Practice Essentials
Common variable immunodeficiency (CVID) is a disorder that involves the following:
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Low levels of most or all of the immunoglobulin (Ig) classes
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Lack of B lymphocytes or plasma cells that are capable of producing antibodies
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Frequent bacterial infections
A diagnosis of CVID is reserved for persons with an undefined B-cell dysfunction. Lymphoma is a common cause of death in patients with CVID.
Signs and symptoms
Three complications must be considered in patients with CVID:
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Recurrent infections - Permanent damage to the bronchi may occur, resulting in bronchiectasis
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Malignancy - Lymphomas of a B-cell phenotype are of particular concern
Dermatologic manifestations
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Alopecia areata
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Alopecia universalis
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Nonnecrotizing granulomas - Sarcoidlike [8]
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Cutaneous vasculitis including polyarteritis nodosa [9]
A syndrome similar to sarcoidosis can affect patients with CVID. [10] It is characterized by noninfectious cutaneous granulomas, with underlying visceral granulomas of the lungs, liver, spleen, or conjunctiva in most patients. These cutaneous granulomas are nonspecific in patients with CVID and can appear as follows:
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Maculopapular rash
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Infiltrated erythematous papules, plaques, excoriated papules, and ulcers
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Nodules with ulcerations
Lesions frequently appear on the face and extremities and are always sterile. They often resolve with treatment of the underlying disease.
See Clinical Presentation for more detail.
Diagnosis
Laboratory studies
In patients with CVID, laboratory studies can reveal the following:
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Serum IgA and IgG levels - Decreased (not absent)
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Serum IgM levels - Decreased (occasionally)
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Circulating T and B lymphocytes - Can be assessed by using monoclonal antibodies for immunofluorescence staining
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T-cell function - In vivo measurement is possible by using an anergy panel to assess localized immunologic skin responses
Imaging studies
In patients with CVID, high-resolution CT scanning of the chest may be more useful than plain chest radiography or pulmonary function testing in detecting pulmonary abnormalities.
Histology
Histologic changes may be observed in the lymph nodes of patients with CVID. Findings may include the following:
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Reactive follicular hyperplasia
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Atypical hyperplasia
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Granulomatous inflammation
Nonsarcoidal, nontuberculoid, asymptomatic cutaneous granulomas seen in CVID show well-demarcated areas of fibrinoid degeneration of collagen that stain homogeneously and are surrounded by histiocytes in a palisading arrangement (suggestive of granuloma annulare). [11]
Procedures
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Biopsy - Should be considered to exclude infection or malignancy in enlarging lymph nodes
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Bronchoscopy or endoscopy - Can provide information regarding specific lesions or infectious processes
See Workup for more detail.
Management
The mainstay of treatment for CVID is immunoglobulin replacement therapy, which reduces arthritic symptoms, infection recurrence, and the severity and/or incidence of the autoimmune disease. Immunoglobulin may be administered intravenously or subcutaneously.
Surgery is required to treat complications of CVID, such as the following:
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Chronic sinusitis - May require endoscopic sinus surgery
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Severe autoimmune thrombocytopenia or hemolytic anemia - Can be treated with splenectomy
See Treatment and Medication for more detail.
Background
Common variable immunodeficiency (CVID), the most common clinical primary immunodeficiency in adults, is a disorder that involves the following: (1) low levels of most or all of the immunoglobulin (Ig) classes, (2) a lack of B lymphocytes or plasma cells that are capable of producing antibodies, and (3) frequent bacterial infections. [12] A diagnosis of CVID is reserved for those with an undefined B-cell dysfunction. [13] Combining DNA sequencing with gene expression, methylation, proteomic, and metabolomics data holds the promise of greatly expanding knowledge about CVID. [14, 15]
CVID is diverse, both in its clinical presentation and in the types of deficiency. Although decreased serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) are characteristic, approximately 50% of patients with the deficiency also have diminished serum immunoglobulin M (IgM) levels and T-lymphocyte dysfunction. In CVID, the T-cell compartment is strongly impacted, with premature arrest in thymic output, leading to T-cell exhaustion and immune dysregulation. [16] About 20% of those with CVID develop an autoimmune disease. [17] In addition, autoinflammatory, granulomatous, and/or lymphoproliferative disorders may become evident. [15]
Also see the article Pediatric Common Variable Immunodeficiency.
Pathophysiology
In patients with common variable immunodeficiency (CVID), numerous immune-system abnormalities are reported, the most common of which is defective antibody formation. Consequently, both humoral and cell-mediated lymphocytic responses are affected. Some CVID patients may have a defect in the T-cell ability to help B cells, and/or B-cell response to T-cell help. [18] Innate immunity defects may modify clinical status and findings in these patients. [19]
Changes in the humoral response
The basic pathophysiologic process in CVID is a simple failure in the differentiation of B lymphocytes. However, evidence shows that this defect in the pathway is not common among patients. One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells. This finding suggests a defect in B-cell expression in surface molecules.
Such cellular deficits have been traced to the second messenger and translocation pathways of B cells. These deficits include problems with protein kinase C activation and tyrosine phosphorylation. Findings from other studies suggest the complete absence of IgG and IgA production, an increased rate of spontaneous apoptosis, impaired DNA repair, and the presence somatic mutations affecting B-cell regulation.
