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APDS Symptoms & FAQ

When you know more about APDS, you can do more.

 

APDS, or activated PI3K delta syndrome, is a rare primary immunodeficiency that affects 1 to 2 people per million. It occurs when there are variations to the genes PIK3CD or PIK3R1.

While people with APDS may suffer from a wide variety of symptoms, the most common are frequent and severe infections of the ears, sinuses, and upper and lower respiratory tracts. Infections usually begin in infancy. People with APDS are susceptible to swollen lymph nodes or an enlarged spleen (splenomegaly), as well as autoimmunity and inflammatory symptoms.
People with APDS are at a higher risk for cancers like lymphoma, but most people with APDS do not develop cancer.

See the below diagram for more information about some typical APDS symptoms.

Typical APDS Symptoms

Common APDS Patient Symptoms

Most Common APDS Symptoms

People with APDS usually suffer from any two or more of the symptoms below.

Ear, Sinus, and Respiratory Tract Infections - Frequent and severe ear, sinus, and/or respiratory tract infections have been reported to effect 96-100% of patients with APDS. Furthermore, 59% - 85% of patients experienced at least one episode of pneumonia. These infections typically start in infancy or early childhood, and can progress to permanent lung or hearing damage.

 Ear, Sinus, and Respiratory Tract Infections

Frequent and severe ear, sinus, and/or respiratory tract infections have been reported to effect 96-100% of patients with APDS. Furthermore, 59% – 85% of patients experienced at least one episode of pneumonia. These infections typically start in infancy or early childhood, and can progress to permanent lung or hearing damage.

Chronic Cough or Difficulty Breathing - Up to 60% of patients with APDS have been reported to have permanent lung damage called bronchiectasis. This results in shortness of breath, coughing up phlegm (mucus) and chest pain. This has occurred more frequently in patients with variants in PIK3CD (called APDS1): 34-60% of patients with APDS1 have been reported to suffer this lung condition, while 13-27% of patients with variants in PIK3R1 (called APDS2) have. The bronchial tubes in your lungs need to be elastic so they can pump oxygen through your lungs. Bronchiectasis is a condition where these tubes widen and thicken. This makes them inelastic, and it becomes difficult to move oxygen through them. It also becomes easy for bacteria and mucus to accumulate in the widened spaces. The result is frequent infections, which along with overproduction of B and T cells in the airways can lead to permanent damage to the lungs.

Chronic Cough or Difficulty Breathing

Up to 60% of patients with APDS have been reported to have permanent lung damage called bronchiectasis. This results in shortness of breath, coughing up phlegm (mucus) and chest pain. This has occurred more frequently in patients with variants in PIK3CD (called APDS1): 34-60% of patients with APDS1 have been reported to suffer this lung condition, while 13-27% of patients with variants in PIK3R1 (called APDS2) have. The bronchial tubes in your lungs need to be elastic so they can pump oxygen through your lungs. Bronchiectasis is a condition where these tubes widen and thicken. This makes them inelastic, and it becomes difficult to move oxygen through them. It also becomes easy for bacteria and mucus to accumulate in the widened spaces. The result is frequent infections, which along with overproduction of B and T cells in the airways can lead to permanent damage to the lungs.

Enlarged Tonsils, Lymph Nodes, or Spleen - Immune cells can build up in certain areas of your body, making them appear enlarged or swollen. This "lymphoproliferation” has occurred in the tonsils, lymph nodes, spleen, and/or liver of 71-89% of people with APDS. Often times, people have undergone surgery to have their tonsils, adenoids, or spleen removed before they are diagnosed with APDS.

Enlarged Tonsils, Lymph Nodes, or Spleen

Immune cells can build up in certain areas of your body, making them appear enlarged or swollen. This “lymphoproliferation” has occurred in the tonsils, lymph nodes, spleen, and/or liver of 71-89% of people with APDS. Often times, people have undergone surgery to have their tonsils, adenoids, or spleen removed before they are diagnosed with APDS.

Nodules in the Airway or Digestive Tract - Overproduction of B and T cells have been shown to appear as nodules in the airway or digestive tract for 24-36% of people with APDS. In the airways, these nodules make it hard for the lungs to work as well as they should. When the nodules appear in the digestive tract, they can cause gastrointestinal issues like diarrhea, abdominal pain or cramping, blood in stool, or the inability to absorb nutrients from food.

Nodules in the Airway or Digestive Tract

Nodules in the Airway or Digestive Tract – Overproduction of B and T cells have been shown to appear as nodules in the airway or digestive tract for 24-36% of people with APDS. In the airways, these nodules make it hard for the lungs to work as well as they should. When the nodules appear in the digestive tract, they can cause gastrointestinal issues like diarrhea, abdominal pain or cramping, blood in stool, or the inability to absorb nutrients from food.

