IgM-enriched immunoglobulin human 5g/100ml solution for infusion vials

BackgroundSepsis is a major cause of mortality and morbidity globally, with around one-quarter of all sepsis-related deaths occurring in children under the age of 5. We conducted a meta-analysis and systematic review of the literature to evaluate the clinical effectiveness of an IgM-enriched immunoglobulin preparation in pediatrics patients and neonates with sepsis.MethodsSystematic searches of PubMed, the Cochrane Library and Embase databases were performed in November 2022, with no date limitations, to identify studies in which IgM-enriched immunoglobulin was used as adjunctive therapy in neonatal and pediatric patients with sepsis.ResultsIn total, 15 studies fulfilled the eligibility criteria, 13 neonatal studies and 2 pediatric studies. Pooled estimates from all studies indicated that mortality rates were significantly lower in patients who received treatment with the IgM-enriched immunoglobulin compared with controls (OR 0.41; 95% CI 0.32–0.55). Further analyses in neonatal studies, alone, showed a significant benefit with longer treatment durations (>3 days) vs. the recommended treatment duration (3 days) (OR 0.32; 95% CI 0.22–0.47) vs. (OR 0.61; 95% CI 0.41–0.92). Treatment with IgM-enriched immunoglobulin was associated with a lower mortality risk compared with controls in prospective studies vs. retrospective analyses (OR 0.37; 95% CI 0.27–0.51) vs. (OR 0.73; 95% CI 0.41–1.30).ConclusionsThis systematic review suggests that adjunctive treatment with IgM-enriched immunoglobulin may reduce the risk of mortality in neonatal and pediatric populations. However, large randomized controlled trials are required to further substantiate and evaluate these findings.

Abstract licence: CC BY 4.0

PurposeHumoral immunity proteins-immunoglobulins, complement proteins, and antimicrobial peptides-have key antimicrobial and immunomodulatory functions in sepsis. We hypothesised that their circulating levels are lower in non-survivors, potentially resulting in impaired bacterial clearance and persistent or recurrent infections.MethodsWe performed a systematic review and meta-analysis evaluating differences in humoral immunity proteins between survivors and non-survivors in adult patients with sepsis. PubMed and Embase were searched without date restrictions. Random-effects meta-analyses were used to estimate pooled standardised mean differences (SMD) with 95% confidence intervals (CI). Sensitivity analyses included data from the MIMIC-IV ICU database, and further supplemented by three proteomic studies.ResultsThirty-six studies including 6,330 patients were analysed. Thirteen reported on immunoglobulins, 17 on complement proteins, and 7 on the antimicrobial peptide heparin-binding protein (HBP). Survivors had significantly higher levels of complement proteins C3 (SMD 0.53 [0.07-0.99]) and C4 (SMD 0.51 [0.09-0.94]) compared to non-survivors. Conversely, C4a (SMD - 1.17 [-1.77 to - 0.56]) and IgA (SMD - 0.21 [-0.39 to - 0.03]) were significantly lower in survivors. No differences were found for IgG (SMD 0.00 [-0.18 to 0.18]), IgM (SMD - 0.02 [-0.13 to 0.08]), C5, C5a, or HBP. Sensitivity analyses using MIMIC-IV (n = 2,452) and proteomic datasets supported these findings. Proteomic data revealed early depletion of classical complement components (C3, C4B) and regulatory proteins in non-survivors.ConclusionSepsis non-survivors exhibit lower C3 and C4 levels and higher C4a, consistent with complement activation and/or depletion. Complement proteins may serve as potential biomarkers and therapeutic targets in sepsis.

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ObjectiveTo provide an updated systematic review and meta-analysis of the estimated pooled of anti-Annexin A5 antibodies (AnxA5-Abs) and Annexin A5 resistance (A5R) across antiphospholipid syndrome (APS) phenotypes.MethodsPubMed, EMBASE, and the Cochrane Library were searched from inception to June 2018 and updated in August 2025. Eligible studies included adults tested for AnxA5-Abs (IgG/IgM) and/or A5R who fulfilled revised Sapporo/Sydney APS clinical criteria. Pooled prevalences were estimated using Freeman-Tukey random-effects models and stratified by phenotype, serologic status, and autoimmune disease. Univariable and multivariable meta-regression evaluated predictors of IgG AnxA5-Abs and A5R. The protocol was registered in PROSPERO (CRD42018099462).ResultsFifty-eight studies were included, comprising 6960 patients and 2417 controls. In obstetric APS cohorts, pooled IgG AnxA5-Abs prevalence was 21.2% (95% CI 7.4-39.2) versus 4.0% (1.7-7.1) in controls; thrombotic APS showed 10.3% (5.7-15.8). IgM AnxA5-Abs were less frequent and showed weaker associations. IgG AnxA5-Abs prevalence was higher in seropositive APS (27.1%) and seronegative APS (20.4%) than in mixed/unstratified APS (11.7%). Among systemic lupus erythematosus (SLE) patients with APS-related clinical manifestations, IgG AnxA5-Abs prevalence was 31.7% versus 16.3% in SLE controls without clinical APS manifestations. A5R prevalence was higher in obstetric (29.9%) and thrombotic APS (28.8%) than in controls (17.5%). Obstetric APS independently predicted higher IgG AnxA5-Abs prevalence.ConclusionIgG AnxA5-Abs and A5R are enriched in Sapporo-defined obstetric APS, with weaker and less consistent associations in thrombosis-only APS. These findings support the biological plausibility of AnxA5 disruption in obstetric APS and identify AnxA5-related biomarkers as promising candidates for future validation. However, prospective external validation using standardized assays, pre-specified thresholds, and demonstration of incremental prognostic value are essential prerequisites before clinical risk stratification use.

Abstract licence: CC BY-NC-ND

Introduction In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. Methods and analysis The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. Ethics and dissemination The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell’Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. Trial registration details The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov ( NCT04182737 ) on 2 December 2019.

Abstract licence: CC BY-NC 4.0