The Pathologist’s Approach to Acute Lung Injury
Mary Beth Beasley, MD
Context.—Acute lung injury and acute respiratory distress
Nsyndrome
are significant causes of pulmonary morbidity and
are frequently fatal. These 2 entities have precise definitions
from a clinical standpoint. Histologically, cases from patients
with clinical acute lung injury typically exhibit diffuse
alveolar damage, but other histologic patterns may occasionally be encountered such as acute fibrinous and
organizing pneumonia, acute eosinophilic pneumonia, and
diffuse hemorrhage with capillaritis.
Objective.—To review the diagnostic criteria for various
histologic patterns associated with a clinical presentation
of acute lung injury and to provide diagnostic aids and
discuss the differential diagnosis.
cute pulmonary injury may occur secondary to an
A
extensive number of direct or indirect pulmonary
insults and often results in acute hypoxemic respiratory
failure. Most patients with this condition will have acute
respiratory distress syndrome (ARDS) clinically. In 1994,
the American-European Consensus Conference on ARDS
formally defined ARDS as the presence of acute hypoxemia with (1) a ratio of partial pressure of arterial oxygen
to the fraction of inspired oxygen (PaO2:FIO2) of 200 mm
Hg or less, (2) bilateral infiltrates that are consistent with
pulmonary edema radiographically, and (3) no clinical
evidence of cardiac failure. A less severe category, termed
acute lung injury (ALI), was defined by the same criteria
but with a PaO2 to FIO2 of 300 mm Hg.1 While the
definitions are not without their critics, they have
provided a basis for a more uniform approach to the
study of ALI/ARDS including epidemiology, pathogenesis, treatment, and clinical trial design. The actual
incidence of ALI/ARDS has been difficult to approximate
because of varying criteria for diagnosis.2,3 A populationbased cohort study in King County, Washington,4 examined the incidence and mortality of ALI and ARDS by
using the consensus criteria and found that the incidence
of ALI was 78.9 per 100 000 person-years and the incidence
of ARDS was 58.7 per 100 000 person-years. This same
study reported an average mortality rate of 41.1% for
ARDS and 38.5% for ALI. Although the average mortality
rate in the study was lower than the historically reported
Accepted for publication September 3, 2009.
From the Department of Pathology, The Mount Sinai Medical Center,
New York, New York.
The author has no relevant financial interest in the products or
companies described in this article.
Reprints: Mary Beth Beasley, MD, Department of Pathology, The
Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY
10029 (e-mail: mbbeasleymd@yahoo.com).
Arch Pathol Lab Med—Vol 134, May 2010
Data Sources.—The review is drawn from pertinent
peer-reviewed literature and the author’s personal experience.
Conclusions.—Acute lung injury remains a significant
cause of morbidity and mortality. The pathologist should
be aware of histologic patterns of lung disease other than
diffuse alveolar damage, which are associated with a
clinical presentation of acute lung injury. Identification of
these alternative histologic findings, as well as identification of potential etiologic agents, especially infection, may
impact patient treatment and disease outcome.
(Arch Pathol Lab Med. 2010;134:719–727)
mortality rates for ARDS of 50% to 60%, the mortality rate
was found to increase with age and was 60% in persons
older than 85 years. Therefore, in spite of the myriad
advances in understanding the pathogenesis of ALI/
ARDS, this entity clearly remains a significant cause of
morbidity and mortality.
From a pathologic standpoint, most cases of clinical ALI
and ARDS will have diffuse alveolar damage (DAD)
histologically.5,6 Other histologic patterns encountered in a
clinical setting of ALI/ARDS include acute eosinophilic
pneumonia (AEP) and the more recently described acute
fibrinous and organizing pneumonia (AFOP).7,8 Organizing pneumonia (OP) is often included in the pathologic
differential of clinical ALI. However, most patients with
OP typically present with a subacute, less fulminate
clinical course and generally do not meet clinical criteria
for ALI, but OP will be discussed in this article primarily
as part of the differential diagnosis.9,10 Diffuse alveolar
hemorrhage may also occasionally present with clinical
ALI/ARDS.5 It is important to note that clinicians think of
ALI/ARDS in terms of the previously discussed clinical
guidelines, while pathologists tend to use the term acute
lung injury in reference to the pathologic findings—
particularly in reference to small biopsies, as discussed
below—when precise classification of findings is not
possible. As such, communication is important to avoid
any misinterpretation of the findings. The aim of this
review is to cover the major features of the common
histologic patterns seen in association with clinical ALI/
ARDS, the differential diagnosis, and an approach to
biopsy specimens.
