Pediatric Common Variable Immunodeficiency 

Updated: Oct 16, 2018
Author: C Lucy Park, MD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Practice Essentials

Common variable immunodeficiency (CVID), one of the most prevalent primary immunodeficiency diseases, is a heterogeneous group of immunologic disorders of unknown etiology. CVID is characterized by marked reduction in serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA), as well as reduced immunoglobulin M (IgM) in about half of cases.[1]

Signs and symptoms

Clinical manifestations of CVID include the following:

  • Recurrent infections

  • Autoimmune disease

  • Lymphoid hyperplasia

  • Granulomatous diseases

  • Malignancy

Recurrent infections may include the following:

  • Pyogenic sinopulmonary tract infection, especially after puberty

  • In some cases, infections with unusual organisms (eg, Pneumocystis jiroveci, mycobacteria, various fungi)

  • Mycoplasma pneumoniae infections in the urinary tract, joints, and deep abscesses

  • Persistent diarrhea and malabsorption caused by Giardia lamblia

  • Severe and recurrent infections with herpes simplex

  • Unusual enteroviral infections with a chronic meningoencephalitis and a dermatomyositis-like illness; presenting symptoms are either acute or insidious, with signs of encephalitis, seizures, headache, sensory motor disturbances, and personality changes

Autoimmune conditions in patients with CVID are as follows:

  • Idiopathic thrombocytopenic purpura (ITP)

  • Hemolytic anemia

  • More rarely, autoimmune neutropenia

  • Other solid organ–specific autoimmune diseases (eg, pernicious anemia, thyroid diseases, vitiligo)

  • Insulin-dependent diabetes

  • Psoriasis

  • Systemic lupus erythematosus

  • Rheumatoid arthritis

  • Juvenile rheumatoid arthritis

  • Uveitis

  • Severe gastroenteropathy with severe malabsorption, nodular lymphoid hyperplasia, and chronic inflammatory bowel disease (eg, ulcerative colitis, Crohn disease)

Physical examination findings may include the following:

  • Generalized lymphadenopathy and splenomegaly

  • Failure to thrive in young children, secondary to frequent infection and increased energy expenditure

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of CVID is based on the following:

  • Defective functional antibody formation (eg, low IgG response to vaccination)

  • Decreased (not absent) serum immunoglobulin (Ig)G and IgA levels (usually)

  • Decreased serum IgM level (generally, but not invariably)

  • Exclusion of other known causes of antibody deficiency

See Workup for more detail.

Management

A major component of medical care is anti-infective and prevention of further infectious episodes by regular infusion of human immunoglobulin and antimicrobial therapy. Patients with autoimmune manifestations may require immunosuppressive therapy.

Immunoglobulin replacement is intravenously administered on a regular basis, as follows:

  • Tailor dose and frequency to the Ig trough levels and to clinical symptoms

  • Measure serum IgG level before each infusion, and accordingly adjust the dose of IVIG

  • Maintain trough serum IgG concentrations at 400–500 mg/dL in adults

  • For most patients, a dose of 400-600 mg/kg every 3–4 weeks suffices to reduce the frequency of infection

  • Some patients with chronic lung disease require up to 600–800 mg/kg per month

  • Once established on a regular regimen, IVIG can be administered at home

Subcutaneous infusion of Ig (SCIG) is an alternative method for patients with difficult venous access or for those who experience serious side effects from IVIG.

Anti-infective treatment is as follows:

  • Infections should be treated early with full doses of antimicrobial agents

  • Whenever possible, narrow-spectrum drugs should be used on the basis of microbial sensitivity testing

  • Prophylactic antibiotics should be avoided

  • Antiviral agents may be useful in some patients with persistent or severe viral infections

Some patients with a severe autoimmune process may require immunosuppressive therapy with one of the following:

  • Systemic corticosteroids

  • Cyclosporin A

  • Anti-CD20 monoclonal antibody (rituximab)

  • Anti-TNF monoclonal antibody (infliximab)

See Treatment and Medication for more detail.

Background

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+IgDdim), transitional B cells (CD38+++IgM+++), plasmablasts (CD38+++IgM-), mature B cells (CD19+CD21+), and CD21lo B cells (CD19+CD21lo). Expansion of CD21lo B cells in the peripheral blood of patients with common variable immunodeficiency was reported; these were associated with deficiency in activating the calcium pathway.

Several groups have reported classification of common variable immunodeficiency based on B-cell subtype using flow-cytometry techniques. Paris[2] and Freiburg[3] 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.[4] 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.

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.

Other defects described in common variable immunodeficiency include the following:

  • Lack of protein kinase C activation following stimulation with phorbol ester or anti-µ antibody

  • Increased spontaneous apoptosis associated with increased expression of CD95 (APO-1/Fas)

  • Impaired B-cell signal transduction cascade associated with abnormalities in protein tyrosine phosphorylation

  • Chromosomal radiosensitivity, presumably due to impaired ability to repair DNA

  • Loss of IgM memory B cells, correlating with clinical features of recurrent pneumonia caused by encapsulated microbes and bronchiectasis

  • Impaired TLR9 signaling in B cells and plasmacytoid dendritic cells (PDCs), leading to lower expression of costimulatory molecules and reduced production of proinflammatory cytokines

  • Impaired TLR 7/8 signaling in B cells

  • Reduced or absent plasma cells in bone marrow was associated with increased complications and adverse clinical outcomes

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.

