IgA and IgG Subclass Deficiencies 

Updated: Aug 14, 2014
Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

B cells are lymphocytes responsible for the production of antibody. The most common type of primary immunodeficiency (>50% of cases) involves deficient antibody production. Primary humoral deficiencies vary from complete absence of B cells, serum immunoglobulin (Ig), or both to lacunar deficits that involve specific antibody responses to polysaccharides. The spectrum of antibody deficiency is broad, ranging from decreased total IgG levels to normal IgG levels and from primary B-cell defects to combined immunodeficiencies with antibody abnormalities associated with other immune and often nonimmune abnormalities.

Although this article discusses agammaglobulinemia and hypogammaglobulinemia, the emphasis is on selective Ig deficiencies, including the decreased production of IgA and the various IgG subclasses and impaired antibody responses to specific antigens such as polysaccharide proteins present on certain bacteria.

Pathophysiology

When IgA-bearing B lymphocytes fail to mature into IgA-secreting plasma cells, serum IgA levels are reduced, and specific IgA deficiency results. If B-cell development arrest leads to clinically significant decreases in or an absence of all Ig production, the result is agammaglobulinemia or hypogammaglobulinemia (see Agammaglobulinemia). Some, although reduced, numbers of IgA-bearing B cells are in the circulation, or IgA-bearing plasma cells are in the GI lamina propria in most cases with IgA deficiency. Failure of terminal B-cell differentiation is attributed to (1) an intrinsic B-cell defect, (2) inadequate or defective T-helper cells, (3) presence of or excessive IgA-specific T-cell suppressor cells, and (4) passage of maternal anti-IgA antibodies that suppress fetal IgA development.

In intrinsic B-cell defect, the alpha1 gene may be deleted along with other heavy-chain genes. Ig heavy-chain genes are located on chromosome 14q32 in the following order: 3'-XV-D-J-mu-delta-gamma1-psi/epsilon1-alpha1-psi/gamma1-gamma2-gamma4-epsilon-alpha2-5'. Therefore, homozygous deletions of large portions of the Ig heavy-chain locus result in individuals with complete absence of 3 or more Ig classes (IgG2, IgG4, IgA1, occasionally IgE). Investigators have described gene deletions of the heavy chain for Cƒ×1, Cƒ×2, Cƒ×4 and CƒÑ1 genes (in a patient with IgG1, IgG2, IgG4 and IgA1 deficiency) and Cƒ×2, Cƒ×4, CƒÕ, and CƒÑ1 genes (in patients with IgG2, IgG4, IgE, and IgA1 deficiencies). However, in general, the molecular mechanisms of IgG subclass deficiencies have not been clearly delineated.

Selective IgA deficiency is probably the most common of the primary immunodeficiency disorders, but it may also be asymptomatic. Therefore, in surveys of patients followed for immunodeficiency, common variable immunodeficiency is the most common, followed by IgA deficiency.[1] In 1993, Plebani et al described 2 siblings who appeared to be healthy and who did not have increased infections despite extensive deletion of immunoglobulin heavy chain locus.[2] They did have normal responses to immunization with protein and polysaccharide antigens. However, the authors did not measure secretory IgA.

Deficient secretory IgA with normal serum IgA levels is reported in few patients. The importance of IgA can be demonstrated in animal models that lack IgA and have problems clearing rotavirus infection.[3] Lack of severe infections in patients with IgA and secretory IgA deficiency may be attributed to compensatory increases in secretory IgM. Other concomitant immune defects may be required to increase the risk for respiratory and GI infections and various autoimmune diseases frequently described in patients with IgA deficiency. These concomitant immune defects may include deficiencies of certain IgG subclasses or of mannose-binding lectin (MBL).[4] The most common IgG-subclass deficiency associated with IgA deficiency is that of IgG2. IgA-IgG2 deficiency can also be seen with other IgG-subclass deficiencies, especially that involving IgG4.

