Primary Humoral Immunodeficiency: What Low Antibodies Can Mean

Primary humoral immunodeficiency (PHI) is a type of primary immunodeficiency (PI), a general category of conditions that affect the immune system. PHI affects immune cells called B cells, and it’s the most common type of PI.

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In this article, we’ll cover the symptoms of PHI, subtypes of this condition, and how it’s diagnosed and treated.

How Does PHI Affect the Immune System?

PHI is a condition that mainly affects a type of white blood cell called a B cell. It’s also called an antibody deficiency.

People with PHI have fewer B cells than normal, or their B cells don’t work correctly. Usually, when the body encounters a microbe like a bacterium or virus, the immune system reacts to the invader. Part of the reaction involves B cells. B cells make a protein called an antibody (also called an immunoglobulin). Antibodies attach to different parts of the invading microbe and signal to other immune cells to destroy it. This is an important part of clearing and fighting an infection.

When B cells aren’t working correctly, it affects how well the body can deal with infections. This is what happens when someone has PHI. There might be issues with antibody production or antibody response to microbes. Levels of antibodies in the blood are usually low. There might also be fewer B cells than normal.

How Is PHI Different From Other Primary Immune Deficiency Conditions?

There are 10 main categories of primary immunodeficiencies. PHI is one of those categories, and many different gene mutations (changes in DNA) can cause PHI. Depending on the specific mutation, different parts of the B cell and the antibody-making process might be affected. What makes PHI distinct from other types of PI is that it mainly affects B cells and antibody levels. Other primary immunodeficiencies are caused by problems with different white blood cells, like T cells. They might cause symptoms similar to PHI, but they’re not the same condition.

What Are the Signs and Symptoms of PHI?

Because B cells and antibodies are so important for clearing infections, one of the main symptoms of PHI is recurrent infections. These frequent infections are often caused by certain types of bacteria.

Antibodies are particularly important in the immune response of the sinuses, respiratory system, and ear canal. Severe cases of PHI are sometimes diagnosed in babies, typically after they are 6 months old, when antibodies passed on from their mother run out. However, more than 50 percent of PHI diagnoses happen in adults.

Frequent Bacterial Infections

The types of infections most common in people with PHI include:

• Ear infections — These can affect different parts of the ear, especially the middle ear.
• Sinus infections — These occur when the sinuses become inflamed, leading to congestion, facial pressure, and thick nasal discharge.
• Pneumonia — This infection causes inflammation in the lungs, often resulting in coughing, fever, chest pain, and trouble breathing.

People with PHI are at increased risk of certain types of infections. These include:

• Encapsulated bacteria — These have a protective outer layer that makes them harder for the immune system to fight and include the species Streptococcus pneumoniae and Haemophilus influenzae. These bacteria usually cause lung and respiratory tract infections.
• Viruses, parasites, and bacteria that infect the gastrointestinal tract — Giardia lamblia, Salmonella enterica, and rotaviruses infect the digestive tract and cause diarrhea that doesn’t go away without treatment.

Invasive Infections

Sometimes, people with PHI can develop more invasive and severe infections, where bacteria invade deeper into the body. These include bacteremia, where bacteria enter the bloodstream, and meningitis, where bacteria infect the tissues around the brain.

Lung Damage

When people with PHI get recurrent lung infections, they might also develop bronchiectasis. In this condition, the airways become damaged and fill with mucus. This makes someone more likely to develop respiratory infections. The symptoms of bronchiectasis include:

• Coughing with lots of mucus
• Coughing up blood
• Shortness of breath
• Wheezing

What Are the Subtypes of PHI?

There are four main subtypes of PHI. Each of these subtypes can be caused by many different gene mutations.

Agammaglobulinemia

In this condition, people have very low levels of (or no) B cells and very low levels of antibodies. This includes all three major categories of antibodies, called immunoglobulin (Ig) G, IgM, and IgA antibodies.

