UK Critical Care Genomics (UKCCG) group

FUNCTIONAL GENOMIC INFLUENCES ON DISEASE PROGRESSION AND OUTCOMES IN SEPSIS DUE TO PNEUMONIA OR PERITONITIS

BACKGROUND TO STUDY

Sepsis is the systemic inflammatory response to infection and is the commonest cause of death in adult intensive care units. There are up to 750,000 cases of severe sepsis a year in the USA, and around 21,000 cases per annum in the UK, while the incidence of severe sepsis in hospitals has been conservatively estimated at 2 per 100 admissions and the incidence amongst patients in intensive care units at around 6-10 per 100 admissions. In the UK severe sepsis accounts for about 46% of all bed days in intensive care units. Mortality rates, which are closely related to the severity of illness and the number of organs which fail are high (20-60%) and there may be more than 200,000 deaths from severe sepsis every year in the USA, and more than 1400 deaths per day worldwide. The impact on health care expenditure and resource utilisation has been considerable (annual total hospital costs for these patients in the USA have been estimated at approximately $17 billion and in Europe at 7.6 billion euros).

Early attempts to combat the high mortality associated with sepsis concentrated on cardiovascular and respiratory support. Despite some success, mortality rates remained unacceptably high and often death was merely postponed until they were overwhelmed by a dysfunctional host response (characterised by persistent or recurrent sepsis, intractable hypotension and failure of vital organs). Current evidence suggests that this response is largely independent of the site of infection and the responsible organism. Efforts to further reduce mortality by manipulating haemodynamics or modulating the host response have generally proved disappointing, perhaps in part because of our limited understanding of the complex mechanisms which regulate innate immunity and the inflammatory response. Importantly, also such interventions have usually been applied unselectively to heterogeneous groups of patients, without considering the potential influence of their genetic diversity on the response to treatment.

It has long been recognised that individuals vary considerably in their susceptibility to infection as well as in their ability to recover from apparently similar infectious illnesses. In 1988 it was clearly demonstrated that premature death in adults, especially when due to infectious and vascular causes is a strongly heritable trait.