CT Approach to Lung Injury

Kaitlin M. Marquis, MD • Mark M. Hammer, MD • Kacie Steinbrecher, MD • Travis S. Henry, MD • Chieh-Yu Lin, MD, PhD
Adrian Shifren, MD • Constantine A. Raptis, MD
See the invited commentary by Kligerman et al in this issue.
Author affiliations, funding, and conflicts of interest are listed at the end of this article.

Diffuse alveolar damage (DAD), which represents

the pathologic changes seen after acute lung in-
jury, is caused by damage to all three layers of the
alveolar wall and can ultimately result in alveolar
collapse with loss of the normal pulmonary ar-
chitecture. DAD has an acute phase that predom-
inantly manifests as airspace disease at CT owing
to filling of the alveoli with cells, plasma fluids,
and hyaline membranes. DAD then evolves into a
heterogeneous organizing phase, with mixed air-
space and interstitial disease characterized by vol-
ume loss, architectural distortion, fibrosis, and pa-
renchymal loss. Patients with DAD have a severe
clinical course and typically require prolonged
mechanical ventilation, which may result in
ventilator-induced lung injury. In those patients
who survive DAD, the lungs will remodel over
time, but most will have residual findings at chest
CT. Organizing pneumonia (OP) is a descriptive
term for a histologic pattern characterized by in-
tra-alveolar fibroblast plugs. The significance and
pathogenesis of OP are controversial. Some au-
thors regard it as part of a spectrum of acute lung
injury, while others consider it a marker of acute
or subacute lung injury. At CT, OP manifests with
various forms of airspace disease that are most
commonly bilateral and relatively homogeneous
in appearance at individual time points. Patients
with OP most often have a mild clinical course,
although some may have residual findings at CT.
In patients with DAD and OP, imaging findings
can be combined with clinical information to sug-
gest the diagnosis in many cases, with biopsy re-
served for difficult cases with atypical findings or
clinical manifestations. To best participate in the
multidisciplinary approach to patients with lung
injury, radiologists must not only recognize these
entities but also describe them with consistent
and meaningful terminology, examples of which
are emphasized in the article.
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RSNA, 2023 • radiographics.rsna.org

CHEST IMAGING
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Supplemental RadioGraphics 2023; 43(7):e220176
https://doi.org/10.1148/rg.220176
Material
Content Codes: CH, CT
Abbreviations: ARDS = acute respiratory
distress syndrome, DAD = diffuse alveolar
Invited damage, EVALI = e-cigarette or vaping–
Commentary associated lung injury, NSIP = nonspecific
interstitial pneumonia, OP = organizing
Quiz questions for this
article are available
pneumonia
in the supplemental
material.
TEACHING POINTS
„ The appearance of DAD at CT reflects its underlying pathogenesis, with spe-
cific findings depending on the time at which the patient is imaged after the
insult. In the acute phase, patients with DAD most commonly show bilateral
patchy—but often extensive—airspace opacities (ground-glass and consoli-
dation) with areas of lobular and geographic sparing.
„ Progression to organizing phase DAD, which is a mixed airspace and inter-
stitial process at CT, takes place over days to weeks after the initial insult.
Overall airspace opacification, particularly in regions of ground-glass opacity,
improves as the initial capillary permeability edema resolves. However, as al-
veoli collapse, volume loss develops with areas of progressive atelectasis and
traction bronchial dilatation. Because of this, regions of consolidation can con-
tract and become more dense than in the early phase; this does not represent
worsening but simply the natural course of DAD.
„ The majority of patients who survive DAD will have permanent abnormalities
at follow-up CT. There is no single CT appearance that results, and the specif-
ic findings are variable, likely reflective of the degree and duration of illness,
variable outcomes of the complex remodeling of the damaged lung, VILI,
and superimposed complications incurred during hospitalization. CT findings
that can be observed in patients after DAD include persistent airspace opac-
ities (predominantly ground-glass, less commonly consolidative), fibrotic-like
changes (intralobular septal thickening, traction bronchiectasis, and rarely hon-
eycombing), parenchymal bands or scars, architectural distortion, and areas
of permanent parenchymal destruction (pneumatoceles, focal emphysema).
„ The CT appearance of OP is extremely variable. Although the term OP pattern
is frequently used, this is largely unhelpful and potentially even misleading for
the radiologist, as even cursory experience with OP would lead a reader to
quickly recognize that there is no single characteristic pattern. Attempting to
characterize one single CT pattern is an oversimplification that will lead to
underdiagnosis and misinterpretation of OP. In addition, it is not possible to
reliably correlate CT findings of OP with an underlying trigger: OP is a non-
specific response, and individual triggers can produce a wide spectrum of CT
findings in different patients. Similarly, the same triggers that can cause OP
can result in DAD in more severely ill patients.
„ The most common CT manifestation of OP is airspace disease (consolida-
tive, ground-glass, or mixed) that is bilateral and reasonably symmetric. OP
is more commonly peripheral and mid to lower lung predominant, but upper
lobe involvement is not infrequent and thus should not be used as a negative
for the diagnosis of OP (rare cases may be exclusively upper lobe). OP can be
diffuse, and these manifestations will overlap in appearance with the acute
phase of DAD.
Introduction
Lung injury is a common indication for patients to undergo
CT of the chest. From a histopathologic standpoint, the most
severe manifestation of acute lung injury, diffuse alveolar
damage (DAD), involves damage to all three layers of the alve-
olar wall and ultimately results in alveolar collapse with loss
of the normal pulmonary architecture. Patients with DAD
are typically very ill with respiratory compromise that often
requires mechanical ventilation, have a protracted clinical
Volume 43 Number 7
Marquis et al
course with high mortality, and are likely to suffer perma-
nent functional impairment if they survive (1–3). Organizing
pneumonia (OP) is the other major histopathologic pattern of
lung injury and is characterized by intra-alveolar fibroblastic
proliferation, widened septa, and relatively preserved archi-
tecture. Patients with OP are less severely ill, their condition
may spontaneously improve or be managed with corticoste-
roids, and they most commonly return to their baseline level
of respiratory function.
Less common histologic manifestations of lung injury are
also recognized, including acute fibrinous and OP (AFOP)
and granulomatous OP (GOP). Interestingly, while both DAD
and OP can manifest clinically in patients with acute-onset re-
spiratory symptoms, some authors regard DAD and OP as op-
posite ends of a spectrum of acute lung injury, whereas others
see DAD as the pathologic pattern of acute lung injury while
regarding OP as a histologic pattern of a subacute reparative
response (2,4–6). In subsets of cases, DAD and OP coexist.
While these distinctions and the relationship between
DAD and OP are still a matter of debate, it is critical to recog-
nize that these entities represent common end points of lung
injury and are not specific to the original insult. The descrip-
tion of lung injury often emphasizes the insult (or trigger).
This is the impetus for descriptive terms such as coronavirus
2019 (COVID-19) pneumonia, e-cigarette or vaping–associated
lung injury (EVALI), and immunotherapy-related lung disease.
While these terms have relevance from a clinical perspective—
patients who are exposed to these and other insults do develop
a respiratory illness—their use in the context of histopathologic
and imaging manifestations is problematic. Indeed, studies ex-
amining pathologic specimens in these groups of patients over-
whelmingly demonstrate OP and DAD, the proportional rep-
resentation of which is correlated with the severity of illness
and whether the specimens were obtained with surgical biopsy
or autopsy (7–10). Likewise, as one would expect on the basis
of the histopathologic studies, the imaging findings of these
groups have extensive overlap, as they are all ultimately reflec-
tive of common pathways of lung injury (Fig 1).
From the vantage point of the radiologist, this is good news.
Instead of needing to learn the specifics of an ever-expanding
list of diseases, an understanding of the imaging manifesta-
tions of lung injury is advantageous, as one needs to recognize
only a limited number of entities resulting from an ever-ex-
panding list of insults. While this may seem straightforward,
lung injury is a complex and often poorly understood topic.
Both DAD and OP have variable and overlapping imaging
findings, as well as other potential mimics. Furthermore, the
terminology used by radiologists to describe lung injury and
its evolution is inconsistent.
The purpose of this article is to provide a comprehensive
framework that will serve to organize the radiologist’s approach
to lung injury. An important emphasis is correlation of the CT
findings with their underlying pathogenic mechanisms. Keys
for participation in the multidisciplinary approach to these
patients—including suggested terminology, differential diag-
noses, and use of biopsy—are also discussed. This information
will be of value in diagnosis and follow-up, ultimately facilitat-
ing optimal image interpretation and patient care.
2 radiographics.rsna.org
July 2023 Marquis et al

