Abstract: Background: The traditional treatment for activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome (APDS) has shown limited efficacy in preventing infections. Recently, rapamycin has been used in the clinical treatment of children with APDS type1 (APDS1) caused by PIK3CD gene mutations. Objective: To investigate the efficacy and safety of rapamycin in the treatment of APDS1. Design: Case series report. Methods: This study included consecutive cases diagnosed with APDS1 via genetic testing and treated with oral rapamycin from June 2017 to June 2023 at the Children's Hospital of Zhejiang University School of Medicine. The use of rapamycin for treating non-tumorous lymphoproliferation due to APDS in children is off-label in China. Before treatment, parents were fully informed of the risks and signed informed consent. The oral dosage of rapamycin was 1 mg·m-2·d-1. Main outcome measures: The number of pneumonia episodes within 12 months and ultrasound assessment of liver, spleen, and lymph node enlargement. Results: Among the four children treated with rapamycin for APDS1, three were male and one was female. The average age of onset was 35.5±17.9 months, and the average age at diagnosis was 56.5±35.0 months. Whole-exome sequencing revealed a de novo heterozygous mutation in the PIK3CD gene (c.3061G>A, p.E1021K) in all cases. All presented with recurrent coughing and had hepatosplenomegaly and lymphadenopathy. All had pneumonia. There were 2 cases of recurrent mumps, 2 cases of growth retardation, and one case each of atopic dermatitis, inflammatory bowel disease, and Wegener's granulomatosis. Bronchoscopy showed cobblestone-like bulge in the bronchial mucosa in three cases. All had reduced CD19+ B cells and inverted CD4+/CD8+ ratios; three had elevated IgM levels, and one had decreased IgG. Prior to rapamycin, all received IVIG, anti-infective treatment and corticosteroids, yet continued to suffer from recurrent respiratory infections and hepatosplenomegaly. Additionally, three developed thrombocytopenia and two had anemia. Rapamycin was administered orally to all children from 1 to 44 months after diagnosis for 12 to 58 months. Following 12 months of rapamycin treatment, the average annual number of pneumonia episodes decreased from 5.3 to 1.0. There was significant improvement in hepatosplenomegaly and superficial lymphadenopathy, and Hb and PLT levels returned to normal. However, there were no statistically significant differences in immunological parameters before and after treatment. No rapamycin-related adverse effects, tumors, or deaths were observed during follow-up. Conclusion: Rapamycin is relatively safe and has some efficacy in treating APDS1.

Key words: PIK3CD, PI3Kδ overactivation syndrome, Rapamycin, Clinical symptoms, Treatment