Challenges in investigating patients with isolated decreased serum IgM: The SIMcal study

Abstract

The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM-deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centres) to our previously published Dutch cohort (secondary centre). Fifteen centres (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age-matched cut-off values varied widely between centres; when using the ESID diagnostic protocol reference values, only six patients (five adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22-0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30-0.36; P = 0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found.

Keywords: primary immunodeficiency; primary selective IgM deficiency; unclassified antibody deficiency.

Figure 1

Centre‐specific age‐matched cut‐off values of serum IgM (g/L) Each line represents the lower limit of normal for serum IgM used by a centre. The grey area represents serum IgM levels which are decreased according to the ESID diagnostic protocol values.19 The first serum IgM levels of the ten patients with true sIgMdef according to centre‐specific cut‐off values are plotted (C1,2,4 from Belgium; C3 from Iran; C5, A3 from the Netherlands; A1,2,4,5 from the Czech Republic). Of these, four patients were excluded when ESID diagnostic protocol values were used (shown in grey). ESID, European Society for Immunodeficiencies; sIgMdef, selective IgM deficiency

Figure 2

Gender distribution per age group in the patients with possible and true sIgMdef Light grey, male; dark grey, female. The number of children reported per country is shown for the male children. T, Turkey; Tu, Tunisia; I, Italy; B, Belgium; Ir, Iran; S, Spain; N, The Netherlands

Figure 3

First serum IgM levels in the children from the tertiary centre cohort A. The first serum IgM levels (y‐axis) and age at the date of the first serum sample (x‐axis). The grey dots represent the five children with true sIgMdef, and the red dots the 43 children with possible sIgMdef. The grey area in the graph represents decreased IgM levels according to the ESID diagnostic protocol values [18]. B. Mean first serum IgM levels + 95% CI in the different countries. sIgMdef, selective IgM deficiency

Figure 4

Classification of patients with decreased serum IgM in the tertiary (n = 98) and secondary (n = 359) centre cohorts Abbreviations: sIgMdef, selective IgM deficiency; unPAD, unclassified primary antibody deficiency

Figure 5

First serum IgM levels in the adults from the tertiary and secondary centre cohorts Tertiary centre cohort n = 13, blue; secondary centre cohort n = 42, yellow. The first serum IgM levels (y‐axis) and age at the date of first serum sample (x‐axis) (A). The grey area in the graph represents decreased IgM levels according to the ESID diagnostic protocol values [18]. Mean first serum IgM levels + 95% CI (g/L) in the different clinical manifestations of adults from both tertiary and secondary centres (B), and in those with (n = 30) and without (n = 25) symptoms that could be related to antibody deficiency (C). *Two‐sided t test; P < 0.05