Given that most biopsy specimens from patients with
clinical ALI/ARDS will demonstrate a histologic pattern
of DAD, some authors have questioned the value of
obtaining a wedge biopsy specimen from patients with
ALI/ARDS. Patel et al5 examined a series of wedge biopsy
Pathologist’s Approach to Acute Lung Injury—Beasley
719
samples obtained from patients with clinical ALI/ARDS
and determined that while most specimens did show
DAD, diagnostic findings were found that prompted a
change in therapy in nearly one-third of cases. Most of
these cases involved the discovery of a definitive
infectious etiology.5 As will be discussed below, evaluation for an infectious cause is an important contribution
that the pathologist can make in evaluating a biopsy
specimen from a patient with acute lung injury.
CLINICAL AND PATHOLOGIC OVERVIEW OF
HISTOLOGIC PATTERNS ASSOCIATED WITH ALI/ARDS
Diffuse Alveolar Damage
Diffuse alveolar damage is the classic histologic manifestation of ALI/ARDS. Clinically, patients present with
severe hypoxemia and typically require mechanical ventilation. The histologic findings will vary depending on
when a biopsy is obtained during the course of the
disease.11 Radiographically, patients with DAD are classically described as having diffuse bilateral pulmonary
infiltrates (‘‘white out’’) by conventional chest x-ray.
Computed tomography scans, however, often demonstrate
that the distribution is actually nonhomogenous and is
greater in the dependent portions of the lung.12,13 The
pathogenesis of DAD has been widely studied, and an
extensive review is beyond the scope of this article. Briefly,
damage to the capillary endothelium and alveolar epithelium result in exudation of edema fluid and cellular
breakdown products, with subsequent pneumocyte hyperplasia and fibroblastic proliferation as the lung attempts to
repair the damage. The entire process is propagated by a
complex and ever-expanding collection of cytokines and
other cellular factors. The interested reader is referred to
several excellent reviews on the pathogenesis of DAD/
ARDS.14–18 Additionally, recent work on the genetic factors
influencing susceptibility and development of ARDS19,20
has also provided new insights into pathogenesis and has
led to the identification of biomarkers that may help predict
outcome as well as serve as potential therapeutic targets.
Histologically, DAD is typically divided into 2 phases:
the acute/exudative phase and the organizing/proliferative phase. The acute phase generally occurs during the
first week following pulmonary insult, with the organizing phase occurring after the first week; however, the
processes actually represent a continuum and overlapping
features may be encountered, particularly late in the first
week. Some authors additionally include a final fibrotic
stage. In cases related to a single insult, the disease
progresses in a relatively linear fashion. However, in some
cases, a patient may experience repeated insults that may
lead to variable features within a biopsy specimen.21
The acute/exudative phase is usually easily recognizable. The findings are generally diffuse and relatively
uniform, but may occasionally be more focal.22 While the
earliest changes may be seen only ultrastructurally, by day
2 intra-alveolar edema and interstitial widening are
apparent. Hyaline membranes may be seen at this point
and may reach a peak 4 to 5 days after the initial insult.
