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Activated PI3K delta syndrome (APDS)
APDS is an inherited condition affecting the immune system, leading to recurrent infections, particularly of the respiratory tract, as well as problems with lymph nodes and an increased risk of certain cancers, such as lymphoma. It primarily affects white blood cells, which are crucial for fighting off illness.
Overview
Activated PI3K delta syndrome (APDS) is a rare, inherited primary immunodeficiency. This condition is caused by a problem with a specific signalling pathway, known as the PI3Kδ pathway, which becomes overactive. This overactivity mainly affects certain white blood cells, such as T-cells and B-cells, which are vital components of the immune system [PMID:33671882]. As a result, individuals with APDS often experience a range of immune-related issues, including recurrent infections, particularly in the airways, and abnormal growths of lymphoid tissue.
APDS can present differently among affected individuals, with symptoms varying in type and severity. The challenges posed by APDS generally become noticeable during childhood, though diagnosis can sometimes occur later in life. Early recognition and appropriate management are important for improving outcomes and reducing the long-term complications associated with the syndrome.
Symptoms & clinical features
Individuals with APDS typically experience a variety of symptoms, largely due to the immune system not functioning correctly. Recurrent infections are a common feature, often affecting the respiratory tract (lungs, sinuses, ears) and sometimes leading to chronic lung disease [PMID:24177437]. These infections can be caused by bacteria, viruses, or fungi.
Another frequent symptom is lymphoproliferation, which means an overgrowth of lymphoid tissue. This can lead to enlarged lymph nodes (lymphadenopathy), an enlarged spleen (splenomegaly), and sometimes an enlarged liver (hepatomegaly). Some individuals may also develop autoimmune conditions, where the immune system mistakenly attacks healthy body tissues, or exhibit symptoms such as recurrent fevers, chronic diarrhoea, and inflammation in the bowel [PMID:28795767].
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Affected organs
APDS primarily affects the immune system, with many symptoms arising from issues within the lymphoid organs. These include lymph nodes, the spleen, and the tonsils, which can become abnormally enlarged due to lymphoproliferation. The respiratory system, including the lungs and airways, is frequently affected by recurrent and chronic infections, which can sometimes lead to structural damage like bronchiectasis.
Other organs that may be involved include the gastrointestinal tract, where inflammation and chronic diarrhoea can occur. The liver can also be enlarged (hepatomegaly). The overactive immune response can sometimes lead to issues in the blood, such as anaemia (low red blood cell count) or low platelet counts, and may also increase the risk of certain types of cancer, particularly lymphoma.
Risks & severity
The severity of APDS can vary significantly between individuals, even within the same family. Symptoms typically emerge during childhood, but a diagnosis might not be made until adulthood in some cases. The condition is progressive, meaning symptoms can worsen over time. A major long-term risk associated with APDS is the increased likelihood of developing certain cancers, especially B-cell lymphomas, which may occur at a younger age than typically expected [PMID:28795767].
Chronic infections can lead to permanent damage in organs like the lungs, contributing to conditions such as bronchiectasis. Autoimmune manifestations, including cytopenias (low blood cell counts), also add to the complexity and potential severity of the condition. Regular monitoring and appropriate management are crucial to address these risks and manage the diverse symptoms.
Genetic causes
APDS is caused by pathogenic variants in one of two genes: PIK3CD or PIK3R1. These genes provide instructions for making components of the PI3Kδ (phosphatidylinositol-3-kinase delta) pathway, which plays a critical role in the growth, survival, and function of immune cells, especially B and T lymphocytes [PMID:24177437].
Pathogenic variants in PIK3CD typically lead to an overactive (gain-of-function) PI3Kδ enzyme. Likewise, certain pathogenic variants in PIK3R1 (often referred to as 'loss-of-function' of the regulatory subunit) can also result in uncontrolled activation of the PI3Kδ pathway. This sustained overactivity interferes with the normal development and function of immune cells, leading to the characteristic immune dysregulation seen in individuals with APDS.
- PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
- PIK3R1 phosphoinositide-3-kinase regulatory subunit 1
Inheritance pattern
APDS is inherited in an autosomal dominant pattern. This means that only one copy of an altered PIK3CD or PIK3R1 gene in each cell is sufficient to cause the condition. In most cases, an affected individual inherits the altered gene from one parent who also has the condition. However, some cases result from a new pathogenic variant in the gene that occurs for the first time in the affected individual, meaning neither parent carries the altered gene.
