1. Diffuse alveolar damage is the most common histologic pattern seen in acute lung injury and acute respiratory distress syndrome. It is characterized by hyaline membranes, edema, and inflammation in two phases - acute/exudative and organizing/proliferative.
2. Other histologic patterns that can present similarly include acute eosinophilic pneumonia, diffuse alveolar hemorrhage with capillaritis, acute fibrinous and organizing pneumonia, and organizing pneumonia. These differ in their inflammatory cell profiles and distributions within the lung.
3. A careful histologic examination coupled with clinical information is needed to distinguish between these patterns and make an accurate diagnosis, which guides further management and prognosis. Transfusion-
2. DEFINITION (OLDER)
• In 1994, the American-European Consensus Conference
on Acute Respiratory Distress Syndrome defined ARDS
• An acute condition characterized by bilateral pulmonary
infiltrates and severe hypoxemia in the absence of
evidence for cardiogenic pulmonary edema.
• PaO2/FiO2 <300 = Acute Lung Injury (ALI)
PaO2/FiO2 <200 = Acute Respiratory Distress Syndrome (ARDS)
• A study by Rubenfeld et al reported an average mortality
rate of 41.1% for ARDS and 38.5% for ALI.
Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant
outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149(3, pt 1):818– 824.
Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685–1693.
3. HISTOPATHOLOGY
• Most cases of clinical ALI and ARDS have diffuse alveolar
damage (DAD) histologically.5,6
• Other histologic patterns
• Acute Eosinophilic Pneumonia (AEP)
• Acute Fibrinous And Organizing Pneumonia (AFOP).7,8
• Diffuse Alveolar Hemorrhage (DAH)
5. Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung biopsy in ARDS. Chest. 2004;125(1):197–202.
6. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–1349.
7. Tazelaar HD, Linz LJ, Colby TV, Myers JL, Limper AH. Acute eosinophilic pneumonia: histopathologic findings in nine patients. Am J Respir
Crit Care Med. 1997;155(1):296–302.
5. 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
6. ETIOLOGY
• 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.
• Among the infectious etiologies,
• Viruses,
• Legionella,
• Mycoplasma, and
• Rickettsia
• Immunosuppressed patient- Pneumocystis jiroveci and other
fungi.
Travis WD, Pittaluga S, Lipschik GY, et al. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired
immune deficiency syndrome: review of 123 lung biopsies from 76 patients with emphasis on cysts, vascular invasion, vasculitis, and
granulomas. Am J Surg Pathol. 1990; 14(7):615–625.
7. PATHOGENESIS
Pneumocyte
hyperplasia
Fibroblastic
proliferation
Exudation of
edema fluid
Neutrophil
activation
Cellular
breakdown
products
Damage to the
capillary and
alveolar epithelium
Ware LB. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med. 2006;27(4):337–349.
Suratt BT, Parsons PE. Mechanisms of acute lung injury/acute respiratory distress syndrome. Clin Chest Med. 2006;27(4):579–589.
Parsons PE. Mediators and mechanisms of acute lung injury. Clin Chest Med. 2000;21(3):467–476.
Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage—the role of oxygen, shock, and related factors: a review. Am J Pathol.
1976;85(1):209– 228.
Belperio JA, Keane MP, Lynch JP III, Strieter RM. The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung
injury. Semin Respir Crit Care Med. 2006;27(4):350–364.
9. DIFFUSE ALVEOLAR DAMAGE
• Histologically, DAD is typically divided into 2 phases:
• Acute/exudative phase- during the first week following pulmonary
insult
• Organizing/proliferative phase- after the first week
• Some workers identify fibrosis as an end event
• Single insult- Relatively linear fashion.
• Repeated insults- Variable features within a biopsy
specimen.
Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med. 2000;21(3):435–466.
11. ACUTE/EXUDATIVE PHASE
• Uniform or focal
• By day 2 intra-alveolar edema and interstitial widening are
apparent.
• Hyaline membranes- 4 to 5 days after the initial insult.
• Composed of cellular and proteinaceous debris and
• Appear as dense, glassy eosinophilic membranes lining the
alveolar ducts and alveolar spaces.