Figure 1. The “chest disease life cycle”: (1) The chest disease life cycle begins with the discovery of a new trigger.
Potential triggers include infectious agents, recreational drugs, medical therapies, and environmental exposures.
(2) This trigger will cause acute and subacute illnesses with variable combinations of constitutional, respiratory, and
gastrointestinal symptoms. (3) A subset of patients who manifest respiratory symptoms will undergo imaging with
chest radiographs and CT. At CT, imaging findings will be variable, ranging from mild ground-glass opacity to diffuse
and confluent consolidation, and largely depend on the severity and duration of the illness. While most patients who
survive the initial illness will improve, others with more severe illness may have residual scarring and fibrosis. (4) As
new triggers are identified, the scientific community rushes to study the imaging appearance of a particular insult,
such as coronavirus 2019 (COVID-19), EVALI, or immunotherapy-related pneumonitis. These findings are published
throughout the medical literature, creating the misconception that a trigger may be identified based on the imaging
appearance. (5) Eventually, histopathologic assessments confirm that the pathophysiologic mechanism underlying
these illnesses is lung injury, DAD and OP most commonly. It is essential for the radiologist to recognize that while
certain imaging findings may be more common with a particular trigger, the imaging manifestations reflect nonspe-
cific injury to the alveolar capillary unit and are not unique to the trigger.

Diffuse Alveolar Damage
Pathogenesis and Histopathologic Features
DAD is a descriptive term for the histopathologic changes that
follow an acute insult to the alveolar-capillary interface, which
consists of (a) the alveolar epithelium (type I and type II pneu-
mocytes), (b) the capillary endothelium, and (c) the intervening
interstitial space (the fused basement membranes of the epi-
thelium and endothelium, connective tissue, fibroblasts, and
tissue macrophages) (2). DAD begins with damage to all three
layers of the alveolar wall; the term diffuse is derived from this
transmural damage to the alveolar-capillary unit and is not re-
lated to the extent of involved lung parenchyma.
Endothelial damage permits leakage of plasma fluid into
the interstitium and alveoli. Epithelial and basement mem-
brane damage is widespread with sloughing into the alveoli.
This admixture of plasma proteins and sloughed epithelial
components forms hyaline membranes, the histologic hall-
mark of acute phase DAD. Hyaline membranes are reddish or
pinkish secondary to eosinophilic material. During the acute
phase, which occurs in the first few days after an insult, the
process is airspace predominant with minimal interstitial in-
flammation. In some cases, thrombi may also form in small
arteries (2).
The organizing phase of DAD evolves days to weeks after
the acute phase. In this stage, alveolar type II pneumocyte hy-
perplasia and metaplasia occur as an attempt to repopulate
Volume 43 Number 7
the damaged epithelium and basement membrane. Fibro-
blasts proliferate in the alveolar septa and sometimes in the
small airways. These events can ultimately lead to alveolar
collapse with associated volume loss. Later, the collapsed al-
veoli become incorporated into alveolar walls, which can re-
sult in increased interstitial thickness. Small infarcts may also
be seen owing to the presence and organization of thrombi in
small arterioles.
While damaged lung undergoes organization, ongoing
and recurrent injury may result in acute phase DAD in other
previously unaffected areas. Thus, specimens often show
overlap of both acute and organizing phases of DAD. Finally,
OP—with its less severe alveolar-capillary unit damage and
intra-alveolar fibroblast plugs—may also be present. In total,
the organizing phase of DAD has a heterogeneous appearance
and is a mixed airspace and interstitial process (2) (Figs 2, 3).
Different descriptions for this phase of the process may be
used by pathologists, including DAD itself, organizing lung
injury pattern, and subacute lung injury pattern.
Clinical Considerations: Causes, Manifestations, and
Management
DAD most commonly occurs secondary to a definable insult,
with important triggers summarized in Table 1. In some cases,
the cause of DAD is not identifiable. These patients with idio-
pathic DAD are described as having acute interstitial pneumo-
nia (also historically referred to as Hamman-Rich syndrome)
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July 2023 Marquis et al

Diffuse Alveolar Damage

Acute Phase DAD
1. Injury to all 3 layers of the alveolar
capillary interface (alveolar epithelium,
capillary endothelium and intervening
intersal space including fused basement
3. Hyaline membrane
membrane)
Sloughed alveoli, plasma
2. Damage triggers an immune membranes and fluid coalesce
response allowing cells to fill the
alveoli through the leaky
capillaries

Neutrophil
Organizing Phase
Fibroblast
Macrophage
Alveolar collapse
Type 1 Alveolar pneumocyte Type 2 pneumocytes proliferate
to replace injured epithelium
Type 2 Alveolar pneumocyte
Fibroblast proliferaon
Red blood cell

Figure 2. Diagram shows the pathogenesis of DAD.

Figure 3. Evolution and histologic pattern of DAD. (A) Diagram shows the evolution of DAD over time. DAD has two phases, characterized by an early ex-
udative phase (1–7 days) and a proliferative or organizing phase (9–17 days). The acute phase begins within the 1st week after injury to the alveolar-capillary
interface and results in capillary leak and noncardiogenic edema. This fluid aggregates with plasma cells and damaged epithelium, forming the character-
istic eosinophilic hyaline membranes. (Fig 3A adapted, with permission, from reference 2.) (B, C) Histologic pattern of DAD. Photomicrograph (B) shows the
characteristic eosinophilic hyaline membranes (arrows) filling alveolar spaces, a process that peaks at 3–4 days. (Hematoxylin-eosin [H-E] stain; original mag-
nification, 40.) Photomicrograph (C) shows the organizing stage of DAD, which evolves days to weeks after the initial injury. This stage is characterized
histologically by hyperplasia of type II alveolar pneumocytes (arrows) as well as fibroblastic proliferation, which attempt to repopulate the damaged epithelial
basement membrane. Histologically, the development of fibrosis after acute lung injury is primarily related to remodeling of the alveoli and interstitium, re-
sulting in architectural distortion and alveolar collapse. (H-E stain; original magnification, 40.)

