Diagnosis of APDS

This post describes how to diagnose APDS, and immunological lab results that should raise concern.

The clinical laboratory phenotype of patients identified to date with the E1021K mutation and APDS phenotype is distinctive in both children and adults and may be easily identified using standard diagnostics available in Primary Immunodeficiency Centres. Overall there is picture of altered humoral and cellular immunity although the serological profile may be more subtle than is seen in known humoral immune defects such as X-Linked Agammaglobulinaemia or Common Variable Immunodeficiency and is more similar to that reported in Hyper IgM Syndromes.

Immunoglobulin isotypes may show an increase in IgM and reduction in IgG2 with a normal or low total IgG. Vaccine responses may be suboptimal, however the profile is variable with some patients demonstrating normal vaccination responses particularly to protein antigens. As with other humoral immune deficiencies, suboptimal response pneumococcal vaccines (both plain polysaccharide and conjugate vaccine) is more consistently impaired. Lymphopaenia affecting both T and B cell subsets is seen in some patients. Extended lymphocyte profiling has however provided the most distinctive signature. Using the Euroclass B cell profiling panel (Wehr et al. 2008), there is trend for reduced number of class switched (IgM-CD27+) and IgM memory (IgM+CD27+) B cells and a dramatic expansion of cells of Transitional phenotype (CD38high, IgMhigh) with numbers reaching up to 90% of the circulating B cell population. T cell profiling is also distinctive. Whilst absolute T cell counts may be normal, a marked expansion of cells of CD25-CD45RA-/CD127- phenotype (consistent with effector memory T cells) in both CD4 and CD8 compartments is seen. This is a population that has best been described in the context of chronic HIV infection and is thought to represent chronic immune activation. A summary of routine investigations that may help in the diagnosis of APDS is given in the table below:

Immunology findings

Serum IgGNormal or reduced
Serum IgANormal
Serum IgMIncreased
Serum IgG2Reduced
Vaccine responses to Streptococcus pneumoniaNormal or reduced
Vaccine responses to Haemophilus influenzaeNormal or reduced
Vaccine responses to TetanusNormal or reduced
CD19+IgM+CD27+ B cellsNormal or reduced
CD19+IgM-CD27- B cellsNormal or reduced
CD19+IgM+CD38+ B cellsSignificantly increased
CD3+CD4+CD25-CD127- Helper T cellsIncreased
CD3+CD4+CD25-CD45RA- Helper T cellsIncreased
CD3+CD8+CD25-CD127- cytotoxic T cellsSignificantly increased
CD3+CD8+CD25-CD45RA- cytotoxic T cellsSignificantly increased

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