Childhood interstitial lung disease-application of a stepwise diagnostic classification

Childhood interstitial lung disease (chILD) represents a heterogeneous group of rare pulmonary disorders. Practical diagnostic approaches tested for feasibility and impact in comprehensive cohorts are lacking. Objective of this study was to assess a simple etiologically focused classification approach, clarify the role of genetic testing, and quantify the impact of non-pulmonary organ manifestations. We hypothesized that chILD can be classified in a clinically meaningful and versatile way by answering three questions: Which children have an etiological chILD diagnosis due to (1) identified (exposure-related) cause/lung injury, or (2) systemic disease? (3) In how many children without etiological diagnosis can a genetic cause be identified? We also calculated the predictive value of non-pulmonary organ involvement for underlying systemic conditions. Among 1,686 patients, 24.9% were grouped as ILD with an identified cause/lung injury, 21.6% as ILD with a convincing diagnosis of systemic disease, 18.1% as ILD with genetic diagnosis of systemic disease, 10.1% as ILD with genetic diagnosis affecting the lungs only, and 25.3% as ILD without genetic diagnosis. The average genetic diagnostic yield was 52.8%, with higher rates in interstitial pneumonia (64.0%) or pulmonary alveolar proteinosis (87.2%). The presence of [≥]two non-pulmonary organ manifestations increased the likelihood of an underlying systemic disease by two to three-fold. An etiological diagnostic strategy effectively classifies chILD and guides genetic testing. Exome sequencing should be considered if [≥]two non-pulmonary organs are involved or if the initial diagnosis becomes uncertain due to an unusual disease course or signs of a second underlying condition. Contributors statementMG managed the project, provided patients data, designed data collection software, and monitored data collection. He contributed to the paper through conceptualization and supervised the process, including data curation, formal analysis, validation, statistical analysis and visualizations. He contributed to the writing (original draft, review, and editing) and secured funding. CKR contributed through data curation, formal analysis, investigation, methodology development, validation, analysis, and visualization of the data, as well as writing the original draft, review, and editing. All collaborators of chILD EU registry were involved in the primary data collection process and contributed to the multidisciplinary team responsible for differential diagnosis. FundingOf relevance for this study were grants from the Deutsche Forschungsgemeinschaft (DFG, Gr970/9-1 and 9-2) Bonn, Germany (Trial registration number: NCT02852928) Competing InterestsAll authors have completed the ICMJE uniform disclosure form and declare the following: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work within the past three years; and receipt of honoraria from Boehringer-Ingelheim for participation in the InPedILD initiative, which did not influence the content or conclusions of the submitted work. This article has an online data supplement.