6.1 Primary Immunodeficiency

Primary Immunodeficiency

What Is Primary Immunodeficiency?

Primary immunodeficiency (PID) describes a group of more than 500 recognized inherited disorders in which a component of the immune system is intrinsically defective, leading to increased susceptibility to infection, autoimmunity, and malignancy. PID is far less common than secondary immunodeficiency, which is acquired from an external cause such as malnutrition, HIV infection, immunosuppressive medication, or malignancy. Every PID work-up should exclude a secondary cause first, and HIV testing is a standard part of the initial evaluation.

Warning Signs That Should Trigger Evaluation

The most widely used screening tool in pediatric practice is the Jeffrey Modell Foundation's "10 Warning Signs of Primary Immunodeficiency." A child with two or more of the following warrants immunologic evaluation:

The exam favors vignettes built around this pattern: an infant or toddler whose infections are too frequent, too severe, caused by unusual organisms, or poorly responsive to standard treatment.

Major Categories of Primary Immunodeficiency

PID is classified by which arm of host defense is defective. Four categories dominate written exam questions.

1. Antibody (B-Cell) Deficiencies -- the largest group

• X-linked agammaglobulinemia (XLA, Bruton agammaglobulinemia): a mutation in the BTK (Bruton tyrosine kinase) gene blocks B-cell maturation, so B cells and all immunoglobulin classes are nearly absent. Because it is X-linked, it affects boys only. Infants are protected by transplacental maternal IgG for the first months of life, then present around 6 months of age with recurrent sinopulmonary infections -- otitis media, sinusitis, pneumonia -- caused by encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. A classic exam clue is absent or hypoplastic tonsils and lymph nodes, since these structures depend on B cells. Treatment is lifelong immunoglobulin replacement therapy.
• Selective IgA deficiency: the single most common PID, often clinically silent. When symptomatic, it causes recurrent sinopulmonary and gastrointestinal infections. The key exam trap: affected patients can develop anaphylaxis to blood products containing IgA because they may form anti-IgA antibodies, so transfusions require washed or IgA-deficient components.
• Common variable immunodeficiency (CVID): low IgG with low IgA and/or IgM; typically presents later in childhood or adulthood with recurrent infections plus autoimmune or granulomatous disease.

2. Combined (T- and B-Cell) Immunodeficiencies

Severe combined immunodeficiency (SCID) is the most severe PID, historically called "bubble boy disease." Both T-cell and B-cell immunity fail (the most common form is X-linked, from a defective common gamma chain gene, IL2RG). Infants look deceptively well at birth, then decompensate by 3-6 months with failure to thrive, chronic diarrhea, persistent oral candidiasis, and opportunistic infections such as Pneumocystis jirovecii pneumonia. A classic chest radiograph finding is an absent thymic shadow. Live vaccines (rotavirus, BCG) are contraindicated and can be fatal in an unrecognized SCID infant. Many countries now screen every newborn using the T-cell receptor excision circle (TREC) assay on the dried blood spot, which detects low thymic T-cell output before infections occur. Definitive treatment is hematopoietic stem cell transplantation (HSCT), ideally performed before infectious complications develop.

DiGeorge syndrome (22q11.2 deletion) causes T-cell lymphopenia from thymic hypoplasia rather than full SCID. The classic presentation combines conotruncal cardiac defects (tetralogy of Fallot, truncus arteriosus), hypocalcemic seizures from hypoparathyroidism, and characteristic facial dysmorphism (hypertelorism, low-set ears, micrognathia). Infants have recurrent viral and opportunistic infections; chest radiograph may show a small or absent thymic shadow, mimicking SCID, but immunoglobulin levels are usually normal. Management includes calcium supplementation, infection surveillance, and targeted prophylaxis; severe T-cell failure may require thymus transplantation.

3. Phagocyte Disorders

• Chronic granulomatous disease (CGD): a defect in the NADPH oxidase complex impairs the phagocyte oxidative ("respiratory") burst, so neutrophils cannot kill catalase-positive organisms (Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Aspergillus, Nocardia). This produces recurrent deep abscesses, suppurative lymphadenitis, and granuloma formation that can obstruct the GI or GU tract. Diagnosis uses the nitroblue tetrazolium (NBT) test or the more sensitive dihydrorhodamine (DHR) flow cytometry assay; the most common inheritance pattern is X-linked (CYBB gene).
• Leukocyte adhesion deficiency (LAD): a defect in neutrophil adhesion molecules (CD18 integrins) prevents neutrophils from leaving the bloodstream. Classic clues are delayed separation of the umbilical cord (more than 3-4 weeks), poor wound healing, recurrent skin and soft-tissue infections without pus formation, and a markedly elevated peripheral white cell count.

4. Complement Deficiencies

• Terminal complement pathway deficiencies (C5-C9) impair formation of the membrane attack complex and are classically associated with recurrent or invasive Neisseria infections (meningococcemia, disseminated gonococcal infection). Screen with a CH50 assay.
• Early complement deficiencies (C1, C2, C4) are associated with lupus-like autoimmune disease rather than infection.
• C1 esterase inhibitor deficiency causes hereditary angioedema -- an exam trap, since it causes recurrent swelling, not increased infection risk.

Basic Initial Workup

Exam Traps to Remember

• Isolated IgA deficiency usually needs no treatment, but blood products must be washed or IgA-deficient to avoid anaphylaxis.
• SCID infants often look well at birth (protected by maternal IgG) and decompensate only around 3-6 months -- do not be reassured by a normal newborn exam.
• LAD presents with a paradoxically elevated white cell count and no pus, the opposite of what students expect from a "deficiency."
• An absent thymic shadow on chest x-ray in a floppy, failure-to-thrive infant with thrush is SCID until proven otherwise.