A healthy result should fall into the range 41 - 129 mg/dL.
There are five classes of antibodies (immunoglobulins) that help the body fight infection: IgG, IgA, IgM, IgD, and IgE. Immunoglobulins make up the antibodies that fight infection. Most of the antibodies in the blood and other fluids that surround the body’s tissues and cells are of the IgG class. IgG is divided into four subclasses: IgG1, IgG2, IgG3, and IgG4. People are said to have an IgG subclass deficiency when they lack or have very low levels of one or two IgG subclasses, but have normal levels of other immunoglobulins.
Each IgG subclass plays a slightly different role in protecting the body against infection. Therefore, a person lacking a specific IgG subclass will be vulnerable to certain kinds of infections but not others. For example, the IgG1 and IgG3 subclasses contain antibodies against serious bacterial infections such as diphtheria and tetanus, as well as antibodies against viral proteins. In contrast, the IgG2 subclass contains antibodies against the polysaccharide coating of certain disease-producing bacteria that can cause ear and sinus infections, pneumonia, blood infections and meningitis.
Conditions of IgG Subclass Deficiency:
Recurring ear and sinus infections, sinusitis, bronchitis, and pneumonia are the most frequent illnesses in people with IgG subclass deficiencies. Some people have an increased frequency of infections by an early age; others will not experience infections until later.
Diagnosis of IgG Subclass Deficiency:
A person is considered to have a selective IgG subclass deficiency if blood levels of one or more of the IgG subclasses are below the normal range based on age, and the levels of other immunoglobulins (total IgG, IgA, and IgM) are normal or near normal.
As a person may have no or very low levels of one or more IgG subclasses while maintaining a normal level of total IgG, diagnosis requires measurement of IgG subclasses in addition to serum IgG, IgA, and IgM. IgG4 deficiency often occurs in combination with IgG2 deficiency.
It’s important to remember that the definition of “normal” IgG subclass concentrations varies over time, and from lab to lab. Normal values usually represent a small range below and above the average for a person’s age.
An additional subset of patients have normal levels of immunoglobulin and normal IgG subclasses, yet fail to develop protective antibody levels in response to infections with Streptococcus pneumoniae or vaccines against the bacteria. These people are thought to have a specific antibody deficiency and are usually grouped with patients with IgG subclass deficiency.
Measurement and interpretation of IgG Subclass levels:
IgG subclass deficiency is defined as a reduction in 1 or more subclasses of IgG (IgG1 and IgG2 in particular) by more than 2 SDs below the mean for age-matched controls. Deficiencies in IgG1 or IgG2 are more likely to cause low serum IgG levels because these are the major components. IgG1 levels stabilize by the age of 5 years; however, adult levels of IgG2, IgG3, and IgG4 may not be achieved until adolescence.16 Thus, the interpretation of subclass levels is additionally problematic because levels of each subclass increase at different rates during development. The significance of isolated IgG subclasses is controversial. Laboratories have different age-appropriate reference ranges; aliquots of the same serum may result in different levels from different laboratories.
15 Reduced levels of 1 or more subclasses may be found in healthy individuals, making precise clinical interpretation challenging. If performed, proper evaluation of IgG subclasses should include measurements on 2 separate occasions at least 1 month apart while the patient is free of infections.6 Determination of IgG subclasses may be useful in patients with selective IgA deficiency, in which IgG2 deficiency is found in approximately 10% of patients.15 However, quantitation of IgG subclasses provides insufficient information about antibody function; therefore, specific functional antibody response to proteins and polysaccharide antigens is important. Without clear deficits of functional antibody, IgG subclass deficiency is not likely to be clinically significant.
- People with persistently low levels of one or two IgG subclasses and a normal total IgG level have a selective IgG subclass deficiency.
- People with IgG subclass deficiency require more extensive diagnostic evaluation including the demonstration of a poor antibody response to vaccine challenge before one is diagnosed with a clinically significant IgG subclass deficiency necessitating specific treatment that may include Ig replacement therapy.
