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.^[6]Patients with bacterial infections alone have markedly improved survival compared with those that have other disease-related complications.

Recurrent infections

Recurrent pyogenic infections of sinopulmonary tract was reported in 94% of patients.^[5]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 jiroveci, 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.

Resnick et al described 6 patients with P jiroveci, 3 were being treated with steroids, 1 was being treated with steroids and 6-mercaptopurine for GI inflammatory disease, and 2 were not receiving any immunosuppressive therapy.

In European registry data, serious infections were not related to presenting levels of serum immunoglobulin G (IgG).

Autoimmune complications

In contrast to X-linked agammaglobulinemia (XLA), common variable immunodeficiency is associated with a high frequency of autoimmune manifestation. Resnick reported autoimmunity in about 28.6% with one or more autoimmune manifestation.

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).

Granulomatous diseases and l ymphoid hyperplasia

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, lymph nodes, 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, BAFFR (B-cell activating factor of the TNF family receptor, TNFRSF13C), CD81, CD20, and CD21.^[7]

Table 1. Genetic Defects in Common Variable Immunodeficiency (Open Table in a new window)

Genetic defect	Chromosomal location	Inheritance	Phenotype	B cells
TNFRSF13B (TACI); approximately 10% of cases	17p11.2	Autosomal dominant (AD)	Common variable immunodeficiency, selective immunoglobulin A deficiency (SIgAD)	< 5% of cases involve absent TACI expression; 95% of cases have normal TACI expression on B cells; low-to-absent IgA levels; autoimmune disease; lymphoproliferative disease; splenomegaly; reduced class-switched memory B cells
TNFRSF13C (BAFF-R); < 1% of cases	22q13.2	Autosomal recessive (AR)	Late-onset, incomplete penetrance	Absent BAFF-R on B-cell surface; reduced class-switched and non–class-switched memory B cells; increased transitional B cells; impaired response to polysaccharide antigen
ICOS; approximately 2% of cases	2q33	AR	Early and late onset	Absent ICOS on activated T cells; reduced class-switched memory B cells; nodular lymphoid hyperplasia; autoimmunity; predisposition to neoplasm
CD19; < 1% of cases	16p11.2	AR	Early and late onset	Low-to-absent CD19 on B cells; reduced class-switched memory B cells; low CD21+ expression on B cells; normal number of CD20+ cells in peripheral blood
CD81; < 1% of cases		AR	Unclear	Impaired Ca⁺⁺ flux after BCR stimulation; autoimmunity; impaired response to protein and polysaccharide antigens; nearly absent CD19 expression
CD20; < 1% of cases		AR	Unclear	Reduced switched memory B cells; impaired somatic hypermutation; impaired response to pneumococcal polysaccharide antigens
CD21; < 1% of cases		AR	Unclear	Reduced class-switched memory B cells; hypogammaglobulinemia; reduced binding of C3d-containing immune complexes and EBV-gp350 to B cells; impaired response to pneumococcal polysaccharide antigens

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.^[8]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 anti-rheumatic or anti-epileptic drugs, including azathioprine, cyclosporine, D-penicillamine, gold, sulfasalazine, carbamazepine, levetiracetam, oxcarbazepine, and phenytoin. Immunoglobulin may be normalized after months to years of medication avoidance. Drug-associated common variable immunodeficiency or SIgAD suggests that a pathogenetic process may involve common key steps in individuals with the permissive genetic background.

Each BAFF-R, CD20, and CD81 gene defects is represented by only one consanguineous family and is proof of a definite causal relationship requires for identification of additional affected families.

Differential Diagnoses

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Table 1. Genetic Defects in Common Variable Immunodeficiency

