What Is Activated Phosphoinositide 3-kinase Delta Syndrome (APDS)?
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a primary immunodeficiency disease caused by the activation of function mutations in the PIK3CD gene. Most patients of APDS experience their first infection in early childhood. However, symptoms can start at any age. The common symptoms of APDS are repeated upper respiratory tract infections, ear infections, sinus infections, pneumonia (lung infection), and bronchitis. Other symptoms of APDS include lymph node swelling, gastrointestinal irritation, enlarged spleen, and liver, along with a high risk for lymphoma. Recurrent ear and respiratory tract infections can cause permanent hearing loss and bronchiectasis (scarring of the lungs).
What Are the Two Types of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS)?
The two types of APDS include:
- APDS1: It occurs due to changes in the PIK3CD gene.
- APDS2: It occurs due to changes in the PIK3R1 gene.
Both the above types of APDS are inherited in an autosomal dominant pattern in families and have similar symptoms. Treatment for APDS generally involves lowering inflammation, management of symptoms, and preventing infections. The treatment includes antibiotics to overcome the infections, immunoglobulin replacement, anti-inflammatory drugs, and hematopoietic stem-cell transplant (HSCT).
What Are the Signs and Symptoms of Activated Phosphoinositide 3-Kinase Delta Syndrome?
The most common symptoms include:
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Ear infections.
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Sinus infections.
Recurrent respiratory tract infections can cause scarring of the lungs (bronchiectasis). This is more commonly seen in APDS1 than in APDS2. Viral infections are also seen, particularly infections with herpes simplex viruses and Epstein-Barr virus. These infections are difficult to treat and may never completely be cured.
People with APDS might also show the following symptoms, which sometimes result in hospitalization:
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Develop enlarged lymph nodes.
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An enlarged liver (hepatomegaly) or spleen (splenomegaly).
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Inflammation of the intestine.
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Severe diarrhea.
Skin infections are commonly seen. In some cases, people might develop autoimmunity, making the body’s immune system attack its own healthy cells. A shorter stature is more common in APDS2. Patients with APDS also show a higher risk of increased risk of developing lymphoma and other blood cancers. Autoimmune disease can have a severe impact on various body organs and body. In APDS, the most common sign of autoimmune disease includes:
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Reduced levels of red blood cells cause anemia.
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Fewer platelets lead to bleeding problems and easy bruising.
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Growth delay.
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Short stature.
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Neurodevelopmental delay.
Another characteristic feature of activated PI3K-delta disease is the abnormal clumping of white blood cells. These clumps can cause enlargement of lymph nodes (lymphadenopathy).
Which Population Is Most Affected?
APDS has been reported in people worldwide and is not more prominent in any one ethnic group. It affects both males and females equally. The exact number of patients with this disease is unknown.
How Is Activated Phosphoinositide 3-kinase Delta Syndrome Caused?
APDS is caused by a pathogenic variant in the PIK3CD gene (APDS1) or the PIK3R1 gene (APDS2). Both these genes are essential for the growth, survival, and function of specific types of immune cells (T cells and B cells). These are marked white blood cells that act against the infection. Pathogenic differences in these two genes affect the B cells' and T cells' functioning. People with APDS usually show B cells and T cells that do not function properly, leading to inflammation of the infections, intestine, and autoimmune disease.
The passage of APDS1 and APDS2 show a dominant pattern in families. Dominant genetic diseases occur as a result of a mutation in a single copy of the gene that is essential for causing a particular disease. The mutated gene can be inherited from one of the parents or might result in an altered gene in the affected individual. The risk of inheriting the mutated gene from the affected parent is fifty percent for each pregnancy. The risk of this disease is the same for both females and males.
How Is Activated Phosphoinositide 3-kinase Delta Syndrome Diagnosed?
The diagnosis of APDS is based on clinical examination, symptoms, a detailed family history, and laboratory testing to find abnormalities in the functioning of immune cells. Because APDS resembles other immunodeficiencies, genetic testing is essential to diagnose properly. Genetic testing for immunodeficiencies is related to the use of a gene panel. Genetic testing is generally performed with a blood or saliva sample. It is advised to visit a genetics professional before undergoing genetic testing to assess the condition's risks, benefits, and limitations.
How Is Activated Phosphoinositide 3-kinase Delta Syndrome Treated?
Treatment for APDS mainly focuses on managing the symptoms. APDS can be treated by using a combination of long-term immunoglobulin replacement therapy. This therapy helps to support the immune system. Immunosuppressive medications help with symptoms caused by inflammation and autoimmunity. Further, individuals with APDS also require daily antibiotics to avoid infections before they occur.
Children with APDS might require tympanostomy tubes (ear tubes) due to frequent ear infections. Some patients might have their tonsils removed due to swelling and sinus infections. People with highly severe APDS might also require respiratory support, like extra oxygen and chest physiotherapy. Further, occupational, physical, and speech therapy might help with some long-term complications.
In patients where APDS does not respond to standard therapy, hematopoietic stem cell transplant (HSCT) has been used. In APDS, HSCT includes replacing the bone marrow with new stem cells that might become healthy, functioning immune cells. HSCT is used as a treatment for various primary immunodeficiencies and also for certain types of blood cancers.
In 2023, the U.S. Food and Drug Administration (FDA) approved Leniolisib to treat APDS in adults and children 12 years of age and older. People with APDS might also require to visit a variety of specialists like immunologists, infectious disease specialists, pulmonologists, ear, nose, and throat specialists, and gastroenterologists. Genetic counseling is usually advised for families with an affected child.
Conclusion:
APDS can affect each individual differently. Some people show mild symptoms, while others might be severely affected. In most cases, the symptoms of APDS begin in childhood. However, symptoms can occur at any age. Sometimes no symptoms develop until adulthood. There are some cases where the patients who have been diagnosed with APDS do not show any symptoms.
