The clinical relevance of IgM and IgA anti-pneumococcal polysaccharide ELISA assays in patients with suspected antibody deficiency

Abstract

Unlike immunoglobulin (Ig)G pneumococcal polysaccharide (PnPS)-antibodies, PnPS IgA and IgM-antibodies are not routinely determined for the assessment of immunocompetence. It is not yet known whether an isolated inability to mount a normal IgM or IgA-PnPS response should be considered a relevant primary antibody deficiency (PAD). We studied the clinical relevance of anti-PnPS IgM and IgA-assays in patients with suspected primary immunodeficiency in a large teaching hospital in 's-Hertogenbosch, the Netherlands. Serotype-specific-PnPS IgG assays were performed; subsequently, 23-valent-PnPS IgG assays (anti-PnPS IgG assays), and later anti-PnPS IgA and IgM assays, were performed in archived material (240 patients; 304 samples). Eleven of 65 pre- and six of 10 post-immunization samples from good responders to PnPS serotype-specific IgG testing had decreased anti-PnPS IgA and/or IgM titres. Of these, three pre- and no post-immunization samples were from patients previously classified as 'no PAD'. Determination of anti-PnPS IgA and IgM in addition to anti-PnPS IgG did not reduce the need for serotype-specific PnPS IgG testing to assess immunocompetence [receiver operating characteristic (ROC) analysis of post-immunization samples: anti-PnPS IgA + IgG area under the curve (AUC) = 0.80, 95% confidence interval (CI) = 0.63-0.97; anti-PnPS IgM + IgG AUC 0.80, 95% CI = 0.62-0.98; anti-PnPS IgA + IgG + IgM AUC = 0.71, 95% CI = 0.51-0.91; anti-PnPS IgG AUC = 0.93, 95% CI = 0.85-1.00]. Our data show that patients classified as having an intact antibody response based on measurement of serotype-specific PnPS IgG can still display impaired anti-PnPS IgM and IgA responses, and that the additional measurement of anti-PnPS IgA and IgM could not reduce the need for serotype-specific IgG testing. Future studies are needed to investigate the clinical relevance of potential 'specific IgA or IgM antibody deficiency' in patients with recurrent airway infections in whom no PAD could be diagnosed according to the current definitions.

Keywords: ELISA; Pneumovax; anti-pneumococcal polysaccharide IgA; anti-pneumococcal polysaccharide IgG; anti-pneumococcal polysaccharide IgM; antibody deficiency; pneumococcal polysaccharide response; pneumococcal vaccination response; serotype-specific assay.

FIGURE 1

Pre‐ (a) and post‐immunization (b) anti‐pneumococcal polysaccharide (PnPS) immunoglobulin (Ig)A and IgM titres distinguished four immunological groups: (1) IgA/IgM both decreased, (2) only IgA decreased, (3) only IgM decreased and (4) IgA/IgM both normal [the lower limit of the normal range (LLNR) cut‐offs: 6 U/ml for pre‐ and 78 U/ml for post‐immunization anti‐PnPS IgA; 15 U/ml for pre‐ and 60 U/ml for post‐immunization anti‐PnPS IgM, according to Parker et al. [13]). Poor serotype‐specific PnPS IgG responders are coloured grey; good serotype‐specific PnPS IgG responders are coloured black. In Fig. 1a, the anti‐PnPS IgA values of two samples have been rounded from 0.0 to 0.1 U/ml to make these points visible in the logarithmic scale

FIGURE 2

Patients previously classified as ‘no PAD’ based on their immunoglobulin (Ig)G response, with abnormal results in the anti‐pneumococcal polysaccharide (PnPS) IgA and/or IgM assays. Abbreviations: PAD, primary antibody deficiency; PID, primary immunodeficiency; RTI, respiratory tract infections; sIgAdef, selective IgA deficiency; sIgMdef, selective IgM deficiency; unPAD, unclassified primary antibody deficiency

FIGURE 3

Pre‐ and post‐immunisation cumulative anti‐pneumococcal polysaccharide (PnPS) immunoglobulin (Ig)M, IgA and IgG titres for good (black dots) and poor (grey dots; outliers marked as open circles) responders as assessed by serotype‐specific PnPS IgG testing. P‐values were calculated with Mann–Whitney U‐tests

FIGURE 4

Receiver operating characteristic (ROC) curves of sensitivity versus specificity for the sum of Z‐scores of pre‐ and 4–8 weeks post‐immunization pneumococcal immunoglobulins versus serotype‐specific immunoglobulin (Ig)G response to vaccination: (a) anti‐PnPS IgG + IgA Z‐scores, (b) anti‐PnPS IgG + IgM Z‐scores, (c) anti‐PnPS IgG + IgA + IgM Z‐scores