Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency, defined by low serum IgG together with low IgA or IgM, poor antibody response to vaccines, and recurrent bacterial infections starting in late childhood or adulthood. Population estimates place prevalence at roughly 1 in 25,000-50,000 in Europe and North America, with most patients diagnosed between ages 20 and 45 after a mean diagnostic delay of 4-9 years.
Common variable immunodeficiency (ICD-10: D83.0-D83.9; principal code D83.9) is a heterogeneous primary immunodeficiency characterized by impaired B-cell differentiation into antibody-producing plasma cells, resulting in low total IgG (more than 2 standard deviations below age-matched normal) combined with low IgA or low IgM, poor antibody response to T-cell-independent and -dependent vaccines (pneumococcal polysaccharide and tetanus or diphtheria toxoid), and absence of other defined causes of hypogammaglobulinaemia. The European Society for Immunodeficiencies (ESID) 2019 criteria require age over 4 years, exclusion of secondary causes (drug-induced, protein-losing states, malignancy), IgG below 2 SD with low IgA or IgM, and either poor vaccine response or low switched memory B-cells. CVID is genetically heterogeneous; monogenic causes are identified in 15-25% of cases (TACI/TNFRSF13B, ICOS, CD19, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD), while most cases are polygenic and influenced by environmental factors. Beyond infections, CVID is recognized as a syndrome of immune dysregulation: 20-30% develop autoimmune disease (immune thrombocytopenia, autoimmune haemolytic anaemia, autoimmune thyroid disease), 10-20% develop granulomatous and lymphocytic interstitial lung disease, 10-15% develop enteropathy with chronic diarrhoea and malabsorption, and lifetime lymphoma risk is approximately 4-fold higher than the general population.
The key symptoms of Common Variable Immunodeficiency are: Recurrent or chronic sinusitis, otitis media, bronchitis, and pneumonia caused by encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) — typical from late childhood or early adulthood., Chronic productive cough, sputum production, and recurrent chest infections with bronchiectasis on high-resolution CT in 30-50% of long-standing cases., Persistent or recurrent diarrhoea (more than 2 weeks per year), abdominal cramping, malabsorption, and weight loss in approximately 10-15% of patients., Symmetrical or asymmetrical lymphadenopathy, splenomegaly, and rarely hepatomegaly from lymphoid hyperplasia., Easy bruising, mucosal bleeding, petechiae, or unexplained anaemia from immune thrombocytopenia or autoimmune haemolytic anaemia., Recurrent skin or soft-tissue infections, conjunctivitis, or pyoderma in some patients., Persistent gingivitis, dental caries, and oral candidiasis from impaired mucosal immunity..
Diagnosis combines clinical history, immunoglobulin measurement, functional vaccine response testing, and exclusion of secondary causes. The ESID 2019 criteria require: age over 4 years; markedly low IgG (more than 2 SD below age-matched normal) together with at least one of low IgA or low IgM; absent or poor antibody response to vaccines (pneumococcal polysaccharide and tetanus or diphtheria toxoid, with conjugate vaccines as additional input); and exclusion of other causes including drug-induced hypogammaglobulinaemia (anti-CD20 monoclonal antibodies, antiepileptic drugs, sulfasalazine), protein-losing enteropathy or nephrotic syndrome, lymphoid malignancy, congenital agammaglobulinaemia, and HIV. Initial laboratory work-up includes full blood count with differential, serum immunoglobulins (IgG, IgA, IgM, IgE), IgG subclasses, lymphocyte subsets (CD3, CD4, CD8, CD19, CD56, switched memory B-cells), specific antibody responses to pneumococcal capsular polysaccharide and tetanus toxoid (pre- and 4-week post-vaccination titres), urinalysis for protein, faecal calprotectin and faecal alpha-1-antitrypsin if enteropathy is suspected, HIV serology, and serum protein electrophoresis. Imaging includes high-resolution CT of the chest at baseline and every 2-3 years to detect bronchiectasis and granulomatous-lymphocytic lung disease, and abdominal ultrasound or CT to assess splenomegaly and lymphadenopathy. Genetic testing (whole exome or targeted CVID panel) is increasingly recommended, especially in early-onset disease, syndromic features, or refractory autoimmunity. Bone marrow biopsy is reserved for unexplained cytopenia or suspected malignancy. Differential diagnosis is broad and includes X-linked agammaglobulinaemia (boys with absent B-cells), hyper-IgM syndrome, selective IgA deficiency, transient hypogammaglobulinaemia of infancy, drug-induced hypogammaglobulinaemia, multiple myeloma with hypogammaglobulinaemia, and chronic lymphocytic leukaemia.
Outcomes have transformed since the introduction of immunoglobulin replacement. Patients with infection-only CVID have near-normal life expectancy when treatment starts before significant lung damage. Resnick et al. (Blood 2012) reported overall 35-year survival of 64% from diagnosis in adults, with non-infectious complications (GLILD, lymphoma, autoimmune cytopenia, enteropathy) being the principal cause of premature death rather than infection itself. Patients with autoimmune cytopenia, GLILD, or enteropathy have substantially higher mortality (3-11 fold). Lymphoma is approximately 4-fold more common than general population. Quality of life is affected by chronic infusions, infections, and complication management; subcutaneous immunoglobulin and home infusion programmes substantially improve patient autonomy. Earlier diagnosis (reducing the current 4-9 year delay) is the single most important determinant of better outcomes; widespread immunoglobulin testing in recurrent infections shortens the diagnostic interval.
An allergist/immunologist or haematologist with primary immunodeficiency expertise is essential to confirm the diagnosis, plan immunoglobulin replacement, manage complications, coordinate vaccines, and provide genetic counselling. Multidisciplinary input from pulmonology, gastroenterology, infectious disease, and rheumatology is needed for organ-specific complications.
Find specialists →Infections respond to standard antibiotics; immunoglobulin replacement reduces frequency over 6-12 months. Bronchiectasis is irreversible once established but progression slows. Autoimmune cytopenias resolve over weeks to months with appropriate immunosuppression. GLILD stabilizes or improves over 6-12 months with rituximab-based therapy. Lifelong follow-up and lifelong immunoglobulin replacement remain the norm.
Encourage 150 minutes of moderate aerobic exercise weekly plus resistance training twice a week. Patients with bronchiectasis benefit from pulmonary rehabilitation and daily airway clearance. Avoid swimming in untreated freshwater because of bacterial exposure risk.
Choose a centre with a dedicated primary immunodeficiency clinic, in-house immunoglobulin infusion service, access to home subcutaneous immunoglobulin, genetic testing for inborn errors of immunity, and links to a national or international PID registry (USIDNET, ESID). Ask about transition pathways for paediatric to adult care.
Medically reviewed by AIHealz Medical Editorial Board · May 13, 2026
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