(2,11). (Note that acute interstitial pneumonia is a misnomer, as
DAD represents a combined airspace and interstitial process.)
It is likely that such patients have DAD related to an undiag-
nosed mild infectious or otherwise not yet discovered trigger
rather than a spontaneous process. This hypothesis is supported
by patients with idiopathic DAD often reporting an antecedent
febrile illness or constitutional symptoms (2,12).
Patients with DAD present with acute-onset shortness of
breath, developing over 6–72 hours, but symptoms can be pres-
ent for up to a week. Fever varies considerably on the basis of
the cause, and there may be a history of an antecedent viral
syndrome or known insult. In contrast to patients with OP, pa-
tients with DAD are often severely hypoxemic and require me-
chanical ventilation. Most patients with DAD meet the criteria

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July 2023
Table 1: Examples of Common Causes of Lung Injury
Pulmonary insult
Medications or drugs
Infections
Aspiration
Toxic inhalants (vaping, smoke inhalation)
Near drowning
Radiation pneumonitis
Pulmonary contusion or laceration
Transfusion-related acute lung injury (TRALI)
Systemic insult
Sepsis
Severe trauma
Pancreatitis
Surgery
Burn
Component of another disease or process
Connective tissue diseases (rheumatoid arthritis, systemic
lupus erythematosus, scleroderma, polymyositis or derma-
tomyositis)
Acute exacerbation of interstitial lung disease (ILD)
Vasculitis (granulomatosis with polyangiitis, microscopic
polyangiitis)
Pulmonary infarct
Lung cancer
Idiopathic
Acute interstitial pneumonia = idiopathic DAD
Cryptogenic organizing pneumonia = idiopathic OP
Note.—This is not intended to be an all-inclusive list, given that
almost any insult can result in lung injury and that new triggers
are continually being identified.
for acute respiratory distress syndrome (ARDS), as defined by
the Berlin Criteria. The Berlin Criteria are summarized in Table
2 and depend on the acuity of presentation, imaging findings,
and impaired oxygenation in the absence of heart failure or
volume overload (13).
While DAD is frequently described as the pathologic cor-
relate of ARDS, these entities do not always coexist. Uncom-
monly, patients can have DAD but not meet the clinical criteria
for ARDS. This can occur in acute exacerbations of interstitial
lung disease and primary graft dysfunction in patients with
lung transplants (4,14–17) (Fig S1). More importantly, in au-
topsy and lung biopsy studies in patients meeting clinical cri-
teria for ARDS, only half of patients were found to have DAD
at histopathologic analysis, with the second most common
histopathologic diagnosis being acute pneumonia without
DAD (1,14,18–21). This distinction has been correlated with
outcomes, as several studies have reported increased mortal-
ity in patients with ARDS and DAD compared with patients
with ARDS but without DAD (1,14,22). Furthermore, patients
with ARDS and DAD were considered by Lorente et al (23) as
having a specific subphenotype that included a lower ratio of
Pao2 to fraction of inspired oxygen (Fio2), decreased dynamic
respiratory system compliance, and a higher sequential organ
failure assessment (SOFA) score. In this study, patients with
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Marquis et al
Table 2: Berlin Criteria for ARDS
Aspects of
Criteria Descriptions of Criteria
Timing Within 1 week of a known clinical insult or
new or worsening respiratory symptoms
Chest imaging Bilateral opacities not fully explained by effu-
(chest radiog- sions, lobar or lung collapse, or nodules
raphy or CT)
Origin of edema Respiratory failure not fully explained by
cardiac failure or fluid overload, objective
assessment to exclude hydrostatic edema if
Mild: Pao2/Fio2 = 200 to ≤300 mm Hg with
no risk factors present
PEEP/CPAP ≥ 5 cm H2O
Hypoxemia
Moderate: Pao2/Fio2 = 100 to ≤200 mm Hg
(Pao2/Fio2)
with PEEP/CPAP ≥ 5 cm H2O
Severe: Pao2/Fio2 ≤ 100 mm Hg with PEEP/
CPAP ≥ 5 cm H2O
Note.—CPAP = continuous positive airway pressure, Fio2 =
fraction of inspired oxygen, PEEP = positive end-expiratory
pressure.
ARDS and DAD were also more likely to die of refractory hy-
poxemia and less likely to die of shock. As such, given differ-
ences in prognosis and the potential for different treatment
pathways, ARDS and DAD are not equivalent and should not
be used interchangeably. Of particular relevance for radiolo-
gists, the term ARDS represents a clinical syndrome and not
an imaging diagnosis. Thus, this term should not be used in
radiology reports in an attempt to describe imaged disease.
Treatment of DAD is largely supportive, frequently requiring
mechanical ventilation and more advanced support techniques
including extracorporeal membrane oxygenation (ECMO)
therapy. Corticosteroids are variably used but are probably
beneficial (24). Patients often have an extended course in the
intensive care unit, which may be complicated by nosocomial
infections. Hospital mortality for patients with DAD is high,
reported to be approximately 40% (3). Patients who survive an
episode of DAD have a wide range of outcomes and frequently
have residual functional impairment (25,26).
CT Features
The appearance of DAD at CT reflects its underlying pathogen-
esis, with specific findings depending on the time at which the
patient is imaged after the insult. In the acute phase, patients
with DAD most commonly show bilateral patchy—but often
extensive—airspace opacities (ground-glass and consolidation)
with areas of lobular and geographic sparing (Fig 4). Depen-
dent atelectasis is also common. Smooth septal thickening may
be present and produce a “crazy-paving” pattern. These find-
ings often develop rapidly (over the course of hours to days), a
characteristic best appreciated on sequential chest radiographs.
The airspace disease seen in the acute phase of DAD re-
flects the initial sequela of damage to the alveolar-capillary
unit, specifically noncardiogenic pulmonary edema related to
increased permeability and alveolar opacification related to
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July 2023 Marquis et al

Figure 4. Acute phase DAD in a 57-year-old woman 2 months after diagnosis of anti-MDA5 dermatomyositis. Axial
CT images show extensive ground-glass opacities with mid to lower lung predominance and spared areas of normal
lung. Of note, while there is mild smooth septal thickening in the lung bases, this is not the predominant feature. The
upper lungs were essentially entirely spared (not shown). The differential diagnosis for these findings includes acute
phase DAD and extensive OP. The patient died 3 weeks later; autopsy demonstrated acute phase DAD with pulmo-
nary edema and widespread diffuse early subpleural fibrosis and focal microscopic honeycombing in the lower lobes.

hyaline membrane formation as well as cells leaking into the
alveoli (4). Previous work on the role of CT in patients with
early acute lung injury who met criteria for ARDS did suggest
that in patients with direct pulmonary insults such as pneu-
monia, involvement tended to be asymmetric, while indirect
systemic insults, such as sepsis or medication toxic effects,
more commonly manifested as symmetric ground-glass and
dorsal consolidation. These studies evaluated limited num-
bers of patients, and universal application is difficult, particu-
larly considering that patients may have coexisting direct and
indirect triggers (27–30).
Progression to organizing phase DAD, which is a mixed
airspace and interstitial process at CT, takes place over days
to weeks after the initial insult. Overall airspace opacification,
particularly in regions of ground-glass opacity, improves as
the initial capillary permeability edema resolves. However, as
alveoli collapse, volume loss develops with areas of progres-
sive atelectasis and traction bronchial dilatation. Because of
this, regions of consolidation can contract and become more
dense than in the early phase; this does not represent worsen-
ing but simply the natural course of DAD (Figs 5, 6, S2). Later,
regions of fibrosis, architectural distortion, and parenchymal
loss can result as the normal lung architecture is destroyed,
with collapse of the alveoli and incorporation of alveolar de-
bris into alveolar walls (Fig 7). In addition, new areas of focal
capillary permeability edema can develop owing to superim-
posed acute phase DAD (2,4) (Fig 8).
Since DAD impairs gas exchange, mechanical ventilation
is often required. Pulmonary compliance is also decreased,
and high pressures are then diverted to the remaining aer-
ated portions of the lungs, which are frequently anterior (14).
While lung-protective strategies—including optimized positive
end-expiratory pressure (PEEP) ventilation, prone positioning,
and conservative fluid management—are used to minimize
ventilator-induced lung injury (VILI), barotrauma may still re-
sult (31,32). Findings of barotrauma in ventilated patients with
DAD include pulmonary interstitial emphysema, pneumotho-
rax, pneumomediastinum, and pneumatocele formation. As
a late complication, ventilator-associated fibrosis can develop
with an anterior predominance, as the consolidated dependent
lung is relatively protected (4). The combined findings of evolv-
ing organizing phase DAD and VILI lead to an increasingly het-
erogeneous appearance at CT (Fig S3).
Patients with organizing phase DAD are at risk for additional
complications. Owing to an inflammatory prothrombotic state,
there is an increased risk of pulmonary embolism (33–37). In
addition to identifying the emboli themselves with dedicated
CT pulmonary angiography, development of parenchymal
features suggestive of pulmonary infarction should prompt
further investigation for superimposed pulmonary embolism.
Nosocomial pneumonias are another important complication.
New areas of focal airspace disease (particularly if they are
centrally necrotic, nondependent, or not associated with local
volume loss, as is typical of organizing phase DAD) or discrete
centrilobular nodules should prompt microbiologic testing and
the addition of antibiotic therapy if not already in use. In our
experience, however, nosocomial pneumonias in patients with
DAD may be difficult to identify at CT given the extensive back-
ground parenchymal abnormality (38).
The majority of patients who survive DAD will have per-
manent abnormalities at follow-up CT (39–46). There is no
single CT appearance that results, and the specific findings are
variable, likely reflective of the degree and duration of illness,
variable outcomes of the complex remodeling of the dam-
aged lung, VILI, and superimposed complications incurred
during hospitalization. CT findings that can be observed in
patients after DAD include persistent airspace opacities (pre-
dominantly ground-glass, less commonly consolidative), fi-
brotic-like changes (septal thickening, traction bronchiecta-
sis, and rarely honeycombing), parenchymal bands or scars,
architectural distortion, and areas of permanent parenchymal
destruction (pneumatoceles, focal emphysema). There is typ-
ically no favored craniocaudal distribution, but the fibrot-
ic-like changes may have an anterior distribution, particularly
damage related to VILI (39,42,43,47) (Fig S4). Whether related
to the prior DAD itself or concomitant effects of the trigger,