Changes in the cell-mediated response
A number of factors and cofactors stimulate Ig secretion from B cells harvested from patients with CVID. These factors include B-cell mitogens, soluble T-cell factors, specific B-cell differentiation factors, the Epstein-Barr virus, interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 10 (IL-10). Perhaps the most potent stimulant is the CD40 ligand, which is expressed by activated CD4+ cells. In fact, in 40% of patients with CVID, the CD40 ligand is expressed in low levels on activated T cells. In these patients, decreased IL-2 production after T-cell receptor stimulation is also present.
A common defect is the response to antigens by CD4+ T lymphocytes. After immunization, some patients with CVID have decreased numbers of circulating responsive CD4+ T cells. Other patients have an increased number of CD4+ T cells, but they also have an increased rate of apoptosis of these cells. Signal transduction appears to be the primary defect in these T cells. Rezaei et al report on the meningococcal vaccination response in CVID patients. They suggest it may help define subgroups of patients, which may lead to better monitoring and new therapeutic strategies. [20]
Of all patients with CVID, 25-30% often have increased numbers of CD8+ T cells and a reduced CD4/CD8 ratio (< 1). The cause is an increase in cyclic adenosine monophosphate levels and the increased activation of protein kinase A. On physical examination, patients with this subtype often have splenomegaly and bronchiectasis. In addition, 60% of patients with CVID have a diminished response to T-cell receptor stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon gamma. However, the T-cell receptors show no evidence of abnormality; in fact, genetic findings indicate normal heterogeneity of the genetic rearrangements. Therefore, most patients with CVID can be said to have antibody deficiency secondary to T-cell signaling abnormalities, as well as defective interactions between T and B lymphocytes. Laino et al report that the prevalence of distinct clinical complications of CVID is higher in patients with B- and T-cell abnormalities. [21]
Both the transient and permanent recovery of Ig production has been reported in both patients with HIV and in patients with hepatitis C infection. This finding may indicate that CVID is associated with potentially reversible defects in humoral and/or cellular immunoregulatory factors.
TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. One series found that 4 of 19 unrelated individuals with CVID and 1 of 16 individuals with IgA deficiency had a missense mutation in 1 allele of TNFRSF13B (encoding TACI). [22] TTACI mutations can result in CVID and IgA deficiency. Four genes have been documented to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19. [23] Heterozygous mutations in TNFRSF13B are also associated with CVID, [13] whereas the other 3 genes are recessive. [24, 25] Those with a mutation in the TNFRSF13B gene may require further investigation.
Autosomal dominant CVID has been linked to chromosome 4q. [26] One study supports the existence of a disease-causing gene for autosomal dominant CVID/IgA deficiency on chromosome 4q. Other possible loci for dominant CVID genes are on chromosomes 5p and 16q.
Etiology
The primary cause of common variable immunodeficiency (CVID) remains unknown despite 40 years of research. Part of the problem is the heterogeneity of the disease.
Genetic factors may be involved. In approximately 20% of patients with CVID, a first-degree family member has a selective IgA deficiency. This finding may indicate that the genes are linked.
When more than one family member is affected with CVID, approximately 5% of the patients have a concurrent IgA deficiency.
Further results reveal specific localization to the C4A gene and, rarely, to the C2 gene in the class III region of the major histocompatibility complex on chromosome 6.
No clear pattern of inheritance has been observed. Because most patients represent sporadic cases and because they have no family history of immunodeficiency, different modes of inheritance such as autosomal dominant with variable penetrance, autosomal recessive, and X-linked forms have been reported. [27]
An autosomal recessive pattern of inheritance is suggested when more than one family member is affected.
CVID is associated with the use of antirheumatic or antiepileptic drugs. If such an association is later proven to be a causal relationship, the genetic etiology may turn out to be a genetic predisposition to the disease. A common insult to the B-cell differentiation pathway may be involved.
Epidemiology
The prevalence of common variable immunodeficiency (CVID) is approximately 1 case per 50,000 population worldwide.
Race-, sex-, and age-related frequency
CVID does not show a predilection for any specific race.
CVID equally affects males and females.
CVID can occur in infants, young children, adolescents, or even those aged 20-40 years or older. CVID can become evident at any time from infancy to after the fourth decade of life. Peaks of onset occur in children aged 1-5 years and in persons aged 16-20 years. More than two thirds of patients are aged 21 years or older when CVID is diagnosed.
Prognosis
The prognosis depends on the presence of severe autoimmune disease, recurrent infections causing structural lung damage, and the development of a malignancy. A 20-year survival rate is 64% for male patients and 67% for female patients. In general, the expected survival rate for male and female patients is 92% and 94%, respectively. Death may result from various causes. In 1 series, neoplasia became a common complication in the elderly during follow-up. [28]
Other major factors in determining the prognosis is the extent of end-organ damage and the success of prophylaxis against future infections.
Polyclonal lymphocytic infiltration is a clinical predictor associated with a 5-fold increased risk of lymphoid malignancy. [29]
Elevated serum IgM and reduced circulating CD8 proportions may be predictive markers for polyclonal lymphocytic infiltration and autoimmunity. [29]
Those who develop granulomatous lymphocytic interstitial lung disease tend to experience early mortality. Clues to this complication may include splenomegaly and a low serum IgA level. [30]
Patient Education
Patients and their families should be educated about the early signs of infection so that aggressive treatment is not delayed.
One helpful organization is the Immune Deficiency Foundation, which provides a wealth of information to health care providers and patients and their families.
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Intravenous immunoglobulin infusion. Courtesy of Wikimedia Commons (Steve Brew, own work).
