Excerpt from Interstitial Lung Disease in Children

Synonyms, Key Words, and Related Terms: ILD, diffuse infiltrative lung disease, pulmonary disease, lung disease, interstitial disease, idiopathic pulmonary fibrosis, IPF, usual interstitial pneumonia, UIP, desquamative interstitial pneumonia, DIP, bronchiolitis obliterans with interstitial pneumonia, BIP, lymphoid interstitial pneumonia, LIP, giant cell interstitial pneumonia, GIP, respiratory bronchiolitis interstitial lung disease, RBILD, nonspecific interstitial pneumonia, NSIP, bronchiolitis obliterans organizing pneumonia, BOOP, pulmonary histiocytosis X, Langerhans cell histiocytosis, LCH, acute interstitial pneumonia, AIP, idiopathic BOOP, nonclassifiable ILD

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Background: Interstitial lung diseases (ILDs) in childhood are a diverse group of conditions primarily involving the alveoli and perialveolar tissues, leading to derangement of gas exchange, restrictive lung physiology, and diffuse infiltrates as revealed on radiographs. Since ILDs usually involve the distal airspaces as well as the interstitium, the term diffuse infiltrative lung disease has been suggested and is more accurate, although ILD is used most often in the literature.

As a result of the rarity of ILDs and the important differences between ILDs in children and in adults, a great deal of confusion exists regarding nomenclature, classification, and management. Idiopathic pulmonary fibrosis (IPF, also termed cryptogenic fibrosing alveolitis [CFA]), the most prominent adult ILD, occurs mostly after the fifth decade of life and is almost never seen in children. In children, the majority of ILDs are found to have an underlying cause, in contradistinction to adults. In addition, the clinical significance of the histologic classification (described in greater detail below) differs between children and adults. Usual interstitial pneumonitis (UIP), which is the pattern associated with IPF in adults, is rarely described in children. Desquamative interstitial pneumonitis (DIP), which is associated with steroid responsiveness and a better prognosis in adults, has a poor prognosis in children, particularly in infants.

The management of ILD in children also differs from that in adults. Correct diagnosis is critical, requiring a comprehensive search for possible underlying causes. Case reports abound describing unique presentations and anecdotal responses to various therapeutic interventions. Definitive management of ILDs, particularly those of unknown etiology, is unclear at present and may require, as Hillman suggests, an international registry and multicenter trials.

Pathophysiology: Childhood ILD is not a disease but a group of disorders (see Causes). However, most ILDs share a common pathophysiologic feature, namely, structural remodeling of the distal airspaces, leading to impaired gas exchange. Generally, this remodeling has been believed to be the sequela of persistent inflammation; however, more recently, the paradigm has shifted away from inflammation to tissue injury with aberrant wound healing resulting in collagenous fibrosis. Most research in this field is based on adult histopathology and data from animal models.

Wound healing and fibrosis are complex pathophysiologic processes involving numerous cell types and cellular processes, such as adhesion, migration, proliferation, apoptosis, and a vast array of soluble mediators, extracellular matrix molecules, and signaling intermediates. Detailed discussion of the pathophysiology of lung fibrosis can be found in several excellent reviews (Katzenstein, 1998; Selman, 2001; Crouch, 1990). In childhood ILD, these processes occur in an organ that is still developing, further complicating the pathophysiology.

Most types of ILD occur following some type of injury to the distal airspaces, such as adenoviral infection or exposure to organic dust, resulting in damage to the epithelial or endothelial layers and the associated basement membrane. In an animal model of lung fibrosis using bleomycin, apoptosis of the alveolar epithelium was demonstrated to be a key inciting event. Blood or plasma leaks into procoagulant-rich airspaces and clots, forming a provisional matrix that contains fibronectin, fibrin, and numerous mediators released from activated platelets and injured cells (the "hyaline membranes" of acute lung injury). This fibrinous exudate usually forms the base for subsequent repair and remodeling.

Fibroblasts, which normally are present in the attenuated interstitial spaces between alveoli and surrounding distal airways, are activated by exposure to plasma proteins .....