Potential treatment for HUS fails in major clinical trial

Sep 19, 2003 (CIDRAP News) – A drug that researchers hoped would offer the first effective treatment for hemolytic uremic syndrome (HUS)—a sometimes fatal kidney condition that can result from eating food contaminated with Escherichia coli O157:H7—has proved ineffective in a major clinical trial.

Researchers tested a drug designed to bind Shiga toxin, which is produced by E coli O157:H7, so that it can't move from the gut into the bloodstream. But children treated with the drug did no better than those who received a placebo, according to the report in the Journal of the American Medical Association.

"The outcome of this trial casts doubt on the likelihood of success of strategies to prevent continued gastrointestinal absorption of Shiga toxin," states the report by Howard Trachtman, MD, of Long Island Jewish Medical Center, New Hyde Park, N.Y., and colleagues. With no effective treatment available for HUS, the authors recommend increased efforts to keep Escherichia coli O157:H7 and other Shiga toxin–producing strains of E coli out of the food supply.

The study was a randomized, double-blind trial involving 145 children suffering from diarrhea-related HUS at 26 tertiary care centers. Ninety-six children received the binding agent orally for 7 days, and the other 45 children received a similar dosage of a cornmeal placebo. The severity of disease in the two groups was similar at baseline.

The two groups had nearly the same rates of death and serious extrarenal events: 18% in the treatment group and 20% in the placebo group. Three patients in the treatment group and one in the placebo group died. Dialysis was necessary for 42% of the treatment group and 39% of the placebo group.

The study was the largest controlled trial of a potential treatment for diarrhea-associated HUS to date, according to the authors. They write that one possible reason for the drug's ineffectiveness was that therapy may have been started too late, given that most of the patients were transferred to the trial sites from other hospitals and that only 23% of patients had viable Shiga toxin–producing strains of E coli or free Shiga toxin in their stool samples when treatment was started.

In an accompanying editorial, Richard L. Siegler, MD, a pediatric nephrologist from the University of Utah, writes that the trial results leave prevention as the main approach to decreasing the toll of illness and death due to HUS. He calls for developing "novel" ways to reduce E coli O157:H7 in livestock and implementing a "zero-tolerance policy" for contaminated foods and beverages—steps that could necessitate giving the US Department of Agriculture more regulatory authority.

But prevention will never entirely eliminate HUS, Siegler writes. E coli that produce Shiga toxin are found not just in livestock, but also in "dozens of other animals, water supplies, and fruits and vegetables (especially those fertilized with manure). . . . Therefore, it is imperative to continue to develop and test vaccines for both children and livestock." This will take time and will generate concerns about cost-effectiveness, given that HUS annually affects only about 1.5 out of 100,000 children, he adds.

Trachtman H, Cnaan A, Christen E, et al. Effect of an oral Shiga toxin–binding agent on diarrhea–associated hemolytic uremic syndrome in children. JAMA 2003;290(10):1337-44 [Abstract]

Siegler RL. Postdiarrheal shiga toxin–mediated hemolytic uremic syndrome. (Editorial) JAMA 2003;290(10):1379-81