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Purpose <p>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.</p> Methods <p>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.</p> Results <p>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 (<i>n</i> = 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Antoine Villa,
  • Fiona Dewar,
  • Walter Pisciotta,
  • Ankit Rai,
  • Sven Kerneis,
  • Gül Batum,
  • Tom McDonnell,
  • Marie Scully,
  • Timothy D. McHugh,
  • Kai Hilpert,
  • Derek Gilroy,
  • Aline de Nooijer,
  • Mihai G. Netea,
  • Morten Hedetoft,
  • Jesús F. Bermejo-Martin,
  • Masayuki Akatsuka,
  • Corina C. Heinz,
  • Fabienne Venet,
  • Guillaume Monneret,
  • Jennifer Meessen,
  • Tzu Hsuan Cheng,
  • Ming Zhang,
  • Pietro Caironi,
  • Evangelos J. Giamarellos-Bourboulis,
  • Mari C. de la Torre Terrón,
  • Henning Ebelt,
  • Emma Rademaker,
  • Mikael Bodelsson,
  • Jonas Tverring,
  • Yuxin Mi,
  • Julian C. Knight,
  • Merry L. Lindsey,
  • Raymond J. Langley,
  • Stephen F. Kingsmore,
  • Dave Brealey,
  • Mervyn Singer,
  • Nishkantha Arulkumaran

摘要

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.