Classification and Pathology

Although the classification of ILD in children remains nonstandardized, the European consortium and the North American consensus group have proposed classifications based on a multicenter review. It is helpful to separate diseases into ILD on the basis of age, disorders of known and unknown etiology, and diseases related to systemic disorders (Table 397-1). A diffuse developmental disorder of the lung is likely due to a primary aberration in lung and/or pulmonary vascular development. Growth abnormalities reflecting deficient alveolarization are largely secondary to impaired prenatal or postnatal alveolarization from restriction of fetal thoracic space, limitation of pulmonary blood supply, or chronic lung disease of prematurity (bronchopulmonary dysplasia). Abnormal alveolar growth may also be associated with a variety of chromosomal abnormalities such as trisomy 21 (Chapter 76). In neuroendocrine cell hyperplasia of infancy, which is distinct to infants and young children, the pathologic findings include hyperplasia of neuroendocrine cells within the bronchioles, and the lung histologic background is nearly normal. Pulmonary interstitial glycogenosis is characterized by diffuse accumulation of mesenchymal cells in the alveolar interstitium with accumulation of monoparticulate glycogen in the interstitial cell cytoplasm that is confirmed by ultrastructural examination. Disorders suggestive of surfactant metabolism dysfunction (Chapter 399) can explain many of formerly idiopathic pediatric ILDs. The more severe surfactant dysfunctions, such as surfactant protein (SP)–B mutations, usually manifest as respiratory failure in neonate. Congenital pulmonary alveolar proteinosis (Chapter 398) is more typical of ABCA3 mutations, and chronic pneumonitis of infancy is predominant histologic pattern seen in SP-C mutations. Diffuse ILD can occur without a known immunodeficiency or systemic disorder, but it can also be seen as a pulmonary manifestation of other systemic disease processes, such as collagen vascular disorders and sarcoidosis. Persistent pulmonary symptoms can occur after respiratory infections caused by adenoviruses (Chapter 254), influenza viruses (Chapter 250), Chlamydia pneumoniae (Chapter 217), and Mycoplasma pneumoniae (Chapter 215). Aspiration is a frequent cause of chronic lung disease in childhood. Children with developmental delay or neuromuscular weakness are at an increased risk for aspiration of food, saliva, or foreign matter secondary to swallowing dysfunction and/or gastroesophageal reflux (Chapter 315). An undiagnosed tracheoesophageal fistula (Chapter 311) can also result in pulmonary complications related to aspiration of gastric contents and interstitial pneumonia. Children experiencing an exaggerated immunologic response to organic dust, molds, or bird antigens may demonstrate hypersensitivity pneumonitis. Children with malignancies may have ILD related to the primary malignancy or an opportunistic infection or secondary to chemotherapy or radiation treatment.

Clinical Manifestations

A detailed history is needed to assess the severity of symptoms and the possibility of an underlying systemic disease in a patient with suspected ILD. Identification of precipitating factors, such as exposure to molds or birds and a severe lower respiratory infection, is important in establishing the diagnosis and instituting avoidance measures. A positive family history, especially in an affected infant, is suggestive of a genetic or familial disease, such as a surfactant dysfunction. Tachypnea, dyspnea, cough, and failure to thrive are commonly present. The majority of patients develop hypoxia and hypercarbia, usually a late complication. Symptoms are usually insidious and occur in a continuous, not episodic, pattern. Tachypnea, crackles, and retractions are noted on physical examination in the majority of children with ILD, but chest auscultation findings can be normal. Wheezing and fever are not common complaints. Cyanosis and a prominent 2nd heart sound are suggestive of severe disease. Anemia or hemoptysis suggests a pulmonary vascular disease or pulmonary hemosiderosis. Rashes or joint complaints are consistent with an underlying connective tissue disease.

Diagnosis

Noninvasive tests are initially used to determine the extent and severity of the disease. Chest radiographic abnormalities can be classified as interstitial, reticular, nodular, reticulonodular, or honeycombed. The chest radiographic appearance may also be normal despite significant clinical impairment and may correlate poorly with the extent of disease. High-resolution CT (HRCT) of the chest better defines the extent and distribution of disease and can provide specific information for selection of a biopsy site. Volume-controlled full-inspiratory and end-expiratory protocols used during HRCT can provide more information, possibly showing air trapping, ground-glass patterns, mosaic patterns of attenuation, hyperinflation, bronchiectasis, cysts, or nodular opacities. Serial HRCT scans may be of benefit in monitoring disease progression and severity.

Pulmonary function tests (PFTs) including infant PFTs, are important in defining the degree of pulmonary dysfunction and in following the response to treatment. In ILD, pulmonary function abnormalities demonstrate a restrictive ventilatory deficit with decreased lung volumes and reduced lung compliance. The functional residual capacity (FRC) is often reduced but usually less than vital capacity (VC) and total lung capacity (TLC). The residual volume (RV) is usually maintained; therefore, ratios of FRC : TLC and RV : TLC are often increased. Diffusing capacity of the lung is often reduced. Exercise testing may detect pulmonary dysfunction, even in the early stage of ILD. Bronchoalveolar lavage (BAL) may provide helpful information regarding secondary infection, bleeding, and aspiration, and allows cytologic and molecular analyses. Although BAL does not usually determine the exact diagnosis, it can be diagnostic for disorders such as pulmonary alveolar proteinosis. Lung biopsy for histopathology by conventional thoracotomy or video-assisted thoracoscopy is usually the final step and is often necessary for a diagnosis. However, biopsy may have a lower diagnostic yield in young children because of heterogenous lung changes and often nonspecific histologic findings. Genetic testing for surfactant dysfunction mutational analysis is now available. Evaluation for possible systemic disease may also be necessary.

Treatment

Supportive care of patients with ILD is essential and includes supplemental oxygen for hypoxia and adequate nutrition for growth failure. Antimicrobial treatment may be necessary for intercurrent infections. Some cases may respond to bronchodilators. Anti-inflammatory treatment with corticosteroids remains the initial treatment of choice. Controlled trials in children are lacking, however, and the clinical responses reported in case studies are variable. The usual dose of prednisone is 1-2 mg/kg/24 hr for 6-8 wk with tapering of dosage dictated by clinical response. Alternative, but not adequately evaluated, agents include hydroxychloroquine, azathioprine, cyclophosphamide, cyclosporine, methotrexate, immunoglobulin, granulocyte-macrophage colony-stimulating factor (GM-CSF), and pulsed high-dose steroids. Investigational approaches involve specific agents directed against the action of cytokines, growth factors, or oxidants. Lung transplantation for progressive or end-stage ILD is successful in some infants and children. Appropriate treatment for underlying systemic disease is indicated. Preventive measures include avoidance of all inhalation irritants, such as tobacco smoke and, when appropriate, molds and bird antigens. Supervised pulmonary rehabilitation programs may be helpful.

Prognosis

The overall mortality of ILD is very variable and depends on specific diagnosis. Some children recover spontaneously without treatment, but other children steadily progress to death. Pulmonary hypertension, failure to thrive, and severe fibrosis are considered poor prognostic indicators.

Genetic Counseling

A high incidence of ILD in some families suggests a genetic predisposition to either development of the disease or severity of the disorder. Genetic counseling may be beneficial if a positive familial history is obtained.