Children's Interstitial Lung Disease (ChILD)

Updated: Jan 05, 2015
  • Author: James S Hagood, MD; Chief Editor: Michael R Bye, MD  more...
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Overview

Background

Interstitial lung diseases (ILDs) in childhood are a diverse group of conditions that primarily involve the alveoli and perialveolar tissues, leading to derangement of gas exchange, restrictive lung physiology, and diffuse infiltrates on radiographs. Because ILDs can involve the distal airspaces as well as the interstitium, the term diffuse infiltrative lung disease has been suggested. This nomenclature may be more accurate than ILD, but children's interstitial lung disease (chILD) has become the preferred term. In 2004, the Rare Lung Diseases Consortium, a network of clinical and research centers and patient support organizations, was formed to accelerate clinical research in rare lung diseases, including chILD. [1]

As a result of the rarity of ILDs in children and the important differences between childhood ILD and ILDs that affect adults, a great deal of confusion surrounds their nomenclature, classification, and management. Idiopathic pulmonary fibrosis (IPF, also known as cryptogenic fibrosing alveolitis [CFA]), the most prominent adult ILD, mostly occurs after the fifth decade of life; this entity is not found in children. Unlike in adults, most ILDs in children are found to have an underlying cause. In addition, the clinical significance of the histologic classification differs significantly between children and adults.

For example, usual interstitial pneumonitis (UIP), 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 very poor prognosis in children, particularly in infants. Neuroendocrine cell hyperplasia in infancy (NEHI) and pulmonary interstitial glycogenesis (PIG) are histologic patterns unique to children.

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 describing unique presentations and anecdotal responses to various therapeutic interventions abound. Definitive management of ILDs, particularly those of unknown etiology, is unclear at present. The recently formed consortium of centers, perhaps in collaboration with centers worldwide, may facilitate use of standardized diagnostic criteria and develop a network for clinical trials.

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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. In general, this remodeling has been believed to be the sequela of persistent inflammation; however, more recently, the paradigm has shifted away from inflammation to one of tissue injury with aberrant wound healing resulting in collagenous fibrosis. Until recently, most research in this field has been based on adult histopathology and data from animal models.

Wound healing and fibrosis are complex pathophysiologic processes that involve numerous cell types and cellular processes, such as adhesion; migration; proliferation; apoptosis; and a vast array of soluble mediators, extracellular matrix (ECM) molecules, and signaling intermediates. Detailed discussion of the pathophysiology of lung fibrosis can be found in several excellent reviews. [2, 3, 4] In chILD, these processes occur in an organ that is still developing, further complicating the pathophysiology.

Many types of ILD follow 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, as well as in models of surfactant-dysfunction mutations (SDMs), apoptosis of the alveolar epithelium was demonstrated to be a key inciting event.

Fibroblasts, which are normally present in the attenuated interstitial spaces between alveoli and surrounding distal airways, play a key role in lung remodeling, which is characterized by proliferation and excessive elaboration of matrix molecules such as collagen. Fibroblasts also affect remodeling through production of proteases, protease inhibitors, cytokines, and chemokines. Recent data indicate alternate origins of fibroblasts, such as circulating precursors known as fibrocytes, which hone in on injured tissues, and transdifferentiation of other cells, such as epithelial-mesenchymal transition (EMT).

Inflammation is present in many types of ILD, and many forms of ILD are triggered by inflammatory events, such as infection or hypersensitivity. Neutrophils and lymphocytes are prominent in bronchoalveolar lavage (BAL) samples in many types of ILD. In DIP, the airspaces are filled with cells that were once believed to be desquamated epithelium but which are, in fact, activated macrophages. The mediators released by inflammatory cells, particularly IL-1 and transforming growth factor (TGF)-beta, are potent activators of fibroblast-mediated remodeling. Almost every type of inflammatory cell, including eosinophils and mast cells, have been described in various types of ILD and can interact with fibroblasts and other parenchymal cells. However, lung inflammation does not necessarily result in fibrotic remodeling, and fibrosis can occur in the absence of inflammation; therefore, inflammation has a prominent, but not a central, role in lung remodeling and fibrosis.

