Immunology · Inborn Error of Immunity

Recognizing the Signs: When to Suspect an Inborn Error of Immunity

At a Glance

An Inborn Error of Immunity (IEI), or primary immunodeficiency, should be suspected if you experience severe, persistent, unusual, or recurrent infections. Key warning signs include frequent pneumonias, reliance on IV antibiotics, and unexplained autoimmune or inflammatory symptoms.

Identifying an Inborn Error of Immunity (IEI) involves looking at the “whole picture” of how the immune system functions. While many people think of these conditions only as “catching too many colds,” the reality is more complex. An IEI can cause the immune system to be underactive (leading to infections) or overactive and “confused” (leading to inflammation and autoimmunity) ^[1]^[2].

The 10 Warning Signs

To help families and doctors recognize these conditions earlier, the Jeffrey Modell Foundation developed a list of 10 warning signs. If you or your child experience two or more of these, you should discuss an immunology evaluation with your doctor ^[3]^[4]:

Four or more new ear infections within one year.
Two or more serious sinus infections within one year.
Two or more months on antibiotics with little effect.
Two or more pneumemias within one year.
Failure of an infant to gain weight or grow normally (failure to thrive).
Recurrent, deep skin or organ abscesses (pockets of infection).
Persistent thrush (yeast infection) in the mouth or fungal infection on the skin.
Need for intravenous (IV) antibiotics to clear infections.
Two or more deep-seated infections, including sepsis (blood infection).
A family history of primary immunodeficiency.

The “SPUR” Criteria

Beyond the 10 signs, immunologists often look for infections that meet the SPUR criteria. These are infections that are ^[5]^[6]:

Severe: They require hospitalization or IV treatments.
Persistent: They don’t clear up with standard courses of medicine.
Unusual: They are caused by rare germs that typically don’t make people sick.
Recurrent: They keep coming back even after successful treatment.

Signs of Immune Dysregulation

Modern research shows that many patients with IEI present with immune dysregulation rather than—or in addition to—infections. This happens when the immune system attacks the body’s own healthy tissues ^[1]. Watch for:

Autoimmunity: Conditions like autoimmune cytopenias (where the body destroys its own blood cells), inflammatory bowel disease (IBD), or Lupus-like symptoms ^[7]^[8].
Autoinflammation: Unexplained, recurrent fevers or episodes of joint pain and swelling ^[1].
Lymphoproliferation: Chronic swelling of the lymph nodes or an enlarged spleen ^[9].
Severe Allergy: Unusually severe eczema or asthma that is difficult to control ^[10]^[11].

Differences Across the Lifespan

Symptoms of IEI can look very different depending on when they first appear.

Age Group	Common Presentations
Infants	Severe skin rashes (eczema), persistent diarrhea, and “failure to thrive” (not meeting growth milestones) ^[12]^[13].
Children	Recurrent ear and sinus infections, and complications from live-virus vaccines ^[4].
Adults	Bronchiectasis (permanent damage to the lungs’ airways) and late-onset autoimmune conditions like unexplained low platelet counts. Notably, Common Variable Immunodeficiency (CVID) is one of the most frequently diagnosed symptomatic IEIs in adults ^[14]^[15].

Early detection is critical, as many of these manifestations can be managed effectively once the underlying genetic cause is identified ^[16]^[17].

Common questions in this guide

What are the SPUR criteria for infections?

The SPUR criteria help identify suspicious infections that are Severe, Persistent, Unusual, or Recurrent. These types of infections may indicate an underlying immune system problem that requires a specialist's evaluation.

Can primary immunodeficiency cause autoimmune diseases?

Yes, many patients with an inborn error of immunity develop autoimmune issues, such as inflammatory bowel disease or low blood counts. This happens because the immune system becomes overactive or confused and mistakenly attacks the body's healthy tissues.

Does primary immunodeficiency only start in childhood?

No, primary immunodeficiency can first appear in adulthood. Conditions like Common Variable Immunodeficiency (CVID) are frequently diagnosed in adults, often presenting with lung damage or late-onset autoimmune issues.

What should I do if my child has multiple ear infections?

If your child has four or more new ear infections within a single year, it is considered one of the 10 warning signs of a primary immunodeficiency. You should discuss an immunology evaluation with your pediatrician.

Curated prompts to bring to your next appointment.

1.Do my child's (or my) recurrent infections meet the criteria for being 'Severe, Persistent, Unusual, or Recurrent' (SPUR)?
2.Could the autoimmune symptoms I'm experiencing (like inflammatory bowel issues or low blood counts) actually be a sign of an underlying inborn error of immunity?
3.Are there specific 'red flags' in my family history that suggest we should pursue genetic testing?
4.If my symptoms started in adulthood, does that change which specific IEIs we should be looking for?
5.Should we be screening for 'silent' symptoms like bronchiectasis (lung damage) even if my current infections are under control?

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

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This page is for educational purposes only to help you recognize signs of inborn errors of immunity. It does not replace a formal evaluation by an immunologist or primary care physician.

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