Other defects include the following:

  • Reduction in regulatory T cells (Tregs) that is associated with autoimmune manifestation, granulomatous disease, and splenomegaly (Reduced Tregs correlated significantly with the expansion of CD21low B cells.)

  • Reduced expression of markers of Tregs, such as FoxP3, granzyme A, and pStat5 that correlated with the degree of Tregs dysfunction

  • Reduced thymic and bone marrow output, reduced TREC(+) and KREC(+) lymphocytes

  • Lymphopenia and poor lymphocyte proliferation

  • Increased CD8+ cell numbers

  • Lack of antigen-specific T cells

  • Restricted T-cell receptor repertoire

  • Oligoclonal expansion of CD8+ T cells

  • Decreased CD4+ CD45RA+ T cells

  • Decreased production of IL-2, IFN-gamma, IL-4, IL-5, IL-10, and IL-12

  • Impaired T-cell activation

  • Impaired intracellular tyrosine kinase expression

  • Reduced Zap-70 mobilization

  • Deficient CD28 co-signaling

  • Accelerated T-cell death and increased expression of CD95

  • Monocytoid and plasmacytoid dendritic cell defects

Mortality/Morbidity

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

Resnick et al summarized morbidity and mortality among 473 patients with common variable immunodeficiency at Mt. Sinai Hospital, NY over the past 4 decades.[5] Reduced survival was associated with age at diagnosis, lower baseline IgG, higher IgM, and fewer peripheral B cells. The risk of death was 11 times higher for patients with noninfectious complications. Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and GI disease, but not with bronchiectasis, autoimmunity, other cancers, or granulomatous disease.

Chapel et al reported European common variable immunodeficiency registry data that included 326 patients followed for at least 10 years since onset of symptoms.[6] 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.

Epidemiology

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

European Society for Immunodificiencies (ESID) Registry reported 2880 in the internet-based database in 2011. Prevalence (per 100,000 inhabitants) varies greatly by countries (France 0.977. Spain .567, Netherlands 0.865, United Kingdom 0.604, Italy 0.719, Germany 0.524, Poland 0.073).

Demographics

Common variable immunodeficiency has been reported in many different races. Common variable immunodeficiency equally affects males and females. 

This is most frequently diagnosed in adults aged 20–40 years. However, about 28% of subjects are given a diagnosis before age of 21 years. Median age at characteristic symptom onset was 24 years for males and 27 years for females, but males were diagnosed with common variable immunodeficiency earlier at a median age of 30 years than females at a median age of 33.5 years.[5]

 

Presentation

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.

 

DDx

 

Workup

Laboratory Studies

A diagnosis of common variable immunodeficiency (CVID) is based on defective functional antibody formation, usually accompanied by decreased (not absent) serum immunoglobulin (Ig)G and IgA levels, generally (not invariably) decreased serum IgM, and exclusion of other known causes of antibody deficiency.

Serum Ig levels are consistently depressed but are generally higher in patients with common variable immunodeficiency than in patients with X-linked agammaglobulinemia. Interpretation of results must consider the marked variations in normal Ig levels that accompany aging; always use age-related normal values for comparison. Normal values should be provided by the laboratory. Serum immunoglobulins are commonly measured by radial immunodiffusion or immunoturbidimetric methods. Electrophoresis and immunoelectrophoresis are not satisfactory techniques for the quantification of immunoglobulins.

IgG subclass determination is of limited value in assessing patients with clinical immunodeficiency because functional antibody deficiency may be present despite normal IgG subclass levels. Conversely, deficient levels of a single subclass of IgG may be found in individuals who have effective specific antibody production and are clinically normal.

Diminished immunoglobulin levels may be caused by loss and decreased synthesis. An indirect indication of loss may be obtained by measuring serum albumin or alpha-1-antitrypsin, which is usually lost concomitantly through GI or renal tracts.

Assessment of the ability to produce functional antibodies can be obtained by measuring antibody responses to natural antigens or those antigens to which the population commonly is exposed. This assessment can also be done by measuring antibody responses following active immunization with protein or polysaccharide antigens.

Isohemagglutinins are IgM antibodies to ABO blood group antigens that are polysaccharide. All individuals, except the 3% of the population who have blood group AB, develop isohemagglutinin titers during the first year of life; therefore, normal infants aged up to 8-10 months and people with the AB blood group lack significant isohemagglutinins.

In children who have completed immunizations with diphtheria, pertussis, and tetanus (DPT) or Hib-conjugated vaccines, the antibody response to protein antigens can be tested in adults and older children by measuring IgG antibodies to tetanus or diphtheria toxoid and H influenzae type b (Hib) polysaccharide antigen. Approximately 80% of children have detectable antibodies to these antigens after 3 immunizations during their first year of life. If the child's antibody level is low, administer 1 booster injection, then measure for antibodies 4 weeks later.