Genetic defect	Chromosomal location	Inheritance	Phenotype	B cells
TNFRSF13B (TACI); approximately 10% of cases	17p11.2	Autosomal dominant (AD)	Common variable immunodeficiency, selective immunoglobulin A deficiency (SIgAD)	< 5% of cases involve absent TACI expression; 95% of cases have normal TACI expression on B cells; low-to-absent IgA levels; autoimmune disease; lymphoproliferative disease; splenomegaly; reduced class-switched memory B cells
TNFRSF13C (BAFF-R); < 1% of cases	22q13.2	Autosomal recessive (AR)	Late-onset, incomplete penetrance	Absent BAFF-R on B-cell surface; reduced class-switched and non–class-switched memory B cells; increased transitional B cells; impaired response to polysaccharide antigen
ICOS; approximately 2% of cases	2q33	AR	Early and late onset	Absent ICOS on activated T cells; reduced class-switched memory B cells; nodular lymphoid hyperplasia; autoimmunity; predisposition to neoplasm
CD19; < 1% of cases	16p11.2	AR	Early and late onset	Low-to-absent CD19 on B cells; reduced class-switched memory B cells; low CD21+ expression on B cells; normal number of CD20+ cells in peripheral blood
CD81; < 1% of cases		AR	Unclear	Impaired Ca⁺⁺ flux after BCR stimulation; autoimmunity; impaired response to protein and polysaccharide antigens; nearly absent CD19 expression
CD20; < 1% of cases		AR	Unclear	Reduced switched memory B cells; impaired somatic hypermutation; impaired response to pneumococcal polysaccharide antigens
CD21; < 1% of cases		AR	Unclear	Reduced class-switched memory B cells; hypogammaglobulinemia; reduced binding of C3d-containing immune complexes and EBV-gp350 to B cells; impaired response to pneumococcal polysaccharide antigens

Table.

Brand (Manufacturer)	Virus Inactivation process	pH; Additives *	Osmolality (mOsm/kg)	Parenteral Form & Final Concentrations	IgA Content µg/ml	Route of administration
Bivigam (Biotest Pharmaceuticals)	Cold ethanol fractionation, solvent/detergent, nanofiltration	4.0-4.6; glycine, polysorbate 80	Unspecified	Liquid 10%	< 200 µg/ml	IV
Flebogamma DIF(Grifols)	Pasteurization, solvent/detergent treatment, nanofiltration, low pH treatment	5.1-6; D-Sorbitol	240-370	Liquid 5%, 10%	< 50 µg/ml in 5% solution, < 100 µg/ml µg/ml in a 10% solution	IV
Gammagard S/D Low IgA (Baxter)	Cold ethanol fractionation, solvent detergent (S/D) treatment	6.4-7.2;Albumin,Glycine,Glucose, PEG, tri-n-butyl phosphate, octoxynol, polysorbate 80	5%: 636; 10%:1250	Lyophilized powder5%, 10%	< 1 µg/ml in a 5% solution	IV
Gammaplex(Bio Products)	Solvent/detergent, nanofiltraion, low pH incubation	4.8-5.1; D- sorbitol, glycine, polysorbate 80	420-500	Liquid 5%	< 10 µg/ml	IV
Octagam (Octapharma)	Cold ethanol fractionation, solvent/detergent, pH4 treatment	5.1-6.0;maltose	310-380	Liquid 5%	< 200 µg/ml	IV
Privigen(CSL Behring)	pH 4 incubation, nanofiltration, depth filtration	4.6-5.0;L-proline	240-440	Liquid 10%	< 25 µg/ml	IV
Gammagard Liquid(Baxter)	Solvent detergent (S/D), nanofiltration, low pH incubation at elevated temp	4.6-5.1; Glycine	240-300	Liquid 10%	37 µg/ml	IV or Subcutaneous
Gamunex-C(Grifolis)	Caprylate precipitation, depth filtration, chromatography, pH 4 incubation	4-4.5; Glycine	258	Liquid 10%	46 µg/ml	IV or Subcutaneous
Gammaked (Kedrion Biopharma)	Caprylate precipitation, depth filtration, chromatography, low pH incubation	4.0-4.5; glycine	258	Liquid 10%	46 µg/ml	IV or Subcutaneous
Cuvitru (Shire)	Fractionation, SD treatment, nanofiltration, low pH treatment	4.6-5.1; glycine	280-292	Liquid 20%	80 µg/ml	Subcutaneous
Hizentra (CSL Behring)	Cold alcohol freactionation, octanoic acid fractionation, and anion exchange chromatography	4.6-5.2; L-proline, polysorbate 80	380	Liquid 20%	< 50 µg/ml	Subcutaneous
HyQvia (Baxter Healthcare)	Solvent/detergent, nanofiltration, lowpH incubation	4.6-5.1; recombinant human hyaluronidase (7.4)	240-300 (recombinatnt human hyaluroidase (290-350)	Liquid 10%	37 µg/ml	Subcutaneous