How Is Primary Immunodeficiency Diagnosed? 8 Steps and Tests

Everyone gets sick sometimes. But when infections happen again and again, become severe, or don’t get better with usual treatments, they may be clues that the immune system needs a closer look.

Primary immunodeficiency (PI), also called inborn errors of immunity (IEI), may go unnoticed for years because its symptoms are often subtle, but medical tests can help connect the dots. This article discusses the tests commonly used to find out if someone has PI.

When To Suspect Primary Immunodeficiency

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. The first stage usually starts with a medical history and physical exam, along with basic blood tests.

A medical history and a physical exam are not lab tests, but they help guide which tests may be needed next. Later stages involve more specialized testing, with the goal of identifying a specific type of PI, ruling out other causes, and finding possible genetic causes.

Below are some of the most common steps and tests used to diagnose PI.

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:

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

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:

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

A CBC with differential gives more information about specific types of white blood cells. Lower-than-normal levels of different types of blood cells could indicate there’s a problem with the immune system. In fact, low white blood cell counts can be one of the first signs of PI.

For example, low levels of lymphocytes (a type of white blood cell) 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 white blood cells can provide clues regarding rarer types of PI.

4. Flow Cytometry

Flow cytometry is a lab test that helps doctors count and study 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 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. SCID screening has been a standard part of newborn screening in the U.S. since 2018.

Many babies with SCID and other types of PI will look healthy immediately after birth. 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.

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