—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 3 - Diffuse Alveolar Damage (DAD)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
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 performed.

Microscopic Description


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).

Discussion
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 components.

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 is understood.

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)
Acute aspiration
Sepsis
Shock
Radiation
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
Edema
Hyaline Membranes
Thrombi
II. Later (Organizing) Stage – 1 to 2 or more weeks following injury
Interstitial Fibrosis (fibroblasts)
Alveolar Pneumocyte Hyperplasia
Epithelial Metaplasia and Atypia
Thrombi
Architectural Remodelling (collapse and overdistension)

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