What Distinguishes Primary Immunodeficiency From Another Disorder? 6 Related Conditions and Complications

Primary immunodeficiency (PI) occurs when a person is born with a genetic mutation (change) that prevents the immune system from working properly. PI is sometimes called “an inborn error of immunity.” PI isn’t a single condition. Each person with PI may have a different experience, and symptoms can change over time. More than 500 types of PI have been identified. These fall into 10 broad categories, based on which part of the immune system is affected.

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PI conditions can vary in severity and how much they affect a person’s health or ability to fight infection. They can also lead to hematologic (blood-related) changes, such as low levels of healthy blood cells. These may include:

• Lymphocytes, which are white blood cells that help fight infections
• Red blood cells, which carry oxygen throughout the body
• Platelets, which help the blood clot and stop bleeding

When the immune system isn’t working properly, the body may also make too many lymphocytes that don’t function as they should. This overproduction is called lymphoproliferation. In some cases, it may increase the risk of lymphoma, a type of blood cancer.

In addition to increased infections, PI may also lead to complications like autoimmune diseases, lung damage, or gastrointestinal (GI) problems.

Read on to learn about common signs of PI, related conditions, and possible complications.

Primary vs. Secondary Immunodeficiency

PI conditions are caused by genetic mutations that affect how the immune system works. This means a person is born with the condition, even if symptoms don’t appear or a diagnosis isn’t made until later in life. These inherited conditions are what set PI apart from other types of immune system problems.

On the other hand, immune deficiency can also be caused by other outside factors. These are known as secondary immunodeficiency conditions. Secondary immunodeficiency is much more common than PI, and many factors can lead to it. These include:

• Infections — These can weaken the immune system, especially infections like HIV.
• Malnutrition — This means not getting enough nutrients to support immune health, which can be particularly common in older adults and people living with severe chronic illnesses.
• Certain cancers — These can directly or indirectly suppress immune function.
• Cirrhosis — This liver disease interferes with the body’s ability to filter toxins.
• Autoimmune conditions — These may affect how the immune system functions.
• Medications that suppress the immune system — These include chemotherapy, transplant rejection drugs, and autoimmune disease treatments.

The signs and symptoms of primary and secondary immunodeficiency often overlap. Your healthcare provider may need to run many tests to rule out secondary causes before confirming a PI diagnosis.

What Are Common Signs of Primary Immunodeficiency?

One of the most common signs of PI is having infections that are frequent, severe, or unusual. These infections may be caused by viruses, bacteria, fungi, or parasites, depending on which part of the immune system is affected.

Infections in people with PI may:

• Be harder to treat
• Not respond well to standard medications like antibiotics
• Last longer or be more severe than usual

In some cases, people with PI get infections that are rare in the general population.

For more on the symptoms of PI, take a look at this guide.

Related Conditions and Complications

The genetic mutations that cause PI can also lead to other health issues. One of the most common complications of PI is autoimmune disease. In autoimmune conditions, the immune system mistakenly attacks the body’s own cells and tissues. The autoimmune issues associated with PI can be quite varied. Below, we describe some of these PI-related conditions.

1. Autoimmune Cytopenia

Autoimmune cytopenia is the most common autoimmune complication in people with PI. In some cases, it may even be the first sign of PI, especially in people who don’t get frequent infections.

With autoimmune cytopenia, the immune system attacks blood cells, including red blood cells, white blood cells, or platelets. The symptoms depend on which blood cells are affected. For example, if the immune system attacks platelets, it can lead to easy bruising and bleeding that’s slow to stop. If the immune system attacks red blood cells, it can cause anemia, a condition that may require blood transfusions.

2. Rheumatoid Arthritis

Some autoimmune disorders linked to PI affect the joints and connective tissues. The most common is inflammatory arthritis, including rheumatoid arthritis. Other possible conditions include systemic lupus erythematosus and Sjögren’s disease.

Although exact numbers are hard to determine across all PI types, studies suggest that about 3 out of every 100 people with common variable immunodeficiency (CVID), a type of PI, developed inflammatory arthritis.

In rheumatoid arthritis, the immune system produces proteins called antibodies that mistakenly attack the lining of the joints. This leads to inflammation, pain, and swelling. Joints commonly affected include the fingers, toes, knees, and ankles. Over time, the condition can worsen and limit joint movement.

3. Severe Allergies

People with certain types of PI are at higher risk of developing severe allergies and hypersensitivities. These can include allergies to pollen, food, animals, or other environmental triggers.

Severe allergy symptoms can include:

• Swelling of the face, lips, tongue, or throat
• Difficulty breathing
• Hives and skin rashes
• Sneezing
• Itchy, watery eyes
• Stuffy or runny nose
• Cough or wheezing
• Vomiting or diarrhea

Other allergic conditions that can occur alongside PI include eczema (an inflammatory skin condition) and allergic asthma (an airway condition triggered by allergens that causes breathing difficulty).

One study found that about 70 percent of people diagnosed with PI also had allergies or asthma. This suggests such conditions may be more common in people with PI than in the general population. People with antibody deficiencies or combined immunodeficiencies are the most likely to develop severe allergies.

4. Inflammatory Bowel Disease

Digestive problems are a common complication in people with PI. About one-third of people with PI experience GI symptoms, and it’s essential to get a diagnosis that considers how the PI may be contributing to those issues. One frequently reported complication is inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis.

Common symptoms of IBD include:

• Diarrhea
• Abdominal pain
• Bloody stool (poop)
• Vomiting
• Unintended weight loss

These digestive problems can happen when immune cells don’t function properly. In some cases, the immune system may attack the lining of the gut or overreact to certain foods, leading to ongoing inflammation.

5. Lung Damage

Immune system abnormalities and long-term inflammation in PI can sometimes lead to lung damage. Repeated or severe respiratory infections — such as pneumonia — can harm the lungs over time.

One type of lung damage linked to PI is interstitial lung disease (ILD), a condition in which chronic inflammation leads to scarring in the lungs. In a study of people with CVID, up to 20 percent also had ILD.

Signs of chronic lung damage may include:

• Shortness of breath
• Dry cough
• Fatigue (exhaustion that doesn’t improve with rest)
• Chest discomfort

6. Higher Risk of Some Cancers

People with some types of PI may have a higher risk of developing certain kinds of cancer — and sometimes at a younger age than the general population.

The highest-risk cancer is lymphoma, a type of blood cancer. Studies suggest that people with PI are as much as 10 times more likely to develop lymphoma than people without PI. Lymphoma happens when certain white blood cells (T cells or B cells) grow and divide out of control. The increased risk of lymphoma is especially seen in people with CVID.

According to research cited in The Journal of Allergy and Clinical Immunology, men with PI also have higher rates of both skin cancer and thyroid cancer, and women with PI have a specifically higher risk of skin and stomach cancers.

Treating Primary Immunodeficiency-Related Conditions

The health conditions that occur alongside PI can appear at any time. As someone is treated for PI, the related conditions and complications they experience may also change. Sometimes, separate treatment is needed to manage these conditions.

Autoimmune complications are often treated with medications that suppress the immune system. While these treatments can help control inflammation and symptoms, they may also increase the risk of infections.

Your healthcare provider will work with you to find the right balance of managing your symptoms while protecting your overall immune health.

Join the Conversation

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

Have you or a loved one been diagnosed with a primary immunodeficiency disorder? Have you been treated for PI complications or related conditions? Share your tips and experiences in a comment below.