Agammaglobulinemia is the most serious form of PHI. Agammaglobulinemia is usually diagnosed in babies between 6 and 9 months old, when the protection from their mother’s antibodies starts to fade. X-linked agammaglobulinemia, a form of this condition that is passed down in families, was the first PI disorder researchers identified.

Common Variable Immunodeficiency

In common variable immunodeficiency (CVID), people have normal or low levels of B cells, but low class-switched memory B cells. These B cells “remember” past infections and can quickly make the right antibodies to fight them.

For people with CVID, levels of IgG are low, as well as either low IgA or IgM antibodies. It’s often diagnosed in adulthood between the ages of 20 and 40. Autoimmune diseases — where the body attacks its own tissues and organs — often happen alongside CVID.

Hyper IgM Syndrome

In this rare condition, people have normal or high levels of IgM antibodies but low levels of IgG, IgA, and IgE antibodies. This condition is usually diagnosed early in life. People with hyper IgM syndrome are often prone to infections with unusual microbes that don’t normally cause sickness in the general population (called opportunistic infections).

Selective IgA Deficiency

This is the most common PI, and between 1 in 100 and 1 in 1,000 people have this condition. The main sign is having low levels of IgA antibodies, while IgG and IgM levels are normal. Many people with selective IgA deficiency are asymptomatic, meaning they don’t have any symptoms.

Other, rarer types of PHI exist. In some conditions, people might have issues making certain types of antibodies (called specific antibody deficiency). In other cases, low antibody levels are temporary in childhood and resolve by themselves. This is the case in transient hypogammaglobulinemia of infancy.

How Is PHI Diagnosed?

The steps in diagnosing a PHI condition include testing antibody levels, assessing how well antibodies are working, and looking at B-cell levels. Often, an immunologist (a doctor who is trained in immunology) is the specialist you’ll visit for a PHI diagnosis.

Here are the specific tests frequently used in PHI diagnosis:

• Immunoglobulin level testing — The levels of immunoglobulins (antibodies) in your blood, including IgG, IgM, and IgA antibodies, can be measured in the lab. The results are compared to the general population.
• Vaccine response testing — To see if your B cells make antibodies when they need to, your doctor might give you a vaccine and measure the antibodies your body produces a few weeks later. A common vaccine used for this reason is the tetanus shot.
• B-cell analysis — Using a blood sample and a procedure called flow cytometry, doctors can look at how many B cells you have, what type they are, and how well they work. This testing can help clarify which parts of the immune system are missing and whether you have PHI.
• Genetic testing — Testing for the more than 50 known gene mutations related to PHI can help determine if you have this condition.

How Is PHI Treated?

The best way to treat someone’s PHI depends on their specific condition and symptoms. However, immunoglobulin replacement therapy is a standard treatment for some common types of PHI.

Immunoglobulin Replacement Therapy

In immunoglobulin replacement therapy, you receive immunoglobulins from blood donors to replace what’s missing in your bloodstream. Plasma is pooled from thousands of different donors. Because this process doesn’t fix the underlying cause of the condition, you’ll have to receive treatment every one to four weeks as the replacement antibodies disappear from your system.

Immunoglobulin replacement therapy is recommended in the following cases, where the risk of infections is high:

• Agammaglobulinemia, when all antibody types are severely low and B cells are missing or very low
• PHI conditions where at least two antibody categories are very low, including CVID or X-linked agammaglobulinemia

If you have questions about your PHI condition or treatment plan, talk to your healthcare team. Because so many different mutations can cause PHI, everyone with PHI has different needs. Your healthcare team can help you decide on the best plan for you.

Talk With Others Who Understand

On myPIteam, people come together to learn more about life with primary immunodeficiency disorders.

Have you or a loved one been diagnosed with a primary humoral immunodeficiency condition? What was the diagnosis and treatment process like? Share your tips and experiences in a comment below.