INTRODUCTION — The clinical presentation, pathogenesis, diagnosis, and treatment of immunoglobulin G (IgG) subclass deficiency are presented here. The physical and biologic properties of IgG subclasses are reviewed separately. (See "IgG subclasses: Physical properties, genetics, and biologic functions".)
DEFINITIONS — The term "IgG subclass deficiency" refers to a significant decrease in the serum concentrations of one or more subclasses of IgG in a patient whose total IgG concentration is normal .
Clinically significant deficiency — IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.
For children 4 to 10 years of age, levels below the following are considered abnormal:
●IgG1 level <250 mg/dL
●IgG2 level <50 mg/dL
●IgG3 level <15 mg/dL
●IgG4 level <1 mg/dL
For individuals older than 10 years of age, levels below the following are considered abnormal:
●IgG1 level <300 mg/dL
●IgG2 level <50 mg/dL
●IgG3 level <25 mg/dL
●IgG4 level <1 mg/dL
In one study, up to 20 percent of an unselected population had levels of one or more of the IgG subclasses below these lower limits of normal, a finding that has fueled ongoing debate about whether or not IgG subclass deficiency truly represents an inborn error of immunity (formerly called a primary immunodeficiency) (table 2) [10,11].
EPIDEMIOLOGY — Among patient populations with more frequent or severe infections, IgG subclass deficiency is a common finding:
●In two large series from France, IgG subclass deficiency was detected in 21 percent of 483 patients with abnormally frequent, prolonged, or severe infections who had been recruited from clinical immunology, pediatrics, and infectious diseases departments [5,9]. IgG3 was the most frequently deficient subclass, which has also been observed in other studies [2-4,12].
●The sex distribution of IgG subclass deficiency differs in children and adults. In children, IgG subclass deficiencies are more common in boys by a ratio of 3:1 [2,3]. In contrast, there is a predominance of females after 16 years of age. This shift in sex distribution may be due to hormonal influences upon the development and maturation of the immune system.
PATHOGENESIS — The primary mechanisms underlying IgG subclass deficiency are unclear. Gene deletions, transcription errors, cytokine dysregulation, immunosuppressive therapy, and allotypic variations are some mechanisms that have been described:
●Gene deletions – Heterozygous gene deletions result in reduced serum levels of the corresponding subclass. Deletions have been described for genes C-gamma-1, C-gamma-2, and C-gamma-4 . Rare homozygous gene deletions, resulting in the complete absence of a subclass, have been reported . Homozygous deletions of large portions of the immunoglobulin heavy chain gene, resulting in the absence of multiple immunoglobulin classes, are also described. Such patients may have no detectable IgG1, IgG2, IgG4, IgA1, or IgE [15,16]. Such deletions are thought to arise from unequal crossover, resulting from extensive homology among the immunoglobulin heavy chain genes on chromosome 14.
●Transcription errors – The mechanism of germline transcription may be negatively altered in a significant number of patients with IgG4 subclass deficiency. Restriction fragment length polymorphisms 5' of the S-gamma-4 loci within the gamma-chain constant region gene complex have been specifically documented in patients with IgG4 deficiency patients compared with controls .
●Effect of allotype – Some IgG subclass deficiencies appear to be influenced by allotype. A lack of the G2m(n) allotype was demonstrated in both IgG2-deficient and IgG3-deficient White patients, and homozygosity for the G3m(g) and G3m(b) allotypes was found in IgG3-deficient patients [18,19]. The genes that encode the IgG subclasses, as well as the influence of allotype on subclass levels and allotype nomenclature, are discussed separately. (See "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Genetics'.)
CLINICAL MANIFESTATIONS — IgG subclass deficiency may be asymptomatic or associated with recurrent infections and a heterogeneous group of related disorders. Interpretation of the available medical literature is complicated by the fact that many series have considered both asymptomatic and symptomatic patients together. Early studies (beginning in the 1970s) of patients with recurrent infections did not routinely assess antibody function .
Asymptomatic — Most individuals lacking one or more IgG subclass are asymptomatic [21-28]. In addition, there are patients with complete deficiencies of multiple subclasses (combinations of IgG1, IgG2, IgG4, IgE, or IgA) who remain healthy and free of infections [29-32].
