Researching the Effects of Sepsis on Quality Of Life, Vitality, Epigenome and Gene Expression During RecoverY From Sepsis (REQOVERY)

Researching the Effects of Sepsis on Quality Of Life, Vitality, Epigenome and Gene Expression During RecoverY From Sepsis (REQOVERY)

Sepsis is a life-threatening dysregulated immune response to infection associated with multi-organ failure and a high mortality rate.While researchers have focused mainly on acute sepsis, post-sepsis care of survivors has long been neglected despite the observation that many sepsis survivors suffer from debilitating post-sepsis syndrome. This syndrome is characterized by frequent hospital readmissions and increased mortality due to persistent immune dysfunction, cardiovascular disease, and cognitive impairment, causing poor quality of life and a substantial burden on the healthcare system. Disconcertingly, the number of sepsis survivors at risk for hospital readmission continues to rise.7 Of the post-sepsis symptoms, post-sepsis immunosuppression is perhaps the most clinically important. While sepsis presents as an initial phase of hyperinflammation (a "cytokine storm"), it is followed by an immunosuppressive phase that is now understood to last weeks to months and predisposes survivors to lethal secondary infections and sepsis recurrence. A third of deaths eight years post-sepsis are caused by recurrent sepsis.We hypothesize that changes in the transcriptome and DNA methylome in immune cells of survivors might be the underlying driver for prolonged immunosuppression, and may also be correlated with long-term morbidity and mortality post-sepsis, as well as other symptoms of post-sepsis syndrome including PTSD and cardiovascular disease.

Study Overview

• Status: Enrolling by invitation
• Conditions: Sepsis; Infection
• Intervention / Treatment: Other: Exposure of interest: study DNA methylation (epigenetics) and gene expression (transcriptomics) of blood leukocytes

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients between 18-85 years old admitted to the emergency department (ED) of the University Medical Center Groningen (UMCG) with suspected sepsis according to the sepsis-3 criteria who survive their ED admission at three months. A control group will compose of age and sex-matched ED patients admitted for non-infectious causes. Both the septic patients and controls have already been enrolled in the Acutelines study.

Description

Inclusion criteria sepsis group:

• Adult patients, aged between 18 and 85 years
• Able to provide informed consent themselves or informed consent can be obtained via next of kin or legal guardian
• Included in Acutelines, where blood sample was drawn upon ED admission
• Satisfy the Sepsis-3 criteria for sepsis (Figure 2), combined with clinical suspicion of infection and/or fever (body temperature > 38.5°C)
• Survive at 3 months post discharge
• Inclusion criteria control group:Adult patients, aged between 18 and 85 years
• Able to provide informed consent themselves or informed consent can be obtained via next of kin or legal guardian
• Included in Acutelines, where blood sample was drawn upon ED admission
• Non-infectious reason of admission (specifically syncope, electrolyte disturbance, intoxication, gastro-intestinal bleeding)

4.3 Exclusion criteria

The participants should not meet any of the following exclusion criteria:

• Transfer from another hospital
• Emergency room visit in connection with accidental exposure of bodily material to patient ("needle stick injury")
• Visit an emergency room in connection with organ transplantation
• Discharged home without hospital admittance after ED visit
• Unable to give blood
• Immunosuppressive therapies such as corticosteroids (>10mg) or small molecule immune suppressants within the last three months, or biologicals administered within the last year
• Radiotherapy or systemic chemotherapy within the last three months
• Known pregnancy; the presence of pregnancy will be verified by asking the potential participant
• A hospitalization of more than 21 days