• Generally, inflammation is relatively sparse
12. Early stage of Acute stage of Diffuse alveolar damage.
The lungs are heavy, firm, red and boggy.
13. Diffuse alveolar damage, acute/exudative phase. Alveolar septa show
edematous widening and sparse inflammation and are lined by prominent
hyaline membranes
(hematoxylin-eosin).
14. Thrombi may be observed in cases of diffuse alveolar damage and are
secondary to localized alterations in the coagulation pathway.
(hematoxylin-eosin, original magnification 3200)
15. ORGANIZING PHASE
• The organizing phase is characterized by relatively
uniform interstitial fibrosis.
• Loose and myxoid and appears bluish-gray on hematoxylin-eosin
sections
• Associated with type 2 pneumocyte hyperplasia.
• The hyaline membranes 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
17. Diffuse alveolar damage, organizing phase
The alveolar septa are expanded by myxoid-appearing fibrous tissue and
pneumocyte hyperplasia. A residual hyaline membrane is still visible
(hematoxylin-eosin, original magnification 3200)
18. ORGANIZING PHASE
• Squamous metaplasia
may also be present
• Misdiagnosis as
carcinoma can be
avoided by
• Distribution of the
squamous epithelium
along air spaces
• The lack of overt cytologic
features of malignancy
19.
20. PROGNOSIS
• Some cases of DAD will gradually resolve
• Continued interstitial fibrosis with architectural remodeling
and progressive respiratory compromise.
• Among patients who survive, most will experience some
degree of residual functional impairment.
Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med. 1990;11(4):593–619.
Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med. 2000;21(3):435–466.
22. TRANSFUSION-RELATED ACUTE LUNG
INJURY
• Associated with transfusion of plasma containing blood
components
• Mild dyspnea to fulminant respiratory failure
• Fatal in 5% to 10% of cases, although most patients
recover with supportive measures.
• Radiographs demonstrate findings essentially identical to
those of ARDS.
23. TRANSFUSION-RELATED ACUTE
LUNG INJURY
• Since a clinical diagnosis, reports of pathologic findings
are few and generally restricted to fatal cases.
• Findings identical to those of DAD with classic hyaline
membranes.
• Pulmonary edema with neutrophil accumulation within
alveolar capillaries seen in few cases. 32–34
• Warranted further study.
Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005;33(4):721–726.
Kopko PM, Popovsky MA. Pulmonary injury from transfusion-related acute lung injury. Clin Chest Med. 2004;25(1):105–111.
Danielson C, Benjamin RJ, Mangano MM, Mills CJ, Waxman DA. Pulmonary pathology of rapidly fatal transfusion-related acute lung
injury reveals minimal evidence of diffuse alveolar damage or alveolar granulocyte infiltration. Transfusion. 2008;48(11):2401–2408.
25. ACUTE FIBRINOUS AND
ORGANIZING PNEUMONIA
• Acute fibrinous and organizing pneumonia (AFOP) is a
more recently described histologic pattern
• Patchy or relatively diffuse
• Alveolar spaces are filled with organizing fibrin balls
• The alveolar septa may show mild interstitial widening or
lymphocytic infiltrates,
• Significant eosinophils or neutrophils should not be seen.
26. ACUTE FIBRINOUS AND
ORGANIZING PNEUMONIA
• Diagnosis of exclusion
• Organizing fibrin can occur as a nonspecific reaction
adjacent to lesions such as
• granulomas
• abscesses
• neoplasms
• 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
27. Acute fibrinous and organizing pneumonia is characterized by intra-alveolar
fibrin balls
(hematoxylin-eosin, original magnification 3100).
30. EOSINOPHILIC PNEUMONIA
• Most commonly presents with a subacute clinical course
• Occasionally presents with fulminant respiratory failure,
often associated with fever.
• Exclude peripheral blood eosinophilia typical of chronic eosinophilic
pneumonia.
• Both AEP and EP may be associated with underlying
etiologies such as
• Infection, particularly with parasites or fungus,
• Toxic inhalation,
• Allergic drug reaction, or
• Idiopathic.
