eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Common Variable Immunodeficiency

Author: C Lucy Park, MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago
Contributor Information and Disclosures

Updated: Nov 2, 2009

Introduction

Background

Common variable immunodeficiency (CVID) is one of the most prevalent primary immunodeficiency diseases. Common variable immunodeficiency is a heterogeneous group of immunologic disorders of unknown etiology, characterized by impaired antibody responses. Patients with common variable immunodeficiency have marked reduction in serum levels of both immunoglobulin G (IgG) and immunoglobulin A (IgA); about half of these patients also have reduced immunoglobulin M (IgM). Diagnosis is based on exclusion of known causes of humoral immune system defects.

Most patients with common variable immunodeficiency present as sporadic cases, although familiar cases with various inheritance modes have been reported, including autosomal dominant with variable penetrance, autosomal recessive, or X-linked.

Pathophysiology

The common immunologic defect in patients with common variable immunodeficiency is defective antibody formation. As is expected in a heterogeneous group of diseases, many different immune system defects have been reported in this group of patients.

B-cell defect

The basic and common immunologic defect in common variable immunodeficiency is a failure of B-lymphocyte differentiation into plasma cells that produce the various immunoglobulin (Ig) isotypes. Earlier studies suggested a primary B-lymphocyte defect as a cause of common variable immunodeficiency in a small group of patients. B lymphocytes from these patients failed to differentiate into Ig-producing cells when stimulated with pokeweed mitogen (PWM) in vitro, even when cocultured with normal T cells; they were also L-selectin negative. These studies described failure of B-cell differentiation because of altered B-cell surface–molecule expression.

Primary B-cell dysfunction secondary to newly discovered genetic defects has been described in a small number of patients with common variable immunodeficiency (see Causes). These include CD19 deficiency and mutations in the genes that encode TACI (the transmembrane activator and calcium-modulating cyclophilin ligand interactor, TNFRSF13B), ICOS (the inducible costimulator of activated T cells), and BAFFR (the B-cell activating factor of the tumor necrosis factor [TNF] family receptor, TNFRSF13C). CD19 plays a crucial role in regulating B-cell responses to antigens and B-cell survival.

TACI is one of the TNF receptor superfamily members. TACI plays an indispensable role in isotype switching, terminal differentiation of B cells, and T-cell–independent antibody responses. TACI mutations that lead to immunodeficiency account for an estimated 10-15% of patients with common variable immunodeficiency. ICOS mutation is associated with absent ICOS expression on the surface of activated T cells and results in reduced class-switched memory B cells. The BAFFR defect is also associated with reduced class-switched and nonswitched memory B cells.

B cells develop in bone marrow from pluripotent hemopoietic stem cells through rearrangement of immunoglobulin heavy-chain and light-chain genes and initial positive and negative selection in the bone marrow. Mature B cells expressing both IgM and IgD leave bone marrow and enter secondary lymphoid organs. Within the secondary lymphoid follicles, affinity maturation and class switching take place through somatic hypermutation of the variable region genes and class-switch recombination. These B cells become either memory B cells or long-lived plasma cells that home back to the bone marrow and produce high-affinity antibodies.

Enumeration of the B-cell subsets in peripheral blood may be useful in classifying of common variable immunodeficiency. These subsets include class-switched memory B cells (CD27+IgD-IgM-), nonswitched memory B cells (CD27+IgD+IgM+), IgM memory B cells (CD27+IgM+IgD^dim), transitional B cells (CD38+++IgM+++), plasmablasts (CD38+++IgM-), mature B cells (CD19+CD21+), and CD21^lo B cells (CD19+CD21^lo).

Several groups have reported classification of common variable immunodeficiency based on B-cell subtype using flow-cytometry techniques. Paris¹ and Freiburg² classifications are based on the presence or absence of class-switched memory B cells. A EUROclass trial unified the 2 classifications and attempted to provide clinical links with B-cell subset phenotypes and clinical manifestations.³ The data included 303 patients with common variable immunodeficiency and suggested that severe reduction in the number of class-switched memory B cells is associated with granulomatous disease, splenomegaly, and autoimmune cytopenias.

