacerbation. The clinician should regard ILAs as
an important comorbidity that should be considered inplanning treatment and subsequent monitoring. Because
positive pressure ventilation might be a risk factor for
developing acute respiratory distress in patients with
ILAs, a low-volume, low-pressure ventilatory approachshould be considered for those needing mechanical732

Figure 6: Computer-based classification of interstitial lung abnormalities
with the histogram approach(A) CT images with subpleural non-fibrotic interstitial lung abnormalities andemphysema in a participant in the COPDGene study. (B) CT image overlays ofcomputer-based classification of interstitial lung abnormalities using artificial
intelligence, showing objective quantification of different injury patterns.
Regions of interstitial lung abnormality are shown in blue. Normal parenchyma(red), emphysema (green), and paraseptal emphysema (yellow) are also
subtyped.88

ventilation. Medications that are known to cause ILD
should be avoided if possible.

What is the role of quantitative evaluation?
Methods for quantitative evaluation of ILAs include
assessment of the proportion of high-attenuation areas,
local histogram evaluation, and deep learning-based
textural evaluation. Automatic quantification of CT densityof the lungs has been used to identify the proportion oflung voxels with high-attenuation areas, typically between–600 and –250 Hounsfield units (the normal CT
attenuation of the lung is about –750 Hounsfield units).12,13
High-attenuation areas are associated with elevated serum
concentrations of inflammatory biomarkers, reduced FVC
and exercise capacity, and higher mortality (including
higher mortality from ILD).12,55 The presence of highattenuation areas is also associated with a higher
prevalence of ILAs at follow-up CT.78 Despite these clear
epidemiological associations, high-attenuation areas
appear to be neither sensitive nor specific for subsequentappearance of ILAs.79 For this reason, the use of the term
subclinical ILD as a synonym for increased highattenuation areas is not recommended. The clinicalsignificance of high-attenuation areas remains unclear,
and assessment in individual patients is limited by themultiple technical and patient-related reasons for anelevated proportion of high-attenuation areas, including
scanner variation, inadequate inspiration, obesity, andpulmonary atelectasis.24
Quantitative imaging provides an objective recognitionof regional disease pattern of the lung that can increase thediagnostic reliability and severity assessment of ILD.
Computer-based CT approaches to identify interstitial
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Position Paper

A

C

B

D

Panel 3: Key uncertainties with interstitial lungabnormalities
•
•
•
•
•
•
•

Figure 7: Quantification of progression for interstitial lung abnormalities
with data-driven texture analysis(A) A baseline CT scan shows subpleural non-fibrotic interstitial lungabnormalities with fibrotic changes. (B) CT 5 years later shows clear progression.
(C) Baseline data-driven textural analysis shows overall extent of fibrosis as 1·5%(red). (D) Data-driven textural analysis of follow-up scan at 5 years shows thatthe extent of fibrosis increased to 4·6% (red).

subtypes are based on density histogram analysis, texturebased analysis, and deep learning approaches.80–87 In
general, these approaches are sensitive enough to detect
ILD in patients at high risk and provide a more reproducible
assessment than visual CT scoring.79 For ILAs, individuals
with a lower percentage of normal lung by local histogrammeasurements had a higher prevalence of clinical impair­ment, poorer quality of life, higher risk of death, andassociation with the common variant in the promoter ofthe MUC5B gene (figure 6).17 Using a different local
histogram-based system in 217 individuals undergoing
resection for lung cancer, the fibrosis score correlatedwith the presence of ILAs and was an independent
predictor of decreased disease-free survival.71 A study infamily members of individuals with familial pulmonary
fibrosis showed that data-driven texture analysis could
detect early interstitial changes with 84% sensitivity and86% specificity (figure 7).89 However, the role of quantitative
CT as a screening tool for ILAs requires further validation.
Potential sources of variation in quantitative imaging
of ILAs include dependence on training data, variation
in inspired lung volumes, sensitivity to image noisefrom CT acquisition dose, vendor differences and re­construction method, and variation in segmenting thesubpleural fibrotic lung from the chest wall. Annotateddatasets are needed to provide a reference benchmark toestablish the robustness of each approach. Consideringthat the characteristics of ILAs are subtle and varied, thestability of assessment by computer-based analysis
should be tested, improved, and applied in further
studies. New advances in artificial intelligence and deeplearning might overcome some of these limitations.86,87,90–94

Outline of future research needs and priorities
The preliminary radiological criteria for ILAs presented
in this Position Paper require robust evaluation todetermine their reproducibility and application to clinicalwww.thelancet.com/respiratory Vol 8 July 2020

