AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Common variable immunodeficiency (CVID) is the most prevalent of the primary immunodeficiency diseases. CVID is a heterogeneous group of immunologic disorders of unknown etiology, characterized by impaired antibody responses. Patients with CVID have marked reduction in serum levels of both immunoglobulin G (IgG) and immunoglobulin A (IgA); about half of these patients also have reduced immunoglobulin M (IgM). Diagnosis is based on exclusion of known causes of humoral immune system defects. Most patients with CVID present as sporadic cases, although reports exist of familiar cases with various inheritance modes, including autosomal dominant with variable penetrance, autosomal recessive, or X-linked.

Pathophysiology

The common immunologic defect in patients with CVID is defective antibody formation. As would be 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 CVID 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 CVID 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, and 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 CVID: CD19 deficiency and mutations in the gene encoding TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor, TNFRSF13B). CD19 plays a crucial role in regulating B-cell responses to antigens and B-cell survival. TACI is one of the tumor necrosis factor receptor superfamily members. TACI plays an indispensable role in isotype switch, and terminal differentiation of B cells, and T-cell–independent antibody responses. TACI mutations leading to immunodeficiency account for an estimated 10-15% of patients with CVID.

Other studies have observed a lack of protein kinase C activation and translocation to the plasma membrane when B cells of patients with CVID were stimulated with phorbol ester or anti-µ antibody. B-cell lines from a subset of patients with CVID showed absent IgG and IgA production and increased spontaneous apoptosis that was associated with increased expression of CD95 (APO-1/Fas). A subset of patients with CVID showed impaired B-cell signal transduction cascade associated with abnormalities in protein tyrosine phosphorylation. Another subset exhibited chromosomal radiosensitivity, presumably due to impaired ability to repair DNA.

Mutations interfering with the regulation of the Ig gene expression, deficiency of memory B cells, and somatic hypermutation (SHM) abnormalities have been reported in patients with CVID. 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 CVID. Others reported that loss of IgM memory B cells correlates with clinical disease, recurrent pneumonia, and bronchiectasis in patients with CVID. B cells from these patients were unable to undergo isotype switching and to up-regulate activation markers on B cells when stimulated in vitro.

T-cell defect

An overwhelming body of literature suggests that most patients with CVID have intact B lymphocytes of immature phenotype. CVID B cells can secrete immunoglobulins (Ig), although often limited to IgM, if given the appropriate in vitro stimulation. Ig secretion has been induced from CVID 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 CVID have low expression of CD40 ligand on activated T cells. At least 30% of patients have lymphopenia due to the low number of CD4⁺ subsets. These patients also show decreased in vitro production of interleukin (IL)-2 when their peripheral blood mononuclear cells are stimulated in vitro. Decreased IL-2 production after T-cell receptor stimulation is correlated with diminished CD40 ligand expression. Reduced expression of ICOS (inducible costimulator of activated T cells) was reported in some autosomal recessive CVID families 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 of patients with CVID show low frequency of antigen-specific precursor T cells following immunization with the neoantigens, keyhole-limpet hemocyanin, and dinitrophenol (DNP)-Ficoll. Many patients with CVID 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.

Others have reported that most patients with CVID show increased production of interferon gamma by circulating CD8⁺ subsets, increased numbers of DR⁺/CD4⁺ T cells with up-regulated Fas expression and an increased rate of 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.

Increased endogenous cyclic adenosine monophosphate (cAMP) levels in T cells from patients with CVID are associated with increased activation of protein kinase A type I (PKAI) in T cells and with decreased proliferative response to anti-CD3 stimulation. 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 CVID 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 vitro activation.

Approximately 60% of patients with CVID have diminished proliferative responses to T-cell receptor stimulation and decreased induction of gene expression for IL-2, IL-4, IL-5, and interferon gamma. T-cell receptors show no evident abnormality; T-cell receptor gene analyses indicate normal heterogeneity of gene rearrangements. Tumor necrosis factor (TNF) production from T cells and monocytes is increased in a subgroup of patients with granulomas. 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 CVID, with a small subgroup of patients having very low responses. These results support the hypothesis that most patients with CVID have antibody deficiency secondary to abnormalities in T-cell signaling and defective T- and B-cell interactions.