Symptomatic — Patients with symptomatic IgG subclass deficiency most commonly present with recurrent sinopulmonary infections. The infections vary in frequency and severity and include otitis media, rhinosinusitis, and pneumonia, which are usually due to common respiratory bacterial pathogens [1,25,26,33,34]. More serious infections that can occur include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections .
Associated disorders — IgG subclass deficiencies are associated with other inborn errors of immunity, atopic disorders, chronic airway diseases, and autoimmunity.
●IgG subclass deficiencies are most strongly associated with IgA deficiency . Approximately 15 percent of IgA-deficient patients also have IgG subclass deficiency, such as IgA, IgG2, and IgG4 deficiency [36,37]. Associations have also been reported between IgG subclass deficiency and ataxia-telangiectasia , as well as selective IgM deficiency . (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Ataxia-telangiectasia".)
●Atopic disease is more common in patients with IgG subclass deficiency compared with the general population [2,40,41].
●Chronic airway diseases, particularly asthma and chronic obstructive pulmonary disease, are found with a high frequency among patients with IgG subclass deficiency [2,40,42-44].
●Autoimmune conditions, such as vasculitis and cytopenias, are more common in patients with IgG subclass deficiency [45,46].
IgG1 deficiency — Most patients with IgG1 deficiency have generalized hypogammaglobulinemia since IgG1 normally comprises almost two-thirds of the total serum IgG (table 3). Thus, most patients with significant IgG1 deficiency are classified as common variable immunodeficiency (CVID), a diagnosis that also requires decreased levels of IgA and/or IgM. Only patients with selective IgG1 deficiency and normal levels of total IgG should be diagnosed with IgG1 deficiency. (See "IgG subclasses: Physical properties, genetics, and biologic functions" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)
Selective IgG1 deficiency with normal total IgG is uncommon. In a large study, selective IgG1 deficiency was detected in 119 of 3005 patients (4 percent) with frequent and/or repeated infections . These patients, predominately adults, had low IgG1 levels with normal levels of the other IgG subclasses, IgM, and IgA, thus excluding the diagnosis of CVID. Approximately 80 percent suffered from recurrent, predominately sinopulmonary infections, and 20 percent had asthma. In children <5 years old, IgG1 deficiency may be transient hypogammaglobulinemia of infancy. (See "Transient hypogammaglobulinemia of infancy".)
IgG1 deficiency occasionally occurs with concomitant elevations in IgA or IgM or in combination with IgG3 deficiency [11,20].
IgG2 deficiency — IgG2 subclass deficiency is more prevalent among children than adults and is one of the most frequently identified disorders in children with recurrent infections [3,48]. It has been described both as an isolated finding and in combination with IgG4 and/or IgA deficiency [36,49].
IgG2 is predominantly responsible for the antibody response against polysaccharide capsular antigens. As a result, IgG2-deficient patients are at increased risk for infections with Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Neisseria meningitidis [50-53]. Sinopulmonary infections, including rhinosinusitis, otitis media, and bronchitis, predominate. However, more severe infections may also occur, such as pneumonia and meningococcemia [52,53]. Obstructive lung disease and bronchiectasis have been reported with longstanding disease . (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)
Compared with adults, healthy children have lower levels of IgG2. In addition, IgG2 levels rise to adult levels more slowly than do other subclasses (figure 1). IgG2 levels are 20 percent of adult levels at 1 year of age, 50 percent at 5 years of age, and 75 percent at 14 years of age. By comparison, IgG1 and IgG3 levels rise more rapidly and reach approximately 50 percent of adult levels by one year of age and 75 percent by five years of age.
IgG2 subclass deficiency has been reported in association with a variety of disorders:
●Autoimmune disorders, including systemic lupus erythematosus, juvenile diabetes mellitus, primary Sjögren syndrome, autoimmune cytopenias, and vasculitides, such as IgA vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) [45,55-57].
●Other inborn errors of immunity, including ataxia-telangiectasia, defects in the production of interferon gamma, and chronic mucocutaneous candidiasis [38,58,59]. (See "Ataxia-telangiectasia" and "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Chronic mucocutaneous candidiasis".)
