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Synonyms and related keywords: immune deficiency, immune globulin deficiency, IgG deficiency, IgG subclass deficiency, insufficient antibody production, gammaglobulin deficiency, hypogammaglobulinemia, immune deficiency, immunity, immunology, immune function, immunologic system interaction, autoimmune disorders, T-cell disease, B-cell dysfunction, complement deficiency, immunological disturbances, white blood cell diseases, WBC diseases, immunotherapy, intravenous immune globulin treatment, IVIG treatment, IV immunoglobulin treatment, common variable immunodeficiency, CVI, ataxia-telangiectasia, Sjogren syndrome, Sjogren's syndrome, X-linked agammaglobulinemia, congenital agammaglobulinemia, transient hypogammaglobulinemia of infancy

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 immunoglobulin class is IgG (73%), which has a molecular weight of 150 kd (see Image 1). IgG is present in plasma and external secretions and is expressed on the B-cell membrane.

IgG is further subdivided into 4 subclasses: IgG1, IgG2, IgG3, and IgG4 (see Image 2). 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.

A deficiency in a tyrosine kinase designated as Bruton tk, in honor of Bruton, was discovered. In 1952, Bruton described classic B-cell deficiency in an 8-year-old boy with X-linked agammaglobulinemia. The patient presented with frequent pyogenic infections, and all 5 major immunoglobulin isotypes were undetectable. In the early 1960s, following the discovery of the IgG subclasses, certain associations were also recognized between individual subclass deficiencies and recurrent infection. IgG deficiencies may occur as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types (eg, combined immunodeficiency). Moreover, IgG subclass deficiencies may be observed even if the total IgG concentration is normal.

Pathophysiology

B and T cells are responsible for specific immunity, otherwise known as adaptive immunity. Abnormal production of these cells may be observed in clinical states in which production is atypically excessive (eg, lymphoproliferative diseases such as lymphoma and leukemia) or in immunodeficiency disorders in which production is aberrantly low.

IgG exists in both 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 (Beers, 2004).

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 combined IgG deficiency, which manifests as a deficiency of IgG accompanied by inadequate levels of other immunoglobulin isotypes. This must be differentiated from common variable immunodeficiency (CVI).

These disorders occur in persons of any age or sex. Immunoglobulin deficiencies were previously referred to as late-onset agammaglobulinemia, and now they are classified as hypogammaglobulinemia syndromes. Both pediatric and adult populations may be affected by a group of unclassified antibody deficiencies that is considered a form of CVI. See Common variable immunodeficiency for more details.

IgA deficiency is the most common immune deficiency, and approximately 20% of patients also show a lack of IgG2 and IgG4. These individuals have greater risk of infection than patients with either isolated IgA or IgG deficiency.

Frequency

United States

Although the frequency of isolated IgG deficiency is not known with certainty, IgG subclass deficiency is probably more common and occurs in families with CVI. Some reports indicate that the prevalence of IgG deficiency may be 1 case per 10,000 persons. However, the frequency of IgG subclass deficiencies varies according to geographic area, although they are more common than other immunodeficiencies.

Mortality/Morbidity

• Early diagnosis and treatment of IgG deficiency is essential to prevent and control both morbidity and mortality.
• IgG subclass deficiencies are highly variable, even within an affected individual. Additional deficiencies may develop as a result of switching between different IgG subclasses.

Sex

• Males and females are affected.

Age

• Children and adults are affected. Children cannot make IgG2 until aged at least 24 months; 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, IgG3 deficiency is predominant. IgG1 levels in children are usually higher than in adults.
• Although children rapidly attain adult levels of IgG1 and IgG3, the development of IgG2 and IgG4 is slower (see Image 3). In some children, this period of maturation may take 16 years before full attainment of adult levels.

History

• IgG deficiency
• • One should look for evidence of organ-specific infection, systemic infections, dental and oral disease, autoimmune disease, and a family history of such conditions.