Hyaline membranes are composed of cellular and
proteinaceous debris and appear as dense, glassy eosinophilic membranes lining the alveolar ducts and alveolar
spaces (Figure 1). Generally, inflammation is relatively
sparse unless the DAD is evolving from a preexisting
pneumonia. Thrombi may be present and may be quite
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extensive (Figure 2).21,23 The formation of thrombi in DAD
is due to localized alterations in the coagulation pathway
and should not be considered evidence of an underlying
thromboembolic disorder in the patient.24,25
The organizing phase may prove more problematic on
biopsy specimen examination. This phase is characterized
by relatively uniform interstitial fibrosis associated with
quite pronounced type 2 pneumocyte hyperplasia (Figure 3). Squamous metaplasia may also be present and in
some cases may be quite pronounced (Figure 4). The
hyaline membranes characteristic of the acute phase
gradually disappear as they become incorporated into
the alveolar septa; however, residual hyaline membranes
may be identifiable depending on the timing of the biopsy
in the course of disease. Cytologic atypia may be quite
pronounced in both the type 2 pneumocytes as well as
squamous metaplastic areas and should not be confused
with malignancy. Similarly, mitotic figures may be
observed in the pneumocytes. The fibrosis in DAD tends
to be loose and myxoid and will appear bluish-gray on
hematoxylin-eosin sections, in contrast to the collagenous
fibrosis typically seen in other disorders such as nonspecific interstitial pneumonia and usual interstitial pneumonia. Organizing fibroblastic tissue may be observed in air
spaces, particularly the alveolar ducts (alveolar duct
fibrosis), but this feature is typically not prominent and
does not constitute the dominant finding as seen in cases
of OP.21,26
Following the organizing phase, some cases of DAD
will gradually resolve while others may develop continued interstitial fibrosis with architectural remodeling and
progressive respiratory compromise. Among patients
who survive, most experience some degree of residual
functional impairment.2,21,26
The histologic findings of DAD may result from a large
number of potential etiologies that include numerous
infectious agents, drug reactions, collagen vascular/
immune-mediated diseases, ingestant/inhalant exposure,
shock, sepsis, and numerous other agents. Among the
infectious etiologies, viruses (Figure 5), Legionella, Mycoplasma, and Rickettsia are most frequently cited, but it is
important to note that most any infectious agent can
produce DAD.1,5,21,27 This is of particular importance in the
immunosuppressed patient, a context in which agents
such as Pneumocystis jiroveci and other fungi are not
infrequently encountered.28
Diffuse alveolar damage in which no known causative
etiology can be elucidated is clinically termed acute
interstitial pneumonia, which also corresponds to cases
historically referred to as Hamman-Rich syndrome.17,23,29
Transfusion-related acute lung injury (TRALI) deserves
mention in the discussion of DAD/ARDS, as TRALI is
increasingly recognized from a clinical standpoint. Transfusion-related acute lung injury is a clinical syndrome
associated with transfusion of plasma containing blood
components and is most frequently associated with
antibodies to white blood cells in transfused blood
components. Patients may experience a wide range of
respiratory compromise ranging from mild dyspnea to
fulminate respiratory failure, which is fatal in 5% to 10% of
cases, although most patients recover with supportive
measures. Radiographs demonstrate findings essentially
identical to those of ARDS.30–32 As TRALI is typically a
clinical diagnosis, reports of pathologic findings are few
and generally restricted to fatal cases. As would be
Pathologist’s Approach to Acute Lung Injury—Beasley
expected given the clinical presentation, several case
reports33 describe findings identical to those of DAD with
classic hyaline membranes. Other reports describe only
pulmonary edema with neutrophil accumulation within
alveolar capillaries, although neutrophils within alveolar
spaces have also been reported. It has been postulated that
the lack of hyaline membranes in many reported cases
suggests a differing pathologic mechanism from DAD,
which has warranted further study.32–34
Acute Fibrinous and Organizing Pneumonia
Acute fibrinous and organizing pneumonia (AFOP) is a
more recently described histologic pattern associated with
acute lung injury in which the alveolar spaces are filled
with organizing fibrin balls, in contrast to the true hyaline
membranes found in DAD. The process may be patchy or
relatively diffuse. The alveolar septa may show mild
interstitial widening or lymphocytic infiltrates, but significant eosinophils or neutrophils should not be seen