31. EOSINOPHILIC PNEUMONIA
• Characterized by
• Intra-alveolar fibrin and macrophages
• Admixed with numerous eosinophils.
• Hyaline membrane formation similar to DAD
• In some cases, eosinophils may infiltrate blood vessel
walls.
32. 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).
33. Low power view of biopsy specimen
with clinical features suggestive of
eosinophilic pneumonia.
On closer inspection, abundant
eosinophils are supportive of the
diagnosis
34. EOSINOPHILIC PNEUMONIA
• The histologic differential of AEP
• DAD
• AFOP
• Churg-Strauss syndrome
• Necrotizing vasculitis and granulomas
• Clinical findings of systemic vasculitis
• The presence of eosinophils should be sought in all cases
with histologic findings of DAD.
• AEP is sensitive to steroid therapy
• Dramatic recovery when appropriate therapy is instituted.
Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. N Engl J
Med. 1989;321(9): 569–574.
36. DIFFUSE ALVEOLAR HEMORRHAGE
• Diffuse alveolar hemorrhage (DAH) with capillaritis presents
with fulminant respiratory failure.
• Diffuse intra-alveolar blood admixed with hemosiderin-laden
macrophages containing coarse hemosiderin granules.
• Capillaritis
• Neutrophils within the alveolar septa
• Resultant vascular necrosis
• Minimal or absent involvement of the air spaces.
• Organizing fibroblastic tissue may be present and form
‘‘dumbbell’’ shapes crossing the alveolar septa
38. 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).
39. HEMORHHAGE IN BIOPSY
• Hemosiderin-laden macrophages 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
• Iron stains may highlight the coarse nature of true hemosiderin,
• Pigmented ‘‘smoker’s type’’ macrophages may also contain stainable iron
• 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.
• Cellular reactive changes in the adjacent alveolar septa and
• Focal areas of air space organization.44–46
40. DIFFUSE ALVEOLAR HEMORRHAGE
• When hemorrhage is significant from a histologic
standpoint, clinical correlation is necessary (hemoptysis)
• A diagnosis of DAH should be entertained only when a
patient presents with diffuse alveolar infiltrates.
• DAH may occur with or without associated capillaritis;
• Cases with capillaritis may present with clinical manifestations of
ALI.
41. ASSOCIATIONS
• 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
• Wegener granulomatosis
• Other entities that have been reported in association with DAH
include
• Primary antiphospholipid antibody syndrome,
• Mixed cryoglobulinemia,
• Behcet syndrome, and
• Henoch-schὄnlein purpura
• Infections (HIV, listeriosis).
43. ORGANIZING PNEUMONIA
• Organizing Pneumonia generally presents with a
• subacute clinical course
• without fulminate respiratory failure
• NO fulminant respiratory failure and NO mechanical
ventilation
• OP is frequently included in the pathologic differential
diagnosis of ALI and other histologic patterns associated
with ALI
44. ORGANIZING PNEUMONIA
• Patchy accumulation of intra-alveolar organizing
fibroblastic tissue,
• Primarily centered around bronchioles.
• Intra-bronchiolar fibroblastic tissue 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
45. Organizing pneumonia is characterized by patchy intra-alveolar organizing
fibroblastic tissue. The surrounding alveolar septa contain mild lymphocytic
infiltrates
(hematoxylin-eosin, original magnification 3100).
46. ORGANISING PNEUMONIA
• More diffuse
• Normal lung parenchyma is
uncommon
• Interstitial expansion/
myxoid fibrosis
• Marked pneumocyte
hyperplasia
ORGANISING DAD
• Patchy, bronchiolocentric
• Intervening normal lung
parenchyma
• Interstitial changes are
relatively mild, Lymphocytic
NO interstitial fibrosis.
• Pneumocyte hyperplasia is
similarly not as prominent
47. BERLIN DEFINITION (NEW)
• JAMA. 2012;307:2526-2533
• “Acute lung injury” no longer exists.
• Under the Berlin definition, patients with PaO2/FiO2 200-
300 would now have “mild ARDS.”
