Common variable immunodeficiency

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Common variable immunodeficiency (CVID) is a heterogeneous group of immunodeficiency. To emphasise the heterogeneity, some prefer the term common variable immunodeficiency disorders.[1] A small percent (~2%) are attributable to monogenic variations or mutations including PLCG2, PIK3CD, FCGR2A ,HLA, IKZF1, ICOS, CD19, CD20, CD21, CD27, CD81, TWEAK, CTLA4, LRBA, GATA2, CXCL12, NFKB1, NFKB2, TNFRSF13B, TNFRSF13C, and NLRP12 (list not exhaustive), but most are sporadic[2] or possibly a result of several interacting genes and an environmental trigger.

Diagnostic Criteria

The European Society for Immunodeficiencies and the Pan-American Group for Immunodeficiency proposed a definition in 1999: "CVID is probable in a male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and fulfills all of the following criteria:

  1. Onset of immunodeficiency at greater than 2 years of age
  2. Absent isohemagglutinins and/or poor response to vaccines
  3. Defined causes of hypogammaglobinaemia have been excluded according to a list of differential diagnosis."

Recognising that the spectrum of disease is more complex, a 2016 consensus definition includes these criteria (reproduced verbatim):[3]

  1. Most patients will have at least 1 of the characteristic clinical manifestations (infection, autoimmunity, lymphoproliferation). However, a diagnosis of CVID may be conferred on asymptomatic individuals who fulfill criteria 2 to 5, especially in familial cases.
  2. Hypogammaglobinaemia should be defined according to the age-adjusted reference range for the laboratory in which the measurement is performed. The IgG level must be repeatedly low in at least 2 measurements more than 3 weeks apart in all patients. Repeated measurement may be omitted if the level is very low (<100–300 mg/dL depending on age), other characteristic features are present, and it is considered in the best interest of the patient to initiate therapy with IgG as quickly as possible.
  3. IgA or IgM level must also be low. (Note that some experts prefer a more narrow definition requiring low IgA level in all patients.)
  4. It is strongly recommended that all patients with an IgG level of more than 100 mg/dL should be studied for responses to T-dependent (TD) and T-independent (TI) antigens, whenever possible. In all patients undergoing such testing, there must be a demonstrable impairment of response to at least 1 type of antigen (TD or TI). At the discretion of the practitioner, specific antibody measurement may be dispensed with if all other criteria are satisfied and if the delay incurred by pre-vaccination and post-vaccination antibody measurement is thought to be deleterious to the patient’s health.
  5. Other causes of hypogammaglobulinemia must be excluded (Table I).
  6. Genetic studies to investigate monogenic forms of CVID or for disease-modifying polymorphisms are not generally required for diagnosis and management in most of the patients, especially those who present with infections only without immune dysregulation, autoimmunity, malignancy, or other complications. In these latter groups of patients, however, single gene defects may be amenable to specific therapies (e.g., haematopoietic stem cell transplantation) and molecular genetic diagnosis should be considered when possible.

References