  • Patients with IgG deficiency usually experience recurrent pyogenic respiratory tract infections similar to those observed in persons with other B-cell deficiencies. Prior studies have shown IgG deficiencies are the basis for the persistent sinusitis and allergic diseases 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 specific antibody deficiency.

  • When deficiency of a single IgG subclass occurs (often IgG2), the patient has normal total IgG concentrations and a defect in the production of specific immunoglobulins in response to immunization. The patient is usually asymptomatic, although even minor reductions in serum concentrations can be associated with an increased risk of infection with Streptococcus pneumoniae, Haemophilus influenzae type b, and Staphylococcus aureus.

  • IgG subclass deficiencies usually occur in pairs (eg, IgG1 and IgG3, IgG2 and IgG4). IgG2 is often affected. Persons with deficiencies involving IgG2 display the highest frequency of infectious complications, generally of the respiratory tract (Aucouturier, 1989). Because IgG2 antibodies are critical to immune responses to organisms with polysaccharide capsules, most patients experience recurrent sinopulmonary infections with encapsulated bacteria (Sikora, 2003). However, other clinical presentations, such as atopic disease (eg, asthma), congenital cardiomyopathy, and autoimmune diseases, may be observed.

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

  • Most patients with IgG2 deficiency have recurrent respiratory conditions such as bronchiectasis, bronchopneumonia, bronchitis, obstructive lung disease, and 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.

Physical

• IgG deficiency
• • The most frequent clinical problem is repeated infections of the upper and lower respiratory tracts. Many cases of IgG deficiency are diagnosed in healthy individuals whose initial presentations may include headache, cough, fever, and other constitutional symptoms associated with respiratory tract infections and otitis media. These patients may have bulging, cloudy, immobile tympanic membranes and effusions of the middle ear.

  • One should look for evidence of chronic infection and organ damage such as clubbing, cyanosis, lymphadenopathy, bronchiectasis, vitiligo, arthropathy, and poor dentition.

• IgG subclass deficiency
• • Most patients with IgG1 deficiency have clinical findings indistinguishable from those with CVI, 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. CVI 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 CVI.

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

  • IgG2 deficiency occurs either as an isolated entity or in association with IgG4 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 cell wall 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.

  • 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.

  • IgG4 deficiency occurs in 10-15% of the general population and is of uncertain clinical significance. Heiner et al has described selective IgG4 deficiency in patients with severe recurrent respiratory tract infections and bronchiectasis.

  • When IgG deficiency occurs with low levels of both IgG4 and IgA, it is usually associated with ataxia-telangiectasia.

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 process of differentiation factors in activated B cells
  
  
  
  • Insufficient cytokine receptor expression
     
• Although the precise etiology of 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
    
    
    • 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 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.
       
  • X-linked agammaglobulinemia
    
    
    • X-linked agammaglobulinemia was the first identified immune deficiency. In 1952, Colonel Bruton first described this condition in an 8-year-old boy at Walter Reed General Hospital. X-linked agammaglobulinemia occurs in 1 in 50,000-100,000 births. This disease is primarily restricted to males.
    
    
    
    • Although the entity was originally named congenital agammaglobulinemia, the term is a misnomer because symptoms do not occur at birth and affected males may have small amounts of serum IgG (40-100 mg/dL). In addition, serum IgA, IgM, IgD, or IgE concentrations are not detectable, and B cells cannot be demonstrated in the blood or lymphoid tissues of affected patients.
    
    
    
    • The disorder is caused by a deficiency of the enzyme tyrosine kinase, which has been named Bruton tyrosine kinase 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.
    
    
    
    • High doses of intravenous immune globulin (IVIG), ie, 400 mg/kg given at 4-week intervals, help prevent infections and keep infants healthy.
       