Other studies have observed a lack of protein kinase C activation and translocation to the plasma membrane when B cells of patients with common variable immunodeficiency were stimulated with phorbol ester or anti-µ antibody. B-cell lines from a subset of patients with common variable immunodeficiency displayed absent IgG and IgA production and increased spontaneous apoptosis that was associated with increased expression of CD95 (APO-1/Fas).

A subset of patients with common variable immunodeficiency displayed impaired B-cell signal transduction cascade associated with abnormalities in protein tyrosine phosphorylation. Another subset exhibited chromosomal radiosensitivity, presumably due to impaired ability to repair DNA.

Mutations interfering with the regulation of the Ig gene expression, deficiency of memory B cells, and somatic hypermutation (SHM) abnormalities have been reported in patients with common variable immunodeficiency. Memory B cells develop in the germinal centers where SHMs are introduced, followed by antigen-mediated selection of cells with high affinity for the antigen. Low level of SHM, which correlated with increased frequency of severe respiratory tract infection, has been reported in patients with common variable immunodeficiency. B cells from these patients were unable to undergo isotype switching and were unable to upregulate activation markers on B cells when stimulated in vitro.

Others reported that loss of IgM memory B cells correlates with clinical features of recurrent pneumonia caused by encapsulated microbes and bronchiectasis in common variable immunodeficiency.

T-cell defect

An overwhelming body of literature suggests that most patients with common variable immunodeficiency have intact B lymphocytes of immature phenotype. Common variable immunodeficiency B cells can secrete immunoglobulins (Ig), although often limited to IgM, if given the appropriate in vitro stimulation. Ig secretion has been induced from common variable immunodeficiency B cells using B-cell mitogens with soluble T-cell factors, monoclonal B-cell differentiation factors, Epstein-Barr virus (EBV), anti-CD40 plus interleukin (IL)-4 and IL-10. CD40 ligand (CD154) is expressed by activated CD4⁺ cells and is pivotal in inducing B-cell proliferation and differentiation.

Approximately 40% of patients with common variable immunodeficiency have low expression of CD40 ligand on activated T cells. At least 30% of patients with common variable immunodeficiency have lymphopenia due to the low number of CD4⁺ subsets. These patients also have decreased in vitro production of IL-2 when their peripheral blood mononuclear cells are stimulated in vitro. Decreased IL-2 production with stimuli via T-cell receptors is correlated with diminished CD40 ligand expression. Reduced expression of ICOS was reported in some families with autosomal recessive common variable immunodeficiency due to homozygous mutations in the ICOS gene. ICOS deficiency results in severe B-cell defect, which is caused by impaired T-cell help.

T cells in patients with common variable immunodeficiency have low frequency of antigen-specific precursor T cells following immunization with the neoantigens keyhole-limpet hemocyanin and dinitrophenol (DNP)-Ficoll. Many patients with common variable immunodeficiency have a defect in CD4⁺ T-cell priming to antigens, as measured by the number of circulating responsive CD4⁺ T cells following immunization. Many patients have a reduction in CD4⁺ CD45RA⁺ ("unprimed") T cells, suggesting activation of T cells.

Most patients with common variable immunodeficiency reportedly have increased production of interferon gamma by circulating CD8⁺ subsets, increased numbers of DR⁺/CD4⁺ T cells with up-regulated Fas expression, and an increased apoptosis. The abnormality appears to reside in CD4⁺ T cells and can be overcome by stimulating T cells with phorbol myristate acetate (PMA) and ionomycin, an alternative T-cell activation pathway. This is consistent with defective signal transduction in T cells.

Increased endogenous cyclic adenosine monophosphate (cAMP) levels in T cells from patients with common variable immunodeficiency are associated with increased activation of protein kinase A type I (PKAI) in T cells and with decreased proliferative response to anti-CD3. A selective antagonist of PKAI induces a significant increase in anti-CD3-stimulated proliferative responses, particularly in CD4⁺ lymphocytes. Approximately 25-30% of patients with common variable immunodeficiency have increased numbers of CD8⁺ lymphocytes, normal or decreased CD4⁺, and reduced CD4/CD8 ratios (<1). This increase in CD8⁺ T cells has been observed most often in patients with splenomegaly and bronchiectasis. These cells coexpress human leukocyte antigen (HLA)-DR and IL-2 receptors, suggesting in vivo activation.