For nonimmunized children, recommended doses of diphtheria-tetanus (DT) or Hib-conjugate vaccines may be administered. Obtain blood 4 weeks after the last immunization and determine IgG antibodies. Alternatively, administer 3 doses of killed poliomyelitis vaccine (1 mL IM at 2-wk intervals); take a blood sample 4 weeks after the last injection and determine antibody level (usually by virus neutralization).

Antibody responses to polysaccharide antigens depend less on T cells; they are poor immunogens in children younger than 2 years. Assessment of responses to polysaccharide antigens is important in patients older than 18-24 months because these responses may be deficient in some patients who can respond normally to protein antigens. Pneumococcal (unconjugated) or meningococcal vaccines are commercially available polysaccharide antigens. Protein conjugated pneumococcal vaccine elicit antibody responses that are T-cell dependent. Therefore, antibody responses should be measured to polysaccharide antigens that are not present in the protein-conjugated pneumococcal vaccine. Alternatively antibody response to typhoid-Vi antigen can be measured following typhoid vaccine administration.

Hepatitis B is not a reliable antigen for testing immune competence because of the high frequency of nonresponders in the population, particularly in persons older than 40 years. Bacteriophage PhiX174 (a bacterial virus noninfective in humans) has been shown to be a potent, safe, and useful antigen; it allows measurement of antigen clearance and primary and secondary immune responses. Bacteriophage fX174 is not commercially available, and only a few research laboratories have used it for human in vivo testing.

In vivo T-cell function can be measured by skin testing for delayed cutaneous hypersensitivity (DCH). The prototype is the tuberculin skin test.

DCH is a localized immunological skin response and depends on functional thymus-derived T lymphocytes. Frequently used antigens include mumps (1 mg/mL), trichophyton (1:30), purified protein derivative (PPD) (2-10 IU), Candida (1:100 dilution, or 1:10 if negative with 1:100), or tetanus fluid toxoid (1:100). Several antigens must be used for DCH testing. Perform the tests by intradermal injection of 0.1 mL of antigen. Read results in 48-72 hours for the maximal diameter of induration. This test must be carried out by intradermal injection of antigens.

Erythema is not an indication of DCH. A positive DCH finding is informative, whereas negative DCH test findings may be difficult to interpret. This is because DCH is influenced by age, steroid therapy, severe illness, previous exposure to testing antigens, concurrent stress, and recent immunization.

Enumerate circulating T and B lymphocytes.

This is achieved by immunofluorescent staining of lymphocytes with monoclonal antibodies. Commonly used antibodies are CD19 and CD20 (for B cells), CD3 (for T cells), CD4 (for subsets of helper T cells), and CD8 (for T-suppressor lymphocytes). However, CD3 and CD8 are also expressed on natural killer (NK) cells. Monoclonal antibodies against CD16, CD56, and CD57, although not lineage-specific, may be useful for enumeration of NK cells to distinguish these cells from T cells.

Some patients with common variable immunodeficiency have low numbers or undetectable peripheral B cells. These patients, especially males, may have atypical X-linked agammaglobulinemia and should be studied for mutations of the Btk gene. Female patients with agammaglobulinemia and undetectable peripheral B cells may have phenotypic X-linked agammaglobulinemia. Some female patients with agammaglobulinemia were found to have mutations in the µ heavy-chain gene or l5 gene.

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+IgM-IgD-), non-switched memory B cells (CD19+CD27+IgM+IgD+), IgM-only memory B cells (CD19+CD27+IgM+IgDdim), transitional B cells (CD19+CD38+++IgM+++), plasmablasts (CD19+CD38+++IgM-), mature B cells (CD19+CD21+), and CD21lo B cells (CD19+CD21lo).

To test functional integrity of lymphocytes in a patient, lymphocytes can be isolated and stimulated with various agents in vitro.

Lymphocytes can be activated in vitro by the following:

  • Mitogens, such as phytohemagglutinin (PHA) or concanavalin A (Con A), stimulate T-cell proliferation. Pokeweed mitogen (PWM) stimulates T-cell and B-cell proliferation.

  • Antigens, such as PPD, Candida, streptokinase, and tetanus toxoid, can activate lymphocytes if the patient has had a prior encounter with the antigen. Superantigens, such as toxic shock syndrome toxin (TSST), can activate lymphocytes without prior encounter.

  • Allogeneic cells stimulate T-cell proliferation in mixed lymphocyte culture.

  • Lymphocytes can be activated in vitro by antibodies against T-cell surface molecules involved in signal transduction, such as to CD3, CD2, CD28, and CD43.

T-lymphocyte activation can be directly assessed by the following:

  • Assess the expression of activation markers on T cells, such as CD69, IL-2 receptor a (CD25), transferrin receptors (CD71), and major histocompatibility complex (MHC) class II molecules (HLA-DR). Detection of activation markers by immunofluorescent or immunohistochemical staining can provide rapid results.

