IgM-enriched immunoglobulins (Pentaglobin) may improve the microcirculation in sepsis: a pilot randomized trial

Roberta Domizi,Simona Pantanetti,Elisa Damiani,Silvia Ciucani,Paolo Giaccaglia,Andrea Carsetti,Claudia Scorcella,Abele Donati,Erika Casarotta,Elena Lamura,Erica Adrario,Vincenzo Gabbanelli

doi:10.1186/s13613-019-0609-5

Roberta Domizi, Simona Pantanetti + Show 10 more

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https://doi.org/10.1186/s13613-019-0609-5

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Abstract

BackgroundPolyclonal or IgM-enriched immunoglobulins may be beneficial during sepsis as an adjuvant immunomodulatory therapy. We aimed to test whether the infusion of IgM-enriched immunoglobulins improves microvascular perfusion during sepsis.MethodsSingle-centre, randomized, double-blind, placebo-controlled phase II trial including adult patients with a diagnosis of sepsis or septic shock for less than 24 h. Patients received an intravenous infusion of 250 mg/kg (5 mL/kg) per day of IgM-enriched immunoglobulins (Pentaglobin, n = 10) for 72 h or placebo (NaCl 0.9%, n = 9). At baseline and after 24 and 72 h of infusion, the sublingual microcirculation was assessed with Incident Dark Field videomicroscopy. Thenar near-infrared spectroscopy (NIRS) was applied with a vascular occlusion test to assess tissue oxygenation and microvascular reactivity. Levels of interleukin (IL) 1-beta, IL-6, IL-8, IL-10 and tumour necrosis factor alpha were measured in the serum.ResultsThe perfused vessel density (PVD) for small vessels (diameter < 20 micron) increased in the Pentaglobin group (from 21.7 ± 4.7 to 25.5 ± 5.1 mm/mm2) and decreased in the placebo group (from 25 ± 5.8 to 20.7 ± 4.1 mm/mm2, p for interaction < 0.001, two-way analysis of variance). The absolute between-group difference at 72 h was 4.77 (standard error 2.34), p = 0.140. The microvascular flow index for small vessels increased at 24 h in the Pentaglobin group (from 2.68 [2.38–2.78] to 2.93 [2.82–3], p < 0.01) and decreased at 72 h in the placebo group (from 2.83 [2.60–2.97] to 2.67 [2.48–2.73], p < 0.05). Changes in general parameters, cytokines and NIRS-derived parameters were similar between the two groups, except for IL-6 and IL-10 that significantly decreased at 72 h only in the Pentaglobin group.ConclusionsA 72-h infusion of IgM-enriched immunoglobulins (Pentaglobin) in patients with sepsis or septic shock may be associated with an increase in sublingual microvascular perfusion. Further studies are needed to confirm our findings.Trial registration NCT02655133, www.ClinicalTrials.gov, date of registration 7th January 2016, https://www.clinicaltrials.gov/ct2/show/NCT02655133.

Highlights

Polyclonal or immunoglobulin M (IgM)-enriched immunoglobulins may be beneficial during sepsis as an adjuvant immunomodulatory therapy
The administration of polyclonal or IgM-enriched immunoglobulins as an adjuvant immunomodulatory therapy gave encouraging results in both pre-clinical and clinical studies [6], the evidence supporting a reduction in mortality is still too weak to justify a widespread use in septic patients [7]
Since we found significant inter-individual variability in microcirculatory parameters at baseline, we performed a secondary analysis by calculating the delta values in each group and performed an analysis of covariance (ANCOVA) for repeated measures to evaluate the interaction between the factors “time” and “treatment” by controlling for the baseline value of the outcome of interest, with the Bonferroni post hoc test to assess differences between the two group at each time-point

Summary

Introduction

Polyclonal or IgM-enriched immunoglobulins may be beneficial during sepsis as an adjuvant immunomodulatory therapy. A recent meta-analysis showed a significant reduction in circulating B cells and immunoglobulin M (IgM) levels in sepsis non-survivors as compared to survivors [5]. The administration of polyclonal or IgM-enriched immunoglobulins as an adjuvant immunomodulatory therapy gave encouraging results in both pre-clinical and clinical studies [6], the evidence supporting a reduction in mortality is still too weak to justify a widespread use in septic patients [7]. The potential benefits of immunoglobulins (especially IgM-enriched preparations) are related to their anti-inflammatory activity (pathogen recognition and clearance, toxin scavenging, inhibition of inflammatory mediators production, cytokine neutralization, complement-scavenging properties) and to their antiapoptotic effects on immune cells [8]. No clinical studies exist that evaluated the microvascular effects of immunoglobulins in septic patients

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