IgG deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Overview

IgG deficiency is a form of hypogammaglobulinemia where the serum concentrations of one or more subclasses of IgG are diminished relative to other immunoglobulin isotypes, meanwhile total IgG concentration is noral. IgG deficiency is a laboratory finding that may be not associated with significant clinical presentations. The diagnosis of a clinically significant IgG deficiency needs evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

Most patients with IgG deficiency are usually asymptomatic. Symptoms of IgG deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia or even more serious infections that can occur such as osteomyelitis, meningitis, septicemia, diarrhea, and skin infections.

IgG has four subclasses: IgG₁, IgG₂, IgG₃, and IgG₄. It is possible to have either a global IgG deficiency, or a deficiency of one or more specific subclasses of IgG. Since IgG1 forms about 70 percent of total IgG patients with IgG1 deficiency are classified as common variable immunodeficiency (CVID), a diagnosis that also needs reduced levels of IgA and/or IgM.

IgG2 subclass deficiency is the main clinically relevant form of IgG deficiency and is more prevalent among children than adults and is one of the most frequently identified disorders in children with recurrent infections in children or may present as transient hypogammaglobulinemia of infancy (THI), and may occur with or without additional reduction in IgA or IgM. IgG₃ deficiency is not usually encountered without other concomitant immunoglobulin deficiencies, and IgG₄ deficiency is very common but usually asymptomatic.

The diagnosis of a clinically significant IgG deficiency needs evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge. 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 and appropriate antibiotic therapy for infections and the use of prophylactic antibiotics for patients with repeated sinopulmonary infections.

Intravenous or subcutaneous immune globulin replacement should be reserved for patients with clearly impaired responses to protein and/or polysaccharide antigens and/or if the use of prophylactic antibiotics does not cause fewer infections or in patients with persistent and symptomatic chronic rhinosinusitis .

Historical Perspective

In 1952, Bruton reported a condition in an 8-year-old boy with recurrent episodes of bacterial infections and sepsis with the same serotypes of pneumococcus, while he had intact lymphoid tissue and B-cells but had decreased IgG levels and he had no antibodies against this pathogen.

In the 1960s, by the discovery of the IgG subclasses, further aspects of IgG deficiency and recurrent infection, were uncovered. and thrown new light on the understanding of IgG deficiencies subclasses, as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types. Moreover, how even if the total IgG concentration is normal, deficiencies of one or more individual IgG subclasses, may be observed.

Classification

IgG deficiency may be classified according to individual IgG subclasses deficiency into four subtypes:

• IgG1 deficiency : since IgG1 normally comprises almost two-thirds of the total serum IgG most patients with IgG1 deficiency have generalized hypogammaglobulinemia.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. Selective IgG1 deficiency with normal total IgG is uncommon.
• IgG2 deficiency : is more prevalent among children than adults and is one of the most frequently identified disorders in children with recurrent infections.It has been described both as an isolated finding and in combination with IgG4 and/or IgA deficiency.
• IgG3 deficiency : is more common in adults than children. It may occur alone or in combination with other subclass deficiencies, especially IgG1.
• IgG4 deficiency : is considered to be common in the general population, meanwhile the majority of patients are asymptomatic. It may occur alone, or in combination with IgG2 deficiency, and with IgA-IgG2 deficiencies

Pathophysiology

Immunodeficiency diseases are described according to involvement one or more of the 4 major components of the immune system. These components are:

1. B cells
2. T cells
3. phagocytes
4. complement

B-cell or humoral immunity is mediated by the immunoglobulins. There are five types or classes of immunoglobulin: IgG, IgA, IgM, IgD, and IgE. The IgG class of antibodies is composed of four different subtypes of IgG molecules called the IgG subclasses. These are designated IgG1, IgG2, IgG3, and IgG4. 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

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 cause the reduction in the serum concentration of the corresponding subclass. Deletions have been detected for genes C-gamma-1, C-gamma-2, and C-gamma-4 . Homozygous deletions of large portions of the immunoglobulin heavy chain gene, causes the absence of multiple immunoglobulin classes, and are also described. Such patients may have no detectable IgG1, IgG2, IgG4, IgA1, or IgE .
• Transcription errors: Changes of germline transcription and limitation fragment length polymorphisms 5' of the S-gamma-4 loci within the gamma-chain constant region gene complex have been described among patients with IgG4 deficiency compared with controls.

• Effect of allotype: Some IgG subclass deficiencies may be affected by allotype. The absence of the G2m(n) allotype and homozygosity for the G3m(g) and G3m(b) allotypes has been discoverd among Caucasian patients.

