IgG Subclass Deficiency

At a Glance

IgG subclass deficiency is defined as the decrease of one or more subclasses of IgG antibodies with normal or near normal levels of other immunoglobulin classes. It can present as either as a complete deficiency in instances in which the serum level of a IgG subclass are below detection or as a relative deficiency in which the IgG subclass levels are below normal range for age. There are four IgG subclasses, IgG1, IgG2, IgG3, and IgG4, and their concentrations change with age. IgG2 subclass deficiency is most common in children, whereas the IgG3 subclass deficiency has the highest prevalence in adults.

A consequence of this disorder is a defect of humoral immunity, although it does not necessarily lead to clinical manifestations. Children with IgG subclass deficiency present most commonly with recurrent ear infections, sometimes as early as the second year of life. Severe otitis media can lead to hearing loss. Later, they can develop recurrent or chronic sinusitis, bronchitis, and/or pneumonia, which can lead to lung function impairment and bronchiectasis. In rare cases, patients suffer from recurrent episodes of meningitis or bacterial sepsis. Some patients develop autoimmune disorders, such as asthma.

Overall, the morbidity of patients suffering from selective IgG subclass deficiencies is not as severe as that of patients suffering from combined immunoglobulin deficiencies affecting all major immunoglobulin classes, as seen in ADA deficiency or X-linked agammaglobulinemia. It is important to note that many patients experience no symptoms, whereas others develop symptoms later in life.

There are slight differences in the presentation of each IgG subclass deficiency.

Patients with IgG1 and IgG3 deficiency commonly present with infections of the lower airways, which can progress to chronic lung disease. 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.

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. Patients 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 teleangiectasia 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.

Overall, one should think about IgG subclass deficiency in a patient with frequent upper and/or lower respiratory tract infections requiring more than six courses of antibiotics and a lack of functional antibodies produced in response to vaccines.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

IgG subclass deficiency should be suspected in patients suffering from abnormally frequent and/or prolonged or severe infections that cannot be explained by the usual clinical and laboratory data.

The work-up for IgG subclass deficiency should start with determination of serum immunoglobulin concentrations (IgG, IgM, and IgA). It is very important to interpret these results using age specific normal ranges. IgG subclass deficiency may be present, even when the total IgG is normal or near normal, since a decreased level of one IgG subclass may be accompanied by increased levels of one or more of the other subclasses. Therefore, measurement of all four IgG subclasses is required for an accurate diagnosis of IgG subclass deficiency, even when the total IgG level is within or only slightly below the reference range of healthy individuals. This is typically done using an enzyme-linked immunosorbent assay (ELISA) or a radial immunodiffusion test.

Finding a decreased level of one of the IgG subclasses does not automatically indicate presence of IgG subclass deficiency. Of higher importance is the ability to provide an antibody response to protein and polysaccharide antigens. IgG1 and IgG3 are typically responsible for response to protein antigens, whereas IgG2 and IgG4 are typically responsible for response to polysaccharide antigens.

Therefore, one should test for IgG responses to previous infections and previous known immunizations, such as diphtheria, tetanus, measles, or pneumococci. Patients who have IgG2 subclass deficiency are often unable to produce specific antibodies after receiving the Pneumococcal vaccine. It is helpful to purposefully immunize patients to determine how much response is made. These patients are unable to produce protective levels of antibody when immunized with unconjugated polysaccharide vaccines against Streptococcus pneumonia or Heamophilus influenza.

Some patients may also be unable to produce protective levels of antibodies when immunized with polysaccharides also conjugated to proteins. Patients with IgG subclass deficiencies usually make normal amounts of antibodies to protein vaccines, such as the diphtheria and tetanus toxoids in the routine DPT immunizations.

Also, it is important to assess lymphocyte populations, particularly B cells. In patients with IgG subclass deficiency, the numbers of B and T cells are usually normal and T cells function normally when tested. However, various minor abnormalities of T- and B-cell counts and function have been reported.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

It is very difficult to assess the IgG subclass levels in patients treated with intravenous immunoglobulins (IVIG). Therefore, if needed, IgG subclass testing should be performed prior to IVIG treatment.

What Lab Results Are Absolutely Confirmatory?

There are no absolute confirmatory tests. It is important to interpret IgG subclass results in the context of the clinical findings and the ability to produce specific antibodies when immunized to common childhood vaccines.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The concentrations of IgG subclasses vary over time. The levels of IgG at birth are very low, increase over time, and approach adult levels at about 2 years of age. The rate of IgG subclass increase varies between children, resulting in a very broad normal range for IgG subclasses. It is not uncommon for a young child to have lower than normal levels of one or more IgG subclasses but have entirely normal levels when tested later. Because of this, if a mild IgG subclass deficiency is discovered, particularly in young children, a reevaluation should be conducted after several months before the final diagnosis is made.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

It is important to note that the normal ranges of IgG subclasses vary between laboratories.