What Is Primary Immunodeficiency?

Primary immunodeficiency (PI) is a group of more than 400 disorders that affect the immune system. In people with PI, the immune system is weakened or missing important components, making it harder for the body to fight off infection and certain diseases, including autoimmune diseases and cancers.

Treatments for PI boost the immune system and can help many people live healthy lives. Keep reading to find out what you need to know about primary immunodeficiency symptoms, causes, treatments, and outlook.

Unlike secondary immunodeficiencies, which are caused by other health issues (such as HIV or cancer treatments), primary immunodeficiency is present from birth and can result in frequent, severe, or unusually hard-to-cure infections.

There are many different types of primary immunodeficiency, categorized based on which part of the immune system is affected.

B-cell Deficiencies These affect the body’s ability to produce antibodies, the proteins that normally fight harmful bacteria, leading to increased risk of infections like pneumonia, sinus infections, and ear infections.

T-cell Deficiencies These affect the function of T cells, which are essential for fighting infections. People with T-cell deficiencies are more vulnerable to bacterial and fungal infections. Conditions include DiGeorge syndrome, also known as congenital thymic aplasia, and chronic mucocutaneous candidiasis.

Combined Immunodeficiencies A mix of B-cell and T-cell problems, these cause a higher risk of serious infections. Conditions include severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, immunodeficiency with ataxia-telangiectasia, and major histocompatibility complex deficiency.

Defective Phagocyte These affect white blood cells that help “eat” and destroy invaders, leading to frequent bacterial infections. Conditions include chronic granulomatous disease and leukocyte adhesion deficiency syndrome.

Often the first signs of primary immunodeficiency are having repeated, persistent, or unusual infections that are hard to treat. Other symptoms vary depending on the type of immune cells affected and may include:

• Certain types of infections: These may include ear infections, sinus infections, pneumonia, bronchitis, meningitis, skin infections, and thrush (a fungal infection of the mouth or skin, also called candidiasis).

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• Infections that don’t respond well to treatment: This includes infections that take a long time to get better, need multiple courses of antibiotics to overcome, or require hospitalization, or infections that come back after treatment is stopped.
• Enlarged spleen: Symptoms can include vague abdominal discomfort or pain in the left upper abdomen or left shoulder.

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• Sickness after a live vaccine: Live vaccines include the MMR and MMRV, chicken pox (varicella), bacille Calmette–Guérin (used to prevent tuberculosis), infant rotavirus, and oral polio virus.
• Failure to thrive in infants and children: This includes slower than expected growth and physical development.
• Chronic diarrhea or digestive issues: Some types of PI affect the gut, leading to ongoing digestive problems.
• Autoimmune conditions: Some types of PI can lead to the body mistakenly attacking its own cells, tissues, and organs and cause autoimmune conditions such as lupus, rheumatoid arthritis, or type 1 diabetes.

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Primary immunodeficiency is caused by genetic changes that affect one or many components of the immune system, including cells and proteins. The genetic changes can make the immune system less active than normal, defective, or totally absent.

Most, but not all, of these genetic changes are inherited. So although anyone can develop primary immunodeficiency, it’s more likely to happen in people with a biological family history.

Getting a diagnosis of primary immunodeficiency — especially for adults — can be difficult. People average 9 to 15 years from symptom onset to diagnosis, and experts believe that more than 70 percent of people with a PI are undiagnosed.

“A lot of times people just think having frequent infections is normal, and so they may not seek a diagnosis,” says John Ramey, MD, an immunologist at Roper St. Francis Healthcare in Charleston, South Carolina.

If you’re having the same type of infection over and over again, it may be an immune problem that makes you more susceptible, and you may want to talk with your doctor about a referral to an allergist or immunologist to get further testing, says Dr. Ramey.

Diagnosing primary immunodeficiency involves a combination of medical history, physical exams, and specialized blood tests to evaluate immune system function.

Diagnostic Procedures

Several tests help doctors confirm a diagnosis of primary immunodeficiency.

Blood Tests Blood tests can measure levels of immunoglobulins (infection-fighting proteins), as well as the levels of blood cells and immune system cells. People who have levels of certain blood cells that are outside the standard range may have PI.

Flow Cytometry This laser-based lab test can detect chemical physical differences of cells or particles and may also be used to check the number and types of immune cells. A blood, tissue, or bone marrow sample may be used.

