Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS)

Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) – Treatment Options

Introduction
Activated PI3K-Delta Syndrome (APDS) is a rare primary immunodeficiency caused by gain-of-function mutations in the PIK3CD (APDS1) or PIK3R1 (APDS2) genes, leading to hyperactivation of the PI3Kδ pathway. This results in impaired immune regulation, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and increased risk of lymphoma. Diagnosis is confirmed by genetic testing. Management focuses on preventing infections, controlling immune dysregulation, and targeting the underlying pathway.

1. Supportive and Preventive Therapies

• Immunoglobulin replacement therapy (IVIG or SCIG):

  • Provides passive immunity, reduces frequency and severity of infections.

• Prophylactic antibiotics:

  • Trimethoprim-sulfamethoxazole or azithromycin for recurrent respiratory infections.

• Vaccinations:

  • Inactivated vaccines recommended; live vaccines are contraindicated due to immunodeficiency.

2. Targeted Therapies (Pathway-Specific)

• Leniolisib (PI3Kδ inhibitor):

  • Oral selective inhibitor approved for APDS in adolescents and adults.

  • Improves immune dysregulation, reduces lymphadenopathy and splenomegaly, normalizes B- and T-cell function, and decreases infection frequency.

• Sirolimus (rapamycin):

  • mTOR inhibitor used off-label to reduce lymphoproliferation, autoimmunity, and immune dysregulation.

• Other PI3Kδ inhibitors (investigational):

  • Research ongoing into novel small-molecule inhibitors with better safety profiles.

3. Management of Complications

• Autoimmune manifestations:

  • Corticosteroids, rituximab, or other immunosuppressants for autoimmune cytopenias and inflammatory complications.

• Lymphoproliferative disease:

  • Regular monitoring for lymphoma.

  • Chemotherapy or rituximab if malignancy develops.

• Chronic lung disease (bronchiectasis):

  • Airway clearance techniques, physiotherapy, and management of respiratory infections.

4. Curative Options

• Hematopoietic stem cell transplantation (HSCT):

  • Considered in severe or refractory APDS.

  • Can restore normal immune function, but carries significant risks.

5. Lifestyle and Preventive Measures

• Avoidance of crowded places and exposure to respiratory pathogens.

• Regular pulmonary monitoring to prevent progressive lung damage.

• Healthy diet, exercise, and avoidance of smoking or environmental pollutants.

6. Multidisciplinary Care

• Immunologists: For long-term management and monitoring immune function.

• Hematologists/Oncologists: For lymphoma surveillance and treatment.

• Pulmonologists: For chronic lung complications.

• Rheumatologists: For autoimmune manifestations.

• Genetic counselors: For family risk assessment and support.