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Meta-Analysis
. 2025 Dec 22;30(1):41.
doi: 10.1186/s13054-025-05758-0.

Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis

Antoine Villa  1 , Fiona Dewar  1 , Walter Pisciotta  1   2 , Ankit Rai  1 , Sven Kerneis  1 , Gül Batum  1 , Tom McDonnell  3 , Marie Scully  4 , Timothy D McHugh  5 , Kai Hilpert  6 , Derek Gilroy  7 , Aline de Nooijer  8 , Mihai G Netea  8 , Morten Hedetoft  9 , Jesús F Bermejo-Martin  10 , Masayuki Akatsuka  11 , Corina C Heinz  12 , Fabienne Venet  13   14 , Guillaume Monneret  14 , Jennifer Meessen  15 , Tzu Hsuan Cheng  16 , Ming Zhang  16   17 , Pietro Caironi  15   18 , Evangelos J Giamarellos-Bourboulis  19 , Mari C de la Torre Terrón  20 , Henning Ebelt  21 , Emma Rademaker  22 , Mikael Bodelsson  23 , Jonas Tverring  23 , Yuxin Mi  24 , Julian C Knight  24 , Merry L Lindsey  25   26 , Raymond J Langley  27 , Stephen F Kingsmore  28 , Dave Brealey  1 , Mervyn Singer  1 , Nishkantha Arulkumaran  29
Affiliations
Meta-Analysis

Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis

Antoine Villa et al. Crit Care. .

Abstract

Purpose: Humoral 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.

Methods: We 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.

Results: Thirty-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.

Conclusion: Sepsis 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.

Keywords: Complement; Humoral immunity; ICU; Immunoglobulins; Mortality; Sepsis.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. This study was a systematic review and meta-analysis based on previously published studies and de-identified, publicly available datasets (e.g., MIMIC-IV). For all included studies, the original investigators confirmed that appropriate ethical approvals and informed consent were obtained. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
PRISMA flowchart. Flowchart of included and excluded trials
Fig. 2
Fig. 2
Meta-analysis of complement proteins in patients with sepsis. Forest plots comparing the levels of different complement proteins between survivors and non-survivors in the ICU. Each individual study is represented by a square, with its size proportional to the study's weight in the meta-analysis. Horizontal bars indicate 95% confidence intervals. The blue diamond represents the pooled effect estimate from the random-effects model. Heterogeneity values (I²) are provided for each analysis
Fig. 3
Fig. 3
Meta-analysis of immunoglobulins in patients with sepsis. Forest plots comparing the levels of different immunoglobulin proteins between survivors and non-survivors in the ICU. Each individual study is represented by a square, with its size proportional to the study's weight in the meta-analysis. Horizontal bars indicate 95% confidence intervals. The blue diamond represents the pooled effect estimate from the random-effects model. Heterogeneity values (I²) are provided for each analysis
See this image and copyright information in PMC

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