Immunoglobulin G Deficiency

Background

Immunodeficiency diseases are commonly classified into disorders that affect one or more of the 4 major limbs of the immune system. These limbs are (1) B cells, ie, humoral immunity; (2) T cells, ie, cell-mediated immunity; (3) phagocytes; and (4) complement.

B-cell immunity is mediated by the immunoglobulins and is commonly referred to as humoral immunity. Humoral immunity is differentiated from T-cell immunity, which is commonly referred to as cellular immunity, and from phagocytic cell immune function. Immunoglobulins, which are protein molecules that contain antibody activity, are produced by the terminal cells of B-cell differentiation known as plasma cells. Immunoglobulins have important roles in humoral immunity, and they consist of 5 major classes or isotypes: immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin D (IgD), and immunoglobulin E (IgE). The most abundant class of immunoglobulins in the blood is IgG (73%), which has a molecular weight of 150 kd. IgG is present in plasma and external secretions and is expressed on the B-cell membrane.

View Image

Immunoglobulin G deficiency. Schematic representation of an immunoglobulin G molecule. CH indicates constant region of heavy chain; CL, constant regio....

IgG is further subdivided into 4 subclasses: IgG1, IgG2, IgG3, and IgG4. Fortunately, for ease of recall, the serum concentrations of the subclasses directly correlate with their numerical nomenclature, such that IgG1 is found in greater concentrations than IgG2, and so forth.

View Image

Immunoglobulin G deficiency. Human immunoglobulin G subclasses.

In 1952, Bruton described classic X-linked agammaglobulinemia due to B-cell deficiency in an 8-year-old boy. The child presented with frequent pyogenic infections, repeated episodes of sepsis with the same serotypes of pneumococcus, and multiple episodes of mumps, yet he had no antibodies against these pathogens. Serum protein electrophoresis had just become available, and it revealed that the g fraction was missing from the child’s blood. Subsequently, patients were described who had detectable lymphoid tissue and B-cells but had decreased IgG levels and/or lacked specific antibodies. These conditions are now recognized as fitting the categories of hyper-IgM syndromes and common variable immunodeficiency (CVID). A new subset of the latter was recently characterized by reduced C1 esterase inhibitor levels.^[1]

In the early 1960s, following the discovery of the IgG subclasses, certain associations were also recognized between individual subclass deficiencies, decreased ability to respond to certain types of antigens (ie, bacterial polysaccharides), and recurrent infection. IgG deficiencies may occur as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types. Moreover, even if the total IgG concentration is normal, deficiencies of one or more individual IgG subclasses, significant decreases in specific IgG antibodies, or both may be observed.

For information on deficiencies of other immunoglobulin types, see the Medscape Reference articles IgA Deficiency, IgD Deficiency, and IgM Deficiency.

• References

Pathophysiology

B and T cells are responsible for specific immunity, otherwise known as adaptive immunity. Adaptive immune responses require rearrangement of the genes responsible for the specific recognition structures, ie, immunoglobulins for humoral immunity and T-cell receptors for cellular immunity. Inability to form these recognition structures or blocks in the differentiation and development of either of these cell types results in primary immune deficiency. Abnormal production of these cells may also be observed in clinical states in which production of abnormal cell types is pathologically excessive (eg, lymphoproliferative diseases such as lymphoma and leukemia) or in immunodeficiency disorders in which production is aberrantly low.^[2] Humoral immune defects can also result from excessive loss of antibody proteins (eg, protein-losing enteropathy, certain forms of nephritis), even though the B-cell mass may be normal in those conditions.

IgG is well distributed in intravascular and extravascular spaces and is important in the secondary antibody responses (immune memory). It plays an important role in host defense against infection. IgG protects tissues from bacteria, viruses, and toxins. Different subclasses of IgG neutralize bacterial toxins, activate complement, and enhance phagocytosis by opsonization.^[3]

Importantly, note that a low IgG level, with normal IgA and IgM levels, does not necessarily equate with antibody deficiency. The evaluation of specific antibody responses is essential for the diagnosis and for appropriate treatment.

For ease of discussion, IgG deficiencies may be divided into 2 categories. The first is selective IgG deficiency, which consists of an isolated deficiency of IgG with normal levels of IgA, IgM, IgD, and IgE. The second is a deficiency of IgG accompanied by inadequate levels of other immunoglobulin isotypes. This may occur in various conditions, including X-linked agammaglobulinemia (X-LA), common variable immunodeficiency (CVID), and hyper-IgM syndromes.

These disorders occur in persons of any age or sex. Selective immunoglobulin deficiencies were previously referred to as late-onset agammaglobulinemia, and now they are classified under the general designation of antibody deficiency. Both pediatric and adult populations may be affected by specific or selective antibody deficiencies, CVID, or both. See Common variable immunodeficiency for more details.

IgA deficiency is the most common immune deficiency. Although some "normal" blood donors may be found to be deficient in IgA, approximately 20% of patients who lack IgA are also deficient in IgG2 and IgG4. These individuals appear to have a greater risk of infection than patients with isolated IgA deficiency.

• References

Epidemiology

Frequency

Although the frequency of isolated IgG deficiency is not known with certainty, deficiencies in specific IgG antibody or IgG subclass is probably more common and occurs in families with common variable immunodeficiency (CVID). Some reports indicate that the prevalence of IgG deficiency may be 1 case per 10,000 persons.