Prenatal Testing Parents who have a child with primary immunodeficiency may choose to be tested for certain immunodeficiency disorders during future pregnancies. Samples of the amniotic fluid, blood cells, or cells from the tissue that will become the placenta are tested.

Treatments vary depending on the type of primary immunodeficiency. For most people, treatment involves managing infections and treating the underlying disease to prevent future infections.

Although there aren’t many disease-specific medications, there are newly approved treatments for two types of PI.

In some cases, people with PI also have another serious condition such as an autoimmune condition or cancer, which would require additional treatments.

Managing Infections

Preventing and treating infections is central to the treatment of PI.

Treating Infections Infections need rapid and aggressive treatment with antibiotics, antifungals, or antivirals, as appropriate, sometimes with a longer course (taking the medicine for more days or weeks) than is usually prescribed. Infections that don’t get better may require hospitalization and high-dose, IV treatment.

Treatments to Restore the Immune System

In some cases, the immune system can be essentially rebuilt or reconstituted with a stem cell transplant or via gene therapy.

Gene Therapy Although gene therapy has been approved by the U.S. Food and Drug Administration (FDA) for a few rare genetic diseases, it’s not yet approved for any type of PI. In the United States, it’s only available through enrollment in a clinical trial.

Drugs for Specific Types of PI

In recent years, two drugs have been approved for two ultra-rare forms of PI.

Certain lifestyle habits can reduce the chances of getting an infection or developing complications.

Avoid infections. It's especially important for people living with primary immunodeficiency to take precautions to avoid infections. These actions can help.

• Wash your hands frequently.
• Take good care of your teeth and see your dentist regularly for checkups.
• Practice good health habits, including getting the recommended amount of physical activity, eating a balanced diet with plenty of fruits and vegetables, and get enough sleep.
• Avoid crowds and close contact with people who are sick.

Ongoing Care

See your doctor regularly and seek treatment right away if you think you have an infection.

“We ask our patients with primary immunodeficiency to call us as soon as they feel like they're getting sick so we can get them on the appropriate treatment. Don’t wait a few days, because you’re likely to get sicker than normal patients,” says Ramey.

Genetic mutations cause most types of PI. Since primary immunodeficiency is usually inherited and present from birth, it’s not preventable.

With appropriate treatment, most people with primary immunodeficiency can lead relatively normal lives. The outlook depends on the type and severity of PI, but many people have fewer infections as they get older, especially with ongoing care.

It’s estimated that more than six million people worldwide, or 1 in 10,000 people, have a type of primary immunodeficiency, though the majority of cases go undiagnosed.

Primary immunodeficiency may increase the risk of developing other conditions later in life, including:

• Autoimmune Diseases People with PI may have a higher risk of developing autoimmune conditions such as lupus or rheumatoid arthritis.
• Cancer Some types of PI increase the risk of developing certain types of cancer, especially lymphoma.

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Life with primary immunodeficiency can be challenging. Frequent illnesses and hospitalizations can be demoralizing and isolating. Support groups can be helpful, as well as other social support options, such as social workers or therapists.

Organizations that provide support and information for people living with PI include:

Immune Deficiency Foundation (IDF)

This patient-focused organization supports people living with primary immunodeficiency through education, advocacy, and community.

Jeffrey Modell Foundation / Primary Immunodeficiency Resource Center

This foundation provides a range of tools and resources tailored for both patients and doctors. The site offers educational materials, awareness campaigns, and access to a global network of expert centers.

International Patient Organization for Primary Immunodeficiencies (IPOPI)

A global patient advocacy group, IPOPI empowers individuals and families living with primary immunodeficiencies. Their site includes educational resources, patient stories, and support tools tailored for a worldwide audience.

• Primary immunodeficiency (PI) is a group of more than 400 rare genetic disorders that weaken the immune system, making people more vulnerable to infections, autoimmune diseases, and certain cancers.
• Because symptoms can vary and mimic other conditions, PI often goes undiagnosed, sometimes for years.
• With timely diagnosis and ongoing care, most people with PI can live healthy, active lives.
• If you experience frequent or unusual infections that don’t respond well to treatment, talk to a healthcare provider about getting evaluated by an immunologist.