A Historical Perspective and Modern Techniques in Pulmonary Pathology
Moderators: Dr. Henry D. Tazelaar, Dr. Ming S. Tsao and Dr. Brendan Mullen
Section 2 -
A Saga of Acute Lung Injury: Diffuse Alveolar Damage (DAD) – Past, Present, and Future
Joseph F. Tomashefski, Jr.
MetroHealth Medical Center and Case Western Reserve University
Diffuse Alveolar Damage (DAD) refers to a histopathological pattern of progressive acute lung injury
following a variety of different insults
The morphology of DAD is closely allied to its clinical
counterpart, the Acute Respiratory Distress Syndrome (ARDS), a fulminant form of respiratory failure
dominated by acute onset, severe hypoxemia (PaO2/FIO2 ≤200 mm Hg),
bilateral diffuse radiographic lung infiltrates, and the exclusion of cardiogenic pulmonary edema by a
normal pulmonary capillary wedge pressure (≤18 mm Hg)
Among the myriad causes of ARDS, the
most frequent are sepsis, pneumonia, major trauma, and aspiration of gastric content which together
account for up to 85% of cases . Traditionally the mortality rate of ARDS has exceeded 50%; however,
mortality has shown a recent decline .
Historical Context and Terminology
The first gross pathological description of DAD is attributed to Laennec who in 1821 described
idiopathic anasarca of the lung . The modern history of DAD, however, is traced to the battlefields
of World War I and subsequent conflicts of the twentieth century, where a syndrome of pulmonary edema was
identified following massive traumatic injury . The close association of DAD/ARDS with warfare
resonates in names, such as "traumatic wet lung," "shock lung," " post-traumatic pulmonary
insufficiency," and "Da Nang lung," which have described the entity . The features of the clinical
syndrome were further elucidated during the Vietnam War when mobile battlefield surgical units and rapid
evacuation provided immediate life-saving resuscitation from massive injuries only to have victims
succumb to subsequent respiratory failure .
An important defining study was that of Ashbaugh and Petty, who in 1967 recognized that acute
non-cardiogenic pulmonary edema was not exclusively a post-traumatic event, but could also arise from
non-traumatic lung insults in the civilian setting . These investigators also emphasized the
histological presence of hyaline membranes reminiscent of the neonatal respiratory distress syndrome .
The term "adult respiratory distress syndrome" (ARDS)
was coined by the same authors at a later date .
The value of mechanical ventilation and positive end expiratory pressure in the treatment of this
disorder was emphasized, and the possible pathogenetic role of altered lung surfactant was proposed in
the initial publication . The nomenclature was later changed to acute respiratory distress
syndrome, since the condition is not limited to adults . A further refinement in clinical terminology
was proposed in 1994 with the term "Acute Lung Injury" (ALI) to expand the spectrum of the disease and
include patients with a lesser degree of hypoxemia (PaO2/FIO2 ≤300
The term "Diffuse Alveolar Damage" (DAD) was proposed by Katzenstein, Bloor and Liebow in 1976 to
describe the pathological features and temporal sequence of acute lung injury. These pathologists
implicated variable initiating insults and the effects of therapy, including the role of toxic levels of
inspired oxygen. The division of the process into an exudative phase of acute response followed by a
reparative fibroproliferative phase still serves as the paradigm for the histopathology of ARDS .
Morphological studies of DAD/ARDS in the 1970's and 1980's defined the histopathological features and
explored their clinical correlates, in the context of the etiology of acute lung injury. The studies of
Bachofen and Weibel, and others, using ultrastructural morphometry, documented quantitative shifts of
lung compartments with progression of disease and verified increased intrapulmonary neutrophils .
The largest morphological study of the lung in ARDS was undertaken in 1979 by Pratt and colleagues in
a multicenter trial of extracorporeal membrane oxygenation (ECMO)
. Numerous morphological
parameters were evaluated but no single feature was found to be specific of any given etiology .
Philip Pratt was a leader among pathologists investigating ARDS during that time. As one of the first
pathologists to recognize the toxic effects of oxygen in hospitalized patients, Pratt emphasized a role
for oxygen toxicity in ARDS. He viewed the alveolar duct as a prime target of injury and defined
"alveolar duct fibrosis" as a seminal lesion . While still recognized as an important contributory
factor in acute lung injury, oxygen toxicity has been relegated to a lesser role in favor of other
pathogenetic mechanisms (see below).
During this period another major emphasis, spearheaded by Drs. Reid and Zapol in Boston, was vascular
injury as an initiating and contributory factor in ARDS . Using vascular casts and postmortem
angiography these investigators documented widespread obliteration of lung vessels reflecting intense
endothelial injury, and the important role of disordered coagulation . In situ thrombosis was
recognized to be ubiquitous and an important contribution to overall lung injury
Morphological Variants of DAD
A number of variants of DAD/acute lung injury have been defined based on different histological
patterns, clinicopathological correlations, or distribution of injury within the lung.
