Activated PI3 kinase delta syndrome – Diagnostics – Overview of Information and Clinical Research

Activated PI3K delta syndrome (APDS) is a rare immune disorder that often begins in early childhood with frequent infections of the ears, sinuses, and lungs. Because its symptoms overlap with other immune conditions, diagnosis can take years, but genetic testing offers a definitive answer and opens the door to understanding this complex condition.

Introduction: Who Should Undergo Diagnostics

If you or your child experience frequent infections that keep coming back, especially in the ears, sinuses, or lungs, it might be time to consider more detailed testing. Activated PI3K delta syndrome, often called APDS, is a condition that affects the immune system, making it difficult for the body to fight off bacteria and viruses. The challenge is that APDS often looks like other immune problems, which means many people live with symptoms for years before getting the right diagnosis.^[1]

Doctors should consider testing for APDS when someone has a combination of symptoms that don’t quite fit together in the usual way. For example, a child who not only gets repeated respiratory infections but also has swollen lymph nodes, an enlarged spleen, or unusual growths in the airways or intestines might have APDS rather than a more common immune deficiency.^[2] Adults can also be diagnosed with APDS, sometimes after years of being treated for other conditions, because the severity of symptoms varies widely from person to person. Some individuals with APDS have severe, life-threatening infections, while others experience only mild symptoms or none at all.^[2]

It’s especially important to seek diagnostic testing if several unusual health problems appear together. These might include recurrent sinopulmonary infections (infections of the sinuses, ears, or lungs), viral infections that won’t go away (such as herpes viruses), digestive problems that resemble inflammatory bowel disease, or autoimmune conditions where the body attacks its own tissues.^[3] If a family member has already been diagnosed with APDS, other relatives should also be tested, even if they feel healthy, because the condition is inherited and family members may carry the genetic change without showing symptoms.^[1]

⚠️ Important

Distinguishing APDS from other primary immunodeficiencies can be difficult because many symptoms overlap. Before APDS was discovered in 2013, patients were often diagnosed with Common Variable Immunodeficiency (CVID) or another antibody deficiency. That’s why keeping detailed records of your symptoms and their frequency is crucial for helping your doctor make the correct diagnosis.

Children are often the first to show signs of APDS, typically before their first birthday, with ear infections, upper respiratory infections, or pneumonia that keep returning despite treatment.^[10] Over time, these repeated infections can damage the airways, leading to a condition called bronchiectasis, where the passages from the windpipe to the lungs become permanently widened and scarred.^[2] Recognizing the pattern early and seeking appropriate testing can help prevent this kind of long-term damage.

Diagnostic Methods: Identifying APDS and Distinguishing It From Other Conditions

The journey to an APDS diagnosis often begins with signs that something is wrong with the immune system, but pinpointing the exact problem requires several steps. Many people with APDS first undergo standard blood tests that check the levels of different types of antibodies, also called immunoglobulins. These proteins help the body recognize and fight infections. In APDS, doctors typically find low levels of certain antibodies (IgG, IgA, and IgE) and unusually high levels of another type called IgM.^[14]

When blood test results show these unusual antibody patterns alongside symptoms like repeated infections or swollen lymph nodes, doctors begin to suspect a primary immunodeficiency. However, these findings alone cannot confirm APDS because several other immune conditions produce similar results. This is where genetic testing becomes essential.^[1]

Genetic testing is the only way to definitively diagnose APDS.^[1] This test looks for specific changes, called variants or mutations, in two genes: PIK3CD and PIK3R1. These genes provide instructions for making parts of an enzyme called phosphatidylinositol 3-kinase delta, or PI3K delta for short. This enzyme plays a vital role in the development and function of immune cells, particularly B cells and T cells, which are types of white blood cells that fight infections.^[2]

