Activated PI3K Delta Syndrome

Activated PI3K delta syndrome (APDS) is an autosomal dominant combined immunodeficiency from gain-of-function variants in PIK3CD (APDS1) or loss-of-function splice variants in PIK3R1 (APDS2). It causes recurrent infection, lymphoproliferation and immune dysregulation from early childhood.

Pathophysiology. Both defects over activate phosphoinositide 3-kinase delta signalling in lymphocytes. Naive T cells are lost and senescent, short lived effector T cells accumulate, and B cells arrest at the transitional stage, with poor class switching.

It is rare. Onset is usually in infancy or childhood, and diagnosis is often delayed.

Lymphoma develops in up to about 15% of patients.

• Recurrent sinusitis, otitis media, pneumonia and bronchiectasis from early childhood
• Chronic or recurrent EBV and CMV viraemia, severe herpesvirus infection
• Lymphadenopathy, splenomegaly and nodular mucosal lymphoid hyperplasia
• Autoimmune cytopenias (immune thrombocytopenia, autoimmune haemolytic anaemia, neutropenia)
• Enteropathy and chronic diarrhoea
• Lymphoma, often EBV-related
• Growth delay and neurodevelopmental delay (more in APDS2)

• Immunoglobulins: low IgG and IgA, with normal or high IgM.
• Lymphocyte subsets: low naive CD4 and CD8 T cells, expansion of CD57-positive senescent T cells, low class switched memory B cells, raised transitional B cells, and often low total B cells.
• Genetic testing of PIK3CD and PIK3R1 (confirmation).
• Specific antibody responses to protein and polysaccharide vaccines.
• Viral load by PCR for EBV and CMV.
• Imaging: high resolution CT of the chest, and CT or ultrasound of the abdomen for nodes and spleen.
• Lymph node biopsy for rapid or asymmetric enlargement, to exclude lymphoma.

Differential diagnosis.

• Common variable immunodeficiency
• Autoimmune lymphoproliferative syndrome
• CTLA-4 haploinsufficiency and LRBA deficiency
• STAT3 gain-of-function disease
• Chronic active EBV infection
• Primary lymphoma
• Hyper IgM syndromes

• Selective PI3K delta inhibitor: leniolisib 70 mg orally twice daily about 12 hours apart, with or without food, for patients aged 12 years and over weighing at least 45 kg. It reduces lymphoproliferation and improves naive B cells. Check liver enzymes, blood count and pregnancy status at baseline, and use effective contraception. Avoid strong CYP3A4 inducers and inhibitors and BCRP substrate interactions. Younger children are treated under specialist direction.
• Sirolimus for lymphoproliferation or cytopenias: start 1 to 2 mg orally once daily in adults and adjust to a trough of 5 to 10 microgram/L. Monitor trough weekly after dose change, then every 3 months, with lipids, creatinine, urine protein, oral ulcers and wound healing. Avoid grapefruit and CYP3A4 interactions.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Antibiotic prophylaxis: azithromycin 500 mg orally three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms. Pneumocystis prophylaxis: co-trimoxazole 960 mg three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week).
• Cytopenias: prednisolone 1 mg/kg orally daily (maximum 60 mg) with taper, or rituximab 375 mg/m2 intravenously weekly for 4 doses after hepatitis B screening. Rituximab can worsen hypogammaglobulinaemia and EBV control, so replacement is continued.
• Viraemia: monitor EBV and CMV PCR every 3 months. Treat CMV disease with valganciclovir 900 mg orally twice daily for 21 days (reduce at creatinine clearance under 60 mL/min).
• Vaccines: inactivated vaccines only; avoid live vaccines.
• Haematopoietic stem cell transplantation for severe disease or lymphoma, with higher complications than in many other immunodeficiencies.

Special groups.

• Women of childbearing age: leniolisib is contraindicated in pregnancy, so counsel and test before starting.

Monitoring. Trough IgG, full blood count, liver enzymes and creatinine every 3 months. EBV and CMV PCR every 3 months. CT neck, chest and abdomen yearly, or sooner for symptoms. Spirometry and gas transfer yearly.

Referral and escalation. Refer to immunology. Urgent for rapidly enlarging nodes, cytopenia, B symptoms, or opportunistic infection.