ALI without DAD: Various conditions such as drug toxicity (e.g.,
aspirin, cytosine arabinoside), near-drowning, high-altitude pulmonary edema, rapid lung re-expansion,
neurogenic pulmonary edema, and Hantavirus–associated lung injury, all present clinically as ARDS,
However, in each of these conditions, alveolar and interstitial edema, without hyaline membranes, is the
main histological finding. It is probable that certain mechanisms of endothelial injury promote vascular
leakage without the spectrum of changes of DAD. On the other hand, pathological descriptions of these
entities are few, and those which are available may represent very early disease, prior to the formation
of hyaline membranes .
Regional (Localized) DAD: The term DAD implies diffuse bilateral lung
involvement. Thoracic CT scans, however, show a more patchy lung distribution. Histologically, DAD also
represents a continuum in its extent of lung involvement. In patients who die of respiratory failure
secondary to ARDS, the lung usually is globally affected, but focal areas may be inexplicably spared.
Specific causes of acute lung injury such as uremia, acid aspiration, radiation or viral infection can
produce DAD that remains localized within the lung. Exudative and proliferative lesions may also occur
as localized secondary reactions adjacent to necrotizing lesions such as pneumonia or infarcts. In some
patients with the clinical syndrome of ALI/ARDS, lesions of DAD remain localized or multifocal, often
with accentuation in the upper lobes. Regional alveolar damage of this type has been speculated to be a
result of oxygen toxicity .
Mixed Phase DAD: The sequence (i.e., exudative, proliferative, and
fibrotic phases) proposed by Katzenstein has persisted as the temporal model for the evolution of DAD
. In reality, this time-honored construct is overly simplistic since, in many cases, lesions of
exudative and proliferative phase occur concomitantly . Proliferative activity has been documented
as early as 3 days following the onset of symptoms and type III procollagen peptide appears in BAL fluid
within 24 hours of the onset of symptoms
Conceivably, added insults due to pneumonia, mechanical
ventilation or oxygen toxicity superimposed upon the initial injury result in dyssynchronous "waves" of
Recurrent DAD: There are isolated reports of patients who develop
repeated episodes of DAD . The factors related to this situation are uncertain, and the phenomenon
is largely anecdotal.
Acute Interstitial Pneumonia (AIP): Acute Interstitial Pneumonia is a
rapidly progressive, often fatal, form of interstitial fibrosis which is histologically similar to the
proliferative phase of DAD . The histological and clinical features of this disorder are also
similar to those of the classical Hamman-Rich Syndrome . AIP is now regarded by many as idiopathic
DAD, and therefore represents a diagnosis of exclusion. Compared to typical ARDS, however, patients with
AIP tend to have a more protracted onset and more frequently progress to end stage fibrosis.
Histologically hyaline membranes and intralumenal fibrosis also tend to be less prominent. A subset of
patients at the outset have underlying interstitial fibrosis upon which AIP is superimposed (i.e., acute
exacerbation of IPF)
Acute Fibrinous and Organizing Pneumonia (AFOP): This entity, recently
described by Beasley et al., is a histological pattern of acute lung injury in which intraalveolar
fibrin balls are associated with organizing loose connective tissue but without hyaline membranes.
Patients present with an acute or subacute course, and have a mortality rate similar to that of DAD. The
authors suggest that AFOP may represent a fibrinous variant of DAD .
Fibrosing Non-Specific Interstitial Pneumonia (NSIP): In the original
description of NSIP by Katzenstein et al, two cases appeared to represent slowly resolving DAD/ARDS .
In addition to alveoloseptal fibrosis, remnants of alveolar duct fibrosis including ring-like expansion
of the duct and contiguous fibrous-walled cysts which differ from traditional honeycomb lung may be seen
in fibrotic phase DAD .
A wide variety of pneumotoxic agents delivered by vascular or inhalational routes have been used in
many different animal species to study mechanisms of injury to the alveolo-capillary unit. Experimental
models have importantly complemented clinical and morphological studies in increasing our understanding
of acute lung injury. However, there are relatively few models that simulate the progressive clinical
and pathologic derangements seen in patients with ARDS. Interventions used to recreate the acute phase
of non-cardiogenic pulmonary edema typically produce a selective effect on lung capillary endothelium.
