Common Variable Immunodeficiency

Notes

Immunodeficiency Disorders | Immunology | Paediatrics | Primary Immunodeficiency | Primary Immunodeficiency Disorders

Overview

Common Variable Immunodeficiency (CVID) is the most frequent clinically significant primary antibody deficiency, characterised by hypogammaglobulinaemia and impaired antibody responses. It typically presents with recurrent bacterial infections, autoimmunity, granulomatous disease, and an increased risk of malignancy. CVID affects both sexes equally, with a prevalence of ~1 in 25,000–50,000 individuals. Diagnosis is often delayed, with onset usually in childhood or early adulthood. Despite “common” in its name, it remains rare, though more frequently encountered than severe combined immunodeficiency (SCID) or chronic granulomatous disease (CGD).

Definition

Hypogammaglobulinaemia: Abnormally low levels of serum immunoglobulins (IgG ± IgA/IgM).
Primary immunodeficiency: Genetic or idiopathic immune system defect leading to recurrent or unusual infections.
Granulomatous disease: Localised aggregation of immune cells (macrophages, T-cells) in response to persistent antigenic stimulation.
Autoimmunity: Failure of self-tolerance leading to immune attack on host tissues (e.g., autoimmune cytopenias, thyroid disease).

CVID

C – Chronic/recurrent infections
V – Variable presentation (autoimmunity, granulomas, GI disease)
I – Immunoglobulin low (IgG ± IgA/IgM)
D – Defective antibody response

Anatomy & Physiology

Normal physiology: B-cells mature in bone marrow, then differentiate into plasma cells that produce immunoglobulins (IgG, IgA, IgM, IgE).
Immunoglobulins provide:
- IgG → systemic protection, memory response
- IgA → mucosal immunity (respiratory, gut)
- IgM → first-line antibody in acute infections
In CVID → failure of B-cell differentiation and impaired class switching → reduced immunoglobulin levels and poor vaccine responses.

Remember

Unlike X-linked agammaglobulinaemia (absent B-cells), in CVID B-cells are present but dysfunctional.

Aetiology

Exact cause unknown; multifactorial.
Genetic associations: mutations in ICOS, TACI (TNFRSF13B), BAFF-R, CD19, CD20, CD21, CD81 in some cases.

Risk Factors

Family history of primary immunodeficiency.
Certain HLA haplotypes associated with autoimmunity in CVID.
Higher risk in Caucasian populations.

Pathophysiology

Genetic/idiopathic defect in B-cell signalling or T-cell–B-cell interaction.
Failure of terminal B-cell differentiation → impaired plasma cell formation.
Hypogammaglobulinaemia (↓ IgG, ± IgA/IgM).
Poor vaccine response and inability to mount protective antibodies.
Consequences: recurrent infections, autoimmunity, granulomatous inflammation, increased malignancy risk.

Think

CVID = “B-cells present, but antibodies absent or dysfunctional.”

Clinical Manifestations

Recurrent infections:
- Sinopulmonary (pneumonia, sinusitis, otitis)
- GI (Giardia, Campylobacter → chronic diarrhoea, malabsorption)
Autoimmunity: autoimmune haemolytic anaemia (AIHA), immune thrombocytopenia (ITP), autoimmune thyroid disease.
Granulomatous disease: lung, liver, spleen, GI tract.
Lymphoproliferation: lymphadenopathy, splenomegaly.
Malignancy risk: non-Hodgkin lymphoma, gastric carcinoma.

Remember

Recurrent pneumonia with bronchiectasis + autoimmune cytopenias in a young adult should trigger suspicion of CVID.

Diagnosis

Diagnostic Criteria (ESID/PAGID):

Age >2 years.
Hypogammaglobulinaemia: low IgG + low IgA and/or IgM.
Poor/absent response to vaccines (protein and polysaccharide antigens).
Exclusion of other defined causes of hypogammaglobulinaemia.

Investigations

Serum immunoglobulin levels (↓ IgG, ± IgA/IgM).
Flow cytometry: normal/near normal B-cell numbers but defective memory B-cells.
Vaccine response testing (tetanus, pneumococcal).
Stool O&P (Giardia).
Imaging: HRCT for bronchiectasis.

Differential Diagnosis )

Condition	Key Differentiating Feature
X-linked agammaglobulinaemia	Absent B-cells on flow cytometry
Selective IgA deficiency	Only IgA low; usually milder
Secondary hypogammaglobulinaemia	Drugs (rituximab, steroids), malignancy, protein loss
HIV/AIDS	Low CD4 count, positive HIV testing

Treatment

Lifelong immunoglobulin replacement therapy (IVIG or SCIG).
Aggressive treatment of infections (antibiotics, antivirals).
Immunosuppression for autoimmunity (corticosteroids, rituximab).
Avoid live vaccines.
HSCT reserved for select severe cases (not routine).

Think

IVIG is the cornerstone of CVID management → reduces infections and improves survival.

Complications & Prognosis

Complications
- Chronic lung disease (bronchiectasis, interstitial lung disease).
- GI disease (enteropathy, malabsorption, granulomatous inflammation).
- Autoimmune disease (ITP, AIHA, thyroid disease).
- Malignancy (non-Hodgkin lymphoma, gastric carcinoma).
Poor prognostic factors
- Early age at diagnosis.
- Granulomatous disease.
- Lymphoproliferation and splenomegaly.
- Recurrent pneumonia with established bronchiectasis.

Remember

Mortality often due to chronic lung disease or malignancy rather than acute infection.

References

Bonilla FA, Barlan I, Chapel H, et al. International Consensus Document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(1):38–59.
Gathmann B, Mahlaoui N, Gérard L, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116–26.
Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116(1):7–15.
Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277–86.
Yazdani R, Abolhassani H, Aghamohammadi A. Common variable immunodeficiency: Epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management. J Investig Allergol Clin Immunol. 2020;30(1):14–34.