●Secondary immunodeficiency states, such as human immunodeficiency (HIV) infection and allogeneic bone marrow transplantation [60,61].
●Several other disorders, including cystic fibrosis, severe H1N1 influenza, growth hormone deficiency, febrile seizures, Hodgkin lymphoma, and allergic colitis [62-69].
Data on the natural history of IgG2 subclass deficiency are limited:
●The course of IgG2 deficiency was evaluated in a retrospective analysis of 120 children ≥2 years old with recurrent infections and failure to respond to a majority of serotypes after S. pneumoniae immunization with the polysaccharide vaccine . IgG2, IgA, and IgA-IgG2 deficiency were identified in 19, 11, and 3 percent, respectively . After three years, immunoglobulin concentrations and polysaccharide responses had normalized in 87 percent.
●In another series of 49 children with IgG subclass deficiency, of whom 76 percent had IgG2 deficiency, greater morbidity was observed, and a lower percentage of children showed normalization over time . Ten percent of these children had bronchiectasis. On follow-up, 46 percent of the patients showed progressive immunodeficiency. Progression to CVID has been described in other case reports .
IgG3 deficiency — IgG3 subclass deficiency is more common in adults than children . It may occur alone or in combination with other subclass deficiencies, especially IgG1 [18,72]. IgG3 is responsible for the immune response against Moraxella catarrhalis and to the M component of Streptococcus pyogenes, and these organisms are frequently implicated in infections in IgG3-deficient patients .
Clinically, patients with symptomatic IgG3 deficiency commonly suffer from the same types of recurrent sinopulmonary infections as those with other subclass deficiencies. Antibody responses to polysaccharide antigens may be normal or impaired [4,26,73]. In a series of 121 adult patients who suffered from severe, recurrent bacterial lung infections and had isolated low IgG3 levels, response to pneumococcal polysaccharide vaccine was impaired in 34 percent .
Asthma, chronic bronchitis, gastrointestinal infections, and recurrent lymphocytic meningitis have also been reported in patients with IgG3 deficiency [4,5,26,73,75]. Case reports note associations with diabetes mellitus type 1, IgAV, recurrent herpes simplex infection, recurrent erysipelas, and complement component 2 deficiency [4,72].
IgG4 deficiency — IgG4 deficiency is believed to be common in the general population, and the majority of affected people are asymptomatic . IgG4 subclass deficiency has been described alone, in combination with IgG2 deficiency, and with IgA-IgG2 deficiencies [22,36,76]. Recurrent pulmonary infections and bronchiectasis are reported in symptomatic patients [28,76-78].
IgG4 deficiency has been reported in association with various other disorders, including ataxia-telangiectasia, chronic mucocutaneous candidiasis, growth hormone deficiency, allergic colitis, and Down syndrome [59,61,66,67,72,79].
EVALUATION — Patients with IgG subclass deficiency most commonly present with recurrent sinopulmonary infections. An initial approach to patients with recurrent infections, including key aspects of the clinical history and physical exam, is reviewed in detail separately. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)
Initial laboratories — The initial laboratory evaluation should include:
●A complete blood count and differential
●Total serum IgG, IgA, IgM, and IgE levels
●IgG subclasses (some investigators obtain IgG subclasses at the initial evaluation, whereas others measure them only if vaccine response is impaired)
●Antibody titers to proteins and polysaccharide antigens, such as diphtheria toxoid, tetanus toxoid, H. influenzae type b (Hib), and S. pneumoniae
●Total hemolytic complement (CH50) and alternative hemolytic complement (AH50)
If the results of any of these laboratories are abnormal, then a problem with that component of the immune system should be pursued first. (See "Laboratory evaluation of the immune system".)
Referral and further evaluation — Referral to an immunology specialist is indicated, if possible, for patients with recurrent sinopulmonary infections and either normal or abnormal results to the initial screening laboratory tests mentioned above. (See 'Initial laboratories' above.)
