Learn about the ABC’s of APDS, An Underdiagnosed And Progressive Primary Immunodeficiency

By Eveline Wu, MD, MSCR

Until 2013, no one knew what caused the life-altering symptoms of activated PI3K delta syndrome, also known as APDS. But that year, researchers characterized the rare primary immunodeficiency,¹ and just a decade later, in 2023, a targeted treatment has been approved to help address the underlying defect of APDS.

For physicians, these rapid-succession discoveries highlight the importance of recognizing the disease and confirming its diagnosis with genetic testing. Only through careful attention to these details can we systematically identify patients with APDS and improve our ability to treat them.

Doctors practicing in several clinical specialties can encounter APDS. Due to its wide-ranging symptoms, patients typically consult primary care providers, otolaryngologists, pulmonologists, hematologists/oncologists, gastroenterologists, rheumatologists, and allergists/immunologists.²

To help ensure that no diagnoses are missed, doctors in each of these specialties must know the ABCs of APDS.

Understanding APDS
One of nearly 500 inborn errors of immunity, APDS is driven by variants in either the PIK3CD or PIK3R1 genes, leaving patients susceptible to chronic infections and/or autoimmune responses — most from an early age.³

An autosomal dominant disorder, APDS has a 50% likelihood of being passed to a child if either parent carries one of its driver variants. Inheritance accounts for most cases of APDS, whereas about 20% arise from de novo, or spontaneous, variants.³

Beyond that, there are no known associations defining who is most likely to develop the disorder, which is estimated to affect just 1 to 2 people per million.

A Constellation of Symptoms
In the clinic, APDS can be perplexing due to its array of symptoms, which mimic the manifestations of other immunodeficiencies, autoimmune conditions, or cancers. Moreover, APDS tends to present differently from patient to patient — even among relatives who share an inherited genetic variant.³

That’s why doctors need to be aware of all the ways the disease can manifest. These include:^2,3-10

• Recurrent and sometimes severe infections involving the nose, sinuses, ears, and lungs;
• Frequent and often severe infections with viruses such as herpes simplex, Epstein-Barr, and cytomegalovirus;
• Enlargement of the lymph nodes, spleen, and/or liver;
• Autoimmune conditions, particularly cytopenias that lower blood cell counts;
• Enteropathy, or chronic inflammation of the gastrointestinal tract, which can result in recurrent diarrhea;
• And earlier than expected malignancies with hematologic cancers such as lymphoma.

These symptoms can shorten the life spans of patients due to recurrent episodes of pneumonia that cause permanent lung damage, increased infection risk following treatment with immune-suppressing medications, or the complications of cancer.

Not surprisingly, these symptoms can substantially decrease quality of life for patients and their families. Frequent doctor’s visits, as well as recurrent illnesses and hospital stays, tend to result in missed days of school and work. And it’s not unusual for patients and others in their households to opt out of social activities to avoid exposure to infection.^11-13

Anxiety can take a toll, as well, affecting patients both before and after diagnosis.¹¹

Diagnosis is No Longer Elusive
For many patients, that anxiety is aggravated by long searches for answers about their health. A retrospective review of 243 APDS-diagnosed patients⁷ has shown that it has taken an average of 7 years for someone with APDS to receive an accurate diagnosis. That bears out in the real world; I’ve encountered patients at either end of the spectrum, including one diagnosed at 2 years old and another at 20 years old, despite having had symptoms since infancy.

Today, we have gained helpful knowledge to avoid these frustrating and potentially dangerous delays.

Doctors who suspect a primary immunodeficiency typically take a detailed family history and conduct blood tests to identify changes in B and T cells — an excellent start. But now that APDS has been characterized, there’s only one way to make a definitive diagnosis: genetic testing.

Without it, cases of APDS may be misdiagnosed. For instance, a doctor who suspects common variable immune deficiency might be inclined to skip genetic testing altogether, while a physician who suspects hyper IgM syndrome might choose a genetic panel specific to that condition.

A better option is to order a panel that can detect a broad array of immunodeficiencies — including APDS. It’s important to offer such assays not only to new patients but to those tested years ago before the APDS variants were identified.

Physicians can easily order these panels, as they are available to eligible patients in the U.S. and Canada at no charge through the navigateAPDS program, along with pre-and post-test genetic counseling. Doctors can choose either the Invitae Primary Immunodeficiency Panel or the Inborn Errors of Immunity and Cytopenias Panel, and if patients are found to have an APDS pathogenic variant, their family members can receive testing through the program, too.

Managing APDS
By confirming APDS diagnoses, genetic testing opens the door to improved disease management — starting with heightened lymphoma surveillance.

It also introduces the possibility of a treatment designed to correct the underlying immune defect that causes APDS.

A recently approved medication is changing the standard of care because it targets the driving mechanism of APDS, rather than symptoms of the disease. Previously, the only therapy capable of accomplishing that was hematopoietic stem cell transplantation, an invasive strategy that U.S. doctors rarely use in this setting.¹⁴

Patients with APDS are also treated with therapies that are not indicated for the disease and do not target its underlying cause. These include: ¹⁴

• Antimicrobial therapies to prevent and treat infections, such as antibiotics, antivirals, and antifungals;
• Immunoglobulin replacement therapy to replenish antibodies with the goal of preventing infections;
• Medications that modulate or suppress the immune system to treat autoimmune responses, such as steroids or B-cell inhibitors; and
• mTOR inhibitors to control lymphoproliferation.

I’m excited that we now have an FDA-approved treatment for APDS. With that in mind, I encourage patients and my fellow physicians who might encounter these immune-related symptoms to go and learn more about APDS, in part by connecting with the specialists who treat it.

Your vigilant attention to the signs and symptoms of this progressive disease may shorten the journey to an APDS diagnosis and enable focused disease management.

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Eveline Wu, MD, MSCR, is an Associate Professor of Pediatrics the University of North Carolina at Chapel Hill. She is the Division Chief of Pediatric Rheumatology and Director of the Clinic Immunology Program for Pediatric Allergy and Immunology. She is also actively engaged in clinical and translational research projects focused on autoimmune disease and immunodeficiencies. Dr. Wu has received consulting fees from Pharming Healthcare, Inc and Enzyvant Therapeutics, Inc.

References:

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