Stanford School of Medicine

Surgical Pathology Criteria

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Acute Interstitial Pneumonia - Diffuse Alveolar Damage


  • Acute onset lung disease characterized by diffuse hyaline membrane formation followed by organization

Alternate/Historical Names

  • Adult respiratory distress syndrome (clinical term for disease with this pattern)

Diagnostic Criteria

  • Diffuse alveolar damage (DAD) is a pattern that has many causes including
    • Infection, aspiration, shock, toxins, burns, transfusions and drugs
    • When idiopathic, it is termed acute interstitial pneumonia (AIP)
    • Both idiopathic and secondary DAD share an acute onset and poor prognosis
      • Roughly 50% mortality in six months
  • Clinical
    • Sudden onset of dyspnea, cough over 1-2 weeks
      • Occasionally subacute
    • May occur at any age
  • High resolution computed tomography (HRCT)
    • Consolidation (early phase) developing into bilateral diffuse ground glass opacities
    • Late phase may show cyst formation or diffuse honeycombing
  • Histopathologic features
    • Changes in first week are exudative
      • Necrosis of alveolar lining cells with extravasation of fibrin
      • Prominent, diffuse hyaline membranes in alveolar lumens
        • Intra-alveolar balls of fibrin may be seen in acute fibrinous and organizing pneumonia variant, see below
    • Fibroproliferative organizing phase follows in air spaces and interstitium
      • Loose edematous fibroblastic tissue
        • Little dense collagen deposition
      • Hyaline membranes are resorbed by organization
        • Fragments may remain in lumens and incorporated into interstitium
    • Late scarring phase
      • Scarring may result in diffuse honeycomb change
      • Alveoli lined by reactive alveolar lining cells with hobnail appearance
        • Mitotic figures and marked reactive atypia may be seen
      • Squamous metaplasia of bronchiolar and adjacent air spaces is frequent
        • Mitotic figures and marked reactive atypia may be seen
    • Mild to moderate interstitial infiltrate of plasma cells, lymphocytes and neutrophils
      • Eosinophils infrequent
    • Organizing thrombi may be seen in small to medium sized pulmonary arteries
  • DAD pattern may occur in the setting of acute exacerbation of a chronic interstitial lung disease such as UIP
    • Underlying architectural changes such as peripheral honeycombing may help identify the diagnosis
    • Clinical or radiographic history of pre-existing pulmonary disease is very helpful
  • Acute Fibrinous and Organizing Pneumonia has been proposed as a variant (Beasley 2002)
    • Patchy involvement of alveoli by balls of fibrin

Gerald J Berry MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 11/20/10

Differential Diagnosis

Usual Interstitial Pneumonia Acute Interstitial Pneumonia
Temporal heterogeneity Temporally uniform
Honeycomb change prominent Honeycomb change only in late stage
Patchy distribution with subpleural accentuation Diffuse, uniform throughout
Hyaline membranes not seen Hyaline membranes prominent in early stage


Nonspecific Interstitial Pneumonia Acute Interstitial Pneumonia
Predominantly interstitial Prominent intra-alveolar component
No hyaline membranes Hyaline membranes prominent in early stage
Intra-alveolar organization rare and focal Prominent intra-alveolar organization in intermediate stage
Honeycomb change rare Diffuse honeycomb change may be seen in late stage
Insidious onset, chronic disease Acute onset


Cryptogenic Organizing Pneumonia Acute Interstitial Pneumonia
Patchy distribution Diffuse
No hyaline membranes Hyaline membranes prominent in early stage and fragments in organizing phase
No collagen deposition, architecture preserved Diffuse honeycomb change may be seen in late stage


Acute Interstitial Pneumonia / Diffuse Alveolar Damage Acute Eosinophilic Pneumonia
Eosinophils infrequent Prominent eosinophils in lavage and biopsy specimens
Not steroid responsive, poor prognosis Steroid responsive, no relapses
Diffuse alveolar damage pattern may be seen in acute eosinophilic pneumonia


  • Specific causes of DAD pattern must always be ruled out
    • These include infection, aspiration, shock, toxins, burns, transfusions and drugs
  • DAD pattern may be superimposed on a chronic process such as UIP in the setting of an acute exacerbation
    • Defining feature
      • Hyaline membranes, intact or organizing
    • Features that should suggest superimposed AIP/DAD
      • Squamous metaplasia of respiratory bronchioles
      • Fibrin thrombi in small arteries
      • Type II pneumocyte hyperplasia
    • Clinical and radiographic history is important

Classification / Lists

Smoking Related Lung Diseases

Idiopathic Interstitial Lung Diseases

Other Diffuse Parenchymal Lung Diseases



  • Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr.  Non-neoplastic Disorders of the Lower Respiratory Tract, AFIP Atlas of Nontumor Pathology, First Series, Fascicle 2, 2002.
  • American Thoracic Society; European Respiratory Society. ATS/ERS 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 Jan 15;165(2):277-304.
  • Visscher DW, Myers JL. Histologic spectrum of idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006 Jun;3(4):322-9.
  • 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 Sep;126(9):1064-70.
  • Olson J, Colby TV, Elliott CG. Hamman-Rich syndrome revisited. Mayo Clin Proc. 1990 Dec;65(12):1538-48.
  • Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol. 1986 Apr;10(4):256-67.
  • Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial  lung disease. Histopathology. 2010  [Epub ahead of print].
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