- IgG subclass deficiencies may be associated with other immunoglobulin abnormalities. One common pattern is IgG2 and IgG4 subclass deficiency associated with IgA deficiency.
- IgG subclass deficiencies are also an integral component of other well-known primary immunodeficiency diseases, such as Wiskott-Aldrich Syndrome and Ataxia-Telangiectasia.
- IgG subclass deficiencies are sometimes associated with poor or partial responses to pneumococcal polysaccharides, specifically IgG2 deficiency with or without IgG4 deficiency.
Selective IgG1 deficiency is very rare, as it is usually associated with deficiency of either IgG3, or other immunoglobulin classes, such as in common variable immunodeficiency. Isolated IgG1 deficiency has been reported in chronic fatigue syndrome. As IgG1 is the most abundant IgG subclass, its deficiency often results in hypogammaglobulinemia.
IgG1 and IgG3 deficiency:
People with this combination are commonly present with infections of the lower airways, which can progress to chronic lung disease.
IgG2 and IgG4 deficiency:
Conversely, IgG2 and IgG4 deficiencies manifest in the form of otitis media and sinusitis. IgG2 deficiency is the most common type of IgG subclass deficiency, either as an isolated finding or together with IgG4 deficiency. People with this defect have recurrent infections with encapsulated bacteria such as Streptococcus pneumonia and/or Haemophilus influenza type B. IgG2 deficiency often results in infectious complications, such as bronchiectasis, bronchopneumonia, bronchitis, obstructive lung disease, and asthma. It has also been associated with ataxia telangiectasia and systemic lupus erythematosus (SLE). Children with SLE and IgG2 and IgG4 deficiency may present with cardiac tamponade, instead of the more common nephropathy and arthritis. The impact of decreased concentration of IgG4 cannot be easily assessed, since IgG4 may be present in low concentrations in healthy children. Nevertheless, it was shown that low concentrations of IgG4 are present in a large percentage of patients with recurrent respiratory tract infections.
People with any form of IgG subclass deficiency occasionally suffer from recurrent respiratory infections similar to the ones seen in other antibody deficiency syndromes, chiefly infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. An increased frequency of viral upper respiratory infections may not be an indication of antibody deficiency. Therefore, it is critical to distinguish between infections caused by respiratory viruses from those due to bacterial pathogens.
A few people with IgG subclass deficiency may appear very similar to patients with severe immunoglobulin deficiencies. Rarely, IgG subclass deficient patients may have recurrent episodes of bacterial meningitis or infections of the bloodstream (sepsis).
The finding of an IgG subclass deficiency should prompt reevaluation over a period of months before determining that the patient is truly immunodeficient. Subclass deficiencies need to be carefully interpreted taking into account the clinical status of the patient as well as the person’s ability to produce specific antibodies in response to vaccines.
Measurement of IgG subclasses can be recommended in the presence of known associated abnormalities, particularly if recurrent infections are also present.
These circumstances include:
- IgA deficient patients with recurrent infections to determine if there is an associated IgG2 and IgG4 subclass deficiency
- Wiskott-Aldrich and Ataxia-Telangiectasia patients at the onset of recurrent infections
- Specific Antibody Deficiency patients with normal total immunoglobulins
- Recurrent or chronic infections of the ears, sinuses and lungs need comprehensive treatment to prevent permanent damage that might result in hearing loss or chronic lung disease. It is also important to encourage patients to continue normal activities of daily living, such as school or work.
- The mainstay of treatment includes appropriate use of antibiotics to treat and prevent infections. The type and severity of infection usually determines the type of antibiotic used and the length of treatment.
- Ig therapy is an option for selected symptomatic patients that have persistent IgG subclass deficiencies, documented poor responses to polysaccharide vaccines and who fail prophylactic antibiotic therapy. The decision to begin Ig replacement therapy needs to be carefully discussed with the healthcare provider
- People with frequent infections and persistent IgG subclass deficiencies with normal anti-polysaccharide antibodies should also be treated using adequate prevention, vaccine and antibiotic therapy, perhaps even considering the use of Ig replacement if other treatment fails.
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