How Is Primary Immunodeficiency Diagnosed? 8 Tests

Frequent and severe infections that don’t go away can be a sign of an underlying problem with the immune system. Primary immunodeficiency (PI) may go unnoticed for years because its symptoms are often subtle, but medical tests can provide valuable clues. This article discusses the tests commonly used to find out if someone has PI.

Thanks! You've successfully submitted your vote.

Sign up to view the results!

Continue with Facebook

Sign up with your email

By joining, you accept our Terms of Use, and acknowledge our collection, sharing, and use of your data in accordance with our Health Data and Privacy policies.

Already a Member? Log in

When To Suspect Primary Immunodeficiency

Healthcare providers may recommend specific testing if they notice warning signs of primary immunodeficiency. The signs may include infections that occur more often than usual, last longer than expected, or don’t respond to standard treatments.

The earlier PI is diagnosed, the better. Catching it early can reduce the risk of long-term complications and make treatment more effective. Unfortunately, PI is easy to miss. This is partly because the symptoms of PI can look like other common illnesses, especially in children. In adults, milder symptoms may not appear until later in life, making diagnosis even more difficult. On average, it takes over four years to get a PI diagnosis. For those with milder types of PI, it can take up to 10 years.

Recognizing possible warning signs of PI is the first step. Once a healthcare provider suspects PI, they’ll order a series of tests to help with the diagnosis. Your primary care provider may refer you to a specialized center where an immunologist (a doctor who specializes in diagnosing and treating disorders of the immune system) can make the diagnosis.

Healthcare providers often use four stages of testing for primary immunodeficiency. Each stage involves increasingly specialized testing, with the goal of pinpointing a specific type of PI, ruling out other causes, and identifying possible genetic causes for certain issues.

We’ll explore some of the most common diagnostic tests for PI below.

1. Medical History

Your medical history will help your healthcare provider understand the history of your symptoms and your risk factors. They’ll ask you about past illness, how often infections happen, and how they respond to treatment.

Another important factor your healthcare provider will ask about is your child’s vaccination history. If your child had an unusual reaction to a vaccine or still got sick from a vaccine-preventable illness, it could be a sign that their immune system isn’t working properly.

Your healthcare provider will also ask questions about your family history to look for patterns that may suggest PI. About 2 out of 3 infants and children diagnosed with PI have family members who also have PI.

2. Physical Exam

A physical exam can help your healthcare provider spot signs that the immune system isn’t working properly. They’ll check for signs of infection, such as:

• Fever
• Cough
• Shortness of breath
• Nasal congestion
• Mouth sores
• Swollen lymph nodes
• Diarrhea
• Pain

Healthcare providers will also assess weight gain and growth over time. Poor growth in children can be a sign of a chronic (ongoing) health problem, like PI.

3. Complete Blood Count

A complete blood count (CBC) is a blood test that gives your healthcare provider more information about your general health. It measures the levels of different blood cells, including:

• Red blood cells (RBCs) — Carry oxygen from your lungs to the rest of your body
• White blood cells (WBCs) — Help fight infections and support the immune system
• Hemoglobin — Carries oxygen in RBCs
• Platelets — Help your blood to clot

A CBC with differential gives more information about specific types of WBCs. Lower-than-normal levels of different types of blood cells could indicate there’s a problem with the immune system. In fact, low WBC counts can be one of the first signs of PI. For example, low levels of lymphocytes (a type of WBC) may suggest T-cell deficiency. In some cases, this can be caused by a life-threatening form of PI called severe combined immunodeficiency (SCID). Abnormal levels of other WBCs can provide clues regarding rarer types of PI.

4. Flow Cytometry

Flow cytometry is a lab test that helps doctors count and study special cells in your blood called lymphocytes, such as:

• B cells — Make proteins called antibodies that help destroy germs
• T cells — Find and kill cells that are infected with viruses or that might become cancerous
• Natural killer (NK) cells — Quickly attack infected or abnormal cells before other immune cells get involved

This test can help healthcare professionals distinguish between different types of PI. For example, people with X-linked agammaglobulinemia (XLA) may not have any B cells.