Mortality/Morbidity

Early diagnosis and treatment of IgG deficiency is essential to prevent and control both morbidity and mortality. IgG subclass deficiency is associated with shorter treatment-free and overall survival in chronic lymphocytic leukemia.^[4]

IgG subclass levels are highly variable, even within individuals at different points in time. Their development in early childhood varies from subclass to subclass; IgG 2 is the slowest to reach adult values. Additional deficiencies may become apparent because of defective switching between different IgG subclasses.

Age

Both children and adults are affected. Children younger than 24 months cannot make much IgG2; hence, measuring the IgG2 subclass concentration before this age is not meaningful.

The most common subclass deficiency in early childhood is IgG2 deficiency; in adults, IgG1 and IgG3 deficiencies predominate. IgG1 accounts for a higher proportion of the total IgG in children as compared to adults. Although children rapidly attain adult levels of IgG1 and IgG3, the development of IgG2 and IgG4 is slower. In some children, maturation of the full range of IgG subclasses may be delayed until the teenage years. Note the figure below.

View Image

Immunoglobulin G deficiency. Changes in serum immunoglobulin G concentrations during infancy and childhood.

One recent study found an isolated IgG3 subclass deficiency was the most common IgG subclass deficiency in Thai children. IgG3 subclass deficiency, either isolated or combined with other IgG subclass deficiency, was found in 85.5% of 55 children, most of whom were first evaluated for recurrent sinusitis.^[5]

• References

History

IgG deficiency

One should look for a pattern of organ-specific infection (ie, otitis media, sinopulmonary infection), recurrent infections with same organism, systemic infections, dental and oral disease, autoimmune disease, and a family history of such conditions.^[6]

Patients with selective IgG deficiency, IgG subclass deficiency, specific IgG antibody deficiency, or a combination of these usually experience recurrent or chronic pyogenic respiratory tract infections similar to those observed in persons with other B-cell deficiencies. Bronchiectasis may develop, and prior studies have shown that IgG antibody deficiencies may be the basis for the persistent sinusitis and other conditions that mimic allergic diseases that are commonly observed in these individuals.

IgG subclass deficiency

The clinical importance of IgG subclass deficiency is controversial. Persons with chromosomal deletions of some IgG subclasses have been reported to be healthy, and the demonstration of a low IgG subclass level is not sufficient to diagnose antibody deficiency. One must demonstrate deficiency of specific antibody responses to documented infections or vaccine antigens.^{[7, 8, 9]}

When deficiency of a single IgG subclass occurs (often IgG2), the patient may have a normal total IgG concentration and a defect in the production of specific immunoglobulins in response to immunization. The patient may be asymptomatic between episodes of acute infection, although even minor reductions in the total serum concentration can be associated with a deficiency of specific antibodies (eg, antibodies to bacterial polysaccharides) and increased risk of infection with Streptococcus pneumoniae, Haemophilus influenzae type b, and Staphylococcus aureus.

The normal range for IgG reported in most laboratories is broad, and the contribution of antibodies with any given specificity to the overall total IgG level, or even the total level of an individual subclass, may be relatively small. Therefore, measurements of specific antibodies and responses to polysaccharide and protein antigens are more useful, in most cases, than total IgG or IgG subclass measurements. This may be especially true in cases of monoclonal gammopathy. Thus, serum protein immunoelectrophoresis should be performed in all cases in which antibody deficiency coexists with normal levels of total IgG or IgG subclass.

IgG subclass deficiencies often occur in pairs (eg, IgG1 and IgG3, IgG2 and IgG4), following the general principle that IgG1 and IgG3 are directed against protein antigens and IgG2 is directed against polysaccharide antigens. However, this is a generalization, and a significant fraction of the antipneumococcal antibodies in most individuals with normal levels is within the IgG3 subclass. Because IgG1 accounts for 60-75% of the total IgG, patients with significant deficiencies of IgG1 alone or IgG1 and IgG3 are likely to have low total IgG levels, as well. Subnormal IgG3 with non-protective S. pneumoniae IgG levels may contribute to enhanced susceptibility to respiratory tract infections.^[10]

Among patients with selective subclass deficiencies and normal total IgG levels, those with deficiencies involving IgG2 display the highest frequency of infectious complications, generally of the respiratory tract.^[11] Because IgG2 antibodies are critical to immune responses to organisms with polysaccharide capsules, most patients experience otitis and recurrent sinopulmonary infections with encapsulated bacteria.^[12] However, other clinical presentations, such as atopic disease (eg, asthma) and autoimmune disease, may be observed.

Patients often have impaired antibody responses to immunization with polysaccharide vaccines, and they often manifest recurrent symptomatic infections.^[8] Patients with IgG2 and IgA deficiencies are particularly affected.

Many patients with IgG2 or specific polysaccharide antibody deficiency have recurrent respiratory conditions such as bronchiectasis, bronchopneumonia, bronchitis, obstructive lung disease, and hyper-reactive airways, which often presents as " asthma."

Patients with monoclonal gammopathy of unknown significance and multiple myeloma often have functional antibody deficiencies. Bacterial infection as a result of such a deficiency is a common morbid complication.

