Genomic Advances in Sepsis (GAinS)

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Genomic Advances in Sepsis (GAinS)
A Multi-centre, UK based, genomic association
study of the genetic determinants of the
susceptibility to, and outcome from, severe
life-threatening infection and sepsis.
Paula HuttonGAinS Research Coordinator John
Radcliffe Hospital Oxford
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Hypothesis

• Functional polymorphisms of genes regulating the
  host response to infectious insults and gene-gene
  interactions, will influence levels and activity
  of key proteins and hence the onset, progression
  and severity of an infectious illness, the
  development of organ failures and outcome.

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To Identify Genomic Influences On

• Susceptibility of patients with infectious
  diseases to the development of severe sepsis
  sepsis/septic shock and organ failures
• Outcome from sepsis/severe sepsis/septic shock
• Outcome from specific organ failures

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Sepsis Incidence

• Commonest form of death in adult intensive care
  units in the UK
• UK-21,000 cases per annum
• 6-10 of all ICU admissions
• Annual total hospital costs in Europe approx 7.6
  billion euros

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Why is this study important?

• Intellectual knowledge base
• Guide drug discovery
• Guide interventional therapy
• Predict outcome

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Is individual host response variable?

• Clinical Observation - Patients with similar
  microbiological insults may exhibit very
  different clinical responses and outcomes.

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How can we characterise the host?

• Phenotype
• i.e. the expressed characteristics
• Genotype
• This is the "internally coded, inheritable
  information" carried by all living organisms (the
  genetic code)

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Data Collection

• Charleson co-morbidity
• Antibiotic administration
• Additional Infection Audit
• Ethnicity
• Discharge and outcome data

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Data Collection

• Data collected day 1, 2, 3, 5 and 7
• Data collection to calculate
• Apache 2
• SOFA scores
• Sepsis/severe sepsis/septic shock criteria

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Sampling

• 20mls blood for DNA
• Store at room temperature until dispatch to the
  genome centre (WHRI)

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Patient Populations

• Community Acquired Pneumonia (CAP)
• Faecal Peritonitis (FP)

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CAP Definition

• Febrile illness associated with
• Cough, sputum production
• Dyspnoea
• Leucocytosis
• Radiological evidence of pneumonia
• Pneumonia onset is pre-hospital admission or
  within 48hrs of hospital admission
• 2 Clinicians agree with diagnosis

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FP Definition

• Inflammation of the serosal membrane lining the
  abdominal cavity secondary to contamination by
  faeces as diagnosed at laparotomy.

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Consent in incapacitated adults

• Patient consent
• NOK consent
• Follow-up consent

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Inclusion Criteria

• Patients gt 18 years of age
• Admission to ICU or HDU
• Willing to consent (Pt or NOK)

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Exclusion Criteria

• Patient or NOK unable to give consent
• Patient already enrolled in interventional
  research study
• Patient pregnant
• Advanced directive to withhold or withdraw life
  sustaining treatment
• Patient immunocompromised

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Recruitment numbers

• Recruitment aim
• Over a 3 year period
• In 40 participating centres
• 5,000 CAP patients
• 2,000 FP patients
• Largest Genomics association study in Sepsis

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Primary End Points

• Susceptibility to development of sepsis/severe
  sepsis/septic shock in CAP and FP patients
• Development of specific organ failures
  identified by SOFA scores
• Outcome - death or survival (in ICU and at 6
  months)

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Secondary End Points

• Severity of illness APACHE II
• Duration of organ support
• Shock reversal
• Duration of ICU and hospital stay

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GenOSept (Genetics of Sepsis and Septic Shock in
Europe)

• Developed with GAinS
• Combined with GAinS
• Add Pancreatitis and Meningococcal disease
• 1 year recruitment

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Website link

• http//www.ukccg-gains.org/

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GAinS study summary

• UK based
• Genetics study
• Largest to date
• Focus CAP/FP septic patients
• Genetic influence on the response to and outcome
  from sepsis