Herpes Infections - People with APDS are particularly vulnerable to frequent, severe, or persistent herpesvirus infections, which have affected 36-49% of people with the disease. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can cause mononucleosis and pneumonitis. CMV can also occur in the eye. Herpes simplex can appear as mouth or skin sores and eye infections. Varicella Zoster Virus (VZV) causes chicken pox or shingles. In some cases, EBV and CMV can be present in the blood. This is called "viremia." EBV has been shown to progress to lymphoma in 6% of people with APDS. Your provider may order antibody tests to determine if you have been exposed to or are currently fighting a herpes infection.

Herpes
Infections

People with APDS are particularly vulnerable to frequent, severe, or persistent herpesvirus infections, which have affected 36-49% of people with the disease. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can cause mononucleosis and pneumonitis. CMV can also occur in the eye. Herpes simplex can appear as mouth or skin sores and eye infections. Varicella Zoster Virus (VZV) causes chicken pox or shingles. In some cases, EBV and CMV can be present in the blood. This is called “viremia.” EBV has been shown to progress to lymphoma in 6% of people with APDS. Your provider may order antibody tests to determine if you have been exposed to or are currently fighting a herpes infection.

- 51% of people with APDS have been reported to experience digestive tract issues such as bowel inflammation or chronic diarrhea, typically starting around 5 years of age. Another common GI issue for people with APDS is called malabsorption. This means that the food you eat is not properly broken down in the small intestine. When this happens, the nutrients in the food are not absorbed and used, and the person is unable to gain weight, despite eating. This may also lead to fatigue.

Gastrointestinal (Digestive) Tract Issues

51% of people with APDS have been reported to experience digestive tract issues such as bowel inflammation or chronic diarrhea, typically starting around 5 years of age. Another common GI issue for people with APDS is called malabsorption. This means that the food you eat is not properly broken down in the small intestine. When this happens, the nutrients in the food are not absorbed and used, and the person is unable to gain weight, despite eating. This may also lead to fatigue.

Autoimmune and Autoinflammatory Disorders - In autoimmune and autoinflammatory diseases, the immune system mistakenly attacks the body, which has occurred in around 30% of people with APDS. This can affect nearly every organ system, and can result in conditions such as arthritis, diabetes, eczema, liver or kidney disease, and others. There is no one test to detect these different types of autoimmune and inflammatory disorders, but your provider may order a blood test called ANA that indicates general autoimmunity, and other antibody tests and imaging scans may also be ordered.

Autoimmune and Autoinflammatory Disorders

In autoimmune and autoinflammatory diseases, the immune system mistakenly attacks the body, which has occurred in around 30% of people with APDS. This can affect nearly every organ system, and can result in conditions such as arthritis, diabetes, eczema, liver or kidney disease, and others. There is no one test to detect these different types of autoimmune and inflammatory disorders, but your provider may order a blood test called ANA that indicates general autoimmunity, and other antibody tests and imaging scans may also be ordered.

Low Numbers of Blood Cells - Roughly 1/3 of people with APDS have reported having low numbers of blood cells, called cytopenias ("cyto" means cell; "penia" means deficiency). One type of cytopenia is anemia, which means low numbers of red blood cells. White blood cells (immune cells) and platelets can also be low in some types of cytopenia. These conditions usually have started later in childhood (around 10 years, on average) and can be detected in routine blood work. Cytopenias are usually a form of autoimmunity in APDS. This means immune cells are attacking these blood cells.

Low Numbers of
Blood Cells

Roughly 1/3 of people with APDS have reported having low numbers of blood cells, called cytopenias (“cyto” means cell; “penia” means deficiency). One type of cytopenia is anemia, which means low numbers of red blood cells. White blood cells (immune cells) and platelets can also be low in some types of cytopenia. These conditions usually have started later in childhood (around 10 years, on average) and can be detected in routine blood work. Cytopenias are usually a form of autoimmunity in APDS. This means immune cells are attacking these blood cells.

Developmental Delay - Speech delay or other neurological conditions have been reported to affect 10-31% of people with APDS. Struggling to gain weight or to grow has affected 45-62% of people with APDS2 (caused by variants in the PIK3R1 gene) in particular.

Developmental Delay

Speech delay or other neurological conditions have been reported to affect 10-31% of people with APDS. Struggling to gain weight or to grow has affected 45-62% of people with APDS2 (caused by variants in the PIK3R1 gene) in particular.

 

 

 

Lymphoma - Has been reported to develop in 12-25% of people with APDS. It tended to appear around 18-23 years of age, although it can occur even earlier, or not at all. In APDS, about 6% of lymphoma cases developed from chronic Epstein-Barr virus (EBV) infection. In other cases, lymphoma develop from prolonged dysregulation of the B and T cells; this means they grow out of control for a long time.

Lymphoma

Has been reported to develop in 12-25% of people with APDS. It tended to appear around 18-23 years of age, although it can occur even earlier, or not at all. In APDS, about 6% of lymphoma cases developed from chronic Epstein-Barr virus (EBV) infection. In other cases, lymphoma develop from prolonged dysregulation of the B and T cells; this means they grow out of control for a long time.

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Frequently Asked Questions about APDS

What is APDS?