  • Measure blastogenesis and/or proliferation of cells. The blastogenic response to soluble PHA or Con A requires presence of monocytes for stimulation of T cells. PWM stimulates both T cells and B cells, although T cells must be present for the B cells to be stimulated. The mixed lymphocyte reaction (MLR) results from T-cell reactivity to MHC antigens displayed on B cells and monocytes. Note that when normal irradiated or mitomycin C-treated lymphocytes are the stimulators of an MLR, the normal T cells in the culture may secrete factors that induce blastogenesis in the patient's lymphocytes. Therefore, using B-cell lines or T-cell depleted normal cells as the stimulators is preferable. Following in vitro stimulation of B cells with B-cell activators, culture supernatant can be tested for secreted Ig.)

  • Measure the release of cytokines or mediators, such as interleukin (IL)-2, IL-4, IL-5, IL-6, interferon-gamma, and tumor necrosis factor (TNF), in the culture supernatant.

  • Measure the secretion of immunoglobulin in the culture supernatant.

Anemia may be secondary to autoantibodies. Severe lymphopenia may raise suspicions that a patient has severe combined immunodeficiency or other primary T-cell defects. Small platelets in an infant boy suggest Wiskott-Aldrich syndrome. Neutropenia or thrombocytopenia may occur secondary to autoantibodies. Various organ-specific autoantibody production has been reported in patients with common variable immunodeficiency. Tests for autoantibody production should correlate to the patient's presenting symptoms and organ involvement.

Protein expression for BAFF-R, TACI, and CD19 on B cells and ICOS on activated T cells by flow cytometry are available in only a few specialized reference laboratories.

Genetic testing for mutation of TNFRSF13B, the gene encoding TACI (transmembrane activator and CAML interactor), can be performed using a small amount of blood sample through a polymerase chain reaction (PCR). Genetic testing can help to distinguish common variable immunodeficiency and other antibody deficiency syndromes. (Reference laboratory for genetic testing: Correlagen Diagnostics (617) 577-0152; Mayo Medical Laboratories (800) 533-1710, (507) 266-5700)

Imaging Studies

High-resolution CT scanning of the chest may be more sensitive in monitoring of pulmonary abnormalities in these patients than chest radiography or pulmonary function testing.

Other Tests

Studies for infectious agents: Make every effort to diagnose infections and identify infectious agents. The diagnosis of infection is complex and beyond the scope of this chapter.

Pulmonary function test: All patients who are able to perform forced expiratory maneuvers, usually those older than 6 years, should have periodic monitoring of pulmonary function.

Procedures

Bronchoscopy or endoscopy may be necessary for diagnosis of specific lesions or infectious process.

Noninfectious pulmonary disease should be aggressively pursued with diagnostic lung biopsy because the pathology may indicate the prognosis.[9]

Histologic Findings

Lymph node biopsy

Typical histologic findings of lymph nodes from patients with common variable immunodeficiency are reactive follicular hyperplasia, atypical hyperplasia, or granulomatous inflammation.

Intestinal biopsy

Histology of intestine may demonstrate villous atrophy or infection with cryptosporidia or G lamblia. Presence or absence of plasma cells in the submucosal tissue can be examined by hematoxylin and eosin (H and E) stain, and immunohistologic stain may be informative. Lymphoid cells are found in intestinal submucosa of normal infants older than 15-20 days.

Staging

Malignancies complicating common variable immunodeficiency are staged by conventional guidelines for immunocompetent patients.

 

Treatment

Medical Care

A major component of medical care is anti-infective and prevention of further infectious episodes by regular infusion of human immunoglobulin and antimicrobial therapy. Patients with autoimmune manifestations may require immunosuppressive therapy.

Immunoglobulin Replacement Therapy

Immunoglobulin (Ig) replacement therapy, by intravenous infusion or subcutaneous injection, remains the mainstay of therapy. The primary goal is the prevention of infection. Ig replacement therapy has decreased the frequency of life-threatening infections in these patients significantly. Most patients with common variable immunodeficiency (CVID) and sinopulmonary disease without severe bronchiectasis do well once they are placed on regular intravenous immunoglobulin therapy. If replacement therapy is started early, and if appropriate amounts are given with sufficient frequency, the cycle of recurrent infections and progressive lung damage can be arrested. However, silent progression of bronchiectasis was reported in a small number of patients while receiving adequate Ig replacement therapy.

Currently available immunoglobulin products in the United States are derived from pooled human plasma (see Medication). The manufacturing processes include cold ethanol fractionation of Ig and viral inactivation and removal steps. Biological activity of the IgG molecule, not simply the antibody titer, but opsonic and complement activity and circulating half-life, may be affected by discrete steps in the manufacturing and isolation of IgG. Only one report has compared two different IVIG products. In this randomized double-blind multicenter study, the Gamunex (purified using caprylate treatment and chromatography) treated group had a significantly lower number of infections compared with the group treated with Gamimune N (solvent-detergent treated) from the same company (annual infection rates were 0.18 compared with 0.43; p=0.023).