The importance of IgG-subclass deficiency is reflected in the isotypes of IgG antibodies produced against microbial antigens. Antibodies against pneumococcal polysaccharide antigens are predominantly IgG2 and, to a lesser degree, IgG4. In contrast, antibodies against protein antigens, such as tetanus, are predominantly IgG1 and, to a lesser degree, IgG3. Finally, antibodies against large extracellular parasites, such as Schistosoma and Filaria organisms, exclusively belong to IgG4 subclass.[5]

This difference in isotypes of IgG antibodies may also extend to IgG antibodies against common dietary proteins, such as wheat (gliadin). Constantin et al (2005) found a difference in isotypes of antigliadin IgG antibodies in patients with celiac disease and those with IgE-mediated food allergy to wheat.[6]

Selective IgA deficiency is associated with an increased incidence of autoimmune and allergic diseases. This association may be due to increased exposure and subsequent sensitization with allergens due to the absence of secretory IgAs, which serve as blocking antibodies and which appear to have a role in tolerance induction.

Epidemiology

Frequency

United States

Selective IgA deficiency is the most common primary immunodeficiency, with a prevalence ranging from 1 in 223-1000 in community studies to 1 in 400-3000 in healthy blood donors. These various results may reflect differences in population selection or diagnostic criteria. To establish the diagnosis, some investigators use a serum IgA level of less than 5-10 mg/dL, whereas others used less than 2 standard deviations from age-appropriate control levels.

International

Large population studies in various Caucasian countries show a frequency of 1 in 400-500 or 0.2-0.25%.[7, 8]

The prevalence of IgA deficiency in these studies appears to be similar to those reported in the United States.

Mortality/Morbidity

The risk for frequent and recurrent infections seems to be lower in patients with selective B-cell deficiency than in patients with agammaglobulinemia (patients who do not make any Ig). However, they have an increased risk of developing atopic or autoimmune diseases. Many patients have selective IgA or IgG subclass deficiency but remain asymptomatic. However, the clinician must be aware of any potential risk of atopic or autoimmune diseases to conduct careful monitoring. In patients with IgA and/or IgG subclass deficiency, treatment decisions depend on their clinical features (eg, the degree of their morbidity with infections and concomitant diseases). In general, IgA deficiency with concomitant immune defects such as defects in specific antibody production have higher rates of recurrent infections and bronchiectasis.[9, 10]

Individuals with selective IgA or IgG subclass deficiency are usually asymptomatic. However, certain infections such as by influenza virus may be more persistent.[11] Patients with IgA-IgG2 deficiency do frequently have recurrent and chronic sinopulmonary infections.

Data from many clinical studies suggest that patients with IgG subclass deficiency are particularly susceptible to various infections, but no direct cause-and-effect relationship has been established. This lack of data may be due to the difficulty of accurately measuring IgG subclass levels and to intravariability and intervariability of IgG subclass levels in individuals.

Patients with IgG subclass deficiency appear to have an increased incidence of asthma or sinusitis.

Although patients with deficiencies in IgA subclasses are usually asymptomatic, their incidence of allergic and autoimmune disorders appears to be high. In one Turkish study,[12] the most common clinical conditions associated with IgA deficiency were various infections (84%), allergies (43%), and autoimmune disorders (17%). Another study examining selective IgA deficiency in Israel found 40% with infections (mainly pneumonia and ear infections), 32% with allergies, 21% with autoimmune diseases, and 5% with malignancies.[13] Therefore, treatment of the associated medical conditions must be considered. There have been other recent surveys questioning the association of IgA deficiency and atopy,[14, 15] although the latter may have been underpowered since they looked at the Asian population. Other studies indicated an increased risk for upper airway obstruction and food hypersensitivity.[16]

Recently, attention has been focused on psychiatric conditions that have been associated with IgA deficiency.[17]

Race

Large population studies in various Caucasian countries show a frequency of 1 in 400-500 or 0.2-0.25%[7, 8] IgA deficiency also appears to be more prevalent in blacks than in whites, whereas Asians have the lowest incidence, with only 7 cases found in 22,609 blood donors in one survey.[18] A study of over 20,000 Turkish school children shows an incidence of 1:188 (0.52%).[19]

IgA deficiency is associated with defects of other Igs, especially those of the IgG subclass, with a high frequency. IgG2 deficiency is reported in 19% and 8% of Swedish and American patients with IgA deficiency, respectively.

