Grant: Project Grant

Globally, there are over 2.8 million cases of Shiga toxin-producing E. coli (STEC) infection each year. In 2012, the Centers for Disease Control and Prevention estimated that 96,534 high-risk (i.e. O157) STEC infections occur yearly in the US. Over 60% of these infections occur in children, half of whom are <5 years old. Hemolytic uremic syndrome (HUS) is the most serious complication of STEC infections and has a mortality rate of 1-3% and 30% develop chronic renal disease. Despite significant advances in our understanding of the pathophysiology of STEC infection, no treatments have emerged in the 35 years since STEC were determined to cause HUS. Care remains limited to avoiding antibiotics, and providing support if and when HUS develops. Data indicate that anti-bacterial and anti-toxin interventions are futile by the time of HUS presentation. By that point, the density of pathogen in stool and concentration of fecal-free Shiga toxin in fecal filtrates are low and diminishing, oral toxin binders are ineffective, and antibiotics increase the likelihood of developing HUS. We will test a promising proactive intervention to diminish the risk of developing HUS and/or reduce its severity using aggressive and early intravascular volume expansion. We will employ an innovative embedded, pragmatic, 26-site, cluster-crossover, randomized clinical trial design to evaluate if admission to hospital for promotion of hydration status (i.e. intravascular volume expansion) results in better outcomes compared with the current practice of watchful waiting and symptomatic support for those who do develop HUS. We seek to determine if this intervention will reduce the incidence of renal injury. If effective, the results from this study will lead to a change in clinical practice and reduce the burden of long-term complications associated with HUS survivorship. We will also create a biorepository, which future research will employ to identify prognostic markers and therapeutic targets.