Reportedly, IVIG significantly decreased the frequency of lower respiratory tract and severe infection; however, IVIG did not change the frequency of nonrespiratory or upper respiratory infections. Also IVIG did not change the clinical course of autoimmune manifestations in patients with common variable immunodeficiency.

Intravenous infusion of immunoglobulin

Ig replacement is intravenously administered on a regular basis. The half-life of IgG widely varies among patients with common variable immunodeficiency but is usually longer than 18-23 days in healthy individuals. Tailor dose and frequency to the Ig trough levels and to clinical symptoms. Measure serum IgG level before each infusion, and accordingly adjust the dose of IVIG. Maintain trough serum IgG concentrations at 400-500 mg/dL in adults, a value close to the lower limit of normal. For most patients, a dose of 400-600 mg/kg every 3-4 weeks suffices to reduce the frequency of infection. Some patients with chronic lung disease require up to 600-800 mg/kg per month. Once established on a regular regimen, IVIG can be administered at home.

Adverse reactions to IVIG include nonanaphylactic reactions, anaphylactic reactions, transmission of infectious agents, and acute renal failure.

Nonanaphylactic reactions

These are the most common reactions to IVIG and manifest by backache, nausea, chills, low-grade temperature, or vomiting within the first 30 minutes of infusion.

Headache, chills, flushing, chest tightness, dyspnea, fever, myalgia, nausea, and fatigue may begin at the end of the infusion and continue for several hours. Slowing the infusion rate or interrupting the infusion for a few minutes can prevent most of these reactions.

Febrile or phlogistic reactions are thought to be secondary to immune aggregates that fix complement, either IgG aggregates or IgG-antigen, complexes.

These reactions tend to occur more frequently in patients with severe hypogammaglobulinemia, particularly at the initiation of treatment, and in those with intercurrent infections or bronchiectasis. These symptoms may be treated with acetaminophen, diphenhydramine, and/or hydrocortisone.

To minimize the risk of these reactions, treat or eradicate preexisting infection before administering IVIG for the first time or after a hiatus in therapy. Initiate therapy with one-half the calculated dose of IVIG and then repeat the dose 2 weeks later before going to a 3-week to 4-week schedule. Alternatively, premedication with antipyretics, diphenhydramine, and/or corticosteroids may be given.

Reactions caused by fluid volume, salt, or protein overload may be problematic for patients with cardiovascular limitations, particularly at higher doses. Closely monitor these patients during and after infusions; administer diuretics if necessary.

Anaphylactic reactions

True anaphylactic reactions to IVIG are rare. Patients who have selective IgA deficiency (SIgAD) or common variable immunodeficiency with undetectable IgA may develop IgE antibodies against IgA, following exposure to serum IgA. These patients may develop anaphylactic reactions during subsequent IVIG administrations.

Exercise caution during IVIG administration to patients with common variable immunodeficiency, particularly those with no detectable IgA.

The prekallikrein activator has been associated with hypotension and circulatory collapse, and IgG aggregates may result in anaphylaxis via complement activation.

The World Health Organization (WHO) recommendations for IVIG include no prekallikrein activator activity, low IgA content, and IgG aggregate content.

Transmission of infectious agents

The potential for transmission of pathogens cannot be completely ruled out. In 1993 and 1994, transmission of hepatitis C virus (HCV) was reported in recipients of one of two IVIG products that did not undergo viral inactivation steps during manufacturing. All IVIG products currently marketed in the United States now undergo viral inactivation and removal.

In order to reduce potential contamination of pathogens, all plasma for manufacture is tested at various levels and retested by viral marker and nucleic acid technology (NAT).

Viral inactivation is achieved by dry heat, pasteurization, or irradiation solvent-detergent treatment, low pH exposure, or caprolate treatment. Viral removal is necessary to reduce the risk of transmission of nonenveloped viruses and include precipitation, chromatography, and filtration including nanofiltration.

Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and HCV, are readily inactivated and can be effectively removed.

No case of HIV infection has resulted from treatment with IVIG because retroviruses are readily inactivated by the cold ethanol precipitation. The main concern is prions that transmit spongiform encephalopathy or referred to as variant Creutzfeldt-Jacob disease (vCJD).

Currently, no blood tests or inactivation methods are applicable to prions. Fortunately, prions have not been detected directly in human blood and the potential for efficient removal of prions by the current manufacturing processes have been documented.

Acute and chronic renal failure has been reported, most often in patients with preexisting renal disease who received sucrose-containing IVIG solutions. IVIG products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients at risk for acute renal failure include patients with any degree of preexisting renal insufficiency, diabetes mellitus, age older than 65 years, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Those products containing sucrose as a stabilizer accounted for a disproportionate share of the total number.

For patients at increased risk, monitoring BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Other rare reactions to IVIG include aseptic meningitis, lymphocytic pleural effusion, thromboembolism, coagulopathy, and immune hemolysis. Suspected causes of these adverse events are hyperosmolarity, presence of activated factor XI, and high sodium content. However, these are from anecdotal observation, and establishing precise guidelines for reducing the risk of adverse events is difficult.

