Laboratory Studies
See the list below:
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Because B cells produce circulating levels of immunoglobulin (Ig)G, IgA, and IgM, any or any combination of them may be low depending on the stage of B-cell maturation that is affected. In addition, all or any combination of the IgG subclasses IgG1, IgG2, IgG3, or IgG4 may be low. Physicians must compare the patient's specific levels to age-appropriate control data.
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In 1971, the World Health Organization first defined selective IgA deficiency as a serum IgA level of less than 5 mg/dL, with normal levels of IgG and IgM and intact T-lymphocyte function.
An international consensus panel defined primary IgA deficiency as a serum IgA level of less than 7 mg/dL (< 0.07 g/L) in any patient older than 4 years. Therefore, IgA deficiency is an IgA level of less than 5-7 mg/dL. Other causes of hypogammaglobulinemia must be excluded. Patients with primary IgA deficiency also have a normal IgG antibody response to vaccination.
The gradual increase in production of IgA with aging makes a comparison with age-appropriate values necessary. Therefore, awareness of whether the local laboratory uses age-matched control values is important.
Similarly, whether the IgA measurement is based on nephelometry is important because levels less than 10 mg/dL are not reliable using this method. [39] The Mayo Clinic can accurately determine levels less than 2 mg/dL. IBT Laboratories can accurately measure values down to 7 mg/dL.
The international consensus panel has stated, "a male or female patient greater than 4 years of age who has a serum IgA at least 2 standard deviations below normal for age but normal serum IgG and IgM and in whom other causes of hypogammaglobulinemia have been excluded" has probable primary IgA deficiency.
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Partial IgA deficiency is defined as a serum IgA level less than that expected for the patient's age (ie, < 2 standard deviations from the mean). [39] This finding is most common in children because of development of their IgA-specific B-cell system is delayed. When followed up serially, serum IgA levels increase in about half of these patients, increasing toward normal values by the time children are aged 5 years. However, individuals whose IgA level is less than 5 mg/dL usually do not have this transient IgA deficiency. Patients with partial IgA deficiency may have rheumatic complaints of joint pain or swelling and morning stiffness. [43]
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A diagnosis of primary IgA deficiency requires the ability to have a normal IgG antibody response to vaccination with childhood vaccines, such as those for diphtheria, pertussis, varicella, hepatitis B, and H influenzae. Therefore, a patient who has or who develops an impaired antibody response may also develop combined IgG subclass deficiency or common variable immunodeficiency (CVID).
Prevaccination and postvaccination serum antibody titers are ideally tested simultaneously and compared to enhance the reliability of the results. However, children younger than 2 years do not respond well to polysaccharide vaccines.
The new consensus statement implies that a diagnosis of primary IgA deficiency requires the ability to have a normal IgG antibody response to vaccination. A patient who develops an impaired antibody response possibly may have developed CVID or combined IgG subclass deficiency.
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Further laboratory studies can clarify the association of B-cell deficiency with other disorders (see History). Identifying concomitant allergy in patients with chronic respiratory infections may require in vivo or in vitro allergy testing and management.
As many as one half of patients with selective IgA deficiency have milk precipitins (precipitable IgG antibody against cow's milk), and they may have symptoms suggesting a milk protein allergy. Circulating immune complexes are also described in these individuals. Most of these patients do not have symptoms that can be attributed to the presence of these antibodies.
The need to obtain other studies often depends on the diseases (if any) associated with B-cell deficiency. Although there is an increased incidence of various autoantibodies, it is not certain whether their presence will result in autoimmune disease. Some have interpreted these studies to indicate a compensatory defense mechanism against infections and to control excessive inflammation. [44]
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Some patients may have a concurrent IgG subclass deficiency and may not respond well to polysaccharide antigens. Determining their specific antibody levels to antigens from pneumococcal, meningococcal, or H influenzae bacteria may help distinguish antigen-specific antibody deficiency (ASAD) or specific antibody deficiency (SAD) because these patients are more prone to develop recurrent infections and serious sequelae such as bronchiectasis. Measurements of the response to pneumococcal polysaccharides is preferred, [45] although others prefer antibody response to meningococcal vaccination. [46] The response to bacterial polysaccharide antigens depends on the age of the patient and the immunogenicity of the different bacterial serotypes.
Patients suspected of antigen-specific antibody deficiency have normal antibodies-to–protein antigens. They also have normal or near normal serum Ig levels, excluding CVID.
This syndrome rarely is diagnosed in children younger than 2 years because children who are approximately that age usually do not respond to most vaccine-derived polysaccharide antigens.
Some physicians recommend measuring preexisting pneumonococcal antibodies first and then checking the results before giving the polysaccharide vaccine. High preimmunization antibodies have been associated with local and systemic reactions (usually fever), which should be treated with appropriate medications.