Further evaluation involves:
●Assessment of the patient's responses to past infections and vaccination, including booster immunization antibody responses (also called vaccine challenge)
●Measurement of IgG subclass levels (if not done earlier)
IgG subclass levels — The following are important points about the measurement of IgG subclasses:
●Low IgG subclass concentrations should be confirmed on at least one other occasion, two to four weeks after the first measurement [80,81].
●IgG subclass levels change rapidly from birth to two years of age (figure 1).
Different methods are used for the quantitative determination of IgG subclasses, which include enzyme-linked immunosorbent assays, radial immunodiffusion, nephelometry, and radioimmune assays. IgG subclass standard sera is calibrated against IgG subclass levels in World Health Organization reference serum 67/97.-
Assess antibody function — The function of the patient's IgG antibodies can be assessed by measuring antibody titers to previously administered vaccines or natural infections. If titers are not in the protective range, a vaccine challenge is performed, which refers to the administration of vaccines with measurement of pre- and postimmunization titers. Vaccine challenge serves as a correlate of the patient's ability to respond effectively to natural infections and is a means of determining the clinical significance of an IgG subclass deficiency. Lack of response, especially to S. pneumoniae and H. influenzae vaccines, correlates with clinical susceptibility to recurrent sinopulmonary infections [6,20,26,33,36,41,49,50].
Types of vaccines — There are two forms of pneumococcal vaccines, pure pneumococcal polysaccharide vaccine (PPSV), which is unconjugated, and pneumococcal conjugate vaccine (PCV). The widely used PCV13 (example brand name Prevnar 13) contains 13 serotypes. The PPSV (example brand name Pneumovax) contains 23 serotypes. Post-pneumococcal antibody responses are typically measured four weeks after immunization, and a protective response is indicated by attainment of protective antibody levels. PPSV can be administered at the age of two years, but antibody responses are most consistent after the age of five years. There is only a conjugated Hib vaccine.
The patient's response to PPSV is used to assess the ability to respond to polysaccharide antigens, while the response to PCV and Hib assess the response to protein antigens. A more detailed discussion of how to assess antibody function and interpret vaccine responses is found separately. (See "Assessing antibody function as part of an immunologic evaluation".)
Children under two years of age — Immune response to protein antigens can be assessed in children less than two years old by measuring S. pneumoniae serotype antibody responses after immunization with the conjugated pneumococcal vaccine (eg, PCV13) and measuring Hib antibody titers in response to conjugated H. influenzae vaccination. It is the author's experience that young children who respond poorly to full immunization with conjugated pneumococcal vaccines often subsequently respond poorly to polysaccharide vaccines when they are older. As a result, the measurement of antipneumococcal and anti-Haemophilus antibodies in children who have received conjugated vaccines for these pathogens is informative. These tests are commercially available, usually in panels of 13 to 23 serotypes. (See "Assessing antibody function as part of an immunologic evaluation", section on 'Children under two years of age'.)
DIAGNOSIS — The diagnosis of a clinically significant IgG subclass deficiency requires all three of the below components :
●The clinical history of recurrent sinopulmonary infections.
●The laboratory finding of deficiency of one or more IgG subclasses with the exception of isolated IgG4 deficiency, typically to levels less than 2 standard deviations below the age-specific mean, in the presence of normal or near-normal total serum IgG concentrations. (See 'Lower limits of normal' above.)
These levels should be assessed on at least two occasions while the patient is free of acute infections, using methods that are capable of detecting values in the very low ranges (ie, 1 to 8 mg/dL), such as enzyme-linked immunosorbent assays.
●The demonstration of an inadequate antibody response, typically to polysaccharide vaccine challenge. Vaccine challenge is reviewed in detail separately. (See "Assessing antibody function as part of an immunologic evaluation".)
Patterns of vaccine response with different subclass deficiencies — Vaccine responses of patients with IgG subclass deficiencies are characterized by the following:
●Patients with clinically significant symptomatic IgG1 subclass deficiency usually have hypogammaglobulinemia and are diagnosed with other disorders. Patients with IgG1 subclass deficiency, similar to patients with common variable immunodeficiency (CVID), have impaired antibody responses to polysaccharide antigens only or to both polysaccharide and protein antigens. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Transient hypogammaglobulinemia of infancy" and "Primary humoral immunodeficiencies: An overview".)
