Lung Biopsy Interpretation
Case 3 -
Diffuse Alveolar Damage (DAD)
Anna-Luise A. Katzenstein & Jeffrey L. Myers
This 43 year old man was hospitalized for shortness of breath, fever, pleuritic chest pain, and
headache that began several days before admission. He was found to be severely hypoxemic with a
pO2 of 53 and oxygen saturation of 86% on 4 liters of oxygen. Chest x-ray showed bilateral
lung opacification. The patient had a history of a similar illness one year previously requiring
mechanical ventilation and treated with antibiotics and corticosteroids. He had a history of crack
cocaine use in the past, but vigorously denied recent use. He was taking methadone for chronic back pain
and had a history of gastroesophageal reflux disease. He was intubated and a thorascopic lung biopsy
Case 3 - Figure 1 - Low magnification view showing interstitial thickening and hyaline membranes lining alveolar septa.
Case 3 - Figure 2 - Higher magnification showing the homogeneous eosinophilic hyaline membranes lining thickened alveolar septa.
The main finding in this biopsy is the presence of extensive hyaline membrane formation. The alveolar
septa are also thickened by edema and scattered fibroblasts, and alveolar pneumocyte hyperplasia is seen
along some as well. This histologic appearance is characteristic of the early or exudative stage of
diffuse alveolar damage (DAD). An additional focal finding is an acute inflammatory cell infiltrate
within airspaces. Acute inflammation is usually not a feature of DAD and generally indicates a
superimposed bacterial infection, although in this case there may be another cause (see below).
DAD is one of the more common lesions encountered in biopsy
specimens, and it is also one of the most frustrating, since little information about etiology can be
gleaned from the pathology findings. Patients are usually severely hypoxemic with diffuse lung
infiltrates and fulfill criteria for the acute respiratory distress syndrome (ARDS). Most are being
treated with mechanical ventilation and high concentrations of oxygen.
DAD represents the histologic manifestation of severe acute lung injury
of which there are a myriad of causes (Table 1). Many can be identified from the clinical setting (a
history of trauma, sepsis, toxic inhalants, or drug reactions, for example). Patients who are biopsied,
however, usually do not have an identifiable predisposing cause, and, unfortunately, with the exception
of some infections, there are usually no clues as to etiology from the microscopic slides. In such cases
clinicians should be advised to carefully obtain a drug history, to search for possible underlying
connective tissue diseases, to investigate the possibility of a viral or other unusual infection by
serologies and cultures, and to carefully question the patient about possible toxic inhalants. Patients
who have idiopathic DAD may fall into the category of acute interstitial
pneumonia or Hamman-Rich disease. Patients with the latter disease
usually have a history of a recent flu-like illness, and fever is commonly present. Histologically, most
cases show the organizing stage of DAD.
Pathologically, DAD is characterized by an orderly sequence of pathologic changes that occur following
acute lung injury (Table 1). The changes can be divided into two overlapping stages, an early or exudative stage and a later or organizing stage. It is important to
remember that these stages are not necessarily progressive, and the process can stop at any time. The
early stage occurs within one or two days following injury and is
characterized by interstitial and intraalveolar edema followed by hyaline membrane formation. Hyaline
membranes are membranous, eosinophilic structures that form along alveolar ducts and walls. They are the
histologic hallmark of early DAD and are composed of cellular debris, plasma proteins and surfactant
The organizing stage of DAD becomes prominent one or more weeks following
injury and is characterized by epithelial and fibroblast proliferation. The epithelial changes affect
both alveolar and bronchiolar epithelium. Hyperplastic, hob-nail shaped type 2 pneumocytes line alveolar
septa and may show considerable cytologic atypia. Nuclear proteins important in cell cycle regulation
such as p53 and WAF1 have been demonstrated by immunohistochemistry in the hyperplastic pneumocytes, and
staining for tumor necrosis factor (TNF) has also been noted. The latter cytokine may have a role in the
fibroblast proliferation of organizing DAD. The hyperplastic pneumocytes often show striking cytologic
atypia that can be a source of false positive cytology diagnoses in bronchoalveolar lavage specimens.
Squamous metaplasia is frequently found in bronchiolar epithelium and atypia may be so severe that the
changes superficially resemble squamous cell carcinoma. Spindle and stellate shaped fibroblasts and
myofibroblasts are present in lightly stained, myxoid appearing matrix within the thickened alveolar
septa. These cells stain immunohistochemically for alpha-smooth muscle actin, certain proteoglycans such
as versican and decorin, and for the cytokines, platelet derived growth factor and insulin-like growth
factor-1. Staining has also been demonstrated for type 1 procollagen, suggesting early collagen
synthesis. Remnants of hyaline membranes can usually still be found at this stage, both along the
alveolar surface and admixed with the fibroblasts within the alveolar septa. End-stage, honeycomb lung
characterized by enlarged airspaces surrounded by fibrosis may develop as early as 3 to 4 weeks following
injury. Small thrombi, often undergoing organization, commonly accompany the other changes in both
stages of DAD, and they may be prominent.
It is important to understand that the term diffuse in DAD
refers to the extent of the lesion within an alveolus rather than in the entire lung. That is, all
components of the alveolus (epithelium, endothelium, and interstitial space) are diffusely involved,
although the process of DAD does not necessarily involve the lung diffusely. The term "regional DAD" has
been applied to cases of localized DAD, but is not really necessary if the original meaning of the term
The patient presented here had a history of cocaine use in the past, and DAD has been
reported in this setting. He vigorously denied recent use, however. He was also receiving methadone
therapy for chronic pain and had had a previous similar episode of respiratory failure one year
previously. We have reported 6 patients with recurrent DAD, five of whom were receiving narcotics for
chronic pain, and we suspect that there may be an association. Some additionally had gastroesophageal
reflux and/or were receiving psychotropic drugs. Acute inflammation, like that in the current patient,
was associated with the DAD in 3 of our cases of recurrent DAD, suggesting perhaps that this finding
might be a marker of drug toxicity.
Table 1. Causes of DAD
|Infections (esp. viral in immunocompetent, and pneumocystis in immunocompromised persons)|
|Toxic inhalants (oxygen, chlorine gas, smoke, others)|
|Drugs (chemotherapy, others)|
|Ingestants (paraquat, kerosene, rapeseed oil- toxic oil syndrome)|
|Miscellaneous (toxic shock syndrome, high altitude, acute lupus pneumonitis, post transfusion, uremia, etc.)|
|Idiopathic (acute interstitial pneumonia/Hamman-Rich disease)|
Table 2. Pathologic Features of DAD
|I. Early (Acute) Stage – 12 hours to 1 week following injury|
|II. Later (Organizing) Stage – 1 to 2 or more weeks following injury|
|Interstitial Fibrosis (fibroblasts)|
|Alveolar Pneumocyte Hyperplasia|
|Epithelial Metaplasia and Atypia|
|Architectural Remodelling (collapse and overdistension)|
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