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

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

doi:10.1186/s13054-025-05758-0

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

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^*

^*Corresponding author for this work

Sepsis and Inflammation

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Journal	Critical Care
Volume	30
Early online date	22 Dec 2025
DOIs	https://doi.org/10.1186/s13054-025-05758-0
Publication status	Published - 26 Jan 2026

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Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsisFinal published version, 2.06 MBLicence: CC BY

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Villa, A., Dewar, F., Pisciotta, W., Rai, A., Kerneis, S., Batum, G., McDonnell, T., Scully, M., McHugh, T. D., Hilpert, K., Gilroy, D., de Nooijer, A., Netea, M. G., Hedetoft, M., Bermejo-Martin, J. F., Akatsuka, M., Heinz, C. C., Venet, F., Monneret, G., ... Arulkumaran, N. (2026). Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis. Critical Care, 30. https://doi.org/10.1186/s13054-025-05758-0

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title = "Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis",

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.",

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

note = "{\textcopyright} 2025. The Author(s).",

year = "2026",

month = jan,

day = "26",

doi = "10.1186/s13054-025-05758-0",

language = "English",

volume = "30",

journal = "Critical Care",

issn = "1466-609X",

publisher = "Springer Science + Business Media",

}

Villa, A, Dewar, F, Pisciotta, W, Rai, A, Kerneis, S, Batum, G, McDonnell, T, Scully, M, McHugh, TD, Hilpert, K, Gilroy, D, de Nooijer, A, Netea, MG, Hedetoft, M, Bermejo-Martin, JF, Akatsuka, M, Heinz, CC, Venet, F, Monneret, G, Meessen, J, Cheng, TH, Zhang, M, Caironi, P, Giamarellos-Bourboulis, EJ, de la Torre Terrón, MC, Ebelt, H, Rademaker, E, Bodelsson, M, Tverring, J, Mi, Y, Knight, JC, Lindsey, ML, Langley, RJ, Kingsmore, SF, Brealey, D, Singer, M & Arulkumaran, N 2026, 'Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis', Critical Care, vol. 30. https://doi.org/10.1186/s13054-025-05758-0

TY - JOUR

T1 - Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis

AU - Villa, Antoine

AU - Dewar, Fiona

AU - Pisciotta, Walter

AU - Rai, Ankit

AU - Kerneis, Sven

AU - Batum, Gül

AU - McDonnell, Tom

AU - Scully, Marie

AU - McHugh, Timothy D

AU - Hilpert, Kai

AU - Gilroy, Derek

AU - de Nooijer, Aline

AU - Netea, Mihai G

AU - Hedetoft, Morten

AU - Bermejo-Martin, Jesús F

AU - Akatsuka, Masayuki

AU - Heinz, Corina C

AU - Venet, Fabienne

AU - Monneret, Guillaume

AU - Meessen, Jennifer

AU - Cheng, Tzu Hsuan

AU - Zhang, Ming

AU - Caironi, Pietro

AU - Giamarellos-Bourboulis, Evangelos J

AU - de la Torre Terrón, Mari C

AU - Ebelt, Henning

AU - Rademaker, Emma

AU - Bodelsson, Mikael

AU - Tverring, Jonas

AU - Mi, Yuxin

AU - Knight, Julian C

AU - Lindsey, Merry L

AU - Langley, Raymond J

AU - Kingsmore, Stephen F

AU - Brealey, Dave

AU - Singer, Mervyn

AU - Arulkumaran, Nishkantha

PY - 2026/1/26

Y1 - 2026/1/26

N2 - 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.

AB - 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.

U2 - 10.1186/s13054-025-05758-0

DO - 10.1186/s13054-025-05758-0

M3 - Article

C2 - 41430733

SN - 1466-609X

VL - 30

JO - Critical Care

JF - Critical Care

ER -

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

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