D1.336 - Sirolimus for the treatment of the Immunodeficiency Linked to PIK3CD (APDS1)

Background: Activated PIK3CD syndrome (APDS1) was first described in 2013. This rare inborn error of immunity is included in the predominantly antibody deficiency category and is characterized by frequent infections, lymphoproliferation and propensity to malignancy and autoimmunity. Due to heterogeneous clinical manifestation, the diagnosis is often late and complications, such as bronchiectasis and lymphoma, may occur. Treatment should be individualized and is still controversial. A written informed consent for publication was obtained from the patient´s mother.

Case report:  13- year-old female was born at full-term, without complications in the neonatal period. She has non-consanguineous healthy parents and no relevant family history. Symptoms started with 6 months, with visible cervical and inguinal lymph nodes. From 8 months to 10 years, she developed recurrent infections (pneumonias, otitis), post-vaccination varicella and an abscessed submental lymph node, that required hospitalization. At the age of 12, she was diagnosed with bilateral ovarian dysgerminoma and underwent surgical resection. Physical examination showed cervical and inguinal lymphadenopathy and hepatosplenomegaly. Laboratory tests: pneumococcal serologies with all serotypes below 1.3, IgG negative for hepatitis B. IgG was 1527 mg/dl, IgM 235mg/dl, IgA 159 mg/dl and IgE 23 mg/dl. CD4 (563 cells/μL) and CD19 (40 cells/μL) lymphocytes were low. Immunophenotyping after stimulation showed increased Treg cells and increase in CD39. Abdominal CT revealed retroperitoneal, pelvic, and inguinal enlarged lymph nodes and hepatosplenomegaly. Thoracic CT showed small airways disease, mosaic attenuation and atelectatic bands (bronchiectasis) and prominent axillary lymph nodes. The diagnosis of APDS was made after the genome result (pathogenic variant in PIK3CD). Initial treatment was prophylactic antibiotic and prednisolone, but it was not effective. Sirolimus 3 mg/day was then initiated and she presented a quick response, without adverse events. She is clinically well, without new infections. Lymphoproliferation was controlled, with remission of hepatosplenomegaly and lymphadenopathy.

Conclusion: Patients with APDS1 exhibit various immunological alterations due to the activating mutation in PIK3CD. Treatment with sirolimus, an mTOR inhibitor, aims to reduce the activation and uncontrolled proliferation of immune cells. In this case, sirolimus proved to be a highly effective and safe therapy.