Included among the numerous activators of acute lung injury are endotoxin, bacterial sepsis, fibrin
microemboli, oleic acid, hydrochloric acid aspiration, or hyperoxia (to name but a few)
overlapping morphological features in these models resemble the ultrastructural changes seen in the
exudative phase of DAD: i.e., interstitial edema, leukostasis, fibrin deposition, and evidence of
endothelial injury and necrosis. In general these models of acute lung injury do not evolve to
Two important agents which had been extensively used to simulate the fibroproliferative phase of DAD
are bleomycin and paraquat, both of which prominently injure Type 1 alveolar epithelial cells, and
produce a pattern of lung injury in which an early phase of inflammation and edema is followed by
interstitial fibrosis. The effect of each of these agents is enhanced, with a greater degree of fibrous
remodeling, in the presence of hyperoxia, harking back to Pratt's admonitions on the role of oxygen
1990's and Beyond – The Role of Inflammatory Mediators
Numerous inflammatory mediators, are increased in the blood or BAL fluid of patients with ALI/ARDS
In early studies, activation of complement (C5a) was linked to accumulation and activation
of neutrophils . A host of chemokines, cytokines and lipid signaling molecules are now included in
the inflammatory mediator milieu . A key concept is that cytokine balance is an important
determinant of the duration and degree of the inflammatory response . The relationships among
cytokines are extremely complex in acute lung injury, with both pro-inflammatory (e.g., TNF-a,
IL1-ß) and anti-inflammatory (endogenous inhibitors of TNF-a, IL1-ß) mediators increased
Other mediators such as IL-8 (neutrophil chemotaxis), IL-1, and endothelial adhesion molecules
(ICAM-1, E-selectin, P-selectin)
are also increased in ALI, and likely play important roles . Most
mediators have not proven to be prognostic markers in ARDS, and trials of anti-inflammatory strategies
targeting specific cytokines like IL1- ˙ and TNF-˙ were unsuccessful . Recent emphasis has been
placed on transcriptional factors such as nuclear factor-˙ B (NF-κB) as regulating the
Apoptosis in ALI
One important area of current active study is on the role of apoptosis (programmed cell death) in the
evolution of ALI/ARDS . Evidence of apoptosis in humans and experimental models, however, is
confusing and tentative. Studies are hampered by the relatively ineffective means to currently assess
apoptosis. Neutrophil apoptosis is inhibited by soluble mediators, most importantly GM-CSF, and high
levels of GM-CSF in BAL fluid have been associated with improved survival in early ARDS. In some animal
models, however, enhancement of neutrophil apoptosis is beneficial to the host. The biological
importance of neutrophil apoptosis in ARDS is uncertain. Epithelial apoptosis also occurs in ARDS .
Guinee et al. found that bax, a bcl-2 analog that promotes apoptosis, is upregulated in alveolar
pneumocytes of humans with DAD
The Fas/FasL system is considered to be important in regulating
lung epithelial cell apoptosis and is probably involved in the pathogenesis of acute lung injury. There
is little information about endothelial cell apoptosis in ARDS. Limited evidence suggests that
circulating mediators, especially TNF-a, may induce endothelial apoptosis .
Since 1967 the mortality of ARDS has declined
Improved survival has evolved concomitantly
with advances in critical care. An important recent development are lung protective ventilatory
strategies using smaller tidal volumes . Ongoing studies using prone positioning to improve
mechanical ventilation have been thus far inconclusive . Previous clinical trials using ECMO failed
to show increased survival .
Pharmacological interventions in ARDS have been limited and largely unsuccessful. Despite the
significant presence of inflammation and degradation of alveolar surfactant in ARDS, neither
corticosteroids nor surfactant replacement therapy have been shown to improve survival in large scale
A variety of forms of anticoagulant therapy have also been evaluated with
only limited success. Activated protein C has recently been proven useful in severe sepsis .
Treatment with systemic vasodilators in an attempt to improve ventilation-perfusion matching were
unsuccessful due to the deleterious effects of systemic vasodilatation. However, limited success has
been achieved with the selective lung vasodilator inhaled NO, especially when used in combination with
ventilation strategies in patients with severe ARDS. Randomized controlled trials of inhaled NO,
however, have shown no overall improvement in mortality, but efficacy may exist for selected patients
As simply stated by Matthay, "important discoveries relevant to the pathogenesis [of ALI] have been
made, [however] what we do not know still exceeds what we do" . A recent workshop sponsored by NHLBI
on research directions in ALI emphasized the importance of continued high quality clinical trials
studying prevention and treatment, correlation of biochemical and biological markers with clinical
variables, and a better understanding of genetic factors. Further elucidation of cell – cell interaction
using modern genomic and proteomic techniques will be important as will be the pursuit of animal models
that more closely mimic the human disease. Delineation of different pathogenetic mechanisms relative to
the various causes of ARDS is another worthy future goal .
In summary, the important contributions of the traditional morphological approach of studying acute
lung injury have paved the way for a new era of probing the elusive pathogenesis of ARDS at the molecular
and genetic level.
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