Primary Immunodeficiencies

"Immunodeficiency refers to the absence, dysfunction, or impaired development of one or more components of the immune system, resulting in increased susceptibility to infections, autoimmunity, inflammation, allergy, and malignant neoplasms." "Primary immunodeficiencies, collectively known as inborn errors of immunity (IEI), result from pathogenic genetic variants that affect immune development or function." StatPearls (2026) counts "Nearly 500 distinct genetic defects"; NIAID (2019) says "more than 200 different forms."

Read the organism. "Recognition of recurrent infections caused by a particular pathogen often provides a clue to the underlying immune defect." Encapsulated bacteria (pneumococcus, Haemophilus, meningococcus) "suggest an opsonization defect" — antibodies. Pneumocystis, Candida, nontuberculous mycobacteria or Aspergillus "suggest T-cell or phagocytic defects." Catalase-positive organisms such as Staphylococcus aureus, Serratia and Aspergillus "are characteristic of chronic granulomatous disease." "Complement deficiencies predispose to recurrent Neisseria spp infection."

More than infection. "Although recurrent infections remain a defining feature, many IEI also present with autoimmunity, immune dysregulation, allergy, inflammation, lymphoproliferation, or malignant neoplasms." Secondary immunodeficiency, by contrast, arises "from acquired conditions that impair an otherwise normal immune system" — infections, immunosuppressive medicines, cancer, malnutrition.

SCID — the most severe. "SCID is the most profound form of T-cell immunodeficiency, characterized by severe defects in T-cell development, often accompanied by impaired B-cell and natural killer cell function." NIAID: "Infants with SCID appear healthy at birth but are highly susceptible to severe infections. The condition is fatal, usually within the first year or two of life, unless infants receive immune-restoring treatments." "Infants typically present with failure to thrive, persistent candidiasis, chronic diarrhea, severe or opportunistic infections, and absent lymphoid tissue."

DiGeorge (22q11.2 deletion). The deletion affects an estimated 1 in 4,000 people and is probably underdiagnosed because its features vary so widely (MedlinePlus Genetics). A defect of the pharyngeal arches: "Facial dysmorphism, cleft palate, hypocalcemia, and congenital cardiac defects suggest DiGeorge syndrome." Absent parathyroids cause "hypocalcemia of variable severity, ranging from neonatal seizures and tetany to subclinical hypocalcemia." "Complete DiGeorge syndrome, characterized by complete absence of thymic tissue and profound T-cell lymphopenia, affects less than 1% of individuals with 22q11.2 deletion but represents a life-threatening condition requiring thymus transplantation."

Antibody deficiencies. "X-linked agammaglobulinemia manifests after maternal antibodies wane, with recurrent bacterial infections and absent tonsils." CVID "commonly presents with recurrent sinopulmonary infections, lymphadenopathy, splenomegaly, or bronchiectasis," usually diagnosed "between ages 20 and 45." Selective IgA deficiency "is the most common primary immunodeficiency overall," but "most are largely asymptomatic."

CGD. "CGD occurs when white blood cells called phagocytes are unable to kill certain bacteria and fungi, making people highly susceptible to some bacterial and fungal infections."

Immunoglobulin. "Immunoglobulin replacement therapy is the mainstay of treatment for antibody deficiencies (X-linked agammaglobulinemia, common variable immunodeficiency, hyper-IgM syndromes, and other conditions with impaired antibody production)." It "is administered as intravenous immunoglobulin or subcutaneous immunoglobulin," and "Patients who do not undergo curative therapy require lifelong immunoglobulin replacement therapy." It "reduces sinopulmonary infections but does not completely prevent chronic lung disease."

Cure. "Hematopoietic stem cell transplant (HSCT) is the definitive curative therapy for many IEI, including SCID, CGD, Wiskott-Aldrich syndrome, hyper-IgM syndrome, leukocyte adhesion deficiency, and other severe combined or phagocyte defects." "Gene therapy has become an increasingly important curative strategy for selected monogenic IEIs."

IVIG safety. Boxed warning: "Thrombosis may occur with immune globulin (IGIV) products." Rate matters: "most of the adverse events are due to the fast infusion rates," so "The slowest initial infusion rates are necessary to prevent any undesirable situation." IgA deficiency is the anaphylaxis trap: "IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions," and for transfusion "they should be administered IgA poor or washed red cells."