• Onset of ARDS must be acute, as defined as within 7
days of some defined event
• sepsis
• pneumonia
• simply a patient’s recognition of worsening respiratory symptoms.
49. APPROACH
• When evaluating a biopsy specimen from a patient with
clinical ARDS
• Clinical information as much as possible
• Information regarding disease onset and progression,
• Suspected underlying etiologies,
• Radiographic information, and
• Whether or not the patient is on mechanical ventilation
50. APPROACH
• Histologic manifestations of DAD in particular, may be
associated with underlying etiologic agents, or they may
be idiopathic.
• Careful evaluation for potential infectious etiologies.
• Special stains for microorganisms, namely
• Gram’s stain
• Acid-fast stain
• Grocott’s methenamine-silver or similar silver stain, and a
• Carefully scrutinize for viral cytopathic changes.
• Harbor fungal, pneumocystis, mycobacterial, or bacterial
infections that may affect the clinical treatment
51. Numerous fungal organisms
(Aspergillus)
(Grocott’s methenamine-silver, original
magnification 3200).
Acute Fibrinous And Organizing
Pneumonia
(Hematoxylin and eosin original magnification
3200).
Mary Beth Beasley, MD. The Pathologist’s Approach to Acute Lung Injury. Arch Pathol Lab Med. 2010;134:719–727
52. Diffuse alveolar hemorrhage (DAH) with cytopathic changes of
cytomegalovirus infection (arrows)
(hematoxylin-eosin, original magnification 3200).
53. HEMORRHAGIC BIOPSY
• Fresh hemorrhage secondary to the biopsy procedure is
very common
• Blood and associated fibrin within air spaces should not
be overinterpreted as 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.
54. SMALL BIOPSY
• A definitive diagnosis of AFOP or OP should generally be
made on a large wedge-shaped biopsy specimen.
• In practice,one is more frequently presented with a small
biopsy specimen, particularly in the initial stages of the
clinical workup.
• More frequently, a precise diagnosis may not be possible.
56. • Important features to evaluate include
• Presence of intra-alveolar edema and/or myxoid interstitial fibrosis,
• Presence of marked pneumocyte hyperplasia, especially with
bizarre cytologic features, and
• Presence of alveolar fibrin or debris.
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.
57. 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
58. SUMMARY
• ARDS clinically represents a significant cause of
pulmonary morbidity and mortality.
• Most patients with these conditions will have a histologic
pattern of DAD, followed by AFOP, AEP, and DAH with
capillaritis
• Determination of potential infectious etiologies is
important from the pathologic perspective
• Caution should be used in interpreting small biopsy
specimens.
59. SUMMARY
• Clinical correlation and communication with the clinician
are critical to avoid over-interpretation of findings in small
biopsy specimens, and
• It is generally better to be conservative, especially if
correlative information is not available.
60.
61. CONTRIBUTIONS
• Tazelaar HD, Linz LJ, Colby TV, Myers JL, Limper AH. Acute eosinophilic
pneumonia: histopathologic findings in nine patients. Am J Respir Crit Care Med.
1997;155(1):296–302.
• Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD. Acute fibrinous and
organizing pneumonia: a histological pattern of lung injury and possible variant of
diffuse alveolar damage. Arch Pathol Lab Med. 2002;126(9):1064– 1070.
• Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress syndrome.
Clin Chest Med. 2000;21(3):435–466.
• Tomashefski JF Jr, Davies P, Boggis C, Greene R, Zapol WM, Reid LM. The
pulmonary vascular lesions of the adult respiratory distress syndrome. Am J
Pathol. 1983;112(1):112–126.
• Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol.
2001;13(1):12–17.
• Travis W, Colby TV, Koss MN, Rosado-de-Christenson ML, Muller NL, King TE Jr.
Idiopathic interstitial pneumonia and other diffuse parenchymal lung diseases. In:
Non-Neoplastic Disorders of the Lower Respiratory Tract. Washington, DC:
American Registry of Pathology and Armed Forces Institute of Pathology;
2002:49–231. Atlas of Nontumor Pathology; 2nd series.