●Patients with IgG2 subclass deficiency (possibly in combination with selective IgA and/or IgG4 deficiency) have defective polysaccharide vaccine responses with some regularity. By comparison, such patients typically have normal baseline immunity to protein antigens and respond normally to protein vaccines.
●Patients with selective IgG3 deficiency usually have normal antibody responses, although differing degrees of impaired specific antibody responses have been noted [73,83,84].
●Patients with IgG4 deficiency typically produce normal antibody responses to both protein and polysaccharide antigens.
DIFFERENTIAL DIAGNOSIS — Other conditions must be considered in patients with clinical features suggestive of IgG subclass deficiency but lacking either of the two criteria for the diagnosis (ie, low IgG subclass levels or poor antibody response to vaccine challenge).
●Functionally normal – Patients with low IgG subclass levels but normal immune responses to vaccination may be immunologically normal. Many such patients have been described. This combination of findings in a child may represent the evolution of transient hypogammaglobulinemia of infancy. (See "Transient hypogammaglobulinemia of infancy".)
●Secondary immunodeficiency – Patients with IgG subclass deficiency, normal immune responses to vaccination, and recurrent sinopulmonary infections may have secondary hypogammaglobulinemia. Secondary hypogammaglobulinemia can result from either decreased production or increased loss.
•Malignancy (chronic lymphocytic leukemia or lymphoma) can result in decreased immunoglobulin production .
•Viral infections (eg, Epstein-Barr virus, human immunodeficiency virus [HIV], cytomegalovirus, and congenital rubella) and systemic illnesses causing bone marrow suppression are other secondary causes of hypogammaglobulinemia.
•Certain medications, including systemic glucocorticoids, sulfasalazine, and the antiseizure medications zonisamide, phenytoin, and carbamazepine, have been associated with acquired cases of IgG subclass deficiency [85-89]. (See "Glucocorticoid effects on the immune system" and "Primary humoral immunodeficiencies: An overview", section on 'Differential diagnosis'.)
•Abnormal loss of immunoglobulins can be observed in protein-losing enteropathies, nephrotic syndrome, burns, and other traumas.
•Cigarette smoking has also been associated with lower IgG2 subclass levels .
MANAGEMENT — Most patients with IgG subclass deficiencies do well with appropriate treatment and suffer significantly fewer sinopulmonary infections. Treatment of patients with IgG subclass deficiency includes the following:
●Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines
●Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (eg, asthma, allergic rhinitis)
●Increased vigilance and appropriate antibiotic therapy for infections
●Intravenous or subcutaneous immune globulin replacement
Vaccination — All patients with IgG subclass deficiency and poor responses to polysaccharide vaccines should receive a conjugated pneumococcal vaccine in order to boost immunity to this common respiratory pathogen. There are no data examining efficacy of these vaccines in patients with IgG subclass deficiency, although benefits have been observed in children with specific antibody deficiency (SAD). As an example, in one study of patients with vaccine nonresponse, the conjugated pneumococcal vaccine produced a protective response in 80 to 90 percent of patients ≥2 years of age who failed to respond to the unconjugated polysaccharide vaccine . A similar response may occur in patients with subclass deficiency, as clinical improvement is often observed after this intervention.
Recommendations for H. influenzae type b (Hib) immunization are published periodically by the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) and include patients with antibody deficiency [92,93]. The ACIP recommended that conjugated Hib vaccine be administered in patients with IgG2 subclass deficiency and those with SAD [92,93]. (See "Prevention of Haemophilus influenzae type b infection".)
Treatment of infections — Prompt recognition and treatment of sinopulmonary bacterial infections is a significant component of management of these patients since infections are less likely to clear spontaneously in patients with antibody defects. When possible, infections should be verified through sinus and lung imaging, complete blood counts, and culture data. (See "Acute bronchitis in adults" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Acute bacterial rhinosinusitis' and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical evaluation'.)