When one parent has an autosomal dominant condition, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and develop the condition. Family members of an affected individual may choose to discuss their genetic risks with a genetic counsellor.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing APDS typically involves a combination of clinical evaluation and genetic testing. Clinicians suspect APDS based on the presence of characteristic symptoms, such as recurrent infections, enlarged lymph nodes, or autoimmune issues. Blood tests might show abnormalities in immune cell populations or function.
Confirmation of APDS involves genetic testing to identify pathogenic variants in the PIK3CD or PIK3R1 genes. This testing is usually performed by specialist NHS laboratories and falls under specific R-codes within the NHS Genomic Medicine Service. Patients are generally referred for genetic testing by a specialist clinician, such as an immunologist or a clinical geneticist, working within the NHS framework.
Management & lifestyle
Managing APDS typically involves a multidisciplinary approach focused on preventing and treating infections, controlling lymphoproliferation, and monitoring for complications like lymphoma. Treatment strategies are individualised based on the specific symptoms and severity in each person. NHS care pathways generally involve regular monitoring by immunologists and other specialists.
Antibiotics, antiviral, or antifungal medications are used to treat infections, and sometimes long-term prophylactic (preventative) treatment may be considered. Immunoglobulin replacement therapy may be given to boost the immune system in some individuals. Certain medications, known as PI3Kδ inhibitors, are specifically designed to target the overactive pathway and have shown promise in managing symptoms in some individuals. Regular surveillance for lymphoma is also a key part of ongoing care. Patients and their families are encouraged to work closely with their healthcare team to develop a comprehensive management plan.
UK care pathway
In the UK, individuals suspected of having primary immunodeficiencies like APDS typically access care through the NHS. A referral to a clinical immunologist or clinical genetics service is usually the first step. These specialists can assess symptoms, arrange appropriate diagnostic tests, and coordinate ongoing care. Genetic testing for APDS, often covered by NHS Genomic Medicine Service R-codes, is carried out by accredited laboratories. Genetic counsellors are available to provide information and support to individuals and families regarding inheritance patterns and genetic implications.
Frequently asked questions
Is APDS a type of cancer?
No, APDS is not a cancer itself, but it significantly increases the risk of developing certain types of cancer, particularly lymphoma. This increased risk is due to the underlying immune system dysregulation caused by the condition.
Can APDS be cured?
Currently, there is no known cure for APDS. However, treatments are available to manage the symptoms, prevent severe complications, and improve the quality of life for affected individuals. Research into new therapies is ongoing.
Will my children inherit APDS?
APDS is inherited in an autosomal dominant pattern. If you have APDS, there is a 50% chance with each pregnancy that your child will inherit the pathogenic variant and therefore the condition. Genetic counselling can provide more personalised information and support.
How often do I need to be seen by a doctor if I have APDS?
The frequency of medical appointments will depend on your individual symptoms, severity of the condition, and treatment plan. Regular follow-ups with specialists, typically an immunologist, are essential for monitoring your health and managing the condition effectively.
What lifestyle changes can help with APDS?
There are no specific lifestyle changes that can cure APDS, but a healthy lifestyle can support overall well-being. This includes a balanced diet, regular exercise, and avoiding exposure to infections where possible. Always discuss any lifestyle changes with your healthcare team.
References
- Wolf HM, Candotti F, Spelsberg R. Diagnostic odyssey of patients with the rare immunodeficiency activated PI3 kinase delta syndrome (APDS): case study from expert and patient surveys. Frontiers in immunology. 2026. PMID: 41859081
- Gilchrist CA, Petri WA Jr. Inborn Errors of Immunity Linked to Cryptosporidiosis. The Journal of infectious diseases. 2026. PMID: 42844665
- Conti F, Moratti M, Sabattini E. Expert insights on Hodgkin's lymphoma development in an activated PI3K delta syndrome patient undergoing leniolisib treatment. Frontiers in immunology. 2024. PMID: 39872539
- Thauland TJ, Pellerin L, Ohgami RS. Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome. Frontiers in immunology. 2019. PMID: 31031754
- Rivalta B, Amodio D, Giancotta C. Case Report: Successful Treatment With Monoclonal Antibodies in One APDS Patient With Prolonged SARS-CoV-2 Infection Not Responsive to Previous Lines of Treatment. Frontiers in immunology. 2022. PMID: 35799775
- Rana V, Jindal A, Krishna V. Recurrent Panuveitis as a Manifestation of a Novel PIK3CD Gene Mutation: A Diagnostic and Management Challenge. Ocular immunology and inflammation. 2025. PMID: 39932361