(Figure 6). Organizing fibroblastic tissue may be present
to varying degrees but is not the dominant finding, and
the fibroblastic tissue may retain a central fibrinous core.8
The differential diagnosis of AFOP is primarily with
DAD and eosinophilic pneumonia (EP). Prominent organizing fibrin may be seen in some cases of DAD. Such
cases also contain foci of more typical hyaline membranes,
although they may be relatively focal. Hyaline membranes
should be sought in all cases with prominent organizing
fibrin and should be properly classified as DAD and not as
AFOP. Eosinophilic pneumonia, described below, may
have prominent intra-alveolar fibrin and greatly resemble
AFOP histologically. Cases of AFOP should not have
significant eosinophils and should also lack significant
macrophage accumulation. As eosinophils disappear
rapidly from tissue following initiation of steroid therapy,
partially treated EP may be a consideration if a biopsy is
obtained after administration of steroids. Peripheral blood
eosinophilia is not a feature of AFOP and may help
distinguish these cases on a clinical level. Cases of alveolar
hemorrhage may also contain organizing fibrin but the
presence of hemosiderin-laden macrophages and other
features described in the hemorrhage section below
should point to the correct diagnosis. Similarly, AFOP
may have areas of organizing fibroblastic tissue but this is
not the dominant finding, as seen in cases of OP.8
A diagnosis of AFOP should only be made on a large
biopsy specimen when one can be more certain that there
are not otherwise diagnostic features of DAD or EP.
Similarly, abundant fibrin may be encountered in acute
bacterial pneumonias and cases with marked neutrophils
should not be classified as AFOP. Additionally, organizing fibrin can occur as a nonspecific reaction adjacent to
lesions such as granulomas, abscesses, or neoplasms or
may occur in subpleural lung parenchyma adjacent to
acute pleuritis.8 For these reasons, the finding of organizing alveolar fibrin on a small biopsy specimen should be
interpreted conservatively and carefully correlated with
clinical and radiographic information.
In the original study of AFOP, the overall mortality rate
was similar to that seen in DAD and it was felt that AFOP
likely represented a histologic variant of DAD. Acute
fibrinous and organizing pneumonia was additionally
found to be associated with a wide range of potential
etiologies similar to those seen in DAD, and some cases
were felt to be idiopathic. Most patients presented with
Arch Pathol Lab Med—Vol 134, May 2010
severe respiratory failure. However, a significant number
of patients with the AFOP pattern presented with a
subacute clinical course not requiring mechanical ventilation and eventually recovered. Histologic features distinguishing these 2 prognostic groups were not identified.
Therefore, while at least some cases of AFOP appear to be
related to DAD, further study is needed to further define
the significance of this pattern, particularly in regard to
the subacute clinical cases.8 From a practical standpoint at
this time, the primary issue for the practicing pathologist
is recognizing the AFOP pattern as being associated with
acute lung injury and understanding its spectrum of
potential clinical associations.
Eosinophilic Pneumonia
Eosinophilic pneumonia most commonly presents with a
subacute clinical course but occasional cases present with
fulminate respiratory failure, often associated with fever.
Such cases, termed acute eosinophilic pneumonia (AEP), may
not be associated with the peripheral blood eosinophilia
typical of chronic eosinophilic pneumonia.7 Both AEP and
EP may be associated with underlying etiologies such as
toxic inhalation, drug reaction, or infection, particularly
with parasites or fungus, or may be idiopathic.35–38
Interestingly, AEP has also been reported in patients after
recent initiation of cigarette smoking.39,40
Eosinophilic pneumonia in general is characterized by
intra-alveolar fibrin and macrophages in variable proportions, admixed with numerous eosinophils. Eosinophils
may also be present in the interstitial tissue and
eosinophilic microabscess formation may be observed. In
some cases, eosinophils may infiltrate blood vessel
walls.41,42 In AEP, these features may be present to varying
degrees with the additional finding of hyaline membrane
formation identical to that seen in the acute phase of DAD
(Figure 7).7 The histologic differential of EP/AEP is
primarily with DAD and AFOP, as described in the 2
previous sections. Churg-Strauss syndrome does not
typically present with clinical ALI/ARDS but may arise
in the histologic differential of EP. The finding of
necrotizing vasculitis and granulomas should distinguish
cases of Churg-Strauss syndrome from EP, along with
clinical findings of systemic vasculitis.
