Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis
(2026) In Critical Care 30(1).- 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... (More)
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.
(Less)
- author
- Villa, Antoine
; Dewar, Fiona
; Pisciotta, Walter
; Rai, Ankit
; Kerneis, Sven
; Batum, Gül
; McDonnell, Tom
; Scully, Marie
; McHugh, Timothy D.
; Hilpert, Kai
; Gilroy, Derek
; de Nooijer, Aline
; Netea, Mihai G.
; Hedetoft, Morten
; Bermejo-Martin, Jesús F.
; Akatsuka, Masayuki
; Heinz, Corina C.
; Venet, Fabienne
; Monneret, Guillaume
; Meessen, Jennifer
; Cheng, Tzu Hsuan
; Zhang, Ming
; Caironi, Pietro
; Giamarellos-Bourboulis, Evangelos J.
; de la Torre Terrón, Mari C.
; Ebelt, Henning
; Rademaker, Emma
; Bodelsson, Mikael
LU
; Tverring, Jonas
LU
; Mi, Yuxin
; Knight, Julian C.
; Lindsey, Merry L.
; Langley, Raymond J.
; Kingsmore, Stephen F.
; Brealey, Dave
; Singer, Mervyn
and Arulkumaran, Nishkantha
(Less) - organization
- publishing date
- 2026
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Complement, Humoral immunity, ICU, Immunoglobulins, Mortality, Sepsis
- in
- Critical Care
- volume
- 30
- issue
- 1
- article number
- 41
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:41430733
- scopus:105028423711
- ISSN
- 1364-8535
- DOI
- 10.1186/s13054-025-05758-0
- language
- English
- LU publication?
- yes
- id
- 86b59209-f020-41ac-8370-5ab545fb9f8d
- date added to LUP
- 2026-02-17 14:29:44
- date last changed
- 2026-04-29 02:45:26
@article{86b59209-f020-41ac-8370-5ab545fb9f8d,
abstract = {{<p>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.</p>}},
author = {{Villa, Antoine and Dewar, Fiona and Pisciotta, Walter and Rai, Ankit and Kerneis, Sven and Batum, Gül and McDonnell, Tom and Scully, Marie and McHugh, Timothy D. and Hilpert, Kai and Gilroy, Derek and de Nooijer, Aline and Netea, Mihai G. and Hedetoft, Morten and Bermejo-Martin, Jesús F. and Akatsuka, Masayuki and Heinz, Corina C. and Venet, Fabienne and Monneret, Guillaume and Meessen, Jennifer and Cheng, Tzu Hsuan and Zhang, Ming and Caironi, Pietro and Giamarellos-Bourboulis, Evangelos J. and de la Torre Terrón, Mari C. and Ebelt, Henning and Rademaker, Emma and Bodelsson, Mikael and Tverring, Jonas and Mi, Yuxin and Knight, Julian C. and Lindsey, Merry L. and Langley, Raymond J. and Kingsmore, Stephen F. and Brealey, Dave and Singer, Mervyn and Arulkumaran, Nishkantha}},
issn = {{1364-8535}},
keywords = {{Complement; Humoral immunity; ICU; Immunoglobulins; Mortality; Sepsis}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Critical Care}},
title = {{Systematic review and meta-analysis of humoral immunity proteins and mortality in sepsis}},
url = {{http://dx.doi.org/10.1186/s13054-025-05758-0}},
doi = {{10.1186/s13054-025-05758-0}},
volume = {{30}},
year = {{2026}},
}