Summary
Activated PI3K delta syndrome (APDS) is a rare primary immunodeficiency. About 30–40 people in the UK are known to be affected by the condition.
First discovered in 2013, APDS is an inherited disorder that affects both males and females. Prior to the discovery of APDS, patients may have been given a diagnosis of Common Variable Immunodeficiency (CVID).
People with APDS are unable to fight infections because their immune system does not work properly. In APDS, the white blood cells, particularly those called B-cells and T-cells, are abnormal and incapable of handling infections properly. They can’t recognise and attack bacteria and viruses to prevent infection.
Causes of APDS
APDS is caused by changes in the genes (either the PIK3CD or PIK3R1 gene) that control the production of an enzyme called phosphoinositide 3-kinase delta (PI3K delta). This enzyme is important for the normal development and division (proliferation) of B-cells and T-cells.
Two types of APDS have been identified. People who have genetic changes in the PIK3CD gene are referred to as having APDS1. People with genetic changes in the PIK3R1 gene are known as having APDS2.
The genetic changes, or variants, found in either the PIK3CD or PIK3R1 gene lead to the enzyme PI3K delta being more active than normal (overactive). Unfortunately, this overactivity means that the development and control of B-cells and T-cells is abnormal, so their ability to fight off infections is reduced.
Clinical symptoms
People with APDS may present in childhood or later in life with severe, persistent and recurrent bacterial and viral infections (usually in the lungs, nose or ears), a persistent cough that usually brings up phlegm, enlarged tonsils, swollen lymph nodes and often an enlarged spleen and liver.
Young patients may experience delays in their development, and all patients might show signs of autoimmunity and inflammatory conditions. These can include anaemia, low platelet counts, inflammation of the colon (colitis, often seen as persistent diarrhoea and long-term abdominal pain) and inflammation of the kidneys (glomerulonephritis, seen as pink or blood-stained urine and swelling of the hands, feet, face and abdomen). This is due to the abnormal B-cells and T-cells in APDS mistakenly attacking normal body cells (a process known as autoimmunity).
People with APDS are prone to more significant problems from viral infections such as Epstein-Barr virus (EBV), Cytomegalovirus (CMV), herpes simplex virus (HSV) and Varicella-zoster virus infections (VSZ).
In addition to the abnormal development and control of B-cells and T-cells, the overactive enzyme in APDS results in faster production of white blood cells than is normal (lymphoproliferation). This leads to these cells clumping together in small glands in the body called lymph nodes and the nodes becoming enlarged. These clumps, or dense collections, of cells in the lymph nodes usually occur in the airways or intestines of affected individuals. While some of these conditions are non-cancerous (benign), APDS does increase the risk of developing a form of blood cancer called B-cell lymphoma.
Common symptoms seen in people with APDS
- Recurrent, severe infections
- Swollen or enlarged lymph nodes in the neck, chest or abdomen
- Enlarged spleen or liver
- Bronchiectasis – a widening of the tubes (bronchi) that lead to the air sacs of the lung; can arise owing to repeated bouts of infections
- Recurring and long-lasting viral infections
- Gut (gastrointestinal) problems
- Autoimmune or autoinflammatory conditions, e.g. a reduction in the number of blood cells (cytopenia), autoimmune thyroiditis and arthritis
- Lymphoma (cancer of the immune system)
- Non-immune cell cancers
Diagnosis
Sometimes people may experience a lengthy delay in the diagnosis of APDS, involving multiple visits to various specialists. However, making a correct and early diagnosis of APDS is crucial so that the right treatments can be given to help prevent disease progression and permanent organ damage or malignancy.
The diagnosis of APDS is based on the signs or symptoms that an individual has, laboratory tests and genetic testing.
Laboratory tests used to diagnose APDS include:
- a complete blood cell count
- measurement of immunoglobulin (antibody) levels
- a detailed analysis of the levels and types of white blood cells, such as the different subtypes of B-cells and T-cells.
Genetic testing is used to confirm a diagnosis of APDS since abnormalities in other blood tests overlap with many conditions.
APDS can affect both males and females. In most people with APDS, a single copy of the faulty gene passed on from one parent and a normal copy from the other parent. This is a pattern of inheritance called autosomal dominant inheritance.
Sometimes new genetic changes can occur unexpectedly in people with no history of the disorder in their family. If the genetic change occurs at the time of conception (in the egg or sperm), then it is considered ‘sporadic’ and the disorder could pass to the next generation.
All offspring of an individual affected with APDS have a 50% (1 in 2) chance of inheriting the abnormal gene and being affected by the disorder. The risk is the same for every pregnancy, so family planning is an important consideration and genetic counselling is recommended. All family members of a person with a confirmed diagnosis of APDS should be genetically tested. While family members may not have the same symptoms or any symptoms, they may still carry the genetic condition and pass it onto their biological children.
For more information, please read our leaflet Genetic aspects of primary immunodeficiency.
Infections can be managed quickly with antibiotic, antifungal or antiviral drugs. If there is a substantial risk of repeated infections, then ongoing preventative (prophylactic) use of these drugs may be considered to prevent infections from recurring.
For people with poor immunoglobulin (antibody) production, immunoglobulin replacement therapy may be recommended. The aim of immunoglobulin replacement therapy is to prevent infections and offer protection from possible further infections that can result in damage to organs, such as the lungs.
Drugs, such as steroids, sirolimus (belonging to a family of medicines known as mTOR inhibitors) or the monoclonal antibody rituximab, can be given to modify the response of the immune system, reduce the size of the spleen or lymph nodes and improve blood counts.
‘Targeted therapies’ are becoming available that specifically target the overactive PI3K delta enzyme. These are known as PI3K delta inhibitors and a phase 3 randomised controlled study has demonstrated promising results in cases where there is excessive production of white blood cells (lymphoproliferation).
Haematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation (BMT), is a potential cure for APDS. The process involves harvesting the bone marrow – the soft spongy tissue found in the centre of the bones – from a healthy donor and introducing it into a person with APDS. The bone marrow contains the stem cells that are responsible for making the cells of the immune system. In transferring healthy stem cells to a person with APDS, the expectation is that the stem cells will populate the recipient’s bone marrow and start to generate healthy immune cells capable of fighting infections.
HSCT has been used successfully as a treatment of severe APDS, but the procedure carries risks. If HSCT is offered, then the risks will be discussed fully with the patient by the specialist transplant team.
Table 1. An overview of treatments for APDS
Other supportive care in the treatment of APDS may include medicines to reduce fever and pain, bronchodilators to improve breathing, and medicine to reduce coughing (antitussives). For lung problems, deep breathing exercises and other respiratory treatments may be advised, such as chest or sinus drainage, or chest physiotherapy.
Immunisations
People with APDS should keep up to date with their vaccinations as recommended by their specialist health team.
The lifestyle adjustments required for people with APDS depend on the severity of the individual symptoms each person has. Exposure to potential bacteria and viruses that could cause infection can be reduced by practising good personal, food and environmental hygiene; taking precautions when swimming (avoiding lakes/ponds), minimising contact with dirt, soil or animals; and avoiding contact with people with infections.
Patients’ health will be monitored regularly, including checks for swollen lymph nodes and the start of signs and symptoms of lymphoma, which are typically high temperature, night sweats, tiredness, itching and unexplained weight loss.
Q. Does having APDS affect body systems other than the immune system?
A. The enzyme PI3K is present in all body tissues. This means that APDS can affect functions outside of the immune system, including the central nervous system.