Sex

Most studies of healthy individuals without medical concerns reveal no sex predilection.

Age

Most selective IgA or IgG subclass deficiencies manifesting with clinical symptoms are detected during early childhood. The frequency and severity of infections decrease as patients' age, and their quantitative Ig levels may increase. Indeed, patients with IgA deficiency may compensate over time with increased IgG1 and IgG3 antibody levels. On the contrary, some patients initially identified as having IgG2 and IgA deficiency may progress to have typical common variable immunodeficiency (CVID) with panhypogammaglobulinemia.

 

Presentation

History

See the list below:

  • As many as 85-90% of patients with immunoglobulin (Ig)A deficiency are asymptomatic.[20] A compensatory increase in IgM production and subsequent increase in secretory IgM in the mucosal lumen may account for lack of clinical symptoms, but the data are conflicting. Another explanation for lack of clinical symptoms is normal levels of secretory IgA despite decreased serum IgA levels. However, patients with IgA deficiency can present with broad spectrum of medical conditions, including recurrent sinopulmonary infections, atopic disorders (atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy), GI disease (especially celiac disease), neurologic diseases, autoimmunity, and malignancy.

    • Gastric carcinomas or lymphomas are malignancies frequently associated with IgA deficiency.

    • Various autoimmune diseases are associated with IgA deficiency, including rheumatoid arthritis, systemic lupus erythematosus, Graves disease, type 1 diabetes, celiac disease, myasthenia gravis, pernicious anemia, and immune thrombocytopenic purpura. Strong association with major histocompatibility complex (MHC) and several non-MHC genes, such as interferon-induced helicase 1 and c-type lectin domain family 16, have been found for both autoimmune disorders and IgA deficiency. Some doubt has been raised with myasthenia gravis.[21] Even in absence of overt clinical symptoms, sera of patients of IgA deficiency often reveal a wide spectrum of autoantibodies.

    • For example, the prevalence of IgA deficiency in patients with thyrotropin-receptor autoantibodies (TRAb) was 10-times higher than expected in the general population.[22] Conversely, TRAb seropositivity is common among IgA-deficient populations, suggesting a predisposition toward Graves disease.

    • Various GI diseases also are associated with IgA deficiency. These diseases often cause chronic diarrhea with or without malabsorption. Persistent and recurrent infection with Giardia lamblia, and autoimmune GI diseases (eg, celiac, ulcerative colitis, regional enteritis) must be considered and ruled out in patients with IgA deficiency and GI symptoms. Biopsy specimens may show nodular lymphoid hyperplasia with flattened villi. Conversely, selective IgA deficiency or partial deficiency is present in 2% of celiac disease patients, especially in those patients with other autoimmune diseases.[23]

    • Recurrent sinopulmonary infection is the illness most frequently encountered in patients with selective IgA deficiency (up to above 80% in some series). These infections often alert the clinician to order a test of serum Ig levels. Reduced IgA levels establish the diagnosis. Most upper and lower respiratory tract infections are caused by relatively less virulent microbes, or patients present without overt causative pathogens. Patients with a concomitant IgM or IgG subclass deficiency present with recurrent infection more frequently than patients with isolated IgA deficiency. In a retrospective study of 129 patients with chronic rhinosinusitis, 72% had low baseline antipneumococcal titers and 12% were diagnosed with specific antibody deficiency (SAD) based on an inadequate antibody response to the pneumococcal vaccine.[24] These patients also tend to have lower IgA levels.

    • IgA deficiency is also frequently detected in patients with various neurologic disorders. Genetic defects that affect DNA repair enzymes cause ataxia telangiectasia and Nijmegan breakage syndrome. These lead to progressive neurodegenerative disorders. They are also associated with declining IgA levels with age. Anti-convulsants can cause hypogammaglobulinemia or selective IgA deficiency.