A large number of other pathophysiologic events are increasingly recognized as having clinically significant effects on lung remodeling. Markers of angiogenesis have been prominent in several animal models of ILD and substantially affect outcomes. The ECM is a complex, biologically active structure that signals cells either by direct means or by means of its soluble breakdown products and that binds, sequesters, and presents growth factors and other mediators to cells. The ECM is altered in ILDs, and alterations in the ECM may also have a causative role.

Resolution of fibrotic remodeling involves a complex series of orderly steps, including matrix breakdown and restructuring, reepithelialization, and apoptosis of fibroblasts and inflammatory cells.

Fibrotic remodeling is responsible for most of the morbidity and mortality associated with ILD. Remodeling of distal airspaces results in hypoxemia. Persistent hypoxemia results in pulmonary hypertension and vascular remodeling, leading to cor pulmonale. The increased work of breathing associated with reduced compliance results in increased energy expenditure, which, combined with the effects of inflammatory mediators, can result in cachexia. Portions of the lung may be replaced by fibrotic septae between dilated airspaces, the so-called honeycomb changes of endstage interstitial disease. Although the events described above are necessary for repair of the injured lung, excessive activation or failure of resolution of any of these pathways can result in disabling fibrosis.

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Epidemiology

Frequency

United States

ILD is rare in children. Because of a lack (until recently) of consensus on case definition, the broad differential diagnosis, and the lack of organized reporting systems (eg, a national database), determining the precise incidence or prevalence of ILDs is impossible. Cases tend to cluster in infancy, and 10-16% appear to be familial.

Most of the literature is composed of case reports and small series. One of the largest reported series is a combined retrospective and prospective study by Fan et al performed over a 15-year period at a leading referral center for ILD. [5] The investigators reported 99 patients, in whom the case definition included respiratory symptoms lasting longer than one month, diffuse infiltrates depicted on chest radiography, and absence of known bronchopulmonary dysplasia (BPD), heart disease, malignancy, immunodeficiency, autoimmunity, cystic fibrosis (CF), aspiration, or acquired immunodeficiency syndrome (AIDS). A more recent retrospective study that attempted a relatively complete case ascertainment of children undergoing biopsy for ILD in 11 referral centers in the United States and Canada over a 5-year period (1999-2004) reported 187 cases in children younger than 2 years old. [6]

International

A national survey of cases of chronic ILD in immunocompetent children aged 0-16 years in the United Kingdom and Ireland over a three year period (1995-1998) yielded an estimated prevalence of 3.6 per million. [7]

Mortality/Morbidity

The same factors that make estimating the incidence of ILD difficult make estimating its mortality rates difficult.

  • In the series of 99 patients discussed above, the probability of surviving 24, 48, or 60 months was 83%, 72%, and 64%, respectively.6 Mean survival interval from onset in this group of patients was 47 months.
  • Factors associated with poor outcome included pulmonary hypertension at the time of diagnosis and a final diagnosis of DIP or pulmonary vascular disease.
  • In general, accurate definitive diagnosis should be pursued before attempting to predict associated morbidity or mortality. Certain specific histologic diagnoses in newborns adversely influence prognosis; these include diffuse developmental disorders and patterns associated with certain surfactant protein mutations. Without lung transplantation, the prognosis for most of these conditions is poor. [6] However, for other types of ILD, such as NEHI, significant morbidity but no mortality has been reported.

Race

No data are available in the pediatric literature concerning differences in racial incidence or prevalence.

Sex

There appears to be a slight male predominance (roughly 60:40) in reported cases of chILD.

Age

Approximately 50% of chILD cases occur in infants, but presentation can occur throughout childhood and adolescence.

  • In one of the largest series, the mean age at onset was 43 months (range, 0-212 mo). The median age at onset was 8 months, but the median age at evaluation was 30 months. These data indicate that some clustering of ILD occurs in infancy, and that, as is seen in adults, the delay between the onset of symptoms and appropriate diagnostic evaluation is often lengthy.
  • Recently identified pediatric ILD syndromes unique to infancy, including NEHI, PIG, and chronic pneumonitis of infancy, may present at or shortly after birth. SDMs often cause severe symptoms during the newborn period (see Causes).
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