Children with apparent selective deficiency in IgG4 most often represent developmental variations in maturation of IgG4 production and most often do not have a significant immune deficiency per se. However, combined IgG2-IgG4 deficiency may be associated with severe deficiency in polysaccharide antibodies, which can result in chronic or recurrent otitis leading to deafness, sinopulmonary disease, or both.

• References

Physical

IgG deficiency

The most frequent clinical problems in any type of IgG deficiency are repeated episodes of otitis and recurrent or chronic infections of the upper and lower respiratory tracts. Many cases of specific IgG antibody deficiency are diagnosed in seemingly healthy individuals who have recurrent or chronic sinusitis and whose initial presentations may include headache, cough, and intermittent or low-grade fever, with or without other constitutional symptoms. These patients may frequently have perforated, scarred or bulging, cloudy, immobile tympanic membranes and chronic effusions of the middle ear.

In patients with X-linked agammaglobulinemia (X-LA), tonsils, cervical lymph nodes, and other palpable lymphoid tissue is sparse. If this is kept in mind, in most cases, the diagnosis of X-LA can be made on the basis of the history and physical examination alone, even if the family history is negative. Patients with X-LA commonly present with neutropenia and may have gram-negative infections, sepsis, or both.

One should look for evidence of chronic infection and organ damage such as scarring of the tympanic membranes, hearing impairment, clubbing, cyanosis, lymphadenopathy, bronchiectasis, vitiligo, arthropathy, and poor dentition.

IgG subclass deficiency

Most patients with IgG1 deficiency have clinical findings indistinguishable from those with common variable immunodeficiency (CVID), in which most cases occur as combined deficiencies with low levels of other immunoglobulins rather than isolated IgG1 deficiency. This is because IgG1 is the predominant IgG subclass in the serum. CVID in the presence of normal IgG1 levels is rare.

IgG1 deficiency is usually observed in combination with other immunoglobulin deficiencies. Collectively, this is considered a form of CVID.

Case reports show a relationship between bronchiolitis obliterans and patients who have low IgG levels following bone marrow transplantation.

IgG2 deficiency may occur either as an isolated entity or in association with IgG4 or IgA deficiency. Some patients with IgG2 deficiency may be asymptomatic, which may be because of the shift of the antibody response to another IgG subclass or IgG isotype. Children with IgG2 and IgG4 deficiency who also have systemic lupus erythematosus may present with cardiac tamponade rather than more common presentations of systemic lupus erythematosus, such as arthritis or nephropathy.

Because IgG2 is important in response to polysaccharides, encapsulated bacteria (eg, H influenzae type b, S pneumoniae) are common causes of infection in these patients. Antibodies reactive with bacterial capsular antigens are thought to be predominantly of the IgG2 isotype. Patients may be unable to produce specific antibodies after immunization with purified polysaccharide antigens (eg, pneumococcal vaccine polyvalent [Pneumovax]). More than 10% of these patients also present with dermal or visceral vasculitis, and sequelae of pyogenic infections (ie, recurrent otitis or sinusitis) are common.

IgG3 deficiency has been associated with recurrent upper and lower respiratory tract infections and may occur in combination with IgG1 deficiency. IgG3 may be very important in primary response to viral respiratory agents. Also, IgG3 is the predominant antibody response to Moraxella catarrhalis, an organism frequently isolated from patients with chronic sinusitis. A significant fraction of the IgG antibodies against pneumococcal polysaccharides may be of the IgG3 subclass.

IgG4 deficiency occurs in 10-15% of the general population and is of uncertain clinical significance. Heiner et al have described selective IgG4 deficiency in patients with severe recurrent respiratory tract infections and bronchiectasis,^[13] but many patients with low levels of IgG4 are asymptomatic.

When IgG deficiency occurs with low levels of both IgG4 and IgA, it may be associated with ataxia-telangiectasia (AT). These AT patients may have an IgG2 deficiency, which is associated with a lower survival rate than those with a normal IgG and those with normal IgG2 levels.^[14]

• References

Causes

Over the years, an intensive investigative effort has ensued in an attempt to find the etiology of IgG and IgG subclass deficiencies. However, these studies are controversial because of the heterogeneous nature of IgG deficiencies. The most commonly accepted etiological theories include the following:

• Defective isotype-switching mechanisms and terminal differentiation of B cells
• Failure of signaling processes for differentiation and class switching in activated B cells (The X-linked hyper-IgM syndrome is good example of this, in which the defect is actually in T-cell expression of a co-stimulatory molecule [CD-40L] necessary to induce class switching in B cells [see below].)
• Insufficient cytokine or receptor expression
• Protein-losing conditions such as enteropathy and nephropathy can result in apparent selective deficiency of IgG, since IgM has a much higher molecular weight and may not be lost, and some loss of IgA can occur without making its level frankly abnormal.

Although the precise etiology of selective IgG deficiency is unknown, it may be associated with a wide variety of physiologic conditions or pathologic entities. The following is a brief outline of these conditions.

Intense exercise or excessive physical stress

Intense exercise has been associated with IgG deficiency.

Low levels of IgG, IgA, and lymphocytes and diminished natural killer cell activity have been observed in some studies.

Some studies show that excessive exercise leads to progressive cooling and drying of respiratory mucosa and increased exposure of bronchi to air contamination. Cooling and drying slow cilial movement and increase viscosity of the mucus. This leads to decreased clearance of micro and toxic particles, which may impair mucosal B-cell function, thereby reducing local antibody secretion.