There are two types of APDS, depending on which gene is affected. APDS type 1 (APDS1) is caused by changes in the PIK3CD gene, while APDS type 2 (APDS2) results from changes in the PIK3R1 gene.^[3] The genetic variants found in APDS are classified as “gain-of-function” changes, meaning they cause the PI3K delta enzyme to be overactive. This overactivity disrupts the normal development of B cells and T cells, making them less effective at fighting infections and causing them to die earlier than they should.^[2]

Before genetic testing became widely available, many patients with APDS were diagnosed with other conditions. The symptoms of APDS often resemble those of Common Variable Immunodeficiency (CVID), a more common antibody deficiency, which is why APDS was sometimes called “CVID-like” before it was properly understood.^[1] Making the correct diagnosis is crucial because it changes the course of treatment and can significantly improve outcomes for patients.

Once someone is diagnosed with APDS through genetic testing, it’s important for their family members to also be tested. APDS is an autosomal dominant condition, which means a child needs to inherit the genetic change from only one parent to develop the disorder.^[10] However, in some cases, the genetic change occurs spontaneously, meaning the person is the first in their family to have it—this is called a de novo variant.^[14] Even if family members don’t have symptoms, they may still carry the genetic variant and could pass it on to their children, so testing is recommended for relatives of confirmed patients.^[1]

Beyond blood tests and genetic testing, doctors may use other diagnostic tools to assess the extent of complications from APDS. For example, imaging tests such as CT scans can reveal damage to the lungs, including bronchiectasis or unusual growths called nodular lymphoid hyperplasia in the airways or digestive system.^[2] These growths are not cancerous, but they indicate that white blood cells are clumping together abnormally, which is a characteristic feature of APDS.

Laboratory tests may also show that a person with APDS has low numbers of white blood cells overall, a condition called lymphopenia. Specifically, they often have reduced numbers of B cells and T cells, which are critical for fighting infections.^[2] Additional specialized tests can measure how well these immune cells are functioning, providing more information about the severity of the immune deficiency.

Diagnostics for Clinical Trial Qualification

Clinical trials are research studies that test new treatments or ways of diagnosing diseases. For people with APDS, participating in a clinical trial can provide access to cutting-edge therapies that are not yet widely available. However, to join a clinical trial, patients must meet specific criteria, which usually include undergoing certain diagnostic tests to confirm their eligibility.^[1]

The most fundamental requirement for enrolling in an APDS clinical trial is confirmation of the diagnosis through genetic testing. Researchers need to know that participants truly have APDS, which means they must have a documented genetic variant in either the PIK3CD or PIK3R1 gene.^[3] This genetic confirmation ensures that the trial results are accurate and that the treatment being tested is appropriate for the condition.

In addition to genetic testing, clinical trials for APDS typically require baseline laboratory tests to assess the current state of the immune system. These tests might include measuring levels of different types of antibodies (immunoglobulins), counting the numbers of various white blood cells (including B cells, T cells, and other immune cell types), and evaluating how well these cells are functioning.^[13] This information helps researchers understand the severity of each participant’s condition and track how it changes during the trial.

Imaging studies, such as CT scans or ultrasounds, may also be required to document the presence and extent of complications like enlarged lymph nodes, an enlarged spleen, or lung damage. These baseline images provide a starting point for measuring whether a new treatment is effective in reducing these problems over time.^[13]

Some clinical trials focus specifically on patients with certain complications of APDS. For example, a trial testing a drug that targets lymphoproliferation (the abnormal growth and accumulation of immune cells) might only accept participants who have enlarged lymph nodes or an enlarged spleen at the time of enrollment.^[3] In these cases, additional diagnostic tests or measurements may be needed to confirm that the patient meets the specific entry criteria.

⚠️ Important

Age restrictions are common in clinical trials. Some trials, such as those for the targeted drug leniolisib, were initially open only to participants aged 12 and older. If you or your child are interested in participating in a clinical trial, check the specific eligibility criteria, as they can vary significantly between studies.

