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

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.

Focusing on Good Responders to Pneumococcal Polysaccharide Vaccination in General Hospital Patients Suspected for Immunodeficiency. A Decision Tree Based on the 23-Valent Pneumococcal IgG Assay.

Background and Aim: Recently, the 23-valent IgG-assay was suggested as screening assay to identify poor responders to pneumococcal polysaccharide (PnPS)-vaccination with the serotype-specific assay as a second-line test. However, in a low pre-test probability general hospital setting predicting good responders could be more valuable to reduce the number of samples needing serotyping. Methods: Serotype-specific PnPS antibody-assays were performed for suspected immunodeficiency in two Dutch general hospitals (Jeroen Bosch Hospital, 's-Hertogenbosch; Elisabeth Tweesteden Hospital, Tilburg). 23-Valent PnPS antibody-assays were subsequently performed in archived material. Data were analyzed using receiver operating characteristic curves (AUC) and agreement indices (ICC). Results: Sera of 284 patients (348 samples) were included; 23-valent IgG-titres and the corresponding sum of PnPS-serotype specific antibodies showed moderate correlation (ICC = 0.63). In 232 conjugated-pneumococcal-vaccine-naïve patients (270 samples), a random 23-valent IgG-titer could discriminate between samples with and without ≥7/11, ≥7/13, or ≥6/9 pneumococcal serotypes when both cut-off values 0.35 and 1.0 µg/ml were used (AUC 0.86 and 0.92, respectively). All patients with a pre-immunization-titer ≥38.2 µg/ml and/or post-immunization-titer ≥96.1 µg/ml and none with a post-immunization-titer ≤38.5 µg/ml exhibited a good response to PnPS vaccination. Using these breakpoints as screening test to predict good responders, only 24% of patients would require further serotyping, as opposed to 68% if breakpoints to predict poor responders would have been used. Conclusion: In a low pre-test probability setting, the 23-valent IgG-assay proved to be a reliable screening test for good responders in conjugated-pneumococcal-vaccine-naïve patients, reducing the overall number of patient samples needing further serotyping, thus reducing overall costs of pneumococcal vaccination response assessment.

Mild Hypogammaglobulinemia Can Be a Serious Condition.

Background: Most patients with primary antibody deficiency (PAD) suffer from less well-described and understood forms of hypogammaglobulinemia (unclassified primary antibody deficiency, unPAD). Because of the moderately decreased immunoglobulin levels compared to CVID, unPAD is generally considered to be clinically mild and not very relevant. Objective: To describe our cohort of-mainly-unPAD patients, and to analyze whether subgroups can be identified. Methods: Data were prospectively collected (February-2012 to June-2016) as part of a standardized, 1-day Care Pathway for suspected primary immunodeficiency. The TNO-AZL Questionnaire for Health-Related Quality of Life (HRQoL) was part of the pre-first-visit intake procedure. Results: Three hundred and twenty patients were referred to the Care Pathway. Data from 23/27 children and 99/113 adults who were diagnosed with PAD and gave informed consent were available for analysis. 89/99 adults had unPAD, the majority (74%) were female and 44% already showed bronchiectasis. HRQoL was significantly decreased in all domains, meaning that a lot of unPAD patients had to cope simultaneously with pain, negative feelings and impairments in cognition, home management tasks, sleep, social interaction, and work. The most prominently impaired HRQoL domain was vitality, indicating these patients feel extremely tired and worn out. Conclusion: These results highlight the need for more attention to the potential patient burden of unPADs. A larger cohort is needed to increase our understanding of unPADs and to analyze whether distinct subgroups can be identified. For now, it is important for the clinician to acknowledge the existence of unPAD and be aware of its potential consequences, in order to timely and appropriately manage its effects and complications.