Smoking

Although high concentrations of toxic materials in cigarette smoke are considered the primary cause of severe symptoms in patients with chronic bronchitis, IgG deficiency also may be a secondary factor in the etiology of this illness.

Aging

Substantial evidence now demonstrates a decline in immune function with senescence. In addition to a reduction in serum immunoglobulin concentrations, serum titers of antibodies to bacterial antigens of low affinity decline with age. Depressed T-cell function is also present in elderly persons.

This negative effect is usually balanced by a tendency to produce more potent antibodies of high affinity, particularly if the patient responds to immunization with recall antigens.

X-linked agammaglobulinemia

X-linked agammaglobulinemia (X-LA) was the first identified immune deficiency. In 1952, Colonel Bruton first described this condition in an 8-year-old boy at Walter Reed Army Hospital. X-linked agammaglobulinemia occurs in 1 in 50,000-100,000 births. This disease is primarily restricted to males, although autosomal forms of inheritable hypogammaglobulinemia have also been reported and are equally likely in either sex.

Although these entities were originally named congenital agammaglobulinemia, the term is a bit of a misnomer. Because IgG is transferred across the placenta, affected babies have normal IgG levels for the first few months of life, and symptoms rarely occur within the first several months of life. The condition can be diagnosed by the lack of B cells in peripheral blood and should be suspected in any male with recurrent otitis, absent or small tonsils, and a lack of palpable lymphoid tissue. Serum IgA, IgM, IgD, or IgE concentrations are not detectable.

The disorder is caused by a deficiency of a tyrosine kinase important in signaling for B-cell development, which has been named Bruton tyrosine kinase (BTK) in honor of Colonel Bruton.

Infants rarely manifest infections during the first 6 months of life because they have transplacentally acquired serum IgG. However, after 6-12 months, infections caused by highly pathogenic bacterial organisms occur (eg, S pneumoniae, Streptococcus pyogenes, H influenzae type b). Infections include bronchitis, otitis media, pneumonia, and meningitis.

Intravenous immune globulin (IVIG), ie, 400-600 mg/kg given at intervals of 3-4 wk, helps prevent infections and is the standard of care for patients with X-LA, autosomal hypogammaglobulinemia or agammaglobulinemia, and common variable immunodeficiency (CVID).

Common variable immunodeficiency

Following the discovery of X-LA, investigators realized that some patients of both sexes had similar clinical manifestations. Some of these patients have autosomal agammaglobulinemia, but most have CVID, particularly if the onset of increased or unusual infections occurs in young adulthood. This condition was previously called late-onset hypogammaglobulinemia.

The same spectrum of organisms that infects patients with X-linked agammaglobulinemia also may cause infection in patients with CVID. Most patients with CVID are diagnosed in their third or fourth decades, but the average interval between the onset of increased infections and other symptoms is 8-12 y.

CVID also differs from the congenital form by the finding of normal B-cell numbers and by the possible presence of detectable levels of serum IgG, IgA, and IgM, albeit at low serum concentrations.

CVID is now recognized to be the result of any of several immune defects involving both B- and T-cell deficiencies, and it is commonly associated with manifestations of autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, hemolytic anemia, pernicious anemia) and with leukemia and lymphoma. Splenomegaly is common, and these patients are at greatly increased risk of lymphoma and other cancers.^[6]

Transient hypogammaglobulinemia of infancy

Although most IgG deficiencies are inherited defects, transient hypogammaglobulinemia appears to be an acquired defect resulting from a delayed onset of IgG or IgA synthesis.

Infants transplacentally obtain maternal IgG antibodies during the third trimester of gestation. Because the biologic half-life of IgG is approximately 21-28 days, the lowest levels of infant serum IgG are seen at postnatal months 2-4.

In some infants, this physiologic nadir of serum IgG concentration is prolonged because of a delay in the maturation of B-cell responses. This may persist as long as 17-19 months in full-term infants and 36 months in premature infants. During this time, the infant is susceptible to recurrent bacterial infections, and the condition is referred to as transient hypogammaglobulinemia of infancy. Fortunately, this type of immunodeficiency often resolves spontaneously by age 4 years, and affected infants do not usually require IgG replacement.

Combined immune deficiencies

As a result of either decreased or absent circulating B cells, serum IgG levels are also low or absent in patients with combined immune deficiencies.

Examples of combined immune deficiencies include reticular dysgenesis and Swiss-type agammaglobulinemia.

Hyper-IgM syndrome

Four types of hyper-IgM syndrome are described. In type 1, the CD40 ligand (CD40L or CD154) is affected (see media file below). In type 2, activation-induced cytidine deaminase is affected. In type 3, the CD40 is affected. In type 4, according to new research, either (1) the class-switch recombination–specific factor of the DNA repair machinery is affected or (2) survival signals are delivered to switch B cells.

Hyper-IgM syndrome may be inherited in an X-linked or autosomal recessive manner. The X-linked form of the disease, type 1, is caused by mutations in the gene encoding the CD40 ligand. CD40 ligand is a transmembrane glycoprotein expressed on activated T cells and some other cell types that binds CD40 on B cells to signal the B cells to proliferate and develop memory. CD40-CD40L interactions are also important in other cell-cell interactions, and patients with mutations in these proteins have a spectrum of opportunistic infections that is broader than those expected in antibody deficiency per se. This may include systemic fungal infections and chronic infection with Cryptosporidium parvum, which can be particularly serious.