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Some controversy surrounds the laboratory definition of ASAD and SAD. Any acceptable definition of a normal response to immunization must account for age-related differences in the serotype-specific antibody concentration and in the number of serotypes inducing an arbitrarily defined adequate response. The definition should depend on familiarity with the clinical laboratory performing these types of tests. Serotypes 6A, 9N, 14, and 23F have low immunogenicity.
Some suggest that absence of response means that the patient had no response to all of the pneumococcal serotypes tested. A low or partial response is an adequate response to 50% of the serotypes tested in a child aged 2-5 years and to more than 70% in a child older than 6 years. Data supports that a response of 50% or higher following the 23-valent pneumococcal vaccine is normal. [47]
Others suggested that SAD be diagnosed by the absent of a response in two assays, one using the 23-valent pneumococcal vaccine as a screening test and the definitive measurement of specific serotypes such as 14, 19F and 23F. [26]
Some measured the response to 5 serotypes, defining SAD as those with an inadequate response to at least 4 (3, 4, 9N, 18C, and 19F). [25] Others define SAD as those with fewer than 9 of 12 responses to vaccination with polyvalent pneumococcal vaccine. [31]
Protective effect of pneumococcal strains is observed with antibody concentrations of greater than 300 ng (or >2 mcg/mL).
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To identify an IgA deficiency caused by drugs, administer a substitute drug for 3-6 months before retesting the serum IgA level.
Imaging Studies
See the list below:
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No particular radiologic finding is specific for the B-cell deficiency syndromes described in this article. However, bronchiectasis appears to be associated with IgG subclass deficiency or specific polysaccharide antibody production deficiency. [29]
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In addition, patients with cystic fibrosis was reported to have low IgG2 at high frequency as much as 29%. [48] Therefore, these patients' pulmonary status should be periodically evaluated with a high-resolution CT to determine the presence of bronchiectasis.
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The development of pulmonary sequelae appears to be 5 times more frequent in IgG subclass deficiencies than in selective IgA deficiency. [49]
Other Tests
See the list below:
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Chronic sinusitis can be a therapeutic challenge because therapy with antibiotics, N -acetylcysteine, and topical intranasal beclomethasone fails to clear pathogens and does not decrease sinus inflammation. Documentation with sinus CT may be helpful.
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Patients with chronic diarrhea and malabsorption may have blunting of the villi, as seen on jejunal biopsy specimens. In patients with selective IgA deficiency, IgM-secreting plasma cells are observed in the lamina propria instead of IgA plasma cells. However, the overall lymph node architecture is normal in selective IgA deficiency.
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Pulmonary function testing may show an obstruction pattern in certain patients with hypogammaglobulinemia, indicating asthma. The prevention of permanent lung damage should be a major goal of medical management. Therefore, periodic measurements of their pulmonary status may be helpful to monitor a major source of morbidity in these patients.
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The incidence of airway hyperactivity may also be increased.
Tables
Brand(Manufacturer) |
Manufacturing Process |
pH |
Additives (IVIg products containing sucrose are most 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]) |
Parenteral Form and Final Concentrations |
IgA Content mcg/mL |
Carimune NF (CSL Behring) |
Kistler-Nitschmann fractionation; pH 4, nanofiltration |
6.4-6.8 |
6% solution: 10% sucrose, < 20 mg NaCl/g protein |
Lyophilized powder 3%, 6%, 9%, 12% |
Trace |
Flebogamma (Grifols USA) |
Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization |
5.1-6 |
Sucrose free, contains 5% D-sorbitol |
Liquid 5% |
< 50 |
Gammagard Liquid 10% (Baxter Bioscience) |
Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation |
4.6-5.1 |
0.25M glycine |
Ready-for-use Liquid 10% |
37 |
Gamunex (Talecris Biotherapeutics) |
Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation |
4-4.5 |
Does not contain carbohydrate stabilizers (eg, sucrose, maltose), contains glycine |
Liquid 10% |
46 |
Gammaplex (Bio Products) |
Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation |
4.8-5.1 |
Contains sorbitol (40 mg/mL); do not administer if fructose intolerant |
Ready-for-use solution 5% |
< 10 |
Iveegam EN (Baxter Bioscience) |
Cohn-Oncley fraction II/III; ultrafiltration; pasteurization |
6.4-7.2 |
5% solution: 5% glucose, 0.3% NaCl |
Lyophilized powder 5% |
< 10 |
Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) |
Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated |
6.4-7.2 |
5% solution: 0.3% albumin, 2.25% glycine, 2% glucose |
Lyophilized powder 5%, 10% |
< 1.6 (5% solution) |
Octagam (Octapharma USA) 9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events |
Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization |
5.1-6 |
10% maltose |
Liquid 5% |
200 |
Panglobulin (Swiss Red Cross for the American Red Cross) |
Kistler-Nitschmann fractionation; pH 4 incubation, trace pepsin, nanofiltration |
6.6 |
Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl |
Lyophilized powder 3%, 6%, 9%, 12% |
720 |
Privigen Liquid 10% (CSL Behring) |
Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration |
4.6-5 |
L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) |
Ready-for use liquid 10% |
< 25 |
