Interstitial Lung Disease Other than UIP
Moderators: Brian Chiu and William D. Travis
Section 3 -
Acute Lung Injury Patterns Other Than DAD
Mary Beth Beasley
Providence Portland Medical Center
Portland , OR
Acute lung injury (ALI), from a pathologic standpoint, has historically referred to the histologic
patterns of injury resulting from an injury occurring at a single point in time. Katzenstein included
both diffuse alveolar damage (DAD) and bronchiolitis obliterans-organizing pneumonia (BOOP), now known as
organizing pneumonia (OP), under the encompassing term "acute lung injury" in her excellent monograph.
The term was meant to emphasize the recent onset of the changes as well as their temporal uniformity.
DAD was felt to result for widespread injury while BOOP resulted from more localized injury to the
From a clinical standpoint, ALI and the acute respiratory distress syndrome (ARDS) have been more or
less synonymous and have lacked precise definitions. The initial description of what would become known
as ARDS was described by Ashbaugh and colleagues in 1967. In this paper, 12 patients were described with
severe tachypnea and hypoxemia resistant to supplemental oxygen evolving in an acute fashion over the
course of only hours. Lung compliance was decreased, patients required mechanical ventilation, and
radiographs revealed infiltrates indistinguishable from pulmonary edema. Histologic examination revealed
hyaline membranes. In a subsequent paper in 1971, Ashbaugh and Petty coined the term "adult respiratory
syndrome" and reviewed 40 cases with heterogeneous inciting events but with a common pathological
response in the lung. In the subsequent decades attempts have been made to create more precise
definitions in order to more uniformly define patients with ALI/ARDS. In 1994, the North
American-European Consensus Conference (NAECC) on ARDS proposed a revised definition of ARDS and ALI as
- North American-European Consensus Definition
- Acute Respiratory Distress Syndrome (ARDS):
- PaO2:FiO2 < 200mmHg
- Bilateral infiltrates radiographically consistent with pulmonary
- No clinical evidence of cardiac failure
- Acute lung injury (ALI)
- PaO2:FiO2 < 300mmHg
- Criteria otherwise the same
While this simplified definition is not without its critics, it does provide
objective criteria with the intent of providing a uniform definition for evaluating incidence and
outcomes as well as for enrollment in clinical trials.
Determining the incidence of ALI/ARDS has been hampered by a lack of uniformity in defining the
syndrome. A recent cohort study from the University of Washington using the NAECC criteria found an
incidence of 78.9 cases per 100,000, although other studies using varying criteria have estimated a lower
rate. Historically, the mortality rate for ALI/ARDS has been greater than 50%. The University of
Washington study demonstrated an average mortality rate of 38.5%, although the mortality rate increased
with patient age, reaching >60% in patients over 85. The findings would indicate that while some
improvement has been made, ALI/ARDS remains a significant cause of morbidity and mortality.
The vast majority of biopsy specimens from patients with ALI/ARDS with show a histologic pattern of
DAD. For this reason, the value of open lung biopsy has been questioned by some authors given the lack
of specificity of the findings with regard to outcome and treatment guidance. A recent study by Patel,
et al, did show that open lung biopsy revealed information which resulted in a change of therapy in
nearly a third of cases. The majority of these involved identification of a specific infection agent,
while others revealed a histologic pattern other than DAD which warranted a change in therapy. DAD is
being discussed in depth at another session during this congress, so this session will focus on
histologic patterns other than DAD which may occur in the clinical setting of acute lung injury. These
patterns are as follows:
It should be noted that using current clinical criteria, typical cases of OP/BOOP do not usually meet
the criteria for true ALI.
- Acute Fibrinous and Organizing Pneumonia (AFOP)
- Acute Eosinophilic Pneumonia (AEP)
- Diffuse Alveolar Hemorrhage with Capillaritis (DAH-C)
Acute Fibrinous and Organizing Pneumonia (AFOP):
AFOP was originally described in 2002 as a histologic pattern of acute lung injury which did not fit
with the classic features of either DAD or OP. The majority of patients presented with a fulminate onset
of respiratory failure and the overall mortality rate was 60%. A minority of patients presented with a
subacute clinical course and ultimately recovered. Based on the overall findings it was felt AFOP likely
represented a variant of DAD, although the relationship of AFOP to OP and AEP needs to be further
evaluated in regard to the less fulminate cases.
All of the cases of AFOP showed similar findings consisting of prominent intra-alveolar fibrin balls
without associated hyaline membrane formation, significant neutrophils or eosinophils. The fibrin balls
were associated with varying degrees of organizing pneumonia, which typically retained a central fibrin
core. The process was frequently patchy but not exclusively peribronchiolar, and some cases were
relatively diffuse. The alveolar septa in the regions of the alveolar fibrin typically contained mild to
moderate chronic inflammatory cell infiltrates. Myxoid interstitial fibrosis may be present but is
generally not marked, and the prominent type 2 pneumocyte hyperplasia typically seen with DAD is not
encountered. Significant intra-alveolar macrophage accumulation, as frequently encountered in
eosinophilic pneumonia was not seen.