Another form of X-linked hyper-IgM (X-HIM) syndrome is associated with anhydrotic ectodermal dysplasia, which is secondary to missense mutations in one of the genes encoding nuclear factor kappa B.

Autosomal recessive forms have been associated with mutations of activation-induced cytidine deaminase (AICDA) and uracil-DNA-glycosylase (UNG). These enzymes are both involved in the cutting and splicing of the immunoglobulin genes necessary for B-cell class switching.

Patients with X-HIM syndrome usually have increased IgM levels, depressed IgA and IgG levels, and absent IgE levels. A normal or high serum IgM level is the clue in the differential diagnosis of this disease. Patients with X-HIM syndrome experience infections with opportunistic pathogens such as Cryptosporidium parvum and Pneumocystis carinii. The severity of disease and frequency of infections are reduced by IgG replacement unless severe neutropenia is present. IgG replacement, however, may not prevent protozoan or fungal infections.

The major form of X-HIM syndrome results from mutations in the gene encoding for CD40L (CD154). The image below is a schematic representation of the interaction of the co-stimulatory surface receptors involved in the communication network between T and B cells. A critical element in the switch from IgM to IgG is the interaction of T-cell CD40L and B-cell CD40. Patients' genetically determined lack of T-cell CD40L (CD154) leads to hyperproduction of IgM and deficiency of IgG and other Ig isotypes that require B-cell class switching.

View Image

Immunoglobulin G deficiency. Schematic representation of the molecular interaction of CD40 on B cells, with CD40L on T cells involved in the switch fr....

In a study by Jain and colleagues, activated T cells from patients with X-HIM syndrome produced markedly reduced levels of interferon gamma.^[15] The cells also failed to induce synthesis of interleukin 12 by antigen-presenting cells, and their induction of tumor necrosis factor-alpha was greatly reduced. In addition, patients' circulating T lymphocytes, both CD4⁺ and CD8⁺, contained a markedly reduced antigen-primed population as determined by CD45RO expression. These findings suggest that the interaction of CD40 on dendritic cells with CD154 on T cells is important in T-cell activation, and co-stimulation of T cells by CD80-CD86 interactions are not sufficient. This study suggests an explanation for patients' increased susceptibility to certain opportunistic infections, besides their defect in B-cell class switching.

Drugs and radiation

Nonsteroidal drugs and immunosuppressive medications, including alkylating agents, antimetabolic agents, antilymphocytic agents, cyclophosphamide, cyclosporine, and steroids, may be associated with IgG deficiency.

Certain anticonvulsant agents (eg, phenytoins) may cause similar reactions. For example, in epileptic patients taking phenytoin, a non–dose-dependent depression in IgA levels occurs. In one study, up to 9% of patients were found to have depressed IgA concentrations compared with age-matched controls. Furthermore, 40% of the patients with low serum IgA concentrations had mild-to-moderate depression of serum IgG and/or IgM concentrations.

Low levels of IgG are relatively common among individuals who undergo radiation therapy.

Thymoma

Some patients with thymomas have an associated IgG deficiency. In most cases, the thymoma is composed of a benign type of spindle cell, and both B- and T-cell deficiency have been reported. Panhypogammaglobulinemia and deficient cell-mediated immunity usually occur. This condition is usually referred to as Good syndrome.

Removal of the thymoma does not reverse the immunoglobulin deficiency, and patients may benefit from IgG replacement therapy to prevent recurrent infection.

Other clinical conditions

In studies performed to improve the accuracy of early diagnosis of retinoblastomas, markedly reduced blood and lacrimal fluid IgG levels have been found in persons with stage III-IV retinoblastoma.^[16]

A relationship between febrile convulsion and IgG subclass deficiencies has also been demonstrated. One study found that IgG subclass deficiencies may be responsible for an increased incidence of febrile infections, which result in a higher incidence of seizures in children who are predisposed to febrile seizures.^[17]

IgG2, IgG4, and IgA subclass deficiencies may play a role in the pathogenesis of allergic colitis in children.^[18] Infants with a definitive diagnosis of noninfective colitis displayed a high prevalence of IgA, IgG2, and IgG4 deficiencies.^[19]

Although some reports have suggested a strong relationship between IgG subclass patterns and atopic disorders, other studies have not found this association.

IgG subclass deficiency

The classification of IgG subclass deficiencies as primary immune deficiencies is controversial.^[20] IgG subclass levels that are below 2 standard deviations of age matched normals are considered deficient.^[21] However, completely asymptomatic individuals have been described who totally lacked IgG1, IgG2, or IgG4 because of immunoglobulin heavy-chain gene deletions. In symptomatic individuals, IgG3 subclass deficiency usually occurs in association with deficiencies of other IgG subclasses.

Most experts feel that patients with subclass deficiency must be evaluated for functional antibody responses to both polysaccharides and proteins before considering treatment with gammaglobulin.^{[21, 20]} Clinically significant IgG subclass deficiency has been defined as that which has both recurrent infections and impaired functional antibody responses.^[21] The diagnostic category specific or selective IgG antibody deficiency better describes these patients.