    • Food allergy and other atopic disorders (eg, allergic conjunctivitis, rhinitis, allergic urticaria, atopic dermatitis, asthma) are more common in patients with IgA deficiency than in the general population.

  • Controversy surrounds the clinical relevance of IgG subclass deficiency because many patients with IgG2 subclass deficiency (level of 0) can be asymptomatic. Therefore, the patient's ability to produce specific antibodies against polysaccharide antigens is important in determining the need for therapeutic intervention. One report indicated that as many as 20% of children with recurrent or chronic infections due to encapsulated bacteria have IgG subclass deficiency.

  • Although the IgG2 isotype is generally thought to dominate the antibody responses to polysaccharide antigens, a direct causal relationship between decreased serum IgG2 and infection with encapsulated organisms has not been definitively shown. The concept that antibodies against polysaccharide antigens are mainly IgG2 (with some IgG4) and that most antibodies against protein antigens are predominantly IgG1 and IgG3 does not appear to be universally valid. Notable crossover among IgG isotypes appears to occur with both protein and polysaccharide antigens.

  • In contrast, antibody deficiency against microbial polysaccharide antigens is a well-established clinical entity and has been referred to as either antigen specific antibody deficiency (ASAD) or specific antibody deficiency (SAD). These patients generally present with recurrent upper and/or lower respiratory infections due to an encapsulated organism (Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, or Staphylococcus aureus). Examining patients with increased susceptibility to airway infections show 8-15% with SPAD.[25, 26, 27] The latter authors suggest a particular high association with a history of otitis media and chronic otorrhea.

  • Patients may also present with concomitant atopic disorders (eg, asthma, atopic dermatitis). Authors have indicated a need to assess antibody responses to polysaccharide vaccines (eg, Pneumovax) in patients with bronchiectasis of unknown etiology.[28] This is strongly indicated for IgA deficiency patients with a history of recurrent or chronic otitis media and/or sinusitis, IgG2 subclass deficiency, and low levels of baseline specific antibodies.[29, 9, 10]

    • Frequent, recurrent episodes of otitis media are most commonly observed in patients with selective IgA deficiency and decreased IgA or IgG subclass levels (especially IgG2).[30] These patients also frequently have specific antibody deficiency due to bacterial polysaccharide antigens. Frequent infections were reported in 92% of patients with SAD (sinusitis, 77%; pneumonia, 42%; otitis media, 25%; bronchitis, 28%).[31]

    • As many as 50% of patients with idiopathic bronchiectasis have an absence of antipolysaccharide IgA or IgG2 antibodies.[28] Although others find such a defect only in 11%.[29] However, laboratory measures of IgA-IgG subclass antibodies against pneumococcal antigens are not readily available. Costa Carvalho et al (2005) also reported the absence of a positive association between unresponsiveness to unconjugated pneumococcal vaccines (for polysaccharide antigens [Pneumovax]) and IgA and/or IgG subclass deficiencies in children with recurrent sinusitis.[32]

  • Deficiency of antibodies of certain IgG subclasses may have clinical relevance in identifying patients with relatively severe atopic dermatitis.[33] It may also be associated with nonresponsiveness to interferon alfa in patients with hepatitis B viral infection.[34]

  • There has been much speculation but few hard data on a new syndrome termed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococci) or pediatric acute-onset syndrome (PANS).[35, 36] Although no definitive immunodeficiency has yet been described, treatment with IVIG has been successful in some patients.

Physical

See the list below:

  • Patients appear to be healthy between infections.

  • Any abnormal physical findings may indicate various diseases to which patients with selective IgA deficiency have an increased susceptibility.

  • Patients with IgA deficiency and abnormalities of chromosome 18 may present with the following:

    • Facial abnormalities

    • Ear abnormalities

    • Hand abnormalities

    • Growth retardation

    • Muscular hypotonia

    • Mental retardation

Causes

In most cases, IgA-deficiency appears to occur in a sporadic fashion, but familial inheritance is described in a mode of autosomal-recessive or autosomal-dominant pattern with variable or incomplete expression. IgA deficiency is also most commonly found in family members with common variable immunodeficiency (CVID).