  • Common variable immunodeficiency
    
    
    • Following the discovery of X-linked agammaglobulinemia, investigators realized that some patients of both sexes had similar clinical manifestations. Although this entity was originally called late-onset agammaglobulinemia, in current practice it is referred to as CVI.
    
    
    
    • The same spectrum of organisms that infect patients with X-linked agammaglobulinemia also may cause infection in patients with CVI, but the average age of patients with CVI is 25-40 years.
    
    
    
    • CVI also differs from the congenital form by the finding of normal B-cell numbers and by the presence of detectable levels of serum IgG, IgA, and IgM, which are usually found at low serum concentrations.
    
    
    
    • CVI 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.
       
  • 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 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 attained by postnatal months 2-4.
    
    
    
    • In some infants, this physiologic drop of serum IgG concentration is prolonged, sometimes for 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 is affected. In type 2, activation-induced cytidine deaminase is affected. In type 3, the CD40 ligand 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 that binds CD40 on B cells to signal the B cells to proliferate and develop memory.
    
    
    
    • Another form of X-linked hyper-IgM (XHIM) syndrome is associated with anhydrotic ectodermal dysplasia, which is secondary to missense mutations in the gene encoding nuclear factor kappa B.
    
    
    
    • The autosomal recessive form has been associated with mutations of activation-induced cytidine deaminase. Another autosomal recessive form described involves mutations of the uracyl-DNA-glycosylase UNG gene.
    
    
    
    • Patients with XHIM syndrome usually have increased IgM levels but depressed IgA and IgG levels. A normal or high serum IgM level is the clue in the differential diagnosis of this disease. Patients with XHIM 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 the neutropenia is severe.
    
    
    
    • Recently, XHIM syndrome has been shown to result from mutations in the gene that codes for CD40L (CD154). Image 4 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 leads to hyperproduction of IgM and deficiency of IgG.
    
    
    
    • In a study by Jain and colleagues, activated T cells from patients with XHIM syndrome produced markedly reduced levels of interferon gamma. The cells also failed to induce synthesis of interleukin 12 by antigen-presenting cells, and they induced greatly reduced levels of tumor necrosis factor-alpha. In addition, patients' circulating T lymphocytes, both CD4⁺ and CD8⁺, contained a markedly reduced antigen-primed population as determined by CD45RO expression. These findings were related to defects in antigen priming that most likely are due to a lack of CD154 expression and insufficient co-stimulation of T cells by CD80-CD86 interactions. Collectively, this study offers an explanation for the molecular basis of a defective switch mechanism in XHIM syndrome and a basis for patients' increased susceptibility to certain opportunistic infections.
       
  • 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.
    
    
    
    • 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 retinoblastomas (Khvatova, 1992).
    
    
    
    • A relationship between febrile convulsion and IgG subclass deficiencies has also been demonstrated. One study found that IgG subclass deficiencies may be responsible for the infection connected with febrile seizures or related to the path of febrile seizures in some children (Caksen, 2001).
    
    
    
    • IgG2, IgG4, and IgA subclass deficiencies may play a role in the pathogenesis of allergic colitis in children (Ojuawo, 1998). Infants with a definitive diagnosis of noninfective colitis displayed a high prevalence of IgA, IgG2, and IgG4 deficiencies (Ojuawo, 1997).
    
    
    
    • 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
• • IgG subclass deficiency may be divided into 2 types: inherited and acquired. The hereditary component of IgG2 deficiency has been known for more than 25 years. Although partial gene deletions may be the cause of certain cases of IgG subclass deficiencies, the precise etiology of this disorder remains unknown.
  
  
  
  • IgG subclass deficiency is one member of the primary B-cell deficiency group, which includes X-linked agammaglobulinemia, IgA deficiency, immune deficiency with increased IgM, CVI, and transient hypogammaglobulinemia of infancy.
  