Approximately 60% of patients with common variable immunodeficiency have diminished proliferative responses to T-cell receptor stimuli and decreased induction of gene expression for IL-2, IL-4, IL-5, and interferon gamma. T-cell receptors of patients with common variable immunodeficiency have no evident abnormality; T-cell receptor gene analyses indicate normal heterogeneity of gene rearrangements. TNF production from T cells and monocytes is increased in a subgroup of patients with granulomatous diseases. Standard tests to assess T-cell function, including in vitro proliferation in response to mitogens, antigens, and allogeneic cells, are subnormal in as many as 50% of patients with common variable immunodeficiency with a small subgroup of patients having very low responses. These results support the hypothesis that most patients with common variable immunodeficiency have antibody deficiency secondary to abnormalities in T-cell signaling and defective T-cell and B-cell interactions.

The recovery of Ig production (mostly IgG and IgM) transiently or permanently following human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection has been reported in patients with common variable immunodeficiency. These cases indicate that common variable immunodeficiency is associated with potentially reversible defects in immunoregulatory factors and intact B-cell systems.

Other defects

A decrease in the number of peripheral blood dendritic cells (DCs) was noted in patients with common variable immunodeficiency. Low numbers of DCs correlated with a greater incidence of autoimmunity, splenomegaly, and granulomatous disease and a higher incidence of clinical complications. DCs play a role in B-cell growth and differentiation of plasma cells into immunoglobulin-secreting plasma cells. Others reported defective functions of DCs in patients with common variable immunodeficiency, inducing weak proliferation of allogeneic T cells and producing significantly low amounts of interleukin 12 upon CD40 signaling.

Increased functional capacity in both classic and alternative complement pathways in patients with common variable immunodeficiency was noted. Many patients with common variable immunodeficiency with increased levels of complement split products, presumably from complement activation, had autoimmune manifestations. Others reported a strong inverse correlation between mannose-binding lectin levels and the frequency of lower respiratory tract infection and bronchiectasis in patients with common variable immunodeficiency.

Frequency

United States

Estimated incidence of common variable immunodeficiency is approximately 1 case per 30,000 population based on data over the last 2 decades.

International

Incidence is similar to that in the United States.

Mortality/Morbidity

The prognosis for patients with common variable immunodeficiency is reasonably good if they do not have bronchiectasis and chronic lung damage or severe autoimmune disease or malignancy.

Chapel et al reported European common variable immunodeficiency registry data that included 326 patients followed for at least 10 years since onset of symptoms.⁴ The 75th percentile for survival was 25 years after diagnosis, and the 60th percentile for survival was 41 years after diagnosis. No associations between survival and sex or initial serum IgG, IgA, or IgM levels were noted. In the European registry, the highest mortality rates were in patients with the enteropathy phenotype or the polyclonal lymphocytic infiltrative phenotype. An association between increased mortality and lymphoid malignancy was also noted.

In an earlier report from the United States, the most frequent cause of death was lymphoma, followed by cor pulmonale from chronic pulmonary infection and liver failure caused by viral or autoimmune hepatitis. Parameters associated with mortality in this report included lower levels of serum IgG, poorer T-cell responses to phytohemagglutinin, and a lower percentage of peripheral B cells.

Race

Common variable immunodeficiency has been reported in many different races.

Sex

Common variable immunodeficiency equally affects males and females.

Age

Although the usual age at presentation is in the second or third decades of life according to some reports, other reports described the onset of clinical disease as early as the first decade of life, with peaks of onset in children aged 1-5 years and in persons aged 16-20 years. Likewise, age of diagnosis demonstrated bimodal peaks at 6-10 years and 26-30 years. More than two thirds of the patients were adults who were older than 21 years at the time of initial diagnosis.

Clinical

History

Clinical manifestations of common variable immunodeficiency (CVID) include recurrent infections, autoimmune disease, lymphoid hyperplasia, granulomatous diseases, and malignancy. Recurrent infection was the only presenting symptom in 26% of patients reported by the European common variable immunodeficiency registry.⁴ Patients with bacterial infections alone have markedly improved survival compared with those that have other disease-related complications.