Management of other sinopulmonary disease — Aggressive management of any conditions predisposing to recurrent sinopulmonary infections (especially allergic rhinitis and asthma) is critical to improving the clinical outcome of patients with IgG subclass deficiency. Atopic disorders occurred in 55 to 58 percent of the children with SAD with or without IgG2-IgA deficiency in one report .
Management of allergic rhinitis and asthma includes allergy evaluation and trigger avoidance, nasal and inhaled glucocorticoids, bronchodilators, and antihistamines. (See "Pharmacotherapy of allergic rhinitis" and "An overview of asthma management".)
Patients with IgG subclass deficiencies appear to respond normally to allergen immunotherapy for allergic rhinitis and asthma and should receive this therapy when appropriate. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)
Prophylactic antibiotics — Patients with recurrent sinopulmonary infections despite the previously described measures usually require prophylactic antibiotics. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies.
●One of the largest studies examined 120 children aged 2 to 15 years of age . Seventy-two percent were successfully managed with prophylactic antibiotics. Those who did not respond subsequently required immune globulin replacement therapy.
●In another series of 59 children, prophylactic antibiotics were administered if the patient had more than six upper respiratory tract infections (RTIs) in one year, with or without an immunostimulant bacterial lysate, and immune globulin was administered to those who did not experience adequate improvement [12,94]. During the years the children were followed, 90 percent required one of these therapies, and 15 percent received immune globulin. In the treated group, the frequency of infections decreased from 13±7 to 6±4 per year .
In the author's clinic, approximately one-half of children require prophylactic antibiotics. The specific prophylactic antibiotic selected should cover the bacteria that most commonly cause sinopulmonary infections, such as S. pneumoniae (including penicillin-resistant strains), nontypable H. influenzae, and M. catarrhalis.
The choice of agent and dose should be based upon resistance patterns within a community. Specific regimens of antibiotic prophylaxis for children and adults are presented separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)
Immune globulin therapy — Judicious use of immune globulin therapy is appropriate if the use of prophylactic antibiotics does not result in fewer infections and/or in patients with persistent and symptomatic chronic rhinosinusitis. This therapy should be reserved for patients with clearly impaired responses to protein and/or polysaccharide antigens [95-97]. Most of the patients requiring this intervention have impaired antibody responses to bacterial polysaccharide antigens with IgG2 +/- IgG4 deficiency, although there are reported cases of benefit in IgG3 deficiency as well . Intravenous immune globulin therapy, at a standard dose range of 400 to 600 mg/kg, can be infused every three to four weeks . Immune globulin can also be replaced subcutaneously at weekly intervals. (See "Immune globulin therapy in inborn errors of immunity".)
The role of immune globulin in patients with IgG3 deficiency is not as clear. However, several studies have reported clinical improvement in patients with IgG3 deficiency as a result of this intervention [71,73,83,99,100]. In the largest study, which included 33 patients with IgG3 deficiency, patients with more than four antibiotic-requiring RTIs per year were treated with immune globulin, and the number of infections before and during treatment was compared . Reduction in the number of RTIs was seen in 29 of 33 patients with IgG3 deficiency: 23 experienced a ≥50 percent reduction, and 6 had a reduction of <50 percent.
Immune globulin therapy should be administered for one to two years initially, at which point the patient's status should be reevaluated to determine if the number and/or severity of infections have been reduced. Not all patients with IgG subclass deficiencies benefit from immune globulin replacement, and the therapy should be discontinued if not effective in that individual . (See 'Monitoring' below.)
PROGNOSIS — The prognosis of IgG subclass deficiency is influenced by the age of the patient as well as the degree of deficiency.
●Evidence suggests that the majority of children younger than six to eight years of age with clinically significant IgG subclass deficiency and diminished specific antibody responses will normalize both antibody responsiveness and IgG subclass level(s) [10,41]. This appears to be particularly true for young children with IgG2 and IgA deficiency and impaired responses to polysaccharide antigens. In contrast, if the condition persists beyond the age of six years, it is likely to be permanent.
●Adults with clinically significant IgG subclass deficiency and diminished specific antibody responses will rarely achieve normalization of a deficient IgG subclass level . It is the author's experience that a subset of these patients progress to common variable immunodeficiency (CVID). Development of chronic pulmonary diseases, such as bronchiectasis, is also a risk for such patients, and they must be monitored closely . (See "Pulmonary complications of primary immunodeficiencies", section on 'Monitoring for pulmonary disease'.)