This condition may exist in the presence of total IgG levels that are technically within the normal range. In some cases of polyclonal B-cell activation, such as systemic lupus erythematosus, Epstein-Barr virus, or HIV infection, selective IgG antibody deficiency may occur in the presence of elevated total IgG levels. Specific IgG antibody deficiency can also be seen in the presence of monoclonal gammopathy, which may also give a normal total IgG level.

IgG1 subclass deficiency is usually associated with decreased total IgG levels, and is more commonly found in adults.

IgG4 subclass deficiency is common and may be found in as many as 20% of adults and children, depending on the assay used. It is rarely clinically significant.^[20]

IgG2 subclass deficiency is the most common subclass deficiency associated with recurrent infection. It may be accompanied by IgG4 deficiency, IgA deficiency, or both.

Pure IgG subclass deficiency is rare in association with chronic lymphocytic leukemia.^{[22, 23]}

• References

Laboratory Studies

Values or all immunoglobulin (Ig) levels for pediatric patients must be compared with normal laboratory values for age.

Many experts doubt the utility of IgG subclass measurements.^{[24, 20]} Measuring functional or specific antibodies is important for determining the clinical relevance of a particular IgG subclass deficiency, and these tests can be obtained by several commercial reference laboratories. Patients may have normal total serum immunoglobulin and IgG subclass levels and still fail to make certain antibodies to bacterial or viral pathogens. The specific antibodies include tetanus/diphtheria antibodies (IgG1) and pneumococcal and meningococcal polysaccharides (IgG2 and IgG3).^{[25, 26]}

Several methods are available for measuring IgG subclasses, the most common of which is enzyme-linked immunosorbent assay (ELISA) with either monoclonal or polyclonal antibodies. Radial immunodiffusion is rarely used in modern laboratories. Results vary according to the exact method and antibody combinations used. Therefore, results should be compared to age-specific norms generated in the same laboratory.

• References

Imaging Studies

Radiographic studies may help monitor pulmonary infections, document sinusitis, and identify the development of chronic pulmonary changes such as bronchiectasis.

• References

Other Tests

Pulmonary function studies also may be useful.

Cultures obtained by bronchoscopy or sinus endoscopy may be helpful in cases of chronic bronchitis, cough, or both.

• References

Medical Care

The goals of therapy in patients with immunoglobulin G (IgG) deficiency are 3-fold.^[27] First, treat the acute infection with antibiotics. Because agammaglobulinemia may lead to failure of opsonization in serum, acute infections require aggressive and longer courses of antibiotic treatment than is required in normal patients. Emphasis must be placed on encapsulated organisms such as S pneumonia and H influenzae. Second, institute prophylaxis with IgG replacement. Third, prevent or treat pulmonary disease secondary to repeated bouts of bronchitis and pneumonia. This is necessary because structural lesions in the lungs escalate the lung infection rate and the possibility of cor pulmonale. Do not underestimate the likelihood of death in these patients secondary to pulmonary disease. Physiotherapy with drainage may be helpful to clear respiratory secretions.^[28]

Historically, IgG was given subcutaneously or intramuscularly because the IgG preparations contained aggregated IgG and impurities that often caused serious reactions when administered intravenously. However, presently, intravenous immunoglobulin (IVIG) replacement therapy is generally accepted as the treatment of choice for selected patients with IgG subclass deficiency and persons with other immunodeficiencies including primary immune deficiencies.^{[28, 29]} The aim of treatment is to prevent or greatly reduce the frequency and severity of acute serious bacterial infections. In recent years, home infusions of IgG administered subcutaneously (IGSC) have become increasingly popular. This mode of therapy has been shown to result in higher health-related quality of life as compared to hospital- or office-based intravenous therapy.^[30]

Although the deficiency in any given patient may be just in an individual subclass or a range of specific antibodies (ie, against polysaccharides), IgG replacement doses and regimens are similar in all immunodeficiencies because individual IgG subclass components have not yet been developed. Current IgG preparations are 95-99% IgG with minimal quantities of IgA, IgM, IgD, and IgE and have a half-life of 20 days. However, prior to immunoglobulin treatment, repeated measurements of IgG level, specific antibody, or subclass are necessary for documentation of selective deficiencies.^{[7, 8, 9]}

Immunoglobulin preparations for replacement therapy are prepared from large pools of plasma obtained from thousands of donors. These pools are subsequently fractionated by cold ethanol fractionation and additional chromatography steps. All donors are screened for potential infectious disease agents, including HIV and hepatitis B and C viruses. Following treatment with physical and chemical viral inactivating regimens, as well as nanofiltration, these preparations are remarkably free of transmissible infectious agents. However, because they are blood products, the risk of transmitting infectious agents is always present.

Currently, the accepted therapy for IgG deficiency is the intravenous administration of 300-600 mg/kg of IgG once every 3-4 weeks, or 100-200 mg/kg/wk subcutaneously.^[31] Higher doses have been shown to be more effective in reducing infections in patients with histories of chronic or recurrent sinopulmonary infections.^[31] Monitoring trough immunoglobulin levels may help define the optimal time between doses because immunoglobulin clearance varies from patient to patient. Consensus guidelines suggest that IgG trough levels (drawn just before the next infusion) should be at least 500 mg/dL. However, patients with chronic sinopulmonary disease often do better with higher trough levels.

