Categorizing diffuse parenchymal lung disease in children

For the cases referred to the KLR the categorization system for DPLD suggested by Deutsch et al. [1] was further developed; three additional categories were introduced (Additional file 1: Table S1) to accommodate cases with “unclear respiratory distress syndrome” in the mature neonate (Ax) and in the almost mature neonate (Ay) and “unclear respiratory distress syndrome” in the non-neonate (By). These categories allow the future analysis of unclear cases. In addition, the rather wide category “disorders masquerading as ILD” was dissolved into two more specific categories: “DPLD related to lung vessels structural processes” (B4) and “DPLD related to reactive lymphoid lesions” (B5) (Fig. 1).

Practical categorization rules were initially set up by the KLR (Table 1) to assure consistent categorization. 2322 children were referred to the KLR between 1997 and 2012. DPLD was suspected in a child with (1) respiratory symptoms and signs such as cough, tachy-/dyspnea at rest or with exercise, crackles, retractions, digital clubbing, failure to thrive, or respiratory failure, and (2) hypoxemia, and (3) diffuse radiological abnormalities and (4) if feasible and available, abnormalities in pulmonary function testing. Minimum duration of symptoms was 4 weeks.

During capture of the cases with suspected DPLD the referring physician mostly specialized in pediatric pulmonology on the level of a tertiary or university hospital diagnosed the patients in cooperation with the radiologist and in cases with biopsy the pathologist. Available material included a clinical history, biochemical, radiological, histological and genetic data of varying level of detail. A diagnosis was independently also established by each of the KLR experts: F. B., a pathologist; P. L. a geneticist; M. G., a pediatric clinician and pulmonologist (Additional file 2: Figure S1).

A four-step algorithm was used for categorization (Table  1 ): in a first step, a “final working diagnosis” was defined by consensus discussion, entered into the data-base and used for categorization and sub-categorization. In a second step it was analyzed if the final working diagnosis was related to DPLD. In a third step it was decided whether the patient suffered from a lung only condition or if the lung disease was part of a systemic disease. Of note, the latter are not restricted to the diagnosis of category B1. Other organ systems than the lungs may also be involved in diseases of categories B3, B4, B5, A1 and in particular A2 (Fig. 1, Additional file 1: Table S1). In a fourth step, the appropriate category and subcategory were selected, preferring the strongest causal explanation of the condition and the most conclusive supporting evidence taking into account the categorization rules shown in Table 1. A total of 791 children of 2322 children in the KLR qualified for childhood DPLD and were further categorized into one of the 12 DPLD categories (Fig. 1, Additional file 1: Table S1) and the respective subcategories.

The validity and observer-dependency was tested in 2012 using a systematic sample of 100 DPLD cases from the cohort of 791 children previously categorized according to the KLR algorithm. 100 cases were selected randomly and in proportion to their frequency in the KLR categories. All 100 cases were pseudonymized for blinded and independent re-categorization by two pediatric pneumologists, familiar with the KLR categorization system (Fig. 1, red lowever part, Additional file 3: Tables S2, Additional file 4: Table S3). One of the physicians involved in re-rating was already involved in the initial categorization, the other was an independent physician. A final working diagnosis was newly established by each re-rater and allocated in the KLR categorization system, again according to the rules indicated in Table 1 and the workflow detailed in Additional file 2: Figure S1, red part. As re-rating of the categorization was the goal of the study the initial categorization obtained during routine work-flow was set as the correct one. The overall frequencies of diagnostics available for the establishment of the final working diagnosis, categorization and sub-categorization are indicated in Additional file 5: Table S4.

All participants gave their written informed consent to participate in the KLR consultation and diagnosis program. The retrospective analysis of the data was approved by the institutional review board (EK 026–06). Prospective collection and analysis of data was approved in the GOLD.net project (EK 257–10), and analysis was performed under the project FP7-305653-chILD-EU (EK 111–13).