5. Immunoglobulin Blood Test

An immunoglobulin (Ig) blood test measures the amount of different types of antibodies (also known as immunoglobulins) in your blood. Antibodies are immune proteins that help fight infection.

Healthcare providers typically check the levels of four types of antibodies:

• IgG — This is the most common antibody. It protects you from infections by remembering germs you’ve had before or vaccines you’ve received.
• IgA — This is found in areas like your nose, mouth, lungs, and intestines. It helps guard against germs that enter through these parts of your body.
• IgM — This is the first antibody your body makes when you’re fighting a new infection.
• IgE — This helps protect against parasites and plays a role in allergic reactions.

Low levels of certain antibodies (called antibody deficiency) could mean there’s a problem with the immune system and more testing is necessary.

6. Antibody Response Tests

An antibody response test checks how well the immune system can make new antibodies. To perform this test, a healthcare provider will give a vaccine, such as a tetanus, diphtheria, or pneumococcal vaccine. They’ll check antibody levels right before and about four weeks after giving a vaccination. In a normal immune system, the vaccine should increase specific antibodies. A weak or missing antibody response to a vaccine can help doctors identify which part of the immune system isn’t working the way it should.

7. Newborn Screening

Newborn screening tests help to identify health conditions that can seriously affect a child’s health. In the U.S., nearly all babies go through newborn screening tests one to two days after birth. Primary immunodeficiency screening has been a standard part of newborn screening in the United States since 2018.

Many babies with SCID and other types of PI will look healthy immediately after birth. But newborn screening can help with early diagnosis so babies can get treatment before serious problems occur.

To test for SCID, a laboratory will measure levels of T-cell receptor excision circles (TRECs) in the baby’s blood. TRECs are small pieces of DNA (genetic material) that are cut out as the T cells develop.

A normal TREC level means it’s unlikely the baby has a health condition that affects their T cells. Low or missing TRECs suggest that the baby may have low T cells (called T-cell deficiency). If this is the case, more testing will be necessary. Flow cytometry can help count the number of T cells in the blood.

Between 40 percent and 50 percent of babies with an abnormal TREC result have T-cell deficiency. About 1 in 3 children with T-cell deficiency are diagnosed with SCID. Other types of PI that can cause T-cell deficiency include:

• Combined immunodeficiency (CID) — This is a less severe form of SCID. The immune system doesn’t work well, but it’s not completely missing like it is in SCID.
• DiGeorge syndrome — This is a condition a baby is born with that can affect the immune system, thymus gland, heart, and other parts of the body.
• Ataxia-telangiectasia — This is a rare condition that causes ataxia (problems with movement and balance) and telangiectasia (small red lines that appear on the skin or eyes). It also weakens the immune system.

8. Genetic Testing

Genetic tests identify changes or variants in a person’s DNA that may cause PI. DNA is made up of sequences that carry instructions for how the body’s cells and proteins should function. Changes in these sequences can alter how the immune system works and lead to PI.

Healthcare providers may use genetic testing to confirm a PI diagnosis based on symptoms and other test results. Genetic tests can also help provide a precise diagnosis of a specific type of PI when the diagnosis is unclear. People without symptoms of PI may get genetic testing if they have a high risk of developing PI.

It’s important to keep in mind that not all DNA changes cause disease. Additionally, some types of PI don’t have a known genetic cause. This means that some people may not be able to get a genetic diagnosis at this time. Genetic test results can also reveal unexpected information. Genetic counseling may help you understand the risks and benefits of genetic testing.

Talk With Others Who Understand

On myPIteam, people share their experiences with primary immunodeficiency disorders, get advice, and find support from others who understand.

Have you or someone in your family been diagnosed with a primary immunodeficiency? Let others know in the comments below.