Subcutaneous infusion of immunoglobulin

Subcutaneous infusion of Ig (SCIG) is an alternative method for patients with difficult venous access or for those who experience serious side effects from IVIG. Vivaglobin (ZLB Behring) is the first product to be approved in the United States for SCIG therapy for the prevention of serious infection in patients with primary immune deficiency diseases (PIDD) (see Table 2).

Vivaglobin is given on a weekly basis using an infusion pump, allowing patients to self-administer the injection at home. Recommended weekly dose of Vivaglobin is 100-200 mg/kg administered subcutaneously. The dose may be adjusted over time to achieve the desired clinical response and serum IgG levels. Initial dose can be calculated by multiplying the previous IVIG dose by 1.37, then dividing this dose into weekly doses based on the patient's previous IGIV treatment interval; for example, if IVIG was administered every 3 weeks, divide by 3. This dose of Vivaglobin provides a systemic IgG exposure comparable to that of the previous IVIG treatment. Weekly administration of this dose leads to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared with monthly IVIG treatment.

The SCIG is well accepted by patients, mostly administered at home, and the risk of infusion reactions is even less than for intravenous infusions. SCIG was well tolerated in patients who had a history of severe reactions to IVIG infusions with the same product.

In clinical trials, the most frequent adverse event was injection-site reaction, consisting of mild or moderate swelling, redness, and itching. No serious local site reactions were observed, and reactions tended to decrease substantially after repeated use. Other adverse events irrespective of causality included headache, GI disorder, fever, nausea, sore throat, and rash. As with all immune globulin (Ig) products, patients receiving Ig therapy for the first time, receiving a new product, or not having received Ig therapy within the preceding 8 weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting.

As with all immune globulin products, Vivaglobin is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with SIgAD who have known antibody against IgA. Vivaglobin is derived from human plasma. As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

Antimicrobial Treatment

Infections should be treated early with full doses of antimicrobial agents. Whenever possible, narrow-spectrum drugs should be used on the basis of microbial sensitivity testing. Prophylactic antibiotics should be avoided because they increase the hazard of infection with fungi or other resistant organisms. Antiviral agents may be useful in some patients with persistent or severe viral infections.

Treatment of Autoimmune Manifestations with Systemic Corticosteroids and Other Immunosuppressants

Most patients with common variable immunodeficiency and arthritis report reduced arthritic symptoms once they are placed on regular IVIG replacement therapy. GI diseases associated with common variable immunodeficiency, with a few cases of ulcerative colitis, did not benefit from regular infusion (even high dose) of IVIG.

Corticosteroid

In some patients with a severe autoimmune process, steroids or other immunosuppressive drugs may be needed. Use these drugs with caution and only in patients who have autoimmune disorders that cause significant clinical disease. In general, a short course of steroid therapy is well tolerated.

Cyclosporin A

Use of cyclosporin A with favorable outcome in a patient with common variable immunodeficiency and lymphoid interstitial pneumonitis has been reported.

Anti-CD20 monoclonal antibody (rituximab) and anti-TNF monoclonal antibody (infliximab)

Successful treatment of autoimmune thrombocytopenia and neutropenia using anti-CD20 monoclonal antibody administration was reported. Anti-TNF monoclonal antibody, infliximab, has been used successfully in the treatment of cutaneous granulomas in a patient with common variable immunodeficiency. A review of patients with granulomas reported no benefit with rituximab, etanercept, or infliximab in the treatment of granulomatous disease.

IL-2

An experimental preparation of IL-2 conjugated with polyethylene glycol (PEG) was administered to a select group of patients with CVID because of the observation that lymphocytes from a subgroup of patients with CVID, when activated in vitro, produce markedly decreased amounts of IL-2. After several months of therapy, a significant increase was noted in in vitro Ig production by patients' B lymphocytes, in vitro IL-2 production, and serum antibodies. Long-term outcomes of this therapy remain to be seen.

Other Treatments Directed to Involved Organs

Specific therapy directed to involved organs should be based on clinical manifestations and nature of the disease. Patients with common variable immunodeficiency and chronic lung disease frequently manifest airway obstructive disease indistinguishable from asthma. These patients may require inhaled corticosteroids and other long-term asthma medications along with albuterol therapy as needed. Patients with bronchiectasis may benefit from mucolytic inhalation therapy and chest physiotherapy.

Surgical Care

Often, patients with common variable immunodeficiency need a surgical procedure for treatment of complications (eg, endoscopic sinus surgery for chronic sinusitis). Some patients require splenectomy secondary to severe autoimmune thrombocytopenia or hemolytic anemia. Postoperative complications include sepsis and fistula. Perform a biopsy in patients with rapidly enlarging lymph nodes to rule out infection or malignancy.

Consultations

Patients with common variable immunodeficiency and multiple organ system involvement may benefit from a multidisciplinary team of consultants.

