An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy

Abstract

Background: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults.

Methods: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient's or family's quality of life, and death.

Results: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having "childhood ILD syndrome"; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research.

Conclusions: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.

Figure 1.

Venn diagram depicting a conceptual framework, which demonstrates the relationships among diffuse lung disease (DLD), childhood interstitial lung disease (chILD) syndrome, and specific chILD diagnoses. Note that chILD syndrome is a subset of DLD, and more common causes of respiratory disease, such as cystic fibrosis and infection, must be excluded before proceeding with investigations directed at diagnosing specific chILD entities. In addition, there are “masqueraders” of DLD, including cardiac, pulmonary vascular, and lymphatic disorders. Although there are recognized specific chILD diagnoses, some may be asymptomatic when identified, such as in certain individuals with known SFTPC mutations. Specific chILD diagnoses comprise only a portion of chILD syndrome, as some cases remain unclassified. Future discovery of additional specific diagnostic entities will more fully define chILD syndrome.

Figure 2.

Proposed general diagnostic approach for childhood interstitial lung disease (chILD) syndrome: neonatal onset of severe respiratory disease. (A) Negative family history of specific chILD entities or other ILD (including adult ILD). Dotted lines indicate paths that may be considered depending on clinical context. (B) Positive family history of specific chILD entities or other ILD (including adult ILD; note: genetic analysis of surfactant proteins may take several weeks; lung biopsy may be necessary to guide clinical decision making in rapidly progressive cases). In this and subsequent figures, controlled ventilation high-resolution computed tomography (CVHRCT) is included as the preferred method of CT imaging. However, see text for discussion of CVHRCT versus HRCT. CF = cystic fibrosis; CHD = congenital heart disease; EM = electron microscopy; HIV = human immunodeficiency virus.

Figure 3.

Proposed general diagnostic approach for childhood interstitial lung disease (chILD) syndrome. Evaluation of chronic/persistent symptoms in infants presenting at over 1 month of age. In this and subsequent figures, controlled ventilation high-resolution computed tomography (CVHRCT) is included as the preferred method of CT imaging. However, see text for discussion of CVHRCT versus HRCT. BAL = bronchoalveolar lavage; CF = cystic fibrosis; CHD = congenital heart disease; EKG = electrocardiogram; EM = electron microscopy; iPFT = infant pulmonary function test; NEHI = neuroendocrine cell hyperplasia of infancy.

Figure 4.

Genetic approach to childhood interstitial lung disease (chILD) diagnosis. Possible genetic mechanisms are listed at right, ordered depending upon age of the patient at presentation (top to bottom), as well as selected phenotypic characteristics. Arrows point to initial gene(s) to be analyzed; if results of initial studies were negative, arrows on right indicate additional genetic studies to be considered. PAP = pulmonary alveolar proteinosis; PPHN = persistent pulmonary hypertension of the newborn; RDS = respiratory distress syndrome.

Figure 5.

Neuroendocrine cell hyperplasia of infancy (NEHI). Single controlled ventilation high-resolution computed tomography image (at TLC) of the lower chest of a 4-month-old with tachypnea and hypoxemia. The scan demonstrates sharply defined areas of ground glass opacity most marked in the right middle lobe and lingula. Diffuse air trapping was seen on expiratory images, affecting both the ground glass areas and the remaining lung. No additional abnormalities were identified. NEHI was confirmed by lung biopsy.

Figure 6.

(A) Pulmonary interstitial glycogenosis. The alveolar interstitium is widened by bland-appearing vacuolated foamy cells that contain glycogen. Due to loss of glycogen during tissue processing, only rare biopsies, such as this one, will have periodic acid-Schiff (PAS)–positive material within the interstitial cells. For most biopsies, intracellular glycogen is best demonstrated by ultrastructural (i.e., electron microscopic) examination (PAS stain). (B) Neuroendocrine cell hyperplasia of infancy (NEHI). In a normal-appearing background, this bronchiole contains multiple clusters of Bombesin-immunopositive neuroepithelial cells, a characteristic finding in NEHI (Bombesin immunohistochemistry [197]). (C) Surfactant protein (SP)-C mutation. This biopsy from a patient with an SpC mutation shows a chronic pneumonitis of infancy pattern with uniform alveolar epithelial hyperplasia, mild interstitial widening with small numbers of lymphocytes, and patchy intra-alveolar accumulation of foamy macrophages and cholesterol clefts. No proteinaceous material is evident in this region, but it is typically a minor feature in this pattern (hematoxylin and eosin).