  
  
  • Kemper and colleagues demonstrated that IgG2 deficiency existed in patients with preterminal chronic renal failure and in patients receiving peritoneal dialysis. These findings suggest that the IgG2 deficiency is not simply a reflection of its removal by peritoneal dialysis, but rather, that it may be a predisposing factor in the pathogenesis of chronic renal failure. Regardless of causation, patients may benefit from IVIG treatment. This is the best-understood subclass deficiency, and most of these patients also have IgG4 deficiency, IgA deficiency, or both.
  
  
  
  • IgG subclass deficiency may occur in patients with monoclonal gammopathies and may contribute to infectious complications in such patients.

Other Problems to be Considered

The wide range of normal levels of IgG subclasses in children makes the differential diagnosis of IgG deficiency difficult until the patient is aged 2 years, at which time the IgG concentration approaches adult levels.

Lab Studies

• The criterion standard for IgG measurement is currently nephelometry. Values for pediatric patients must be compared with normal laboratory values for age.
• IgG subclass measurement may be helpful, but debate still continues on the utility of such measurements (Adkinson, 2004). Measuring functional and/or specific antibodies is helpful for determining the clinical relevance of a particular IgG subclass deficiency. Patients could 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), pneumococcal and meningococcal polysaccharides (IgG2), and viral respiratory agents (IgG1, IgG3).
• In neutropenic patients who have recurrent infections, IgG subclass determination and bone marrow analysis may be indicated. Determination of IgG subclass levels and antibodies against carbohydrate antigens such as phosphocholine may be considered in patients who have susceptibility to recurrent infections. However, determination of functional antibody titers to tetanus/diphtheria antibodies (IgG1); Pneumococcus, Haemophilus, and Meningococcus polysaccharides (IgG2); and viral respiratory agents (IgG1, IgG3) is more valuable.
• Although total serum IgG levels are low in most patients with IgG subclass deficiency, levels are sometimes normal. Several methods are available for measuring IgG subclasses, the most common of which are enzyme-linked immunosorbent assay and radial immunodiffusion with either monoclonal or polyclonal antibodies. Results vary according to the method used.
• IgG2 measurements alone are inadequate because patients with IgG2 deficiency often have another IgG subclass deficiency (eg, IgG4). In addition, IgG2 levels should be measured in patients with IgA deficiency because some studies have demonstrated frequent coexistence of these 2 conditions.

Imaging Studies

• Regular radiographs may help monitor pulmonary infections.
• In some patients with IgG subclass deficiency, high-resolution computed tomography may be helpful to show bronchial changes and interstitial lesions associated with current lung disease.

Other Tests

• Pulmonary function studies also may be useful.

Medical Care

The goals of therapy in patients with IgG deficiency are 3-fold. First, treat the acute infection with antibiotics. Because agammaglobulinemia may lead to failure of opsonization in serum, acute infections require an aggressive and longer course antibiotic treatment than normal. Emphasis must be placed on encapsulated organisms such as S pneumonia and H influenzae. Second, institute prophylaxis with IVIG infusion. 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 (Mandell, 2000).