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DNA methylation (epigenetics) using the Illumina MethylationEPIC kit. Changes in DNA methylation at gene promoter/enhancer sites will be correlated through the NetworkAnalyst platform.	The primary objective of the current project is to measure changes in DNA methylation (i.e. epigenetics) of blood leukocytes between sepsis survivors at ED admission and three months after hospital discharge.	baseline versus 3 months follow up
Gene expression (transcriptomics/qPCR) will be measured using the Illumina Hi-Seq instrument. Differential gene expression will be correlated through the NetworkAnalyst platform.	The primary objective of the current project is to measure changes in gene expression (i.e. transcriptomics) of blood leukocytes between sepsis survivors at ED admission and three months after hospital discharge.	baseline versus 3 months follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nutrition status measured with PS-SGA Short Form and SNAQ form. (both questionnaires)	study the association between epigenetic and transcriptomic signatures in sepsis and survivors with nutrition status. PS-SGA short form looks at weight loss, upper arm circumference, apetite and functionallity. PS-SGA short form scores weight, food intake, symptoms, activities and functionalilyti (nummeric; 0-52).	3 months
Mortality. Mortality status will be obtained from the Municipal Personal Records Database (BRP), containing reliable and complete registration all Dutch citizens	study the association between epigenetic and transcriptomic signatures and mortality in sepsis survivors and non-survivors and healthy controls. Mortality will be retrieved from the electronic health records (EHR) from the hospital and municipal registration. The cause of death will be retrieved from the EHR from the hospital, general practitioner and Dutch statistics' office (CBS).	1 year
Demographics	To study the association between epigenetic and transcriptomic signatures in sepsis survivors with demographics. Information about demograpics will be retrieved from the electronic health records (EHR) from the hospital.	3 months
Intoxications	To study the association between epigenetic and transcriptomic signatures in sepsis survivors with intoxications. Information about intoxications will be retrieved from the electronic health records (EHR) from the hospital.	3 months
Medication use	To study the association between epigenetic and transcriptomic signatures in sepsis survivors with medication use. Medication use will be retrieved from the electronic health records (EHR) from the hospital, general practitioner and pharmacy.	3 months
Sepsis severity defined with SOFA score	study the association between severity of sepsis and the epigenetic and transcriptomic signatures in sepsis. SOFA scores will be available for patients admitted because of an infection.	3 months follow up
Fatigue assessed with piper fatigue scale	To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with fatigue.Piper Fatigue Scale-12 (PFS-12; 0-10, higher scores reflect more fatigue among four subscales (a) behavior, (b) affect, (c) sensory, (d) cognition)	3 months
Mood assessed with the Patient Health Questionnaire-2 ( (questionnaire)	To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with mood. Patient Health Questionnaire-2 (PHQ-2; 0-6, higher score corresponds to reduced mental health)	3 months
Somatic symptoms (e.g. Patient Health questionnaire-15)	To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with somatic symptoms. Patient Health Questionnaire-15 (PHQ-15; 0-30, minimal-high somatic symptom severity)	3 months
Activities of daily living as determined by EQ-5D-5L (if abnormal also Katz-ADL-6)	To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with activities of daily living. EuroQol-5D (EQ5D; simple descriptive profile and a single index value for health status; higher values corresponding with better health) with visual analogue scale (VAS; 0-100, worse-best experienced health). Katz ADL-6 (0-6, fully dependent-independent)	3 months
Physical activity (e.g. Short Questionnaire to Assess Health-Enhancing Activity) (SQUASH) and 'Utrechtse activiteiten lijst' (UAL))	To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with physical activity	3 months
Co-morbidity (a.o. Charlson comorbidity index)	To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with comorbidity. Co-morbidity will be retrieved from the electronic health records (EHR) from the hospital, general practitioner and pharmacy. Data will be registered according to the Charlson' co-morbidity index (CCI; 1-2 mild co-morbidity, 3-4 moderate co-morbidity, 5 severe co-morbidity)	3 months
Vital parameters	Heart rate (bpm), blood pressure (mmHg), oxygen saturation (SpO2, SaO2, PaO2), breathing frequency (per min), consciousness (Glasgow coma scale), pain score (VAS), nausea/vomiting (y/n), defecation (y/n), urination (y/n), body weight (kg), length (cm), fluid balance (ml/day).	At baseline and three months.
Length-of-stay in hospital/intensive care unit (ICU)	Length-of-stay in hospital and on intensive care unit (ICU) in days	0-3 months

Collaborators and Investigators

• Sponsor: Hjalmar Bouma

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2021
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: August 27, 2021
• First Submitted That Met QC Criteria: September 10, 2021
• First Posted (Actual): September 22, 2021

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Recovery; Epigenetic; Transcriptome; Post sepsis syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: 202100108

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No