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Presentation

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.^[7]

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.^{[8, 9, 10]}

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.^[11]

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.^[12]Because IgG2 antibodies are critical to immune responses to organisms with polysaccharide capsules, most patients experience otitis and recurrent sinopulmonary infections with encapsulated bacteria.^[13]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.^[9]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.

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,^[14]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.^[15]

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.^[7]

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.

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

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In a study by Jain and colleagues, activated T cells from patients with X-HIM syndrome produced markedly reduced levels of interferon gamma.^[16]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.^[17]

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.^[18]

IgG2, IgG4, and IgA subclass deficiencies may play a role in the pathogenesis of allergic colitis in children.^[19]Infants with a definitive diagnosis of noninfective colitis displayed a high prevalence of IgA, IgG2, and IgG4 deficiencies.^[20]

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.^[21]IgG subclass levels that are below 2 standard deviations of age matched normals are considered deficient.^[22]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.^{[22, 21]}Clinically significant IgG subclass deficiency has been defined as that which has both recurrent infections and impaired functional antibody responses.^[22]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.^[21]

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.^{[23, 24]}

Differential Diagnoses

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Media Gallery

Immunoglobulin G deficiency. Schematic representation of an immunoglobulin G molecule. CH indicates constant region of heavy chain; CL, constant region of light chain; VH, variable region of heavy chain; and VL, variable region of light chain.
Immunoglobulin G deficiency. Human immunoglobulin G subclasses.
Immunoglobulin G deficiency. Changes in serum immunoglobulin G concentrations during infancy and childhood.
Immunoglobulin G deficiency. Schematic representation of the molecular interaction of CD40 on B cells, with CD40L on T cells involved in the switch from immunoglobulin M to immunoglobulin G.

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Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Robert Y Lin, MD Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology, and Director of Utilization Review, Department Medicine, New York Downtown Hospital

Robert Y Lin, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, New York Allergy & Asthma Society

Disclosure: Nothing to disclose.

Janet Vafaie, MD Private Practice

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Michael R Simon, MD, MA Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital

Michael R Simon, MD, MA is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, American Federation for Medical Research, Michigan Allergy and Asthma Society, Michigan State Medical Society, Royal College of Physicians and Surgeons of Canada, Society for Experimental Biology and Medicine

Disclosure: Have a 5% or greater equity interest in: Secretory IgA, Inc. ; siRNAx, Inc.<br/>Received income in an amount equal to or greater than $250 from: siRNAx, Inc.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Melvin Berger, MD, PhD Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC

Melvin Berger, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Clinical Investigation, Clinical Immunology Society

Disclosure: Received salary from CSL Behring for employment; Received ownership interest from CSL Behring for employment; Received consulting fee from America''s Health insurance plans for subject matter expert for clinical immunization safety assessment network acvtivity of cdc.