The recovery of Ig production (mostly IgG and IgM) transiently or permanently following human immunodeficiency virus (HIV) or hepatitis virus C (HVC) infection has been reported in patients with CVID. These cases indicate that CVID 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 CVID with granulomatous disease. 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 CVID, 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 CVID was noted. Many patients with CVID 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 CVID.

Frequency

United States

Estimated incidence of CVID is 1 case per 10,000-50,000 population.

International

Incidence is similar to that in the United States.

Mortality/Morbidity

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

• The survival rate 20 years after diagnosis of CVID is 64% for males and 67% for females, compared to the expected 92% population survival rate for males and 94% for females.
• In one large series, the most frequent cause of death was lymphoma. Other causes of death relate to cor pulmonale from chronic pulmonary infection, liver failure caused by viral or autoimmune hepatitis, respiratory insufficiency associated with malnutrition, inflammatory bowel disease with malnutrition, and other viral infections.
• Parameters associated with mortality in this report were lower levels of serum IgG, poorer T-cell responses to phytohemagglutinin, and a lower percentage of peripheral B cells.

Race

CVID has been reported in many different races.

Sex

CVID affects males and females equally.

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Clinical manifestations of CVID include recurrent infections, autoimmune disease, lymphoid hyperplasia, granulomatous diseases, and malignancy.

• Recurrent infections
  • Recurrent pyogenic infections of upper and lower respiratory tracts are the main clinical manifestations of CVID. Symptoms may appear during childhood or, more often, after puberty. Bronchiectasis may develop if optimal therapy is delayed. Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus are the organisms most commonly involved.
  • A few patients with CVID present with unusual organisms, such as Pneumocystis carinii, mycobacteria, or various fungi. Mycoplasma pneumoniae infections in the urinary tract, joints, and deep abscesses have been reported.
  • Persistent diarrhea and malabsorption caused by Giardia lamblia also have been reported in patients with CVID. GI symptoms disappeared after G lamblia was eradicated with metronidazole.
  • Severe and recurrent infections with herpes simplex are common, and herpes zoster eventually developed in as many as 20% of patients with CVID.
  • 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 CVID has been reported; this patient developed paralytic poliomyelitis 7 years after the last administration of trivalent oral poliovirus vaccine.
• Autoimmune diseases and CVID
  • In contrast to X-linked agammaglobulinemia (XLA), CVID is associated with a high frequency of autoimmune and granulomatous diseases.
  • Some patients develop rheumatoid arthritis, hemolytic anemia, thrombocytopenia, neutropenia, thyroid abnormalities, vitiligo, or keratoconjunctivitis sicca.
  • Approximately 20% of these patients have a severe gastroenteropathy with severe malabsorption resembling celiac sprue, nodular lymphoid hyperplasia, and chronic inflammatory bowel disease such as ulcerative colitis and Crohn disease.
  • A small number of patients develop achlorhydria and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, alopecia totalis, hyperthyroidism, vasculitis, and lymphoid interstitial pneumonia.
  • Although regular Ig 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.
• Lymphoid hyperplasia and granulomatous diseases
  • Atypical lymphoid hyperplasia due to clonal expansion of B or T lymphocytes has been reported in as many as one third of patients with CVID. Extranodal sites, such as the lungs, GI tract, skin, spleen, liver, and parotid gland, may be involved by these lymphoproliferative processes. Lymph nodes show a reactive follicular hyperplasia, atypical hyperplasia, or granulomatous inflammation. Nodular lymphoid hyperplasia in the GI tract with clonal rearrangement of the Ig heavy chain gene or clonal T-cell receptor (TCR) gene rearrangement has been described in otherwise benign cases of lymphoid proliferation in patients with CVID.
  • Granulomas have been reported in approximately 8-22% of patients with CVID. These patients were more likely to have deficient T-cell proliferation to mitogens and antigens. Published studies have reported 22 patients with CVID and 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, gastrointestinal 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 monoclonal antibody against tumor necrosis factor-alpha receptor in a few patients with CVID has been reported.
  • One report described a possible role of human herpesvirus 8 (HHV-8) in the lymphoproliferative disorders in patients with CVID. They reported high copy of HHV-8 genome in peripheral blood mononuclear cells as well as in the lymph node.
• Increased risk of developing malignant neoplasms
  • Patients with CVID have a high risk of developing malignant neoplasms, such as non-Hodgkin lymphoma, GI carcinoma, or malignant lymphoma. Most of these are of the B-cell immunophenotype and frequently are associated with EBV.
  • Lymphoma occurs 300 times more frequently in women with CVID than in affected men. Malignant lymphomas in patients with CVID occur most frequently in the fifth to seventh decade and not in childhood. These malignant lymphomas usually are extranodal and histologically are intermediate- to high-grade non-Hodgkin lymphomas. Most of these lymphomas are of the B-cell immunophenotype and may be associated with EBV. Patients with CVID also are at risk for gastric carcinoma 47 times higher than normal. 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 CVID have generalized lymphadenopathy and splenomegaly. Other positive physical examination findings depend on their clinical presentation and organ involvement (see History). Young children with CVID may present with failure-to-thrive (FTT) based on 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 probably has a variety of causes, and a single etiology is unlikely. The search for gene(s) that underlie CVID has been difficult, partly because of the heterogeneity of CVID. Although most cases are sporadic, at least 10% are familial with autosomal dominant more common than autosomal recessive inheritance.

