Common Variable Immunodeficiency

Medical Experts

Contributor

Lin

Leo Lin, MD, PhD

Medical Director, Immunology Assistant, ARUP Laboratories

Assistant Professor (Clinical), University of Utah

Common variable immunodeficiency (CVID), the most common clinically significant primary immunodeficiency disease (PID), manifests in children and adults with a wide variability of symptoms and range of severity. CVID is characterized by recurrent or chronic infections (especially bacterial sinopulmonary infections), gastrointestinal complications, and in some, autoimmune disease, granulomatous disease, or enteropathy without recurrent infections. Patients with CVID are also at increased risk of developing lymphoma. The exact causes of CVID are unknown at this time; a monogenic cause of the disease has been identified in some patients, but in the majority of individuals, CVID remains a diagnosis of exclusion. CVID is primarily established through laboratory testing of immunoglobulin concentrations, circulating B lymphocytes (B cells), and antibody responses to vaccination. Early identification and initiation of treatment with intravenous and subcutaneous immunoglobulin can improve both the quality of life and longevity of patients with CVID.

Quick Answers for Clinicians

What are the criteria for diagnosing common variable immunodeficiency (CVID)?

The European Society for Immunodeficiencies (ESID) clinical criteria includes:

At least one of the following: increased susceptibility to infection, autoimmune manifestations, granulomatous disease, unexplained polyclonal lymphoproliferation, and/or affected family member(s) with antibody deficiency
Marked decrease of immunoglobulin G (IgG) and IgA with or without low IgM concentration (<2 standard deviations of the normal levels for their age) with at least 2 measurements
At least one of the following: poor antibody response to vaccines and/or low numbers of isotype-switched memory B cells
No evidence of profound T-cell deficiency

The ESID requires that a diagnosis of common variable immunodeficiency (CVID) not be made before 4 years of age or before the exclusion of all secondary causes of hypogammaglobulinemia.

Is common variable immunodeficiency (CVID) typically diagnosed in childhood or adulthood?

The majority of individuals with common variable immunodeficiency (CVID) are diagnosed after childhood. Current diagnostic criteria advise caution when considering a diagnosis of CVID in a child younger than 4 years old. In young children, the immune system may not have matured sufficiently. Still, pediatric CVID is a serious condition and presents a diagnostic challenge, considering the immaturity of the immune system and possible inborn errors of immunity. Therefore, regular monitoring is imperative to make an expedient diagnosis and ensure that treatment can begin before further damage occurs.

Indications for Testing

Any individual with a history of recurrent, severe infections, allergic disorders, and autoimmunity may warrant testing for immunodeficiency, including CVID. Refer to the ARUP Consult Primary Immunodeficiency Disorders topic for details about the general approach to diagnosing primary immunodeficiencies.

Laboratory Testing

Serum Quantitative Immunoglobulins

Immunoglobulin deficiency can be detected by determining total immunoglobulin G (IgG), IgA, and IgM levels, which is generally the first step in the workup of immunoglobulin disorders, including CVID. A hallmark characteristic of CVID is a marked decrease in IgG concentration, accompanied by reduced IgA and/or IgM concentrations. The normal range of IgG concentration varies by age, so age-adjusted reference ranges should be used.

Abnormal test results should prompt exclusion of other primary (eg, XLA and X-linked lymphoproliferative disease) and secondary (eg, medication, bone marrow failure) causes of hypogammaglobulinemia.

Immunoglobulin results may appear normal in some individuals with CVID because immunoglobulin levels are not sensitive indicators of specific immunity. For this reason, if a strong suspicion of CVID exists, antibody titers to previously administered vaccines should also be evaluated.

Antibody Titers

Immune function is evaluated by specific antibody titers to both protein (eg, tetanus, diphtheria) and polysaccharide (eg, pneumococcus) antigens. Protein-based vaccines generate long-lasting immunity, whereas polysaccharide-based vaccines generate a weaker immunologic response. If any vaccination titer is below normal, revaccination and an assessment of titers 4-6 weeks later (often referred to as a “vaccine challenge”) is warranted.

B-Cell Subset Analysis by Flow Cytometry

The overall number of B cells is normal in the majority of individuals with CVID, although some may have reduced levels of circulating memory B cells, which are capable of producing antigen-specific IgG and IgM. These low numbers of isotype-switched memory B cells may be used as alternate criteria to low antibody responses to vaccines. Although CVID is classified as a humoral immunodeficiency, T-cell abnormalities may be identified in individuals with CVID.

Genetic Testing

Current definitions of CVID exclude patients with a known causative variant disorder; if a genetic variant is identified, the individual’s diagnosis is changed to reflect the genetic cause.

Genetic testing for CVID may be considered in cases with an early age of disease onset or with autoimmune or inflammatory complications; in those with other affected family members; and to exclude other immunodeficiencies that arise from known genetic defects, such as hyper-IgM syndrome, which has been found to be associated with defects in the CD40L and CD40 genes.