First step in managing activated PI3K delta syndrome is recognizing it

Key takeaways:

• Activated PI3K delta syndrome symptoms can be progressive, leading to end-organ damage.
• APDS is caused by genetic variants in PIK3CD or PIK3R1.
• Symptoms progress along a timeline that begins in childhood.

Every day, doctors across various specialties diagnose cases of inflammatory arthritis, enteropathy, hyperinsulinemic hypoglycemia, nodular lymphoid hyperplasia, autoimmune cytopenia and lymphoma.

Most do not stop to consider that these seemingly unrelated conditions could be part of a larger syndrome. Yet, any of these illnesses could be symptoms of the rare primary immunodeficiency activated PI3K delta syndrome (APDS), especially if they manifest alongside recurrent sinopulmonary or herpesvirus infection or enlarged lymph nodes, liver or spleen.

Overlooking APDS can be dangerous or even deadly for patients, as its symptoms tend to be progressive, leading to end-organ damage. Identifying the disease enables doctors to monitor patients and their families for the development of symptoms and, as necessary, administer appropriate therapeutic regimens.

Nicholas Hartog

So, while the disease is quite rare, it is important for doctors across every specialty to keep it in mind when they see patients with unusual combinations of symptoms.

By working together to recognize and manage this often-hidden disease, clinicians can shorten the diagnostic journey for patients, helping them avert progressive illness and improving their quality of life.

Recognizing APDS

First characterized in 2013, APDS is caused by genetic variants in either of two genes: PIK3CD or PIK3R1. These variations cause an overactive PI3K pathway, interfering with the development and function of immune cells and resulting in frequent infections.

Jolan Walter

As an autosomal dominant condition, APDS can be inherited from just one affected parent, whereas other cases develop due to a de novo gene change.

Symptoms often arise early in infancy, but that pattern can vary widely from patient to patient, even among relatives who share an inherited APDS variant.

In general, symptoms progress along a timeline that begins in childhood:

• Sinopulmonary infections are seen in 96% to 100% of cases. They often can be severe, and they tend to develop when patients are aged younger than 1 year. They can include upper respiratory tract infections, sinusitis, pneumonia, bronchitis and otitis media. Viral infections such as Epstein-Barr virus and cytomegalovirus may also crop up, as well as allergy and asthma.
• Lymphoproliferation, which can include enlarged lymph nodes, spleen and/or liver, begins at a median age of 3 years and can lead to malignancy. In the respiratory and gastrointestinal tracts, it can take the form of mucosal nodular lymphoid hyperplasia, potentially leading to enteropathy. Lymphoproliferation is present in 71% to 89% of cases.
• Bronchiectasis, seen in 51% of cases, is the permanent result of lymphadenopathy and hyperplasia, and it can develop around age 11 years.
• Enteropathy is seen in 51% of cases and tends to manifest around age 5 years, often in connection with height and weight deficiencies.
• Recurrent herpesvirus infections are seen in 36% to 49% of cases and may manifest as both acute and chronic viral reactivations.
• Autoimmune and autoinflammatory disorders can appear at a median of age 10 years, including autoimmune thyroidosis, arthritis, glomerulonephritis, sclerosing cholangitis, cirrhosis, diabetes, autoimmune hepatitis and/or eczema. These disorders are observed in 17% to 42% of cases.
• Autoimmune cytopenias such as anemia, thrombocytopenia and neutropenia may be seen in as many as 30% of cases.
• Neurodevelopmental delay and neuropsychiatric disorders are seen in 10% to 31% of patients with APDS, starting from early childhood.
• Lymphoma arises at a median age of 18 to 23 years in 12% to 25% of patients with APDS. While lymphoma is a leading killer in this population, leukemias and solid-organ cancers can also occur.

Making a differential diagnosis

The goal of clinicians in supporting these patients should be to first .

Because these individuals are likely to visit a host of specialists, all clinicians should understand that any patient with two or more of the symptoms on the APDS checklist may have the disease. These patients are excellent candidates for genetic testing, which can definitively distinguish between APDS and other primary immunodeficiencies, such as common variable immune deficiency (CVID), hyper IgM syndrome, or autoimmune lymphoproliferative syndrome.

In some cases, no-cost testing of patients and their blood relatives may be available through nonprofit patient advocacy organizations or programs sponsored by pharmaceutical companies.

Doctors who are not well-versed in genetic testing should not give up. Rather, they should refer their patients to allergists/immunologists or geneticists/genetic counselors at academic centers.

Often, genetic testing will return an actionable result. But if findings are inconclusive, physicians can follow the testing with a clinical investigation that can start with bloodwork and flow cytometry.

APDS may be suspected if B- and T-cell dysfunction are indicated via results such as low to normal concentrations of immunoglobulin G and immunoglobulin A; a normal or elevated concentration of immunoglobulin M; a reversed CD4/CD8 ratio; decreased naïve CD4+ and CD8+ T cells; increased follicular T helper cells; increased transitional B cells; and/or reduced CD19+ B cells.

A definitive diagnosis is essential because it can help define a treatment plan.

Organizing an effort

Not surprisingly, the symptoms of APDS can enormously reduce quality of life. In addition to living with discomfort and fatigue, patients often limit their social interactions to avoid infection. Many spend a lot of time sick either at home or in the hospital, missing days of school or work, and this can lead to anxiety or depression.

Fortunately, since APDS was first characterized, we have enhanced our knowledge about its natural history and learned how patients can benefit from a variety of therapies. While just a handful of patients were initially identified, the literature now describes around 200, enabling researchers to study their symptom patterns and treatment responses.

With that momentum underway, this is the perfect time for clinicians to get familiar with the basics of APDS. Through a concerted multidisciplinary effort, we can not only change patients’ lives, but we can also contribute to a deeper understanding of this complex disease.

References:

For more information:

Nicholas Hartog, MD, is a board-certified physician specializing in pediatric and adult allergy and immunology and head of the pediatric and adult immunodeficiency clinic at Helen DeVos Children’s Hospital and Corewell Health in Michigan. He is head of their pediatric and adult immunodeficiency clinic. He can be reached at allergy@healio.com.

Jolan Walter, MD, PhD, is an international expert in primary immunodeficiencies and immune dysregulation who serves as division chief of the pediatric allergy and immunology programs at University of South Florida Health and Johns Hopkins All Children’s Hospital. She can be reached at allergy@healio.com.