Primary immunodeficiencies
Primary immunodeficiencies (PID) are inherited defects of a discrete immune component, antibody, T cell, phagocyte, or complement, that cause infections which are unusually severe, persistent, or recurrent. Diagnosis rests on quantitative and functional immune testing matched to the infection pattern; treatment centers on immunoglobulin replacement, targeted prophylaxis, and hematopoietic stem cell transplant for the most severe combined defects.
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What this article covers
- Overview
Definition: primary immunodeficiencies (PID) are inherited defects that impair one arm of the immune system (antibody, T cell, phagocyte, or complement) rather than an acquired process such as human immunodeficiency virus (HIV) infection.
- Epidemiology
Overall frequency: selective IgA deficiency is the single most common PID, occurring in approximately 0.5% of the general population, and most affected people are asymptomatic.
- Risk factors
Family history: a relative with early childhood infectious death suggests an X-linked or autosomal recessive pedigree.
- Pathophysiology
Antibody (B-cell) defects: a block from B-cell maturation to class switching removes humoral defense; loss-of-function Bruton tyrosine kinase mutation halts pre-B-cell maturation in XLA, while CVID…
- Clinical features
Antibody defects: recurrent sinopulmonary infection with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae); giardiasis and malabsorption occur in XLA and CVID, and CVID adds…
- Differential diagnosis
HIV infection: also causes progressive helper T-cell (CD4) depletion, but a positive HIV nucleic acid test and an exposure history distinguish it; antibody testing alone is unreliable in infants because of maternal antibody.
- Diagnosis
What establishes the diagnosis: a reproducible, quantitative or functional defect in a specific arm of the immune system matching the infection pattern, most directly a low immunoglobulin with…
- Management
First, treat the active infection: start prompt, culture-directed antibiotics while the immunologic evaluation proceeds, and withhold live vaccines until the immune category is characterized.
- Complications
Chronic structural lung disease: cumulative sinopulmonary infection in antibody defects leads to bronchiectasis, often already present at CVID diagnosis.
- Prognosis
Untreated SCID: without immune reconstitution, SCID is fatal by age 1 to 2 years, almost always from overwhelming infection.
- Prevention
Newborn screening: the TREC assay, part of routine newborn screening in many jurisdictions, identifies most infants with SCID before their first serious infection.
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Related articles
- Common variable immunodeficiency (CVID)
Common variable immunodeficiency is the most common symptomatic primary immunodeficiency, a defect in B-cell differentiation causing low immunoglobulins and recurrent sinopulmonary infections, usually diagnosed after puberty. Diagnosis rests on low IgG with low IgA or IgM plus impaired vaccine responses, and treatment is lifelong immunoglobulin replacement with prompt infection management.
- X-linked (Bruton) agammaglobulinemia
X-linked agammaglobulinemia is a BTK gene defect that arrests B-cell maturation, producing absent peripheral B cells and panhypogammaglobulinemia in boys with recurrent sinopulmonary infection after 6 months of age. Diagnosis rests on quantitative immunoglobulins, B-cell flow cytometry, and BTK sequencing; treatment is lifelong immunoglobulin replacement plus prompt antibiotics and avoidance of live vaccines.
- Complement deficiency
Complement deficiency comprises inherited deficiencies of complement proteins whose clinical pattern predicts the risk: early classical-pathway (C1-C4) deficiency causes lupus-like autoimmunity and pyogenic infection, while terminal pathway (C5-C9) deficiency causes recurrent Neisseria infection. Diagnosis uses CH50 and AH50 screening with individual component levels, and prevention centers on meningococcal vaccination and antibacterial prophylaxis.
- Selective IgA deficiency
Selective IgA deficiency is the most common primary antibody deficiency, defined by a serum IgA level below 7 mg/dL with normal IgG and IgM. Most patients are asymptomatic; management is supportive, treating sinopulmonary and gastrointestinal infections as they occur and using washed or IgA-deficient blood products to prevent anaphylactic transfusion reactions.
- Hyper-IgM syndrome
Hyper-IgM syndrome is a class-switch recombination defect, most often X-linked CD40 ligand deficiency, causing normal or high IgM with very low IgG, IgA, and IgE and severe pyogenic and opportunistic infections early in life. Diagnosis rests on the immunoglobulin pattern with impaired switching, and treatment is immunoglobulin replacement, Pneumocystis prophylaxis, and consideration of stem cell transplantation.