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Activated PI3K-delta syndrome
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Activated PI3K-delta syndrome

Activated PI3K-delta syndrome (APDS) is an immune system disorder characterized by recurrent infections, immune system dysfunction, and an increased risk of certain blood cancers.

Overview

Activated PI3K-delta syndrome (APDS) is a disorder that impairs the immune system. Individuals with this condition often have low numbers of white blood cells (lymphopenia), particularly B cells and T cells. Normally, these cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The severity of the condition varies widely; some people may have multiple, severe infections, while others show mild symptoms or none at all.

Symptoms

Most commonly, people with APDS develop recurrent infections that begin in childhood, particularly in the lungs, sinuses, and ears. Over time, recurrent respiratory infections can lead to bronchiectasis, which damages the passages leading from the windpipe to the lungs and can cause breathing problems. Other features include:

  • Chronic active viral infections, such as Epstein-Barr virus, herpes simplex virus, or cytomegalovirus.
  • Abnormal clumping of white blood cells, leading to enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly).
  • Nodular lymphoid hyperplasia, where white blood cells form solid masses in the lining of the airways or intestines.
  • Autoimmunity, where the body attacks its own tissues and organs.
  • Increased risk of blood cancers, specifically Hodgkin lymphoma and non-Hodgkin lymphoma.

Causes

APDS is caused by variants (mutations) in the PIK3CD gene or the PIK3R1 gene. These genes provide instructions for making subunits of an enzyme called phosphatidylinositol 3-kinase (PI3K), which is involved in white blood cell growth, division, and maturation.

  • APDS Type 1: Caused by variants in the PIK3CD gene.
  • APDS Type 2: Caused by variants in the PIK3R1 gene.

These variants are classified as gain-of-function, meaning the PI3K-delta enzyme becomes overactive. This overactivity alters the differentiation of B and T cells, causing them to die earlier than usual and preventing them from effectively responding to infections. This abnormal proliferation also contributes to lymphadenopathy and the increased risk of lymphoma.

Inheritance

Activated PI3K-delta syndrome is inherited in an autosomal dominant pattern, meaning one copy of the altered gene in each cell is sufficient to cause the disorder.

Frequently Asked Questions

Key distinguishing features include persistent lymphopenia (especially low naïve CD4+ T cells and class‑switched memory B cells), enlarged lymph nodes or spleen, and a history of chronic viral infections (EBV, CMV, HSV). Laboratory work‑up shows elevated IgM with low IgG/IgA, and flow cytometry often reveals abnormal B‑cell subsets. When these immunologic patterns coexist with recurrent bacterial pneumonias, APDS should be considered and confirmed by sequencing the PIK3CD or PIK3R1 genes.
Patients should undergo a baseline full‑body physical exam, CBC with differential, and imaging (e.g., ultrasound of the abdomen and neck, or low‑dose CT if clinically indicated) every 12–24 months. Any new, rapidly enlarging lymph node, unexplained night sweats, weight loss, or persistent cytopenias warrants prompt PET‑CT and hematology referral for possible biopsy. Regular monitoring of EBV viral load can also help, as high loads are linked to lymphoma risk.
First‑line therapy often includes immunoglobulin replacement (IVIG or subcutaneous) to reduce bacterial infections. For the underlying signaling defect, selective PI3Kδ inhibitors such as leniolisib (approved in the U.S. for APDS1) or investigational agents like seletalisib can normalize lymphocyte counts and decrease infection frequency. These targeted drugs are typically introduced after failure of conventional prophylaxis (antibiotics, antivirals) or when severe lymphoproliferation develops. Hematopoietic stem‑cell transplantation remains an option for refractory disease but carries higher risk.
Live attenuated vaccines (e.g., MMR, varicella, oral polio) are generally contraindicated in patients with significant T‑cell lymphopenia or those on PI3Kδ inhibitors, because they can cause uncontrolled infection. Inactivated vaccines (influenza, pneumococcal, COVID‑19) are recommended and may require higher or more frequent dosing to achieve protective titers. Immunization plans should be individualized after reviewing lymphocyte counts and current therapy, ideally in consultation with an immunology specialist.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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