OVERVIEW OF APDS

Information for Gastroenterologists

WHAT IS APDS?

Activated PI3K-delta syndrome (APDS) is a rare primary immunodeficiency (PID), which causes both immune deficiency and immune dysregulation.

First described in 2013,1 APDS was previously known as PASLI disease.2 It is estimated that APDS affects one to two people per million, including both adults and children.1

APDS is a progressive disease, which can cause irreversible organ damage and lymphoma leading to early mortality.3,4

Portrait of young man wearing glasses against a grey background. He is holding his ear and appears to be in pain.

The genetic basis of APDS

APDS is an inborn error of immunity (IEI) caused by variants in either one of two genes encoding phosphoinositide 3-kinase delta (PI3Kδ), which are vital for the development and function of immune cells.5 Children born to a parent with variants in either one of two genes encoding phosphoinositide 3-kinase delta (PI3Kδ) will have a 50% chance of inheriting APDS.6

While almost 40% of patients have a family history of IEIs,6 APDS can also present spontaneously with neither parent being a carrier of the genetic variants which cause the disease.7

Simple human figure infographics in different sizes – small, medium and large. The small and medium figures are coloured black, and the large figure is coloured white.
50% CHANCE AN AFFECTED PARENT WILL PASS AN APDS GENE ON TO THEIR CHILD.

APDS Clinical Manifestations

Clinical features can appear in childhood, from as early as one year old, and become progressively worse over time.3,6,8
Patients with APDS often experience a combination of recurring, progressive gastrointestinal complications related to enteropathy, such as bowel inflammation, chronic diarrhoea and colitis.2,6,9,10

As well as gastrointestinal signs and symptoms, it is important to look out for the wide range of other clinical manifestations associated with APDS, including:3,4,6

• Sinopulmonary infections, including pneumonia
• Lymphoproliferation
• Autoimmune disorders
• Recurrent herpes virus infections

 

Research has suggested that APDS leads to early mortality, due to an accumulation of complications caused by APDS.3,4,9,10 Benign lymphoproliferation can progress to malignancy in patients with APDS, with lymphomas being the most common form.3 It is estimated that there is a 78% cumulative risk for lymphoid malignancy at 40 years of age.3

Recognising clinical features which lead to an early diagnosis of APDS can help prevent long-term complications, irreversible organ damage and early mortality.9

Impact of APDS

As well as living with recurrent and progressive clinical features, patients with APDS often require regular medical intervention, surgeries, outpatient appointments and hospital admissions.3,4,8,11 Along with the physical manifestations, APDS can have a negative impact on mental health, with many patients experiencing stress, anxiety and depression.4,11-14 Furthermore, it takes an average of seven years to be diagnosed with APDS,6 which can exacerbate feelings of anxiety and depression.12

The physical and psychological impacts of APDS cause patients to regularly miss school, work or social activities.13,14

Four teenagers sitting down in a field at sunset, talking and laughing.

Diagnosing APDS

Patients with APDS typically have a variety of acute and chronic clinical features within multiple organ systems.4 However, not all patients with APDS experience the same clinical profile, even those within the same family.1 APDS is often incorrectly diagnosed due to its varied clinical presentation.6

The only definitive way to diagnose APDS is via a genetic test.15

Undiagnosed APDS frequently follows a pattern of multiple referrals, with some patients seeing several specialists over an average of seven years, before a diagnosis is confirmed.6 Timely and accurate diagnosis of APDS is crucial to help prevent long-term complications, irreversible organ damage and early mortality.1,9

Potential APDS patients should be referred to an immunologist for genetic testing.

A young female patient looking down and listening.
  1. Vanselow, S, et al. Front Immunol. 2023 ;14. Published online. Activated PI3Kδ syndrome – reviewing challenges in diagnosis and treatment.
  2. Rao KV, et al. Blood. 2017:130(21):2307-2316.
  3. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.e9.
  4. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.e4.
  5. Lougaris V, et al. Pediatr Allergy Immunol. 2022;33 Suppl 27:69-72.
  6. Jamee M, et al. Clin Rev Allergy Immunol. 2020;59(3):323-333.
  7. Deau MC, et al. [published correction appears in J Clin Invest. 2015 Apr;125(4):1764-5]. J Clin Invest. 2014;124(9):3923 -3928.
  8. Maccari ME, et al. Front Immunol. 2018;9:543.
  9. Redenbaugh V, Coulter T. Front Pediatr. 2021;9:702872.
  10. Angulo I, et al. Science. 2013;342(6160):866-871.
  11. Jiang F, et al. Allergy Asthma Clin Immunol. 2015;11:27
  12. Anderson JT, et al. Clin Immunol. 2022;236:108931.
  13. Rider NL, et al. J Clin Immunol. 2017;37(5):461-475.
  14. Kuburovic NB, et al. Patient Prefer Adherence. 2014;8:323-330.
  15. Chinn IK, et al. J Allergy Clin Immunol. 2020;145(1):46-69.