• A common genetic basis for CVID and selective IgA deficiency (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 CVID have been observed in approximately 20% of cases, including reported cases of sIgAD developing into CVID with time and occasionally vice versa, which suggests these conditions are linked closely and can be progressive or reversible. Deficits in IgG subclasses, most commonly IgG2 and IgG4, are observed in 20-30% of patients with sIgAD.
• Mutations in the gene encoding TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor, TNFRSF13B) were reported in 10-15% of patients with CVID and in a smaller number of patients with IgAD. TACI is 1 of 3 TNF receptor family members and mediates isotype switching in B cells. TACI mutations were associated with both familial and sporadic forms of CVID.
• Studies of families with multiple cases of sIgAD and CVID have shown that susceptibility to CVID or IgA deficiency may be linked to specific alleles of class II and class III genes of the major histocompatibility complex (MHC). A high incidence of deletion of the C4A gene and rare alleles of the C2 gene in the class III MHC region has been reported in patients with sIgAD or CVID. These findings indicate that susceptibility gene(s) may be present in this region on chromosome 6p.
  • Schaffer et al reported linkage of CVID to chromosome arm 16q with autosomal dominant inheritance in their study of 43 families with IgAD and at least one CVID individual.
  • Braig et al reported study of 3 families with CVID, IgAD, and dysgammaglobulinemia, where affection is inherited in an autosomal dominant pattern. Two of the families have linkage to the telomeric region of chromosome arm 5p, whereas the third has linkage to the HLA region.
  • Other gene mutations reportedly associated with CVID are ICOS (inducible costimulator of activated T cells) on 2q, CD19 on 16p, and TAFRSF13B (encodes TACI protein, TNF receptor family) on 17p.
• Recently, multiple allelic deoxyribonucleic acid (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. This examination identified a susceptibility locus in the class III region within a fragment that contains 21 known genes, including the genes for TNF-a, lymphotoxin (LT)-a, and LT-b. 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 MHC haplotypes, which were found in abnormally high frequency in immunodeficient patients, also were 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.
• CVID and sIgAD have been associated with antirheumatic or antiepileptic drugs. Drug-associated CVID or sIgAD suggests that a pathogenetic process may involve common key steps in individuals with the permissive genetic background.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CVID diagnosis is based on defective functional antibody formation, usually accompanied by decreased (not absent) serum IgG 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 they are generally higher in patients with CVID than in patients with XLA. 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 commonly are 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 a-1-antitrypsin, which usually is lost concomitantly through gastrointestinal or renal tracts.
• Functional antibody production: 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 also can be done by measuring antibody responses following active immunization with protein or polysaccharide antigens.
• • Antibodies to natural 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.
  • Antibody response to protein antigens