The presence of eosinophils should be sought in all
cases with histologic findings of DAD. The importance of
this finding lies in the fact that AEP is exquisitely sensitive
to steroid therapy, with most patients making a dramatic
recovery when appropriate therapy is instituted.7,35,36,38
Diffuse Alveolar Hemorrhage With Capillaritis
Occasionally, diffuse alveolar hemorrhage (DAH) with
capillaritis will present with fulminate respiratory failure.5,43 Such cases demonstrate diffuse intra-alveolar blood
admixed with hemosiderin-laden macrophages containing coarse hemosiderin granules. Capillaritis is evidenced
by neutrophils within the alveolar septa with resultant
vascular necrosis (Figure 8). Neutrophilic cellular debris
or fibrin thrombi may also be observed. Capillary necrosis
may be difficult to visualize but the histologic finding of
significant neutrophilic infiltrates within the alveolar
septa with minimal or absent involvement of the air
spaces should strongly suggest capillaritis. Organizing
fibroblastic tissue may be present and form ‘‘dumbbell’’
shapes crossing the alveolar septa (Figure 9). This feature
evolves as capillaritis resolves. Some cases of DAH with
Pathologist’s Approach to Acute Lung Injury—Beasley
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Figure 1. Diffuse alveolar damage, acute/exudative phase. Alveolar septa show edematous widening and sparse inflammation and are lined by
prominent hyaline membranes (hematoxylin-eosin, original magnification 3200).
Figure 2. Thrombi may be observed in cases of diffuse alveolar damage and are secondary to localized alterations in the coagulation pathway.
Such findings should not be misinterpreted as pulmonary emboli (hematoxylin-eosin, original magnification 3200).
Figure 3. Diffuse alveolar damage, organizing phase. The alveolar septa are expanded by myxoid-appearing fibrous tissue and pneumocyte
hyperplasia is prominent. A residual hyaline membrane is still visible (hematoxylin-eosin, original magnification 3200).
Figure 4. Organizing diffuse alveolar damage (DAD) with an unusually large amount of squamous metaplasia. The finding of more typical features
of DAD elsewhere in the biopsy specimen, the distribution of the squamous epithelium along air spaces, and the lack of overt cytologic features of
malignancy should help avoid misdiagnosis as carcinoma (hematoxylin-eosin, original magnification 3100).
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Pathologist’s Approach to Acute Lung Injury—Beasley
capillaritis will also have hyaline membranes, which may
occasionally be the dominant histologic component.44–46
The primary challenge upon encountering hemorrhage
in a biopsy specimen is to determine if the hemorrhage is
of pathologic significance or if it is related to trauma
secondary to the biopsy procedure. Hemosiderin-laden
macrophages are an important finding, which points to
true alveolar hemorrhage. The hemosiderin in these
macrophages is characteristically coarsely granular and
golden brown, in contrast to the finely granular brown
pigment encountered in the lungs of cigarette smokers
(Figure 10, A and B). Iron stains may highlight the coarse
nature of true hemosiderin, but one should keep in mind
that pigmented ‘‘smoker’s type’’ macrophages may also
contain stainable iron; therefore, morphologic features
should take precedence over the finding of stainable iron
alone. Hemosiderin-laden macrophages begin to develop
as soon as 2 days after a bleeding episode and may persist
for as long as several months. As such, the mere finding of
hemosiderin-laden macrophages may not be indicative of
acute or active hemorrhage. Other histologic findings that
point towards active hemorrhage include cellular reactive
changes in the adjacent alveolar septa and focal areas of air
space organization.44–46 When hemorrhage is determined
to be potentially significant from a histologic standpoint,
the finding must be evaluated in the appropriate clinical
context. From a clinical standpoint, significant alveolar
hemorrhage is almost always associated with hemoptysis.