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Figure 5. Acute and organizing phase of DAD in a 65-year-old man

with ARDS after prolonged surgery for sarcoma resection. (A) Axial CT
image on postoperative day 7 shows typical findings of acute phase DAD,
with diffuse bilateral and relatively symmetric airspace opacities with
ground-glass and dependent consolidation as well as areas of subpleural
sparing. The patient had clinical ARDS requiring prolonged postoperative
intubation. (B) Axial CT image on postoperative day 19 shows organizing
phase DAD, with increased opacification and volume loss, architectural
distortion, and bronchial dilatation. (C) Axial CT image 40 days after the
original examination shows substantial improvement, with mild residual
anterior-predominant opacities and architectural distortion.

Figure 6. Acute and organizing DAD with areas of OP in a 36-year-old woman with a history of vaping tetrahydrocannabinol
(THC) who presented with acute respiratory failure. (A) Initial axial CT image shows extensive bilateral ground-glass opacity
with areas of spared lung. These CT findings carry a differential diagnosis of acute phase DAD, extensive OP, non-DAD pul-
monary edema, or acute infectious pneumonia. Cardiac and infectious workups showed negative results, and the patient’s
clinical condition deteriorated. (B) Axial CT image 2 weeks later shows improvement of the left-sided ground-glass opacity
and increased opacification on the right with extensive volume loss and new bronchial dilatation. A right pneumothorax was
also present secondary to barotrauma. This increasing heterogeneity and bronchial dilatation are characteristic findings of
organizing phase DAD. The patient did not survive; autopsy showed acute and organizing DAD with areas of OP.

mosaic attenuation with air trapping from small-airways dis-
ease is often superimposed on the parenchymal abnormalities
(48,49).
The temporal evolution of these CT findings is variable and
not well studied, but in our experience the majority of patients
reach a relatively fixed end point at CT in the 6–24 months
after the original episode of DAD. Evolution over the 1st year
is not uncommon, and patients should not be described as
having permanent changes (fibrosis, bronchiectasis) until CT
findings are shown to be stable over time. Importantly, it is
not typical for patients to develop a progressive fibrotic lung
disease after an episode of DAD; rather, their lungs typically
undergo remodeling, often with some improvement at imag-
Volume 43 Number 7
ing before reaching a new baseline both at imaging and from
a clinical perspective (Fig 9).
Organizing Pneumonia
Pathogenesis and Histopathologic Features
Organizing pneumonia is a descriptive term that refers to a
histologic pattern characterized by intra-alveolar fibroblast
plugs. While some pathologists regard OP as a potential di-
rect sequela of acute lung injury or as part of a spectrum of
response to acute lung injury with DAD, an evolving under-
standing of OP has led others to view it as a marker of a non-
specific subacute reparative response that may or may not be
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July 2023 Marquis et al

Figure 7. Acute interstitial pneumonia in a 23-year-old woman with dyspnea. (A) Axial CT image shows patchy ground-glass opacity with areas of spared
lung and mild anterior bronchial dilatation. Infectious pneumonia was initially diagnosed, but her condition did not improve and progressive respiratory fail-
ure developed. (B) Axial CT image 3 weeks later shows acute and organizing phase DAD, with diffuse ground-glass opacity, progressive volume loss, and
bronchial dilatation. The patient declined clinically and died 1 week later; autopsy demonstrated acute and organizing phase DAD. (C) Gross photograph of
the right lung in cross section shows diffuse consolidation and hemorrhage (arrows). As there was no known trigger, the patient was given a final diagnosis
of acute interstitial pneumonia.

Figure 8. Acute and organizing phase DAD secondary to immunotherapy in a 65-year-old man with hepatocellular carci-
noma who presented with respiratory failure after initiation of immunotherapy. (A) Axial CT image shows bilateral ground-
glass opacity with areas of sparing, consistent with acute phase DAD. (B) Axial CT image 5 weeks later shows organizing
lung injury with temporal heterogeneity, characterized by areas of improved and increased opacification (arrowhead) with
volume loss, architectural distortion, and bronchial dilatation (long arrows). Note that in areas of previously spared lung, there
is new ground-glass opacity (short arrow), consistent with superimposed acute phase DAD, demonstrating that these phases
occur in tandem and simultaneously in different parts of the lung. The patient died 6 days after the second examination.

related to an acute lung injury (2,4–6). Some of this contro-
versy is likely related to the fact that pathologists encounter
the histologic pattern of OP at single time points in a variety
of clinical settings, such as connective tissue disease–related
OP, in which the OP is not the primary reason for the patient’s
clinical presentation.
While there is no consensus on the pathogenesis of OP, for
the purpose of the current discussion, Cottin and Cordier (50)
provide a useful interpretation of its origin by likening the
process to what happens with a skin wound. In their hypoth-
esis, an injury to the alveolar epithelium leads to pneumocyte
cell death and small gaps in the basal lamina, which allow
proteins and inflammatory cells to leak into the airspaces.
This results in accumulation of fibrin and inflammatory
cells, which are replaced by clusters or buds of myofibroblasts
and alternating layers of collagen bundles; these are the in-
tra-alveolar fibroblast plugs, or Masson bodies, the histologic
hallmark of OP. While the fibroblast plugs organize in the
airspaces, alveolar epithelial cells also proliferate and fix the
“holes” caused by the original injury, restoring the integrity of
the alveolar-capillary unit (2,50) (Fig 10).
At histologic analysis, OP is classically described as having
a peribronchiolar distribution, which means that airspaces
associated with distal bronchioles (terminal and respiratory
bronchioles) are preferentially affected, with variable ad-
ditional involvement of the bronchioles and alveolar ducts
themselves (2) (Fig 11). Of note, the bronchiolar involvement
is the explanation for the old term for OP, bronchiolitis oblit-
erans organizing pneumonia; this term is no longer preferred.
The peribronchiolar pattern is not always present, and OP can
also be more diffuse, particularly when seen in the context
of DAD. Spared areas are common, with normal parenchyma
adjacent to involved areas. OP can also be seen with oblitera-
tive bronchiolitis in patients with combinations of small-air-
way and parenchymal injury (2,51).
In OP, the alveolar architecture is typically preserved,
and the alveolar septa may have nonspecific thickening due
to a chronic inflammatory cell infiltrate and pneumocyte

