Diffuse alveolar hemorrhage in children with interstitial lung disease: Determine etiologies!

Abstract

Objective: Diffuse alveolar hemorrhage (DAH) in children is a rare condition resulting from different underlying diseases. This study aimed at describing characteristics and diagnostic measures in children with ILD (children's interstitial lung disease, chILD) and DAH to improve the diagnostic approach by increasing clinician's awareness of diagnostic shortcomings.

Patients and methods: A retrospective data analysis of patients with ILD and DAH treated in our own or collaborating centers between 01/07/1997 and 31/12/2020 was performed. Data on clinical courses and diagnostic measures were systematically retrieved as case-vignettes and investigated. To assess suitability of diagnostic software-algorithms, the Human Phenotype Ontology (HPO) was revised and expanded to optimize conditions of its associated tool the "Phenomizer."

Results: For 97 (74%) of 131 patients, etiology of pulmonary hemorrhage was clarified. For 34 patients (26%), no underlying condition was found (termed as idiopathic pulmonary hemorrhage, IPH). Based on laboratory findings or clinical phenotype/comorbidities, 20 of these patients were assigned to descriptive clusters: IPH associated with autoimmune features (9), eosinophilia (5), renal disease (3) or multiorgan involvement (3). For 14 patients, no further differentiation was possible.

Conclusion: Complete and sometimes repeated diagnostics are essential for establishing the correct diagnosis in children with DAH. We suggest assignment of patients with IPH to descriptive clusters, which may also guide further research. Digital tools such as the Phenomizer/HPO are promising, but need to be extended to increase diagnostic accuracy.

Keywords: children's interstitial lung disease; diffuse pulmonary hemorrhage; human phenotype ontology; idiopathic pulmonary hemosiderosis; pediatric.

Figure 1.

Study enrollment and distribution of patients with diffuse alveolar hemorrhage (DAH).

Figure 2.

Pulmonary hemorrhage as an example for rare pneumological conditions and Human Phenotype Ontology (HPO). A: Schematic diagnostic algorithm for patients with pulmonary hemorrhage. B: Modifications and additions of the the HPO-branch „Abnormality of the respiratory system“. Green, changes in organisation of HPO-branches. Yellow, introduction of new parent terms. Purple, reassignment and restructuring of terms. Blue, entirely new branch. Broken lines symbolize that the HPO contains additional branches/ terms that are not listed in the figure. Figure 2B is inspired by Haimel et al. (50). C: Creation of new HPO-terms within the field of pneumology. D: Number of annotated terms to selected diseases causing pulmonary hemorrhage before/ after creating new annotation. E: Diagnostic ranking by the „Phenomizer“ for patients with pulmonary hemorrhage due to an underlying OMIM^®-disease. Each dot represents a case-vignette with a specific diagnosis. Left graph: cases from our cohort (n = 17). Right graph: case reports from specialized literature (n = 12). Patients with pulmonary hemosiderosis (n=10) are marked in red. Abbreviations: BAL: bronchoalveolar lavage; CDG4: Chronic granulomatous disease, autosomal recessive, 4; FLNA-mutation: Filamin A-mutation; GPA: Granulomatosis with polyangiitis; HHT: hereditary hemorrhagic teleangiectasia; HPO: Human Phenotype Ontology; HUS: Hemolytic uremic syndrome; MAHCC: methylmalonic aciduria and homocystinuria type cblC; PCD: Primary ciliary dyskinesia; SLE: Systemic lupus erythematosus; Pulm. hemosiderosis, IgA-def.: Pulmonary hemosiderosis with IgA-deficiency.