• Recurrent infections
  • Recurrent pyogenic infections of upper and lower respiratory tracts are the main clinical manifestations of common variable immunodeficiency. Symptoms may appear during childhood or, more often, after puberty. Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus are the organisms most commonly involved.
  • A few patients with common variable immunodeficiency present with unusual organisms, such as Pneumocystis carinii, mycobacteria, or various fungi. Mycoplasma pneumoniae infections in the urinary tract, joints, and deep abscesses have been reported.
  • Persistent diarrhea and malabsorption caused by Giardia lamblia also have been reported in patients with common variable immunodeficiency. GI symptoms disappeared after G lamblia was eradicated with metronidazole.
  • Severe and recurrent infections with herpes simplex are common, and herpes zoster eventually develops in as many as 20% of patients with common variable immunodeficiency.
  • Some patients may develop unusual enteroviral infections with a chronic meningoencephalitis and a dermatomyositislike illness. Presenting symptoms are either acute or insidious, with signs of encephalitis, seizures, headache, sensory motor disturbances, and personality changes.
  • Vaccine-associated paralytic poliomyelitis (VAPP) in a patient with common variable immunodeficiency has been reported; this patient developed paralytic poliomyelitis 7 years after the last administration of trivalent oral poliovirus vaccine.
  • In European registry data, serious infections were not related to presenting levels of serum immunoglobulin G (IgG).
• Autoimmune diseases and common variable immunodeficiency
  • In contrast to X-linked agammaglobulinemia (XLA), common variable immunodeficiency is associated with a high frequency of autoimmune and granulomatous diseases.
  • The most common autoimmune conditions in patients with common variable immunodeficiency are cytopenia, idiopathic thrombocytopenic purpura (ITP) in particular, and hemolytic anemia or, more rarely, autoimmune neutropenia. Other solid organ–specific autoimmune diseases (eg, pernicious anemia, thyroid diseases, vitiligo) have prevalence rates of more than 5% in patients with common variable immunodeficiency, which is higher than in the general population. Other conditions include insulin-dependent diabetes, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, and uveitis. Approximately 20% of patients have a severe gastroenteropathy with severe malabsorption, nodular lymphoid hyperplasia, and chronic inflammatory bowel disease, such as ulcerative colitis and Crohn disease.
  • Although regular Ig replacement therapy reduces susceptibility to Giardia species and Campylobacter enteritis, it does not prevent autoimmune mucosal inflammation. Ig replacement therapy does not affect the clinical course of inflammatory bowel disease.
  • Patients who have common variable immunodeficiency and autoimmune conditions appear to have very low numbers of isotype-switched memory B cells in peripheral blood and are more likely to have a mutation in the gene that encodes TACI (TNFRST13B).
• Lymphoid hyperplasia and granulomatous diseases
  • Atypical lymphoid hyperplasia due to clonal expansion of B or T lymphocytes has been reported in as many as one third of patients with common variable immunodeficiency. Extranodal sites, such as the lungs, GI tract, skin, spleen, liver, and parotid gland, may be involved by these lymphoproliferative processes. Lymph nodes show a reactive follicular hyperplasia, atypical hyperplasia, or granulomatous inflammation. Nodular lymphoid hyperplasia in the GI tract with clonal rearrangement of the Ig heavy chain gene or clonal T-cell receptor (TCR) gene rearrangement has been described in otherwise benign cases of lymphoid proliferation in patients with common variable immunodeficiency.
  • Granulomas have been reported in approximately 8-22% of patients with common variable immunodeficiency. These patients were more likely to have deficient T-cell proliferation to mitogens and antigens. Previous studies have reported 22 common variable immunodeficiency patients with sarcoidosis. Granulomas are indistinguishable from those of classic sarcoidosis and are found in the lungs, liver, spleen, and conjunctivae. Others reported involvement of lymph nodes, skin, GI tract, kidney, bone marrow, or brain. These patients were more likely to have increased frequencies of infections, hepatosplenomegaly, iridocyclitis, autoimmune hemolytic anemia, or immune thrombocytopenic purpura. Successful treatment of granulomas with tumor necrosis factor-alpha antagonists has been reported in a few patients with common variable immunodeficiency.
  • One report described a possible role of human herpesvirus 8 (HHV-8) in the lymphoproliferative disorders in patients with common variable immunodeficiency. Authors reported high copy numbers of HHV-8 genome in peripheral blood mononuclear cells as well as in the lymph node in patients with common variable immunodeficiency who have lymphoproliferative disorders.
• Increased risk of developing malignant neoplasms
  • About 2-8% of patients with common variable immunodeficiency develop non-Hodgkin's lymphoma (NHL). Most of these patients have the B-cell immunophenotype and are frequently negative for Epstein-Barr virus (EBV). Lymphoma is 3 times more common in women with common variable immunodeficiency than in men with common variable immunodeficiency. Malignant lymphomas are most common in the fifth to seventh decade of life and are uncommon in childhood. These malignant lymphomas are usually extranodal and frequently locate in mucosal regions. European registry data revealed a correlation between serum immunoglobulin M (IgM) level at presentation and the eventual development of lymphoid malignancy. In contrast, the IgG level did not predict this phenotype.
  • Patients with common variable immunodeficiency also have markedly increased risk for gastric carcinoma than general population. Other malignancies include colon cancer, breast cancer, gastric cancer, prostate cancer, ovarian cancer, oral cancer, and melanoma.

