An overview of etiological factors, clinical presentation and disease management of activated PI3K delta syndrome (APDS)
What are PIs?
Primary immunodeficiencies (PI) are an expanding group of rare genetic disorders with many different clinical manifestations. In 2020, over 400 genetic disorders were recognised.1 It is predicted that the number will increase as science and technology advances. Onset of symptoms of a genetic disorder can appear at any age, although most start at infancy. The hallmark symptoms of immunodeficiencies are routine and severe infections, and autoimmune and autoinflammatory complications.2
Activated PI3K delta syndrome (APDS) is a recently identified primary immunodeficiency first fully described in 2013.3 It is characterised as a primary immune regulatory disorder (PIRD). It is a combined immunodeficiency, meaning both B and T cells are affected, and is caused by variants (changes) in one of two genes.4 Its estimated prevalence worldwide is 1–2 per million as of 2013. For perspective, this means within the US population, based on early estimations (without a unique ICD-10-CM diagnosis code), that ~400-600 individuals may have been diagnosed with APDS. However, as genetic testing becomes more accessible for patients and patients are able to be re-tested (ie, PI panels did not start screening for APDS until ~2017), more patients are anticipated to be identified.
What are B and T cells?
B cell and T cell lymphocytes work together to identify and fight foreign substances called antigens. B and T cells are the primary agents responsible for adaptive immunity. When B and T cell development and replication does not regulate as it should, it can result in a compromised immune system.
APDS is a complex deficiency caused by either one of two identified genes.
APDS is caused by either a variation causing gain-of-function in the PIK3CD gene that encodes PI3Kδ catalytic subunit p110δ (APDS1) or by a variation causing loss-of-function in the PIK3R1 gene that encodes regulatory subunit p85α (APDS2). The ultimate problem, regardless of which genetic variation someone has (APDS1 or APDS2), is the result of hyperactivity of the PI3Kδ pathway.5
APDS can be misdiagnosed as common variable immunodeficiency (CVID) due to its similar clinical presentation.
CVID is an immune system disorder that causes low levels of proteins that help fight infection. Clinically, APDS resembles CVID although less than 10 per cent6 of people with CVID have symptoms in childhood. However, APDS also presents clinical features of cellular immunodeficiency and autoimmunity, making APDS a combined immunodeficiency.5 Having an accurate diagnosis will help to inform physicians as to the right clinical assessments to undertake. For example a person with APDS is at higher risk of developing lymphoma complications.
APDS often evolves over time and presents in multiple clinical manifestations.
The age of diagnosis of APDS varies: the median is 12 years old, with a median diagnostic delay of 7 years.7,8,9 Children may miss developmental milestones with neurodevelopmental delays possible from an early age. Lymphoproliferation (where cells of the lymphatic system grow excessively) can cause a range of symptoms. Abnormal swelling of the lymph nodes may appear. Gastrointestinal symptoms can occur, which can affect an individual’s ability to absorb nutrients, leading to a low body weight and failure to thrive. Splenomegaly (a condition that occurs when your spleen becomes enlarged) is also common in APDS individuals. This is because the spleen is part of the lymphatic system. Autoimmunity usually presents at a median age of 10.5, and bronchiectasis at 11.2, however they may be seen at any age.7,8,9 96–100%10 of people with APDS will present recurrent sinopulmonary infections. These are infections affecting the sinuses, ears and lungs. Malignancy (most commonly lymphoma) can occur from APDS, particularly once individuals with APDS reach late adolescence.
In recognition of the complexity of PIs and the number of years to diagnosis the Jeffrey Modell Foundation has created a list of the 10 warning signs of a primary immunodeficiency that merit a referral to an immunologist: https://bit.ly/310C88J
APDS could be present in multiple family members, as it has an autosomal dominant inheritance pattern.
If an individual receives an APDS diagnosis, genetic testing of the biological mother and father is important due to the autosomal dominant inheritance pattern. An autosomal dominant inheritance pattern means that a single altered gene (variation) in each cell of an individual is disease causing resulting in a 50/50 chance of a child inheriting the condition.
It is possible to be the first person to have APDS in a family. This is called a de novo variant. There is no published data on how common this is, but it is hoped that, through more genetic testing of individuals with APDS, more can be discovered in this area.
Clinical presentation and severity of the disorder can vary greatly among family members. If a person diagnosed with APDS has mild symptoms, this does not necessarily mean their child (if they inherit the gene variation) would have a mild case or even the same symptoms.
APDS causes both immune deficiency and immune dysregulation. The immune deficiency causes frequent infections. The immune dysregulation causes autoimmune complications.
There are several different supportive therapies used to manage the clinical symptoms of APDS; however, none of them are targeted therapies designed to treat the root cause of the condition.
For the immune deficiency, antibiotics, antivirals, and antifungals are used to treat infections’ and a treatment called immunoglobulin replacement therapy (IRT) is used to boost low antibody levels in the body.11
For the immune dysregulation, many individuals will be given steroids. Long-term use of steroids for individuals with APDS may cause unwanted side effects. Other immunosuppressants are also common, as are a class of drugs called mTOR inhibitors. The use of these mTOR inhibitors may require continuous therapeutic drug monitoring.
Individuals with very severe cases of APDS may need a haematopoietic stem cell transplant (HSCT). HSCT is used to ‘reset’ the immune system. It uses chemotherapy to remove harmful immune cells and rebuilds the immune system using haematopoietic stem cells found in blood or bone marrow from a donor.12 This treatment method may be curative for some people but it is not effective for all people with APDS and does not correct non-immune manifestations such as kidney disease. It is also high-risk with the potential of serious complications. Medical professionals will carefully assess the long term risks for individuals based on family history, recent clinical presentation, current immunophenotype and availability of a matched donor when considering this treatment.
In this spotlight on APDS we hope to shine a light on the impact of this rare disease on individuals and families, the challenges for health care professionals in care management and with active research efforts ongoing, the hopes of the community for the future.
For more information on current research activities and clinical trials visit www.clinicaltrials.gov
Activated PI3K delta syndrome (APDS) is a primary immunodeficiency (PI). It may also be referred to as a primary immunodeficiency disorder (PID), primary immune regulatory disorder (PIRD), an inborn error of immunity (IEI) and was previously known as PASLI disease.
References:
[1] Bousfiha A, et al. J Clin Immunol. 2020;40(1):66-81.
[2] McCusker C, Warrington R. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1.
[3] Michalovich D, et al. Front Immunol. 2018;9:369. 10.3389/fimmu.2018.00369.
[4] Deau MC, et al. J Clin Invest. 2014;124(9):3923-3928.
[5] Singh A, et al. Genes Dis. 2019;7(1):67-74.
[6] Microsoft Word – FINALCVID.docx (mft.nhs.uk)
[7] Jamee M, et al. Clin Rev Allergy Immunol. 2020;59(3):323-333.
[8] Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.e9.
[9] Maccari ME, et al. Front Immunol. 2018;9:543.
[10] Carpier JM,Lucas CL, Front Immunol. 2018;8:2015
[11] Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.
[12] All about hematopoietic stem cell transplantation. Medical News Today website. https://www.medicalnewstoday.com/articles/318091. Accessed October 26th, 2021.
