Last updated:
04/04/2023
Years published: 2023
NORD gratefully acknowledges Jessica Oh, MD, Assistant Professor, Division of Allergy and Immunology, Montefiore Medical Center, for assistance in the preparation of this report.
Summary
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare, inherited condition that affects the way the immune system works. The most common symptoms of APDS are frequent upper respiratory tract infections, sinus infections, ear infections, bronchitis and pneumonia (lung infection). Most people with APDS get their first infection in early childhood, but symptoms can begin at any age. Other symptoms include gastrointestinal irritation, lymph node swelling, enlarged liver and spleen and an increased risk for lymphoma. Over time, frequent ear and respiratory tract infections can lead to permanent hearing loss and scarring of the lungs (bronchiectasis).
There are two types of APDS: APDS1 is due to changes in the PIK3CD gene and APDS2 is due to changes in the PIK3R1 gene. Both have similar symptoms and are inherited in an autosomal dominant pattern in families. Treatment for APDS is focused on managing symptoms, preventing infections and lowering inflammation. It includes antibiotics to treat infections, anti-inflammatory drugs, immunoglobulin replacement and hematopoietic stem-cell transplant (HSCT).
Introduction
APDS was first described in 2013 and is one of the primary immunodeficiencies. People with a primary immunodeficiency are born with an immune system that doesn’t work correctly and get frequent infections that can be hard to treat. There are hundreds of primary immunodeficiencies, many with similar signs and symptoms. Specialized testing is often necessary to tell the primary immunodeficiencies apart and make a specific diagnosis.
APDS affects each person differently. Some people have very mild symptoms, while others are much more severely impacted. Most people with APDS begin to have symptoms in childhood. However, symptoms can begin at any age, and some people do not develop symptoms until adulthood. There are some reports of people who have been diagnosed with APDS who do not have any symptoms.
The first signs of APDS are usually infections beginning in early childhood. The most common of these are ear infections, sinus infections and pneumonia. Over time, frequent respiratory tract infections can lead to scarring of the lungs (bronchiectasis). This is more common in APDS1 than APDS2. Viral infections are also common, especially infections with Epstein-Barr virus and herpes simplex viruses. These infections may be difficult to treat and may never completely go away.
People with APDS may develop enlarged lymph nodes, as well as an enlarged liver (hepatomegaly) or spleen (splenomegaly). Inflammation of the intestine can also occur, leading to severe diarrhea which sometimes results in hospitalization. Skin infections are also common.
Some people develop autoimmunity, causing the body’s immune system to attack its own healthy cells. Autoimmune disease can have an impact on many different organs and body systems. In APDS, the most common sign of autoimmune disease is a low level of red blood cells causing anemia, or fewer platelets leading to bleeding problems and easy bruising.
Growth delay, short stature and neurodevelopmental delay have also been seen in people with APDS. Shorter than average stature is more common in APDS2. People with APDS also have an increased risk of developing lymphoma and other blood cancers.
APDS is caused by pathogenic variants in either the PIK3CD gene (APDS1) or the PIK3R1 gene (APDS2). Both genes are important for the growth, survival and function of certain types of immune cells called T cells and B cells. These are specialized white blood cells that help fight infection. Pathogenic variants in these two genes affect how B cells and T cells grow and work. People with APDS often have B cells and T cells that are not functioning normally, leading to infections, inflammation of the intestine and autoimmune disease.
APDS1 and APDS2 are inherited in a dominant pattern in families. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause a particular disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
APDS has been diagnosed in people from around the world and does not seem to be more common in any one ethnic group. It affects males and females equally. The exact number of people with this condition is unknown.
APDS is diagnosed based on the symptoms, clinical examination, a detailed family history and laboratory testing to look for abnormalities in the levels and function of immune cells. Because APDS can look like other immunodeficiencies, genetic testing is necessary to make a specific diagnosis. Genetic testing for immunodeficiencies often involves using a gene panel. Gene panels test for pathogenic variants in a group of genes that are related to disorders that have similar symptoms. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.
Treatment for APDS is focused on managing the symptoms. APDS is treated using a combination of long-term immunoglobulin replacement therapy to help support the immune system and immunosuppressive medications to help with symptoms due to autoimmunity and inflammation. In addition, people with APDS often require daily antibiotics to help prevent infections before they happen.
Children with APDS may require ear tubes (tympanostomy tubes) due to frequent ear infections. Some may have their tonsils removed because of swelling and sinus infections. People with more severe APDS may eventually require respiratory support including extra oxygen and chest physiotherapy. In addition, physical, occupational and/or speech therapy may help with some of the long-term complications.
