Inflammatory sub-phenotypes in sepsis: relationship to outcomes, treatment effect and transcriptomic sub-phenotypes

Antcliffe, David; Mi, Yuxin; Santhakumaran, Shalini; Burnham, Katie L; Prevost, A. Toby; Ward, Josie K; Marshall, Timothy; Bradley, Claire; Al-Beidh, Farah; Hutton, Paula; McKechnie, Stuart; Davenport, Emma E; Hinds, C. J.; O'Kane, Cecilia M; McAuley, Daniel F.; Shankar-Hari, Manu; Gordon, Anthony; Knight, Julian C.

doi:10.1101/2022.07.12.22277463

Cited by 3 publications

(2 citation statements)

References 43 publications

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“…Sixty-five inflammatory mediators were measured in 204 samples from 146 patients from the GAinS study using the ProcartaPlex™ Luminex platform (ThermoFisher Scientific, Waltham, MA, USA), as has been described previously (Antcliffe et al, 2022). Briefly, plasma samples were measured across three 96-well plates with data acquired on Luminex 100 system.…”

Section: Star Methodsmentioning

confidence: 99%

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in response

Burnham

Charles

et al. 2022

Preprint

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Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is an unmet global health challenge. Here we apply high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (non-infected critical illness, post-operative inflammation and healthy volunteers) involving 2622 samples and 4553 liquid chromatography-mass spectrometry analyses in a single batch, at 100 samples/day. We show how this scale of data can establish shared and specific proteins, pathways and co-expression modules in sepsis, and be integrated with paired leukocyte transcriptomic data (n=837 samples) using matrix decomposition. We map the landscape of the host response in sepsis including changes over time, and identify features relating to etiology, clinical phenotypes and severity. This work reveals novel subphenotypes informative for sepsis response state, disease processes and outcome, highlights potential biomarkers, pathways and processes for drug targets, and advances a systems-based precision medicine approach to sepsis.

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Section: Star Methodsmentioning

confidence: 99%

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in response

Burnham

Charles

et al. 2022

Preprint

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“…A version of this manuscript has been made available on a preprint server 24 ( https://doi.org/10.1101/2022.07.12.22277463 ).…”

Section: Introductionmentioning

confidence: 99%

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes

Antcliffe,

Mi,

Santhakumaran

et al. 2024

Thorax

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RationaleHeterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported.ObjectivesWe investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes.MethodsHierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters.Measurements and main resultsWe identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes.ConclusionsThese findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes.Trial registration numberISRCTN20769191,ISRCTN12776039.

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High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response

Mi,

Burnham,

Charles

et al. 2024

Sci. Transl. Med.

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Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography–mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis.

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Inflammatory sub-phenotypes in sepsis: relationship to outcomes, treatment effect and transcriptomic sub-phenotypes

Cited by 3 publications

References 43 publications

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in response

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in response

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response

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