Clinical pathologic classification of interstitial and diffuse lung disease in childhood

Category	Specific entities
Disorders more prevalent in infancy
Developmental lung disorders	Alveolar capillary dysplasia, with and without misalignment of the pulmonary veins Acinar dysplasia and congenital alveolar dysplasia
Alveolar growth abnormalities	Pulmonary hypoplasia – eg, due to oligohydramnios, congenital diaphragmatic hernia, giant omphalocele, thoracic mass lesion Chronic neonatal lung disease (bronchopulmonary dysplasia) – eg, due to prematurity Associated with congenital heart disease Structural changes due to chromosomal abnormalities – eg, trisomy 21 May be a manifestation of certain single-gene disorders, including NKX2-1 and FLNA
Other forms of diffuse lung disease presenting in infancy	NEHI P.I.G.*
Genetic disorders of surfactant dysfunction and related abnormalities	Mutations in the SFTPB, SFTPC, ABCA3, NKX2-1, and RAB5B genes are associated with altered surfactant production^¶ Mutations in the CSF2RA, CSF2RB, SLC7A7, MARS1, GATA2, STAT5B, and OAS1 genes impact the catabolism of surfactant via macrophage dysfunction; clinical manifestations may include pulmonary alveolar proteinosis^Δ
Disorders not specific to infancy
Disorders of the normal host (immunocompetent)	Bronchiolitis obliterans – A clinical syndrome and histologic phenotype that may be caused by infectious (eg, adenovirus) or noninfectious processes (eg, toxic inhalation, chronic hypersensitivity pneumonitis, or connective tissue disease) Infectious/postinfectious processes – May cause chronic airway changes, bronchiolitis obliterans, or organizing pneumonia Related to environmental agents (toxic inhalation or hypersensitivity pneumonitis) Aspiration syndromes Idiopathic pulmonary hemosiderosis Other disorders (eosinophilic pneumonia, AIP, NSIP)
Disorders of the immunocompromised host	Opportunistic infections Related to therapeutic intervention – eg, chemotherapy and/or radiation injury; drug reaction Related to transplantation or rejection syndromes (including bronchiolitis obliterans) Common histologic patterns include LIP and follicular bronchiolitis
Disorders related to systemic disease processes	Immune-mediated Anti-GBM antibody (Goodpasture); acquired pulmonary alveolar proteinosis/antibody to GM-CSF; pulmonary vasculitis syndromes Nonspecific pulmonary manifestations – NSIP, pulmonary hemorrhage syndromes, organizing pneumonia, nonspecific airway changes Collagen-vascular disease – eg, systemic lupus erythematosus, polymyositis/dermatomyositis, systemic sclerosis Storage diseases Sarcoidosis Langerhans cell histiocytosis Malignant infiltrates
Vascular disorders masquerading as ILD	Pulmonary hypertension Congestive vasculopathy and veno-occlusive disease Lymphatic disorders – eg, lymphangiectasia, lymphangiomatosis Pulmonary edema Thromboembolic disease
Unclassified	Captures cases of diffuse lung disease that cannot be classified for any reason; common reasons include end-stage disease, nondiagnostic biopsies, or inadequate biopsy material

NEHI: neuroendocrine cell hyperplasia of infancy; P.I.G.: pulmonary interstitial glycogenosis; AIP: acute interstitial pneumonia; NSIP: nonspecific interstitial pneumonia; LIP: lymphocytic interstitial pneumonia; GBM: glomerular basement membrane; GM-CSF: granulocyte-macrophage colony-stimulating factor.

* Often occurs in conjunction with an alveolar growth abnormality.

¶ NKX2-1 gene mutations may result in reduced expression of the genes responsible for surfactant production and metabolism. In addition, a spectrum of lung disease phenotypes, including abnormal lung development, has been reported in association with NKX2-1/TTF1 gene mutations.

Δ Refer to UpToDate content on genetic disorders of surfactant dysfunction and pulmonary alveolar proteinosis in children.

Adapted from:

Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: Application of a novel classification scheme. Am J Respir Crit Care Med 2007; 176:1120.
Fan LL, Dishop MK, Galambos C, et al. Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme. Ann Am Thorac Soc 2015; 12:1498.

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Clinical pathologic classification of interstitial and diffuse lung disease in childhood