Diffuse lung disease in young children: application of a novel classification scheme

Abstract

Rationale: Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children.

Objectives: A multidisciplinary working group was formed to: (1) apply consensus terminology and diagnostic criteria for disorders presenting with diffuse lung disease in infancy; and (2) describe the distribution of disease entities, clinical features, and outcome in young children who currently undergo lung biopsy in North America.

Methods: Eleven centers provided pathologic material, clinical data, and imaging from all children less than 2 years of age who underwent lung biopsy for diffuse lung disease from 1999 to 2004.

Measurements and main results: Multidisciplinary review categorized 88% of 187 cases. Disorders more prevalent in infancy, including primary developmental and lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and surfactant-dysfunction disorders, constituted the majority of cases (60%). Lung growth disorders were often unsuspected clinically and under-recognized histologically. Cases with known surfactant mutations had characteristic pathologic features. Age at biopsy and clinical presentation varied among categories. Pulmonary hypertension, presence of a primary developmental abnormality, or ABCA3 mutation was associated with high mortality, while no deaths occurred in cases of pulmonary interstitial glycogenosis, or neuroendocrine cell hyperplasia of infancy.

Conclusions: This retrospective cohort study identifies a diverse spectrum of lung disorders, largely unique to young children. Application of a classification scheme grouped clinically distinct patients with variable age of biopsy and mortality. Standardized terminology and classification will enhance accurate description and diagnosis of these disorders.

Figure 1.

Study cohort and proposed classification of diffuse lung disease in children. The study cohort was composed of patients under the age of 2 who had a diagnostic lung biopsy during the designated 5-year interval; exclusion criteria are listed. The clinical–pathologic classification scheme is detailed with numbers of cases and specific entities identified within each category. Some unusual entities not seen are also listed, but there are clearly other entities associated with diffuse lung disease not seen in this cohort that have not been listed.

Figure 2.

Age at biopsy of study population. Of the 187 cases reviewed, 30% underwent lung biopsy by 3 months of age, over half (52%) by 6 months, and 72% in the first year of life.

Figure 3.

Clinical signs and symptoms. Clinical information was collected by retrospective chart review. Diagnoses of gastroesophageal reflux and pulmonary hypertension were reported based on chart record only, without requirement for specific diagnostic testing.

Figure 4.

Lung growth abnormalities. Compared with lung from a normal term infant (A, hematoxylin and eosin [H&E], ×40), there is reduced alveolarization (deficient lung growth) in an infant with pulmonic stenosis with markedly enlarged alveoli (see size relative to bronchioles) (B, H&E, ×40). Deficient alveolarization in a patient with Trisomy 21 is characterized by cystic dilatation of subpleural alveoli (C, H&E, ×40); pulmonary arterioles demonstrate occlusive intimal hyperplasia (insert, H&E, ×200). Lobular simplification in an infant born at 27 weeks gestation is accompanied by patchy pulmonary interstitial glycogenosis (D, H&E, ×40). Inset (H&E, ×200) displays the characteristic cells with round to oval nuclei, vacuolated cytoplasm, and indistinct cell borders.

Figure 5.

Pulmonary interstitial glycogenosis and neuroendocrine cell hyperplasia of infancy. There is diffuse interstitial widening by mesenchymal cells in a 22-day-old term neonate with tachypnea at birth (A, H&E, ×200). The presence of monoparticulate glycogen within the cells, diagnostic of pulmonary interstitial glycogenosis, is demonstrated by ultrastructural examination (inset, A, ×15,200). Clusters of bombesin-immunopositive cells within bronchioles (arrows) and within the lobular parenchyma (arrowheads) are shown from a patient with neuroendocrine cell hyperplasia of infancy (B, bombesin immunostain [polyclonal; ImmunoStar] ×100).

Figure 6.

Histology consistent with surfactant dysfunction disorder. The lung biopsies of an infant with an SFTPC mutation (A, H&E, ×200) and an infant with ABCA3 mutations (C, H&E, ×200) are both characterized by diffuse alveolar septal thickening with uniform prominent type II cells. Accumulation of intra-alveolar macrophages and interstitial infiltrate is more typical in the patient with the SFTPC mutation (chronic pneumonitis of infancy pattern), while granular proteinosis is more prominent in the biopsy of the patient with ABCA3 mutations (pulmonary alveolar proteinosis pattern). Electron micrograph demonstrates the abnormal lamellar bodies with dense inclusions in a 3-month-old with ABCA3 mutations (D, ×16,000). Patchy interstitial fibrosis, characteristic of NSIP, is present in a 22-month-old child who was found to have an SP-C mutation (B, H&E, ×200); a small degree of proteinosis with foamy macrophages is still visible (arrow).