Immunodeficiency Disorders — Causes, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Immunodeficiency disorders occur when one or more components of the immune system are absent, reduced, or dysfunctional, leaving individuals vulnerable to recurrent, severe, or unusual infections. They are classified as primary (genetic or congenital, caused by inherited defects in immune cell development or function) or secondary (acquired, resulting from external causes such as HIV infection, chemotherapy, malnutrition, or immunosuppressive therapy). Primary immunodeficiencies (PIDs) number over 450 distinct disorders and affect approximately 1 in 1,200 individuals globally. The most common PID in adults is Common Variable Immunodeficiency (CVID), characterised by low IgG, IgA, and IgM with poor vaccine responses. In children, X-linked agammaglobulinaemia (XLA) and severe combined immunodeficiency (SCID — 'bubble boy disease') are among the most serious. Secondary immunodeficiency is far more prevalent, with HIV/AIDS affecting approximately 38 million people worldwide.

Primary immunodeficiencies result from genetic mutations affecting B cells (antibody deficiency — XLA, CVID, selective IgA deficiency), T cells (DiGeorge syndrome — chromosome 22q11 deletion), combined B and T cells (SCID — multiple genetic causes including ADA deficiency, RAG1/2 mutations), phagocytes (chronic granulomatous disease — CGD — defective NADPH oxidase), or complement proteins (C1-C9 deficiencies). Secondary immunodeficiency causes include HIV infection (targets CD4+ T cells, leading to AIDS when count falls below 200 cells/μL), haematological malignancies (leukaemia, lymphoma, myeloma), cytotoxic chemotherapy and radiotherapy, prolonged high-dose corticosteroids (prednisolone >20mg/day for >4 weeks), biological therapies (rituximab, anti-TNF agents), solid organ or haematopoietic stem cell transplantation, protein-losing conditions (nephrotic syndrome, severe burns), malnutrition (zinc, selenium, and vitamin D deficiency impair immunity), and extreme prematurity in neonates.

The hallmark of immunodeficiency is recurrent, severe, persistent, or unusual infections — often caused by organisms that rarely cause disease in healthy individuals (opportunistic pathogens). The 10 Warning Signs of Primary Immunodeficiency (Jeffrey Modell Foundation) include: 4 or more new ear infections per year; 2 or more serious sinus infections per year; 2 or more months on antibiotics with little effect; 2 or more pneumonias within one year; failure of a child to gain weight and grow normally; recurrent deep skin or organ abscesses; persistent thrush or fungal infections; need for intravenous antibiotics to clear infections; 2 or more deep-seated infections including septicaemia; and a family history of primary immunodeficiency. Specific features: antibody deficiencies cause bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae); T-cell defects cause viral (CMV, EBV, VZV), fungal (Candida, Pneumocystis jiroveci), and intracellular bacterial infections; CGD causes catalase-positive bacterial and fungal infections (Staphylococcus, Aspergillus, Burkholderia). Autoimmune manifestations (cytopenias, arthritis) occur in 25-30% of CVID patients.

Initial investigations include: full blood count with differential (lymphopenia suggests T-cell or combined immunodeficiency; neutropenia suggests phagocyte defects); serum immunoglobulins (IgG, IgA, IgM — low IgG is the most important screening test); vaccine-specific antibody titres to tetanus and pneumococcal antigens (to assess functional antibody response); and complement function (CH50 and AH50 screens the entire classical and alternative complement pathways). Lymphocyte subset analysis by flow cytometry quantifies CD4+ T cells (HIV monitoring), CD8+ T cells, B cells, and natural killer cells. Specific antibody deficiency (SAD) is characterised by absent post-immunisation pneumococcal IgG responses with normal serum immunoglobulins. Genetic testing by targeted gene panels or whole exome sequencing identifies causative mutations in suspected PID. HIV ELISA and confirmatory Western blot for secondary immunodeficiency. Newborn screening for SCID uses T-cell receptor excision circles (TRECs) — now mandated in many countries. Bone marrow examination for haematological causes.