Physical

In contrast to patients with X-linked agammaglobulinemia, many patients with common variable immunodeficiency have generalized lymphadenopathy and splenomegaly. Other positive physical examination findings depend on their clinical presentation and organ involvement (see History). Young children with common variable immunodeficiency may present with failure-to-thrive (FTT) secondary to frequent infection and increased energy expenditure. FTT may occur secondary to malabsorption syndrome associated with infection, inflammatory bowel disease, or spruelike illness.

Causes

This disorder likely has various causes, and a single etiology is unlikely. The search for gene(s) that underlie common variable immunodeficiency has been difficult, partly because of the heterogeneity. Although most cases are sporadic, at least 10% are familial with autosomal dominant inheritance more common than autosomal recessive inheritance. 

The following genetic defects have been described in patients with common variable immunodeficiency: TACI (transmembrane activator and calcium-modulating cyclophilin ligand interactor, TNFRSF13B), ICOS (inducible costimulator of activated T cells), CD19 deficiency, and BAFFR (B-cell activating factor of the TNF family receptor, TNFRSF13C). 

Table 1. Genetic Defects in Common Variable Immunodeficiency

Open table in new window

Mutations in the gene that encodes TACI were reported in 10-15% of patients with common immunodeficiency and in a smaller number of patients with IgA deficiency. TACI is one of 3 tumor necrosis factor (TNF)–receptor family members and mediates isotype switching in B cells. TACI mutations were associated with both familial and sporadic forms of common variable immunodeficiency. TACI deficiency phenotype varies from asymptomatic hypogammaglobulinemia and SIgAD to full-blown common variable immunodeficiency. This variable penetrance may reflect the ability of BCMA and BAFFR to substitute for TACI functions.

A common genetic basis for common variable immunodeficiency and SIgAD has been suspected because these disorders occur in first-degree relatives of patients. Families of both types of patients have high incidences of abnormal Ig concentrations, autoantibodies, autoimmune diseases, and malignancies. Familial occurrences of SIgAD and common variable immunodeficiency have been observed in approximately 20% of cases, including reported cases of SIgAD developing into common variable immunodeficiency over time and, occasionally, vice versa, which suggests these conditions are closely linked and can be progressive or reversible.

Other gene mutations reportedly associated with common variable immunodeficiency include ICOS on chromosome 2q, CD19 on 16p, and BAFFR on 22q.

Multiple allelic DNA and protein markers were used to examine the extended HLA-DR3, HLA-B8, and HLA-A1 haplotypes in a large American family with several members affected with SIgAD/CVID.⁵ This examination identified a susceptibility locus in the class III region within a fragment that contains 21 known genes, including the genes for TNF-alpha, lymphotoxin (LT)-alpha, and LT-beta. This area, the so-called class IV region, contains a heavy concentration of genes that may play important roles in stress, inflammation, or infection. Others reported that certain major histocompatibility complex (MHC) haplotypes, which were found in abnormally high frequency in immunodeficient patients, were also found in normal members of the pedigree. These findings suggest that the presence of these MHC haplotypes alone is not sufficient for expression of the defects.

Common variable immunodeficiency and SIgAD have been associated with antirheumatic or antiepileptic drugs. Drug-associated common variable immunodeficiency or SIgAD suggests that a pathogenetic process may involve common key steps in individuals with the permissive genetic background.

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