Diet

Patients with common variable immunodeficiency and chronic lung disease may require a high-calorie diet supplementation because of high-energy expenditure. Patients with chronic enteropathy may require an elemental diet.

Activity

Regular physical activity is encouraged.

 

Medication

Medication Summary

Replacement therapy with human immunoglobulin in patients with primary immune deficiencies

Intravenous immunoglobulin

The overall consensus among clinical immunologists is that a dose of intravenous immunoglobulin (IVIG) of 400–600 mg/kg/mo or a dose that maintains trough serum immunoglobulin (Ig) G levels greater than 500 mg/dL is desirable. Patients with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2–3 wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized) are observed. The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences.

Recording all side effects that occur during the infusion is crucial. Periodically monitoring liver and renal function test results, approximately 3–4 times a year, is also recommended. The US Food and Drug Administration (FDA) recommends that, for patients at risk for renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, those >65 years, and those who use nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatment is high, especially in patients with infections and in those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200–300 mg/kg), with the remaining dose given the next day to achieve a full dose. Treatment should not be discontinued. After achieving normal serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are much reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions include dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause.

Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5–10 mg/kg every 6–8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents.

For patients at increased risk, monitoring BUN and creatinine levels before starting treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued. IgE antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few reports of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience, this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in those patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see the table below).

Other rare, serious adverse events include aseptic meningitis, thromboembolic events, immune hemolysis, and transfusion-related acute lung injury. These events are related to hyperosmolality or activated coagulation factor, or high sodium content, or presence of anti-D antibody.

Potential for transmission of pathogens cannot be completely ruled out. In order to reduce potential contamination of pathogens, all plasma for manufacture is tested at various levels and retested by viral marker and nucleic acid technology (NAT). Viral inactivation is achieved by dry heat, pasteurization, or irradiation solvent-detergent treatment, low pH exposure, or caprolate treatment. Viral removal is necessary to reduce the risk of transmission of nonenveloped viruses and includes precipitation, chromatography, and filtration including nanofiltration. Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), are readily inactivated and can be effectively removed.

The main concern is prions that transmit spongiform encephalopathy (referred to as variant Creutzfeldt-Jacob disease [vCJD]). Currently, no blood tests or inactivation methods are applicable to prions. Fortunately, prions have not been detected directly in human blood and the potential for efficient removal of prions by the current manufacturing processes have been documented.

Subcutaneous immunoglobulin infusion

Subcutaneous infusion of Ig (SCIG) is an alternative method for patients with difficult venous access or for those who experience serious side effects from IVIG. Vivaglobin (ZLB Behring) is the first product to be approved in United States for SCIG therapy for the prevention of serious infection in patients with primary immune deficiency diseases (PIDD).

Vivaglobin is given on a weekly basis using an infusion pump, allowing patients to self-administer the injection at home. Recommended weekly dose of Vivaglobin is 100–200 mg/kg administered subcutaneously. Dose may be adjusted over time to achieve the desired clinical response and serum IgG levels. Initial dose can be calculated by multiplying the previous IVIG dose by 1.37, then dividing this dose into weekly doses based on the patient's previous IVIG treatment interval; for example, if IVIG was administered every 3 weeks, divide by 3. This dose of Vivaglobin provides a systemic IgG exposure comparable to that of the previous IVIG treatment.

Weekly administration of this dose leads to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared with monthly IVIG treatment. The SCIG is well accepted by patients, mostly administered at home, and the risk of infusion reactions is even less than for IV infusions. SCIG was well tolerated in patients who had a history of severe reactions to IVIG infusions with the same product.

In clinical trials, the most frequent adverse event was injection-site reaction, consisting of mild or moderate swelling, redness, and itching. No serious local site reactions were observed, and reactions tended to decrease substantially after repeated use. Other adverse events irrespective of causality included headache, gastrointestinal disorder, fever, nausea, sore throat, and rash. As with all Ig products, patients receiving Ig therapy for the first time, receiving a new product, or not having received Ig therapy within the preceding 8 weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting.

As with all immune globulin products, Vivaglobin is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A deficiency who have known antibody against IgA. Vivaglobin is derived from human plasma. As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

 

Table 2. Immune Globulin, Intravenous and Subcutaneous

Table. (Open Table in a new window)

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

*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).

Contents of table are adapted from the Manufacturers' literature.

*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).

 

Follow-up

Further Inpatient Care

Inpatient care may be necessary for any serious clinical conditions associated with common variable immunodeficiency (CVID).

Complications

See History for a discussion of complications.

Prognosis

The prognosis for patients with common variable immunodeficiency is reasonably good unless severe autoimmune disease or malignancy develops and if intravenous immunoglobulin (IVIG) replacement therapy is started early before severe lung damage takes place (see Mortality/Morbidity).

The development of granulomatous-lymphocytic lung disease was associated with a worse prognosis and an increased prevalence of lymphoproliferative disease.[9]

Patient Education

The effort to educate patients and families regarding early signs of infection should be ongoing. The approach in identifying infectious agents and specific antimicrobial therapy needs to be aggressive.