While the focus of the article is on ALI, in a broader scope
hemorrhage may be localized or diffuse, and localized
hemorrhage in particular may occur secondary to a wide
range of etiologies, particularly bronchiectasis or thromboembolism among others. A diagnosis of DAH should be
entertained only when a patient presents with diffuse
alveolar infiltrates. Diffuse alveolar hemorrhage may
occur with or without associated capillaritis; however, it
is typically the cases with capillaritis that may present
with clinical manifestations of ALI.5 Diffuse alveolar
hemorrhage with capillaritis most commonly occurs in
association with immune-mediated disorders. The primary considerations include collagen vascular diseases (most
commonly systemic lupus) and microscopic polyangiitis.
Goodpasture syndrome (anti–glomerular basement membrane antibody syndrome) may present with DAH with or
without associated capillaritis, and Wegener granulomatosis may occasionally present with a primary pattern of
hemorrhage and capillaritis. Other entities that have been
reported in association with DAH include primary antiphospholipid antibody syndrome, mixed cryoglobulinemia, Behcet syndrome, and Henoch-Schönlein purpura
along with some drug reactions and some infections
(human immunodeficiency virus, listeriosis).44–47 As most
of the potential causes of DAH are immune mediated,
specific patterns of immunoglobulin deposition may be
observed by immunofluorescence, particularly Goodpasture syndrome. While interesting, in reality, such studies
are rarely necessary in establishing a diagnosis from a
clinical standpoint. A diagnosis of ‘‘alveolar hemorrhage’’
with a comment regarding the presence or absence of
capillaritis is typically sufficient and the etiology is
confirmed via clinical and serologic findings.
From a histologic standpoint, it should be noted that
some cases of conventional DAD may present with fairly
considerable intra-alveolar hemorrhage, which is more
commonly fresh blood and seen in the acute phase. The
presence of coarse hemosiderin, neutrophilic interstitial
infiltrates, and capillaritis should raise the possibility of an
immune-mediated lung injury.
Organizing Pneumonia
As stated previously, OP generally presents with a
subacute clinical course without fulminate respiratory
failure and is not generally encountered in patients with
clinical ALI/ARDS. Indeed, the clinical finding of fulminate respiratory failure requiring mechanical ventilation
militates against a diagnosis of OP. However, OP is
frequently included in the pathologic differential diagnosis of ALI and, most importantly, is often a consideration
in the differential diagnosis of the other histologic patterns
associated with ALI.
The histologic pattern of OP, as defined in the current
American Thoracic Society/European Respiratory Society
consensus classification of interstitial lung disease, corresponds to the entity formerly termed bronchiolitis obliterans
organizing pneumonia. The clinical term for idiopathic OP is
cryptogenic organizing pneumonia (COP). The OP pattern
may also be seen in association with a number of potential
underlying etiologies such as infection, collagen vascular
disease, and drug reactions, which must be excluded
clinically before a clinical diagnosis of COP is made.29
The OP pattern is characterized by patchy accumulation
of intra-alveolar organizing fibroblastic tissue, which is
primarily centered around bronchioles. Intra-bronchiolar
fibroblastic tissue (bronchiolitis obliterans) may or may
not be present. The alveolar septa in involved areas
generally exhibit mild chronic inflammation. Significant
fibrosis should not be present, and the intervening lung
tissue should be relatively normal (Figure 11).9,10,29
Organizing pneumonia is typically readily distinguished
from DAD histologically. Some cases of organizing DAD
may, however, contain comparatively prominent intraalveolar or alveolar duct fibrosis and therefore, OP may
arise in the histologic differential diagnosis. Organizing
DAD is typically much more diffuse and, even when
relatively prominent air space fibrosis is present, the
dominant finding remains the diffuse interstitial expansion/myxoid fibrosis with marked pneumocyte hyperplasia. In OP, the air space organization is the primary finding
and the interstitial changes are relatively mild, consisting of
lymphocytic interstitial inflammation without significant
interstitial fibrosis. Pneumocyte hyperplasia is similarly not
as prominent. Organizing pneumonia is additionally a
patchy, bronchiolocentric process with the intervening lung
parenchyma appearing relatively normal.
r
Figure 5. Diffuse alveolar damage (DAD) with cytopathic changes of adenovirus infection (arrows). Infectious etiologies should be sought in all
cases of DAD (hematoxylin-eosin, original magnification 3400).