Similar to DAD, the AFOP pattern was associated with a wide range of potential underlying etiologies
(infection, drug reaction, collagen vascular disease) while some remained idiopathic. Peripheral blood
eosiniophil counts were not found to be elevated, but this information was not known on all patients.
Other than the fact that all of the patients who required mechanical ventilation died, no clinical or
histologic feature correlated with eventual outcome and an optimal treatment was not identified.
Acute Eosinophilic Pneumonia (AEP)
Eosiniphilic pneumonia (EP) most typically presents with a subacute clinical course but occasional
cases present with fulminate respiratory failure. Such cases are termed acute eosinophilic pneumonia
(AEP), and may not be associated with the peripheral blood eosinophilia typical of conventional EP.
EP 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. 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
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 once appropriate therapy has been instituted.
Diffuse Alveolar Hemorrhage with Capillaritis (DAH-C)
Occasionally, diffuse alveolar hemorrhage will present with fulminate respiratory failure. Such cases
demonstrate diffuse intra-alveolar blood admixed with hemosiderin-laden macrophages containing coarse
hemosiderin granules. Prominent fibrin may be present and organizing fibroblastic tissue, often
containing hemosiderin granules, may also be observed. Capillaritis is evidenced by neutrophils within
the alveolar septa with resultant vascular necrosis. The vascular damage may be difficult to directly
appreciate but the presence of "too many neutrophils" within the alveolar septa suggests the presence of
capillaritis in the setting of hemorrhage. Organizing fibroblastic tissue may be present and form
"dumbbell" shapes crossing the alveolar septa as the capillaritis resolves, or myxoid interstitial
fibrosis may develop. The fibrosis is typically relatively mild in degree. Some cases of diffuse
alveolar hemorrhage with capillaritis will also have hyaline membranes, which may occasionally be the
dominant histologic component. While severe respiratory failure may occur as a manifestation of most any
collagen vascular disease, it is most commonly encountered in the clinical setting of so-called acute
lupus pneumonitis. Diffuse alveolar hemorrhage may also be encountered with Goodpasture syndrome
(anti-basement membrane antibody syndrome), antiphospholipid antibody syndrome and microscopic
polyangiitis. Some cases of Wegener's granulomatosis may also present with this histologic pattern. In
such cases, immunoflorescence studies may demonstrate immune complex deposition, and serum studies such
as ANCA and anti-GBM may aid in narrowing the clinical differential. While most cases of DAH-C are
associated with immune related disorders, drug reactions and infectious agents may occasionally produce
this histologic pattern.
Differential Diagnosis and Additional Comments
The differential diagnosis of AFOP, AEP and DAH-C is primarily with each other and with DAD, and the
salient features are summarized in the following table:
Summary of major findings in histologic patterns associated with clinical ALI/ARDS
| ||DAD ||AEP ||AFOP ||DAH-C|
|Hyaline membranes ||++ ||+ ||- ||+/-|
|Fibrin balls ||+/- ||+/- ||++ ||+/-|
|Eosinophils ||- ||++ ||- ||-|
|Marked pneumocyte hyperplasia ||++ ||+/- ||+/- ||-|
|Myxoid interstitial fibrosis ||+ ||+/- ||+/- ||-|
|Interstitial neutrophils with capillaritis ||- ||- ||- ||++|
Major discriminating points/issues:
Infectious etiologies should be searched for in all cases of clinical ALI/ARDS
Some cases of DAD may contain fairly prominent intra-alveolar fibrin and may be difficult to separate
from AFOP. True hyaline membrane formation or relatively diffuse myxoid interstitial fibrosis and
prominent type 2 pneumocyte hyperplasia supports a diagnosis of DAD over AFOP.
EP typically contains prominent intra-alveolar fibrin and bears the most histologic overlap with
AFOP. Given that EP is responsive to steroid, the presence of eosinophils to any degree should raise the
possibility of EP over AFOP. Similarly, the possibility of a partially treated EP should be considered
if the AFOP pattern is present in a patient who received steroid therapy prior to biopsy, especially if a
peripheral blood eosinophilic is present. Eosinophils should also be sought in all cases of histologic
DAD given the exquisite sensitivity of AEP to steroid therapy.
Finally, a definite diagnosis of AFOP should not be made on a small biopsy specimen as intra-alveolar
fibrin may occur as a component of other processes or as a non-specific reaction around the periphery of
an unrelated process.
- American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165277-304.
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