ConditionBlood & immune system
Primary Immunodeficiency (Inborn Errors of Immunity)
Primary immunodeficiencies (PIDs), now often called inborn errors of immunity, are more than 450 inherited conditions in which part of the immune system is missing or does not work properly. They cause infections that are more frequent, severe, long-lasting or unusual than normal, and some also cause autoimmunity, inflammation or cancer. Some are detected at birth by newborn screening for severe combined immunodeficiency (SCID). Others, such as common variable immunodeficiency, appear in adults. Treatments include antibody replacement, preventive antibiotics and stem cell transplant.
Also called: PID, primary immunodeficiency disease, inborn errors of immunity, inherited immune deficiency
At a glance
- What they are
- Inherited defects in the immune system.
- Main groups
- Antibody deficiencies (most common), combined T and B cell defects, phagocyte defects, complement defects, immune dysregulation.
- Warning signs
- Frequent ear, sinus or lung infections, poor response to antibiotics, unusual or severe infections, poor growth in infants.
- Tests
- Blood counts, immunoglobulin levels, vaccine responses, lymphocyte subsets, genetic testing.
- Treatment
- Immunoglobulin replacement, preventive antibiotics, vaccine adjustments, stem cell transplant or gene therapy.
When to get help
Call 911 or go to the ER
- High fever, breathing difficulty, confusion or signs of sepsis in someone with a known immune deficiency
- A baby with failure to thrive, persistent thrush, chronic diarrhea and severe infections (possible SCID)
See a doctor within a day or two
- Fever with a central line, or after a stem cell transplant
- An infection not improving after 2 months of antibiotics, or needing IV antibiotics to clear
Book a routine appointment
- Four or more new ear infections in a year, or two or more serious sinus infections or pneumonias in a year
- Recurrent deep skin or organ abscesses
- Persistent thrush in the mouth after age 1
- A family history of immune deficiency or unexplained early infant deaths
Warning signs
The Jeffrey Modell Foundation lists warning signs. Two or more suggest the need for evaluation:
- four or more new ear infections within a year
- two or more serious sinus infections within a year
- two or more months on antibiotics with little effect
- two or more pneumonias within a year
- failure of an infant to gain weight or grow normally
- recurrent deep skin or organ abscesses
- persistent thrush in the mouth or fungal skin infection
- need for IV antibiotics to clear infections
- two or more deep-seated infections, including sepsis
- a family history of primary immunodeficiency
In adults, recurrent bacterial sinus and lung infections, bronchiectasis, unusual infections and autoimmune problems together should prompt testing.
Main types
| Type | Examples | Typical infections or features |
|---|---|---|
| Antibody (B cell) deficiencies | Common variable immunodeficiency (CVID), X-linked agammaglobulinemia, selective IgA deficiency | Recurrent ear, sinus and lung infections with bacteria, gut infections such as Giardia |
| Combined T and B cell | SCID, DiGeorge syndrome (when severe) | Severe viral, fungal and opportunistic infections from infancy |
| Syndromes with immune defects | Wiskott-Aldrich syndrome, ataxia-telangiectasia, hyper-IgE syndrome | Eczema, bleeding, unsteadiness, abscesses depending on the syndrome |
| Phagocyte defects | Chronic granulomatous disease | Deep abscesses, fungal and staph infections |
| Complement defects | C2 deficiency, terminal complement deficiencies | Meningococcal infections, lupus-like illness |
| Immune dysregulation | IPEX, ALPS | Autoimmunity, enlarged lymph nodes and spleen |
| Innate immunity defects | Defects in interferon or TLR pathways | Specific severe viral or mycobacterial infections |
Hereditary angioedema is also classified among inborn errors of immunity, though it causes swelling rather than infections.
Primary immunodeficiencies differ from secondary immunodeficiencies, which are caused by outside factors such as HIV, chemotherapy, immunosuppressive medicines, malnutrition or diabetes.
Other features
- autoimmunity: low blood counts, arthritis, inflammatory bowel disease, thyroid disease
- inflammation: granulomas in the lungs, liver or skin in CVID
- cancer: higher risk of lymphoma in some PIDs
- allergy and eczema in some syndromes
- poor response to vaccines
Diagnosis
- complete blood count with differential
- immunoglobulin levels (IgG, IgA, IgM, IgE)
- vaccine responses: antibody levels to tetanus and pneumococcal vaccines
- lymphocyte subsets (T, B and NK cells) by flow cytometry
- neutrophil function tests, such as the dihydrorhodamine test for chronic granulomatous disease
- complement tests (CH50, AH50)
- genetic testing to identify the specific condition
- newborn screening for SCID using the TREC test, done in all US states
Treatment
- immunoglobulin replacement therapy: IV every 3 to 4 weeks or under the skin weekly, for antibody deficiencies. Lifelong in most cases
- preventive antibiotics or antifungals for some conditions
- prompt, often longer, treatment of infections
- vaccine adjustments: live vaccines are avoided in many PIDs. Household members should be fully vaccinated
- hematopoietic stem cell transplant: curative for SCID and some other severe PIDs, best done early
- gene therapy for certain forms such as ADA-SCID
- targeted biologic medicines for immune dysregulation
- monitoring for lung damage, autoimmunity and cancer
Living with a primary immunodeficiency
Many people with antibody deficiencies, treated with immunoglobulin replacement, lead full, active lives. Hand hygiene, good nutrition, dental care, and a plan for urgent care when fever develops help. Patient organizations provide education and support.
Frequently asked questions
What is a primary immunodeficiency?
A primary immunodeficiency is an inherited condition in which part of the immune system is missing or does not work properly. This leads to frequent, severe or unusual infections, and sometimes autoimmune problems. There are more than 450 different types.
What are the warning signs of primary immunodeficiency?
Warning signs include frequent ear, sinus or lung infections, infections that need IV antibiotics or do not respond to antibiotics, deep abscesses, persistent thrush, poor growth in babies and a family history of immune deficiency.
What is the most common primary immunodeficiency?
Selective IgA deficiency is the most common, though many people have no symptoms. Among those causing significant illness, common variable immunodeficiency (CVID) is the most frequently diagnosed in adults, usually causing recurrent sinus and lung infections.
How is primary immunodeficiency treated?
Treatment depends on the type. Antibody deficiencies are treated with immunoglobulin replacement by IV or under-the-skin infusions. Others need preventive antibiotics or antifungals. Severe forms such as SCID can be cured with a stem cell transplant or, in some cases, gene therapy.
Can adults be diagnosed with primary immunodeficiency?
Yes. Some forms, especially common variable immunodeficiency, are often diagnosed in adulthood, sometimes after years of recurrent infections. Adults with frequent pneumonias, sinus infections or bronchiectasis should ask about immunoglobulin testing.
Sources
This guide was written from current patient and clinical guidance, including:
- Immune Deficiency Foundation: Patient and family handbook
- Jeffrey Modell Foundation: 10 warning signs of primary immunodeficiency
- American Academy of Allergy, Asthma & Immunology: Primary immunodeficiency disease
- International Union of Immunological Societies (IUIS): Classification of inborn errors of immunity
- National Institute of Allergy and Infectious Diseases: Primary immune deficiency diseases