    • In children who have completed immunizations with diphtheria, pertussis, and tetanus (DPT) or Hib-conjugated vaccines: Antibody response to protein antigens can be tested in adults and older children previously immunized with childhood vaccinations 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. Draw blood 4 weeks after the last immunization and determine IgG antibodies. Alternatively, administer 3 doses of killed poliomyelitis vaccine (1.0 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: Antibody responses to polysaccharide antigens depend less on T cells, and 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 will 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 measurement of T-cell mediated immune function
  • In vivo T-cell function can be measured by skin testing for delayed cutaneous hypersensitivity (DHS). The prototype is the tuberculin skin test.
  • DHS is a localized immunological skin response and is dependent on functional thymus-derived T lymphocytes. Frequently used antigens are 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 positive DCH. A positive DCH is informative, while a negative DCH test 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 also are expressed on natural killer (NK) cells. Monoclonal antibodies against CD16, CD56, and CD57, even though they are not lineage specific, may be useful for enumeration of NK cells to distinguish these cells from T cells.
  • Some patients with CVID have low numbers or undetectable peripheral B cells. These patients, especially males, may have atypical XLA 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.
• In vitro activation of lymphocytes: To test functional integrity of lymphocytes in a patient, lymphocytes can be isolated and stimulated with variety of agents in vitro.
• • Lymphocytes can be activated in vitro by the followings.
    • Mitogens, such as phytohemagglutinin (PHA) or concanavalin A (Con A), stimulate T cell proliferation. Pokeweed mitogen (PWM) stimulates T 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 or with superantigens, such as toxic shock syndrome toxin (TSST).
    • Allogeneic cells stimulate T cell proliferation in mixed lymphocyte culture.
    • Lymphocytes can be activated in vitro by antibodies to T-cell surface molecules involved in signal transduction, such as to CD3, CD2, CD28, and CD43.
  • T-lymphocyte activation can be assessed directly by the following:
    • Assess the expression of activation antigens on T cells, such as CD69, IL-2 receptor a (CD25), transferrin receptors (CD71), and 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 a response to 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 MLC, 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 IL-2, IL-4, IL-5, IL-6, interferon-g, and TNF, in the culture supernatant.
    • Measure the secretion of immunoglobulin in the culture supernatant.
• Complete blood count and test for autoantibodies: Anemia may be secondary to autoantibodies, severe lymphopenia may raise suspicions that a patient has SCID or other primary T-cell defects, small platelets in an infant boy suggest Wiskott-Aldrich syndrome, and neutropenia or thrombocytopenia may occur secondary to autoantibodies. A variety of organ-specific autoantibody production has been reported in patients with CVID. Tests for autoantibody production should correlate to the patient's presenting symptoms and organ involvement.
• Genetic testing for mutation of TNFRSF13B, 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 CVID and other antibody deficiency syndromes. (Reference laboratory for genetic testing: Correlagen Diagnostics, Inc. 222 Third St. Suite 1100, Cambridge, MA 02142; telephone: (617) 577-0152.)

