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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 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
Clinical features can appear in childhood, from as early as one year old, and become progressively worse over time.3,6,8
Children often experience recurring, progressive clinical features of APDS from as early as one year, including one or more of the following:6,8,9
• Sinopulmonary infections, including pneumonia
• Lymphoproliferation
• Herpes virus infections
• Failure to thrive
• Neurodevelopmental delay
• Chronic diarrhoea
As the disease progresses, adults with APDS typically suffer from a combination of clinical features affecting multiple organs:3,4,6
• Bronchiectasis
• Asthma
• Lymphoproliferation
• Enteropathy
• Autoimmune disorders
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
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
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
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