Sepsis in Oncology Patients

Study Overview
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Brief Summary
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The overall objective of this prospective observational study is to address the significant knowledge gap that exists around the impact of immune dysfunction on the development and survival from sepsis in patients with cancer. This proposal primarily focuses on establishing the transcriptomic immune profiles of sepsis patients with a background of cancer. This analysis will be complemented with in vitro functional analyses, and in addition will commence a collection of genome-wide data, including a focus on predicting white cell number and function in health. Uniquely, the investigators propose to establish a robust link between these analyses: transcriptomic, in vitro, and genome-wide, to enable them to comprehensively explore septic oncology patient 'immune phenotypes' and effectively identify novel exploitable therapeutic pathways. To this end, this project will collect, analyse and/or sequence DNA, RNA, leukocytes and soluble materials from a cohort of oncology patients presenting to intensive care with sepsis. This cohort will include all-comers with an oncological background but will also focus on two core groups at high risk of sepsis where baseline samples can also be sought prior to major immunosuppressive events in the cancer pathway. These are: Oesophageal/upper gastrointestinal (GI) cancer patients prior to systemic anticancer therapy initiation or surgery Haematological malignancy patients prior to stem cell transplantation. These sub-cohorts will provide a previously unexplored unique insight into the role of pre-existing patient transcriptomic phenotypes.

Detailed Description
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The specific aims will be to perform multi-modal parallel immune phenotyping to determine: The transcriptomic (RNA) phenotypes (or 'signatures') of cancer patients with sepsis The association of these transcriptomic phenotypes with: Leukocyte function in sepsis, as quantified by cell surface and functional assays and plasma soluble mediator content Pre-existing genomic determinants such as leukocyte numbers Severity of, and outcome from, sepsis in oncology patients

Official Title
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Investigation Into the Transcriptomic and Functional Profile of SEPsis in ONCology Patients

Conditions
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Sepsis in Cancer Patients

Intervention / Treatment
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* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Sepsis cohort: Inclusion Criteria: Patients admitted to ICU with a diagnosis of sepsis as per 'Sepsis-3' definitions with a SOFA score [REF] ≥2 secondary to infection from any source ≥18 years of age Written consent from patient, personal or professional consultee, or deferred consent if none of the above available at admission Sepsis cohort Exclusion Criteria: • Death deemed imminent by the clinical team Elective cohort inclusion criteria Patients undergoing elective major upper GI surgery (oesophago+/-gastrectomy) or stem cell transplant for haematological malignancy ≥18 years of age Written consent from patient Elective cohort exclusion criteria • Limitations in place regarding provision of treatment and/or organ support e.g., palliative patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sepsis cohort<br>Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection. | Other: No intervention<br>* No intervention<br>|
| Elective cohort<br>Elective pre-operative upper GI surgical patients or elective stem cell transplant patients will be consented and enrolled at baseline, immediately prior to these procedures. If they go on to develop sepsis within 60 days of their surgery, they will go on to be sampled as per the sepsis cohort | Other: No intervention<br>* No intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of circulating leukocyte transcriptomic phenotypes relating to mortality in sepsis patients with a background of cancer, (in comparison to those previously identified in non-immunosuppressed patients). | Identification of circulating leukocyte transcriptomic phenotypes relating to mortality in sepsis patients with a background of cancer, (in comparison to those previously identified in non-immunosuppressed patients). | end of trial (4 years) | 
| 28 day mortality | 28 day mortality | end of recruitment (3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in the trajectory of transcriptomic phenotypes of patients admitted to ICU with sepsis, and how they relate to severity scorings and mortality/morbidity outcomes | how they relate to severity scorings and mortality/morbidity outcomes | end of trial (4 years) | 
| Differences in the trajectory of functional phenotypes of patients admitted to ICU with sepsis, and how they relate to severity scorings and mortality/morbidity outcomes | how they relate to severity scorings and mortality/morbidity outcomes | end of trial (4 years) | 
| Differences in the trajectory of genomic phenotypes of patients admitted to ICU with sepsis, and how they relate to severity scorings and mortality/morbidity outcomes | how they relate to severity scorings and mortality/morbidity outcomes | end of trial (4 years) | 
| Identification of differences in transcriptomic phenotypes between patient subgroups and on comparison to non-immunosuppressed sepsis patients. Comparison in length of stay measures and quality of life parameters | Comparison in length of stay measures and quality of life parameters | end of trial (4 years) | 
| Identification of differences in functional phenotypes between patient subgroups and on comparison to non-immunosuppressed sepsis patients. Comparison in length of stay measures and quality of life parameters | Comparison in length of stay measures and quality of life parameters | end of trial (4 years) | 
| Identification of differences in genomic phenotypes between patient subgroups and on comparison to non-immunosuppressed sepsis patients. Comparison in length of stay measures and quality of life parameters | Comparison in length of stay measures and quality of life parameters | end of trial (4 years) |