•
•
•
•
•

Reproducibility of radiological criteria
Validity and efficacy of follow-up regimen
Prevalence in the lung cancer screening population
Prevalence in younger cohorts
Risk factors for progression
Natural history of non-fibrotic interstitial lungabnormalities (ILAs)
Optimal extent thresholds for predicting significant
physiological progression, development of clinicallysignificant disease, and mortality by visual andquantitative CT evaluation
Importance of incidentally identified histological evidence
of interstitial abnormality
Quantitative techniques: predictive value for adverse
outcome, technical variability, and inter-patient variability
Role of biomarkers in predicting progression
Strategy for cohort enrichment in clinical trials forpatients with ILAs that are likely to progress
Risk factors and preventive strategies for complications ofcancer treatment surgery, chemotherapy,
immunotherapy, and radiotherapy in patients with ILAs

practice, including in lung cancer screening (panel 3).
The effect of the proposed management plan on inter­mediate and long-term outcomes must be evaluated(figure 5). To under­
stand the prevalence and natural
course of ILAs in the lung cancer screening population,
ILAs should be considered as a specific subcategory
under the significant other findings modifier in the
LungRADS scoring system,95 as used in the USA; theKorean Society of Radiology has already implemented asimilar change.96,97 In addition to clarifying criteria forvisual evaluation of ILAs, quantitative CT methods forevaluation of disease extent and determination ofprogress will need to be developed and validated. An
important element will be the determination of optimal
thresholds on visual and quantitative CT that definesignificant disease by predicting significant physio­logicalprogression, the development of clinically signifi­
cantdisease, and mortality.
Since antifibrotic treatment slows the rate of physio­
logical progression in patients with IPF98,99 and in otherforms of progressive lung fibrosis,100,101 it is possible thatearly treatment in a high-risk population with ILAs
might reduce the rate of progression. However, there isa clear need for further epidemiological, biomarker,
and machine learning studies in existing and novel
cohorts to identify groups at higher risk of progression
and to understand the trajectory of progression of
ILAs to clinically significant pulmonary fibrosis.
The availability of this information would potentially
support the design of future clinical trials in higher-risk
individuals.
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Panel 4: Recommendations for the evaluation andreporting of interstitial lung abnormalities
CT protocol• Thin sections (<1·5 mm) are essential• Prone and expiratory scans might be necessary to confirm
and characterise interstitial lung abnormalities (ILAs)
See Online for appendix

CT description• Axial and craniocaudal distribution• CT findings: including ground-glass abnormality, reticularabnormality, traction bronchiectasis, honeycombing, andcysts• CT category: non-subpleural ILA, subpleural non-fibrotic
ILA, or subpleural fibrotic ILA
Clinical evaluation• Distinguish ILAs from clinically significant interstitial lungdisease (figure 5)• Identify risk factors for progression (panel 2)• Follow-up evaluation (figure 5)
Pathology evaluation• On lung cancer resections, assess background lung fromcancer resections and document histological patterns
diagnostic of suspicion for interstitial lung disease• Review such cases in a multidisciplinary team setting todetermine whether ILAs or clinically significant interstitiallung disease is present

The importance of ILAs as a risk factor for complicationsin the treatment of lung cancer requires further evaluation,for example, in clinical trials of checkpoint inhibitorswith a focus on prevention and management of acutepneumonitis. This analysis could be done retrospectively
from existing CT datasets in clinical trials and could
inform a prospective comparison of specific approaches topreventing progression in the context of thoracic surgery,radiotherapy, and chemotherapy. The role of ILAs as apredictor of acute interstitial pneumonia also merits
further evaluation, given that unsuspected usual interstitial
pneumonia has been identified in 50% of patients who diewith acute interstitial pneumonia.102 We have excluded
preclinical interstitial abnormalities identified during thescreening of individuals at high risk (eg, those withrheumatoid arthritis, scleroderma, occupational exposure,and familial interstitial lung disease) from the scope of thisPosition Paper to simplify the approaches. However, futurestudies and discussions are needed to investigate the roleof ILAs in preclinical interstitial abnormalities identified
during screening of individuals at high risk.”
Further study is needed to determine the importance ofincidentally found histological fibrosis to determine whichcases are more likely to progress to clinically significant
disease. In particular, there is an opportunity to clarify theeffect of specific histological findings and cellularsubpopulations on long-term outcome. Additional related
questions include the natural history and biological cause
734

Search strategy and selection criteria
A medical librarian searched in Medline, Embase, CochraneCentral Registry of Controlled Trials, and the HealthTechnology Assessment database to identify publications
related to interstitial lung abnormalities. We included studies
from database inception through to Feb 13, 2019, andrestricted to English language. Details of the search strategy
are provided in the appendix (pp 1–3). Key search terms were
“interstitial$”, “lung”, “abnormal$”, and “subclinical or
pre-clinical or preclinical”. The literature search resulted in
700 references, of which 616 were excluded (duplicates[n=11] and 605 references with little relevance to the key
questions based on screening of the reference title [n=455] or
the reference abstract [n=150]), yielding 84 manuscripts that
underwent review for inclusion. Review of the text found that
60 of these manuscripts were not relevant to the key
questions, resulting in 24 references that were analysed forthe final Position Paper. Additional references were added bymembers of the writing group.

of non-fibrotic ILAs, of smoking-related interstitial
fibrosis, and of pleuroparenchymal fibro­elastosis. There isalso a need for better understanding of risk factors for thedevelopment of ILAs. Finally, the recognition of ILAs
offers exciting opportunities for identifying pathogenetic
abnormalities in early pulmon­ary fibrosis and early usualinterstitial pneumonia; sequential evaluation of bio­
markers in individuals with ILAs might help to identify
biological abnormalities that predispose to subsequentdevelopment of IPF.