Figure 6. Acute fibrinous and organizing pneumonia is characterized by intra-alveolar fibrin balls in contrast to classic hyaline membranes
(hematoxylin-eosin, original magnification 3100).
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Pathologist’s Approach to Acute Lung Injury—Beasley
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Figure 7. Acute eosinophilic pneumonia. Hyaline membranes, essentially identical to those seen in diffuse alveolar damage, are present but
contain numerous eosinophils on closer inspection (hematoxylin-eosin, original magnification 3400).
Figure 8. Neutrophilic capillaritis is characterized by prominent neutrophils within the alveolar septa. Necrosis of the capillary may be difficult to
visualize, but neutrophilic debris, as seen here, or fibrin thrombi suggest underlying vascular damage (hematoxylin-eosin, original magnification
3400).
Figure 9. Healing capillaritis is characterized by organizing fibroblastic tissue. Often the organizing tissue bridges the previously damaged alveolar
septa in a ‘‘dumbbell’’ fashion, as seen here (hematoxylin-eosin, original magnification 3100).
Figure 10. Hemosiderin secondary to alveolar hemorrhage typically consists of large, coarse granules (A) in contrast to the finely granular pigment
associated with cigarette smoking (B) (hematoxylin-eosin, original magnifications 3400).
Figure 11. Organizing pneumonia is characterized by patchy intra-alveolar organizing fibroblastic tissue. The surrounding alveolar septa contain
mild lymphocytic infiltrates (hematoxylin-eosin, original magnification 3100).
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Pathologist’s Approach to Acute Lung Injury—Beasley
Figure 12. A, In this case of acute fibrinous and organizing pneumonia, numerous fungal organisms compatible with Aspergillus were present
(Gomori methenamine-silver, original magnification 3200). B, These organisms were surprisingly not visible on the corresponding hematoxylineosin section, thus emphasizing the importance of obtaining microorganism stains in such cases (original magnification 3200).
Figure 13. A, Panoramic view of a small biopsy specimen from a patient with clinical features suggestive of eosinophilic pneumonia. B, On closer
inspection, abundant eosinophils are supportive of the diagnosis (hematoxylin-eosin, original magnifications 340 [A] and 3400 [B]).
As with AFOP, a diagnosis of OP/COP should
generally only be made on a large biopsy specimen, and
only when the histologic pattern described above is
present. Organizing fibroblastic tissue may occur as a
component of a number of pathologic processes, such as
hypersensitivity pneumonitis and Wegener granulomatosis, or it may occur as a nonspecific reaction adjacent to an
unrelated lesion. That being said, the opinion that OP
should only be diagnosed with certainty on a large biopsy
specimen is controversial. Certainly, there are instances
when a small biopsy specimen with organizing fibroblastic tissue may be considered consistent with OP/COP
with careful clinical and radiographic correlation.29,48
APPROACH TO BIOPSY SPECIMENS IN PATIENTS WITH
CLINICAL ALI/ARDS
As with any lung biopsy, when evaluating a biopsy
specimen from a patient with clinical acute lung injury, it
is important to have as much clinical information as
possible. Information regarding disease onset and progression, suspected underlying etiologies, radiographic
information, and whether or not the patient is on
Arch Pathol Lab Med—Vol 134, May 2010
mechanical ventilation are important to support or refute
possible differential diagnoses.
