Molecular Diagnosis and Risk Stratification of Sepsis in India

Study Overview
=================
Brief Summary
-----------------
Background: Globally, sepsis is common with an estimated population incidence of 437 cases per 100, 000 person-years and acute mortality of 26%, one of the few major medical conditions whose incidence and resulting mortality continues to rise. However, true burden is likely significantly higher as a recent meta- analysis could find no data from LMIC where 87% of the world's population resides. Objective: Generate new knowledge that will eventually provide rapid and accurate information about an individual patient suffering from sepsis (or critical illness), including which type of microorganism is responsible for the infection and the severity and stage of the patient's immune response. Methods: MARS-India will be a prospective longitudinal, single-centre observational study, conducted in mixed ICU's of a >2000 bedded tertiary teaching hospital in Manipal, India. The investigators will recruit to three groups- sex and age-matched healthy volunteers (n=150) and patients diagnosed with sepsis/septic shock or non-infectious ICU admissions such as severe trauma, severe burns and patients admitted to ICU after major surgery (n=400). The investigators have optimised a workflow to follow and describe the immunoinflammatory status of septic patients (as well as severe trauma/burn and major surgery) during the first 6 months after their initial injury. At fixed time points the investigators will collect blood in PaxGene, heparin, citrate and EDTA tubes in addition to routine bloods and microbiological samples. Rectal swabs and stool will also be taken for microbiome analysis. Immune functional tests will be performed to determine whole-blood cytokine/chemokine production in response to ex-vivo stimulation using an 8-panel assay. Additionally, complete immunophenotyping using flow cytometry including HLA-DR expression and lymphocyte subsets will be obtained.

Detailed Description
-----------------
New sepsis 3.0 definition has for the first time included a dysregulated host response to infection as the cause of organ dysfunction, however, sepsis remains a highly heterogeneous syndrome without an accepted definition of what constitutes a dysregulated host response. The field is only now realising that inclusion of specific characteristics of the host response (transcriptomic or immunological profiles) facilitate stratification of patients with sepsis into subgroups (endotypes), allowing for prognostic enrichment and targeted therapeutic intervention. Unfortunately, new guidelines continue to ignore the role of pathogens, virulence, sites of infection and lower-socio-economic settings. Additionally, it remains to be seen whether parasitic, viral and fungal conditions, common in LMIC, should be lumped with bacterial infections in the definition of sepsis. MARS -India will allow the investigators to compare these parameters and those of multi-drug resistant (MDR) pathogens on the impact of the host response and outcomes in sepsis. Not least develop an accurate temporal association of endotypes and detailed understanding of the immune suppressed phenotype. A functional immunology approach throughout and correlations with changes in the gut microbiome will further fortify our understanding of sepsis pathophysiology to help establish a 'sepsis fingerprint' and framework for novel interventions in future. Epidemiology data in itself will considerably heighten our understanding towards a global perspective on sepsis. Furthermore, little guidance is offered in the Surviving Sepsis Guidelines toward optimal management of the seemingly cured post-acute sepsis patient, who is commonly readmitted with an infection or worse has a significantly reduced life expectancy (>40% 1yr mortality in some studies). MARS-India will also aim to establish the burden of this stage of sepsis in a LMIC setting and study the underpinning pathophysiology in more detail to establish groundwork in uncovering pathways for future therapeutic targeting. It is apparent that biomarkers reflecting activity of targetable immunological pathways will be of paramount importance in managing the septic patient in future.

Official Title
-----------------
Molecular Diagnosis and Risk Stratification of Sepsis in India

Conditions
-----------------
Sepsis, Septic Shock, Sepsis Syndrome

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All patients aged 18 years and over in the intensive care units of Kasturba Hospital, Manipal (and meeting the study population definitions below) Sepsis - defined as the presence of infection diagnosed within 24 hours of ICU admission with probable or definite likelihood, accompanied by organ dysfunction represented by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 points or more. Septic shock is defined as per the recent Sepsis 3.0 consensus guidelines. Serious trauma within 24 hours, with patient directly admitted to ICU (injury severity score (ISS) >15). Severe burns (total surface area burned >30%). Major surgery or pancreatitis/non-infectious inflammation. Exclusion Criteria: Pregnant or breast-feeding women Patients with a 'withdrawal of care' decision at time of inclusion Patients whose anticipated duration of hospitalisation in ICU is estimated <48 hours Extra-corporeal circulation in the month preceding inclusion in the case of cardiac surgery Patient with restricted liberty or under legal protection Expected lifespan <3 months due to pre-existing comorbidities Blood transfusion >4 units in past week Second admission to ICU or previous enrolment in study (within same hospital admission) Transfer from other hospital ICU (if greater than 24hrs in total)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Septic/septic shock patients<br>Patients with underlying confirmed or probable cause of infection leading to sepsis or septic shock will form the active group of interest. | |
| Non-septic/sterile inflammation patients<br>Patient with severe trauma, severe burns and patients admitted to ICU after major surgery or pancreatitis. Active comparator group. | |
| Healthy control patients<br>Active comparator group. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular information of individual host-pathogen response and outcomes in sepsis. | Using RNA sequencing the investigators will map the transcriptional picture of sepsis in a tropical LMIC setting and also map the changes longitudinally. | 2 years | 
| Gut microbiome alterations in correlation to sepsis endotypes and associated post sepsis mortality/re-admission. | This will make use of 16S PCR and shotgun metagenomic sequencing. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantify mortality, morbidity and re-admissions in sepsis survivors from a LMIC setting. | Patients surviving sepsis will be followed up for 6 months post discharge. | 2.5 years | 
| Stratification of septic patients by severity and type of immune response to infection. | This will utilise a multi-omics approach and up-to-date bioinformatic techniques to bring together the previous outcomes with functional immunology profiles. Ultimate aim will be to generate a novel biomarker panel. | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pneumonia, Infection, Tropical Infection, Endotypes, Biomarkers, Immunephenotyping, Lower middle-income countries (LMIC), Microbiome, Post-sepsis survival, Multi-omics