Abstract
Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency or an inborn error of immunity caused by gain-of-function variants in PIK3CD, which encodes the catalytic subunit p110δ of class IA PI3K, or loss-of-function variants in PIK3R1, which encodes p85α, a regulatory subunit of p110δ. The former is termed APDS1, and the latter is termed APDS2. Clinically, it is characterized by recurrent respiratory infections, progressive airway destruction, and bronchiectasis. Many patients exhibit lymphadenopathy and present with hypogammaglobulinemia, specifically hyper-IgM or hypo-IgG, reflecting impaired antibody production. Broadly, it is included within the category of common variable immunodeficiency （CVID）. Prophylactic antibiotic administration and regular immunoglobulin replacement therapy are performed as with CVID. However, since excessive activation of the PI3K signaling pathway is the key pathology, not only mTOR inhibitors but also selective p110δ inhibitors are useful. Patients with APDS frequently develop malignant lymphoma, often requiring chemotherapy or hematopoietic stem cell transplantation, and can sometimes follow a fatal course. Specific treatment with mTOR inhibitors or selective p110δ inhibitors can be effective. Referencing the “10 warning signs for APDS,” modeled after the “10 warning signs for primary immunodeficiency,” facilitates early diagnosis of APDS. Early therapeutic intervention is expected to improve prognosis.