  • Transplacental passage of anti-IgA antibodies also can cause IgA deficiency in an offspring by inducing IgA-specific T-cell suppressor activity. This was suggested in a report of 2 mothers with IgA deficiency whose infants had excessive T-cell suppressor function specific for IgA and IgA deficiency.[37]

  • IgA deficiency is also reported in individuals with various chromosomal abnormalities, particularly those with chromosome 18 abnormalities. Decreased or absent IgA is described in 2 of 6 patients with ring 18, in 5 of 15 patients with deletion of the long arm of 18 (18p-), and in 2 of 5 patients with deletion of the short arm (18q-). Patients with 18p- also have an increased incidence of autoimmune diseases. The actual mechanism is not known because no specific area in chromosome 18 has been consistently associated with IgA deficiency. Specific polysaccharide antibody deficiency has also been described in chromosome 18p deletion.[38] Partial deletions of chromosome 4 (Wolf-Hirschhorn syndrome) have also resulted in immune defects, including CVID, IgA and IgG2 subclass deficiency, IgA deficiency, and impaired antibody responses to polysaccharide antigens.

  • Other data indicate an association with certain major histocompatibility complex (MHC) haplotypes, suggesting a role with another gene located in chromosome 6 that may explain the high prevalence of autoimmune diseases with IgA deficiency. Certain MHC haplotypes, such as human leukocyte antigen (HLA)-A1, HLA-B8, HLA-DR3; HLA-B57, HLA-SC61, HLA-DR7; and HLA-B44, HLA-FC31, HLA-DR7, have been associated with primary IgA deficiency. Linkage with other haplotypes, eg, HLA-A1, HLA-B8, HLS-DR3, HLA-DQB1*0201, C4B-Sf, C4A-null, G11-15, Bf-0.4, C2a, HSP70-7.5, and tumor necrosis factor (TNF)-a5 is described in a family with IgA deficiency or CVID.

  • Certain drugs can induce transient IgA deficiency which resolve after the causative drugs are removed. This is implicated with induction of suppressor T-cell activity specific for IgA. Agents that can cause IgA deficiency with such mechanisms include sulfasalazine, hydantoin, cyclosporine, gold, fenclofenac, sodium valproate, and captopril. Indeed, 20-40% of patients treated with phenytoin may develop IgA deficiency.[39]

  • Certain viral infections, such as congenital rubella infection or Epstein-Barr virus (EBV) infection, may result in persistent IgA deficiency. Infection by other viruses such as parvovirus B19[40] has also been described.

    • Ig heavy-chain genes are located on chromosome 14 in the following order: 3'-V-D-J–mu-delta-gamma1-psi/epsilon1-alpha1-psi/gamma1-gamma2-gamma4-epsilon1-alpha2. Therefore, deletions of the 1 result in absent IgA1 and also may involve IgE, IgG4, and IgG2, or deletions of the 2 may result in absent IgE, IgG2, and IgG4. No individuals have been described with both IgA1 and IgA2 gene deletions. Individuals with a selective IgA subclass deficiency are usually asymptomatic.

    • Patients in whom homozygous deletions have resulted in absent IgG2, IgG4, IgA1, and IgE Igs appear to be healthy and have normal responses to protein and polysaccharide antigens. Therefore, the most valid indication of immunodeficiency may be the child's ability to make specific antibody.

    • During normal development, synthesis of IgG2 and IgG4 lags that of IgG1 and IgG3. Measurement of IgG subclass levels in children younger than 4 years may simply reflect maturational delay.

  • IgG subclass levels can be affected by placental passage, maturational age, presence of infection, protein loss, or the use of drugs, such as corticosteroids. An example of the differential response can be found in measles. In children younger than 3 years, measles IgG antibodies are predominantly IgG3 in isotype whereas those older than 4 years of age, IgG2 antibodies are predominant.[41]

  • Finally, IgG subclasss deficiency may be seen in certain malignancies such as chronic lymphocytic leukemia.[42]

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • 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.

  • 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.

  • 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]

  • 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.

