Genetic markers in sepsis.

Sepsis is a systemic response to severe infection. Clinical sepsis is defined as an infection-induced syndrome including at least two of the features of systemic inflammatory response syndrome: fever or hypothermia (oral temperature .38°C or ,36°C); leukocytosis (.12,000 WBC/mm) or leukopenia (,4,000 WBC/ mm); tachycardia (heart rate .90 beats/minute); and tachypnea (.24 breaths/minute). The causes of the sepsis syndrome are both complex and obscure. Despite advances in the diagnosis and treatment of infectious disease, the appearance of a systemic inflammatory response remains a common sequela of bacterial, viral, or fungal infection. The progression from sepsis to severe sepsis (sepsis with dysfunction of one organ), to multiple organ dysfunction syndrome (MODS), and then to septic death marks steps that typically require escalation of treatment. Although patients with severe sepsis have been treated experimentally with antiinflammatory and immunomodulatory agents, no single agent has reduced the overall mortality. Sepsis remains a major unsolved health problem. The incidence of sepsis has increased during the last 20 years, with more than 500,000 patients developing sepsis each year in the US. The mortality rate is between 35% and 45%. Half of these patients die from a condition that independently predisposes to sepsis (such as severe injury), but at least 100,000 deaths are caused by sepsis alone. Sepsis is the 13th leading cause of death in the US, with a cost of $5 to $10 billion a year. The morbidity and mortality of sepsis were historically ascribed to delayed diagnosis and inadequate antimicrobial therapy. Although diagnostic delays and inadequate therapy undoubtedly occur, many appropriately treated patients fail to recover. More recently, attention has turned to the host response as a determinant of outcomes. Such patient-specific responses, in turn, reflect both heritable (or genetic) characteristics and acquired illnesses. The purpose of this article is to discuss what is known concerning the heritable characteristics of the genetic predisposition to sepsis. Particular heritable characteristics may be causal or, alternatively, represent associations with human disease. The distinction is important. The surgeon occasionally confronts inborn “errors” in single genes that alter protein structure or expression in a way that profoundly affects physiology. For example, the single amino acid substitution that changes ordinary adult Hemoglobin A to Hemoglobin S accounts for the pathology of sickle cell anemia. The surgeon also encounters acquired abnormalities in specific genes and their proteins, particularly abnormalities in regulatory tumor suppressor genes and their proteins. For example, colon mucosa sustaining spontaneous mutagenesis acquires a series of variants in specific genes that collectively facilitate the transition from normal to malignant epithelium. In both of these examples, causality has been demonstrated by fulfillment of modern expressions of Koch’s postulates using genetic manipulation: correction of the molecular abnormality (genotype) corrects the physiology (phenotype). Sepsis is different. Human genetics has not, and likely will not, identify a single or even several genes whose structure or expression fully determines predisposition to or outcomes from sepsis; sepsis alters the expression of hundreds of genes in dozens of tissues. Experimental attempts to modify expression or effect of particular genes using biologic therapeutics, such as the soluble tumor necrosis factor receptor and the interleukin 1 receptor antagonist in order to modify outcomes from clinical sepsis, have failed. This article does not address causality of sepsis. Rather, it examines associations between particular genetic markers (DNA sequences) and sepsis.