• Historically, IgG was given subcutaneously because older methods contained aggregated IgG that was potentially toxic by the intravenous route. However, presently, IVIG replacement therapy is generally accepted as the treatment of choice for selected patients with IgG subclass deficiency and persons with other immunodeficiencies (Mandell, 2000). The aim of treatment is to prevent or greatly reduce the frequency and severity of infections, especially because an infection may consume the small amount of serum immunoglobulin available. Although levels of individual subclasses are deficient, treatment with IVIG is the same in all subclass IgG subclass immunodeficiencies because individual IgG subclass components have not yet been developed. Current IVIG 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 IgG and subclass measurements are necessary for documentation of IgG deficiency.
• Immunoglobulin preparations for replacement therapy are prepared from large pools of plasma obtained from donors. These pools are subsequently fractionated by the cold ethanol fractionation method. All donors are screened for potential infectious disease agents, including HIV and hepatitis B and C viruses. Following treatment with physical or chemical solvent detergent reagents, 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 administration of 200-400 mg/kg prophylactic gammaglobulin once every 3-4 weeks. Larger doses can be given (>400 mg/kg) at 4-week or shorter intervals, which has not been associated with evidence of reduced antimicrobial protection. Monitoring trough immunoglobulin levels may help define the optimal time between doses because immunoglobulin clearance varies from patient to patient. Ultimately, maintain trough levels at 400-500 mg/dL during therapy (Mandell, 2000). According to the results of a 1990-1991 National Institutes of Health Consensus Report, preliminary studies demonstrate that almost any serum IgG level can be obtained using IVIG and that IVIG reduces the rate of infection.
• Although the benefits of IVIG are significant, IVIG may create some infusion-related adverse effects. Of treated patients, 3-12% develop headache, myalgia, chills, fever, and mild nausea upon infusion. If symptoms are intolerable, the infusion rate may be decreased to 0.01 mL/kg/min and the patient's adverse effects can be minimized with antihistamines, acetaminophen, and hydrocortisone (Mandell, 2000).
• 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 of IgG1 or IgG3.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Immune globulins (human)

Accepted medical therapy for patients with IgG deficiency. IVIG is derived from human plasma and is composed of all 4 IgG subclasses. The antibody distribution of IVIG is approximately the same as human serum. The traditional methods of preparation of different commercial products consist of cold ethanol fractionation followed by treatment with a solvent or detergent. Other newer fractionation methods include liquid pasteurization, sodium dodecyl sulphate polyacrylamide gel electrophoresis, and diethylaminoethanol Sephadex fractionation. Another novel method involving large-scale chromatography improves recovery and purity of IgG from pooled plasma (Roifman, 2003).

The products below may be used for hepatitis A, measles (rubeola), rubella, varicella, bone marrow transplantation, chronic lymphocytic leukemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, pediatric HIV infection, and primary immunodeficiency syndromes, including IgG deficiency. Peak levels of IgG are usually obtained 2 days after administration. 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, CVI patients who have no IgG and no IgA are candidates for IVIG therapy.

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. Infusion of IVIG may affect the cardiovascular system by 2 different, possibly synergistic, mechanisms. It may induce expansion of plasma volume, resulting in hypertension and increased oxygen demand, and it may lead to increased plasma and blood viscosity, leading to decreased myocardial perfusion.

Drug Name	Immune globulin, intramuscular (BayGam)
Description	Provides passive immunity by increasing antibody titer and antigen-antibody reaction potential. Even though IVIG is the treatment of choice, it may be used for immunoglobulin deficiency and prophylaxis against hepatitis A, measles (rubeola), varicella, and rubella infections. Can prevent serious infections due to IgG deficiency if serum IgG levels of 200 mg/100 mL are maintained. Intended only for IM administration.
Adult Dose	0.66 mL/kg (at least 100 mg/kg) IM q3-4wk
Pediatric Dose	Not established; suggested dosing is as in adults
Contraindications	Documented hypersensitivity, isolated IgA deficiency, severe thrombocytopenia, coagulation disorders
Interactions	Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not for IV administration; check serum IgA (use an IgA-depleted product if IgA deficient); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, and petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and patients with diabetes, volume depletion, and preexisting kidney disease; should not be used to control outbreaks of measles; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia; infuse in separate line without mixing with other IV fluids or medications; do not perform a skin test (local irritation may be interpreted as a positive reaction); call 800-288-8371 (Bayer Corporation) for technical information

