Common Variable Immunodeficiency (CVID)

Common variable immune deficiency (CVID), also known as humoral immunodeficiency, is a disorder of the immune system characterized by reduced serum levels of immunoglobulins G, A, and M. The underlying causes of CVID are largely unknown. Patients with this condition are prone to infections in the gastrointestinal tract and the upper and lower respiratory tracts. CVID is also associated with a higher risk of developing autoimmune disorders, granulomatous diseases, and malignancy.

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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 of hypogammaglobulinemia
CVID can only be diagnosed by excluding secondary or other primary causes for the clinical picture of hypogammaglobulinemia.
Differential diagnosisExamplesSuggested procedures and tests
Secondary antibody deficiency
Systemic disorders:Excessive loss of Igs (e.g., nephrosis, protein-losing enteropathy, severe burns)
  • Clinical history and presentation
  • Urine analysis for protein
Hypercatabolism of Ig (e.g., proximal myotonic myopathy)
  • Clinical history and presentation
  • Genetic testing
Malignancy:
  • Chronic lymphocytic leukemia
  • Immunodeficiency with thymoma (Good’s syndrome)
  • Non-Hodgkin’s B cell lymphoma
  • Myeloma
  • Clinical history and presentation
  • Bone marrow biopsy
  • Immunofixation electropheresis
  • Diagnostic imaging
Drug induced:
  • Anticonvulsants (e.g., carpamazepine, phenytoin)
  • Gold salts
  • Glucocorticoids
  • D-pericillamine
  • Antimalarial agents
  • Methotrexate
Clinical and medication history
Infectious diseases:
  • Epstein-Barr virus (EBV)
  • Congenital infections with rubella, cytomegalovirus, or toxoplasma gondii
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:
  • X-linked agammaglobulinemia
  • Hyper IgM syndromes
  • Ataxia telangiectasia
  • Late-onset adenosine deaminase deficiency
  • Atypical forms of severe combined immunodeficiency disease
  • X-linked lymphoproliferative disorder (EBV associated)
  • Chromosomal anomalies (e.g., chromosome 18q-syndrome, monosomy 22)
  • Clinical and family history
  • Mode of inheritance
  • Ig levels in serum
  • Lymphocyte phenotype and function in vitro
  • Genetic testing
  • Karyotyping
Table: Daniel Myrtek, PhD, and Ulrich Salzer, MD (2008). Common Variable Immunodeficiency.

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

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