Childhood interstitial lung diseases: an 18-year retrospective analysis

Abstract

Objective: Childhood interstitial lung diseases (ILD) occur in a variety of clinical contexts. Advances in the understanding of disease pathogenesis and use of standardized terminology have facilitated increased case ascertainment. However, as all studies have been performed at specialized referral centers, the applicability of these findings to general pulmonary practice has been uncertain. The objective of this study was to determine the historical occurrence of childhood ILD to provide information reflecting general pediatric pulmonary practice patterns.

Methods: Childhood ILD cases seen at Vanderbilt Children's Hospital from 1994 to 2011 were retrospectively reviewed and classified according to the current pediatric diffuse lung disease histopathologic classification system.

Results: A total of 93 cases were identified, of which 91.4% were classifiable. A total of 68.8% (64/93) of subjects underwent lung biopsy in their evaluations. The largest classification categories were disorders related to systemic disease processes (24.7%), disorders of the immunocompromised host (24.7%), and disorders more prevalent in infancy (22.6%). Eight cases of neuroendocrine cell hyperplasia of infancy (NEHI) were identified, including 5 that were previously unrecognized before this review.

Conclusions: Our findings demonstrate the general scope of childhood ILD and that these cases present within a variety of pediatric subspecialties. Retrospective review was valuable in recognizing more recently described forms of childhood ILD. As a significant portion of cases were classifiable based on clinical, genetic, and/or radiographic criteria, we urge greater consideration to noninvasive diagnostic approaches and suggest modification to the current childhood ILD classification scheme to accommodate the increasing number of cases diagnosed without lung biopsy.

Keywords: childhood lung disease; interstitial lung disease; lung biopsy.

FIGURE 1

Study cohort classification distribution according to the current classification system for childhood diffuse lung disease. The classification scheme was also applied to the cohort who did not undergo lung biopsy (termed “non-biopsy cohort”).

FIGURE 2

Case of lung growth abnormality with previously unrecognized pulmonary interstitial glycogenosis. A, Chest radiograph at 3 weeks of age from a late preterm newborn with trisomy 21, pulmonary hypertension, and respiratory failure at birth. Bilateral diffuse reticular opacities and atelectasis are present. B, Lung biopsy at 3 weeks of age shows deficient alveolarization with enlarged simplified airspaces and limited secondary septation (×10, H&E). C, Patchy alveolar septal widening by immature round to oval mesenchymal cells is present, demonstrating findings of pulmonary interstitial glycogenosis (×40).

FIGURE 3

Twins with NEHI identified through retrospective review. A–D, Chest CT images obtained at 3 years of age in identical twins (A and B, Twin A; C and D, Twin B) with history of respiratory symptoms since 2 months of age. The presence of ground glass opacities in the right middle lobe, lingula, and perihilar regions, without other abnormalities, demonstrates a pattern consistent with NEHI. E and F, Lung biopsy from Twin B performed at 4 years of age shows near normal architecture with minimal peribronchiolar fibrosis and no significant inflammation (E, H&E, ×10). Bombesin immunostaining (F, ×20) was performed after this case was retrospectively identified based on the CT scan. Neuroendocrine cells (black arrow) were prominent in distal bronchioles, providing histologic confirmation of the diagnosis of NEHI.

FIGURE 4

ILD attributable to surfactant dysfunction disorders. A, Chest CT image of a 30-month-old child with persistent retractions, tachypnea, and hypoxemia showing diffuse ground glass opacities and reticular opacities. Birth history was notable for brief requirement for supplemental oxygen. B, The subject’s lung biopsy performed at 30 months of age shows type II pneumocyte hyperplasia and dense accumulation of alveolar macrophages (×40, H&E). The subject was later found to have 2 ABCA3 mutations (p.E292V/c.1742-9 G>A). C, A follow-up CT scan at age 18 years is remarkable for increased septal thickening and architectural distortion suggestive of fibrotic remodeling, although some ground-glass opacity persists. The subject died at age 19 years from respiratory failure. This subject’s genetic diagnosis was previously reported in the literature. D and E, Chest radiographs of a term, 8-month-old infant with chronic retractions and feeding difficulties. The subject’s birth history was remarkable for respiratory failure requiring intubation, mechanical ventilation, and surfactant administration. Findings include hyperexpansion and right upper and middle lobe as well as left upper lobe opacities. Chest CT and lung biopsy were not performed, as clinical suspicion led to genetic testing first. ABCA3 sequencing revealed homozygous E292V/E292V mutations. F, Chest CT revealing irregular focal areas of ground glass opacities and septal thickening from a 1-year-old child with an SFTPC mutation (L181V). This child had history of tachypnea starting at day of life 2, and several subsequent hospitalizations for evaluation of tachypnea and poor feeding with intermittent hypoxemia. A family history of pulmonary fibrosis in older individuals prompted the genetic testing. G, Chest CT image from a 2-month-old former 34-week preterm infant with congenital hypothyroidism, persistent tachypnea, and hypoxemia. Diffuse ground glass opacities and interstitial markings suggestive of a surfactant dysfunction disorder are noted. H, The subject’s lung biopsy performed at 2 months of age shows deficient alveolarization and interstitial thickening (×4, H&E). I, On higher magnification, findings include epithelial hyperplasia with hypercellular interstitial thickening and macrophage accumulation in the alveolar space consistent with surfactant metabolism defect (×40, H&E). Genetic sequencing for SFTPB, SFTPC, and ABCA3 showed no mutations. As this case was identified retrospectively and before current knowledge of NXK2-1 mutations as a cause of ILD and the availability of clinical genetic testing, this subject’s NKX2-1 mutation status is not currently known.