Age is another common criterion for clinical trial eligibility. Some trials are open only to children, others only to adults, and some accept participants across a wide age range. For instance, early trials of leniolisib, a drug that targets the overactive PI3K delta pathway in APDS, enrolled participants aged 12 and older.^[1] Knowing the age requirements beforehand can help families plan whether a trial might be a suitable option.

Clinical trials also assess a patient’s overall health to ensure they can safely participate. This might involve tests to check liver and kidney function, heart health, and the presence of any other medical conditions that could complicate the study or put the participant at risk. Researchers want to ensure that any changes observed during the trial are due to the treatment being tested, not to other health issues.

For individuals interested in exploring clinical trial options, resources are available to help identify studies that are currently recruiting participants. Organizations such as the Immune Deficiency Foundation maintain databases of ongoing trials for primary immunodeficiencies, including APDS.^[1] Discussing clinical trial participation with your doctor can help you understand whether this option is right for you and what diagnostic tests might be needed to determine eligibility.

Prognosis and Survival Rate

Prognosis

The outlook for people with Activated PI3K delta syndrome varies greatly from person to person, even among family members who share the same genetic change. Some individuals experience severe, life-threatening complications, while others have mild symptoms or remain healthy for many years without major problems.^[2] The unpredictable nature of APDS makes it challenging for doctors to forecast how the disease will progress in any given patient.^[6]

Several factors can influence the prognosis. Early diagnosis and appropriate treatment can help prevent some of the most serious complications, such as permanent lung damage from repeated infections or the development of blood cancers like lymphoma.^[3] Over time, repeated respiratory infections can lead to bronchiectasis, a condition where the airways become permanently damaged and widened, causing ongoing breathing problems. This is more likely to occur in people whose APDS goes undiagnosed or untreated for many years.^[2]

APDS also carries an increased risk of developing certain types of cancer, particularly B-cell lymphomas, including both Hodgkin lymphoma and non-Hodgkin lymphoma.^[2] The overactivity of the PI3K delta enzyme causes abnormal growth and accumulation of white blood cells, which can eventually lead to cancerous changes. Regular monitoring and early detection of lymphomas can improve treatment outcomes.

Autoimmune complications, where the body’s immune system mistakenly attacks its own tissues, can also affect prognosis. Some people with APDS develop autoimmune cytopenias (low blood cell counts due to the immune system destroying blood cells), gastrointestinal problems resembling Crohn’s disease, or other autoimmune conditions.^[3] These complications can add to the overall burden of the disease and may require additional treatments.

The introduction of targeted therapies, such as leniolisib, which directly addresses the overactive PI3K delta pathway, has offered new hope for improving outcomes and quality of life for people with APDS.^[3] For individuals with severe or treatment-resistant disease, hematopoietic stem cell transplantation (bone marrow transplant) remains an option that can potentially cure the condition, though it carries significant risks.^[3]

Survival rate

Specific survival statistics for APDS are not well established in the available medical literature, largely because the condition was only identified in 2013 and is considered very rare.^[2] The lack of long-term studies and the small number of diagnosed patients make it difficult to provide precise survival rates or life expectancy data.

What is known is that APDS can significantly impact both lifespan and quality of life, particularly when the condition goes unrecognized or untreated. Some families have experienced multiple members dying young due to complications from undiagnosed APDS. For example, one patient’s family history included relatives who died in their teens and others who died in their 30s and 40s before the genetic cause of their illness was understood.^[9] These cases highlight the serious potential of APDS when left unmanaged.

With earlier diagnosis, appropriate treatment, and close medical monitoring, many people with APDS can lead fuller, more active lives. The availability of immunoglobulin replacement therapy, prophylactic antibiotics, antiviral medications, and newer targeted treatments has improved the outlook considerably compared to the era before APDS was recognized as a distinct condition.^[3] However, the variability in disease severity means that prognosis must be assessed on an individual basis, and ongoing research is needed to better understand long-term outcomes.

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