Diffuse alveolar damage (DAD) is an acute lung injury involving predominantly the interstitium and characterized by two overlapping histologic phases, acute or exudative, and organizing or proliferative (Table 4.1). It is the common histologic finding in patients with adult respiratory distress syndrome (ARDS) (Chapter 21) and acute interstitial pneumonia (AIP) (Chapter 19).

Imaging in patients with DAD corresponds to the underlying disease and is generally similar across different etiologies. Radiographic findings include diffuse bilateral infiltrates, often with “whiteout” of the lungs, with diffuse ground-glass opacities by computed tomography. These findings often obscure underlying processes that may predispose to diffuse alveolar damage, such as idiopathic interstitial fibrosis and areas of consolidation caused by infectious processes.

Patients with DAD are usually assessed by bronchoalveolar lavage and culture. Transbronchial biopsies may be helpful in excluding granulomatous disease, malignancy, and infections but are limited due to sampling. Open lung biopsy is generally done only in cases refractory to therapy without clear cause, in order to exclude infections, capillaritis,
other causes of diffuse alveolar hemorrhage, and, rarely, amniotic or fat embolism. Occasionally, frozen sections are requested in order to establish that representative tissue is present,¹ as autopsy studies have shown that DAD may be regional.²

The two phases of DAD are the exudative (acute) phase and the proliferative (organizing) phase.³ In addition, some patients survive without significant sequelae or may develop fibrotic lung disease. The histologic findings of the two phases and the fibrotic sequelae are present in Table 4.1.

Early findings in the exudative phase are edema, both interstitial and alveolar with capillary congestion, indistinguishable from other causes of pulmonary edema and congestion. The histologic hallmark of acute DAD is hyaline membranes, which develop 24 hours after the beginning of symptoms (Fig. 4.1). They are densely eosinophilic, thick linear structures that line denuded alveolar walls. They are composed of plasma proteins such as fibrinogen, immunoglobulin and complement, and surfactant components. The proliferative phase becomes prominent after 1 to 2 weeks. It is characterized by interstitial thickening, resulting from the proliferation of fibroblasts and myofibroblasts admixed with varying numbers of inflammatory cells, including neutrophils. The cells are embedded in a myxoid stroma rich in acid mucopolysaccharides. Hyperplastic type II pneumocytes characterized by a cuboidal morphology often line the alveolar septa and may show marked nuclear atypia (Fig. 4.2A). Remnants of hyaline membranes can also be seen lining alveolar spaces; however, at this stage, they are often very focal. Squamous metaplasia of terminal bronchiolar epithelium may be prominent, and the cells may show considerable cytologic atypia with enlarged, vesicular nuclei and prominent nucleoli (Fig. 4.2B). The cytologic atypia of the hyperplastic pneumocytes and the squamous cells can be interpreted as malignant on preparations from sputa, bronchoalveolar lavage, or, more rarely, transbronchial biopsy specimens.⁴ Myofibroblastic proliferation progresses with intra-alveolar and interstitial loose fibrosis.

DAD is a pattern of acute lung injury that is nonspecific since it can result from numerous causes and a specific etiology usually determined clinically (Table 4.2).^5,6,7,8 Exceptions are infections that can be diagnosed histologically such as pneumocystis, cytomegalovirus (CMV), and adenovirus (Chapters 39 and 42).

The diagnosis of DAD is commonly posed at autopsy and readily recognizable on surgical lung biopsies. But DAD can also be diagnosed on transbronchial biopsies as hyaline membranes are distinctive and unique to DAD.⁹ The reported sensitivity is, however, relatively low (˜50%).¹⁰