The following may be helpful resources:

  • The Immune Deficiency Foundation (40 W Chesapeake Avenue, Suite 308, Towson, MD 21204; telephone: 800-296-4433; e-mail: idf@primaryimmune.org)

  • The Jeffery Modell Foundation and Primary Immune Deficiency Resource Center (Hotline: 1-866-INFO-4-PI)

  • National Institutes of Health, MedlinePlus, Immune System and Disorders

  • For teenagers, Nemours Foundation, Immune System

  • American Academy of Allergy, Asthma, and Immunology, Tips to Remember: Recurrent of unusually severe infections

 

Questions & Answers

Overview

What is common variable immunodeficiency (CVID)?

What are the signs and symptoms of common variable immunodeficiency (CVID)?

What is the basis for a diagnosis of common variable immunodeficiency (CVID)?

How is common variable immunodeficiency (CVID) treated?

What is the most common immunologic defect in common variable immunodeficiency (CVID)?

Which B-cell defects are found in common variable immunodeficiency (CVID)?

Which T-cell defects are found in common variable immunodeficiency (CVID)?

What is the role of peripheral blood dendritic cells (DCs) in common variable immunodeficiency (CVID)?

What is the role of complement split products in common variable immunodeficiency (CVID)?

Which defects are found in common variable immunodeficiency (CVID)?

What is the morbidity and mortality associated with common variable immunodeficiency (CVID)?

What is the US prevalence of common variable immunodeficiency (CVID)?

What is the global prevalence of common variable immunodeficiency (CVID)?

What are the racial predilections of common variable immunodeficiency (CVID)?

At what age is common variable immunodeficiency (CVID) typically diagnosed?

Presentation

Which clinical history findings are characteristic of common variable immunodeficiency (CVID)?

Which infections are associated with common variable immunodeficiency (CVID)?

Which autoimmune conditions are associated with common variable immunodeficiency (CVID)?

Which granulomatous and lymphoid diseases are associated with common variable immunodeficiency (CVID)?

What is the increased risk for malignancy in common variable immunodeficiency (CVID)?

Which physical findings are characteristic of common variable immunodeficiency (CVID)?

What causes common variable immunodeficiency (CVID)?

DDX

What are the differential diagnoses for Pediatric Common Variable Immunodeficiency?

Workup

How is common variable immunodeficiency (CVID) diagnosed?

What is the role of imaging studies in the workup of common variable immunodeficiency (CVID)?

What is the role of pulmonary function tests (PFTs) in the diagnosis of common variable immunodeficiency (CVID)?

What is the role of bronchoscopy in the workup of common variable immunodeficiency (CVID)?

What is the role of lung biopsy in the workup of common variable immunodeficiency (CVID)?

Which histologic findings of lymph node biopsy findings are characteristic of common variable immunodeficiency (CVID)?

Which histologic findings of intestinal biopsy are characteristic of common variable immunodeficiency (CVID)?

How are malignancies complicating common variable immunodeficiency staged?

Treatment

How are infections prevented in common variable immunodeficiency (CVID)?

What is the role of IVIG in the treatment of common variable immunodeficiency (CVID)?

How is IVIG therapy administered for the treatment of common variable immunodeficiency (CVID)?

What is the nonanaphylactic adverse effects of IVIG therapy for the treatment of common variable immunodeficiency (CVID)?

What causes anaphylactic reactions to IVIG therapy for the treatment of common variable immunodeficiency (CVID)?

What is the risk for transmission of infectious agents through IVIG to treat common variable immunodeficiency (CVID)?

What is the role of SCIG in the treatment of common variable immunodeficiency (CVID)?

What is the role of antimicrobials in the treatment of common variable immunodeficiency (CVID)?

How does IVIG therapy affect arthritis and GI diseases associated with common variable immunodeficiency (CVID)?

What is the role of corticosteroids in the treatment of common variable immunodeficiency (CVID)?

What is the role of cyclosporin A in the treatment of common variable immunodeficiency (CVID)?

What is the role of anti-CD20 monoclonal antibodies in the treatment of common variable immunodeficiency (CVID)?

What is the role of IL-2 conjugated with polyethylene glycol (PEG) in the treatment of common variable immunodeficiency (CVID)?

How are chronic lung diseases treated in patients with common variable immunodeficiency (CVID)?

What is the role of surgery in the treatment of common variable immunodeficiency (CVID)?

Which specialist consultations are beneficial to patients with common variable immunodeficiency (CVID)?

Which dietary modifications are used in the treatment of common variable immunodeficiency (CVID)?

Which activity modifications are used in the treatment of common variable immunodeficiency (CVID)?

Medications

What is the role of medications in the treatment of common variable immunodeficiency (CVID)?

Follow-up

When is inpatient care indicated for the treatment of common variable immunodeficiency (CVID)?

What is the prognosis of common variable immunodeficiency (CVID)?

What is included in patient education about common variable immunodeficiency (CVID)?