primary immunodeficiency

Primary immunodeficiencies result from intrinsic genetic defects (as opposed to secondary immunodeficiencies caused by external factors like HIV, malnutrition, or immunosuppressive drugs). They are categorized based on which arm of the immune system is affected:

1. B-cell (humoral) deficiencies: Most common category. Examples include X-linked agammaglobulinemia (Bruton's, BTK gene mutation, absent B cells, recurrent bacterial infections after maternal antibodies wane), Common Variable Immunodeficiency (CVID, low immunoglobulins, recurrent sinopulmonary infections, increased lymphoma/autoimmune disease risk), Selective IgA deficiency (most common PID, often asymptomatic, risk of anaphylaxis with blood products due to anti-IgA antibodies), and Hyper-IgM syndrome (CD40L defect, impaired class switching).

2. T-cell deficiencies: Include DiGeorge syndrome (22q11 deletion, thymic aplasia, CATCH-22 features) and present with recurrent viral, fungal, and opportunistic infections.

3. Combined B- and T-cell deficiencies: Severe Combined Immunodeficiency (SCID) is the prototype - a medical emergency requiring early bone marrow transplant. Causes include IL-2R gamma chain mutations (X-linked, most common), ADA deficiency, and others. Presents with failure to thrive, chronic diarrhea, opportunistic infections (e.g., Pneumocystis, CMV), and absent thymic shadow on CXR.

4. Phagocyte disorders: Chronic Granulomatous Disease (NADPH oxidase defect, negative nitroblue tetrazolium/DHR test, catalase-positive organism infections like Staph aureus, Aspergillus), Leukocyte Adhesion Deficiency (CD18 defect, delayed umbilical cord separation, recurrent skin/mucosal infections without pus), and Chediak-Higashi syndrome (LYST gene, giant granules, partial albinism, recurrent pyogenic infections).

5. Complement deficiencies: C1 esterase inhibitor deficiency causes hereditary angioedema; terminal complement (C5-C9) deficiencies predispose to recurrent Neisseria infections.

Clinical clues suggesting PID include: recurrent sinopulmonary infections, infections with unusual organisms, failure to thrive, family history, and infections despite appropriate treatment. Workup includes CBC with differential, immunoglobulin levels, lymphocyte subsets (flow cytometry), and specific functional assays. Management ranges from prophylactic antibiotics and IVIG replacement to bone marrow transplantation for severe combined immunodeficiencies. Understanding the specific defect helps predict the pattern of infections (e.g., encapsulated bacteria in antibody deficiencies, opportunistic pathogens in T-cell defects, catalase-positive organisms in CGD).