Conclusions
ILAs are important because they are associated withmortality as well as increased risk of complications fromsurgery, chemotherapy, and radiotherapy. Separating
clinically significant ILD from ILAs is essential. The
morphology and distribution of ILAs should be clearly
described and the descriptive categories of non-sub­pleural, subpleural non-fibrotic, and subpleural fibrotic
ILAs should be recorded in the radiology report, as thisinformation could be useful in predicting progression andmortality (panel 4). Risk factors for ILAs include age,cigarette smoking and other inhalational exposures, andgenetic markers. Although this Position Paper proposes arational strategy that can help to identify when ILAs arelikely to represent clinically significant ILD, future work isneeded to determine the best approach to follow up ILAs
in individuals in whom the evaluation is less definitive.
We believe that establishing a common terminology forcommunication and a clear under­
standing of current
knowledge are important steps towards further advancesin the multidisciplinary approach to ILAs.
Contributors
DAL developed and implemented the systematic search strategy.
CJR advised on the systematic search. All authors participated in the

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Position Paper

literature search. HH, GMH, LR, KKB, AUW, MR-J, AGN, MBB, DCC,
RSJE, CAP, KSL, YI, and DAL wrote the first draft of the Position
Paper. All authors critically reviewed the manuscript and approved thefinal version, taking accountability for the work. The Document
Development and Oversight Committee and the Executive Committeeof the Fleischner Society approved the manuscript before submission
to the journal.
Declaration of interests
HH reports grants from Canon Medical Systems and Konica Minolta;
and personal fees from Canon Medical Systems and Mitsubishi
Chemical, outside the submitted work. GMH reports personal feesfrom Boehringer Ingelheim, Gerson Lehrman Group, and Mitsubishi
Chemical, outside the submitted work. LR reports personal fees from
Biogen and ImmuneWorks; and grants and personal fees from Roche,
Boehringer Ingelheim, Celgene, Nitto, FibroGen, Promedior, Pliant
Therapeutics, Asahi Kasei, Toray, Bristol-Myers Squibb, RespiVant, andCSL Behring, outside the submitted work. KKB reports grants from the
National Institutes of Health; and advisory board participation for
Biogen, Blade, Boehringer Ingelheim, Galapagos, Galecto, Genoa,
Lifemax, MedImmune, the Open Source Imaging Consortium, Pliant,
ProMetic, Third Pole, Theravance, Three Lakes Partners, and Veracyte,
outside the submitted work. AUW reports personal fees from Roche,
Boehringer Ingelheim, and Blade, outside the submitted work.
AGN reports personal fees from Medical Quantitative Image Analysis,
Galapagos, Boehringer Ingelheim, and Roche, outside the submitted
work. RSJE reports grants from the National Heart, Lung, and Blood
Institute, during the conduct of the work; personal fees from
LeukoLabs, Boehringer Ingelheim, and Chiesi; and grants from
Boehringer Ingelheim, outside the submitted work. RSJE is also afounder and co-owner of Quantitative Imaging Solutions, which is acompany that provides image-based consulting and develops software
to enable data sharing. CJR reports grants and personal fees from
Boehringer Ingelheim and Hoffmann-La Roche, outside the submitted
work. RGB reports grants from the National Institutes of Health,during the conduct of the work; and grants from the Alpha1
Foundation and the COPD Foundation, outside the submitted work.
JMG reports grants from Infinitt Healthcare and Dongkook
Lifescience, outside the submitted work. CAP reports personal feesfrom Daiichi Sankyo and AstraZeneca, outside the submitted work.
YI reports grants from the Japanese Ministry of Health, Labour, andWelfare, and the Japan Agency for Medical Research and Development;
and other support from Boehlinger Ingelhem and Shionogi, outside
the submitted work. DAL reports personal fees from Boehringer
Ingelheim, Parexel, and Veracyte, outside the submitted work.
DAL also has a pending patent: systems and methods for automatic
detection and quantification of pathology using dynamic featureclassification (US Patent 15/595,260). All other authors declare nocompeting interests.
Acknowledgments
We are grateful for the help of Shandra Lee Knight (librarian at National
Jewish Health, Denver, USA), who assisted with the development of thesystematic search strategy and did the literature search. We are also
grateful for the librarians Myung-Ah Shim and Jaero Park for their
dedicated support in formatting the manuscript. Both librarians areworking at the Samsung Medical Information and Media Services of
Samsung Medical Center located in Seoul, South Korea. No externalsource of funding was used in the writing of the manuscript or thedecision to submit for publication.
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