Volume 43 Number 7 8 radiographics.rsna.org

July 2023 Marquis et al

Figure 9. Long-term evolution of DAD after coronavirus

2019 (COVID-19) infection. (A) Axial CT image shows findings
of organizing phase DAD during initial hospitalization. (B) Six-
month follow-up axial CT image after discharge shows a de-
crease in opacification, with persistent anterior-predominant fi-
brotic change, architectural distortion, and bronchial dilatation.
(C) Axial CT image at 8 months shows continued decrease in
the ground-glass opacity, with mild residual anterior-predom-
inant septal thickening and architectural distortion. The pa-
tient’s residual dyspnea was stable from 8 to 18 months.
(D, E) Axial CT images at 18 months show no change, with
persistent heterogeneous areas of mosaic attenuation (arrows
in D) that demonstrate air trapping in the expiratory phase (ar-
rows in E), consistent with small-airways disease.

hyperplasia (2). As such, while OP is included in the American
Thoracic Society–European Respiratory Society classification
of idiopathic interstitial pneumonias, it is primarily an airspace
process (2,51).
Clinical Considerations: Causes, Manifestations, and
Management
When OP is the principal process in the lung, it is most of-
ten secondary to a definable pulmonary insult, a diagnosis
described as secondary OP. Causes of secondary OP are vari-
able, similar to DAD, and are summarized in Table 1. Less
commonly, OP can manifest as a primary process in the lung
without a definable pulmonary insult, conferring a diagnosis
of cryptogenic OP. In patients with cryptogenic OP or sec-
ondary OP, symptoms range from none to a flulike illness in-
cluding cough, dyspnea, fevers, malaise, sweats, and weight
loss; this clinical manifestation is typically over the course
of days to weeks and relates to the understanding of OP as
a subacute reparative process. Patients will frequently have
experienced failed empirical antibiotic therapy for presumed
infectious pneumonia.
Volume 43 Number 7
Importantly, there is no known difference in the patho-
genesis or clinical manifestation between cryptogenic OP and
secondary OP. As such, when OP is suspected as a diagno-
sis, an investigation for an underlying definable pulmonary
insult should be performed. If one is found, this insult can
be removed or treated. While spontaneous remission can be
seen in 50% of mild cases of clinical OP, corticosteroids and
other immunosuppressive drugs can be used to provide more
rapid resolution. Relapses are common but are not known to
affect long-term outcomes in terms of morbidity and mortal-
ity (52–54).
OP can also be present as a minor pathologic component of
another disease. This can occur in the context of fibrotic lung
diseases as a minor component (usual interstitial pneumonia,
hypersensitivity pneumonitis) or mixed component (nonspe-
cific interstitial pneumonia [NSIP]) of the process or be seen
as part of an acute exacerbation of an interstitial lung disease.
OP may also occur at the periphery or as a focal manifestation
of other lung diseases, including cancers, infarcts, aspiration,
abscesses, infectious pneumonias, and vasculitis. In these con-
texts, symptoms are often related to the underlying disease
9 radiographics.rsna.org
July 2023
Organizing Pneumonia
1. Damage to alveolar
capillary interface
2. Alveolar basement
membrane denuded
Figure 10. Diagram shows the pathogenesis of OP proposed by Cottin and Cordier (50).
process itself; as a result, treatment is directed at the dominant
disease process. In situations in which OP is thought to result
in an exacerbation of disease, immunosuppressive therapy may
be pursued (52).
CT Features
OP can manifest with a wide range of CT findings. Attempts
to correlate the histopathologic features of OP with its imag-
ing appearances are problematic, as these typically lack gross
pathologic correlates and in turn require assumptions as to
how microscopic findings relate to macroscopic imaging ap-
pearances (55–57). Furthermore, as experience with CT has
grown over the past several decades, it has become evident
that OP can have an incredibly variable appearance at CT.
To better understand this relationship, it is useful to consider
at what structural level of the lung OP typically occurs and how
this relates to what is observed at CT. At CT, the smallest struc-
tural unit of the lung that can be observed is the secondary
pulmonary lobule. Veins and lymphatics travel in connective
Volume 43 Number 7
Marquis et al
3. “Fibroblasc Plug”
Leakage of fluid and
plasma proteins into
alveoli which coalesce
into eosinophilic rich
plugs
4. Repaired alveolar
epithelium and
capillary epithelium
Figure 11. Histologic features of normal alveoli
and OP. (A) Histologic features of normal alve-
oli. Photomicrograph shows normal alveoli as a
single-layer thin membranous structure (arrows)
composed of primarily endothelial cells with a few
alveolar cells. (Hematoxylin-eosin [H-E] stain; orig-
inal magnification, 200.) (B) Histologic features
of OP. Photomicrograph shows fibroblastic plugs
(arrows) filling the alveolar ducts and spaces. Note
that there are normal uninvolved airspaces (*)
nearby. The alveolar septa are mildly thickened
with scattered inflammatory cells, but the airspace
process is the dominant finding. (H-E stain; origi-
nal magnification, 100.)
tissue along the periphery of the secondary pulmonary lobule
(the interlobular septa), while a pulmonary artery branch and
accompanying lobular bronchiole travel centrally.
The lobular bronchiole is best considered a preterminal
bronchiole and gives rise to smaller preterminal and terminal
bronchioles. Terminal bronchioles lead to acini, which are be-
low the resolution of CT. Terminal bronchioles within the acini
branch into primary lobules via respiratory bronchioles, alveo-
lar ducts, and alveoli (58). Gas exchange takes place in the pri-
mary lobules, at the level of respiratory bronchioles and distally.
Importantly, OP and its hallmark filling of the airspaces and
bronchioles with fibroblastic plugs takes place predominantly
at the level of the primary pulmonary lobule, which is below
the resolution of CT. As such, it can be inferred that OP will
lead to airspace disease at CT, which is indeed its predominant
manifestation. As a caveat, it should be noted that while this
process is described as peribronchiolar in terms of its histo-
pathologic features, the bronchioles that are referenced in that
context are well below the level of resolution of CT (Fig 12).
10 radiographics.rsna.org
July 2023
Lobar bronchi
hi
Segmental bronchi
hi
Subsegmental bronchi
chi
Secondary Pulmonary Lobule
"Lobular bronchiole"
(terminal bronchiole)
3-4 pre-terminal and
terminal bronchioles
5-10 acini (respiratory
bronchioles, alveolar ducts and
alveoli)
Figure 12. Diagram shows bronchial divisions and the secondary pul-
monary lobule. The lobular bronchiole, which is typically a terminal bron-
chiole, travels in the center of the secondary pulmonary lobule. Normal
lobular bronchioles are below the resolution of CT but may be seen when
they are plugged, their wall is thickened, or they are dilated. Gas exchange
takes place distal to lobular bronchioles, at the level of the respiratory
bronchioles and distally. These more distal bronchioles and airspaces are
also where OP and its hallmark filling of the airspaces with fibroblastic
plugs occurs. As such, OP is primarily an airspace process at histopatho-
logic analysis and CT.
In considering the CT appearances of OP, it is first helpful
to define some basic principles of what has been observed and
what is expected. First, as described in detail earlier, the most
common feature is airspace disease, which can be consolidative,
ground-glass, or mixed. Whether the airspace disease is consol-
idative or ground-glass has been conjectured to be related to
the extent of involvement of the OP at the level of the primary
lobules, the differing density of the plugs themselves (related
to stage of evolution and proportion of collagen), and the pres-
ence of associated alveolar septal inflammation (56,57,59,60).
Second, patients with OP have spared areas of normal
lung, often immediately adjacent to involved areas. This is
in some ways reflective of the distribution at histopathologic
analysis, which is frequently described as patchy and with ar-
eas of sparing (2). Spared lung can have a subpleural, lobular,
or less commonly peribronchovascular distribution. Of note,
lobular spared areas in OP are larger and often not of the size
of the secondary lobule. The term lobular in this context is
descriptive and typically not related to the structural units of
the lung parenchyma.
These areas of sparing are not specific to OP, as other con-
ditions such as NSIP are known to demonstrate pronounced
Volume 43 Number 7
Marquis et al
sparing (in the case of NSIP, sparing is often subpleural). It
should be noted that some authors refer to the phenomenon
of sparing, particularly lobular sparing, as perilobular disease
(61). We prefer the term sparing, given that the lobules dis-
cussed in this regard are not known anatomic units and be-
cause sparing, which is a fundamental characteristic of OP,
can have distributions other than lobular (Fig 13).
Finally, a third characteristic we have observed in patients
with OP relates to its relative homogeneity within individual
patients at a single time point. To this end, while OP can have
many different CT manifestations in different patients or in
single patients at different time points, the imaging manifes-
tations within a single patient at a single time point tend to be
fairly uniform.
The next step in understanding the CT manifestation of
OP is identifying the most common CT findings and distribu-
tions, helpful accessory findings, and uncommon manifesta-
tions. As stated earlier, the CT appearance of OP is extremely
variable. Although the term OP pattern is frequently used, this
is largely unhelpful and potentially misleading for the radiol-
ogist, as even cursory experience with OP would lead a reader
to quickly recognize that there is no single characteristic pat-
tern. Attempting to characterize one single CT pattern is an
oversimplification that will lead to underdiagnosis and mis-
interpretation of OP. In addition, it is not possible to reliably
correlate CT findings of OP with an underlying trigger; OP is
a nonspecific response, and individual triggers can produce a
wide spectrum of CT findings in different patients. Similarly,
the same triggers that can cause OP can result in DAD in more
severely ill patients (Fig S5).
The most common CT manifestation of OP is airspace dis-
ease (consolidative, ground-glass, or mixed) that is bilateral
and reasonably symmetric (Fig 14). OP is more commonly pe-
ripheral and mid to lower lung predominant, but upper lobe
involvement is not infrequent and thus should not be used as a
negative for the diagnosis of OP (rare cases may be exclusively
upper lobe). OP can be diffuse, and these manifestations will
overlap in appearance with the acute phase of DAD (52). Occa-
sionally, OP can have a peribronchovascular distribution along
larger airways. Note that this is fundamentally different from
the peribronchiolar distribution described in the histopatho-
logic features of OP. Thus, it is not a requirement or even a
more commonly observed CT finding in OP (62) (Fig 15).
Less commonly, OP can manifest at CT as a single focal
airspace opacity. Focal forms of OP may be related to a local-
ized insult; for example, radiation injury or a localized infec-
tion (Fig S6). These focal forms of OP can be consolidative
or ground-glass and can manifest as a pulmonary nodule or
mass. As an extension of this manifestation, multiple larger
nodules or masses are another uncommon manifestation of
OP (52) (Fig 16).
A rare CT manifestation of OP is diffuse small centrilob-
ular nodules. This was originally described in patients who
had inhaled synthetic marijuana but has also been observed
more recently in a minority of patients with EVALI. At his-
topathologic analysis, specimens from these patients showed
extension of the granulation material into lobular bronchioles
(62–65) (Fig 17).
11 radiographics.rsna.org
July 2023 Marquis et al

