Immunodeficiency Disorders — Symptoms, Causes & Treatment | MyMedicPlus

Immunodeficiency disorders are conditions in which the immune system's ability to fight infections and disease is absent, impaired, or reduced. They are classified as primary (inherited, genetic defects in immune system development or function) and secondary (acquired from external causes such as HIV infection, malnutrition, chemotherapy, immunosuppressive drugs, or radiation). Over 450 distinct primary immunodeficiency diseases (PIDs) have been identified, collectively affecting approximately 1 in 1,200 people globally. The hallmark is recurrent, severe, or unusual infections, though some forms also predispose to autoimmunity and malignancy. Secondary immunodeficiency remains far more prevalent globally than primary forms — HIV infection alone affects 38 million people and causes profound T-cell deficiency when untreated, while malnutrition represents the most common worldwide cause of impaired immune function, disproportionately affecting children in low-income settings. Early diagnosis and specialist management of primary immunodeficiencies are essential, as specific curative or highly effective treatments including immunoglobulin replacement and stem cell transplantation can transform outcomes.

Primary immunodeficiencies result from genetic mutations affecting immune cell development, signaling, or function. Common PIDs include: common variable immunodeficiency (CVID — most common symptomatic antibody deficiency in adults), X-linked agammaglobulinemia (XLA — absent B cells), selective IgA deficiency (most common PID, often asymptomatic), severe combined immunodeficiency (SCID — medical emergency in infants), and chronic granulomatous disease (CGD — neutrophil dysfunction). Secondary immunodeficiencies: HIV/AIDS, hematological malignancies, chemotherapy and steroids, solid organ and stem cell transplant immunosuppression, splenectomy, protein-losing states, and severe malnutrition. Combined immunodeficiencies (T and B cell defects) include SCID (multiple genetic subtypes — ADA deficiency, gamma-chain deficiency, RAG1/RAG2 deficiency), Wiskott-Aldrich syndrome, DiGeorge syndrome (22q11 deletion), and ataxia-telangiectasia — each with distinct genetic causes, clinical manifestations, and treatment requirements. Acquired immunodeficiency from HIV infection is driven by progressive CD4+ T lymphocyte depletion below 200 cells/µL, at which point opportunistic infections including Pneumocystis jirovecii pneumonia, Toxoplasma encephalitis, and CMV retinitis become significant risks without combination antiretroviral therapy.

The 'warning signs' suggesting primary immunodeficiency include: 4 or more new ear infections per year, 2 or more serious sinus infections per year, 2 or more pneumonias within 1 year, recurrent deep skin or organ abscesses, persistent oral or skin candidiasis after infancy, infections with unusual or low-virulence organisms (Pneumocystis, Cryptococcus, atypical mycobacteria), failure to respond to antibiotics requiring IV therapy, family history of immunodeficiency, and failure to thrive in infants. Different immune defects predispose to different infection types: antibody deficiencies to bacteria; T-cell defects to viruses and fungi; neutrophil defects to bacteria and fungi. The Jeffrey Modell Foundation's "10 Warning Signs" of primary immunodeficiency are widely used for screening: these include 4+ new ear infections/year, 2+ serious sinus infections/year, 2+ months on antibiotics with little effect, 2+ pneumonias/year, failure to gain weight or grow normally in infancy, recurrent deep skin or organ abscesses, thrush in mouth or fungal infection of skin, family history of PID, and need for IV antibiotics to clear infections.

Initial investigations include full blood count with differential (lymphopenia, neutropenia, absent cell lineages), serum immunoglobulins (IgG, IgA, IgM, IgE — low in antibody deficiencies), and specific antibody responses to tetanus and pneumococcal vaccines (functional antibody testing). Flow cytometry quantifies lymphocyte subsets (CD4, CD8 T cells, NK cells, B cells). Neutrophil oxidative burst assay (dihydrorhodamine test) screens for chronic granulomatous disease. HIV testing excludes acquired T-cell deficiency. Next-generation sequencing identifies causative mutations in suspected PIDs. Chest CT frequently shows bronchiectasis from recurrent pulmonary infections. Whole-exome or whole-genome next-generation sequencing has revolutionised PID diagnosis, identifying causative mutations in novel genes and in patients with atypical presentations that have evaded conventional diagnostic approaches. Newborn screening for SCID using T-cell receptor excision circles (TRECs) from dried blood spots now enables presymptomatic diagnosis before life-threatening infections occur in many high-income countries.

Immunoglobulin replacement therapy (IVIG — intravenous, or SCIG — subcutaneous) is the cornerstone of treatment for antibody deficiencies (CVID, XLA), providing protective IgG levels and dramatically reducing bacterial infection frequency. Hematopoietic stem cell transplantation (HSCT) is curative for most severe PIDs — SCID requires urgent HSCT in the first months of life for survival. Gene therapy has achieved spectacular results in ADA-deficient SCID and X-linked SCID in clinical trials, offering a potential cure without the risks of allogeneic transplantation. Prophylactic antibiotics, antifungals, and antivirals prevent opportunistic infections in specific defects. G-CSF treats severe congenital neutropenia. For HIV/AIDS, combination antiretroviral therapy (ART) restores CD4 T-cell counts and prevents AIDS-defining opportunistic infections — early initiation is now recommended for all patients regardless of CD4 count. Trough IgG level monitoring guides dose adjustments for IVIG/SCIG replacement therapy, with targets typically above 7–8 g/L and higher targets for patients with established lung disease or frequent infections. Pneumocystis jirovecii pneumonia prophylaxis with co-trimoxazole is recommended during periods of significant immunosuppression.

Recurrent infections cause progressive organ damage — particularly bronchiectasis from repeated pulmonary infections in antibody deficiencies — leading to chronic respiratory failure. Granulomatous and autoimmune complications occur in CVID (inflammatory bowel disease, cytopenias, granulomatous lung disease) and CGD. Malignancy risk is elevated in several PIDs — lymphoma in CVID, EBV-related lymphoproliferative disease in T-cell deficiencies. Untreated SCID is uniformly fatal in infancy from overwhelming infections. Complications from immunoglobulin replacement include infusion reactions; long-term home SCIG has significantly improved quality of life.

Early diagnosis is critical — newborn screening programs now include SCID in many countries using T-cell receptor excision circles (TRECs). Genetic counseling is essential for families with PIDs; preimplantation genetic diagnosis is available for several conditions. Avoid live attenuated vaccines (MMR, varicella, yellow fever) in patients with significant T-cell or combined immunodeficiency. All immunodeficiency patients should receive annual influenza vaccination (inactivated) and pneumococcal vaccines (if antibody-competent). Prompt antibiotic treatment of infections, regular monitoring for complications, and multidisciplinary specialist review at an immunology center are fundamental to long-term management.

See your GP for: recurrent, severe, or unusual infections — for example, more than 4 serious bacterial infections per year, infections with organisms that do not normally cause disease in healthy people, infections in unusual locations, or infections that fail to respond to standard antibiotic courses. In children, recurrent ear infections, sinopulmonary infections, failure to thrive, and unusual infections should prompt immunodeficiency assessment. See an immunologist urgently if a family member has a known primary immunodeficiency — genetic testing and early treatment (IVIG, bone marrow transplant) are life-saving in some primary immunodeficiencies. Any child with recurrent infections and failure to thrive, persistent oral thrush after 6 months of age, or any infection with Pneumocystis jirovecii should have urgent immunological evaluation.