Hematopoietic stem cell transplant (HSCT) has been used to treat some people with APDS who do not respond to standard therapy. Hematopoietic stem cells develop in the bone marrow and have the potential to become any type of blood cell. In APDS, HSCT involves replacing the bone marrow with new stem cells that can become healthy, functioning immune cells. HSCT is used as a treatment for several primary immunodeficiencies as well as for certain types of blood cancers.
In 2023, leniolisib (Joenja) was approved by the U.S. Food and Drug Administration (FDA) to treat APDS in adults and children 12 years of age and older.
People with APDS may need to see a variety of specialists. These might include an immunologist, infectious disease doctor, pulmonologist, ear, nose, and throat specialist and gastroenterologist.
Genetic counseling is recommended for families with an affected child.
Therapies targeted at the specific genes affected in APDS (PI3Kδ inhibitors) and drugs known as mTOR inhibitors are being studied as treatments for APDS. mTOR inhibitors have been shown to help regulate the immune system and have been helpful in reducing swelling and inflammation symptoms in some patients with APDS.
Information on current clinical trials is posted on the Internet at: https://clinicaltrials.gov/ct2/results?cond=Activated+phosphoinositide+3-kinase+delta+syndrome.
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Yang X, Xi R, Bai J, Pan Y. Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: Case report and literature review. Medicine (Baltimore). 2023;102(5):e32816. doi:10.1097/MD.0000000000032816.
Fekrvand S, Delavari S, Chavoshzadeh Z, et al. The first Iranian cohort of pediatric patients with activated phosphoinositide 3-kinase-δ (PI3Kδ) syndrome (APDS). Immunol Invest. 2022;51(3):644-659. doi:10.1080/08820139.2020.1863982
Qiu L, Wang Y, Tang W, et al. Activated phosphoinositide 3-kinase δ syndrome: a large pediatric cohort from a single center in China. J Clin Immunol. 2022;42(4):837-850. doi:10.1007/s10875-022-01218-4
Redenbaugh V, Coulter T. Disorders related to PI3Kδ hyperactivation: characterizing the clinical and immunological features of activated PI3-kinase delta syndromes. Front Pediatr. 2021; 9:702872. Published 2021 Aug 5. doi:10.3389/fped.2021.702872
Thouenon R, Moreno-Corona N, Poggi L, Durandy A, Kracker S. Activated PI3kinase delta syndrome-a multifaceted disease. Front Pediatr. 2021; 9:652405. Published 2021 Jun 25. doi:10.3389/fped.2021.652405
Brodsky NN, Lucas CL. Infections in activated PI3K delta syndrome (APDS). Curr Opin Immunol. 2021; 72:146-157. doi: 10.1016/j.coi.2021.04.010
Oh J, Garabedian E, Fuleihan R, Cunningham-Rundles C. Clinical manifestations and outcomes of activated phosphoinositide 3-kinase δ syndrome from the USIDNET cohort. J Allergy Clin Immunol Pract. 2021;9(11):4095-4102. doi: 10.1016/j.jaip.2021.07.044
Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ ayndrome (APDS): a systematicrReview. Clin Rev Allergy Immunol. 2020;59(3):323-333. doi:10.1007/s12016-019-08738-9
Singh A, Joshi V, Jindal AK, Mathew B, Rawat A. An updated review on activated PI3 kinase delta syndrome (APDS). Genes Dis. 2019;7(1):67-74. Published 2019 Oct 14. doi: 10.1016/j.gendis.2019.09.015
Coulter TI, Cant AJ. The treatment of activated PI3Kδ syndrome. Front Immunol. 2018; 9:2043. Published 2018 Sep 7. doi:10.3389/fimmu.2018.02043
Maccari ME, Abolhassani H, Aghamohammadi A, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018; 9:543. Published 2018 Mar 16. doi:10.3389/fimmu.2018.00543
Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol. 2018; 9:369. Published 2018 Feb 27. doi:10.3389/fimmu.2018.00369
Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606.e4. doi: 10.1016/j.jaci.2016.06.021
INTERNET
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PASLI disease. Genetics and Rare Disease Information Center. Published: 02/2023. https://rarediseases.info.nih.gov/diseases/11983/pasli-disease Accessed March 7, 2023.
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PI3-Kinsase disease. National Institute for Allergies and Infectious Disease. Last updated: 04/11/2019. https://www.niaid.nih.gov/diseases-conditions/pi3-kinase-disease Accessed March 7, 2023.
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