Causes

• There are no established causes for IgG deficiency, and mechanisms underlying IgG subclass deficiency are unclear. Genetic, transcription errors, allotypic variations,and immunosuppressive therapy are some mechanisms that have been proposed.

Differentiating IgG deficiency from other Diseases

IgG deficiency must be differentiated from other diseases that cause recurrent episodic infections, especially recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia. IgG defieciency should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:

Disorder	Defect (Mechanism of Development)	Characteristic Features	Clinical Presentation	Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia	Defect in tyrosine kinase gene (BTK) B cells fail to mature	X-linked recessive pattern of inheritance Increased prevalence in males	Recurrent bacterial and enteroviral infections after 6 months of age Pre-disposition to development of infections by encapsulated organisms Pre-disposition to development of Giardia infections Absent lymph nodes and tonsils	Normal CD19+ B cell count Decreased pro-B cells Increased pre-B cells Decreased immunoglobulins of all classes
Selective IgA Deficiency		Most common primary immune deficiency	Majority of the cases are asymptomatic Respiratory and gastrointestinal infections (mucosal infections) Associated with autoimmune diseases Atopy Anaphylaxis to IgA containing products	Serum IgA , 7 mg/dl Normal IgG and IgM levels
Common Variable Immunodeficiency	Defective B cell differentiation	May be acquired in 20'-30 years of age	May present with other autoimmune diseases Associated with bronchiectasis Associated with lymphoma Associated with sinopulmonary infections (Bacterial, entroviral and parasitic such as Giardia)	Decreased plasma cells Decreased immunoglobulins
Autosomal dominant hype IgE syndrome (Job's Syndrome)	Defieciency of Th17 cells due to STAT3 mutation Impaired neutrophils to sites of infection	Distinctive coarse facies Cold (non-inflammatory) Staphylococcal abscesses Retained primary teeth Eczema		Increased levels of IgE Decreased levels of interferon gamma (IFN-gamma)
Severe combined immunodeficiency (SCID)	Defective interleukin-2 receptor gamma chain Adenosine deaminase deficiency Reg 1 and Reg 2 nonsense mutations	IL-2R disease is X-lined ADA deficiency and reg mutations are typically autosomal recessive	Failure to thrive Chronic diarrhea Thrush Recurrent bacterial, viral and protozoal infections Treatment is bone marrow transplant	Decreased T cell receptor excisoon circles (TRECs) Abscence of thymic shadow on chest x-Ray Absent germinal centers of lymph node biopsy Absent T cells on flow cytometery

• Malignancy: can cause the reduction in the immunoglobulin production.

• Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
• Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
• Other causes of primary humoral immunodeficiencies.
• Smoking: may cause IgG2 subclass deficiency.
• Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Epidemiology and Demographics

The prevalence of IgG deficiency is not clear. Some studies estimated that the prevalence of IgG deficiency may be 1 case per 10,000 persons.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 reported in 20 percent of 483 patients with abnormally recurrent, prolonged, or severe infection; IgG3 was the most common deficiency.

In a report of 1175 adults with symptoms suggestive of an antibody deficiency, decreased IgG1, IgG2, IgG3, and IgG4 levels were reported in 28, 17, 13, and 9 percent, respectively.

Age

• IgG deficiency can affect both children and adults. The most common subclass deficiency in early childhood is IgG2 deficiency; in adults, IgG1 and IgG3 deficiencies predominate. In children, IgG1 deficiency accounts for higher cases of the total IgG deficiency in comparison to adults. even though children reach the adult levels of IgG1 and IgG3, but the development of IgG2 and IgG4 is slower. In some children, maturation of IgG subclasses may be delayed until the adolescence.

Gender

• The gender prevalance of IgG deficiency differs in children and adults. In children, IgG deficiency is more common in boys by a ratio of 3:1. In contrast, there is a predominance of females after age 16. This shift in gender distribution may be owing to hormonal influences upon the immune system.

Race

• There is no racial predilection for IgG deficiency.

Risk Factors

Common risk factors in the development of IgG deficiency:

• Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.
• Intense exercise or excessive physical stress
• Smoking
• Aging

Natural History, Complications and Prognosis

Natural History

• The majority of patients with IgG deficiency remain asymptomatic. In addition, there are patients with complete deficiencies of multiple combinations of IgG1, IgG2, IgG4, IgE, or IgA deficiency who remain healthy and free of infections.

Complications

• Common complications of IgG deficiency include bronchiectasis, bronchiolitis obliterans , interstitial lung disease , mediastinal and/or hilar adenopathy, and malignancy.

Prognosis

• Prognosis is mainly affected by the degree of deficiency as well as the age of the patient. Evidence suggests that the majority of children younger than eight years of age with IgG subclass deficiency will normalize IgG subclass level.

