Epidemiology
- Incidence: 1:10,000 to 1:50,000
- The largest group of symptomatic primary immunodeficiencies in adults
- Age of onset in most patients between 20 and 30 years
- Equal incidence between genders
- The median age of death from CVID is 44 years (for females) and 42 years (for males).
Etiology and Pathophysiology
Etiology
- Exact cause unknown
- Most cases are sporadic.
- Genetic mutations account for 10% of cases; however, a monogenic cause cannot be established in the majority of cases.
- Linked to mutations in genes that encode cell surface proteins, cytokine receptors, and major histocompatibility complex
- Familial inheritance accounts for 10%–25%.
- X-linked, autosomal dominant, and recessive patterns have been documented.
Pathophysiology
- B cells are phenotypically normal but unable to develop into immunoglobulin (Ig)-secreting plasma cells, leading to insufficient amounts of antibodies:
- IgG: long-term immunity
- IgA: secretory immunity
- IgM: acute immune response against infections (in 50% of cases this immunoglobulin is deficient)
- Lack of Ig increases the patient’s risk for recurrent infections and developing impaired immune responses, such as autoimmune diseases, granulomatous disease, and malignancy.
- Most often, CVID patients are infected by Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus.
Signs and Symptoms
- Recurrent, mostly bacterial, infections (most commonly pyogenic lung and sinus infections and persistent diarrhea)
- Autoimmune disorders (e.g., rheumatoid arthritis, psoriasis, autoimmune hemolytic anemia, type 1 diabetes mellitus, lupus, vitiligo)
- Granulomatous disease (granulomas in the lungs, lymph nodes, skin, and GI tract that resemble sarcoidosis on histologic examination)
- Lymphoid hyperplasia (lymphadenopathy, splenomegaly, and hepatomegaly)
- High risk of malignancy (commonly associated with lymphoma, gastric, breast, colon, prostate, and ovarian cancer)
- Miscellaneous symptoms (abdominal cramps, constipation, malabsorption, weight loss, anxiety, depression, and severe lethargy)
Diagnosis
Diagnosis is difficult because of the diversity of phenotypes.
- Clinical history
- Note type of frequency of infections and family history (especially looking for history of antibody deficiency)
- Suspect CVID if patients present with a history of recurrent infections, autoimmune disorder, granulomatous disease, or a lymphocytic malignancy and the following physical signs suggestive of CVID:
- Abdomen: abdominal pain, chronic/bloody diarrhea, hepatosplenomegaly
- Head and neck: alopecia, lymphadenopathy
- Respiratory: bronchiectasis, cough, dyspnea, pleuritic chest pain
- Skin: actinic keratosis, atopic dermatitis, eczema, mollusca contagiosum, hyperpigmentation, petechiae, skin cancers, vitiligo
- Systemic: signs of malnutrition, weight loss
- Need to exclude secondary causes of antibody deficiency, hypogammaglobulinemia, T-cell deficiencies, and other primary immunodeficiencies (see table below)
- Laboratory findings
- Marked decrease in IgG (and its subclasses), IgA, and IgM (some cases of CVID will not have diminished IgM but all will have decreased IgG and IgA)
- Poor antibody response to vaccines (tetanus and pneumococcal vaccines)
- Low plasma cell levels
- Can test for specific gene mutations (but not necessary for diagnosis)
- In addition, assessment of comorbid conditions:
- High-resolution computed tomography scanning to detect lung damage
- Culture and sensitivity testing to identify causative organisms and guide antibiotic therapy of recurrent infections
- Biopsy and histologic examination of suspicious lesions to rule out lymphomas
| Differential diagnosis | Examples | Suggested procedures and tests |
|---|---|---|
| Secondary antibody deficiency | ||
| Systemic disorders: | Excessive loss of Igs (e.g., nephrosis, protein-losing enteropathy, severe burns) |
|
| Hypercatabolism of Ig (e.g., proximal myotonic myopathy) |
| |
| Malignancy: |
|
|
| Drug induced: |
| Clinical and medication history |
| Infectious diseases: |
| Direct testing for antigen (EUSA and PCR, serology of any kind is of limited or no value in patients with antibody deficiency) |
| Other primary immunodeficiencies: | ||
|
| |
Summary of findings needed for diagnosis
- At least 1 of the following:
- Increased susceptibility to infections
- Autoimmune disease manifestations
- Granulomatous disease
- Unexplained polyclonal lymphoproliferation
- Family history of antibody deficiency
- AND marked decrease of IgG and IgA +/- decreases in IgM
- AND at least 1 of the following:
- Poor immunological response to vaccines
- Low plasma cell levels
- AND secondary causes of hypogammaglobulinemia excluded
- AND diagnosis established after age four
- AND no evidence of T cell deficiency
Management
- Ig replacement therapy replenishes Ig isotypes either intravenously, subcutaneously, or, rarely, intramuscularly.
- Side effects: swelling at the insertion site, chills, headache, nausea, fatigue, fever, and hives
- Immunosuppressants can also be used to control autoimmune symptoms.
- Antibiotic and/or antifungal therapy for infections
- Short-term corticosteroid therapy may prevent non-anaphylactic reactions (common in this condition).
Differential Diagnosis
Congenital B-cell immunodeficiencies:
- X-linked agammaglobulinemia: also known as Bruton’s agammaglobulinemia, a recessive genetic disorder characterized by the improper development of B cells from immature to mature cells
- Selective IgA deficiency: the most common primary immunodeficiency, characterized by an undetectable serum IgA level in the presence of normal serum levels of IgG and IgM in patients older than 4 years