Figure 13. Patterns of sparing in OP.

(A) Axial CT image in a 75-year-old
woman with OP secondary to nitro­
furantoin use shows bilateral ground-
glass opacity and consolidation with
poly­gonal areas of lobular sparing
(arrows). These findings resolved at
follow-up 2 months later after the med-
ication was discontinued. (B) Axial CT
image in a patient with OP secondary
to vaping (EVALI) shows sparing (arrow)
around the pulmonary bronchi and
vascular branches. While this peribron-
chovascular form of sparing was first
described in patients with EVALI, we
have observed it in patients with OP from other causes, and it is likely not specific to the trigger.
(C) Axial CT image in a 59-year-old woman with OP related to connective tissue disease shows
subpleural sparing (arrow). There are peripheral bilateral ground-glass opacities in the lower lobes
with relative sparing of the subpleural region. While there can be overlap in the appearances of
OP and NSIP in patients with connective tissue disease, these findings developed quickly, were
associated with increased symptoms, and improved with steroid use, consistent with a presump-
tive diagnosis of OP.

Figure 14. Typical imaging appearance of OP in two patients with graft-versus-host disease. Axial CT images show bilateral
and relatively symmetric airspace opacities, with predominantly peripheral consolidation in A and ground-glass opacities in B.

The atoll or reverse halo sign is another helpful finding that
can be seen in OP. This is best defined as an area of spared or
less opacified lung within the center of a circumferential or
more commonly arclike distribution of more dense airspace
disease (57). This finding has been reported in up to 20%–30%
of patients with OP. The reverse halo sign and similar findings
have been described in other diseases, including infarcts, fun-
gal infections (most notably mucormycosis), sarcoidosis, and
granulomatosis with polyangiitis. In these other (non-OP)
Volume 43 Number 7
conditions, the peripheral airspace component typically has a
thicker wall of consolidation and the center is more likely to
be ground-glass opacity rather than normal lung (66).
In the appropriate context, when the atoll or reverse halo
sign is seen at CT, OP should be strongly suggested. A similar
finding that can be seen in OP are linear parenchymal bands,
which may be oriented in any axis but often parallel the pleu-
ral surface. These are not interstitial opacities, as they do not
correspond to the contours of secondary pulmonary lobules.
12 radiographics.rsna.org
July 2023 Marquis et al

Figure 15. Peribronchovascular OP

in a 67-year-old woman receiving
chemotherapy who presented with
dyspnea. (A) Initial axial CT image
shows bilateral ground-glass air-
space opacities that are clustered
around larger airways in a peribron-
chovascular distribution. Results of
transbronchial needle biopsy were
concordant with the imaging find-
ings of OP. (B–D) Follow-up axial CT
images at 1 month (B), 2 months (C),
and 1 year (D) show initial increase
in density of the airspace opacities,
then a progressive decrease, with
only mid ground-glass opacities
remaining at 1 year. Of note, as is of-
ten seen in OP, although the density
of the consolidation changes over
time, it is relatively homogeneous in
appearance at each individual time
point.

Figure 16. Less common manifestations of OP. In cases with atypical manifestations, OP can be considered,
but tissue biopsy will often be required to confirm the diagnosis. (A) Axial CT image in a 49-year-old woman
shows a spiculated nodule in the superior segment of the right lower lobe. She underwent resection for sus-
picion of malignancy; resection demonstrated OP, which was idiopathic. (B) Axial CT image in a 48-year-old
man receiving chemotherapy shows multiple ill-defined nodular consolidations with surrounding ground-glass
opacity in the right lung, concerning for fungal pneumonia. The nodules persisted after a course of antifungals;
resection showed OP, likely secondary to chemotherapy. (C) Axial CT image in a 44-year-old woman with
dyspnea and cough shows mixed consolidative and ground-glass opacity in the right lower lobe with air bron-
chograms that did not resolve with antibiotic treatment. Given the concern for primary lung cancer, the patient
underwent resection. Pathologic analysis demonstrated OP.

