Deficits in humoral immunity can be either quantitative or functional [5]. Measurement of total IgG, IgA, and IgM levels is helpful as an initial screening tool to determine if there may be a defect in humoral immunity. Hypogammaglobulinemia is defined as an IgG level less than two standard deviations below the normal range, and agammaglobulinemia is defined by a total IgG level of <100 mg/dL. In IgG subclass deficiency, total IgG may be normal or low normal, but an IgG subclass may be markedly decreased. The best way to assess antibody function is to measure IgG titers to specific organisms that represent the two main types of antigens—proteins and polysaccharides. An easy way to do this is to measure antibody titers to routine vaccinations. Measurement of antibody titers to tetanus or diphtheria is useful to assess antibody function with regard to protein antigens. Since a low tetanus antibody titer may reflect waning postvaccination immunity, repeat titers should be obtained a month after revaccination. To assess response to polysaccharide antigens, measurement of titers before and after immunization with unconjugated pneumococcal vaccine can be performed. However, infants and young children normally have poor antibody responses to polysaccharide antigens, and the antibody response to vaccination can frequently be incomplete even in school age children. Therefore, the interpretation of immune responses to pneumococcal vaccination can be difficult and needs to be done in the overall clinical context of an individual patient.

The most severe form of antibody deficiency is X-linked agammaglobulinemia (XLA), also known as Bruton’s agammaglobulinemia. The molecular defect in XLA is due to mutations in the Bruton’s tyrosine kinase (BTK) gene. Absence of BTK results in a block in B cell maturation and as a result, there are no B cells present in patients with XLA. XLA is associated with near absent levels of all Ig isotypes. Flow cytometry shows an absence of circulating B cells.

Common variable immunodeficiency (CVID) is a heterogeneous disorder that is characterized by impaired B cell differentiation, leading to varying degrees of hypogammaglobulinemia and diminished antigen-specific responses. Patients with CVID usually have normal numbers of B cells, but the function of these cells is impaired, and quantification of antibody levels will typically reveal markedly reduced serum concentrations of IgG, in combination with low levels of IgA and/or IgM. There may be subtle defects in T cell function as well, but patients rarely develop opportunistic infections as a result. Individuals with CVID are at an increased risk of developing interstitial lung disease, as well as hematologic malignancy, particularly B-cell lymphomas. IgG subclass deficiency refers to a significant decrease in serum levels of one or more of the four subclasses of IgG, in a patient with a normal total IgG. This laboratory finding may not translate to clinical disease, as decreased levels of IgG subclasses are seen in the general population. However, some individuals with IgG subclass deficiency do present with recurrent sinopulmonary infections due to impaired antibody function. In particular, IgG2 deficiency is associated with recurrent respiratory infections with encapsulated organisms in children, and can be seen together with IgA deficiency. Selective IgA deficiency is one of the most common antibody deficiencies. Most individuals with IgA deficiency do not present with infections, since they have normal amounts of functioning IgG, but some do present with recurrent sinopulmonary and/or gastrointestinal infections. Rare cases have been reported of individuals with normal total IgG, IgA, IgM, and IgG subclass levels, but absent specific antibodies to polysaccharide antigens. These patients will demonstrate low titers of anti-pneumoccocal antibodies even after vaccination.