Primary vs. Secondary Immunodeficiency: 6 Differences and 5 Similarities

Some people are born with immunodeficiency — an immune system that doesn’t protect their body the way it should. Others may develop immunodeficiency later in life.

There are two types of immunodeficiency: primary immunodeficiency (PI) and secondary immunodeficiency. Both come with a higher risk of getting sick, more frequent infections, and a need for specialized care. Their causes and treatments, however, are very different.

Understanding the differences and similarities between primary and secondary immunodeficiency can help you have better conversations with your healthcare team and decide together on a care plan.

Differences Between Primary and Secondary Immunodeficiency

Although both affect how the immune system works, primary and secondary immunodeficiency disorders differ in important ways. Here are six key differences.

Primary immunodeficiency diseases are caused by genetic mutations (changes in the instructions that help the body work) that affect how the immune system develops or functions.

In many cases, these mutations are inherited (passed down) from parent to child, which is why many people with PI have a family history of the condition. The genetic changes are there in your chromosomes when you’re born, even if symptoms don’t appear right away.

The inherited genetic component sets PI disorders apart from secondary immunodeficiency disorders, which are acquired because of another treatment, illness, or “secondary” cause.

The medical community is shifting from “primary immunodeficiency” to “inborn error of immunity” (IEI). This newer term reflects that these genetic conditions can involve more than a weakened immune defense. They may also affect multiple organ systems or cause autoimmune complications.

Several medical conditions can lead to secondary immunodeficiency. Worldwide, the most common cause is malnutrition. Without enough nutrition, vitamins, and minerals, the immune system can’t work the way it should.

Other conditions that can cause secondary immunodeficiency include:

• Viral infections, such as HIV, measles, and COVID-19
• Bacterial infections, such as tuberculosis
• Alcohol use disorder
• Kidney disease
• Liver disease
• Premature birth
• Older age
• Some blood cancers, such as lymphoma and multiple myeloma
• Diabetes
• Autoimmune disorders
• Severe burns

The medications most commonly associated with secondary immunodeficiency are immunosuppressive therapies. These include biologics like rituximab, which is often used to treat autoimmune diseases or blood cancers.

Other medical treatments that can cause secondary immunodeficiency include:

• Corticosteroids
• Chemotherapy
• Radiation therapy
• Anti-seizure medications

In adults, secondary immunodeficiency is more common than PI. Because there are so many causes, it’s hard to know just how many people are affected.

Secondary immunodeficiency is very common in people with certain conditions, such as chronic lymphocytic leukemia (CLL). In fact, infections caused by a weakened immune system are the leading cause of death in people with CLL.

By comparison, PI is rare. This group of genetic conditions affects approximately 1 in 2,000 people in the United States.

Symptoms of both primary and secondary immunodeficiency can occur at any age. However, most severe cases of PI, such as severe combined immunodeficiency (SCID), are diagnosed in infancy or early childhood.

Milder forms may not be recognized until adulthood. For example, common variable immunodeficiency (CVID) and specific antibody deficiency are often first diagnosed in adults.

Secondary immunodeficiency develops after other illnesses or treatments that are more common in adults.

For secondary immunodeficiency, treatment usually starts with finding and managing the underlying cause. If the problem is linked to another medical condition, treating that issue may help the immune system return to normal.

For example, antiviral medications can control HIV infection and help prevent further immune damage. If immunosuppressive medications are causing immune dysfunction, stopping or adjusting them may improve immune response.

Additional treatments, such as antibiotics or immunoglobulin replacement therapy, are sometimes needed to help prevent or manage bacterial infections in people with primary or secondary immunodeficiency.

In most types of PI, treatment focuses on preventing and treating recurrent infections. However, newer therapies are being developed to correct the underlying immune system problem.

Cases of secondary immunodeficiency may be temporary, depending on the original cause. If secondary immunodeficiency is linked to an underlying illness, the immunodeficiency may go away once the underlying disease is treated.

PI may be a lifelong condition. Although symptoms may be kept at bay, the condition doesn’t usually go away without intensive treatment.

Similarities Between Primary and Secondary Immunodeficiency

Primary and secondary immunodeficiency share several key features. These similarities help explain why it can be hard to tell the two apart without testing.

The main signs and symptoms of both primary and secondary immunodeficiency are the same — frequent, recurring, hard-to-treat, and chronic infections.

Like PI, secondary immunodeficiency can lead to immune dysregulation, which may cause autoimmune disease and raise the risk of malignancy (cancer).

The terms “primary” and “secondary” describe the cause of immunodeficiency, not how serious the condition is. In both types, symptoms can range from mild to severe.

For example, some people with selective IgA deficiency (low levels of a specific immune protein) may not have any symptoms. People with SCID, however, have serious, life-threatening problems early in life.

There’s also a range of severity in secondary immunodeficiency. People taking immunosuppressant medications after an organ transplant are considered severely immunocompromised. In contrast, age-related changes in the immune system may cause only a mild increase in infection risk.

It can be difficult to tell primary and secondary immunodeficiency apart. In some cases, a secondary immunodeficiency may actually unmask an underlying primary immunodeficiency. Identifying the true cause is key to choosing the right treatment.

You may be referred to an immunologist (a doctor who specializes in immune deficiency) for tests to help determine whether the cause is primary or secondary. Tests may include:

• Complete blood cell count
• Flow cytometry to measure different types of blood cells
• Antibody level testing

Genetic testing can help identify the specific gene change causing the condition. If secondary immunodeficiency is suspected, healthcare providers from other specialties might run more tests to learn more about the underlying cause.

Whether immunodeficiency is inherited or acquired, targeting the source of the problem may improve immune function. Treatment for secondary immunodeficiency focuses on addressing the underlying cause or stopping the treatment that weakens the immune system, when possible.

For PI, treatment has usually focused on preventing and managing infections. However, treatments have been developed that can restore immune function in some types of PI that carry a high risk of death. For example, bone marrow transplantation is an intensive treatment that replaces defective blood-forming cells with healthy ones from a donor.

Gene therapy is a newer type of treatment that is now FDA-approved in the United States for certain PI conditions, with additional therapies approved internationally or undergoing clinical trials. This treatment repairs the genetic defect in a person’s immune cells to enable a functional immune system.

Whether immunodeficiency is primary or secondary, regular medical care is key to managing symptoms and preventing complications. People with either type need routine follow-ups and preventive care to reduce the risk of infection.

Your healthcare team may involve several specialists. Working together, you and your healthcare team can find strategies and treatment options to protect your health over time. If your child has PI, they may need pediatric specialists until early adulthood, when they’ll need to transition to adult care.

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