Autoimmune Hemolytic Anemia and Primary Immunodeficiency: What’s the Link?

Living with primary immunodeficiency (PI), also called inborn errors of immunity (IEI), means your immune system doesn’t always have the tools it needs to fight off infections.

For some people, however, the immune system causes a different problem — it mistakenly attacks the body’s own healthy cells, a process known as autoimmunity.

One condition that can result is autoimmune hemolytic anemia (AIHA), in which the immune system mistakenly attacks red blood cells.

Here’s a look at why these conditions often occur together, what symptoms to watch for, and how to coordinate your care if you’re living with both.

How Can Primary Immunodeficiency Lead to Other Conditions?

One of the most common types of autoimmune conditions linked to PI is autoimmune cytopenia — a group of conditions, including AIHA, in which the immune system mistakenly destroys healthy blood cells.

Autoimmune cytopenia includes several conditions, depending on which type of blood cell is affected. Along with AIHA, these conditions include:

• Immune thrombocytopenia, which lowers platelet level — Platelets help prevent and stop bleeding.
• Autoimmune neutropenia, which lowers white blood cell levels — White blood cells help fight infections.

In a study of more than 2,000 people with common variable immunodeficiency (CVID), one of the most common forms of PI, 26 percent had at least one autoimmune condition. Autoimmune responses can also affect organs beyond the blood, most often the lungs and digestive system.

Beyond autoimmunity, PI has also been linked to a higher chance of developing lymphoproliferative disorders (conditions in which certain immune cells multiply more than they should), such as non-Hodgkin lymphoma.

How Common Is AIHA in People With Primary Immunodeficiency?

Research suggests that about 28 percent of adults with PI develop an autoimmune cytopenia, with AIHA being the most common type.

Looking at it from a different direction tells a similar story. In a separate study, nearly 63 percent of people with AIHA also had an underlying PI.

This doesn’t mean everyone will develop both conditions. However, it does show that doctors are increasingly recognizing the link between AIHA and PI, making it important to consider both conditions together.

What Is Autoimmune Hemolytic Anemia?

AIHA is a rare type of anemia that happens when your immune system makes antibodies that attack and destroy red blood cells faster than your body can replace them.

Types of AIHA and How They’re Diagnosed

Doctors classify AIHA as either primary or secondary:

• Primary AIHA develops without an identifiable cause.
• Secondary AIHA develops because of another condition, such as PI, certain infections, some medications, or another autoimmune disorder.

AIHA is also classified by the temperature that triggers the antibodies:

• In warm AIHA, the most common type, the immune attack happens at normal body temperature.
• In cold AIHA, cooler temperatures trigger the attack, usually affecting blood in exposed areas such as the fingers, toes, and ears.

Doctors typically confirm AIHA with blood tests, including the direct antiglobulin test (DAT), also called the Coombs test. The DAT checks for antibodies attached to red blood cells.

Knowing which type of AIHA you have helps your care team choose the most appropriate treatment and better predict how the condition may change over time.

Symptoms of AIHA

AIHA symptoms can vary, but many are caused by a drop in hemoglobin, the protein in red blood cells that carries oxygen through the body. Common symptoms include:

• Fatigue (extreme tiredness that doesn’t improve with rest) and weakness
• A fast heart rate or shortness of breath
• Dizziness or lightheadedness
• Paler skin or jaundice (a yellow tint to the skin, eyes, gums, or palms)
• Dark-colored urine
• Chills or a low fever

If you notice these symptoms, especially if they show up suddenly or get worse quickly, let your healthcare team know.

Disease Course and Treatment Options

AIHA doesn’t always go away completely, but it can usually be managed with treatment. For the more common warm AIHA, treatment often starts with corticosteroids, such as prednisone, to calm the immune response.

Other treatment options may include immunoglobulin therapy or rituximab, a medication that targets specific immune cells. In more severe cases, treatment may also include splenectomy (surgery to remove the spleen) or a blood transfusion.

If you have PI, your care team has to balance treatment carefully. Treating AIHA often involves immunosuppressive therapy, which calms the immune system but can also raise your risk of infection. That’s why people living with both conditions usually need closer, more frequent follow-up than those managing just one condition.

What Factors Raise the Risk of AIHA?

Not everyone with PI develops AIHA, and researchers are still working out exactly why some people do and others don’t. Two factors seem to matter most: which type of PI you have and how your immune system is regulated.

Types of PI That Carry Higher Risk

When it comes to AIHA risk, the specific type of PI you have matters much more than your age. The risk is highest in conditions in which immune cells are present but don’t work properly, rather than in conditions in which those cells are missing entirely.

AIHA is more common in certain types of PI — including CVID, Wiskott-Aldrich syndrome, autoimmune lymphoproliferative syndrome, IPEX syndrome — that affect how the immune system is regulated.

By contrast, research suggests that PI types involving the absence of certain immune cells, such as severe combined immunodeficiency (SCID), are much less likely to lead to AIHA.

Possible Genetic and Immune Connections

The same genetic changes that cause primary immunodeficiency often disrupt the systems that regulate the immune response. When this regulation breaks down, immune cells can mistakenly attack the body’s own tissues instead of only fighting germs.

Researchers have identified genetic changes, including mutations in the CTLA4 and LRBA genes, that increase the odds of developing AIHA along with certain PI types.

Although more research is needed to fully understand these connections, each new discovery helps doctors better identify who may be at higher risk.

What Should You Know About Having Both Conditions?

If you have primary immunodeficiency and develop signs of AIHA, doctors increasingly see this as a connected condition rather than a coincidence. In fact, hematologists (doctors who specialize in blood disorders) are often advised to look for an underlying immune disorder when someone develops AIHA.

Because of this deep connection, identifying your specific type of PI or the underlying genetic cause is important. The clearer your diagnosis, the better your healthcare team can tailor your treatment.

Once diagnosed, managing both conditions requires a careful balance. Medications that calm the overactive immune response in AIHA can also reduce your body’s ability to fight infections related to PI.

Successfully managing both conditions depends on teamwork. Close, ongoing communication between you, your immunologist, and your hematologist can help your care team adjust treatment safely and find the right balance.

Your Action Plan

The link between PI and AIHA is an immune system that has trouble fighting infections while mistakenly attacking its own red blood cells.

Knowing what to watch for can help with early detection. Fortunately, when caught quickly, AIHA is usually very treatable.

To stay ahead of it, keep track of new fatigue, unusual paleness, dizziness, or yellowing of your skin or eyes, and share these symptoms with your doctors. You can also ask whether regular blood count tests make sense for your specific type of PI.

If you notice new or worsening symptoms, don’t wait until your next scheduled appointment. Reach out to your healthcare team so they can determine whether your symptoms are related to AIHA, another autoimmune condition, or something else.

Join the Conversation

On myPIteam, people share their experiences with primary immunodeficiency disorders, get advice, and find support from others who understand.

If you’re managing PI and an autoimmune condition together, what has helped you stay on top of new or changing symptoms? Let others know in the comments below.