Imaging Studies

• High-resolution computed tomography (CT) of the chest may be more sensitive in monitoring of pulmonary abnormalities in these patients than chest radiographs or pulmonary function tests.

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 pursued aggressively with diagnostic lung biopsy since the pathology may indicate the prognosis (Bates, 2004).

Histologic Findings

• Lymph node biopsy: Typical histologic findings of lymph nodes from patients with CVID are reactive follicular hyperplasia, atypical hyperplasia, or granulomatous inflammation.
• Intestinal biopsy: Histology of intestine may demonstrate villous atrophy or infection with cryptosporidia or Giardia 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 CVID are staged by conventional guidelines for immunocompetent patients.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 CVID and sinopulmonary disease without severe bronchiectasis do well once they are placed on regular IVIG 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, Table 1). 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 of comparing two different IVIG products exists. 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 CVID.

Intravenous infusion of immunoglobulin (IVIG)

Ig replacement is administered intravenously on a regular basis. The half-life of IgG is highly variable among patients with CVID, but it usually is 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 adjust the dose of IVIG accordingly. 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- 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 sIgAD or CVID 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 CVID, particularly those with no detectable IgA.

Prekallikrein activator has been associated with hypotension and circulatory collapse, and IgG aggregates may result in anaphylaxis via complement activation. WHO recommendations for IVIG (1983) include no prekallikrein activator activity, low IgA content, and IgG aggregate content.

Transmission of infectious agents

Potential for transmission of pathogens cannot be completely ruled out. In 1993 and 1994, transmission of hepatitis C virus 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 variety of viral inactivation and removal processes, relatively large viruses, such as HIV, 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 blood urea nitrogen 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 Ig (SCIG)

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 1).

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 will provide a systemic IgG exposure comparable to that of the previous IVIG treatment. Weekly administration of this dose will lead 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, gastrointestinal 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 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.

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 CVID and arthritis report reduced arthritic symptoms once they are placed on regular IVIG replacement therapy. Gastrointestinal diseases associated with CVID, 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 CVID and lymphoid interstitial pneumonitis has been reported.

Anti-CD20 monoclonal antibody and anti-TNF monoclonal antibody: 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 granulomatas in a patient with CVID.

Interleukin 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 CVID 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 CVID need a surgical procedure for treatment of complications (eg, endoscopic sinus surgery for chronic sinusitis. Some patients required splenectomy secondary to severe autoimmune thrombocytopenia or hemolytic anemia. Postoperative complications include sepsis and fistula. Rapidly enlarging lymph nodes should be biopsied to rule out infection or malignancy.

Consultations

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

Diet

Patients with CVID 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Replacement therapy with human immunoglobulin in patients with primary immune deficiencies

Intravenous immunoglobulin (IVIG or IGIV)

The overall consensus among clinical immunologists is that a dose of IVIG of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. Patients (X-linked agammaglobulinemia) 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, q2-3wk) 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 exist in viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized). The choice of brands may be dependent 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. Monitoring liver and renal function test results periodically, approximately 3-4 times a year, is also recommended. The 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 are 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 q6-8h), 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 blood urea nitrogen 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 IgA-deficient patients. A few reports exist of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. In actual experience, however, 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 IgA-deficient patients ( <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 a variety of viral inactivation and removal processes, relatively large viruses, such as HIV, HBV, and 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 (SCIG)

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) (see the Table below).

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 will provide a systemic IgG exposure comparable to that of the previous IVIG treatment.

Weekly administration of this dose will lead 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 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 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.

Immune Globulin, Intravenous

*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 following sources:

1. Manufacturers' literature.
2. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.
3. Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.

Drug Category: Immune globulin, subcutaneous

Provides alternative method of administration for select patients.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care may be necessary for any serious clinical conditions associated with CVID.

Complications

• See History for a discussion of complications.

Prognosis

• The prognosis for patients with CVID is reasonably good unless severe autoimmune disease or malignancy develops, and if 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 (Bates, 2004).

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 Immune Deficiency Foundation (40 W Chesapeake Avenue, Suite 308, Towson, MD 21204; telephone: 800-296-4433; e-mail: idf@primaryimmune.org) provides information for laypersons and healthcare providers.
• 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
• National Institutes of Health, Child Health and Human Development, Health Information and Media - Publication Primary Immunodeficiency.
• US Department of Health and Human Services, National Institutes of Health, Understanding Immune System—How it Works
• For teenagers, Nemours Foundation, Immune System
• American Academy of Allergy, Asthma, and Immunology, Tips to Remember: Recurrent of unusually severe infections

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to measure ability to produce functional antibodies
• Administration of live viral vaccine, such as oral polio or MMR vaccine
• Failure to recognize and properly treat concurrent autoimmune process or malignancy

Special Concerns

• Pregnant CVID patients with chronic lung disease and compromised pulmonary function may experience further compromise in pulmonary function, especially in the third trimester. Newborn infants of CVID patients usually are born with a normal IgG level as long as the mother receives adequate IVIG replacement therapy during pregnancy. IgG is actively transported across the placenta during the third trimester.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Aug 10, 2006