Although the benefits of IgG replacement therapy are unquestionable in appropriate patients, IVIG may be associated with infusion-related adverse effects.^[32] IGSC is often associated with local infusion site reactions but is widely regarded as being much freer from systemic reactions than intravenous therapy. Of treated patients, 3-12% develop headache, myalgia, chills, fever, and mild nausea upon infusion. These symptoms are more common when IgG therapy is newly initiated and may decrease with subsequent infusions. To minimize serious reactions, intravenous infusions should be started no faster than 0.01 mL/kg/min. Patients should be closely monitored until their tolerance of particular regimens is established, and infusions should be temporarily stopped or slowed down if symptoms occur. Adverse effects of IVIG infusions can be minimized with antihistamines, antipyretics, hydrocortisone, or a combination thereof.^[28]

Antibiotics also may be useful for patients who have poor responses to bacterial vaccines; when used, microbicidal agents are preferable.

Vaccination is important in patients who do not have antibodies to Pneumococcus and Haemophilus polysaccharides, regardless of whether they have an absolute deficiency of IgG2. If they do not respond to vaccination with Pneumococcus and Haemophilus polysaccharide vaccines, revaccination with protein-conjugated Pneumococcus and Haemophilus polysaccharide vaccines is indicated. Such vaccination may result in the production of protective antibodies in the IgG1 or IgG3 subclasses.^[8]

• References

Surgical Care

Pulmonary lobectomyor functional endoscopic sinus surgery may be useful to remove structurally abnormal, chronically infected tissues that can serve as foci of infection, which then reseed other areas, causing recurrent infections in areas that have not yet been permanently damaged.

• References

Consultations

ENT and pulmonary consultations are frequently advisable. Other specialists may be needed for specific problems in individual cases.

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. In the modern era, this includes not only preventing acute, severe, life-threatening infections but also preventing morbidity from the slow development of end organ damage due to subclinical chronic infection. Since most of these patients require life-long immunoglobulin replacement, an additional goal is to provide optimal therapy without compromising the patient’s quality of life.^[31]

Concentrated safe and effective immunoglobulin products can now be delivered subcutaneously, intramuscularly, or intravenously.^[33]

• References

Immune globulin, subcutaneous (Vivaglobin)

Clinical Context:  16% human immune serum globulin, pasteurized

• References

Immune globulin, intravenous, 5-10% liquids (Flebogamma, Gammagard, Gamunex, Privigen, Carimune)

• Dosing, Interactions, etc.

Clinical Context:  Immune globulin purified from human plasma, usually supplied as 5% or 10% liquid

• References

Class Summary

Accepted medical therapy for patients with IgG deficiency. Purified human IgG may be given intravenously (IVIG) or subcutaneously (IGSC). Intramuscular IgG and plasma are rarely employed for chronic use in the current era. IVIG and IGSC for use in the United States are derived from human plasma obtained from carefully screened and tested US donors. All preparations available in the United States contain all 4 IgG subclasses, with an antibody distribution approximately the same as human serum. The traditional methods of preparation of different commercial products consist of cold ethanol fractionation followed by further purification, usually employing additional precipitations and one or more steps of chromatography, followed by specific steps to remove or inactivate potential viral pathogens.

Although many physicians use different IVIG preparations interchangeably and with similar overall efficacy, the individual products differ from each other in final purification steps, IgA content, and excipients. Different products may be tolerated differently by different patients. Thus, a patient on established therapy with one particular product may have increased adverse effects if given a different product. Most products in the US market are labeled for use in primary immune deficiency and immune thrombocytopenic purpura (ITP), but other uses are common, and an evidence-based review of the multiple on- and off-label uses of IgG has recently been published.^[34] Immune globulin preparations may have individual differences, and more detailed descriptions may be obtained from other sources, including the Physicians' Desk Reference.

Although generally safe, IVIG has been associated with some adverse reactions in certain patient populations. For example, IVIG should not be given to patients with isolated IgA deficiency. Use of this product in these patients has been associated with severe complications, including anaphylactic shock and death. However, this problem is rare. Most patients have some IgA or no antibody production at all, so production of IgE antibodies against IgA is not common.

In patients with preexisting risk factors for coronary artery disease and atherosclerosis, the administration of IVIG has been associated with thromboembolic events. Reports of myocardial infarction, transient ischemic attacks, and stroke, although rare, have been described in the literature.^[32] Infusion of IVIG may affect the cardiovascular system by different, possibly synergistic, mechanisms. A recent comprehensive review covers many aspects of IVIG therapy.^[31]

IVIG regimens usually are given in the form of infusions of 300-600 mg/kg every 3-4 weeks, since the half-life of IgG in the circulation is approximately 21 days. Higher doses are often preferred in patients with chronic lung or sinus infections. High doses may lead to increased plasma and blood viscosity, leading to decreased myocardial perfusion; preparations containing higher sodium concentrations may contribute to fluid overload; and some preparations may contain activated clotting factors. Furthermore, some preparations may contain leukoagglutinins, antibodies which can lead to microaggregation of white blood cells, causing transfusion-related acute lung injury.^[32] Acute renal failure, positive Coombs tests and frank hemolysis have also been reported following IVIG infusions.^[32] IVIG infusions are frequently accompanied by rate-related adverse effects such as headache, chills fever, myalgia, nausea, or vomiting.

