Interstitial lung diseases in children

Abstract

Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy.

Figure 1

Mechanisms and pathways involved in the response of the alveolar structure of the lung to injury. Abbreviation: Transforming Growth Factor (TGF)-β.

Figure 2

Alveolar structure disorder-associated ILD and ER stress. The (Endoplasmic Reticulum) ER and its protein maturation machinery allow the synthesis of mature secretory and membrane proteins with specific folded conformation. In situations of stress induced by genetic mutations or environmental factors, unfolded or misfolded proteins are retained in the ER and induce a defence mechanism called the ER stress response. The induction of ER chaperones is critical to increase the ER folding capacity allowing the production of correctly folded protein. When this defence mechanism is impaired, the misfolded proteins can either be degraded by the proteasome or form protein aggregates. Protein aggregates are toxic and can cause conformational diseases. Within the alveolar epithelium, misfolding of SP-C could trigger induction of intra-cellular aggregate formation and ER stress, with consequently development of alveolar structure disorder-associated ILD and conformational disease.

Figure 3

Search for ILD etiology in children. ILD is defined by the presence of diffuse infiltrates on chest radiographs or chest high resolution computed tomography, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect (in older children) and/or impaired gas exchange. The search for etiology requires a systematic step-by-step diagnostic strategy for identifying: exposure-related ILD; systemic disease-associated ILD; alveolar structure disorder-associated ILD; and ILD specific to infancy.

Figure 4

Alveolar structure disorder-associated ILD. Depending on the causes, the alveolar structure components can be involved differently and serve as primary targets of the underlying pathological processes. Based on history, clinical presentation, BAL and lung tissue information, the disorders can be gathered in groups according to the predominant alveolar targets: epithelium, vascular or interstitial components.