PATHOLOGY OF ACUTE LUNG INJURY

Dr. Snehal Kosale (Junior Resident II)

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.

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.

CLINICAL AND PATHOLOGIC OVERVIEW

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

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.

PATHOGENESIS

Pneumocyte hyperplasiaFibroblastic proliferation

Exudation of edema fluidNeutrophil activationCellular

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.

Diffuse bilateral pulmonary infiltrates (‘‘white out’’) (chest x-ray)

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.

PHASES

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

Early stage of Acute stage of Diffuse alveolar damage.The lungs are heavy, firm, red and boggy.

Diffuse alveolar damage, acute/exudative phase. Alveolar septa show edematous widening and sparse inflammation and are lined by prominent

hyaline membranes (hematoxylin-eosin).

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)

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

Type I Pneumocyte

Type II Pneumocyte

Capillary

Diffuse alveolar damage, organizing phaseThe alveolar septa are expanded by myxoid-appearing fibrous tissue and

pneumocyte hyperplasia. A residual hyaline membrane is still visible (hematoxylin-eosin, original magnification 3200)

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

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.

TRANSFUSION-RELATED ACUTE LUNG INJURY

Important from a clinical standpoint

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.

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.

ACUTE FIBRINOUS AND ORGANIZING PNEUMONIA

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.

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

Acute fibrinous and organizing pneumonia is characterized by intra-alveolar fibrin balls

(hematoxylin-eosin, original magnification 3100).

‘‘Fibrin balls’’ Patchy involvement

Diffuse involvement Fibroblastic tissue

ACUTE EOSINOPHILIC PNEUMONIA

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.

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.

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).

Low power view of biopsy specimen with clinical features suggestive of

eosinophilic pneumonia.

On closer inspection, abundant eosinophils are supportive of the

diagnosis

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.

DIFFUSE ALVEOLAR HEMORRHAGE

With Capillaritis

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

Diffuse Alveolar Hemorrhage Neutrophilic capillaritis

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).

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

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.

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).

ORGANIZING PNEUMONIAAN IMPORTANT DIFFERENTIAL

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

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

Organizing pneumonia is characterized by patchy intra-alveolar organizing fibroblastic tissue. The surrounding alveolar septa contain mild lymphocytic

infiltrates (hematoxylin-eosin, original magnification 3100).

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

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.

APPROACH TO BIOPSY IN CLINICAL ARDS

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

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

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

Diffuse alveolar hemorrhage (DAH) with cytopathic changes of cytomegalovirus infection (arrows)

(hematoxylin-eosin, original magnification 3200).

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.

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.

WHAT IF

PRECISE DIAGNOSIS IS NOT POSSIBLE

• 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.

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

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.

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.

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.