  • 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]

  • 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.

  • 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).

  • 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:

  • 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]

  • 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.

  • 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:

  • 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.

  • 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.

  • 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.

  • The incidence of airway hyperactivity may also be increased.

 

Treatment

Medical Care

As noted in Medication, even if the patient cannot produce specific antibodies, the decision to treat with intravenous immunoglobulin (IVIg) is controversial. Aggressive use of antibiotics is required for recurrent respiratory tract infections, such as sinusitis, asthma, and bronchitis.

The use of prophylactic antibiotics (eg, during the winter months) has not been well studied but can be considered. Cohort studies indicate that this approach can be successful.[50] If conventional initial intervention with antibiotics is not successful, a trial of IVIg at 400-600 mg/kg for 6 months may be considered. For partial deficiencies (ie, specific antibody deficiency), IVIg can be stopped if no clinical response is observed.

In IgG subclass deficiency, most clinicians reserve IVIg for patients unable to make antibodies to both protein and polysaccharide antigens. Although reports mention a possible beneficial effect of decreased duration of bacterial infection in patients with IgG subclass deficiency,[51] an unpublished, blinded, and randomized trial of IVIg in IgG subclass deficiency showed that IVIg was not effective. However, cohort studies indicate a benefit, especially in those patients with fewer responses to pneumococcal polysaccharide challenge.[31]

Some advocate using IVIg if a patient aged 3 years or older does not respond to the unconjugated vaccine, especially if the titer or quantity to any 1 serotype (eg, type 3 polysaccharide, the most immunogenic) does not increase 2-fold.

Patients with a decreased ability to make antipolysaccharide antibodies should be immunized with polysaccharide-protein conjugate vaccines, such as H influenzae type b (HIB) with diphtheria-tetanus. The conjugated protein allows anti-HIB antibodies to develop, though 2 or 3 doses are usually required.

A conjugated pneumococcal vaccine is now licensed for use in the United States. Conjugated meningococcal vaccine (Menactra) is also now yet available in the United States. Sorensen et al (1998) showed that a significant percentage of children with specific antibody deficiency develop protective antibody levels to the conjugated pneumococcal vaccine (Prevnar) with a subsequently decreased rate of infections.[52] Patients with isolated IgG3 subclass deficiency have a similar dilemma as to whether IVIg is helpful.[53]

OM-85 BV has been used in Europe for over 20 years to stimulate mucosa-associated lymphoid tissue and up-regulate the TH-1 response. One study did not find any increased induction of autoantibodies in IgA-deficient patients.[54] The authors did not comment on any beneficial effect in these patients. More specific therapy may become available if clinical studies on interleukin 21 confirm potential therapy in patients with common variable and selective IgA deficiencies.[55]

Aggressive treatment of underlying allergies and/or asthma may help reduce the frequency and/or severity of recurrent respiratory tract infections, such as sinusitis and bronchitis.

Conventionally treat associated autoimmune diseases. Nothing indicates that patients with a concomitant specific IgA deficiency do worse than those without any immunodeficiency.

Surgical Care

A few patients with chronic upper or lower respiratory infections and subsequent structural changes may need strategic, long-term, broad-spectrum antibiotics, in addition to chest physiotherapy and sinus surgery.

Although many patients benefit from the placement of tympanostomy tubes to manage recurrent otitis media and/or they might undergo endoscopic sinus surgery for chronic sinusitis, the importance of aggressive medical therapy for the underlying immunodeficiency and its accompanied allergic condition cannot be overemphasized.

Consultations

Consultation with a surgeon may be needed for patients with chronic infections of the upper or lower respiratory tracts. Chronic sinusitis may require various ear, nose, and throat (ENT) procedures to promote drainage.

A rheumatologist, allergist/immunologist, or both may be required because of the various autoimmune and allergic diseases present with increased frequency in B-cell disorders.

Diet

Gluten-free and other restricted diets have been tried but are ineffective in these disorders when chronic diarrhea is present.

Activity

Encourage normal activity.

