Hypogammaglobulinemia and Primary Immunodeficiency: Symptoms, Causes, and Treatment

Hypogammaglobulinemia (HG) can be caused by either a genetic mutation (change) passed down from a parent, a random mutation (without any family history), or a secondary cause. If you have the genetic type of hypogammaglobulinemia, you have a form of primary immunodeficiency (PI), also called inborn errors of immunity (IEI). However, HG can also develop as a side effect of other conditions, known as secondary immunodeficiency.

In this article, we’ll describe hypogammaglobulinemia symptoms, causes, and possible treatments.

Causes of Hypogammaglobulinemia

Your immune system helps protect you from infections caused by viruses, bacteria, and fungi. One way your immune system does this is by making immunoglobulins, also called antibodies. These are proteins that help find and fight germs.

In some people, the body doesn’t make enough antibodies. This can lead to low levels of antibodies in the blood, a type of immune deficiency called hypogammaglobulinemia.

HG may be caused by a gene mutation, or it may develop later in life because of another health condition, medication, or treatment. Here’s what to know about the possible causes of HG.

Primary Hypogammaglobulinemia Causes

When HG is genetic, the condition is present at birth and called primary HG.

Some people with primary HG develop symptoms as infants because their maternal antibodies (antibodies inherited from their mother) decrease around 6 months old, while many begin having symptoms in their teens and 20s. However, it can be diagnosed at any age.

Certain specific conditions are types of primary HG, depending on the mutation involved. A few examples include:

• X-linked agammaglobulinemia (XLA) — Also called Bruton agammaglobulinemia, this inherited condition prevents the body from making B cells, which mature into plasma cells and are needed to produce antibodies. XLA is usually diagnosed in children.
• Common variable immunodeficiency (CVID) — The most common type of primary HG in adults, CVID is caused by different gene mutations that affect the B cells’ ability to make antibodies.
• Selective IgA deficiency — In this condition, which can be diagnosed at any age over 4, the immune system has problems making a specific antibody called immunoglobulin A (IgA), while the other antibodies are at a normal level. Some people have very low levels of IgA, and others have none at all.

Secondary Hypogammaglobulinemia Causes

Secondary HG results from another underlying condition or its treatment. Possible causes include:

• Certain types of cancer, including lymphoma and leukemia
• Some autoimmune diseases, such as lupus and rheumatoid arthritis
• Neurologic conditions (affecting the brain, spinal cord, and nerves) like multiple sclerosis
• Lung conditions such as cystic fibrosis and chronic obstructive pulmonary disease (COPD)
• Kidney problems like nephrotic syndrome
• Infections such as human immunodeficiency virus (HIV)

An increasing number of secondary HG cases may be linked to medicines that weaken the immune system. These include corticosteroids and immunosuppressants. Another common cause is B-cell targeted therapy, a treatment used for some cancers and autoimmune diseases.

Researchers don’t fully understand why those diseases lead to HG, but nearly all are treated with immunosuppressive drugs. In many cases, the cause may be the disease itself, the treatment, or both.

It’s important to know whether HG is primary or secondary because treatment may be different depending on the cause.

Diagnosis of Hypogammaglobulinemia

It may be challenging for your healthcare team to tell if your HG is primary or secondary, especially if you also have another condition that can potentially cause it.

Immunoglobulin Blood Tests

The first step in diagnosing HG is a blood test that measures your levels of immunoglobulins — IgG, IgM, and IgA. IgG levels are usually the most important for diagnosing HG.

If you have selective IgA deficiency, your IgA level will be unusually low, while the others might be normal.

Your results will be compared to the average antibody levels for your age. Based on how low your levels are, your healthcare provider will classify your HG as mild, moderate, or severe. Low antibody levels are sometimes temporary, so the test is usually repeated over time to confirm the diagnosis.

Vaccine Responses

Vaccines help the immune system make antibodies. In people with HG, this immune response might be impaired. To test this, your provider may give you a vaccine and then check your blood four to six weeks later for antibody responses to the vaccine.

Other Tests

To find out what’s causing your low antibody levels, your doctor may order tests such as:

• Blood tests and imaging scans to check immune cell levels and organ function
• Genetic tests to screen for primary immunodeficiency mutations
• Biopsies (taking tissue samples to examine under a microscope) if cancer is suspected

Your provider will also ask about any medications you take, review your medical history (especially recurrent or severe infections), and ask if you have a family history of immune deficiency.

Treatment Options for Hypogammaglobulinemia

Hypogammaglobulinemia treatment options depend on whether HG is primary or secondary and how severe it is.

Options for Primary Hypogammaglobulinemia

The management plan for primary HG depends on how low your antibody levels are and whether you’ve had severe infections. Your healthcare provider may recommend:

• Monitoring if your antibody levels are stable and you’re not getting sick
• Using antibiotics when needed to treat an infection or sometimes as a preventive step
• Starting immunoglobulin replacement therapy if your IgG levels are low enough to need regular treatment

Options for Secondary Hypogammaglobulinemia

If a medication is lowering your antibody levels, your doctor or immunologist may recommend stopping or changing it. If HG is caused by another condition, treating that disease often improves antibody levels too. If those steps aren’t options, the management plan may include:

• Closely watching for signs of infections
• Using antimicrobials (such as antibiotics) when needed
• Starting immunoglobulin replacement therapy

Immunoglobulin Replacement Therapy

Immunoglobulin replacement therapy gives you antibodies from healthy donors to help protect against infections. The antibodies come from plasma — the liquid part of blood — that’s collected and combined from many donors.

Most people need repeated treatments on a regular schedule to stay protected from infection. Depending on the type of replacement therapy, the frequency of injections or infusions required can range from daily to every four weeks. Immunoglobulin replacement therapy is a standard treatment for people with primary HG conditions such as CVID and XLA.

Immunoglobulin replacement may be considered for people with secondary HG as well — particularly when antibody levels are low and infections are recurrent — such as after certain immune therapies, depending on your physician’s or immunologist’s clinical evaluation.

Check With Your Doctor

If you think you or someone you love might have HG — or if you have questions about treatment — talk with your healthcare provider. They can help you understand your options and make a plan that fits your needs.

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