What is PI?

Key points:

Primary immunodeficiencies (PIs), also known as inborn errors of immunity (IEIs), are rare, chronic health conditions where part of the immune system is missing or does not work properly.
Infections are the most common symptom of an immune system that isn’t working properly.
Autoimmune conditions, chronic inflammation, recurrent fevers, and cancer can also be signs of immune system issues.
Some PIs, known as primary immune regulatory disorders (PIRDs), also involve problems controlling the immune system.
Secondary immunodeficiency (SI) happens when a condition or factor outside of the immune system affects how well the immune system works. SI is much more common than PI.

Primary immunodeficiencies (PIs) are a group of more than 550 rare, chronic health conditions where part of the immune system is missing or does not work properly [1]. Often, PIs are caused by changes, or variants, in a person’s genes. Not all PIs have an identified genetic cause though.

Some PIs are extremely rare, affecting only a few people worldwide, while others, like common variable immune deficiency (CVID), are more common. All PIs are different, but they all disrupt the body’s immune system. In the medical community, they are also known as inborn errors of immunity (IEI).

What are the signs and symptoms of PI?

Because one of the immune system's main jobs is to protect us from infections, people with many types of PI struggle with infections. This increased susceptibility can lead to infections that:

Keep coming back (recurrent).
Won’t completely clear up or clear very slowly (persistent).
Are caused by germs that don’t usually make people sick (unusual).
Require hospitalization or intravenous medication (severe).
Are shared by family members (others in your family have or have had a similar susceptibility to infection).

People with some types of PI might struggle to fight off just one type of germ, while others have difficulty combating many types of germs and may struggle with multiple types of infections. Infections from PI can happen anywhere in the body, but they often happen in the sinuses (sinusitis), airways (bronchitis), lungs (pneumonia), or digestive system (infectious diarrhea). Many other infections, such as skin infections, deep sores (abscesses), bone infections (osteomyelitis), blood infections (septicemia), and infections of the brain (meningitis and encephalitis) can also happen in people with PI.

It's useful to think about the context of infections in those with PI versus people who don’t have PI. Toddlers can have viral infections for a large part of the year even if their immune system is working well. However, adults usually have far fewer infections because they have developed immunity to common germs. Healthcare providers consider it normal for adults to have up to two sinus infections per year. While most people never have pneumonia, one pneumonia at any age (unless it’s very severe) usually does not trigger an immune evaluation. However, recurrent bacterial pneumonia should be a red flag that there is either a structural problem or an immune system issue.

In some PIs, the immune system is not properly controlled and becomes or continues to be active even when there is no threat from germs. This is called immune dysregulation. Additional symptoms of PI related to immune dysregulation can include:

Larger than usual spleen, liver, or lymph nodes (splenomegaly, hepatomegaly, or lymphadenopathy).
Cancer, especially lymphoma.
Repeated fevers that are not caused by infections.
Inflammatory conditions, such as inflammatory bowel disease (IBD), eczema (atopic dermatitis), or inflammation of the blood vessels (vasculitis).
Autoimmune conditions like lupus, type I diabetes, or the destruction of blood cells or platelets (autoimmune cytopenias).
Food, environmental, or medication allergies.

These symptoms are caused by different types of immune dysregulation, such as:

Autoimmunity, which is when the parts of the immune system (specifically antibodies or T cells) recognize and attack healthy organs and tissue.
Allergies, sometimes called atopy, which is when the immune system overreacts to harmless triggers like pollen or pet dander (allergens).
Autoinflammation, which is when the immune system activates suddenly without a trigger.
Lymphoproliferation, which is when the body makes too many of some types of white blood cells.
Chronic inflammation, which is when the immune system remains active long after it has cleared an infection. Chronic inflammation can also be triggered by a long-lasting infection that the immune system can’t clear, a long-lasting autoimmune response, or constantly being around a trigger like an allergen.

In fact, immune dysregulation is the main symptom for some types of PI referred to as primary immune regulatory disorders (PIRDs), including:

People with PIRD typically have multiple autoimmune or inflammatory diseases like type I diabetes, autoimmune thyroid disease, or inflammation of the blood vessels (vasculitis). These types of PI also cause a person to be at higher risk for infections, but their main symptoms are related to immune dysregulation.

Other types of PI have higher risk of infection as their main symptom but can also cause immune dysregulation, sometimes in only some individuals. These PIs include:

All of these signs and symptoms can be caused by PI, depending on the type of PI and how it disrupts the immune system.

Who does PI affect?

A recent study of medical records estimates that about 1 in every 1,600-1,700 people in the U.S. have some form of PI with documented symptoms [2]. PI can affect anyone, regardless of age, gender, or ethnicity. Some PIs like WAS cause symptoms in babies or young children, but others, like CVID, may not show up until mid- or even older adulthood.

Common misconceptions about PI include that they are only pediatric disorders and that they are all severe conditions.

What is secondary immunodeficiency?

Unlike PI, secondary immunodeficiencies are caused by conditions or factors outside of the immune system that affect how well the immune system works. Secondary immunodeficiencies are much more common than PI and healthcare providers have to rule out secondary causes before making a PI diagnosis.

The most common causes of secondary immunodeficiencies are aging, poor nutrition, taking chemotherapy or other immune-suppressing medications, human immunodeficiency virus (HIV), and protein loss in the intestines or kidneys. It’s important to recognize these conditions because, if the underlying cause can be treated, immune system function usually improves. Managing a secondary immunodeficiency is often similar to managing PI.

References

Poli MC, Aksentijevich I, Bousfiha AA, Cunningham-Rundles C, Hambleton S, Klein C, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. Journal of Human Immunity. 2025;1. doi:10.70962/jhi.20250003
Rider NL, Truxton A, Ohrt T, Margolin-Katz I, Horan M, Shin H, et al. Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data. J Allergy Clin Immunol. 2024;153: 1704–1710. https://doi.org/10.1016/j.jaci.2024.01.011

Understand PI more clearly

How your immune system works

To better understand PI, it's helpful to know more about how your immune system works.

Read about the immune system

Genetics and PI

PIs are mostly caused by changes, or variants, in genes that are important for how the immune system works.

Learn about genetics

Types of PI

There are more than 550 primary immunodeficiencies with distinct definitions, causes, and symptoms.

Explore PI types

Ask IDF

Getting answers can help create peace of mind. Ask us anything and we’ll consult with experts.

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Do you have information to help me select a health insurance plan to cover my needs?

Selecting a health insurance plan can be a challenging process. Basic information to navigate insurance is available for the PI community.

Answers to specific questions, relative to cost and generally covered benefits, can be found by reviewing a plan’s summary of benefits, drug formulary list, provider network directory, and by contacting the insurance company. When speaking to an insurance representative, you should be able to receive answers to all of your questions. If not, ask to speak to someone who can answer them.

While this is often considered a tedious process, it is one of the most important steps you can take to ensure that a plan meets your needs. It is better to know everything you can about your plan before you select it than finding problems and hidden costs after you have made a decision. Please remember, it is okay to ask questions until you receive answers when communicating with insurance representatives.

I was just diagnosed; there’s so much information, where do I start?

We hear you! Your first, best step, is to set up an IDF account and subscribe to emails and/or text alerts. We’ll send you news and helpful resources, and you can change or cancel your subscription at any time.

Next, download or order the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition, which contains comprehensive information about the diagnosis, treatment, and management of primary immunodeficiency.

If you have further questions or are diagnosed with PI and looking for more support, please reach out to us at 410-321-6647.

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice. Additionally, links to other resources and websites are shared for informational purposes only and should not be considered an endorsement by the Immune Deficiency Foundation.

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