APDS is a primary immunodeficiency where the B cells and T cells of the immune system don’t work properly. This leads to two major types of symptoms. The first one is immune deficiency. Normally, B and T cells recognize and attack viruses and bacteria to stop infections. In APDS, B and T cells are often not fully formed or healthy, and they are unable to fight infections.

APDS also causes an overproduction, or proliferation, of B and T cells. This seems like the immune system would fight infections even better, but these cells do not form correctly. Instead of fighting, they accumulate in lymph nodes and organs throughout the body; this is called lymphoproliferation.

Many of the symptoms of APDS are caused by these B and T cells not being able to function properly. Symptoms include infections, chronic cough, difficulty breathing, swollen lymph nodes, an enlarged spleen or liver, digestive tract issues, low numbers of blood cells, and conditions where the immune system mistakenly attacks the body such as arthritis or eczema, and even cancer of the immune system.

How many people around the world suffer from APDS?

 APDS has been reported to affect approximately 1 – 2 people per million and is considered a rare disease.

How do people get APDS?

APDS is a genetic condition and it occurs when there is a variation in either one of two specific genes, PIK3CD or PIK3R1. The genes are inherited, which means that it is something that you are born with and other family members may also have the same genetic condition. Even in families with the same condition, the symptoms of APDS can vary. 

When do people start to suffer from the symptoms of APDS?

The symptoms of APDS start very early in life. Keep in mind that the ages below are midpoint values that have been reported and that some people may experience symptoms earlier or later than described, or not at all.

  • Frequent and severe infections of the ears, sinuses, and airways can begin earlier than 1 year of age.
  • Swollen lymph nodes or an enlarged spleen or liver can start occurring around 3 years of age.
  • Digestive issues such as diarrhea, bloody stool, or abdominal pain or cramps are often seen around 5 years of age.
  • Low numbers of blood cells or other conditions when the immune system mistakenly attacks the body often begin around 10 and a half years of age.
  • Permanent lung damage, resulting in scarring of the airways and difficulty breathing, happens on average around 11-13 years of age.
  • Lymphoma, if it develops, tends to appear at 18-23 years of age, but has been seen earlier.
How do I know if I have APDS?

Based on your symptoms, your doctor may suspect a variety of diseases, including other primary immunodeficiency diseases such as Common Variable Immune Deficiency (CVID) or Hyper IgM syndrome, or blood cell diseases such as Autoimmune Lymphoproliferative Syndrome (ALPS). In fact, people with APDS may frequently be misdiagnosed with these other conditions.

Because APDS can appear in various ways, it can be a challenging diagnosis for many healthcare providers to make.

Your healthcare provider may run blood work based on your symptoms. However, a diagnosis of APDS can only be confirmed with genetic testing. If you have any 2 or more of the symptoms described above, you could qualify for no charge genetic testing. You can speak to your healthcare provider about the navigateAPDS program.

What is it like to live with APDS?

APDS may affect your life a little or a lot, depending on how severe your symptoms are and how they are managed.

Physically, the symptoms of APDS may cause difficulty breathing, coughing or wheezing, and chest or joint pain, which may make it difficult to exercise. It can also contribute to feeling tired all the time. Frequent ear infections may also eventually cause hearing loss.

Infections, diarrhea, and other symptoms may lead to frequent hospitalizations. People with APDS may also undergo multiple surgeries to treat their swollen tonsils, lymph nodes, or spleen before they are accurately diagnosed. Other treatments used to manage your symptoms may be invasive or time-consuming. Frequent visits to many different doctors can also take up a lot of time.

Between the symptoms and doctor’s visits, people with APDS may miss a good deal of school, work, or other daily activities. Sometimes their friends or family members may not understand why they’re sick all the time. This can cause anxiety, depression, and stress, all of which can take a large toll on a person’s mental health.

It’s important to know that you’re not alone. Patient advocacy groups can offer support and community, ultimately helping you feel more in control of your disease. Mental health professionals are also a great resource for helping you cope if you feel like you’re struggling.

How do I find the right doctor?

People with APDS can suffer from a variety of symptoms and may need to be treated by a number of different doctors. Finding the right doctor as early as possible is important. Qualified immunologists may be able to assist in diagnosis and coordination of care. The following organizations can help in locating hospitals and healthcare professionals that specialize in this area.

Jeffrey Modell Foundation

Immune Deficiency Foundation

Further contact information for related patient advocacy organizations and groups is available in our resources section.

Difficulties in APDS Diagnosis

“Typically, a person with APDS will present to a hospital within the first 5 years of life with a predominant and recurring respiratory tract infection. They can also present with swollen lymph nodes. Unfortunately, these general patient symptoms often result in medical professionals pre-diagnosing a range of autoimmune disorders before a Primary Immunodeficiency (PI) diagnosis is considered.

Even if a PI classification is given, a patient can be misdiagnosed with Common Variable Immune Deficiency (CVID) and Hyper IgM. This leads to APDS patients being cared for by a variety of physicians, and managed by treatments that don’t address the underlying genetic defect.”

Nicholas Hartog, MD, is a board-certified pediatric and adult allergy and immunology physician.