Parenchymal bands are less specific than the atoll sign but can
be helpful in suggesting the diagnosis (62).
Patients with OP can demonstrate additional CT findings
in addition to airspace disease. Air bronchograms can be seen
Volume 43 Number 7
within the regions of airspace disease, not uncommonly with
mild bronchial dilatation. Areas of septal thickening, either
isolated or in association with ground-glass opacity (cra-
zy-paving appearance), can be found in a minority of patients.
13 radiographics.rsna.org
July 2023
Figure 17. OP manifesting as diffuse small centrilobular nod-
ules in a 26-year-old man with a history of synthetic marijuana
use. Axial CT image shows diffuse centrilobular nodules. Sur-
gical resection showed that fibroblast plugs of OP were mostly
concentrated in terminal bronchioles, with sparing of the more
distal alveoli. This is a rare manifestation of OP that may be
more likely in cases due to an inhaled trigger.
Potential explanations for septal thickening in OP include
more exuberant septal inflammation or concomitant pro-
cesses such as pulmonary edema or fibrosis.
At long-term follow-up CT in most patients with OP, the
findings completely resolve. However, some patients can have
residual findings at CT, including diminished but residual air-
space opacities and even some mild architectural distortion
in the areas of the original OP; this process may represent re-
sidual intra-alveolar fibroblast plugs or residual scarring. Re-
lapse of OP occurs in less than 25% of patients and is usually
attributed to treatment being stopped or tapered too quickly.
Patients who experience a relapse may have worsening find-
ings at serial chest CT (67) (Fig 18).
As with DAD, mosaic attenuation due to concomitant
small-airways disease may be present. In some patients, an
NSIP-like appearance can develop. Whether this represents
scarring from residual OP that has CT features of NSIP, pro-
gression from OP to NSIP, or a subset of patients with con-
ditions that manifest as an OP-NSIP overlap that originally
manifested as OP is controversial; in reality, each of these
explanations may have validity when applied to individual
patients with corroborating clinical or histopathologic data
(4,68) (Fig 19).
Histologic Variants of Lung Injury
In recent years, several less common variant histologic pat-
terns of lung injury have been described. One is acute fibrin-
ous and OP (AFOP), which is characterized by a dominant
fibrinous exudate (or fibrin balls) within airspaces with ad-
ditional findings that do not meet the criteria for OP or DAD.
CT features of patients with AFOP at histopathologic analysis
are nonspecific, but it typically manifests as airspace disease
that overlaps with that seen in OP and DAD (Fig 20). Some
patients with AFOP at histopathologic analysis can have a
progressive clinical course that mirrors that of DAD (4,69,70).
Granulomatous OP (GOP) is a recently described histologic
pattern characterized by a dominant background of OP in as-
Volume 43 Number 7
Marquis et al
sociation with nonnecrotizing poorly formed granulomas. In
the small series in which GOP was described, patients had
mild clinical symptoms closely resembling those seen with
symptomatic OP. Again, the CT findings are largely those of
airspace disease similar to OP, although a nodular or masslike
configuration was more commonly associated with GOP than
with OP (70). While these entities may be interesting from a
histopathologic perspective, given their rarity and imaging
overlap with DAD and OP, they have limited clinical utility for
the radiologist other than understanding findings that may be
described in pathology reports.
Approach to Lung Injury: Role of the Radiologist
In modern practice, only a minority of patients with DAD and
OP will receive a tissue diagnosis, as most will be given a pre-
sumptive diagnosis based on their imaging findings, clinical
manifestation, and its evolution. This confers an important
role for the radiologist in the multidisciplinary approach to
this important patient population.
The first element of this approach is using consistent and
meaningful terminology. The sequelae of lung injury identi-
fied at CT represent common end points from many different
triggers. Emphasizing the identified process confers to the cli-
nician that the radiologic findings are one component of the
multidisciplinary approach and that potential triggers need to
be identified. As such, it is recommended to avoid using terms
in CT reports that emphasize triggers, such as immunother-
apy-related pneumonitis or EVALI. If the trigger is known, it
can be included as an explanation for a particular process (eg,
OP secondary to immunotherapy).
As discussed earlier, in cases of DAD it is recommended
to avoid use of the term ARDS, given that this refers to a clin-
ical diagnosis, not an imaging diagnosis. In the setting of a
patient presenting with findings suggestive of chronic se-
quelae of known or possible prior lung injury, the temporal
relationship is indicated, as is its relation to prior DAD or OP
(eg, sequelae of prior DAD). In addition, it is recommended
to avoid conflating the sequelae of DAD and OP with other
diseases, even if they have overlapping features. For example,
a patient may present with findings of small-airways disease
superimposed on fibrosis, which could represent sequelae of
prior DAD or hypersensitivity pneumonitis, two different di-
agnoses. A summary of suggested terminology for describing
manifestations of lung injury at CT is provided in Table 3.
The second element of this approach is incorporating DAD
and OP into differential diagnoses using available clinical in-
formation. In some cases, the differential diagnosis is limited.
For example, in a patient receiving immunotherapy who pre­
sents with subacute dyspnea and bilateral peripheral ground-
glass opacities at CT, it is reasonable to suggest the diagnosis
of OP secondary to immunotherapy outright.
Other cases may have a larger differential diagnosis. This
is often true in patients presenting with bilateral airspace dis-
ease who are hypoxemic. At initial imaging, the differential
diagnosis includes noncardiogenic edema related to acute
phase DAD, permeability edema (without diffuse epithelial
injury) from other causes, diffuse OP, cardiogenic edema,
acute infectious pneumonia, and hemorrhage. While some
14 radiographics.rsna.org
July 2023 Marquis et al

Figure 18. Sequelae of OP. (A, B) Idiopathic OP

in a 67-year-old woman. Initial axial CT image (A)
shows posterior lower lobe–predominant ground-
glass and consolidative opacities with areas of spar-
ing and mild bronchial dilatation. Axial CT image (B)
5 weeks after corticosteroid therapy shows return
to a normal appearance. (C, D) OP secondary to
graft-versus-host disease in a 49-year-old patient.
Initial axial CT image (C) shows bilateral reverse
halo signs. Axial CT image (D) obtained 6 weeks
after sirolimus therapy shows an improved appear-
ance. The residual findings appear as less dense
airspace opacities in the same distribution as the
original OP. (E–G) Idiopathic OP in a 60-year-old
woman. Initial axial CT image (E) shows anteri-
or-predominant bilateral ground-glass opacities with areas of sparing. Axial CT image (F) obtained 6 weeks af-
ter treatment with corticosteroids shows an improved appearance. A few months later, the patient experienced
recurrent dyspnea. Axial CT image (G) shows anterior-predominant airspace opacities consistent with OP. Note
the atoll sign in the anterior right upper lobe and the reverse halo sign in the left upper lobe. The recurrent OP
has a different CT appearance than the residual OP. At each time point, however, the OP was fairly homoge-
neous in its appearance.

imaging clues may help in differentiating these entities, such
as pleural effusions and cardiomegaly in cardiogenic pulmo-
nary edema, follow-up imaging and clinical progression are
needed to evaluate for findings of progressive organizing
DAD to confirm the diagnosis (71).
Radiologists must also be familiar with the role of biopsy and
the significance of lung injury identified at biopsy. In difficult
cases with a larger differential diagnosis—particularly cases
with nonresolving consolidations, focal masslike opacities, an
immunocompromised patient, or multiple nodules—imaging

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July 2023 Marquis et al

Figure 19. Polymyositis–rheumatoid arthritis overlap syndrome in a 36-year-old woman who originally presented
with dyspnea 13 years earlier. (A) Axial CT image 13 years earlier shows lower lobe ground-glass opacity and consoli-
dation with focal areas of sparing in the left lower lobe. This appearance and the clinical history were consistent with
OP, which was confirmed at subsequent biopsy. The patient was treated with corticosteroids, and the patient returned
to her functional baseline. (B) Axial CT image 13 years later shows less severe mild lower lobe ground-glass opacity
with some mild bronchiectasis, findings that had been stable for many years. Given the stability and lack of persistent
symptoms, the CT findings are favored to represent the sequelae of the prior OP. However, the imaging appearance
overlaps with that of NSIP, which could have preexisted as part of an overlap syndrome.

opsy may be warranted (72) (Figs 21, S7). Summaries of the

major differential diagnoses for DAD and OP are provided in
Tables 4 and 5.