 

Medication

Medication Summary

The use of antibiotics to treat infections caused by S pneumoniae, H influenzae, and Moraxella catarrhalis must be aggressive. Prophylactic antibiotics can be beneficial in selected cases

Intravenous immunoglobulin (IVIg) is not a conventional therapy and has not been approved by the US Food and Drug Administration (FDA) for selective IgA deficiency, IgG subclass deficiency, or specific antibody deficiency. For empiric use of IVIg in these patients, clinicians must consider the expense and current shortage of IVIg supplies in the United States. In addition, exercise caution in patients with absent IgA serum levels because of the possibility of anaphylaxis with all IVIg preparations, except for Gammagard.

The overall consensus among clinical immunologists is that a dosage of IVIg of 400-600 mg/kg/mo or a dosage that maintains trough serum IgG levels of more than 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia and meningoencephalitis require dosages of 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 dosage to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, frequent infusions (eg, every 2-3 wk) of small doses may maintain the serum level in the reference range. The rate of elimination of IgG may be increased during active infection; measuring serum IgG levels and increasing dosages or shortening intervals may be required.

For replacement therapy in patients with primary immune deficiency, all brands of IVIg are probably equivalent, although viral-inactivation processes differ (eg, solvent detergent washing vs pasteurization, liquid vs lyophilized methods). The choice may depend on the hospital or home-care formulary and on local availability and cost. The dosage, manufacturer, and lot number should be recorded for each infusion to review then for adverse events or other consequences. Recording all adverse effects that occur during the infusion is crucial. Monitoring liver and renal function periodically, approximately 3-4 times yearly, 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, age >65 y, and use nephrotoxic drugs), recommended dosages should not be exceeded, and infusion rates and concentrations should be the minimum practical levels.

Initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments 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 slowed 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 normal serum IgG levels are achieved, adverse reactions are uncommon unless patients have active infections.

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

Anticomplementary activity of IgG aggregates in the IVIg, and the formation of immune complexes are thought to be related to adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and that 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 at 5-10 mg/kg every 6-8 hours, acetaminophen at 15 mg/kg/dose, diphenhydramine at 1 mg/kg/dose, and/or hydrocortisone at 6 mg/kg/dose (maximum, 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but important complication of IVIg treatment. Reports suggest that IVIg products with sucrose as a stabilizer may be associated with a heightened risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest 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, BUN and creatinine levels should be monitored before the start of treatment and before each infusion. If renal function deteriorates, the product should be discontinued.

IgE antibodies to IgA are reported to cause severe transfusion reactions in IgA-deficient patients. A few reports describe true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with Ig. However, in clinical experience, this is 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 patients with Ig deficiency (< 7 mg/dL) who need IVIg because of IgG subclass deficiencies. IVIg preparations with low concentrations of contaminating IgA are advised (see the Table below).

Table. Immune Globulin, Intravenous [56, 57, 58, 59] (Open Table in a new window)

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

Immunoglobulin

Class Summary

Subcutaneous administration of immune globulin may be considered for some patients.

Immune globulin subcutaneous (Vivaglobin)

IgG antibodies that neutralize a wide variety of bacterial and viral agents. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade. Peak serum IgG levels are lower and trough IgG levels are higher than those achieved with IVIG. SC administration results in stable steady-state IgG levels when administered weekly. Available as a 160-mg/mL SC injectable.

 

Follow-up

Further Outpatient Care

See the list below:

  • Because immunoglobulin (Ig)G subclass and/or isolated IgA deficiency are observed most commonly in atopic or autoimmune disorders, treating the concomitant diseases is crucial. Adequate treatment for the underlying allergic component may substantially decrease the rate of chronic upper and lower respiratory infections.

  • Live viral vaccines are not a risk in partial defects. When the diagnosis of partial defects is established, live viral vaccines can be administered. However, the risk occurs when the exact diagnosis is not known. Until concomitant T-cell deficiency is ruled out, live viral vaccines should be avoided in the patient and in siblings or other children in the house because the attenuated virus is excreted and poses a threat to the severely immunodeficient patient.

