Primary vs. secondary immunodeficiency: What's the difference?

This article was first published in the Fall 2026 edition of the ADVOCATE newsletter.

Our immune system defends the body against infection from germs—but sometimes that system breaks down. Immunodeficiency happens when parts of the immune system are missing or don’t work properly. Immunodeficiency, no matter the cause, makes a person more vulnerable to infections and cancers, and more likely to experience rogue immune responses like attacks on healthy cells, uncontrolled inflammation, and allergies.

Immunodeficiencies fall into two major categories—primary immunodeficiency (PI) and secondary immunodeficiency (SI). Although both types can produce similar symptoms and sometimes require similar treatment, they differ in their causes, diagnosis, and management.

Genetic changes, or variants, that affect the development or function of the immune system cause PI. PIs are present at birth, although symptoms may not appear until later in childhood or even adulthood. These conditions may also be referred to as inborn errors of immunity (IEI). There are more than 550 different PIs that affect different parts of the immune system. The most common PIs affect B cells, which produce antibodies. A chronic health condition, PI is rare and often underdiagnosed. 

Unlike PI, SI develops when a person’s immune system is disrupted by external factors, not genetic variants in genes important for immune responses. SI is far more common than PI and may be temporary, reversible, or permanent. Factors that can cause SI include infections like measles or human immunodeficiency virus (HIV), medications or medical treatments, cancer, malnutrition, and chronic diseases like type II diabetes.

Chemotherapy, radiation, and medications ranging from corticosteroids to certain biologics can all interfere with immune function. While most medications are made using chemical processes, biologics are made using cells, tissues, and proteins from living organisms. 

Biologics and other immune suppressing medications have experienced a sharp increase in availability and use. As certain treatments become more widely used, medication-induced immunodeficiency has become one of the fastest-growing types of SI.

For example, more doctors are using CAR T-cell therapy to treat specific types of blood cancer. First approved by the U.S. Food and Drug Administration (FDA) in 2017, the treatment works by engineering a person’s T cells to find and destroy a specific type of white blood cell. For a B cell lymphoma, for example, the CAR-T cells target and eliminate all B cells—whether they are individually healthy or not. Combined with pre-treatment chemotherapy and high-dose steroids, CAR T-cell therapy can cause a severe drop in total B cells and, as a result, low antibody levels (secondary hypogammaglobulinemia).

Today, there are seven types of CAR T-cell therapies available for 18 different forms of blood cancers, including leukemias, lymphomas, and multiple myeloma.

Most patients eventually recover from medication-induced SI, but some develop persistent antibody deficiencies, poor vaccine response, and recurrent infections, just like people with the most common types of PI.

Immunodeficiency, whether primary or secondary, can also lead to autoimmunity, a condition in which the immune system mistakenly attacks the body's own healthy tissues. Autoimmune complications can happen alongside immunodeficiency because the same regulatory pathways that help fight infections also help prevent harmful immune responses against the body. For example, sometimes certain immune-modulating treatments or therapies used for cancer and inflammation can trigger secondary immune imbalances that lead to autoimmune conditions.

Distinguishing between PI and SI often means first ruling out SI. However, it's important to keep in mind that a person can have both SI and PI at the same time. To diagnose SI, doctors focus on factors that may have weakened the immune system. Important questions include:

• Has the person recently started chemotherapy, a biologic, or another medication that can cause SI?
• Is there evidence of cancer or another blood disorder?
• Did infections begin after a specific medication or medical condition developed?

While PI and SI differ in causes, they can both result in poor antibody function, among other outcomes. People with both types of immunodeficiency may benefit from similar treatments, especially if the immune deficiency mainly affects the amount or function of a person’s antibodies. These treatments may include treating infections as they happen, preventing infection with prophylactic antimicrobials, and, most importantly, using immunoglobulin (Ig) replacement therapy.

“A big chunk of our population in primary immunodeficiency are going to develop secondary immunodeficiency. For instance, if we have a typical patient with common variable immunodeficiency, things that go hand in hand with common variable immunodeficiency are autoimmunity and increased risk of malignancy. So, if someone with common variable immunodeficiency develops any of those conditions, for example multiple myeloma, their treatment for multiple myeloma is going to cause an immunodeficiency on top of their immunodeficiency. At some point, we won't know which portion was acquired and which portion was primary. It begs the question, does it matter if they are going to need similar therapy?” said foundation Medical Director Paula Henao, M.D.

Ig therapy provides antibodies from healthy donors that help protect people who cannot make effective antibodies on their own. The goal is to reduce infections, improve quality of life, and prevent long-term complications. Persons with common variable immunodeficiency (CVID) (the most common symptomatic PI), X-linked agammaglobulinemia (XLA), hyper IgM syndrome, and other PIs, as well as people with certain secondary antibody deficiencies, all benefit from Ig replacement therapy.

Finally, it’s important to remember that Ig replacement therapy is individualized and different for every person. Research has shown that the best dose is not determined by achieving a specific antibody level but by preventing infections and improving clinical outcomes.