Immunoglobulin replacement therapy is the cornerstone treatment for antibody deficiencies. Intravenous immunoglobulin (IVIG) is given every 3-4 weeks at 400-600 mg/kg as a hospital infusion; subcutaneous immunoglobulin (SCIG) is given weekly or twice-weekly at home and is preferred by many patients for convenience and stable IgG levels. Both forms are derived from pooled human plasma and provide broad-spectrum antibody protection against bacterial pathogens. Prophylactic antibiotics (co-trimoxazole, azithromycin) prevent specific infections in selected patients. Haematopoietic stem cell transplantation (HSCT) is curative for SCID and some other severe combined immunodeficiencies — best outcomes when performed in the first 3 months of life before infections occur. Gene therapy using viral vectors to correct genetic defects has achieved functional cures in ADA-SCID (Strimvelis) and X-linked SCID (lentiviral gene therapy). Enzyme replacement therapy with pegylated ADA is used for ADA-SCID. Secondary immunodeficiency treatment targets the underlying cause: antiretroviral therapy (ART) for HIV; granulocyte colony-stimulating factor (G-CSF) for chemotherapy-induced neutropenia; dose reduction or cessation of immunosuppressive agents where feasible. Prophylaxis against Pneumocystis jiroveci pneumonia (PJP) with co-trimoxazole is essential when CD4 count falls below 200 cells/μL in HIV or in T-cell depleted transplant patients.

Untreated immunodeficiency leads to accumulating infectious damage across multiple organ systems. Recurrent bacterial pneumonias in CVID and XLA cause progressive bronchiectasis — permanent dilatation and scarring of the bronchi with chronic productive cough, recurrent infections, and eventually respiratory failure. Approximately 30% of CVID patients develop clinically significant bronchiectasis with lung function decline. Chronic giardia and Cryptosporidium infections in antibody deficiency cause malabsorption, chronic diarrhoea, and failure to thrive. Autoimmune complications (haemolytic anaemia, immune thrombocytopenic purpura, inflammatory arthritis) occur in 25-30% of CVID patients and further complicate management. SCID is uniformly fatal within the first 2 years of life without haematopoietic stem cell transplantation due to overwhelming opportunistic infections from bacteria, viruses, and fungi. Untreated HIV progresses to AIDS — CD4 count below 200 cells/μL — with Pneumocystis jiroveci pneumonia (PJP), cryptococcal meningitis, CMV retinitis (causing blindness), MAC (Mycobacterium avium complex), and cerebral toxoplasmosis causing severe morbidity and death. Lymphoma risk is 100x higher in untreated HIV and post-transplant immunodeficiency.

Vaccinations are critical but require careful consideration: live vaccines (MMR, varicella, BCG, rotavirus, yellow fever) are contraindicated in most immunodeficiency states and in patients on significant immunosuppression — killed/inactivated vaccines should be used instead. Immunocompromised patients should receive inactivated influenza vaccine annually and pneumococcal, meningococcal, and Haemophilus influenzae type b vaccines according to specialist guidance. Annual influenza vaccination for all household contacts of immunodeficient individuals. Food safety: avoid raw or undercooked meat, shellfish, unpasteurised dairy, and raw sprouts which risk Listeria, Salmonella, and Cryptosporidium. Environmental precautions: avoid exposure to Aspergillus sources (building sites, compost, cannabis) in T-cell or phagocyte defects. Genetic counselling enables carrier detection in X-linked disorders and assists family planning decisions. Newborn screening programmes allow early HSCT before infectious complications occur in SCID.

Seek urgent medical attention for any signs of severe infection: high fever with rigors, rapidly spreading redness or swelling, difficulty breathing, confusion, or suspected sepsis. Children who fail to thrive, experience recurrent hospitalizations for infections, or do not respond to standard antibiotics within 48-72 hours require urgent immunology evaluation. Adults with two or more episodes of pneumonia, documented by chest X-ray, within one year should be referred to a clinical immunologist. Any person with persistent oral thrush, chronic diarrhoea, or unexplained lymphadenopathy should be evaluated for HIV and immunodeficiency. A family history of early infant death from infections, or known primary immunodeficiency in a sibling, warrants early specialist referral and genetic counselling regardless of current symptoms.