  • Sorensen et al (1998) showed that a significant percentage of children with specific antibody deficiency develop protective antibody levels to the conjugated pneumococcal vaccine (Prevnar) with subsequent decreased infections.[60]

  • In addition, serum IgA subclass levels, IgG subclass levels, or both may increase to normal range in more than 50%.[50] Therefore, regular monitoring of immunoglobulin levels should be done. Conversely, levels may decrease and lose specific immunoglobulin production as some patients progress to common variable immunodeficiency (CVID).

  • Do not make a decision to start IVIg treatment lightly. Although its beneficial effect for patients with agammaglobulinemia or hypogammaglobulinemia is not controversial, its use in IgG subclass deficiency or specific antibody deficiency in the presence of normal total Igs is not routine. In 1999, Lawton pointed out that patients, their parents, or the referring physician often insist on a trial of Ig therapy.[61] When this results in a beneficial effect, discontinuation is often difficult because "the child's health and family peace soon become dependent on continuation of the treatment."[61]

  • In addition to the high cost of IVIg and the emotional stress of monthly infusions, keep in mind the real possibility of IVIg transmitting unknown infectious agents. Hepatitis C virus transmission has been documented with certain IVIg preparations.

  • Families usually agree to a predetermined interval for an empiric trial of IVIg if the clinical problems with recurrent upper and lower respiratory infections appear to be sufficiently severe in patients younger than 4 years. This may occur during the winter, ending in spring. Immunologic testing then can be repeated 3-4 months after the last infusion. Restart treatment only if the antibody response remains abnormal.

Complications

See the list below:

  • Prevent chronic upper and lower respiratory disorders by treating underlying allergic disorders (eg, rhinitis, asthma) with aggressive use of antibiotics to manage bacterial infections (eg, sinusitis, bronchitis, pneumonias). Chronic ear infections can cause hearing loss. Watch for mastoiditis.

  • In one study, chronic pulmonary damage, as determined on chest CT scanning, occurred in about 20% of patients.[49] In the converse, extensive evaluation of patients with bronchiectasis showed that 11% had polysaccharide antibody deficiency to either pneumococcal or HIB vaccines.[29]

  • No good studies have been conducted to examine the potential benefits of prophylactic antibiotics, given systemically or topically (ie, aerosolized), in patients with B-cell disorder. However, it can be invaluable in selected patients.

  • Patients with impaired responses to vaccines may eventually develop CVID, possibly with concomitant T-cell deficiency. Closely follow up such patients and serially assess specific antibody responses (protein and polysaccharide antigens) and IgG subclasses and/or IgA serum levels.

  • Some IgA deficiency also occurs in patients with T lymphocyte deficiency such as ataxia-telangiectasia. Live viral vaccines should be avoided in these patients.

Prognosis

See the list below:

  • The prognosis of patients with these B-cell disorders depends on the severity of the humoral deficiency and on the extent to which other associated disorders, such as atopic or autoimmune diseases, are involved.

  • IVIg therapy offers a good prognosis for patients with the most severe form of antibody deficiency (ie, agammaglobulinemia).

  • In many individuals, selective IgA deficiency occurs without respiratory or intestinal symptoms. The role of selective IgG deficiency role in susceptibility to infections is similarly uncertain because many individuals with selective IgG deficiency are asymptomatic.

  • Most patients with IgA and IgG subclass deficiency who are younger than 4 years do well with appropriate antibiotic therapy and outgrow their frequent or recurrent infections, especially if they can make specific antibodies. Closely monitor patients who have IgG subclass deficiency that does not improve to assess for relatively complete B-cell deficiency such as CVID.[10]

  • Wolpert and Knutsen reported on 120 children with specific antibody deficiency and found that 50% developed normal responses after a mean of 3.1 years.[62] IVIg was administered in 28% of these children. Similar findings were reported by Kutukculer et al.[50]

Patient Education

See the list below:

  • Because of the close association with various allergic and autoimmune disorders, parents and patients must be aware of any underlying chronic atopic disorders.

  • Possible allergic triggers may require additional intervention with allergy testing and medical treatment.