Figure 20. AFOP in a 55-year-old man undergoing chemo-
therapy for T-cell leukemia. He had febrile neutropenia and
negative results at workup for infection. Axial CT image shows
multiple nodular areas of consolidation with air bronchograms.
The differential diagnosis for this imaging appearance is
broad, including infectious (fungal) and noninfectious (vascu-
litis) causes. Results of workup for infection were negative.
Core needle biopsy demonstrated AFOP, which resolved at
follow-up imaging 3 weeks later. AFOP is a rare histologic
phenotype that overlaps with OP and DAD and cannot be dis-
tinguished radiologically.
and clinical information may not provide a definitive diagnosis,
and biopsy should be considered. Of note, lung injury, partic-
ularly OP, identified in tissue from a needle biopsy should be
viewed with skepticism. OP is a nonspecific histologic pattern
and can be a minor component of a larger process, including
tumors and infection; thus, its presence in a biopsy sample does
not exclude an active infection or malignancy. At a minimum,
follow-up imaging is typically required.
In our experience, a presumptive diagnosis is made when
the clinical history, imaging findings, and results of transbron-
chial sampling are concordant. In cases of discordant imaging
and pathology results, repeat transbronchial or excisional bi-
Conclusion
The manifestations of lung injury—most notably DAD and
OP—represent common end points at imaging and histo-
pathologic analysis that can be the result of a nearly limitless
number of insults. Radiologists must be familiar with these
entities for several important reasons. First, understanding
that these are nonspecific responses to lung injury carries the
implication that imaging is one part of a larger multidisci-
plinary process focused on identifying potential triggers. For
individual patients, findings of lung injury at CT can drive
the search for triggers, which can be removed or treated. In
larger patient populations, clusters of unexplained respiratory
illnesses that manifest as OP and DAD should suggest that
new triggers may be causing outbreaks.
Second, identification of OP and DAD can have implica-
tions for patient prognosis and management. Patients with
suspected OP are expected to have a mild course that can be
managed with steroids if necessary, while patients with DAD
are expected to have a more severe course, often requiring
ventilatory support. Finally, understanding OP and DAD al-
lows the radiologist to generate tailored differential diagnoses
and direct tissue biopsy in difficult cases.
Author affiliations.—From the Mallinckrodt Institute of Radiology, 510 S
Kingshighway Blvd, St Louis, MO 63110 (K.M.M., K.S., C.A.R.); Department
of Radiology, Brigham and Women’s Hospital, Boston, Mass (M.M.H.); De-
partment of Radiology, Duke University, Durham, NC (T.S.H.); and Depart-
ment of Pathology & Immunology (C.Y.L.) and Department of Pulmonol-
ogy (A.S.), Washington University, St Louis, Mo. Presented as an education
exhibit at the 2021 RSNA Annual Meeting. Received July 21, 2022; revision
requested August 25 and received October 25; accepted December 2. Ad-
dress correspondence to K.M.M. (email: kmarquis@wustl.edu).
Disclosures of conflicts of interest.—M.M.H. Deputy Editor of RadioGraph-
ics, grants or contracts from National Institutes of Health (unrelated). All

Volume 43 Number 7 16 radiographics.rsna.org

July 2023 Marquis et al

Table 3: Recommended Terminology for Radiology Reports

Recommended Terminology for Radiology

Manifestation of Lung Injury Reports Terms to Avoid
Clinical and imaging findings OP Terms that imply a unique disease related to the trigger (eg,
favor OP EVALI, immunotherapy pneumonitis)
Nonspecific terminology (eg, inflammatory process)
Terms that suggest unique manifestations (eg, OP pattern)
Clinical and imaging findings Acute phase DAD Terms related to a clinical diagnosis (eg, ARDS)
favor acute phase DAD Noncardiogenic (or permeability) edema
related to DAD
Clinical and imaging findings Organizing phase DAD Terms related to a clinical diagnosis (eg, ARDS)
favor organizing phase DAD Terms related to infection if no infection is known or sus-
pected (eg, multifocal pneumonia)
Clinical and imaging findings Lung injury …
overlap between OP and Acute lung injury
DAD Organizing lung injury (if findings of orga-
nization are present)
Chronic sequelae of lung injury Residual findings of prior OP Terms suggesting that the sequelae of the lung injury are
Sequelae of DAD another disease process (eg, hypersensitivity pneumonitis,
Sequelae of prior organizing lung injury NSIP, usual interstitial pneumonia); these can be included
in the differential diagnosis if thought to be possible
Note.—Some imaging manifestations can have an overlapping appearance between OP and DAD, particularly early in their course. In
these cases, lung injury can be used as a proxy for OP and DAD. If the trigger is known, it can be included in the report (eg, OP secondary
to immunotherapy).

Figure 21. (A) Coronal CT image in a 22-year-old

man with swelling, rash, and chest pain shows bilateral
ground-glass opacities, several with central clearing in
an atoll or reverse halo appearance. These CT findings
were strongly suggestive of OP and did not require lung
biopsy. A clinical search for the trigger was performed; a
diagnosis of granulomatosis with polyangiitis was made
after skin punch biopsy and laboratory testing. (B) Axial
CT image of the right upper lobe in a 55-year-old man
with weakness and diaphragm paralysis shows a focal
airspace opacity with an air bronchogram and several
adjacent smaller nodules. The differential diagnosis
for these findings is broad and includes OP as well as
malignancy. Right upper lobectomy demonstrated fo-
cal OP and associated acute and chronic inflammation
with small-vessel vasculitis. These cases illustrate how
tailored differential diagnosis based on CT findings is
integral to the workup and can be used to suggest when
tissue biopsy is needed.

Table 4: Major Differential Diagnoses for DAD with More Common Considerations Listed First

Phase of DAD Timing Differential Diagnoses

Acute phase <7 days Cardiogenic pulmonary edema, noncardiogenic pulmonary edema without diffuse alveolar-cap-
illary interface damage, infectious or aspiration pneumonia, extensive organizing pneumonia,
pulmonary hemorrhage
Organizing phase >7 days Multifocal infectious pneumonia; pulmonary edema, hemorrhage, or infection superimposed on
emphysema or fibrosis; pulmonary infarcts; septic emboli; mucinous adenocarcinoma
Chronic sequelae Months to years Fibrotic hypersensitivity pneumonitis, bronchiolitis obliterans, NSIP, usual interstitial pneumonia
Note.—DAD has extensive differential diagnoses that can be narrowed on the basis of the patient’s clinical scenario and temporal pro-
gression. While the organizing phase of DAD begins at approximately 1 week, there is temporal overlap, with areas of acute phase DAD
superimposed on organizing phase DAD.

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July 2023 Marquis et al

Table 5: Major Differential Diagnoses for OP with More Common Considerations Listed First

CT Findings of OP Relative Frequency Differential Diagnoses

Bilateral airspace disease Common Acute: cardiogenic pulmonary edema, noncardiogenic or permea-
bility edema (including acute phase DAD), pneumonia, infarcts,
hemorrhage
Chronic: chronic eosinophilic pneumonia, desquamative intersti-
tial pneumonia, pulmonary alveolar proteinosis, lipoid pneumo-
nia, mucinous pulmonary adenocarcinoma, metastatic gastro­
intestinal adenocarcinoma, lymphoma
Peribronchovascular opacities Can be seen Sarcoid, vasculitis, mucinous pulmonary adenocarcinoma, Kaposi
sarcoma
Focal airspace opacity Less common Acute: pneumonia, infarct, hemorrhage
Chronic: tumor, lymphoma, scarring
Single or multiple nodules or masses Less common Infection, tumor, vasculitis
Diffuse centrilobular nodules Rare Hypersensitivity pneumonitis, respiratory bronchiolitis, excipient
lung disease (eg, talcosis)
Parenchymal and subpleural bands Nonspecific (30%–50% of cases) Atelectasis, scarring from infection or infarct, interstitial lung
disease (particularly NSIP)
Reverse halo (atoll) sign Up to 20%–30% of cases, but Vasculitis, infarct, invasive fungal infection (angioinvasive asper-
helpful and should raise gillosis, mucormycosis)
strong consideration for OP
Note.—OP has extensive differential diagnoses that can be narrowed on the basis of the patient’s clinical scenario and temporal
progression.

other authors, the editor, and the reviewers have disclosed no relevant
relationships.
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