With the exception of diffuse alveolar hemorrhage with
capillaritis, which most commonly occurs in a relatively
narrow range of immune-mediated settings, all of the
above histologic manifestations of ALI, and DAD in
particular, may be associated with myriad potential
underlying etiologic agents, or they may be idiopathic.29,48
In many cases the etiology will not be apparent from the
histologic findings alone. While the role of the pathologist
is limited in elucidating the etiology, the one thing that can
and should be done in every case is careful evaluation for
potential infectious etiologies. Special stains for microorganisms, namely an acid-fast stain, a Gomori methenamine-silver or similar silver stain, and a bacterial stain
such as Brown-Brenn or Brown-Hopps should be obtained, and cases should also be carefully scrutinized for
viral cytopathic changes. This should be done in all cases
but is of particular importance in cases of DAD and AFOP,
which may harbor fungal, pneumocystis, mycobacterial,
or bacterial infections that may affect the clinical treatment
(Figure 12, A and B).
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725
Figure 14. This small biopsy specimen contains intra-alveolar fibrin
with mild expansion of the alveolar septa and pneumocyte hyperplasia.
Taken in isolation the findings are not specific, but in the appropriate
clinical setting of a patient with diffuse pulmonary infiltrates and
respiratory compromise, the findings can be interpreted as being
consistent with acute lung injury (hematoxylin-eosin, original magnification 3100).
The entities discussed herein are diagnosed with
greatest certainty on a wedge biopsy specimen, and as
previously stated, a definitive diagnosis of AFOP or OP
should generally be made on a large biopsy specimen. In
practice, however, one is more frequently presented with
a small biopsy specimen, particularly in the initial stages
of the clinical workup. In some cases, one may be
fortunate and hyaline membranes may be detectable,
enabling a diagnosis of DAD, or one may be able to
identify features of eosinophilic pneumonia (Figure 13, A
and B) or capillaritis. More frequently, a precise diagnosis
may not be possible. Important features to evaluate
include (1) presence of intra-alveolar edema and/or
myxoid interstitial fibrosis, (2) presence of marked
pneumocyte hyperplasia, especially with bizarre cytologic
features, and (3) presence of alveolar fibrin or debris. If
such features are present, particularly in a patient with
known respiratory failure, it is appropriate to provide a
descriptive diagnosis with a comment that the findings are
suggestive of, or consistent with, acute lung injury
(Figure 14). When a diagnosis of acute lung injury is
suspected, additional features to assess include evaluation
for the presence of (1) microorganisms and viral inclusions, (2) eosinophils, suggesting the possibility of AEP,
and (3) coarse hemosiderin and capillaritis, suggesting an
immune-mediated vasculitis.
It cannot be emphasized enough that clinical correlation
and communication with the clinician are critical to avoid
overinterpretation of findings in small biopsy specimens,
and it is generally better to be conservative, especially if
correlative information is not available. While the above
features may point to acute lung injury in the proper
clinical setting, they are not specific taken alone and out of
context.
Hemorrhagic small biopsy samples may also be
problematic. Fresh hemorrhage secondary to the biopsy
procedure is very common, and blood and associated
fibrin within air spaces should not be overinterpreted as
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hyaline membranes. Fibrin associated with procedural
effect is generally loose and wispy. Only well-formed
hyaline membranes with a dense, glassy eosinophilic
quality should be taken as evidence of DAD. Similarly,
procedural-related hemorrhage should not be overinterpreted as a chronic hemorrhage syndrome. Features of
chronic hemorrhage such as macrophages with coarse
hemosiderin granules and associated reactive pneumocytes, or definitive evidence of capillaritis, should be
present before suggesting this diagnosis.
In summary, ALI and ARDS clinically represent a
significant cause of pulmonary morbidity and mortality.
Most patients with these conditions will have a histologic
pattern of DAD, but AFOP, AEP, and DAH with
capillaritis may also be encountered and constitute
important considerations in the differential diagnosis.
Determination of potential infectious etiologies is important from the pathologic perspective, and caution should
be used in interpreting small biopsy specimens.
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