• Adults with clinically notable IgG subclass deficiency and diminished particular antibody responses will scarcely reach previous normal level of a deficient IgG subclass.

Diagnosis

Diagnostic Criteria

IgG deficiency is a laboratory finding that may be not associated with significant clinical presentations. The diagnosis of a clinically significant IgG deficiency needs evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

The diagnosis of IgG deficiency required the following two diagnostic criteria to meet in the clinical history of recurrent sinopulmonary infections:

1. low IgG subclass levels
2. poor antibody response to the vaccine challenge

Symptoms

• IgG deficiency is usually asymptomatic.
• Symptoms of IgG deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia or even more serious infections that can occur such as osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections.

Physical Examination

• Physical examination of patients with longstanding immune defects may be remarkable for:

• Low body mass index
• Scarring of tympanic membranes or skin
• Signs of chronic lung disease such as chronic cough, absent gag reflex, clubbing, crackles, or wheezing to suggest bronchiectasis
• Ongoing infection signs of chronic sinusitis, oral thrush, warts, or dermatophyte infections

Laboratory Findings

• IgG deficiency is a laboratory finding that may be not associated with significant clinical presentations. The normal amounts for IgG subclasses are wide and differ with the age of the patients.

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

Vaccine Challenge Response

IgG subclass deficiency is a laboratory finding which does not necessarily cause clinical presentations. For final diagnosis of IgG subclass deficiency, patients must be evaluated for antibody dysfunction in both polysaccharides and proteins antigens. The function 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 should be performed with the administration of vaccines with measurement of pre- and postimmunization titers

Titers of IgG antibodies to tetanus and diphtheria in vaccinated children and adults are used to evaluate immune responsiveness to protein antigens. Results are reported as IgG in general, although the antibody responses generated by these vaccines are largely (but not exclusively) composed of IgG1 and IgG3 antibodies, which is sometimes important in the evaluation of IgG subclass deficiency.

Interpretation of Hib titers — The capsular polysaccharide polyribosylribitol phosphate (PRP) is an important antigen in immunity to Haemophilus influenzae type B (Hib). Anti-PRP IgG titers ≥1 mcg/mL are considered protective [28]. Although the polysaccharide PRP is the primary antigen, the conjugate vaccines employ either diphtheria toxoid or the outer membrane protein complex of meningococcus as the immunogenic protein. Therefore, antibodies to the Hib capsular polysaccharide in patients who received the conjugated Hib vaccine reflect a protein response, and protective antibodies against the PRP polysaccharide do not exclude unresponsiveness to the pure pneumococcal polysaccharides. Children in the United States have been receiving conjugated vaccines for prophylaxis against Hib since the early 1990s.

Treatment

Medical Therapy

The mainstay of therapy for IgG deficiency includes the following :

• Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines

• Aggressive management of asthma, allergic rhinitis predisposing to recurrent sinopulmonary infections

• Recognition and treatment of sinopulmonary bacterial infections since infections are less likely to clear spontaneously in patients with antibody defects.
• Prophylactic antibiotics for patients with recurrent sinopulmonary infections. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies.

• Intravenous or subcutaneous immune globulin replacement is indicated if the use of prophylactic antibiotics does not cause fewer infections 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.
• 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.
• Immune globulin therapy should be administered for one to two years initially, at which point the patient's status should be re-evaluated 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.

Prevention

• There are no primary preventive measures available for IgG deficiency.

• Secondary and tertiary prevention strategies following IgG deficiency include avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy,and when infections do occur, broader spectrum and more prolonged antibiotics are often recommended.
• Avoidance: to reduce exposure to others with potentially contagious illnesses: proper handwashing and use of alcohol-based disinfectants should be provided to patients and their families; Co-sleeping among family members should be minimized, and immunization of family members and close contacts
• Careful attention should be paid to patient's oral hygiene and dental health.
• Vaccination Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines Advisory Committee on Immunization Practices (ACIP)
• Recommended that conjugated Hib vaccine be administered in patients with IgG2 subclass deficiency and those with specific antibody deficiency (SAD)
• Antimicrobial therapy: Treating acute infections and prophylactic antimicrobial therapy among patients with recurrent sinopulmonary infections or ongoing lung disease is helpful. Thus, immediate recognition and treatment with antibiotics can help prevent chronic infections and infectious complications. It is important to ensure that the infection has treated completely at the end of a course of antibiotics, as patients with immunodeficiency sometimes necessitate longer durations of therapy. Antibiotic resistance does not seem to be a serious problem in patients with primary immunodeficiency, for causes which are not clearly understood, then the same antibiotics continue to be useful, regardless of prolonged or frequent exposure.