Infection, Sepsis
Conditions
Keywords
Post sepsis syndrome, Epigenetic, Transcriptome, Recovery
Brief summary
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.
Interventions
OTHERExposure of interest: study DNA methylation (epigenetics) and gene expression (transcriptomics) of blood leukocytes
The primary objective is to study DNA methylation (epigenetics) and gene expression (transcriptomics) of blood leukocytes between sepsis survivors at ED admission and three months after hospital discharge
Sponsors
Hjalmar Bouma
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DNA methylation (epigenetics) using the Illumina MethylationEPIC kit. Changes in DNA methylation at gene promoter/enhancer sites will be correlated through the NetworkAnalyst platform. | baseline versus 3 months follow up | 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. |
| Gene expression (transcriptomics/qPCR) will be measured using the Illumina Hi-Seq instrument. Differential gene expression will be correlated through the NetworkAnalyst platform. | baseline versus 3 months follow up | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Demographics | 3 months | 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. |
| Intoxications | 3 months | 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. |
| Medication use | 3 months | 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. |
| Sepsis severity defined with SOFA score | 3 months follow up | 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. |
| Fatigue assessed with piper fatigue scale | 3 months | 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) |
| Mood assessed with the Patient Health Questionnaire-2 ( (questionnaire) | 3 months | 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) |
| Nutrition status measured with PS-SGA Short Form and SNAQ form. (both questionnaires) | 3 months | 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). |
| Activities of daily living as determined by EQ-5D-5L (if abnormal also Katz-ADL-6) | 3 months | 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) |
| Physical activity (e.g. Short Questionnaire to Assess Health-Enhancing Activity) (SQUASH) and 'Utrechtse activiteiten lijst' (UAL)) | 3 months | To study the association between epigenetic and transcriptomic signatures in sepsis and survivors with physical activity |
| Co-morbidity (a.o. Charlson comorbidity index) | 3 months | 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) |
| Vital parameters | At baseline and three months. | 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). |
| Length-of-stay in hospital/intensive care unit (ICU) | 0-3 months | Length-of-stay in hospital and on intensive care unit (ICU) in days |
| Somatic symptoms (e.g. Patient Health questionnaire-15) | 3 months | 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) |
| Mortality. Mortality status will be obtained from the Municipal Personal Records Database (BRP), containing reliable and complete registration all Dutch citizens | 1 year | 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). |
Countries
Netherlands
Outcome results
None listed