IgA and IgM-enriched Immunoglobulins in Primary Immunodeficiencies: a Pilot Study

Abstract

Purpose: Despite well-conducted replacement therapy with polyvalent immunoglobulins (IgRT), some patients with primary immunodeficiencies (PID) continue to experience recurrent or chronic infections. IgA and IgM, essential for mucosal and complement-mediated immunity, are absent or minimal in standard immunoglobulin products. The aim of this study is to evaluate the safety and clinical evolution profiles in PID patients with undetectable IgA/IgM levels and persistent infections despite standard IgRT, after introduction of an IgA- and IgM-enriched immunoglobulin preparation (IgGAM, Pentaglobin^®).

Methods: A compassionate use program (CUP) in France enrolled 20 PID patients with undetectable IgA/IgM levels, receiving IgGAM IV infusions every 7-14 days. Tolerance, infection frequency, hospitalizations, and biological markers (Ig levels, complement activation, salivary IgA) were analyzed prospectively.

Results: Twenty patients were included in the CUP at the time of analysis. No severe adverse event was reported. Half of the patients experienced mild to moderate hypersensitivity symptoms. Mean antibiotic courses dropped from 5.4 to 2.3/year (p = 0.0009) and mean number of hospitalizations decreased from 2.6 to 1.2/year (p = 0.01). Median serum IgA and IgM levels increased three months after IgGAM start. IgM and low levels of IgA were detected in saliva samples, suggesting at least a transient transfer of IgA/IgM from IgGAM into mucosal fluids.

Conclusion: In patients with severe PID and undetectable IgA/IgM, IgGAM was associated with reduced infections and hospitalizations. Controlled studies are needed to confirm the benefit of IgA/M enriched immunoglobulin preparations in PID patients with persistent and/or recurrent respiratory or digestive infections.

Keywords: IgA and IgM-enriched immunoglobulin; Immunoglobulin A; Immunoglobulin M; Inborn errors of immunity; Polyvalent immunoglobulins; Primary immunodeficiency.

Fig. 1

Flow chart of the study. *Stopped after 5 infusions. **Death linked to multifactorial chronic bronchopathy with infection sequela and graft versus host disease after 6 infusions. ***Stopped after 1 infusion. **** Stopped after 6 infusions in the context of progressive multifocal leukoencephalopathy and mild adverse events

Fig. 2

Complement activation assays with IgGAM. (A) In vitro complement activation tests. Serum samples from healthy controls were incubated for 30 minutes at 37 °C with a negative control (PBS), a conventional IgP (Clairyg®), or Pentaglobin®. The complement split product sC5b9 was measured to assess activation of the complement pathway. A paired Wilcoxon test was used to compare sC5b9 levels after incubation with PBS, IgP and Pentaglobin®. (B) In vivo complement assessment before and after Pentaglobin® infusion. Plasma samples were collected from 3 patients immediately before and after several Pentaglobin® infusions. Complement activation was assessed by measuring CH50, C3, C4, and the complement split products sC5b9 and Bb. Each patient is represented by a different color. A Wilcoxon test was used to compare individual values before and after each IgP infusion. For CH50, C3 and C4, the dotted line represents the lower limit of the normal range. For complement split products sC5b9 and Bb, the dotted line represents the upper limit of the normal range. (C) Comparison of complement system activation following infusion in patients with immunodeficiency receiving with standard IgP (n=9 patients, n=9 infusions) or IgGAM (n=3 patients, n = 18 total infusions, Pentaglobin®). Results are presented as fold changes between pre- and post-infusion values. Mann–Whitney tests were used to compare these fold changes between the two treatment groups. * p ≤ 0.05; ** p ≤ 0.01; **** p ≤ 0.0001

Fig. 3

Clinical evolution under IgGAM. (A) Evolution of all infectious events number (at-home antibiotic treatments + hospitalizations for infection) before and after a median time of 7 months under IgGAM. A complete response was defined as no requirement for at-home antibiotic treatment and no hospitalization due to infection during the follow-up period of IgGAM use. A partial improvement was defined as a reduction of at least 25% in both the number of antibiotic courses and hospitalizations. (B) Number of at-home antibiotic courses, hospitalizations and hospitalization days for infection before and during IgGAM treatment.*p ≤ 0.05; ** p ≤ 0.01, *** p ≤ 0.001. Abbreviation: IgGAM: IgA and IgM-enriched immunoglobulin preparation

Fig. 4

Biological evolution under IgGAM. (A) IgG, IgA and IgM serum levels before, 3 months after IgGAM starting, and at last visit (n = 16). (B) IgA and IgM saliva levels in healthy controls (n = 11 for IgA, n = 8 for IgM), in patients before IgGAM, and in patients the day after IgGAM infusion (n = 5 for IgA, n = 4 for IgM). Data are presented as median with interquartile range.*** p ≤ 0.001. Abbreviation: D: day; IgGAM: IgA and IgM-enriched immunoglobulin preparation; HCs: healthy controls; M: month