Hyaline membrane disease, the histologic counterpart of severe respiratory distress syndrome, is the major cause of neonatal respiratory distress in premature infants and more rarely occurs in term infants, usually with a variety of underlying conditions. It is caused by lung immaturity with its developmental deficiency of surfactant, which is necessary to lower alveolar surface tension and maintain open alveoli after expiration. It is usually complicated by poor resorption of lung fluid leading to edema. Lack of surfactant causes collapse of alveoli, and high ventilatory pressures may become necessary to adequately expand the lungs. Grossly, the lungs are typically red and firm, with a solid appearance due to extensive atelectasis. Although lung immaturity with inadequate surfactant is the primary problem in clinically severe cases, therapeutic support with mechanical ventilation and supplemental oxygen may also play a role. Hyaline membranes form along terminal bronchioles as well as alveolar ducts and respiratory bronchioles. They are composed of cellular debris, fibrin and other exudate, and amniotic fluid material and appear microscopically as homogeneous granular to linear eosinophilic material. The hyaline membranes are not usually visible histologically until 6 hours after birth, but they can form as early as 2 to 3 hours after birth if there is prenatal injury. They are well formed by 8 to 12 hours. In the absence of conditions that may foster continual lung injury, they may resorb by 48 hours.

One of the complications of hyaline membrane disease is pulmonary interstitial emphysema (PIE). Because of the high ventilatory pressures sometimes required to maintain oxygenation, barotrauma may cause disruption of the terminal bronchiolar wall or at the lobular periphery, with consequent dissection of air into interlobular septa and peribronchial spaces. The air may dissect either centrally, causing pneumomediastinum, pneumopericardium, and/or pneumoperitoneum, or peripherally, causing pneumothorax. Grossly, air bubbles may be seen on the pleural surface within interlobular septa. Microscopically, the dissection of air results in dilated empty spaces within bronchovascular bundles, interlobular septa, and the pleura. The spaces have no epithelial or endothelial lining. When present for a prolonged period, interstitial air may lead to a foreign body-type reaction, and these spaces may be partially lined by histiocytes and histiocytic giant cells.

With continual lung injury and repair in severe respiratory distress syndrome, chronic changes become superimposed on acute hyaline membrane disease. As a consequence, the lung begins to remodel, and this may begin as early as 36 hours after birth. This remodeling
occurs in three major ways. The first to appear is early fibroplasia in the lobular interstitium. The second is variable plugging of small airways by necrotic debris, with some lobules becoming overexpanded and others collapsed and compressed. This results in uneven ventilation and, when prolonged, fixed collapse and even virtual disappearance of lobules, marked only by linear retractions on the pleural surfaces (pseudofissures). This results in a “cobblestone” appearance of the visceral pleura. The third is fibrous obliteration of the lumens of some small airways, with resultant protection of the distal parenchyma in these regions but lack of access to it via the airways for ventilation. Microscopically, there are variable areas of hyperinflation and collapse. The airway epithelium may show hyperplasia, regenerative changes, or squamous metaplasia, and there may be residual debris within the bronchi and bronchioles. These changes are analogous to diffuse alveolar damage, particularly in its later stages.