Drug Name	Immune globulin, intravenous
Description	Below is a list of trade names with their indications. These products are intended only for IV administration. Gammagard S/D: For PID, B-cell CLL, ITP, and Kawasaki syndrome. Gammar-P: For PID. Iveegam EN: For PID and Kawasaki syndrome. Sandoglobulin: For PID and ITP. Panglobulin: For PID and ITP. Polygam S/D: For PID, B-cell CLL, ITP, and Kawasaki syndrome. Venoglobulin-S: For PID, ITP, and Kawasaki syndrome.
Adult Dose	Gammagard S/D: 5 mL/kg/h IV; patients who tolerate this can be infused with 10% solution starting at 0.5 mL/kg/h, at up to 4 mL/kg/h Gammar-P: 0.01 mL/kg/min IV Iveegam EN: 1 mL/min IV, not to exceed 2 mL/min for the 5% solution; may reduce rate to <1.5 mg/kg/min (0.03 mL/kg/min) Sandoglobulin: 0.2 g/kg IV qmo; increase to 0.3 g/kg or infuse more frequently if inadequate response Panglobulin: 10-20 gtt/min (0.5-1.0 mL) 3% solution initially for primary immunodeficiency Polygam S/D: 5% solution at 5 mL/kg/h; patients who tolerate 5% solution can be infused with 10% solution starting at 0.5 mL/kg/h, at up to 4 mL/kg/h Venoglobulin-S: 0.01-0.02 mL/kg/min (0.6-1.2 mL/kg/h)
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity, IgA deficiency
Interactions	Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA (use an IgA-depleted product if IgA deficient); may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, and petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and patients with diabetes, volume depletion, and preexisting kidney disease; associated laboratory result changes include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia; infuse in separate line without mixing with other IV fluids or medications; if administered through indwelling catheter, flush it with D5W before and after infusion; do not perform a skin test (local irritation may be interpreted as a positive reaction) For technical information Gammagard, Iveegam EN, or Polygam S/D: 800-241-9360 or 800-423-2862, extension 4377 (Baxter Bioscience) Gammar-P: 800-504-5034 (Aventis Behring LLC) Sandoglobulin: 888-669-6682 (Novartis Pharmaceuticals Corporation) Panglobulin: 800-446-8883 or 800-293-5023 (American Red Cross) Venoglobulin-S: 800-421-0008 or 800-292-6118 (Alpha Therapeutic Corporation)

Further Inpatient Care

• 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 treating with IVIG. 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.

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.

In/Out Patient Meds

• Physicians should stress the importance of good nutrition and adherence to recommendations for therapy and prevention. 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 CVI.

Complications

• 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 an IgA-deficient patient, washed red blood cell transfusions should be given.

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 excellent patient education resources, visit eMedicine's Pneumonia Center, Lung and Airway Center, and Asthma Center. Also, see eMedicine's patient education articles Bacterial Pneumonia, Bronchitis, Asthma, Sinus Infection, and Myeloma.

Medical/Legal Pitfalls

• A failure to use the correct method of testing or standardized age-related values could result in an incorrect diagnosis of IgG deficiency.
• A failure to recognize the variations in normal and pathologic levels of total serum IgG and IgG subclass concentrations could result in complications and be a medicolegal pitfall.
• Primary care physicians should be knowledgeable and trained well in order to provide an early diagnosis of IgG deficiency. The patient's major clinical problems should be addressed, and a thorough clinical workup should be completed.
• In children, treatment must be started as soon as suggestive signs and symptoms are identified in order to prevent complications (eg, bronchiectasis). Adult patients with related symptoms should be seen frequently by their primary care physician until the diagnosis is either established or excluded.
• Screening procedures are useful in the diagnosis of these diseases.
• IgG-deficient patients (particularly those with low levels of IgG2) should be informed that pneumococcal or H influenzae type b vaccines that are prepared with isolated polysaccharide antigen might not provide sufficient immunity against these infections. Prospective studies confirmed a failure of response to soluble polysaccharide antigen in patients with high incidences of recurrent infections.
• Rotation of the injection sites should be considered in patients who receive frequent injections.
• Because transient IgG subclass deficiency is associated with a delayed development of the antipolysaccharide antibody response, these children should receive special care against possible infection, regardless of vaccination status.