Diffuse alveolar hemorrhage syndrome in children: Primary immunodeficiency diseases and implications for clinical management.

Background: With the advances in genetic diagnosis in the past decade, primary immunodeficiency diseases (PIDs) have been increasingly identified as emerging causes of (DAH) among children treated in our department. The literature regarding PID-associated DAH are limited. Thus, we aim to enhance the awareness that PIDs can be underlying causes of pediatric DAH and evaluate the implications of genetic diagnosis for treatment.

Methods: This analysis included 68 children with DAH who had undergone genetic tests in the pediatric respiratory ward during the preceding 10 years. Their clinical findings, genetic results, and treatment were retrospectively examined.

Results: In total, 16 children were diagnosed with PIDs. Genetic diagnoses of PIDs yielded in 14 patients revealed involvement of 10 immunity-defective genes (TNFRSF13B, TCF3, NFKB2, PIK3CD, COPA, ADA2, PLCG2, RAG1, BCL11B, and STAT3). The remaining two children had diagnoses of CVID without associated variants. The overall prevalence of PID-associated DAH in our cohort was 23.5% (16/68). The median age at DAH symptom onset was 3.5 (interquartile range: 2.1-9.3) years. In all children, DAH is the primary or even initial clinical manifestation of the PIDs. Of the children, 37.5% (6/16) developed additional autoimmune or inflammatory complications. 50% (8/16) of patients adjusted their therapeutic management according to the genetic diagnosis. 87.5% (14/16) of patients achieved remission.

Conclusion: This study suggests that PID is one of the most important causes of DAH in children. The identification of the PIDs and the causal variants enables genotype-specific treatment, which may offer critical guidance for clinical management.