Usually, infusions are started at a slow rate (0.01 mg/kg/min), which is increased in a stepwise manner, as tolerated by the patient. If symptoms of an infusion reaction begin, these can usually be controlled by slowing or temporarily stopping the infusion. Often, however, medications such as nonsteroid anti-inflammatory drugs (NSAIDs), other antipyretics, or antihistamines may be helpful. Some immunologists may pretreat patients with these medications, corticosteroids, or both to prevent or ameliorate symptoms of infusion reaction. In addition to headaches that accompany infusions, many patients develop headaches as much as 48-72 hours after the infusion is completed. These headaches may range in severity and may include features of migraine, which may respond to triptans. Severe headaches with meningeal signs and aseptic meningitis have also been reported.^[32]

IgG is also frequently administered subcutaneously, usually using small battery-powered ambulatory infusion pumps. In general, one fourth of the monthly IgG dose is administered weekly into 2 or more subcutaneous sites using small (ie, 25-27 gauge) needles over approximately 2 hours.^{[35, 36]} These infusions rarely induce systemic adverse effects, although local redness, swelling, or other injection site reactions may occur.

Many patients report relief from headaches or other reactions associated with IVIG infusions when they switch to IGSC. Because of this freedom from systemic adverse reactions, and since intravenous access is not required, home therapy independent from nurses or other medical professionals is possible and has been reported to result in better health-related quality of life.^{[35, 30]} With IGSC regimens, the IgG is slowly absorbed into the bloodstream, peaking at 48-72 hours, so adverse effects associated with the high peaks achieved with intravenous therapy are obviated. Because additional doses are usually given within a week, before the IgG level drops very much, low troughs and wear-off effects reported by many patients on monthly intravenous infusions are also obviated.^[35]

• References

Further Outpatient Care

Careful health care may reduce the number of infections, which are common problems. Chest physiotherapy may be needed to treat such infections.

• References

Further Inpatient Care

Patients should be monitored at regular intervals to be sure potential complications, including acquisition of potential bloodborne infections, have not occurred. In addition, immunologic and pulmonary status of patients with primary immune deficiency diseases should be monitored by the physician. In most cases, doses of IgG are individualized to achieve optimal freedom from acute infection.

Low IgG levels in patients with IgG deficiency are not necessarily associated with deficiencies of antibody responses to immunization with vaccines (eg, tetanus toxoid). Only a small percentage of patients have impaired responses to certain vaccinations. Therefore, measuring antibody levels after vaccination, particularly pneumococcal polysaccharide vaccine (Pneumovax) and Haemophilus vaccine, is crucial before initiating IgG replacement therapy. If the response to vaccination with the above polysaccharide vaccines is inadequate, revaccination with protein-conjugated polysaccharide vaccines, heptavalent pneumococcal conjugate vaccine (Prevnar) and Haemophilus vaccine, is indicated.

Serological tests for specific infections may be unreliable in patients with primary immune deficiency diseases, and false-positive results (ie, positive IgG titers to EBV, hepatitis A virus, and hepatitis B surface antigen) may result from antibodies contained in IgG preparations.^[37] Therefore, physicians may want to use nucleic acid amplification tests (eg, polymerase chain reaction [PCR]) to document the presence or absence of such infections before beginning therapy.

• References

Inpatient & Outpatient Medications

Physicians should stress the importance of good hygiene, good nutrition, and adherence to recommendations for therapy and prevention of infections. The long half-life of IVIG is advantageous, and this type of therapy provides several weeks of protection against related microorganisms. These results have also been observed in patients with IgG subclass deficiency, X-linked agammaglobulinemia, and common variable immunodeficiency (CVID).

Many patients also benefit from the use of prophylactic or chronic treatment regimens of oral antibiotics. Patients with chronic bronchitis or obstructive pulmonary disease may benefit from bronchodilators, topical corticosteroids, or both. Patients with chronic sinus disease may benefit from expert evaluation and management by ENT specialists; this may include surgery.

• References

Complications

Intravenous immunoglobulin (IVIG), whole blood transfusions, and packed red blood cell transfusions are contraindicated in patients who have IgA deficiency. In these patients, the development of anti-IgA antibodies has been associated with both nonhemolytic transfusion reactions and anaphylaxis. If blood transfusions are required in a patient with IgA deficiency, washed red blood cell transfusions should be given.

• References

Prognosis

Patients on appropriate IgG replacement regimens can expect freedom from serious acute bacterial infections. However, patients with CVID are at increased risk of autoimmune disease and malignancy, particularly mucosa-associated lymphoid tissue (MALT) lymphomas.^[6] In addition, freedom from acute infections or exacerbations does not necessarily imply a lack of progression of bronchiectasis or other chronic conditions.

• References

Patient Education

The patient and the patient's family should be taught how to recognize early signs and symptoms of infection so that the patient may obtain treatment as early as possible.

The patient should be advised to avoid crowded places and people who have active infections.

For patient education resources, see the Pneumonia Center, Lung and Airway Center, and Asthma Center, as well as Bacterial Pneumonia, Bronchitis, Asthma, Sinus Infection, and Myeloma.

A common data pool has been established in Europe as an Internet-based database for clinical and research data on patients with primary immunodeficiencies in order to facilitate epidemiological analyses, development of new diagnostic and therapeutic strategies, and the identification of novel disease-associated genes.^[38]

• References