●Spontaneous resolution is less likely to occur in cases of complete absence of an IgG subclass, regardless of age.
●The risk of lymphoma in patients with IgG subclass deficiencies has not been evaluated.
MONITORING — Monitoring is influenced by the patient's age and the severity of illness.
●In affected younger children (up to six years of age), levels of immunoglobulins and IgG subclasses should be measured yearly. Vaccine response should be assessed again if levels normalize.
●In symptomatic older children with persistent deficiency and in adults, we reevaluate levels annually for several years. If the condition persists throughout this period, then reassessment can be less frequent [41,71,101].
●In patients receiving immune globulin replacement therapy, treatment should periodically be held after one to two years for immunologic and clinical reassessment. When discontinuing immune globulin, it is advisable to do so during the spring months to minimize exposure to viral infections. We generally wait three or four months after discontinuation before performing immune testing. (See "Overview of intravenous immune globulin (IVIG) therapy".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Definitions – "IgG subclass deficiency" refers to a significant decrease in the serum concentrations of one or more subclasses of immunoglobulin G (IgG) in a patient whose total IgG concentration is normal. It is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge. (See 'Definitions' above.)
●Range of clinical manifestations – Most patients with low levels of one or more IgG subclasses are asymptomatic. Those with symptomatic IgG subclass deficiencies typically suffer from repeated sinopulmonary infections. Osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections are reported less often. (See 'Clinical manifestations' above.)
●Specific subclass deficiencies – The different subclass deficiencies may have specific clinical characteristics. (See 'Specific deficiencies' above.)
•IgG1 deficiency almost always presents as hypogammaglobulinemia since IgG1 normally makes up approximately 70 percent of total IgG. Therefore, only those patients with IgG1 deficiency with normal total IgG should be diagnosed with selective IgG1 deficiency.
•IgG2 deficiency, which may occur in combination with IgG4 and/or IgA deficiency, is more common in children. Infections with Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Neisseria meningitidis are characteristic since IgG2 comprises most of the antibody response against polysaccharide capsular antigens.
•IgG3 deficiency is more common in adults and may occur together with IgG1 deficiency. Infections with Moraxella catarrhalis and Streptococcus pyogenes are typical.
•IgG4 deficiency may or may not be associated with symptomatic sinopulmonary infections.
●Evaluation – The initial evaluation of patients suspected of having an antibody defect involves complete blood count and differential; total hemolytic complement (CH50) and alternative hemolytic complement (AH50); total IgG, IgM, and IgA levels; and antibody titers to protein and polysaccharide antigens. The diagnosis of IgG subclass deficiency should be considered in a patient whose initial laboratory tests are normal. In this situation, the patient's responses to past infections and vaccination are assessed, and IgG subclass levels are measured. (See 'Evaluation' above.)
●Diagnosis – The diagnosis of a clinically significant IgG subclass deficiency involves fulfilling the following components (see 'Diagnosis' above):
•The clinical history of recurrent sinopulmonary infections
•One or more low IgG subclasses with normal total IgG
•Inadequate response to vaccination
●Principles of management – Management consists of immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines, aggressive treatment of other conditions predisposing to recurrent sinopulmonary infections (eg, asthma, allergic rhinitis), and increased vigilance and appropriate antibiotic therapy for infections. (See 'Management' above.)
•Prophylactic antimicrobials – We suggest the use of prophylactic antibiotics for patients with repeated sinopulmonary infections despite the above measures (Grade 2C). The choice of agent and dose should be based upon resistance patterns within a community. (See 'Prophylactic antibiotics' above.)
•Immune globulin – We suggest immune globulin therapy for patients with clearly impaired protein and/or polysaccharide vaccine responses in whom the use of prophylactic antibiotics has not resulted in fewer infections (Grade 2C). (See 'Immune globulin therapy' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges J Keith Lemmon, MD, and E Richard Stiehm, MD, who contributed to earlier versions of this topic review.
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